Cristina Mihaela Ghiciuc

PHARMACOLOGY
lecture notes

“Gr. T. Popa” Publisher, U.M.F. Iaşi

2014
Descrierea CIP a Bibliotecii Naţionale a României
GHICIUC, CRISTINA MIHAELA
Pharmacology : lecture notes / Ghiciuc Cristina Mihaela ; referenţi
ştiinţifici: prof. dr. Mihai Nechifor, prof. dr. Cristian Georgescu. - Iaşi : Editura
Gr.T. Popa, 2014
Bibliogr.
ISBN 978-606-544-280-1

I. Nechifor, Mihai (ref. şt.)

II. Georgescu, Cristian Corneliu (ref. şt.)

615

Referenţi ştiinţifici:
Prof. univ. dr. Mihai Nechifor
Catedra de Farmacologie – Toxicologie – Algeziologie,
Universitatea de Medicină şi Farmacie „Gr. T. Popa” Iaşi
Prof. univ. dr. Cristian Corneliu Georgescu
Catedra de Farmacologie,
Universitatea de Medicină şi Farmacie Craiova

Coperta: Marius Atanasiu

Tehnoredactare: Cristina Mihaela Ghiciuc

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 Content

Content ................................................................................................................. 3
Preface .................................................................................................................. 9
Symbols and abbreviations ................................................................................ 11

Introduction ........................................................................................................ 13

Lecture 1 ............................................................................................................ 15
Pharmacodynamics ............................................................................................ 15
1. Mechanisms of drugs action ....................................................................... 15
2. Structure – effect relationship .................................................................... 29
3. Dose – effect relationship ........................................................................... 30
4. Combined effects of drugs: synergism, antagonism .................................. 32
5. Adverse drug reactions ............................................................................... 33

Lecture 2 ............................................................................................................ 39
Principles of pharmacokinetics .......................................................................... 39
1.Drug permeation .......................................................................................... 40
2.Absorption of drugs ..................................................................................... 42
3.Distribution of drugs ................................................................................... 46
4.Metabolism of drugs (biotransformation) ................................................... 50
5.Elimination of drugs .................................................................................... 56
6.Pharmacokinetic parameters........................................................................ 57
7.Effects of repeated doses ............................................................................. 59
8.Pharmacokinetic models.............................................................................. 60

AUTONOMIC NERVOUS SYSTEM AND DRUGS ...................................... 63

Lecture 3 ............................................................................................................ 63
Cholinomimetic drugs .................................................................................... 63
1. Direct-acting cholinomimetic drugs (or Agonists on cholinergic
receptors) ........................................................................................................ 67

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 2. Indirect acting cholinomimetic drugs (Cholinesterase-inhibiting drugs or
Anticholinesterases) ....................................................................................... 70
Lecture 4 ............................................................................................................ 73
Anticholinergic drugs (Cholinoceptor-Blocking Drugs) ................................ 73
1. Antimuscarinic drugs ................................................................................. 73
2. Ganglioplegics ............................................................................................ 81
3. Neuromuscular blocking drugs (curare-like substances) ........................... 82
Lecture 5 ............................................................................................................ 85
Adrenergic system activating drugs ............................................................... 85
1. Adrenergic agonists with direct and mixed action ..................................... 92
2. Stimulants of release of catecholamines .................................................. 101
3. Inhibitors of transmitter reuptake ............................................................. 103
4. Other drugs activating sympathetic system .............................................. 103
Lecture 6 .......................................................................................................... 105
Adrenoceptor-blocking drugs and other sympatholytic drugs ..................... 105
1. Competitive antagonists on adrenergic receptors ................................. 106
1.1. Antagonists on alpha adrenergic postsynaptic receptors (α-blockers)
.................................................................................................................. 106
1.2. Antagonists on beta receptors (β-blockers) ....................................... 110
1.3. Antagonists on alpha and beta receptors (α,β-blockers) .................... 114
2. Inhibitors of cathecolamine synthesis ...................................................... 115
3. Centrally acting sympatholytic agents ..................................................... 115

Lecture 7 .......................................................................................................... 123

Pharmacological influence of smooth muscle activity .................................... 123
1. Drugs that inhibit constriction of smooth muscle (smooth muscle relaxants)
...................................................................................................................... 125
2. Drugs that stimulate constriction of smooth muscle ................................ 140
3. Drugs used to treat asthma and chronic pulmonary obstructive disease .. 147

Lecture 8 .......................................................................................................... 149

Autacoids ......................................................................................................... 149
1.Pharmacologic influence of Histamine ..................................................... 150
2.Pharmacologic influence of Serotonin (5-hydroxytryptamine)................. 155
3.Pharmacologic influence of Angiotensin and renin-angiotensin-aldosteron
system ........................................................................................................... 158
4
 4.Pharmacologic influence of Kallikrein–kininogen–kinin system ............. 164
5.Pharmacologic influence of other endogenous peptides ........................... 165
6.Pharmacologic influence of Lipid-derived autacoids (eicosanoids) ......... 166

Lecture 9 .......................................................................................................... 169

Pharmacological influence of cardio-vascular system ..................................... 169
1. Cardiac glycosides and drugs for chronic heart failure ............................ 169
2. Antiarrhythmic drugs ............................................................................... 174
3. Lipid-regulating drugs .............................................................................. 181
4. Pharmacological influence of cardio-vascular system disorders ............. 188
4.1. Antianginal and other anti-ischemic drugs ........................................ 188
4.2. Antihypertensive drugs ...................................................................... 190
4.3. Pharmacological Treatment of Heart Failure .................................... 191

Lecture 10 ........................................................................................................ 193

1. Diuretics and antidiuretics ........................................................................ 193
1.1. Diuretics ............................................................................................. 193
1.2. Antidiuretics ...................................................................................... 203
2. Agents Used in Anemias and Hematopoietic Growth Factors ................. 206
3. Drugs Used in Disorders of Coagulation ................................................. 211
4. Fluids and electrolytes .............................................................................. 220

CHEMOTHERAPEUTIC DRUGS ................................................................. 223

Lecture 11 ........................................................................................................ 223
1.Pharmacokinetic and pharmacodynamic particularities of chemotherapeutic
drugs ............................................................................................................. 223
2.Antiseptic and disinfectant drugs .............................................................. 230
2.1. Antiseptic and disinfectant drugs with local administration.............. 230
2.2. Antiseptic drugs with systemic administration .................................. 234
3.Antibacterial drugs .................................................................................... 235
3.1.Inhibitors of bacterial cell wall synthesis ........................................... 235
3.2.Inhibitors of bacterial cell function..................................................... 247
Lecture 12 ........................................................................................................ 248
3.3.Inhibitors of bacterial protein synthesis .............................................. 248
3.4.Inhibitors of bacterial nucleic acid synthesis ...................................... 260
3.5.Inhibitors of the synthesis of other bacterial structures synthesis ...... 263
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 3.6. Drugs used to treat tuberculosis ......................................................... 265
3.7. Drugs used to treat leprosy ................................................................ 269
Lecture 13 ........................................................................................................ 270
4.Antifungal drugs ........................................................................................ 270
5.Antiviral drugs ........................................................................................... 276
6.Antiprotozoal and antihelminthic drugs .................................................... 285
7.Cancer chemotherapy ................................................................................ 287
8.Immunopharmacology............................................................................... 290
Lecture 14 ........................................................................................................ 291
Drugs used in the treatment of gastrointestinal diseases.................................. 291
1. Drugs used in gastric ulcer disease........................................................... 291
2. Antiemetic drugs ...................................................................................... 299
3. Antispasmodic drugs ................................................................................ 302
4. Drugs stimulating gastrointestinal motility. ............................................. 304
5. Laxatives .................................................................................................. 305
6. Antidiarrheal agents ................................................................................. 307
7. Pancreatic enzyme substituents ................................................................ 309
8. Drugs stimulating bile and therapy for gallstones .................................... 309
9. Drugs to treat inflammatory bowel disease .............................................. 311
11. Drugs with hepatoprotector effect .......................................................... 311

PHARMACOLOGICAL INFLUENCE OF THE CENTRAL NERVOUS

SYSTEM .......................................................................................................... 313
Lecture 15 ........................................................................................................ 313
1.Opioids ...................................................................................................... 313
2.Cough suppressants and expectorant drugs ............................................... 325

Lecture 16 ........................................................................................................ 327

1.Anxiolytic – sedative – hypnotic drugs ..................................................... 327
2. Local anesthetics ...................................................................................... 337
3. General anesthetic agents ......................................................................... 341

Lecture 17 ........................................................................................................ 348

Antiseizure Drugs (antiepileptic drugs) ........................................................... 348

Lecture 18 ........................................................................................................ 362

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 1.Drugs used in mental illness ...................................................................... 362
2. Drugs of abuse inducing euforia and psychotomimetics.......................... 375

Lecture 19 ........................................................................................................ 376

1.Skeletal muscle relaxants .......................................................................... 376
2. Pharmacologic management of parkinsonism .......................................... 380
3. The treatment of tremor and other movement disorders .......................... 385

Lecture 20 ........................................................................................................ 386

Analgesics, antipyretic and antiiflammatory drugs.......................................... 386
1. Nonsteroidal antiinflammatory drugs (NSAIDS)..................................... 386
2. Analgesic – antipyretic drugs without anti-inflammatory effect.............. 396
3. Disease-modifying antirheumatic drugs ................................................... 398
4. Drugs used in gout .................................................................................... 402

DRUGS AFFECTING ENDOCRINE SYSTEM ............................................ 405

Lecture 21 ........................................................................................................ 405
1.Drugs affecting hypothalamic and pituitary gland hormones ................... 405
2.Drugs affecting thyroid hormones ............................................................. 413
3.Agents that affect bone mineral homeostasis ............................................ 416
Lecture 22 ........................................................................................................ 420
1. Drugs affecting the hormones of the adrenal gland ................................. 420
1.1. Drugs affecting glucocorticoid hormones ......................................... 420
1.2. Drugs affecting mineralocorticoid hormones .................................... 426
2. Drugs affecting pancreatic hormones ....................................................... 428
2.1.Insulin ................................................................................................. 428
2.2.Oral antidiabetic drugs ........................................................................ 431
Lecture 23 ........................................................................................................ 435
Drugs affecting sex hormones ...................................................................... 435
1. Drugs affecting androgens .................................................................... 435
2. Drugs affecting progestins .................................................................... 439
3. Drugs affecting estrogens ..................................................................... 440
4.Hormonal contraception ........................................................................ 443

Index................................................................................................................. 446
References (selective) ...................................................................................... 449
7
8
Preface

9
10
 Symbols and abbreviations

BBB: blood– brain barrier

BCB: blood–cerebrospinal fluid barrier
CNS: central nervous system
GTP: guanosine triphosphate
cGMP: guanosine monophosphate
LSD: Lysergic acid diethylamide
G-CSF: granulocyte colony-stimulating factor
GM-CSF: granulocyte-macrophage colony-stimulating factor
CSF: cerebrospinal fluid
IL-: interleukin-
Chronic obstructive pulmonary disease (COPD)
intrinsec sympathomimetic activity (ISA)

11
12
 Introduction
Pharmacology can be defined as the science of drugs including their origin,
composition, pharmacokinetics, therapeutic use, and toxicology. It is simply
defined as the study of drugs: what they are, how they work and what they do.

The effects of the substance can vary from molecular level to whole body.
Exogenously administered substances may have beneficial or therapeutic effect
or may exert toxic effects.

Drugs are molecules that are used for diagnosis, prevention or treatment (to
ameliorate or to cure) of a disease.
The term drug is also used for addictive / abused / illicit substances (e.g.,
heroin, LSD etc).

Drug nomenclature. There are many names for each drug:

 chemical name: describes the compound from chemical point of view;
 international non-proprietary name (INN or rINN = recommended INN) is
the official or approved name, recommended in all countries members of the
World Health Organization, found in pharmacopoeias;
 proprietary name (brand name or trade name): the name assigned by a
manufacturer (it is commercial property). Many countries used to have their
own names for drug compounds which are more familiar than the
recommended name (e.g. Lignocaine is the old INN for Lidocaine).
Chemical name: acetylsalicylic acid

Proprietary name (brand name): Aspirin®

Official name: Acetylsalicylic acid

Pharmacology has two main areas: pharmacokinetics and pharmacodynamics.

 Pharmacokinetics studies the fate of a drug during its passage through the
body (absorption, distribution, metabolism and excretion, shortly

13
 abbreviated as ADME).
 Pharmacodynamics studies the action of a drug on a physiological,
biochemical or molecular level which, through a subsequent series of events,
results in a pharmacological response (studies the mechanisms of action of
drugs).
There are also other branches of pharmacology:
 Pharmacotherapeutics (clinical pharmacology) studies the use of drugs for
prevention, diagnosis and treatment of diseases.
 Toxicology studies the effects, antidotes and detection of poisons and studies
the effects of drug overdose.
 Pharmacoepidemiology studies the drug effects at the population level.
 Pharmacoeconomics studies the cost and benefit of drugs used
therapeutically.
 Pharmacogenomics studies the variability of the expression of individual
genes relevant to disease susceptibility as well as drug response at cellular,
tissue, individual and populational level. Pharmacogenetics studies the
interindividual variations in DNA sequencing related to drug response. In
practice these two terms, pharmacogenomics and pharmacogenetics, are used
interchangeably.
 Neuropsychopharmacology studies the effect of drugs and medicines on
psychological processes of the brain.
 Immunopharmacology studies the drugs designed to either suppress or
augment the immune system.
 Chronopharmacology studies how the effects of drugs vary with biological
timing and endogenous periodicities.
 Molecular pharmacology studies drugs and their interaction with biological
targets to alter cell function at a molecular level.
 Pharmacognosy studies the physical, chemical, biochemical and biological
properties of medicines derived from plants.

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 Lecture 1
Pharmacodynamics

Learning Objectives:
 List and describe the mechanisms of action for drugs with suitable examples;
 Differentiate between a drug that is an agonist and a drug that is an antagonist;
 Define the structure – effect and dose – effect relationships;
 Discuss the practical utility of therapeutic index, synergism and antagonism of drugs
with suitable examples;
 Classify and discuss the adverse dryg reactions.
 Understand what is meant by pharmacokinetics and pharmacodynamics.

Pharmacodynamics is the study of the action of a drug on a physiological,

biochemical or molecular level which, through a subsequent series of events,
results in a pharmacological response (it studies the mechanisms of action of
drugs). Pharmacodynamics describes the mechanisms of action of drugs which
result in therapeutic or toxic action and the structure-effect and dose-effect
relationships.
Many drugs act on one or more constituents of the cells or tissues in order to
produce biochemical or physiologic changes in the body. Their therapeutic or
toxic effects result from their interaction with molecules from the organism.
The response resulting from drug action is the pharmacological response
(pharmacodynamic effect of drug).
Understanding of drug action is growing rapidly, but it is far from complete.
Advances in molecular pharmacology are opening up many new therapeutic
possibilities.

1. Mechanisms of drugs action

There are several mechanisms of action for drugs:

1.1. Action based on simple physical or chemical property of drug;
1.2. Actions of drugs on different cell structures:

15
 1.2.1. Action on receptors;
1.2.2. Action on enzymes;
1.2.3. Action on ionic channels;
1.2.4. Action on nucleic acids;
1.2.5. Action by forming “membrane pores”;
1.2.6. Action by enhancing release of mediators.

1.1. Mechanisms of drug action based on simple physical or chemical

property of drug
Only a few drugs act by physical or chemical properties:
 osmotic pressure (solutes retain water osmotically):
o osmotic laxatives (solutes are not absorbed from the intestine, retain
water osmotically and distend the bowel increasing peristalsis
indirectly): Lactulose, Sorbitol, Magnesium hydroxide (milk of
magnesia), Magnesium sulfate, Sodium sulfate, Sodium phosphate,
Sodium potassium tartrate;
o bulk laxatives (constituents of dietary fibers absorb water in intestine,
swells and increase water content of feces, softens it and facilitate
colonic transit): Methylcellulose, Psyllium, Ispaghula, Polycarbophil;
o osmotic diuretics (solutes increase the osmolarity of plasma and tubular
fluid, which expand plasma fluid volume, increase renal blood flow
and limit water and electrolyte reabsorption useful to reduce
intracranial and intraocular tension): Mannitol, Isosorbide, Glycerol;
 oncotic pressure (colloid osmotic pressure)
o colloid plasma volume expanders (these solutions contain large
molecules which expand the intravascular space effectively when
infused iv because retain fluid in the vascular compartment): Dextran,
Polygeline, Hetastarch;
 physical processes (reflective agents) that are opaque or reflect radiation:
o radio opaque substances (have the property of casting a shadow on x-ray
films): barium sulphate;
o sunscreens (reflect UV radiation): titanium dioxide, zinc oxide;
 chemical reactions: neutralization of gastric hydrochloric acid by antacids
(Sodium bicarbonate, Calcium carbonate, Magnesium hydroxide, Aluminium
hydroxide etc);
 intermolecular attraction (formation of weak hydrogen or van der Waals
16
bounds between substances):
o Adsorption (the binding of a chemical to a solid or liquid material):
 activated charcoal (many drugs and chemicals are avidly
adsorbed on the surfaces of the charcoal particles, thereby
preventing absorption and toxicity) – it is used to treat
poisonings and overdoses following oral ingestion;
 chemical sunscreens (agents that adsorb a particular range of
wavelengths within the UV spectrum): benzophenones, octil
salicylate etc;
 Cholestyramine is an agent which bind cholesterol and other
drugs (Furosemide, thiazide diuretics, coumarine oral
anticoagulants, Acetaminophen, Digoxin etc) – it is
recommended to administer these drugs either 1 hour before
or 3–4 h after a dose of cholestyramine;
 Protamine sulfate binds to heparin to reverse its actions – it is
antidote in heparin overdosage;
o Chelation (a chemical reaction in which a drug binds to a multivalent
ionic metal forming a ring-shaped molecular complex and removes it
from tissue):
 tetracyclines bind bivalent or trivalent cations (certain antacids,
ferrous ions in oral iron supplements, milk products);
 Dimercaprol is a chelator for metals, especially for heavy metals
(arsenic, gold, mercury etc), used in the treatment of acute
poisoning by arsenic, gold, mercury, bismuth;
 Penicillamine is a chelator that has affinity for certain heavy-
metal ions, including copper, lead, and mercury, indicated for
the treatment of Wilson's disease, lead poisoning;
 Deferoxamine is a chelator that has a high affinity for ferric iron,
indicated in the treatment of iron poisoning.

1.2. Mechanisms of drug action on different cells structures

1.2.1. Action of drugs on receptors
A ligand is any molecule (endogenous or exogenous) which attaches
selectively to particular receptor or sites from the body. Molecular size, shape
and electrical charge of a drug determine whether it will bind a particular
receptor. Receptors are selective in choosing ligands to bind, so this avoids
17
constant activation of the receptor.
Receptor is defined as a macromolecule (typically made of proteins) or a binding site located
on the effector cell that is capable of recognizing signal molecules and initiating the response to
these by transmitting signals to the cell interior (examples of receptors are hormones and
neurotransmitters present in the extracellular space). Some authors use the term receptor to
mean any target molecule with which a drug molecule has to combine in order to exert its
specific effect.
Receptors are capable of combining with drugs in a number of ways, and the forces that attract
the drug to its receptor must be sufficiently strong and long-lasting to permit the initiation of the
sequence of event that ends with the biological response. There are different types of bond that
participate in the formation of the initial drug – receptor complex:
 covalent bonds are very strong and stable (are irreversible bonds);
 electrostatic bonds are weaker than covalent bonds and are more common in drug receptor
interactions:
o ionic bonds are strong electrostatic bonds which occurs between permanently charged
ionic molecules and less strong compared to covalent bonds;
o hydrogen bonds are subtypes of ionic bond which occurs bweteen hydrogen atom and
more electronegative ions such as oxygen and nitrogen;
o van der Waal’s bonds are very weak bonds between dipoles.
 hydrophobic bonds are between high lipid-soluble molecules and lipid part of the cytoplasm
of the cells.
The receptor molecule has two functional domains:
 Affinity site (ligand binding domain) with role in recognition and binding of the ligand,
 Efficacy site which undergoes a functional conformational change.
Affinity is the capacity of a substance to bind on receptors. Affinity of a drug to a receptor can
be:
 high affinity: drug will bind easily to the receptor,
 low affinity: requires a higher concentration of the drug to get a therapeutic response.
Receptor–effector system (signal-transduction pathway) is represented by the:
 receptor;
 any intermediary molecules (transducer, second messenger);
 its cellular target.
Receptor molecules may be linked to one or more intermediary molecules, which are linked to a
separate effector molecule. Other receptors incorporate effector system in the same molecule, so
that drug binding brings about the effect directly, e.g. opening of an ionic channel or activation
of enzyme activity.
There are different types of receptors:
 transmembrane receptors:
o G-protein-linked receptors: adrenergic receptors, muscarinic receptors etc;
o channel-linked receptors: nicotinic receptors, GABAA receptors etc;
o kinase-linked receptors: receptors for insulin, for growth hormone etc;
 intracellular receptors:

18
 o nuclear receptors (receptors that control gene transcription): steroidal receptors.
Receptors have two essential functions:
 recognition of the specific ligand molecule,
 activation of effector system by transduction of the signal into a response.

There are multiple classes and subtypes for the same endogenous ligand.
Adrenergic receptors are divided into alpha (α) and beta (β). There are multiple
subtypes of these receptors (structurally related): α1 and α2, β1, β2 and β3.
No drug causes only a single and specific effect. Drugs are selective in their
action, because they bind to one or a few types of receptors more tightly than to
others and because these receptors control discrete processes that result in
distinct effects.

Agonist (fig. 1) is a substance which activates a receptor to produce an effect

similar to that of a physiological signal molecule. Agonist causes a cellular
system to change its state and produces a measurable biological response.
Agonists bind on both affinity and efficacy sites of receptor.
 Full agonist is a drug that produces the maximal response of the system (a
maximal response equal to the maximal capability of the system to report
cellular response). E.g. Acetylcholine is agonist for muscarinic receptors,
Adrenaline is agonist for alpha and beta adrenergic receptors.
 Partial agonist is a drug which produces a maximal response that is below
the maximal capability of the system. Partial agonist may act as either an
agonist (if no full agonist of receptor is present) or as an antagonist (if a full
agonist is present). E.g. Varenicline is a partial agonist on nicotinic
receptors: it has agonist activity but with lower intrinsic efficacy than
nicotine, therefore acts as an antagonist in the presence of nicotine. Pindolol
is a nonselective beta-blocker with partial agonist activity (also named
intrinsic sympathomimetic activity).
 Inverse agonist is a substance which activates the receptor and reverses the
effects of agonist in tissues with elevated basal activity due to a spontaneous
activation of receptors. E.g. betacarbolins (endogenous substances) are
inverse agonists on benzodiazepine site from GABAA receptor

19
 Fig. 1. Agonist and competitive antagonist

Antagonist is a substance which prevents the action of an agonist on receptor

or the subsequent response, but does not have any effect of its own.
 Competitive antagonists (fig. 1) on a receptor bind only on affinity site of
receptor. E.g. Atropine is competitive antagonist for muscarinic receptors.
Prazosin antagonizes adrenaline on alpha-adrenergic receptors. Propranolol
antagonizes adrenaline on beta-adrenergic receptors.
 Noncompetitive antagonists on a receptor bind irreversible to a different site
on the receptor than the agonist. E.g. Gallamine is an allosteric antagonist on
muscarinic receptors. An allosteric antagonist produces a conformational
change of shape of the receptor, which in turn changes the affinity or
efficacy of the receptor for the agonist and/or changes the receptor function.
Competitive agonists and antagonists may displace one another from the
binding sites because drug – receptor interaction obeys law of mass action.

Substances with the same molecular formula and sequence of atoms, but which
differ only in the three-dimensional arrangement (how groups are oriented in
space) are called stereoisomers. Two stereoisomers that are related to each
other by a reflection ("molecules that are mirror images of one another”) are
termed enantiomers1. Naturally occurring active substances usually contain a
single enantiomer, but many drugs produced by chemical synthesis are used in
the form of racemic mixtures (50/50 mixture of its enantiomers). E.g.,
Omeprazole is a proton pump inhibitor which is marketed as racemic mixture.
Esomeprazole is the S-enantiomer of Omeprazole, which was developed as a
single enantiomer drug because at comparable doses has a clinical advantages

1
To distinguish between enantiomers, chemists use the R and S classification system according to whether its
configuration is right- or left-handed (R comes from the Latin rectus for right, and S from the Latin sinister for left).

20
(higher bioavailability, faster onset of antisecretory activity and less adverse
effects). Similarly, Citalopram is a racemic drug and its enantiomer S-
citalopram is over 100-fold more potent inhibitor of the serotonin reuptake
transporter than R-citalopram, so that it is also marketed as drug.

Signaling mechanisms and drug action

There are different molecular mechanisms to transduce many different signals:
 transmembrane receptor protein that stimulate a GTP-binding signal
transducer protein (G protein-coupled receptors);
 transmembrane receptor protein that stimulate a tyrosine kinase (tyrosine
kinase receptors);
 ligand-gated transmembrane ion channel that can be induced to open or close
by the binding of a ligand (ligand-gated ion-channels);
 transmembrane receptor protein whose intracellular enzymatic activity is
allosterically regulated by a ligand that binds to a site on the protein
extracellular domain;
 intracellular receptors for lipid-soluble ligands that crosses the membrane.

 G protein-coupled receptors (metabotropic receptors)

These are stimulated by biogenic amines, eicosanoids and other lipid-signaling
molecules, peptide hormones, opioids, amino acids such as γ-aminobutyric acid
(GABA), and many other peptide and protein ligands. G protein-coupled
receptors2 are the targets for many drugs. Agonist binding to the receptor leads
to a change in receptor protein conformation. This change propagates to the G-
protein. The interaction between the receptor and the G-protein is transient and
rapidly reversible. In the resting state, the G-protein exists as an unattached αβγ
trimer, with guanosine diphosphate (GDP) occupying the site on the α subunit.
When a receptor is occupied by an agonist molecule, conformational change
occurs on receptor, causing association to the trimer. Coupling of the α-subunit
of trimer to receptor causes the bound GDP from α-subunit to exchange with
intracellular guanosine triphosphate (GTP), the α – β subunit interaction is
disrupted, and the trimer dissociates into a monomeric α subunit (α-GTP
complex) and a dimeric βγ subunit. The α–GTP complex dissociates from the

2
G protein-coupled receptor is comprises a single peptide that has seven membrane-spanning regions and is linked to a
G protein. G proteins are made up of three subunits: an alpha α subunit, a beta β subunit and a smaller gamma γ subunit
(β and γ subunits are associated as a complex).

21
receptor and interacts with a target protein, which may be an enzyme (e.g.,
adenylate cyclase) or a channel. The βγ subunit may also activate a target
protein. Activation of the effector is terminated when GTP molecule is
hydrolysed to GDP. The resulting α–GDP then dissociates from the effector,
and reunites with βγ subunit, forming the trimer.

The key aspect of G-proteins is that there are several types of G-proteins which
interact with different receptors and control different effectors. The types of G-
proteins are:
 Gs is responsible for stimulating adenylate cyclase (hence, the subscript “s”);
 Gi is responsible for inhibiting adenylate cyclase and other effectors (hence,
the subscript “i”);
 Go regulate ion channels;
 Gt couples with rhodopsin to a phosphodiesterase in the visual system;
 Gq is responsible for activation of phospholipase C;
 G12/13 is responsible for ion transporters and may have also other roles.
G protein–regulated effectors include enzymes such as adenylate cyclase,
phospholipase C, phosphodiesterases, and plasma membrane ion channels
selective for Ca2+ and K+. Changes in the activity of these enzymes or channels
lead to changes of the concentration of the intracellular second messenger.

Second messenger systems allow signals from cell surface receptors to be

converted (in seconds) into a cellular response. Second messengers are essential
in conducting and amplifying signals coming from G protein-coupled receptors.
Second messengers are:
 cyclic nucleotides (cyclic AMP, cyclic GMP),
 inositol triphosphate and diacylglycerol (phosphoinositides),
 calcium ion,
 nitric oxide.

The adenylate cyclase – cAMP system is stimulated by different receptors that

couple to Gs proteins and is inhibited by receptors that couple to Gi proteins.
This mechanism controls the concentration of cAMP in the cytoplasm and thus
the cellular response. Examples of receptors that act on adenylate cyclase:
 β-adrenergic receptors couple to Gs proteins, resulting in stimulation of

22
 adenylate cyclase which increases cAMP concentration (which causes
smooth muscle relaxation, increase rate and contraction force of heart);
 presynaptic α2-adrenergic receptors couple to Gi proteins, resulting in
inhibition of adenylate cyclase which decreases cAMP concentration and
opening in cardiac K+ channels (which causes a decrease of heart rate);
 muscarinic M2 receptors couple to Gi proteins, resulting in inhibition of
adenylate cyclase which decreases cAMP concentration and opening in
cardiac K+ channels (which causes a decrease of heart rate).
Other receptors that activate adenylate cyclase include D1 and histamine H2
receptors, other receptors that inhibit adenylate cyclase include D2, opiate (µ
and δ), adenosine A2, angiotensin AT1 and GABA type B receptors (GABAB).

The guanylate cyclase – cGMP system is stimulated by different receptors that

couple to G proteins and activate guanylyl cyclase, which converts guanosine
triphosphate (GTP) to cyclic guanosine monophosphate (cGMP) which
stimulates cGMP-dependent protein kinase. cGMP signaling is important in
only a few cells, for example, intestinal mucosa and vascular smooth muscle,
where it causes relaxation of smooth muscle cells.
Phosphodiesterases (PDEs) are regulated by controlled transcription as well as
by second messengers (cyclic nucleotides and Ca2+) and interactions with other
signaling proteins such as b-arrestin and protein kinases. PDEs are responsible
for the hydrolysis of the cyclic 3,5-phosphodiester bond found in cyclic AMP
and cyclic GMP. PDEs are comprised of a superfamily with 11 subfamilies
distinguished on the basis of amino acid sequence, substrate specificity,
pharmacological properties, and allosteric regulation. The substrate specificities
of the PDEs include enzymes that are specific for cyclic AMP, cyclic GMP, and
both. PDEs play a highly regulated role that is important in controlling the
intracellular levels of cyclic AMP and cyclic GMP. The importance of the
PDEs as regulators of signaling is evident from their development as drug
targets in diseases such as asthma and chronic obstructive pulmonary disease,
cardiovascular diseases such as heart failure and atherosclerotic peripheral
arterial disease, neurological disorders, and erectile dysfunction.

The phospholipase C – phosphoinositide system is stimulated by different

receptors that couple to Gq proteins. Stimulation of phospholipase C splits a
minor component of the cell membrane, phosphatidylinositol-4,5-biphosphate
23
(PIP2) into two second messengers, namely inositol-1,4,5-trisphosphate (IP3)
and diacylglycerol (DAG). IP3 is water-soluble and diffuses through the
cytoplasm to the endoplasmic reticulum and causes the release of stored Ca2+
ions. Action of IP3 is terminated by hydrolysis of a phosphate group of IP3 and
the degradation products undergo rephosphorylation to regenerate the original
membrane substrate (PIP2). DAG is highly lipid-soluble and migrates within
membrane and activates protein kinase C, which regulates cellular activity by
catalyzing covalent phosphorylation of proteins. Muscarinic receptors M1, M3
and m5 couple to Gq proteins, resulting stimulation of phospholypase C which
increase IP3, DAG and intracellular Ca2+ concentrations (responsible for the
contraction of smooth muscles and stimulation secretion of exocrine glands).
Other receptors that activate phospholipase C include alpha α1, histamine H1
and serotonine 5HT2 receptors,

Intracellular Ca2+ concentration can be controlled by changes in membrane

potential (voltage gating), by the activity of G protein-coupled receptors (ligand
gating which stimulate phospholypase C – phosphoinositide system) and by
other mechanisms such as phosphorylation.

Nitric oxide (NO) is generated in vascular endothelial cells in response to

natural vasodilatator agents such as acetylcholine or histamine or to
vasodilatating drugs. After entering the target cell, NO binds and activates a
cytoplasmic guanylyl cyclase leading to relaxation of vascular smooth muscle.

 The tyrosine kinase receptors

These are stimulated by insulin, epidermal growth factor (EGF), atrial
natriuretic peptide (ANP) and other trophic hormones. The receptor protein
kinase is composed of an agonist-binding domain on the extracellular surface of
the plasma membrane (alpha subunit) and a protein kinase domain on the inner
membrane face (beta subunit, which may be a tyrosine kinase, a serine kinase or
a guanyl cyclase).
Insulin mechanism of action is mediated by tyrosine kinase receptors. The
insulin receptor consists of 2 α subunits (entirely extracellular) and 2 β subunits
(transmembrane). Insulin binding to the α subunits activates the kinase, which
is attached to the β subunit, resulting in the autophosphorylation of the tyrosine
which is present on the receptor’s β subunits and phosphorylation of other
24
substrates (small number of specific molecules) so that a signalling cascade is
initiated and biological response ensues.
Cytokine receptors are particular tyrosine kinase-associated receptors (kinase
activity is not related directly to the receptor molecule) stimulated by
interleukins, erythropoietin, and interferons.

 The ligand-gated ion-channels (ionotropic receptors)

These are opened by the binding of neurotransmitters to the channel. Activation
of a ligand-gated ion-channel receptor results in a brief (measured in
miliseconds) opening of the channel. Ligand-gated ion-channel receptors
mediate fast synaptic transmission at the neuromuscular junction and
throughout the central and peripheral nervous system.
There are few ligand-gated ion-channels receptors:
 nicotinic acetylcholine receptors (receptor is a Na+ ion channel and
acetylcholine is the natural ligand),
 gamma-aminobutyric acid type A (GABAA) receptors (receptor is a Cl– ion
channel and γ-aminobutyric acid is the natural ligand),
 5HT3 receptors (receptor is a Na+–K+ ion channel and serotonin is the natural
ligand),
 others: glutamate receptors, glycine receptor, AMPA receptor, P2X
adenosine triphosphate (ATP) receptors.
Nicotinic acetylcholine receptor consists of a Na+ channel which is normally
closed. Binding of two molecules of acetylcholine on the receptor opens the
channel that allows the entry of sodium ions, resulting in depolarization of the
effector cell, generation of an action potential, and activation of contraction in
skeletal muscle. Prolonged contact of acetylcholine receptor with agonist results
in a constant stimulation of the receptor therefore the receptor becomes
incapable of transmitting further impulses (resistance to depolarization, also
called inactivation or desensitization of the receptor) which causes a flaccid
paralysis. Succinylcholine attaches to the nicotinic receptor, causeing the
opening of the sodium channel associated with the nicotinic receptors, which
results in depolarization of the receptor and transient localized contractions of
the skeletal muscle (fasciculations). Because succinylcholine is not immediately
destroyed, continued binding of the depolarizing agent renders the receptor
incapable of transmitting further impulses which causes a resistance to

25
depolarization and a flaccid paralysis.
GABAA receptor consists of a Cl– channel. Binding of GABA on the receptor
opens the channel that allows the entry of chloride ions, resulting in
hyperpolarization of the respective cell which diminishes the generation of
action potentials, causing inhibitory effect on central nervous system (CNS)
activity. Benzodiazepines bind to a specific site on GABA-gated chloride
channel and increase the frequency of opening of Cl– channel; barbiturates bind
on a distinct specific site and increase the duration of opening of Cl– channel.

 The intracellular receptors

These are stimulated by lipid-soluble ligands such as hormones (corticosteroids,
mineralocorticoids, sex steroids, vitamin D, and thyroid hormone), which
produce their effects after a characteristic lag period of 30 min to several hours
(the time required for the synthesis of new proteins) and their effects can persist
for hours or days after administration (because the synthesized proteins remain
active in the cells for hours or days).
Glucocorticoids mechanism of action is mediated by intracellular receptors.
Free glucocorticoid from plasma and interstitial fluid enters the cell and bind to
receptor. In the absence of glucocorticoids, the receptor is bound to hsp90 (heat
shock protein 90), a protein that appears to prevent folding into the active
conformation of the receptor. Binding of hormone ligand to intranuclear
receptor causes release of hsp90 protein and permits conversion to the active
configuration of receptor. The glucocorticoid-bound receptor complex is
actively transported into the nucleus, where interacts with transcription of target
genes.

1.2.2. Action of drugs on enzymes

Many enzymes are a very important target of drug action, other enzymes are
important for biotransformation of drugs (metabolizing enzymes).
The common mode of action of many drugs is inhibition of enzymes. Many
drugs inhibit a particular enzyme without affecting others.
 Competitive inhibition of the enzyme is the most common mode of action on
enzymes. The drug molecule is a substrate analogue that acts as a reversible or
irreversible competitive inhibitor of enzyme:
o reversible inhibition of enzyme: Ibuprofen reversible inhibits
cyclooxygenases (COX);
26
 o irreversible inhibition of enzyme (covalent binding): acethylsalicylic
acid causes irreversible inhibition of cyclooxygenases (COX).
 Drug is a false substrate for enzyme therefore the drug molecule undergoes
chemical transformation to form an abnormal product which diverts the normal
metabolic pathway.
o Sulfonamides are structural analogues of p-aminobenzoic acid (PABA)
which is essential for the synthesis of folic acid (folic acid is required
for DNA and RNA synthesis both in bacteria and mammals).
Sulfonamides compete with PABA for the enzyme dihydropteroate
synthetase and thus inhibits the metabolism of bacteria.
o Captopril competes with angiotensin 1 for angiotensin converting
enzyme and thus inhibits the effects of angiotensin.
 Displacement of coenzyme and replacement with apoenzyme: oral
anticoagulants (e.g., Warfarin etc) displace vitamin K from the enzyme vitamin
K epoxide reductase, an enzyme which is involved in the synthesis of
functional clotting factors, II, VII, IX, and X and also proteins C, S, and Z.
Warfarin exerts its anticoagulant effects by preventing the ability of vitamin K
epoxide reductase to regenerate reduced vitamin K from vitamin K epoxide
form (oxidized form).

1.2.3. Action of drugs on ionic channels

Drugs can affect ionic channels through specific receptors (e.g. G-protein
operated channels) or by directly binding to the channel.
 block sodium channels:
o block voltage-gated sodium channels: local anesthetics (e.g. Lidocaine
etc), class I antiarrhythmic drugs (Quinidine, Procainamide, Lidocaine,
Propafenone etc);
o block sodium influx through sodium ion channel in the renal tubule
luminal membrane: Amiloride (a potassium-sparing diuretic);
 block calcium channels (reduction of the frequency of opening voltage
gated L-type calcium channels: dihydropyridines): Nifedipine, Verapamil,
Diltiazem, Felodipine etc.
 block potassium channels (closure of ATP-sensitive potassium channel in
pancreatic tissues): sulfonylureas antidiabetics (e.g. Tolbutamide, Glyburide
etc);
 stimulate potassium channels (in smooth muscle of arterioles): Minoxidil,
27
 Diazoxide.

1.2.4. Action of drugs on nucleic acids or other subcellular structures

Drugs act on nucleic acids by:
 formation of covalent bonds with nucleotides in DNA. E.g.:
Cyclophosphamide (an alkylating agent from the group of nitrogen mustard
derivatives indicated in cancer chemotherapy), Carmustine and Lomustine
(alkylating agents from the group of nitrosoureas indicated in cancer
chemotherapy) etc.
 intercalation in the DNA. E.g.: Dactinomycin (a cytotoxic antibiotic from
the group of anthracyclines indicated in cancer chemotherapy).
 fragmentation of DNA chains. E.g.: Bleomycin (a cytotoxic antibiotic from
the group of anthracyclines indicated in cancer chemotherapy).
 inhibition of DNA and RNA synthesis. E.g.: Doxorubicin (a cytotoxic
antibiotic from the group of anthracyclines indicated in cancer
chemotherapy).
 binding to ribosomal units. E.g.: Erythromycin and Chloramphenicol inhibit
bacterial protein synthesis by binding to the 50 S ribosomal subunit.
Tetracyclines and aminoglycosides bind to the 30 S ribosomal subunit.

1.2.5. Action of drugs by forming “membrane pores”

 Amphotericin B (systemic antifungal drug) binds to ergosterol, a cell
membrane sterol found in the cell membrane of fungi, and alters the
permeability of the cell by forming Amphotericin B-associated pores in the
cell membranes. The pores allow the leakage of intracellular ions and
macromolecules, leading to cell death.
 Nystatin (topical antifungal drug) has a similar mechanism of action.

1.2.6. Action of drugs by enhancing release of mediators

 Ephedrine, Naphazoline and Phenylephrine  release norepinephrine from
the adrenergic nerve endings.
 Carbachol release endogenous acetylcholine from the cholinergic nerve
endings.
 d-Tubocurrarine, Morphine  release histamine.

28
 2. Structure – effect relationship

Changes in the chemical structure of a substance can increase or decrease the

affinity for different receptors, with resulting modifications in pharmacological
effects. There are changes in the molecule that modify the pharmacokinetic
properties.
 From the same structure may result substances with similar effects: methyl
substitution on norepinephrine, yielding epinephrine, enhances activity at β2
receptors.

Norepinephrine Epinephrine
Activate α and β1-adrenergic receptors Activate α, β1 and β2-adrenergic receptors

 From the same structure may result substances with improved

pharmacokinetic properties: absence of ring –OH group on norepinephrine,
yielding amphetamine, increases the distribution of the molecule to the
central nervous system.

Norepinephrine Amphetamine
Increased bioavailability after oral
administration

 From the same structure may result substances with opposite effects:
histamine is agonist on histamine receptors; its derivative, Cimetidine, is a
H2 receptor antagonist.

Histamine Cimetidine
Histamine receptors agonist H2 receptor antagonist

29
 3. Dose – effect relationship

Dose is the quantity of substance which determines an effect. If drug effect can
be observed directly, then the magnitude of effect can be displayed as a
function of drug concentration in the form of a dose – effect curve (dose –
response curve). A dose – effect curve (fig. 2) represent the relationship
between gradually increasing doses of drug and the responses determined by
these doses. The curve is characterized by a threshold, maximal effect, and
slope. On a semi-logarithmic scale, dose – response curves are characteristically
sigmoidal in shape. Direct proportionality between doses and effects is rare.

Fig. 2. Dose response curve (gradual response and on a semi-logarithmic scale)

Efficacy is the capacity of a drug to produce a therapeutic response.

If two drugs have the same intensity of a biological effect (determine
similar reduction of blood pressure), then these drugs have both the
same efficacy.
Potency is the amount of a drug required to produce a therapeutic response.
If two different doses of two drugs produce the same biological effect,
then the lowest dose of drug is more potent. E.g. if 10 mg of Morphine
produce the same analgesic effect as 100 mg of Pethidine, then
Morphine is 10 times more potent than Pethidine.

Median lethal dose (LD50) is a statistically calculated dose as a minimal dose

required of a substance that causes death in 50% of the tested animals. It is
useful for toxic evaluation, particularly for new substances.
Effective dose 50% (ED50) is a statistically calculated dose as a minimal dose

30
required of a substance that causes desirable effect of the test substance
occurring in 50% of the tested animals.
Toxic dose 50% (TD50) is a statistically calculated dose as a minimal dose
required of a substance to produce that causes toxic effect of the test substance
occurring in 50% of the tested animals or subjects.
Inhibitory concentration 50% (IC50) is the minimal concentration necessary
to inhibit 50% of a measured response in an in vitro system.
The therapeutic index (also named margin of safety) is the ratio between the
drug dose that produces a lethal effect in half of the animal population (LD50)
and the drug dose that produces a therapeutic response in half of the animal
population (ED50):

The therapeutic index is a measure of a drug's safety. A larger value of

therapeutic index (> 10) indicates the safety: a wide margin between
doses that are effective and doses that are toxic. A lower value of
therapeutic index (< 10) indicates that there is a narrow range of safety
between an effective dose and a lethal one. In general, nonprescription
drugs have much higher therapeutic index than prescription drugs.
The clinical therapeutic index of a drug is the ratio of the dose that
produces toxicity to the dose that produces a clinically desired or
effective response in a population of individuals.

where TD50 is the drug dose that produces a toxic effect in half the
population and ED50 is the drug dose that produces a therapeutic
response in half the population.
Factors influencing drug effect:
 age (e.g., in new borns there is immaturity of function of liver and kidney, in
elderly there is a degradation of liver and kidney function); the most used
formulas to calculate doses for children are:
o Young’s formula (for children < 12 years old):
Age (years)
Dose for the child   Adult dose ;
Age (years)  12
o Dilling’s formula (for children > 12 years old):

31
 Age (years)
Dose for the child   Adult dose ;
20
 sex (e.g., male metabolise faster Zolpidem [a sedative-hypnotic drug] than
women);
 body weight: the adult dose is calculated to produce specific effect in a
population with age between 18 to 65 years and weighing about 70 kg, so that
other individuals (obese, children etc) have to receive modified doses to
produce the same response. The most used formulas to calculate doses for
children is Clark’s formula:
Child' s weight (in kg)
Dose for the child   Adult dose ;
70
 route of administration: (magnesim sulphate administered orally may be
colagogue in doses of 4 g or purgative in doses of 15 g, administerd i.v. is
indicated for eclampsia3);
 time of administration (e.g., a single dose of ranitidine administered at
bedtime is more effective than two or three doses administered during the
day);
 environmental factors (e.g., presence of food may delay or increase drug
absorption);
 presence of disease (e.g., liver or kidney failure etc);
 others: accumulation; additive effects; synergism or antagonism;
idiosyncrasy; tolerance.

4. Combined effects of drugs: synergism, antagonism

When two drugs are given simultaneously, they may be either indifferent to
each other or exhibit synergism or antagonism.
4.1. Synergism is the effect that results when the action of a drug is facilitated
or increased by the other drug (the two drugs act in the same direction).
Synergism is of two types:
 Summation or addition occurs when the effects of two drugs having the
same action are additive, e.g. 1 + 1 = 2 (beta-adrenoceptor blocker plus a
thiazide diuretic have an additive antihypertensive effect).

3
Eclampsia is the gravest form of pregnancy-induced hypertension, characterized by hypertension, grand mal seizure,
coma, proteinuria, and edema.

32
 Potentiation (to make more powerful) occurs when one drug increases the
action of another, e.g. 1 + 1 = 3. Sometimes the two drugs both have the
action concerned (trimethoprim plus sulfamethoxazole) and sometimes one
drug lacks the action concerned (Levodopa plus Carbidopa), e.g. 0 + 2 = 3.

4.2. Antagonism occurs when the action of one drug opposes the action of
another. The two drugs simply have opposite pharmacodynamic effects, e.g.
Histamine and Adrenaline on the bronchi exhibit physiological or functional
antagonism; or they compete reversibly for the same drug receptor, e.g.
Flumazenil and benzodiazepines exhibit competitive antagonism.
Depending on the mechanism involved, antagonism may be:
 Competitive antagonism on receptors;
 Non-competitive antagonism:
o physiological antagonism (functional antagonism) describe the
interaction between different substances which act on different
receptors, initiating effects that are functionally opposite, e.g. Histamine
(binds to H1 histamine receptors on vessels, causing vasodilatation) and
Adrenaline (binds to alpha-adrenergic receptors on vessels, causing
vasoconstriction) so that Adrenaline antagonizes the histamine-induced
allergic reactions;
o physical antagonism is based on the physical property of the drug, e.g.
activated charcoal adsorbs different substances;
o chemical antagonism refers to a chemical reaction or formation of a
complex between two substances, e.g. protamine binds to heparin to
reverse its actions;
o allosteric antagonism is due to binding to a allosteric site of receptor e.g.
Gallamine (on muscarinic receptors);
 inverse agonist reverses the effects of agonist in tissues with elevated basal
activity due to a spontaneous activation of receptors, e.g. betacarbolins.

5. Adverse drug reactions

There is general agreement that drugs are prescribed for a primary action in a
certain disease. Some drugs have additional effects as an indirect consequence

33
of a primary drug action. These additional effects can be beneficial (named
secondary effects) or harmful (named adverse drug reactions). Sometimes
drugs are the cause of a serious amount of disturbances, ranging from
inconvenience to permanent disability and death. Clinically important adverse
drug reactions are diverse, any organ system can be the target or several
systems can be involved simultaneously.
The term adverse reaction should be confined to: harmful or seriously
unpleasant effects occurring at doses intended for therapeutic (including
prophylactic or diagnostic) effect. There should be distinguishing between
natural progression of a disease and drug-induced deterioration.
A serious adverse event is defined as one which is fatal; is life-threatening;
causes or prolongs hospitalization; causes disability or incapacity; requires
medical intervention to prevent permanent impairment or damage; is a cancer or
a congenital abnormality.
Toxicity implies a direct action of the drug, often at high dose, damaging cells.
All drugs, for practical purposes, are toxic in overdose. In some cases a
therapeutic dose may be toxic due to an underlying abnormality in the patient,
e.g. disease of the kidney.

5.1. Idiosyncrasy implies an unexpected abnormal reaction to therapeutic dose

of a drug, usually due to genetic abnormality. Examples of idiosyncratic
reactions:
 in persons with G6PDH deficiency, sulfonamides determine hemolysis as an
abnormal response;
 in persons with plasma cholinesterase deficiency, Succinylcholine (a
depolarizing neuromuscular blocker) determines an exaggerated prolonged
skeletal muscle relaxant response.

5.2. Immune responses induced by drugs may be harmful (allergy) or

harmless. Most drugs act as incomplete antigens or haptens, which become
complete antigens in combination with a body protein. Sometimes very small
doses may cause very severe effects.
Drug-induced allergic reactions may be classified according to four types of
hypersensitivity:
 Type I reactions (immediate or anaphylactic type) are characterized by
drug-induced formation of tissue-sensitising IgE antibodies that are fixed to
34
 mast cells or leucocytes and cause release of pharmacologically active
substances (e.g. histamine, leukotrienes, prostaglandins, platelet activating
factor). Reactions (such as eyelids, lips and face edema, urticaria,
angioedema4, anaphylactic shock5) develop within minutes and lasts 1-2
hours. Such reactions are induced by: penicillins, cephalosporines,
aminoglycosides, sulfonamides, iodine or bromide substances,
Acetylsalicylic acid.
 Type II reactions (antibody-dependent cytotoxic type) occur due to the
combination of drug with a protein in the body so that the body no longer
recognizes the protein as self, treats it as a foreign protein and forms
antibodies (IgG, IgM) that combine with the antigen and activate
complement which damages cells. Such reactions are induced by:
Hidralazine (may induce systemic etythematous lupus), penicillin- or
Methyldopa (may induce haemolytic anaemia).
 Type III reactions (immune complex-mediated type) are characterized by
large complexes between antigen and antibody that activate complement and
determine inflammatory reactions such as serum sickness,
glomerulonephritis, vasculitis and pulmonary disease. Such reactions are
induced by: penicillins, aminoglycosides, sulfonamides.
 Type IV reactions (lymphocyte-mediated type) are due to antigen-specific
receptors developed on T-lymphocytes which cause local or tissue allergic
reaction, e.g. contact dermatitis. Such reactions are induced by:
sulfonamides.
Cross-allergy within a group of drugs is usual (e.g., penicillins). When allergy
to a particular drug is established, a substitute should be selected from a
chemically different group. Patients with allergic diseases, e.g. eczema, are
more likely to develop allergy to drugs.

5.3. Tolerance, tachyphylaxis, drug dependence

Tolerance means that the drug loses its effectiveness over time and an
increased dose is required to produce the same physiological response.
Tolerance disappears when the drug is stopped for some time. It can be
congenital (e.g., eskimos are highly tolerant to fat diet) or acquired (e.g., an
4
Angioedema is an allergic reaction on the skin, due to a vascular reaction (dilatation and increased permeability of the
capillaries), and characterized by the development of giant wheals.
5
Anaphylactic shock is a severe shock induced by hypersensitivity to an allergen (such as a drug, foreign protein or
toxin).

35
acquired resistance to the usual dose of a drug repeatedly administered and
more drugs are needed to produce the same effect).
Cross-tolerance is tolerance developed to other drugs of the same group (e.g.
members of opioids with each other such as Morphine and methadone etc).
Tachyphylaxis is an acute form of acquired tolerance in which it is a rapid
decrease in the response to a drug after repeated doses over a short period of
time, but the same response cannot be achieved by increasing the dose. It is
considered a rapid form of tolerance which disappears after a brief drug-free
interval. For example, ephedrine tachyphylaxis is due to depletion of
catecholamine stores and to downregulation of receptors. Nitroglycerine
tachyphylaxis is due possible to depletion of free sulfhidril –SH groups from
tissues.
Drug dependence is a state in which use of drugs for personal satisfaction is
accorded a higher priority than other basic needs, often in the face of known
risks to health. Drug dependence occurs when a patient displays a psychological
or physical need for the drug.
 Psychological dependence is developed when the individual believes that
optimal state of wellbeing is achieved only through drug consumption. It is
based on a desire to continue taking the drug to relieve tension and avoid
discomfort. Drugs producing psychological dependence are cocaine,
amphetamines etc.
 Physical dependence is an altered physiological state produced by repeated
administration of a drug which necessitates the continued presence of the
drug to maintain produces physiological equilibrium. Addiction is a
behavioral pattern characterized by compulsive use of a drug and
overwhelming involvement with its procurement and use. Drugs producing
physical dependence are opioids, barbiturates, alcohol etc. Discontinuation
of the drug results in withdrawal (abstinence) syndrome.

5.4. Teratogenesis, Mutagenesis, Carcinogenesis

 Teratogenesis refers to the capacity of a drug to cause fetal abnormalities
when administered to the pregnant women. The type of malformation
depends on the drug as well as the stage of exposure to the teratogen. Risk
category of drugs during pregnancy:
o Category A includes drugs (e.g. magnesium sulfate etc) which have
studies that demonstrated the absence of risk to the fetus;
36
 o Category B includes drugs (e.g. Erythromycin etc) for which adequate
studies in pregnant women are lacking, but animal studies have failed
to demonstrate a risk to the fetus;
o Category C includes drugs for which there are no adequate studies in
pregnant women or in animals, but potential benefit may warrant use
of the drug in pregnant women despite potential risk (e.g., Morphine,
corticosteroids etc);
o Category D includes drugs for which there is evidence of human fetal
risk (e.g., acetylsalicylic acid, carbamazepine etc);
o Category X includes drugs for which studies demonstrated fetal
abnormalities (e.g., estrogens, Thalidomide etc).
 Mutagenesis refers to the capacity of a drug to cause a change in the
genotype of a cell, which is passed on when the cell divides.
 Carcinogenesis refers to the capacity of a drug to initiate the changes that
result in malignancy (mutations in protooncogenes and tumor suppressor
genes are particularly implicated). Carcinogens can be:
o Genotoxic – causes mutations directly or after conversion to reactive
metabolites;
o Epigenetic – increases the possibility that a mutagen will cause cancer,
though not themselves mutagenic.

5.5. Adverse drug reactions characteristic to antibacterial chemotherapy:

 antibiotic-associated colitis (Clostridium difficile–associated disease) is
acquired almost exclusively in association with antimicrobial use
(Ampicillin, tetracyclines etc); should be treated with Metronidazole or
Vancomycin;
 Herxheimer reaction after the first dose of Penicillin G for therapy of
syphilis (endotoxinic shock due to the release of endotoxin when large
numbers of Treponema pallidum are killed by penicillin);
 red man syndrome (red neck syndrome) after Vancomycin administration
(it is a infusion-related flushing caused by release of histamine);
 gray baby syndrome after Chloramphenicol administration (occurs because
of inability of newborn to metabolize and excrete chloramfenicol by
glucuronoconjugation; drug may accumulate in the CNS resulting in
vomiting, flaccidity, hypothermia, gray color, irregular respirations,
cardiovascular collapse).
37
5.6. Iatrogenic effects (drug-induced illness) are adverse drug reactions which
mimic pathologic disorders. For example, Acetylsalicylic acid and
Indomethacin (nonsteroidal anti-inflammatory drugs) commonly cause gastro-
intestinal irritation and bleeding. So, effective therapy depends not only on the
correct choice of drugs but also on their correct use.

5.7. Polymedication is defined as daily consumption of three or more

medications and consistent with noncompliance with physicians' prescription.
The elderly patients are characterized by the high degree of polymedication.
Polymedication by the elderly poses a high risk for potentially severe drug
interactions. Polymedication increases the risk of iatrogenic disorders, may
affect adherence to treatment, and represents an economic burden for society.

38
 Lecture 2
Principles of pharmacokinetics

Learning Objectives:
 Describe aspects of absorption, distribution, metabolism and excretion of a drug;
 List the principal routes of drug administration and their advantages and
disadvantages;
 List examples of drugs concentrated in different tissues or liquids of the body;
 Name the phases in hepatic metabolism;
 Describe the terms “bound” and “unbound” drug to plasma proteins;
 Describe the term “first pass effect”;
 Describe the terms drug metabolism “enzyme induction” and “enzyme inhibition”;
 List the principal routes of drug elimination;
 Explain concept and significance of pharmacokinetic parameters
 Explain concept and significance of steady state concentration.

Most drugs :
 enter the body (by mouth or injection or…) - must cross barriers to entry
(skin, gut wall, alveolar membrane…..) ABSORPTION TRANSPORT
 are distributed by the blood to the site of action (intra- or extra- cellular) 
cross barriers to distribution (blood-brain barrier, feto-placentar barrier,
capillaries, cell wall ….) DISTRIBUTION
 are biotransformed perhaps to several different compounds by enzymes
evolved to cope with natural materials  this may increase, decrease or
change drug actions METABOLISM
 are excreted (by kidney or …….) which removes them and/or their
metabolites from the body. ELIMINATION

Pharmacokinetics studies the fate of a drug during its sojourn through the
body (absorption, distribution, metabolism and excretion, shortly named
ADME – fig. 3). The absorption, distribution, metabolism, and excretion of a
drug all involve its passage across cell membranes. In most cases, a drug must
traverse the plasma membranes of many cells to reach its site of action. For
most drugs, the magnitude of pharmacological response depends on the

39
concentration of drugs at its site of action. Concentration of drug varies with
time in body fluids or tissue.

Fig. 3. Fate of a substance in the body

Knowledge about the absorption, distribution, metabolism and elimination of

drugs are important from a clinical point of view.

1.Drug permeation

All pharmacokinetic processes involve transport of the drug across biological

membranes.
Drugs are transported across the membranes by passive or active mechanisms.
The ability of a drug to cross a cell membrane depends on whether the drug is
water or lipid (fat) soluble. Lipid-soluble drugs easily cross through cell
membranes; water-soluble drugs can’t. Lipid-soluble drugs diffuse by
dissolving in the matrix of the membrane: a more lipid-soluble drug diffuses
more quickly. Drugs of very low lipid-solubility, including those that are strong
acids or basis, are generally poorly absorbed.
Passive transport requires no cellular energy because diffusion allows the drug
to move from an area of higher concentration to one of lower concentration:
 Passive diffusion is the process of the drug diffusion across the membrane in
the direction of its concentration gradient. The diffusion is faster when there
are greater differences in the concentrations of the drug on the two sides of
the membrane.
 Filtration is the process of the drug passage through aqueous pores in the
membrane or through paracellular spaces. The size of molecules should be
smaller than the diameter of the pores.
 Facilitated diffusion (facilitated transport) is a passively carrier-mediated
transport of drugs, in the direction of its electrochemical gradient. It is a
transmembrane protein which binds one or more molecules or ions, changes
conformation and release them on the other side of membrane. In carrier-
mediated transport (e.g., transporter for glucose), the carrier sites become
40
 saturated at high ligand concentrations and the rate of transport does not
increase beyond this point. Furthermore, competitive inhibition of transport
can occur if a second ligand that binds to the carrier is present.
Active transport in an actively carrier-mediated transport and requires cellular
energy for the movement of the drug molecule from an area of lower
concentration to one of higher concentration.
 Endocytosis is the process by which a substance is engulfed by the cell
membrane and carried into the cell by pinching off of the newly formed
vesicle inside the membrane, e.g. iron associated with transferin is
transported into red blood cells precursors.
 Exocytosis (is the reverse of endocytosis) is the process in which
intracellular vesicles in the cytoplasm fuse with the plasma membrane and
release or "secrete" their contents, e.g. release of neurotransmiters.
 Transcytosis is the process by which various macromolecules are
transported across the interior of a cell.
 Pinocytosis is a type of endocytosis in which a liquid is transported across
the cell by the formation of vesicles and remains in a separate vacuole.
 Special carrier molecules that requires cellular energy for the movement of
certain drug molecules plays an important role in some drug-resistant
neoplastic cells and in excretion of some drugs. Carrier-mediated drug
transport is important in the renal tubule, the biliary tract, the blood-brain
barrier, the gastrointestinal tract. The main carrier-mediated drug transport
systems are:
o P-glycoprotein (P-gp or multidrug resistance type-1 transporter or
MDR-1);
o Multidrug resistance type-2 transporter (MDR-2).
The presence of physical barriers allows for controlled transfer of nutrients and
other substances.
 The blood–brain barrier (BBB) and the blood–cerebrospinal fluid barrier
(BCB) at the choroid plexus are two major barriers between the CNS and
blood. Penetration into brain and CNS is of importance for the action of
drugs on the CNS. Only lipid-soluble molecules are able to penetrate BBB
(e.g. barbiturates, benzodiazepines etc). Inflammation of meninges increases
permeability of BBB (e.g. penicillin).
 The placenta is a complex membrane barrier system that separates the fetus

41
 from the mother and regulates the exchange of nutrients, gases, wastes, and
xenobiotics, including drugs. The placenta is very well perfused and most
lipophilic drugs can readily cross the placenta barrier by diffusion. Passage
of drugs across placenta is of importance because drugs may cause
anomalies in the developing fetus.

2.Absorption of drugs

Absorption is defined as the movement of a drug from its site of administration

into the plasma.
The amount of drug that enters the body depends on the patient’s compliance
with the prescribed therapeutic scheme and on the rate and extent of transfer
from its site of administration to the blood. For solid dosage forms, absorption
first requires dissolution of the tablet or capsule, thus liberating the drug.
The onset of action refers to the time interval from when the drug is
administered to when its therapeutic effect actually begins, the duration action
is the length of time the drug produces its therapeutic effect. Rate of onset
varies depending on the route of administration and other pharmacokinetic
properties. The choice of a certain route of administration of a drug is
determined by the properties of the drug and by the therapeutic objectives.
Factors affecting gastrointestinal drug absorption:
 the formulation of the drug (solution, suspension, or solid dosage form) and
particle size,
 lipid or water-solubility of drug,
 concentration of drug at the site of absorption,
 surface area for absorption,
 blood flow to the site of absorption,
 gastrointestinal motility (excessively movement of gut contents can impair
absorption, gastric stasis slows absorption).
Routes of administration of drugs:
 Enteral route include internal (oral or per os sau p.o.), sublingual and rectal
administration.
 Parenteral route include administration by intravenous (iv), intramuscular
(im), subcutaneous (sc), intradermic, epidural, intrathecal, intrapleural,

42
 intraperitoneal (ip), intraosseous, intraarticular route etc.
 Topical route include application on skin or on mucous membranes such as
cornea (ocular administration), nasal, respiratory (inhalation), vaginal
mucosa.

2.1. Enteral route

2.1.1. Oral route is the most common method of drug administration. Most
drugs are taken by mouth and swallowed. Most drugs are absorbed form
gastrointestinal tract in small intestine (especially, duodenum), little absorption
occurs in other parts of the gastrointestinal tract. There is a degree of gastric
absorption for barbiturates, acethylsalicylic acid, ethanol and water.
 Advantages: it is the safest, most convenient, most economical route of
administration and it is preferred by patient.
 Disadvantages: limited absorption of some drugs because of their physical
properties, destruction of some drugs by digestive enzymes or gastric pH,
variations in absorption in the presence of food or other drugs, irritation to
the gastric mucosa, metabolism by the enzymes of the intestinal flora,
mucosa, or liver before entering the general circulation. Drugs should be
administered to patients who are conscious and can swallow (not to patient
in coma, infants, elderly, some psychiatric patients etc).
 Presence of food determine variations in absorption of drugs:
o food decreases absorption of: Ampicillin, Captopril etc,
o fat food increases absorption of Griseofulvin, coca cola increase
absorption of Ketoconazole etc,
o food does not influence absorption of: Amoxicillin, Doxycycline etc.
 Concomitant presence of other drugs may influence absorption of drugs:
o Decrease absorption of:
 digoxin in the presence of cholestyramine (cholestyramine binds
digoxin and forms a complex therefore it is recommended to
take digoxin 1 h before or 3–4 h after cholestyramine),
 tetracyclines in the presence of bivalent or trivalent cations
(certain antacids, ferrous ions in oral iron supplements, milk
products),
o Increase absorption of Digoxin in the presence of Erythromycin.
Absorption from gastrointestinal tract is not necessary for the action of:

43
 antiacids (e.g., calcium carbonate, sodium bicarbonate etc),
 antihelminthic drugs (e.g, Albendazole, Mebendazole etc).
After oral administration, there are drugs which are not absorbed from
gastrointestinal tract because they act only local:
 aminoglycosides (e.g, Streptomycin),
 digestive enzymes,
 laxatives (except anthraquinone derivatives which are poorly absorbed from
gastrointestinal tract).

2.1.2. Sublingual route involves the placement of drug under the tongue. The
active substance enters directly into systemic circulation (the substances
bypasses the liver). Buccal administration is in the pouch between the cheek
and gum and translingual administration is on the tongue.
 Advantages: rapid absorption (onset of effect is in minutes) convenience of
administration, avoidance of gastro-intestinal tract and bypasses the liver
(100% avoid first pass metabolism).
 Disadvantages: it is effective for a small number of drugs (e.g.
Nitroglycerin).

2.1.3. Rectal route is used to treat local irritation or infection or as alternative

when patient is unconscious or when vomiting is present. Some drugs applied
to the mucosa of the rectum or vagina can be absorbed systemically.
 Advantages: approximately 50% of the drug that is absorbed from the
rectum will bypass the liver (50% avoid first pass metabolism).
 Disadvantages: incomplete and irregular absorption, irritation of the rectal
mucosa.

2.2. Parenteral route introduce drugs directly into systemic circulation or other
vascular tissues:
 intravenous (iv) is the most common parenteral route,
 intramuscular (im) is in large skeletal muscles (such as rectus femoris,
deltoid, triceps, gluteus maximus),
 subcutaneous (sc) is beneath the dermis and into the subcutaneous tissue
(usually in the patient’s upper arm, thigh, or abdomen),
 intradermic,

44
 epidural is into the epidural space,
 intrathecal is into the cerebrospinal fluid,
 intrapleural is into the pleural cavity,
 intraperitoneal (ip) is into the peritoneal cavity,
 intraosseous is into the rich vascular network of a long bone,
 intraarticular is into a joint.
Bioavailability of drugs after iv administration is 100%. This route is used for
drugs that are not absorbed form gastrointestinal tract (e.g. Kanamycin), drugs
unstable in gastrointestinal tract (e.g. insulin) or drugs that are poorly absorbed
from gastrointestinal tract (e.g. Heparin), for unconscious or vomiting patients.
Administration can range from a single iv dose to an ongoing infusion delivered
with great precision.
 Advantages: rapid onset of effect after intravenous administration (drug
action is faster and surer).
 Disadvantages: the preparations has to be sterilized and it is necessary a
qualified person to administrate it. The administration is invasive and
painful. The effect of administered drug is irreversible. By iv administration
can be injected only aqueous solutions, not suspensions or oily preparations.
Suspensions or oily preparations can be administered only deep im. Im
administration should be avoided in anticoagulant treated patients because
produce local hematoma. Larger volumes after im or sc administration may
be painful or may cause infections.
Methods for delaying absorption are used to produce a local effect or to prolong
systemic action:
 addition of adrenaline to a solution of local anesthetic (e.g., lidocaine etc)
reduces absorption of the local anesthetic into systemic circulation;
 use of slow release form of drugs (e.g., procaine penicillin etc);
 subcutaneous implantation of pellets is used to achieve slow and continuous
absorption of some drugs (e.g., estradiol etc).

2.3. Topical route is used to deliver a drug through the skin or a mucous
membrane. Topical administration is used to achieve local effects or for
systemic effects.
2.3.1. Cutaneous administration is used only for highly soluble drugs
(cutaneous absorption can be enhanced by using special oily base or occlusive

45
dressing). Systemic effects have nicotine, estradiol, nitroglycerin and Fentanyl
transdermal patches.
2.3.2. Inhalatory administration is used for very rapid onset of effect (e.g.
Salbutamol – a beta2 agonist with bronchodilatator effect, Isoflurane – a
volatile liquid general anesthetic). Drugs can be self-administered (using a
metered-dose inhaler) or can be administered directly into the lungs through an
endotracheal tube in emergency situations.
2.3.3. Nasal route is used for local effects or systemic effects:
 local effects: Naphazoline (alpha-simpathomimetic drug with local
vasoconstrictor effect) is used for rhinitis.
 systemic effects: Oxytocin and Vasopressin are peptides which are
inactivated when given orally, so these are administrated on nasal mucosa.
2.3.4. Conjunctival mucosa is used for local effects, but for some drugs
systemic absorption can occur and determine unwanted effects (e.g. Timolol –
an antagonist on beta receptors indicated for the treatment of glaucoma6).

3.Distribution of drugs

Distribution is the process by which the drug is delivered from the systemic
circulation to body tissues and fluids. The extent of distribution depends on the
physical and chemical properties of the molecule, protein binding and blood
flow (the drug is quickly distributed to organs with a large supply of blood such
as liver, kidney and heart).
The binding of drug to plasma (and tissue) proteins is a major determinant of
drug disposition (distribution). The distribution of drugs can be in water
compartments in the body or in other tissues (fat, bones). The distribution of
drugs in water compartments in the body:
 vascular compartment (blood) for very large molecules (e.g. Heparin – an
anticoagulant drug for parenteral administration) and for drugs strongly
bound on plasma proteins (e.g. Warfarin – a coumarinic oral anticoagulant
drug),
 vascular and extracellular compartment for large water soluble molecules
(e.g. Gentamicin and other aminoglycosides),

6
Glaucoma is disease characterized by damage to the optic nerve, usually due to excessively high intraocular pressure.

46
 total body water (include intracellular compartment) for small water-soluble
molecules (e.g. ethanol).
The distribution of drugs in fat is for highly lipid-soluble molecules (e.g.,
thiopental – a very short acting barbiturate) and in the bones is for certain ions
(e.g., lead).
Distribution in other tissues is important because it serve as a reservoir that
prolongs drug action in that tissue or at a distant site reached through the
circulation. Such tissue binding and accumulation can produce local toxicity.
Redistribution of the drug from its site of action into other tissues or sites may
result in termination of drug action. Greater the lipid-solubility of a drug, faster
is its redistribution. Example, thiopental (general anesthetic with iv
administration) is a molecule very lipophilic. After a single intravenous bolus,
thiopental is preferentially distributed into the highly perfused and lipophilic
tissues of the brain and spinal cord where produce anesthesia within a single
circulation time. Subsequently, anesthetic action of is terminated in few minutes
due to drug redistribution out of the CNS back into the blood and into other less
perfused tissues such as muscle and viscera, and at a slower rate into the poorly
perfused but very hydrophobic adipose tissue.
Factors affecting drug distribution:
 lipid or water-solubility of drug, dissociation constant of drug;
 degree of plasma protein binding;
 affinity for different tissues, regional differences in pH;
 blood flow – tissue mass ratio;
 diseases like cardiac heart failure, cirrhosis, uremia etc.

Drugs concentrate in different tissues or liquids of the body:

 CNS and adipose tissue: hexobarbital, thiopental etc;
 Cerebrospinal fluid:
o penetration of uninflamed meninges: cephalosporins (third- and fourth-
generation), fluoroquinolones (Ciprofloxacin), sulfonamides,
Trimethoprim etc;
o better penetration if inflamed meninges: penicillins (Penicillin G,
Ampicillin, Oxacillin etc), monobactams (Aztreonam), carbapenems
(Imipenem, Meropenem, Ertapenem), Vancomycin, Rifampicin etc;
 bronchial secretions:

47
 o penicillins and cephalosporins (reach only marginal concentrations),
o fluoroquinolones and macrolides (achieve high concentrations);
 pleural fluid, peritoneal fluid: aminoglycosides (Gentamicin etc),
Vancomycin, penicillins, cephalosporins, tetracyclines etc;
 concentration in cells:
o neutrophils: fluoroquinolones (Ciprofloxacin) etc;
o macrophages: fluoroquinolones (Ciprofloxacin) etc;
 bile: aminopenicillins (Ampicillin, Amoxicillin), antistaphylococcal
penicillins (Oxacillin etc), cephalosporins (third- and fourth-generation),
macrolides, aminoglycosides, tetracyclines, Rifampicin, fluoroquinolones,
Cyclosporine, anticancer drugs (Vincristine, Doxorubicine), opioids
(Morphine, heroin etc), Spironolactone, Indapamide, Digoxin etc;
 liver: vitamin B6, Chloroquine (antimalarial drug) etc;
 tears: minocycline, Rifampicin, antiepileptic drugs;
 sweat: Rifampicin, amphetamines;
 saliva: Minocycline, antiseizure drugs (Phenytoin, Carbamazepine, Valproic
Acid, Ethosuxumide), barbiturates (Phenobarbital etc), benzodiazepines
(Diazepam etc), drugs of abuse (Morphine, heroin, cocaine, amphetamine,
cannabis etc), Theophylline, Digoxin, Quinidine, Lithium etc;
 hair: drugs of abuse (Morphine, heroin, cocaine, amphetamine, cannabis etc),
nicotine, heavy metals etc;
 milk: Penicillin G, aminoglycosides, tetracyclines, sulfonamides,
benzodiazepines, barbiturates (phenobarbital), Theophylline, Morphine,
ethanol, nicotine etc;
 nails: antifungal drugs (Ketoconazole, Itraconazole, Griseofulvin,
Terbinafine), heavy metals, abuse drugs (Metamphetamine, cocaine) etc;
 bones: tetracyclines, lincosamides, quinolones (Ciprofloxacin etc), heavy
metals, biphosphonates (Alendronate etc);
 teeth: tetracyclines;
 prostatic fluid: fluoroquinolones, sulfonamides, trimetoprim etc;
 seminal fluid: caffeine, nicotine, cannabinoids, Propranolol etc.

Binding of drugs to plasma proteins

After absorption, drugs circulate in the bloodstream as free fraction and as drug
reversibly bound to plasma proteins. Drug compound molecules that are

48
dissolved in the blood are in equilibrium with drug bound to plasma proteins.

The amount of drug that is bond to protein depends on: drug affinity for plasma
proteins binding sites, the free drug concentration and the protein concentration.
Binding has a very important effect on drug dynamics since only the free
(unbound) drug interacts with receptors. As the drug dissociates from the
proteins more and more drug undergoes metabolism. It is eliminated by tubular
secretion.
 Free fraction (the unbound fraction of drug) is the total amount of drug
available for diffusion out of the vascular system to sites of pharmacological
activity. Free fraction of drug is:
o pharmacologically active, while the fraction bound to plasma protein is
considered pharmacologically inactive.
o easily metabolized in the liver and other tissues.
o easily eliminated by glomerular filtration.
 The bound fraction of drug is in equilibrium with free drug in plasma and
dissociates when the concentration of the later is reduced due to elimination.
Bound fraction of drug is:
o pharmacologically inactive,
o slower metabolized in the liver and other tissues,
o a reservoir or a temporary storage of the drug.
Plasma proteins that binds drugs:
 Albumin is a major carrier for acidic drugs (e.g. Warfarin, sulfonamides,
nonsteroidal anti-inflammatory drugs etc);
 alpha1-acid glycoprotein binds basic drugs (e.g. Chlorpromazine, tricyclic
antidepressants etc).
 Certain drugs may bind to specific proteins, such as the binding of Quinine
on beta-globulin.
A drug can be bound to many sites on plasma proteins. Conversely, more than
one drug can be bound to the same site. The available binding sites on plasma
proteins can be saturated. These explain interactions among drugs bound to the
same sites. The drug with higher affinity will displace from proteins the drug
with lower affinity (e.g. Phenylbutazone will displace Warfarin).
Clinical significances have the drugs highly bound on plasma proteins. A drug
is said to be highly protein-bound if more than 80% of the drug is bound to
49
protein. Highly protein bound drugs are not removed by haemodialysis.
The classical example is Phenylbutazone/Warfarin interaction. Warfarin
is an anticoagulant drug highly protein bound: ~98% 7.
Other examples of interactions: Phenytoin (anticonvulsant drug) is
protein-bound 90%, Tolbutamide (oral antidiabetic drug) is protein
bound 96%. Drugs that displace these agents are Aspirin, Sulfonamides,
Phenylbutazone.
In neonates and in elderly, albumin content is low, which results in increased
concentration of drugs that primarily bind to albumin (e.g., Phenytoin,
Diazepam).
In diseases:
 In renal failure decreases albumin content and in hepatic failure decreases
albumin synthesis, which result in increased concentration of drugs that
primarily bind to albumin
 In inflammatory state (trauma, burn, infection) increases alpha 1-acid
glycoprotein, which result in increased concentration of drugs basic drugs.

4.Metabolism of drugs (biotransformation)

Metabolism (biotransformation) of drugs means chemical alteration of the

drug in the body to a form that can then be excreted. The metabolism of lipid-
soluble (nonpolar), nonexcretable xenobiotics into polar, water-soluble
compounds is essential for their elimination from the body, as well as for
termination of their biological and pharmacological activity.
Prodrug is an inactive drug that needs conversion in the body to one or more
active metabolites. In general, biotransformation reactions generate more polar,
inactive metabolites that are readily excreted from the body. However, in some
cases, metabolites with potent biological activity or toxic properties are
generated.
Biotransformation of active drug molecules may lead to:
 inactivation of drugs  for most of the drugs (e.g., Ibuprofen is inactivated
by biotransformation),

7
Therefore, for a 5 mg dose, only 0.1 mg of drug is free in the body to determine pharmacodynamics effects. If patient
takes normal dose of aspirin at same time (normally aspirin occupies 50% of binding sites), the aspirin displaces
warfarin so that 96% of the warfarin dose is protein-bound; thus, 0.2 mg warfarin free; thus, doubles the injected dose.

50
 active metabolites  for some drugs (e.g., Diazepam is transformed in
Oxazepam, Codeine is transformed in Morphine),
 toxic metabolites  for a few drugs (e.g., Acetaminophen in high doses is
metabolized to a toxic compound).
Biotransformation of a prodrug may lead to:
 activation of drug (e.g., Levodopa is transformed in Dopamine, Enalapril is
transformed in Enalaprilat);
 toxic metabolites (e.g., Parathion is transformed in paraoxon).
Sites of the enzyme systems involved in the biotransformation of drugs:
 main site for drug metabolism is liver;
 other sites for drug metabolism are kidney, intestine, lung, plasma.
Metabolizing enzymes are divided into two types:
 microsomal enzymes - located on the smooth endoplasmic reticulum,
primarily in the liver, also in other organs (kidney, intestine, lung);
 nonmicrosomal enzymes - present in the cytoplasm and mitochondria of
hepatic cells and in other tissues including plasma.

All biotransformation reactions can be assigned to one of two major categories

called phase I and II reactions. Biotransformation reactions are:
 Phase I reactions (functionalization reactions):
o Oxidation reactions involve insertion of oxygen radical into the drug
molecule, by mixed function oxidases [also known as cytochrome P-
450s, microsomal enzymes, mono-oxygenases] and occurs in the
endoplasmic reticulum,
o Reduction is the converse of oxidation,
o Hydrolysis is the cleavage of a drug molecule by taking up a molecule
of water.
 Phase II reactions (conjugation reactions) include reactions catalyzed by
several superfamilies of conjugating enzymes and involve conjugation with
endogenous substrate to form polar highly ionized molecules, which are
easily excreted through urine or bile:
o Glucuronide conjugation is the conjugation with glucuronic acid (which
is derived from glucose). It is the most important phase II reaction
carried out by UDP-glucuronosyl transferases (UGTs).
o Glutathione conjugation is carried out by glutathione-S-transferases

51
 (GSTs).
o Acetylation is carried out by N-acetyltransferases (NATs).
o Methylation is carried out by methyltransferases (MTs) which takes
methyl from methyl donors such as methionine and cysteine.
o Sulfate conjugation is carried out by sulfotransferases (SULTs).
o Glycine conjugation is the conjugation with glycine, catalyzed by acyl-
Co-A glycine transferases.
o Water conjugation is carried out by epoxide hydrolases.

Phase I reactions
 Oxidation reactions are catalyzed by cytochromes P450 (CYP from
cytochrome P450), monoamine oxidases (MAOs), peroxidases, xanthine
oxidase (XO), or alcohol dehydrogenase.
o The most widely studied gene family of oxidases and the one that
participates more than any other in the oxidation of drugs is the
cytochrome P450 family (CYP). The enzyme families are identified by
Arabic numbers after the prefix CYP. There are:
 FOUR families 1-4 (families are coded with numbers 1 to 4);
 SIX sub-families A-F (are coded with letters A to F);
 up to TWENTY isoenzymes 1-20.
The three key cytochrome P450 or CYP families responsible for drug
metabolism in humans are CYP1, CYP2, and CYP3. Subfamilies are
denoted with uppercase letters (e.g., CYP1A). Individual enzymes are
identified with the family designation, subfamily designation, and
another Arabic numeral (e.g., CYP1A2). CYP3A4 metabolizes the
largest number of drugs (50-60%), CYP2D6 metabolizes nearly 20% of
drugs, CYP2C8/9 metabolizes 15% of drugs, CYP2C19 metabolizes
12% of drugs, others: CYP1A1/2, CYP2E1. Cytochrome P450 enzymes
activity is genetically determined. There are drugs known to inhibit CYP
enzymes and drugs that increase CYP activity, typically by increasing
the amount of enzyme in tissue (enzyme induction). There are variations
in the alleles of some individual CYP enzymes (CYP polymorphism)
which are responsible for significant interindividual variations in rates
of drug metabolism. Some persons lack such activity (are considered
slow metabolisers) which explains higher drug plasma levels (higher
adverse actions), some persons have high levels (are considered fast or
52
 ultrarapid metabolisers) which explains lower plasma levels (and
reduced drug action). More than one-half of patients carry genetic
variations in CYP2D6, 2C9, 2C19, and 1A2 genes that can dramatically
alter patient drug exposures. The most important CYP enzymes for drug
metabolism: CYP3A4; CYP2D6; CYP2C9; CYP2C19; CYP2A6.
o Monoamine Oxidases (MAO) oxidize a wide array of neurotransmitter
amines (adrenaline, noradrenaline, dopamine, serotonin etc). There are
two MAO isoforms, MAOA and MAOB, found in widely varying
proportions in different cells in the CNS and in peripheral tissues.
 In the periphery, MAOA is located in the liver and placenta,
whereas MAOB is located in the liver, platelets, and lymphocytes.
 In the brain, MAOA is located in all regions containing
catecholamines, whereas MAOB is found primarily in regions
containing serotonin.
 Reduction reactions are catalyzed by cytochrome P450 working in the
opposite direction.
 Hydrolysis reactions are catalyzed by esterases or hydrolases.

Phase II reactions either are conjugation reactions, in which electrophilic

adenosine-containing cofactors such as ATP, phosphoadenosine phosphosulfate
(PAPS), acetylcoenzyme A (acetylCoA), uridine diphosphate glucuronic acid
(UDPGA), or S-adenosylmethionine (SAM) react with nucleophilic groups
such as –OH or –NH2, or they can be nucleophilic trapping reactions in which
water, glutathione, or other nucleophiles react with electrophiles. Conjugation
increases the molecular weight of the drug which favours its excretion in bile.
 Glucuronidation is an important way that many diverse organisms
protect themselves against toxins. The enzymes that detoxify
xenobitiotics by glucuronidation are the UDP-glucuronosyltransferases
(UGTs). UGT genes exhibit polymorphic forms.
 Acetylation. Arylamine N-acetyltransferases (NAT) are cytosolic
enzymes which transfer acetate from acetylCoA to primary amines,
hydrazines, sulfonamides, and aromatic amines. Humans express two
functional NATs: NAT1 and NAT2, which exhibit polymorphism.
Allelic variation especially for NAT2 is associated with fast and slow
acetylator phenotypes. The slow acetylator phenotype, if treated with

53
 Isoniazid (INH) is at increased risk of INH-induced arthralgias,
neuropathy, and hepatotoxicity. The addition of glucuronic acid to
substrate molecules tends to increase their polarity and water solubility,
and thus increases the extent of product excretion into bile, urine, or
both.
 Gluthatione conjugation. Glutathione-S-transferases (GSTs) catalysis
of the conjugation of reduced glutathione with a wide array of
electrophilic compounds.

First-pass effect (first-pass metabolism or presystemic metabolism) is a

mechanism which referres to the liver (or sometimes the gut wall) capacity to
extract and metabolize some drugs so efficiently before they enter the
circulation, that the amount reaching the systemic circulation is considerably
less than the amount absorbed. The hepatic first pass effect can be completely
avoided by sublingual or transdermal administration. Examples of drugs that
undergo important first pass-effect: Nitroglycerin, Morphine, Propranolol,
Metoprolol, Salbutamol etc. Practical importance:
 For drugs with high first pass effect, a much higher dose of the drug is
needed when it is given orally than when it is given by other routes.
 Marked interindividual variations in the oral dose due to the differences in
the extent of first pass effect.

Induction of drug metabolism enzymes

Induction of drug metabolism means stimulation of synthesis and activity of
metabolizing enzymes. Enzyme induction involves protein synthesis, therefore
it needs time to reach a maximal effect (up to 3 weeks). Inducers increase the
ability of the enzyme to metabolize the substrates. Enzyme induction can
increase as well as decrease drug activity. Examples of metabolism enzymes
inductors:
 Phenobarbital and other barbiturates [sedative-hypnotic drugs];
 Carbamazepine, Phenytoin, Primidone [antiepileptic drugs];
 Rifampicin [antibacterial drugs used for the treatment of tuberculosis];
 anabolic steroids [hormones], Dexamethasone [glucocortcosteriods];
 3,4-benzpyrene, 3-methylcolantrene [carcinogenic inducers];
 others: Spironolactone [diuretic], ethanol, nicotine.

54
Autoinduction of drug metabolism is the process when a drug increases its own
rate of metabolism as the dose is increased, so that serum concentrations
increase less than anticipated (e.g. Phenobarbital).

Inhibition of drug metabolism enzymes

Inhibition of drug metabolism means inhibition of synthesis and activity of
metabolizing enzymes. Enzyme inhibition may involves the competition for its
binding sites, therefore the onset of action is short (up to 24h). Inhibitors reduce
or block the ability of the enzyme to metabolize the drugs which are substrates
for enzymes; this will have as result an increase of toxicity of the drug.
Examples of metabolism enzymes inhibitors:
 Cimetidine [H2-receptor antagonist],
 Ketoconazole, Itraconazole [antifungal agents];
 Fluoxetine, Paroxetine, Sertraline [antipsychotic drugs];
 Ciprofloxacin, Norfloxacin [antibacterial drugs from the group of
fluoroquinolones];
 Clarithromycin, Erythromycin [antibacterial drugs from the group of
macrolides];
 Sulfonamides [antibacterial drugs];
 Doxycycline [antibacterial drugs from the group of tetracyclines];
 Cloramphenicol [antibacterial drugs from the group of phenicoles];
 Isoniazid8 [antibacterial drugs used for the treatment of tuberculosis].

Factors affecting drug metabolism in humans:

 genetic factors ;
 race (alcohol dehydrogenase is deficient in Chinese, arabics);
 age (drug metabolism is reduced in extremes of life);
 sex (ethanol is slower metabolized in women);
 pathological factors (liver diseases, heart failure etc);
 concomitant administration of other drugs (drug-metabolizing enzyme
induction or inhibition) or of food;
 environmental factors (nicotine, pesticides etc).

8
* Isoniazid is inductor of CYP2E1 and inhibitor of CYP2C9.

55
 5.Elimination of drugs

Drugs are eliminated from the body either unchanged by the process of
excretion or converted to metabolites.
Routes for excreting drugs and their metabolites are: renal, fecal,
respiratory, breast milk, and routes of minor importance such as saliva, tears,
sweat.
5.1. Renal route is the most important route for majority of drugs. Excretion of
drugs and metabolites in the urine involves three distinct processes: glomerular
filtration, tubular secretion, and tubular reabsorption.
 Glomerular filtration occurs only for unbound drug. Glomerular filtration
depends on the plasma protein binding and renal blood flow.
 Tubular secretion is an active transfer of drugs by membrane transporters
(carrier-mediated drug transport systems). Many of the drugs that are
excreted by the kidney share the same transport system and competition can
occur between them, leading to drug interactions. E.g, Penicillin and
Probenecid: Penicillin is cleared only slowly by glomerular filtration, but is
almost completely removed by proximal tubular secretion; Probenecid
blocks the tubular secretion (active transport) of penicillin and therefore
prolongs penicillin duration of action.
 Tubular reabsorption occurs for lipid-soluble drugs (filtered by glomerular
filtration). It is a passive back diffusion of drug from primary urine in the
blood and depends on the lipid-solubility of drugs and the urinary pH.
Changes in urinary pH are used for facilitating elimination of drugs in
poisoning (e.g., alkalinization of urine increase elimination of barbiturates or
salicylates, acidification of urine increase elimination of amphetamines).
Probenecid blocks tubular reabsorption of uric acid and therefore increases
uric acid excretion.
5.2. Fecal route. Drugs present in the feces are fraction from unabsorbed drugs
or drugs excreted from bile through hepatobiliary system. Many of the drugs
are excreted via the kidney and via the bile (e.g. Rifampicin), but there are
drugs which are excreted largely by hepatobiliary system (e.g. Doxycycline).
Most drugs are secreted into bile via the liver, but some are then absorbed from
the intestine – this is called enterohepatic cycle.
5.3. Respiratory route is important mainly for the elimination of inhalational

56
anesthetics (gases such as Nitrous oxide, volatile liquids such as Isoflurane etc).
5.4. Breast milk is important because the excreted drugs will have unwanted
pharmacological effects in the nursing infant: penicillins, tetracyclines,
aminoglycosides, fluoroquinolones (Cyprofloxacin), Ketoconazole, estrogens,
opioids, sedative-hypnotic drugs (benzodiazepines, barbiturates etc), caffeine,
alcohol, nicotine etc.
5.5. Other routes of elimination of drugs are:
 saliva for antiepileptic drugs, Morphine, cocaine, amphetamines,
Minocycline etc;
 tears for Minocycline, Rifampicin etc;
 sweet for Rifampicin etc.

6.Pharmacokinetic parameters

A pharmacokinetic parameter is a constant for a drug that is estimated from the

experimental data (fig. 4).
6.1. Maximum plasma concentration (Cmax) is the highest plasma drug
concentration observed.
6.2. Time to Reach Cmax (Tmax) is the time at which occurs Cmax following
administration of an extravascular dose.
6.3. Area under the curve (often abbreviated to AUC for area under plasma
concentration – time curve) is direct proportional to the total amount of drug
introduced in the plasma compartment. Comparison of the AUC following oral
and iv administration can be used to determine the fraction of the oral dose that
enters the bloodstream and thus to measure bioavailability.

Fig. 4. Plasma concentration versus time curve for a drug after oral administration. The shaded
region represents the area under the curve (AUC).

57
6.4. Bioavailability refers to the rate of absorption and extent of absorption of a
drug from a dosage form which reaches its site of action or a biological fluid
from which the drug has access to its site of action. Bioavailability refers to the
fraction of an ingested dose of a drug that reaches systemic circulation.
Bioavailability may be low because drug absorption is incomplete or because
the drug is metabolized in the gut wall or live before reaching the systemic
circulation. It is useful to compare two different drugs or different dosage forms
of same drug.

6.5. Bioequivalence refers to drug products with the same active ingredients,
identical in strength or concentration, dosage form and route of administration.
They are considered to be bioequivalent when the rates and extents of
bioavailability of the active ingredient in the two products are not significantly
different under suitable test conditions.
6.6. Apparent volume of distribution (Vd) is the volume occupied by a drug
presuming that the body behaves as a single homogeneous compartment and the
drug is immediately and uniformly distributed after administration. Vd has no
direct physiologic meaning and does not refer to a real volume.
The volume of distribution is a constant of proportionality between the quantity
of a drug in the body and its plasma concentration (C). Presuming that the
amount of drug in the body is equivalent to the dose administered iv, volume of
distribution can be calculated as follows:

Vd is useful for the for the calculation of the amount of a new dose. When a
patient received a dose 1 of a drug and the plasma concentration is C1, to get a
plasma concentration C2, it should be administered a dose 2, calculated based
on the constant proportionality of Vd: , so
.
Pathological states (congestive heart failure, cirrhosis of liver etc) or
physiological state (pregnancy, prematurity, infants etc) can alter the Vd of
many drugs by altering distribution of body water, permeability of membranes
or binding proteins.
6.7. Clearance (Cl) of a drug is the volume of plasma from which the drug is

58
completely removed within a unit of time (usually 1 min). Clearance predicts
the rate of elimination in relation with drug concentration. It is calculated as the
ration between rate of elimination and concentration of drug in plasma (C):
rate of eliminatio (mg/min)
Cl  .
concentration (mg/ml)
For majority of drugs, processes involved in elimination are not saturated, so
the rate of elimination is directly proportional to the drug concentration (it is a
first order kinetic). For few drugs (e.g., Phenytoin, Acetylsalicylic acid,
ethanol), there is a saturation of eliminating mechanisms at higher doses, so the
rate of elimination remains constant irrespective of drug concentration (it is a
zero order kinetic or saturable elimination).
6.8. The plasma half–life (t1/2) of a drug is the time it takes for one-half of the
drug to be eliminated by the body (plasma concentration is reduced to half, fig.
5).

Fig. 5. Graphical calculation of half-life

Half-life indicates the time required to attain steady-state concentration.
Knowing how long a drug remains in the body helps determine how frequently
it should be administered. The dosage interval for a drug is also determined by
the half-life of the medication. Factors that affect a drug’s half-life include its
rate of absorption, metabolism, and excretion. Mathematically, half-life is the
ration between natural logarithm of 2 (ln 2) and elimination constant (ke):

7.Effects of repeated doses

Steady state concentration is the concentration achieved when a drug is

administered at a constant rate (amount administered = amount eliminated
59
between doses). At this point, drug elimination will equal the rate of drug
availability. Steady-state is reached in 4-5 half-lives, unless dose interval is
very much longer.

Drug accumulation is produced when the absorbed quantity is higher

compared with the eliminated quantity (amount administered > amount
eliminated). If the frequency of administration exceeds the t1/2 of the drug, its
concentration in a compartment is likely to increase beyond the desirable level
resulting accumulation of the drug within this compartment. The drug will
accumulate in the body until dosing stops. E.g., digoxin [indicated in heart
failure], Amiodarone [indicated as antiaarhythmic drug]. The toxicity could be
avoided by decreasing the dose or increasing the intervals between drug
administration.

8.Pharmacokinetic models

Pharmacokinetics employs mathematical models to describe what happens to a

chemical substance within the body.
Pharmacokinetic models are relatively simple mathematical schemes that
represent complex physiologic spaces or processes. Pharmacokinetic models
incorporate mathematical representations of the ADME processes to provide
equations that relate drug concentrations versus time to biological parameters
inherent in the ADME processes. Pharmacokinetic models are used to:
 predict drug concentrations versus time in plasma, tissue and urine with any
dosage regimen;
 calculate the optimum dosage regimen for each patient individually;
 estimate the possible accumulation of drugs;
 correlate drug concentrations with pharmacologic or toxicologic activity;
 describe how changes in physiology or diseases affect the absorption,
distribution, metabolism or elimination of drugs;
 explain drug interactions.

Single-compartment model (one-compartment model) (fig. 6) is the most

simplified model of human being, which consists of a single compartment in

60
which the drug is introduced rapidly by iv infusion or orally, distribute in all
compartment and from which it can escape either by being metabolized or
excreted. The initial concentration C0 decreases exponentially.
Most drugs exhibit first-order kinetics where the rate of elimination is directly
proportional to drug concentration. Few drugs exhibit zero-order kinetics
(saturation kinetics) where drug is removed at a constant rate, which is
independent of plasma concentration. Drugs with saturation kinetics are
ethanol, phenytoin and salicylate. For these drugs, the duration of action is
more strongly dependent on dose; it is the most common cause of drug
accumulation and toxicity.

Fig. 6. Graphical representation of the plasma concentration (Cp) versus time (t) and ln(Cp)
versus t for a one-compartment pharmacokinetic model of a bolus IV injection.

More complicated compartment models

 Two-compartment model (fig. 7) introduces a separate “peripheral”
compartment to represent the tissues in communication with the “central”
plasma compartment. This model more closely resembles the real situation.
In this model kinetics becomes biexponential. The two components roughly
represent the processes of transfer between plasma and tissues (α-phase) and
elimination from plasma (β-phase).

A. B.
Fig. 7. One compartment model (A) and two compartment model (B)

61
 Multicompartment model are used for drugs or modeling situations, where
more than two compartments are needed. The usefulness of the generalized
equations written for a PK model containing n total compartments is that
they can be employed with three, five, or any other number of model
compartments.
Physiologically-based pharmacokinetic (PBPK) models represent one of the
most complex and powerful pharmacokinetic modeling approaches that are
available. PBPK models include a number of compartments, but unlike the
previously described standard compartmental models, each compartment
represents a specific tissue in the body. Thus the concentration of drug in a
given tissue appears directly in the model. Transport of drug between
compartments is also represented by realistic physiological processes.

62
 AUTONOMIC NERVOUS SYSTEM AND
DRUGS
Lecture 3
Cholinomimetic drugs

Learning Objectives:
 List the steps in synthesis, release and inactivation of acetylcholine;
 Describe phyisiological effects of muscrinic and nicotinic receptor activation;
 Explain difference between direct and indirect acting cholinomimetic drugs with
suitable examples;
 Explain difference between reversible and irreversible anticholinesterases with suitable
examples;
 Therapeutic uses and adverse effects of direct and indirect acting cholinomimetic
drugs;
 Particularities of mechanism of action for reactivators of cholinesterases;
 Antidotes in case of poisoning with organophosphates.

Autonomic nervous system (ANS) regulates involuntary vital function,

including the activity of the cardiac muscle, the smooth muscle, and the
exocrine glands. One component of ANS is the parasympathetic nervous
system (PN), which slows heart rate, increases smooth muscle tone and
exocrine glands activity, and relaxes sphincters; the other component of ANS is
the sympathetic nervous system (SN), that tends to act in opposition to the
parasympathetic nervous system, as by accelerating heart rate and causing
contraction of the blood vessels. The sympathetic nervous system is activated
by stress conditions.
Cholinergic (parasympathomimetic) system is constituted by sympathetic and
parasympathetic nerve fibers that liberate acetylcholine at a synapse when a
nerve impulse passes, which mimics the effect of stimulation of PN.
Adrenergic (sympathomimetic) system is constituted by sympathetic nerve
fibers that liberate cathecolamines at a synapse when a nerve impulse passes,
which mimics the effects of stimulation of organs and structures by the SN.
Cholinergic system activating drugs are drugs which stimulate cholinergic

63
system. Drugs activating the cholinergic nervous system (fig. 8) are classified
as follows:

Fig. 8. Drugs acting on the cholinergic nervous system

Background
Acethylcholine (Ach) is a major neurohormonal transmitter. Ach is an ester of acetic acid and
choline (a quaternary ammonium compound) that cannot penetrate membranes. The half-life
(t1/2) of Ach is very short (miliseconds).
- Synthesis: Ach is synthesized in the cytoplasm of the cholinergic neuron, from choline and
acethyl-coenzyme A, by the enzyme choline acethyltransferase (CAT). Choline is an essential
amino-acid transported from extracellular fluid into the cytoplasm of cholinergic neuron by a
carrier that actively cotransports sodium. Acethyl-coenzyme A is synthesized in mitochondria
from nerve ending.
- Storage: Ach is stored into vesicles from nerve ending.
- Release: Ach is released when an action potential arrives at the nerve ending and determines
an increase in the concentration of intracellular calcium, which promote the fusion of vesicles
with the presynaptic membrane and release of Ach into the synapse. Release of Ach occurs in
small cuanta (1 cuanta = 1000 – 50000 molecules of Ach from a vesicle). After release into
synaptic cleft, Ach binds to either the cholinergic receptors or active site of
acethylcholinesterase (AchE).
□ Binding to cholinergic receptors determines a biological response.
□ Binding to the active site of AchE ends Ach action because cholinesterase cleaves
acetylcholine to acetate and choline. AchE cleaves Ach in 2 steps:
■first step: the complex Ach-AchE is hydrolysed to choline and acetylated enzyme;
■second step: acetylated enzyme is hydrolysed to AchE and acetate.
Choline is transported back into the nerve ending by an uptake system, where it is acetylated

64
and stored until release by a subsequent action potential.
Cholinoreceptors (receptors for Ach) include two classes of receptors: muscarinic and
nicotinic receptors.
 Muscarinic receptors are coupled with protein G. There are 5 subtypes (table): M1, M2, M3,
M4 and M5, located:
□ presynaptic: on cholinergic nerve endings (activation inhibits further Ach release) and
adrenergic nerve endings (activation inhibits NA release);
□ postsynaptic: primarily on autonomic effector cells in the CNS, autonomic ganglia,
heart, smooth muscle, endothelial cells of blood vessels, eye, glands of gastrointestinal,
respiratory and uro-genital tract, sweats glands etc.

Table. Subtypes of muscarinic receptors

Receptor Typical Locations Result of Ligand Biological effects
Name Binding
M1 CNS; most abundant in Formation of IP3 Increase cognitive function (learning
cerebral cortex, and DAG, and memory)
hippocampus and striatum increased Increase seizure activity
Autonomic ganglia intracellular Ca2+ Increase in secretions
Glands (gastric and salivary) Increase in depolarization of
Enteric nerves autonomic ganglia
M2 Myocardium, Inhibition of Heart: decrease heart rate, decrease
smooth muscle, adenylyl cyclase, conduction velocity
some presynaptic sites; opening of K+ Smooth muscle: increase contraction
CNS neurons channels Peripheral nerves: neural inhibition
CNS: neural inhibition, increase
tremors, hypothermia, analgesia
M3 Exocrine glands, vessels Formation of IP3 Glands: increase secretion
(smooth muscle and and DAG, (predominant in salivary gland)
endothelium); CNS neurons increased Smooth muscle: increase contraction
intracellular Ca2+ ( e.g. bladder, bronchia)
M4 CNS neurons; possibly Opening of K+ Facilitation of dopamine release
vagal nerve endings channels, Analgesia
inhibition of
adenylyl cyclase
M5 Vascular endothelium, Formation of IP3 Facilitation of dopamine release
especially cerebral vessels; and DAG, Facilitation of cerebral vascular
CNS neurons increased vessels
intracellular Ca2+

 Nicotinic receptors are ligand gated cation channel: their activation causes opening of the
channel and rapid flow of cations resulting in the depolarisation and on action potential.
□ binding of acetylcholine (the ligand) to the nicotinic receptor, changes the receptor
shape, and let sodium enter the muscle cell  skeletal muscle contraction (Influx of

65
 sodium depolarizes the muscle sarcolemma near the motor endplate. This
depolarisation triggers another type of sodium channel, the voltage-gated sodium
channels which spread the excitation over the muscle cell and leads to the release of
calcium ions (Ca2+) from sarcoplasmic reticulum. Ca2+ initiate a series of biochemical
events involving troponin, tropomyosin and myosin leading to muscle contraction).
- There are 2 subtypes (table ): Nn and Nm.

Table. Subtypes of nicotinic receptors

Receptor Name Typical Locations Result of Ligand Binding
Nn Postganglionic neurons, some presynaptic Opening of Na+, K+
cholinergic endings, autonomic ganglia, channels, depolarization
adrenal medula, CNS
Nm Skeletal neuromuscular junction Opening of Na+, K+, Ca2+
channels, depolarization

Acetylcholine mechanism of action

 molecule of Ach is flexible, this is why it may bind on:
o muscarinic receptors: when methyl profile of Ach is evident;
o nicotinic receptors: when carbonilic profile is evident;
 structure of molecule of Ach is CH3-CO-O-CH2-CH2-N+(CH3)3; the
“onium” group (-N+(CH3)3) does not pass the blood brain barrier;
 the bind of Ach on muscarinic receptors is in 4 points:
Ach molecule: 4 active points Muscarinic receptor: 4 active sites on its surface
 cationic group (onium) interact with  anionic group which is the affinity site
 esteric oxygen interact with  positive charged group
 hydroxil atached to C3 interact with  positive charged group
 methyl atached to C2 interact with  hydrophobic region
 the bind of Ach on muscarinic receptors increase the permeability for Na+,
K+, Cl-, Ca2+:
o heart: increase permeability for K+ and Cl-  membrane
hyperpolarization  decrease heart rate (bradycardia, preceded by a
short period of tachycardia);
o autonomic ganglia, smooth and skeletal muscle: increase permeability
for Na+  increase of peristaltism and muscle tone;
o gland cells: increase permeability for Ca2+  hypersecretion.
 the bind of Ach on nicotinic receptors (ligand gated Na+/K+ channel) is in 2
steps: first, the bind of few molecules of Ach  increase the number of open
channels; second, the bind of a big number of molecules of Ach  block the

66
 channels in open position;
o on Nn  short period of transmition of impulses with membrane
depolarising  followed by blockage of repolarising of membrane;
o on Nm  skeletal muscle fasciculations  followed by skeletal muscle
relaxation.

Pharmacodynamic effects of Acetylcholine

 on cardiovascular system:
o negative chronotropic effect (bradycardia due to inhibition of adrenergic
activation, preceeded by reflex tachycardia), negative inotropic effect
(reduction of the contraction strength), negative dromotropic effect;
o vasodilation (all vascular beds including pulmonary and coronary, due
to action on M3 receptors) and hypotension;
 on smooth muscle:
o Eye: miosis (constriction of ciliary muscle and circular fibers of smooth
muscle of the iris), decrease intraocular pressure (because of a better
drainage of aqueous humour through canal of Schlemm);
o Respiratory tract: bronchoconstriction of smooth muscle;
o Gastro-intestinal tract: increases in tone, amplitude of contractions, and
peristaltic activity, enhances secretory activity;
o Urinary bladder: increase ureteral peristalsis, contract the detrusor
muscle of the urinary bladder, increase the maximal voluntary voiding
pressure, and decrease the capacity of the bladder.
 on exocrine glands: increases secretion from all glands that receive
parasymphatetic inervation (salivary, lacrimal, tracheobronchial, digestive
and exocrine sweat glands).

1. Direct-acting cholinomimetic drugs (or Agonists on

cholinergic receptors)

Acetylcholine has a very brief duration of action, therefore compounds more

selective and with longer duration of action are generally used.
Direct acting cholinomimetic drugs are agonists on muscarinic and / or
nicotinic receptors.

67
Classification of direct acting cholinergic drugs is illustrated in fig 9.

Fig. 9. Classification of direct acting cholinergic drugs

Mechanisms of action of agonists on muscarinic receptors:

 Stimulation of M1 and M3 receptors determine excitatory effects (because of
formation of IP3 and DAG and of increased intracellular Ca2+)  results in
smooth muscle contraction, hypersecretion of exocrine glands, constriction
of the pupil which facilitate the drainage of aqueous humour and reduction
of intra-ocular pressure.
 Stimulation of M2 receptors from cardiac muscle determines inhibitory
effects (because of inhibition of adenylyl cyclase and of opening of K+
channels)  results in decrease heart rate, decrease conduction velocity.
Carbachol has a substantial nicotinic activity because also stimulates the release
of Ach from nerve ending (stimulate nicotinic receptors).
Pilocarpine has a more selective action in stimulating exocrine glands (sweat,
salivary, lacrimal, bronchial) and has less effect on other receptors (smooth
muscles, cardiovascular system).
Varenicline is a selective partial agonist on nicotinic receptors, so it reduces the
symptoms associated with smoking cessation.
Pharmacokinetic particularities of direct acting cholinomimetic drugs
Acetylcholine is rapidly hydrolysed in the body by cholinesterases (see above).
Methacholine action is more prolonged because of the added methyl group
which increases its resistance to hydrolysis by cholinesterases.
Carbachol and Betanechol are not inactivated by cholinesterases, so that their

68
actions are more prolonged than those of acetylcholine.
Nicotine crosses the placenta, so it should be avoided in pregnancy.
Indications of direct acting cholinomimetic drugs:
 Acetylcholine: - for the rapid production of miosis (instillation directly into
the anterior chamber of the eye during ophthalmic surgery);
- for vasodilatation during coronary angiography
(administered intracoronary);
 Methacholine: was used inhalatory to provoke bronchoconstriction in the
diagnosis of bronchial airway hypersensitivity.
 Carbachol: - glaucoma as alternative to Pilocarpine in topic administration
(when resistance or intolerance to Pilocarpine develops);
- relief of postoperative in abdominal distention, in gastric atony
or gastroparesis, postoperatory or postpartum urinary retention (as
alternative to Betanechol), in systemic administration;
 Betanechol: postoperative in abdominal distention, in gastric atony or
gastroparesis, postoperatory or postpartum urinary retention;
 Pilocarpine: - glaucoma (in topic administration, it is the standard
cholinergic agent in the treatment of open-angle glaucoma);
- dry mouth (xerostomia from Sjogren syndrome9 or following
radiotherapy for malignant neoplasms of the head and neck), in systemic
administration;
- antidote in Atropine overdosage;
 Cevimeline: dry mouth (xerostomia from Sjogren syndrome or following
radiotherapy for head and neck neoplasms), in systemic administration;
 Varenicline: smoking cessation (it is superior to nicotine replacement
therapy).
Adverse effects of cholinomimetic drugs:
 abdominal cramps, diarrhoea, nausea;
 sweating, salivation, lachrymation, rhinorrhoea;
 bradycardia;
 bronchoconstriction, increased bronchial secretion;
 nicotine patches causes local hypersensitivity reactions.
Contraindications of cholinomimetic drugs:

9
Sjögren syndrome is an autoimmune disease involving xerostomia (dry mouth), telangiectases, or purpuric spots on
the face, and bilateral parotid enlargement; often associated with rheumatoid arthritis, and Raynaud phenomenon.

69
 bronchial asthma and obstructive airways disease (because
bronchoconstrictor effect could precipitate an asthmatic attack);
 coronary insuficiency (because of reduced coronary blood flow, especially if
it is already compromised), bradycardia or heart block, hypotension;
 hyperthiroidia (because patients may develop atrial fibrillation due to excess
of adrenaline);
 peptic ulcerations (because it increases secretion of gastric glands);
 pregnancy.

2. Indirect acting cholinomimetic drugs (Cholinesterase-

inhibiting drugs or Anticholinesterases)

Indirect acting cholinomimetic drugs (anticholinesteses) are drugs which

block the enzyme acethylcholinesterase (AchE), so that they increase
cholinergic neurotransmission.
Classification of indirect acting cholinergic drugs is illustrated in fig. 10.

Fig. 10. Classification of indirect acting cholinergic drugs

Mechanism of action: These drugs inhibit the AchE in the synapse  this has
as result the decrease of the inactivation of acetylcholine  accumulation of
acetylcholine enhances the activation of the nicotinic and muscarinic receptors.
Anticholinesterase drugs indirectly provide a cholinergic action by prolonging
the life time of acetylcholine. They are either reversible or irreversible

70
inhibitors of AchE, depending on the time of AchE inhibition. Reversible
anticholinestrases are of more clinical value.
 Reversible anticholinesterase drugs:
 Edrophonium (a quaternary alcohol) reversibly bind to the active site of
AchE, thus preventing access of acetylcholine. The electrostatically and
hydrogen bonds explain short life time (on the order of 2–10 min).
 The carbamate esters (Neostigmine, Physostigmine etc) and other structures
(Donepezil, Rivastigmine, Galantamine) undergo a two-step hydrolysis
sequence. The covalent bond of the carbamoylated enzyme is considerably
more resistant to the second (hydration) process, and this step is
correspondingly prolonged (on the order of 30 min to 6 h).
 Ireversible anticholinesterase drugs (organophosphates):
 Organophosphates undergo initial binding and hydrolysis by the enzyme,
resulting in a phosphorylated enzyme complex. The covalent phosphorus –
enzyme bond is extremely stable and hydrolyzes in water at a very slow
rate (hundreds of hours). The phosphorylated enzyme complex may
undergo a process called aging (the breaking of one of the oxygen-
phosphorus bonds of the inhibitor which further strengthens the phosphorus
– enzyme bond). The rate of aging varies with the particular
organophosphate compound. Drugs called "cholinesterase regenerators",
like Pralidoxime or Obidoxime, given before aging has occurred, are able
to split the phosphorus – enzyme bond. They are used in organophosphate
poisoning because they reactivate the enzyme (compete with the
organophosphates and combine with phosphoryl group to make
cholinesterase free). Once aging has occurred, the complex becomes more
stable and it is more difficult to be split, even with cholinesterase
regenerators.
Pharmacokinetics particularities:
 Reversible anticholinesterase drugs (except Physostigmine) are poorly
absorbed from gastro-intestinal tract, therefore much larger doses are
required for oral than for parenteral administration.
 Organophosphates (except for Echothiophate) are well absorbed from the
skin, lung, gut, and conjunctiva.
 Edrofonium lasts for 2-10 min, so it is used only for diagnosis of myasthenia
gravis.
 Only Donepezil, Rivastigmine, Galantamine and Physostigmine passes
71
 blood-brain barrier because they are liposoluble.
 Echothiophate t1/2 is very long, therefore its action lasts 1 week.
Indications:
 Physostigmine (Eserine):
o relief of postoperative urinary retention and neurogenic
bladder10,delayed gastric emptying;
o reversal of anticholinergic effects (e.g., intoxication with Atropine,
tricyclic antidepresants);
o treatment of Alzheimer’s Disease;
o glaucoma;
 Edrofonium: reversal of curare-like substances in anaesthesia and diagnostic
of myasthenia gravis;
 Neostigmine, Pyridostigmine:
o myastenia gravis11 - for symptomatic treatment (Piridostigmine is the
drug of choice); Neostigmine is used also for diagnostic;
o reversal of curare-like substances in anaesthesia (decurarization12):
Neostigmine and Physostigmine are antidotes for nondepolarizing
neuromuscular blocking drugs after surgery;
o relief of postoperative urinary retention and neurogenic bladder;
o reversal of anticholinergic effects (e.g., intoxication with Atropine);
 Distigmine: relief of postoperative urinary retention and neurogenic bladder;
 Ambenonium:
o myastenia gravis - for symptomatic treatment;
o reversal of curare-like substances in anaesthesia (decurarization);
 Demecarium: glaucoma;
 Donepezil, Rivastigmine, Galantamine13: Alzheimer disease;
 Ecothiophate: glaucoma;
 infections with Schistosoma haematobium14: Metriphonate (as alternative).
Adverse effects and contraindications: see above.
10
Neurogenic bladder is a dysfunction of the urinary bladder, caused by a lesion of the nervous system, with loss or
impairment of voluntary control of micturition.
11
Myasthenia gravis is an autoimmune disease caused by antibodies to the nicotinic receptors at neuromuscular
junction. It affects the neuromuscular junction, causing muscle weakness.
12
Curarization is the administration of curare (e.g., D-Tubocurarine etc) to induce skeletal muscle relaxation by its
blocking activity at the neuromuscular junction.
13
Tacrine, the first acethylcholinesterase inhibitor used for Alzheimer disease, has been withdrawn from the market.
14
Schistosoma haematobium is a parasite (genus of trematodes) endemic in North, Central, and West Africa and the
Middle East. It is the only parasite which penetrate directly the human skin from contact with contaminated water, and
migrate with the bloodstream blood to liver, small blood vessels of organs of the intestinal or urinary tract. It has high
risk of mortality.

72
 Lecture 4
Anticholinergic drugs (Cholinoceptor-Blocking Drugs)

Learning Objectives:
 Classify anticholinergic drugs (parasympathetic blockers) with suitable examples;
 Classify antimuscarinic drugs based on their uses with suitable examples;
 List and describe the pharmacological actions of Atropine;
 Differences between central effects of Atropine and Scopolamine;
 Discuss the rationale for using drugs blocking the muscarinic actions of Ach;
 Discuss the clinical features and drug treatment of Atropine poisoning.

Anticholinergic drugs (Parasympatholytics = Cholinolytics = Cholinoceptor-

blocking drugs = Cholinoceptor antagonists) are called parasympatholytic or
cholinolytics because they block the effects of parasympathetic autonomic
system. Anticholinergic drugs are classified on the basis of their specific
receptor affinities (fig. 11).

Fig. 11. Classification of anticholinergic drugs

1. Antimuscarinic drugs

73
Antimuscarinic drugs (muscarinic receptor antagonists or M-cholinolytics) are
agents that block the activity of the muscarinic receptor, causing inhibition of
all muscarinic functions. Similar effect has botulinum toxin, which is an
inhibitor of acethylcholine release from nerve ending.

Classification of antimuscarinic drugs:

1. Natural antimuscarinic drugs
- Atropine (Hyoscyamine),
- Scopolamine (Hyoscine).
2.Semisynthetic and synthetic antimuscarinic drugs
used for the relaxation of
smooth muscle (in
gastrointestinal and
genitourinary disorders)
used for overactive urinary
15
bladder disease
used as antiasthmatics
used in ophthalmology
used in the treatment of
16
pseudoparkinsonism ,
17 18
parkinsonism , dystonias
used as centrally acting
skeletal muscle relaxants
3. inhibitor of acethylcholine release
- botulinum toxin type A and B.
1. NATURAL ANTIMUSCARINIC DRUGS
- quaternary amines: Propantheline, Butilscopolamine,
Pirenzepine, Glycopyrrolate, Clidinium, Tridihexethyl,
Anisotropine, Isopropamide, Methantheline,
Oxyphenonium, Methylscopolamine, Hexociclium;
- tertiary amines: Dicyclomine (Dicicloverine), Mebeverine,
Telenzepine, Oxyphencyclimine, Mepenzolate;
- quaternary amines: Trospium, Emepronium;
- tertiary amines: - non-selective: Oxybutynin, Tolterodine,
Propiverine, Flavoxate;
- selective on M3: Darifenacin;
- selective on M1 and M3: Solifenacin;
- short acting: Ipratropium, Oxitropium;
- long acting: Tiotropium;
Homatropine, Cyclopentolate, Tropicamide;
- centrally and peripheraly acting: Benztropine;
- centrally acting: Trihexyphenidyl, Biperiden,
Orphenadrine, Procyclidine, Diphenciclimine;
Chlorzoxazone, Orphenadrine, Cyclobenzaprine,
Carisoprodol, Chlorphenesin, Metaxolone, Methocarbamol;

15
Overactive bladder is a urological disease characterized by urgency, with or without involuntary urination, and
nocturia.
16
Pseudoparkinsonism is caused by drugs after chronic administration: antipsychotics (neuroleptics) block dopamine
receptors in the nigrostriatal region, Reserpine determine depletion of catecholamines deposits from nerve endings.
17
Parkinson's disease is an idiopathic disease with lesions in locus niger and other extrapyramidal nuclei.
Parkinsonism are manifestations similar to Parkinson's disease in cerebral athero-sclerosis; after a traumatic brain
injury; viral encephalitis; poisoning (e.g., barbiturate intoxication, with mercury, carbon monoxyde) etc. Parkinsonism
has the following important symptoms: bradykinesia (slowness and poverty of movement), muscular rigidity, resting
tremor (which usually is reduced during voluntary movement), and an impairment of postural balance.
18
Dystonia is a sustained muscle contractions that result in writhing or twisting movements and unusual body postures.

74
ATROPINE
Atropine (Hyoscyamine) is found in the plant Atropa belladonna (deadly nightshade) and in
Datura stramonium (known as jimsonweed or Jamestown weed or sacred Datura, or thorn
apple); Scopolamine (Hyoscine) is found in the plant Hyoscyamus niger, or henbane.
Mechanism of action: reversible blockade of muscarinic receptors (Atropine
has high affinity for muscarinic receptors and it is not selective, so that it does
not distinguish between subgroups of muscarinic receptors).
This explains the use as antidote in organophosphate or muscarine intoxication.
This explains the use in small doses as adjuncts to treatment of myasthenia gravis.
Pharmacodynamic effects: Atropine has many pharmacodynamics effects (fig.
12). The effect of Atropine declines rapidly in all organs except the eye (effects
on the iris and ciliary muscle persist for 72 h).

Fig. 12. Main pharmacodynamic effects of antimuscarinic drugs

1. Cardiovascular System:
 Heart: tachycardia by blocking vagal effects on M2 receptors on the sino-
atrial nodal pacemaker (there is an initial bradycardia before the effects of
peripheral vagal block become manifest).
This effect is useful in the treatment of bradicardia, asystolia.
This effect explains tachycardia as adverse effects and the contraindication in coronary
atherosclerosis and in tachycardia (hyperthyroidism, cardiac insufficiency).
 Blood vessels: at toxic doses, and in some individuals at normal doses,
antimuscarinic agents cause cutaneous vasodilation, especially in the upper
portion of the body. The mechanism is unknown. There is little effect on
blood pressure.
2. Smooth muscle (gastro-intestinal, genito-urinary, bronchial):
 antispasmodic effect (decrease the normal tone and amplitude of
contractions)
This effect usually is not sufficient to overcome or prevent the marked spasm.
Intestinal "paralysis" induced by antimuscarinic drugs is temporary; local
mechanisms within the enteric nervous system will usually reestablish at least some
peristalsis after 1–3 days of antimuscarinic drug therapy. This effect explains

75
 constipation as adverse effects (temporary effect for maximum 3 days).
This action is useful in the treatment of intestinal hypertonicity and hypermotility, of
the spasm of biliary and uretered colic. Alternative drugs from synthetic
compounds are Propantheline, Butilscopolamine, Glycopyrrolate, Clidinium,
Dicyclomine, Mebeverine.
 increase the normal tone of sphincters.
This effect is useful in the treatment of urinary incontinence; for this indication are
prefered synthetic derivatives such as Trospium, Emepronium, Oxybutynin,
Tolterodine, Propiverine, Darifenacin, Solifenacin.
This effect explains acute urinary retention as adverse effects and the contraindication
in prostatic hyperplasia.
 bronchodilation in persons with asthma.
This effect is useful as adjuncts to treatment of recent bronchial asthma and for chronic
obstructive pulmonary disease. For this indication are prefered synthetic derivatives
such as Ipratropium, Oxitropium, Tiotropium.
3. Eye:
 cycloplegia (or paralyze of the ciliary muscle): results in loss of the ability to
accommodate, so eye cannot focus for near vision.
 mydriasis (pupillary dilation): results in photophobia, blurring near vision.
These effects are useful in the treatment of iritis, irido-cyclitis; prevent adhesion
between iris and lens or iris and cornea (therapeutic mydriazis). Alternative drugs
from synthetic compounds is Homatropine.
These effects explain elevation of intraocular pressure, blurred vision and photophobia
as adverse effects and the contraindications in glaucoma and for drivers.
4. exocrine glands  reduction of secretion:
 lacrimal glands: reduction of secretion;
This effect explains dry or "sandy" eyes as adverse effects.
 salivary glands: reduction of secretion;
This effect is useful in preanesthesia (especially in buco-pharyngeal area surgery).
This effect explains dry mouth, swallowing and talking difficulties as adverse effects.
 digestive glands: gastric secretions is markedly reduced, but the
concentration of acid is not necessarily lowered because secretion of HCO3–
as well as of H+, of mucin and of proteolytic enzymes is blocked;
This effect explains the contraindication in chronic gastric ulcer.
 sweat glands: reduction of secretion;
This effect is useful in the treatment of hyperhidrosis.
This effect explains dry skin and Atropine fever in children as adverse effects and the
caution to avoid sun exposure. In adults, sweating is depressed enough to raise the
body temperature, but only after large doses or at high environmental temperatures.
In children, even ordinary doses may cause "Atropine fever".

76
 bronchial glands: reduction of secretion;
This effect is useful in preanesthetic medication (for intubation).
This effect explains dry mucous as adverse effects and the increase in the viscosity of
secretions explains the contraindication in severe bronchial asthma.
5. CNS:
 excitatory effects on CNS;
With toxic doses of Atropine, central excitation becomes more prominent, leading to
restlessness, irritability, restlessness, excitement, disorientation, hallucinations,
delirium. This effect explains the contraindication in infants and elderly.
 antiemetic effect: this effect, useful in therapy, is less effective after severe
nausea or vomiting has developed.
 adjuncts to treatment of Parkinson disease or parkinsonism. Alternative
synthetic drugs are Benztropine, Trihexyphenidyl, Biperiden, Orphenadrine.
 spinal cord: block the spinal cord intercalary neuron receptors  skeletal
muscle relaxation.
This effect is useful in acute local skeletal muscle spasm: for this indication are
prefered synthetic drugs such as Chlorzoxazone, Orphenadrine, Cyclobenzaprine.
Pharmacokinetics:
 absorption: rapidly after oral or mucosal (conjunctival) administration;
Systemic Atropine has occular effect for 48–72 h, locally applied Atropine
produces ocular effects for 7-12 days.
 distribution: wide in the whole body, bypasses blood-brain barrier, penetrate
the conjunctiva of the eye; t1/2 = 2 h;
 metabolism: partially in the liver; elimination: by metabolism in the liver and
60% is eliminated unchanged through kidney.
Indications:
 antidote in organophosphate intoxication or muscarine intoxication;
 antispasmodic agent (relaxation of smooth muscle in intestinal hypertonicity
and hypermotility, biliary colicative pain);
 symptomatic bradycardia: Atopine is the first drug of choice for (except
bradycardia from atrioventricular blocks);
 asystolia (when necessary, but only after administration of Adrenaline);
 antiemetic effect;
 reduction of secretions during surgical procedures (it is a good preanesthetic
medication especially in surgical interventions in buco-pharyngeal area);
 hyperhidrosis (inordinate perspiration);

77
 therapeutic mydriasis;
 adjuncts to treatment of: - Parkinson disease or parkinsonism;
- recent bronchial asthma;
- myasthenia gravis.
Adverse effects: ● dry mouth, dry skin, dry or "sandy" eyes;
● blurred vision and photophobia, mydriazis;
● elevation of intraocular pressure;
● palpitations, tachycardia;
● acute urinary retention;
● constipation.
Contraindications: ● glaucoma;
● prostatic hyperplasia;
● gastric ulcer, pyloric stenosis;
● tachycardia, ischemic heart disease, myocardial
infarction, heart failure;
● hyperthyroidism;
● drivers.
Cautions: ● infants and elderly are more susceptible to adverse effects;
● avoid sun exposure; avoid combining Atropine with other drugs
able to cause muscarinic blockade.
In Atropine overdose, the prefered antidote is Physostigmine because it passes
blood-brain barrier.

SCOPOLAMINE
Mechanism of action: similar to Atropine.
Pharmacodynamic effects are similar to Atropine, but the effects are stronger
on salivary and bronchial secretion and on eye, and weaker on heart and
abdominal organs. Only the effects on CNS are different compared to Atropine:
o therapeutic doses normally causes CNS depression: drowsiness,
sedation, amnesia (because blocks short-term memory), fatigue,
dreamless sleep, with a reduction in rapid eye movement (REM) sleep;
o antiemetic effect: this effect is useful in therapy (much less effective
after severe nausea or vomiting has developed);
o euphoria.
Indications:

78
 antiemetic drug: drug of choice for nausea associated with motion sickness;
useful for postoperative nausea and vomiting;
 antispasmodic agent;
 preanesthetic medication and obstetric amnesia (associated with analgesics);
 diagnostic for WPW (Wolff-Parkinson-White19) syndrome.
Adverse effects: similar to Atropine, plus specific effects of Scopolamine on
CNS such as drowsiness, sedation, dizziness, confusion, fatigue.
Contraindications: similar to Atropine.

2. SEMISYNTHETIC AND SYNTHETIC ANTIMUSCARINIC DRUGS

Quaternary and tertiary amine antimuscarinic agents have been developed
to produce more peripheral effects with reduced CNS effects. They are
incompletely absorbed, do not penetrate blood-brain barrier and into the eye,
have longer action and are slowly eliminated.
 Propantheline, Butilscopolamine, Glycopyrrolate and Clidinium (from
quaternary amines), Dicyclomine and Mebeverine (from tertiary amines)
are the most used for gastro-intestinal smooth muscle spasm.
Propantheline, Butilscopolamine have the lowest adverse effects on the
CNS.
 Pirenzepine (antagonist selective on M1 receptors) is indicated for gastro-
intestinal smooth muscle spasm (particularity: no effect on heart).
 Trospium, Emepronium, Oxybutynin, Tolterodine, Propiverine (non-
selective), Darifenacin (antagonists selective on M3), Solifenacin
(antagonists selective on M1 and M3) are indicated for treatment of
overactive urinary bladder disease (urinary incontinence from
meningomielocel, neurological disorders, enurezis).
 Ipratropium, Oxitropium, Tiotropium are indicated inhalatory for recent
bronchial asthma and chronic obstructive pulmonary disease. Disadvantage:
increase the viscosity of mucus.
 Homatropine is indicated for therapeutic mydriasis (iritis, irido-cyclitis,
prevent adhesion between iris and lens or iris and cornea).
 Cyclopentolate, Tropicamide are indicated for diagnostic mydriasis (dilate

19
Wolff–Parkinson–White syndrome (WPW), known as pre-excitation syndrome, is a disorder of the conduction
system of the heart caused by the presence of an abnormal accessory electrical conduction pathway between the atria
and the ventricles.

79
 the pupil to facilitate fundoscopy).
 Benztropine, Trihexyphenidyl, Orphenadrine, Biperiden are antagonists
of CNS muscarinic receptors and are indicated for Parkinson disease,
parkinsonism and for drug-induced parkinsonism (extrapyramidal adverse
effects of antipsychotic drugs and of Reserpine).
 Chlorzoxazone, Cyclobenzaprine, Orphenadrine are antagonists of the
spinal cord intercalary neuron receptors, indicated for indicated for the
treatment of acute local skeletal muscle spasm20.
Adverse effects and contraindications: similar to Atropine.

3. INHIBITOR OF ACETHYLCHOLINE RELEASE

BOTULINUM TOXIN TYPE A AND B
Mechanism of action: inhibits release of acetylcholine at neuromuscular
junction because vesicles cannot dock and fuse with membrane  results
relaxation of skeletal muscles.
Pharmacokinetics: onset and duration of action: 1-4 days: mild change; 7-10
days or longer: maximal effect; 2-4 months: duration may vary.
Indications (local injections):
 acute local skeletal muscle spasm: spasmodic torticollis, blepharospasm,
severe primary axillary hyperhidrosis, achalasia;
 generalized spastic disorders (associated with injury or disease of the CNS),
 cosmetic surgeons (improvement of moderate to severe glabellar frown lines
for ages 18-65).
Adverse effects:
 after injection into facial muscles: change in facial expression (e.g., ptosis),
dry mouth, facial swelling, headache etc. Some patients may be unable to
close the eyelid completely;
 after injection into neck muscles: dysphagia, paralysis of the vocal cords,
weakness of the neck muscles;
 after injection into limbs: local and general weakness;
 antibody formation (explains resistance to treatment);
 muscle atrophy.
Contraindications:

20
Muscle spasm is a powerful involuntary muscle contraction, often of sudden onset and quite painful, which interferes
with voluntary movement.

80
 pregnant or lactating women;
 active infection at injection site;
 myasthenia gravis (and other generalised disorders of muscle activity).

2. Ganglioplegics

Ganglioplegics (antagonists of Nn receptors or ganglionic blockers) have

limited clinical use; they are mainly used in pharmacologic and physiologic
research because they can block all autonomic outflows.
Classification of ganglioplegics:
- Quaternary ammonium compounds Hexamethonium, Pentolinium
- Secondary amines Mecamylamine
- Tertiary amines Pempidine
- Monosulfonium compound Trimethaphan

Mechanism of action: block the action of acetylcholine of both

parasympathetic and sympathetic autonomic ganglia.
Pharmacodynamic effects
 Cardio-vascular system:
o heart: tachycardia, decrease of force of contraction;
o blood vessels: vasodilatation (hypotension and syncope because both
peripheral vascular resistance and venous return are decreased);
 Gastro-intestinal tract: decreased motility;weak decrease of glands secretion;
 Genito-urinary tract: decreased motility and tone of bladder; impaired sexual
function: inhibition of erection and of ejaculation;
 Eye: cycloplegia and moderate mydriasis;
 CNS: quaternary agents and Trimethaphan don’t cross the blood-brain
barrier; Mecamylamine crosses easily the blood-brain barrier: determines
sedation, tremor, choreiform movements, mental aberrations;
 Other organs: salivary glands and sweet glands: inhibition of secretion.

TRIMETHAPHAN
Indications: ● to produce controlled hypotension in neurosurgery (to reduce
bleeding in the operative field);
● hypertensive emergencies (including pulmonary edema,
81
 dissecting aortic aneurysm). Nitroglycerine and Sodium
nitroprusside are now preferred instead of Trimetaphan.
Adverse effects:
 postural and exercise hypotension, syncope, impaired sexual function;
 constipation, urinary retention, attack of glaucoma, blurring of near vision,
dryness of mouth, inhibition of sweating;
 allergic reactions due to the release of histamine.

3. Neuromuscular blocking drugs (curare-like

substances)

Neuromuscular blocking drugs (skeletal muscle relaxants or curare-like

substances) are antagonists of Nm receptors (this receptor consists of 5
subunits surrounding a Na+-Ach-dependent channel).
Classification of Neuromuscular blocking drugs (curare-like substances) is
according to the mechanism of action:
1. nondepolarizing neuromuscular blocking drugs = pachycurares
- long acting - isoquinoline derivatives: Doxacurium, Metocurine;
- steroid derivatives: Pancuronium, Pipecuronium;
- other structure: Gallamine
- intermediate - isoquinoline derivatives: D-Tubocurarine, Atracurium, Cisatracurium;
acting - steroid derivatives: Vecuronium, Rocuronium;
- short acting - isoquinoline derivatives: Mivacurium;
2. depolarizing neuromuscular blocking drugs = leptocurare
- ultrashort acting - Succinylcholine (Suxamethonium).

Mechanism of action: block nicotinic receptors  result inhibition of Na+

channels and excitatory post-synaptic potential. Blockade of end plate function
is accomplished by two basic mechanisms (fig. 14):
 blockade produced by drugs acting as competitive antagonists prevent access
of the transmitter Ach to its receptor and thereby prevent depolarization
(these are nondepolarizing blockers = competitive blockers = pachycurares);
 blockade produced by an excess of a depolarizing partial agonist (these are
depolarizing blockers = leptocurare).

82
 Fig. 14. Mechanism of action of neuromuscular blocking drugs

Pharmacokinetics: all have onium group, therefore they are administered only
parenteral because they don’t passes physiologic barriers.

1. NONDEPOLARIZING NEUROMUSCULAR BLOCKING DRUGS

Mechanism of action: as competitive antagonists for nicotinic Nm receptor,
they block the Na+ channels found in open position. Ach from nerve ending is
not able to combine with Nm receptor to generate end-plate potential, but
increasing the concentration of Ach in the synaptic cleft consecutive to the
administration of cholinesterase inhibitors may reverse the effect of these drugs.
Pharmacokinetics
 muscles with higher blood flow receive more drug and are affected earlier;
 metabolism in the liver, except for:
o Atracurium and Cisatracurium which undergo spontaneous non-
enzymatic degradation in the blood (Hoffman elimination), thus they
are of choice for hepatic or renal insuficiency;
o Gallamine, which is not metabolized;
 elimination: in urine and bile.
Indications: skeletal muscle relaxation for: surgery; laryngoscopy,
bronchoscopy, esophagoscopy; reduction of fractures and dislocations;
electroconvulsive therapy.
Adverse effects:
 release of histamine (cause skin flushing, hypotension, tachycardia, broncho-
spasm, rarely anaphylactoid reaction): moderate release for D-Tubocurarine
and Mivacurium; slight release for Atracurium and Metocurine;
 hypotension (due to ganglionic blockade): D-Tubocurarine, Metocurine;
 tachycardia by blocking of M2 receptors: strong effects: Gallamine;

83
 moderate effect: Pancuronium; slight effect: Rocuronium;
o Vecuronium is cardiovascular stable (it is of choice in cardiac patient).
 decreases blood coagulability: D-Tubocurarine.
Contraindications: glaucoma, eye surgery, myotonic disease.
Advantage: have antidote for the case of over-dosage: cholinesterase inhibitors
such as Neostigmine, Piridostigmine, Ambenonium, Physostigmine.

2. DEPOLARIZING NEUROMUSCULAR BLOCKING DRUGS

Mechanism of action: as partial agonists of Nm receptors, they are similar to
Ach, but persist longer in the synaptic cleft. They open the Na+-Ach-dependent
channel associated with Nm receptor  result in depolarization of receptor.
Initially it is produced skeletal muscle fasciculation, but the continue binding to
receptor blocks the transmitting of further impulses  the initial end plate
depolarization decreases and the membrane becomes repolarized. The
membrane cannot easily be depolarized again because it is desensitized. The
channels behave as if they are in a prolonged closed state, which result in a
flaccid paralysis.
Indications: skeletal muscle relaxation for: endotracheal intubation;
electroconvulsive therapy.
Adverse effects:● hyperkaliemia;
● malignant hyperthermia;
● muscle fasciculations which cause postoperative muscle pain;
● increased intraocular pressure.
Contraindications:
 hyperkaliemia (renal failure, arrhythmias, skeletal muscle paresis, severe
burns, severe sepsis);
 glaucoma (due to the action of Ach on muscarinic receptors);
 prolonged immobilization;
 low plasma cholinesterase activity;
 myotonic disease.
Depolarizing neuromuscular blocking drugs advantages ans disadvantages:
 Advantages: very rapid onset and short duration of action; very good glotic
relaxation.
 Disadvantages: has no antidote; postoperative muscle pain; slight release of
histamine; ganglionic blockade; tachycardia by stimulation of M2 receptors.

84
 Lecture 5
Adrenergic system activating drugs

Learning Objectives:
 Discuss the effects of stimulation of different adrenergic receptors.
 Discuss the effects and clinical uses of natural cathecolamines (Adrenaline,
Noradrenaline and Dopamine), their adverse effects and contraindications.
 Differentiate between drugs direct acting and mixed acting on adrenergic receptors.
 Differentiate between the effects and indications of α-adrenergic agonists with
systemic effects and with local effects.
 Differentiate between the effects and indications of semi-selective and selective β-
adrenergic agonists.
 Differentiate between different sympathomimetic drugs with indirect action.
 Learn other drugs activating sympathetic system.

Adrenergic system activating drugs are drugs which stimulate adrenergic

system. Drugs activating the adrenergic nervous system (fig) are classified as
follows:

Background
Adrenaline (Epinefrine), Norepinefrine, Dopamine
- are major neurohormonal transmitters which present a cathecol group and stimulate adrenergic
system receptors:
- epinephrine (adrenaline or Adr) is the major hormone of the adrenal medulla,
stimulates α1, α2, ß1, ß2 and ß3-adrenergic receptors;
- norepinephrine (noradrenaline or NE) is the principal transmitter of most
sympathetic postganglionic fibers and of certain tracts in the CNS, stimulates α1, α2,
ß1 (the action on ß2-adrenergic receptors is very weak);
- dopamine (DA) is the predominant transmitter of the mammalian extrapyramidal
system and of several mesocortical and mesolimbic neuronal pathways, stimulates
dopaminergic receptors (D1 – D5), α and ß-adrenergic receptors: D >> ß >> α.
- synthesis: Natural catecholamines are synthesized from tyrosine (phenylalanine). Tyrosine is a
non-essential amino-acid transported from extracellular fluid into the cytoplasm of neurons by a
carrier that actively cotransports sodium. In cytoplasm, tyrosine is hydroxilated to
dihydrohyphenylalanine (DOPA) by tyrosine hydroxilase. DOPA is decarboxilated to form
dopamine by a decarboxylase. Dopamine is taken up into the vesicles of the varicosity by a
transporter. Dopamine is converted to norepinephrine within the vesicle via the action of

85
dopamine- -hydroxylase. Norepinephrine is converted to epinephrine in adrenal medulla via
the action of N-methyltransferase. Synthesis of catecholamines stops depending on the type of
cell.
- storage: Catecholamines are stored in vesicles.
- release: Catecholamines are released when an action potential determines an increase in the
concentration of intracellular calcium. Elevated calcium levels promote the fusion of vesicles
(with NE or DA) from nerve ending or of granules (with Adr) from adrenal medulla with the
cell membrane and release of catecholamines.
- after release of catecholamines: Catecholamines bind to receptors leading to a biological
response. The actions of catecholamines are terminated by: - reuptake into nerve terminals
by norepinephrine or dopamine transporter;
- diffuse out of the synaptic space and enter the general circulation;
- metabolic transformation.
- Metabolism of catecholamines:
- Two enzymes are involved in metabolic transformation of catecholamines: monoamine
oxidase (MAO) and catechol-O-methyltransferase (COMT). Both MAO and COMT
are distributed widely throughout the body, including the brain; the highest concen-
trations are in the liver and the kidney. Two different isozymes of MAO are found in
widely varying proportions in different cells: MAOA is responsible for NE, serotonin,
dopamine and tyramine metabolism, MAOB is responsible for dopamine and tyramine
metabolism.
- in the brain, small quantities of NE are inactivated by MAO, which is
present in mitochondria of presynaptic cells; there is no COMT in presynaptic
terminals, but it is found in some postsynaptic cells.
- in the liver: COMT plays a major role in the metabolism of endogenous and
administered catecholamines; MAO is also involved in the metabolism.
- Most of the Adr and NE that enters the circulation (from the adrenal medulla or
following administration or that is released by exocytosis from sympathetic fibers) is
methylated by COMT to metanephrine or normetanephrine. The major metabolite of
catecholamines is 3-methoxy-4-hydroxymandelic acid (incorrectly called vanillyl-
mandelic acid or VMA) and it is excreted in the urine. The corresponding product of
the metabolic degradation of dopamine is homovanillic acid (HVA).

Receptors of sympathetic nervous system (table): Adrenergic receptors are coupled with
protein G. There are 5 subtypes: α 1 (α 1A, α 1B, α 1D, α 1L) and α 2 (α 2A, α 2B, α 2C), β 1, β 2 and β 3.
Dopamine receptors are coupled with protein G. There are 5 subtypes: D1, D2, D3, D4 and D5.
Alpha receptors located postsynaptically  in general, mediate excitation (increased activity
of the effector cells). Vascular smooth muscle is an important site of alpha receptors. SNS
activity maintains vascular tone, and thus blood pressure, by maintaining a tone of
neurotransmitter on vascular alpha receptors.  vasoconstriction.
Beta receptors located postsynaptically  in general, mediate relaxation (decreased activity of
the effector cells), except the heart muscle where mediate excitation:
- blood vessels  vasodilation;

86
 - bronchial smooth muscle  bronchodilation;
- uterine smooth muscle  relaxes;
- heart  increases the automaticity and contractility.
Dopamine receptors located postsynaptically  in general, mediate relaxation  vasodilation.

Table Adrenergic receptors

Receptor Name Typical Locations Result of Ligand Binding
α 1 (post-synaptic) Heart, vascular smooth muscle, intestinal Formation of IP3 and DAG,
and genito-urinary smooth muscle, liver, increased intracellular Ca2+
CNS, lymphocytes, mast cells, pupil
α 2 (pre and post- Platelets, vascular smooth muscle, nerve Inhibition of adenylyl cyclase,
siynaptic) terminals, pancreatic islets activation of K+ channels,
inhibition of Ca2+ channels
β 1 (pre and post- Heart, juxtaglomerular cells, nerve endings, Activation of adenylyl cyclase
siynaptic) CNS, lymphocytes, mast cells
β 2 (post-synaptic) Smooth muscle (vascular, bronchial, gastro- Activation of adenylyl cyclase
intestinal and genito-urinary tract), skeletal
muscle, liver, lymphocytes, mast cells
β 3 (post-synaptic) Adipose tissue Activation of adenylyl cyclase
D 1 (post-synaptic) Vascular smooth muscle, CNS, T Activation of adenylyl cyclase
D 5 (post-synaptic) lymphocytes
D 2 (pre and post- Vascular smooth muscle, nerve terminals Inhibition of adenylyl cyclase,
synaptic) activation of K+ channels,
activation of Ca2+ channels
D 3 (post-synaptic) CNS Inhibition of adenylyl cyclase
D 4 (post-synaptic) CNS, cardiovascular system Inhibition of adenylyl cyclase

Pre and postsynaptic regulation

- presynaptic regulation is modulated by prejunctional autoreceptors (receptors of adrenergic
system) and heteroreceptors (other types of receptors):
- autoceptors: - stimulation of α2 receptors  inhibit the release of norepinephrine;
- stimulation of ß1 receptors  stimulate the release of norepinephrine;
- heteroceptors:
- stimulation of D2 receptors  inhibit sympathetic neurotransmitter release;
- stimulation of M1 receptors, of prostaglandins receptors and receptors for
polypeptides  inhibit the release of sympathetic neurotransmitters.
- postsynaptic regulation occurs after prolonged exposure to the catecholamines (prolonged
exposure result in reduced of the responsiveness of these receptors, a phenomenon known as
desensitization), explained by:
- sequestration of the receptors (they are unavailable for interaction with the ligand);
- down-regulation (disappearance of the receptors either by destruction or decreased
synthesis);

87
 - inability to couple to G protein (because the receptor has been phosphorylated on the
cytoplasmic side by either protein kinase A or adrenergic receptor kinase).

Physiological Effects of Catecholamines (adrenergic receptors stimulation)

1. Cardiovascular System:
 Heart: stimulation of ß1, ß2 receptors  increase calcium influx in cardiac cells  increase
force of contraction (positive inotropic effect), increase pacemaker activity (positive
chronotropic effect), increase conduction velocity (positive dromotropic effect).
Activation of these receptors by sympathetic nervous system transmission or drugs
will result in tachycardia and arrhythmias. Increase of force of contraction and heart
rate increase myocardial oxygen consumption. For these reasons, drugs that stimulate
α1 and ß1 receptors are contraindicated in tachyarrhythmias, angina pectoris.
Due to strong effects on the heart pacemaker, Adrenaline is used in cardiac arrest.
 Blood Vessels (α1 > ß2):
- stimulation of α1 receptors  vasoconstriction (including the cappilaries).
Activation of these receptors will result in vasoconstriction and an increase in
peripheral resistance and systemic arterial blood pressure. Thus, drugs that stimulate α
receptors are contraindicated in hypertension.
Due to a strong effect on the vessels, including cappilaries, Adrenaline is drug of
choice in anaphylactic shock.
Due to vasoconstrictor effect, Adrenaline and Nordrenaline are associated with local
anesthetics (to prolong their action) and are used topically on bleeding surfaces as
hemostatic agents. Also Phenylephrine may be associated with local anesthetics (to
prolong their action).
- stimulation of ß2 receptors  vasodilation.
Skin vessels and splanhnic vessels have α1 > ß2 receptors. Vessels in skeletal muscle
may constrict or dilate depending on the type of receptors which are activated.
- stimulation of D1 receptors  vasodilation of renal, splanchnic (mesenteric), coronary,
cerebral and perhaps other resistance vessels.
This effect is useful in the treatment of cardiogenic shock21 with dopamine (in low
doses) or Dobutamine because activation of the D1 receptors in the renal, splanchnic,
coronary, cerebral vasculature plays a major role in the natriuresis. Dopamine, in high
doses, determines the release of endogenous noradrenaline that stimulate beta
receptors and increase force of heart contraction.
2. Smooth muscle
 Eye:
- stimulation of α1 receptors  constriction of pupillary radial muscle  mydriasis.
This effect is important for Phenylephrine because it is used for diagnosis mydriasis.
- stimulation of α1 receptors  increase the outflow of aqueous humor from the eye  lowers
intraocular pressure.

21
Cardiogenic shock is characterized by a failure of the heart in its pumping function as in myocardial infarction or
congestive heart failure. Clinical symptoms are similar to those of hypovolemic shock.

88
 This effect explains the use of Adrenaline in the treatment of glaucoma.
- stimulation of ß1 and of D1 receptors  increase production of aqueous humour by the ciliary
process  increase intraocular pressure.
The effect on α1 is stronger compared to effect on ß 1 receptors, therefore drugs that
activate ß1 and of D1 receptors will precipitate glaucoma attack.
 Respiratory tract
- stimulation of ß2 receptors  bronchodilation.
This effect explains the use of the ß2-agonists in the treatment of bronchial asthma.
- stimulation of α1 receptors  bronchoconstriction.
 Gastrointestinal tract: - stimulation of ß2 receptors  relaxation of smooth muscle;
- stimulation of α1 receptors  increase sphyncters tone.
 Genitourinary tract
- stimulation of ß2 receptors  relaxation of smooth muscle.
This effect explains the use of the ß2-agonists in the treatment of premature labour.
- stimulation of α1 receptors  increase sphyncters tone.
- stimulation of α1 receptors from the ductus deferens, seminal vesicles, and prostate 
determine ejaculation. Stimulation of α1A subtype in the human prostate  prostate contraction.
3. Metabolic Effects
- stimulation of ß3 receptors  enhance lipolysis in the adipose tissue, which leads to increased
release of free fatty acids and glycerol into the circulation  hyperlipidemia, termogenesis;
- stimulation of ß2 receptors  enhance glycogenolysis in the liver, which leads to increased
glucose release into the circulation  hyperglycemia;
- stimulation of ß2 receptors  promotes the uptake of potassium into cells, leading to a fall in
extracellular potassium  hypokaliemia.
This effect protects against a rise in plasma potassium during exercise.
- increase in metabolism  increase calorigenic action  it is reflected by an increase of 20–
30% in O2 consumption. Catecholamines may determine increase of lactic acid (due to
anaerobe metabolism in muscles) and in high concentration may cause metabolic acidosis.
4. Central Nervous System
- stimulation of α and ß receptors  restlessness, anxiety, headache, dizziness, tremor,
insomnia, nervousiness, increase attention.
- stimulation of D receptors from:
- mesocorticolimbic bundle (from the ventral part of the tegmen to Nucleus
accumbens)  modify emotions. Substances which activate dopaminergic receptors or
increase dopamine concentration in synapses induce symptoms similar to psychoses:
increased vigilance with decreased sleep requirement, insomnia, locomotor
stimulation, logorrhea, reduction of fatigue, anorexia, nausea and vomiting, appearance
of delusion, hallucinations.
- nigrostriatal bundle (D1 and D2 receptors prevail)  reduce symptoms in patients
with Parkinson's disease
Alteration of dopaminergic neurons in substantia nigra  imbalance resulting
from dopamine deficiency and a relative cholinergic hyperactivity  is

89
 responsible for Parkinson's disease disorders, tremor, akinesia22 and rigidity.
- tubero-infundibular bundle located in hypothalamic-pituitary area (D2 receptors
prevail)  inhibition of prolactin secretion.
5. Renine: - stimulation of α2 and of D receptors  decrease renine release;
- stimulation of ß2 receptors  increase renin release.
6. Exocrine glands
 Insulin and glucagon:
- stimulation of α2 receptors  decrease insulin and glucagon secretion;
- stimulation of ß2 receptors  increase insulin and glucagon secretion.
 Thyroid gland: stimulation of ß2 receptors  increase T4 into T3 conversion.
7. Others effects:
 Pilomotor smooth muscle: stimulation of α1 receptors  erects hair;
 Platelets: stimulation of α receptors  increase platelets aggregation  reduce loos of blood
in injuries;
 Sweat apocrine glands (from the palms of the hands and a few other areas): stimulation of α
receptors  increase sweat production (in psychologic stress);
 Chemoreceptor trigger zone: stimulation of D receptors  induce nausea and vomiting.

Mechanism of action of adrenoceptor agonists and other sympathomimetic

drugs:
1. Direct acting stimulants of adrenergic system - that is, they directly
interact with and activate adrenoceptors (α, β, D-receptors);
2. Mixed action (they acts both directly and indirectly) = have both direct
and indirect actions;
3. Indirect acting stimulants of adrenergic system - that is, their actions are
dependent on the endogenous catecholamines, which activate adrenoceptors.
These indirect agents may have either of two different mechanisms:
- displacement of stored catecholamines from the adrenergic nerve ending or,
- inhibition of reuptake of catecholamines already released.
The actions of indirect-acting sympathomimetic amines are subject to
tachyphylaxis (rapid decrease of effectiveness after repeated administration).
One possible explanation is that the pool of neurotransmitter available for
displacement by these drugs is small relative to the total amount stored in the
sympathetic nerve ending.

22
Akinesia is a loss of the ability to move (loss of normal motor function) resulting in impaired muscle movement.

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Classification of adrenoceptor agonists and other sympathomimetic drugs:
1.Direct acting stimulants of adrenergic system
1.1. Adrenergic agonists
α and β agonists - Adrenaline (Epinefrine);
- Noradrenaline (Norepinefrine);
α agonists - with systemic effect: Phenylephrine, Metaraminol, Midodrine,
Methoxamine, Etylephrine, Ethylephrine, Mephentermine;
- with local effect: Naphazoline, Xylometazoline, Oxymetazoline,
Tetryzoline;
β agonists - semiselective agonists (β1, β2-receptor agonists):
- Isoprenaline, Orciprenaline, Ethylnorepinephrine;
- Bufenine, Bamethan;
- selective β1-receptor agonists: Dobutamine, Prenalterol;
- selective β2-receptor agonists:
- Indicated in bronchial asthma:
- short- /intermediate-acting (3-4 h): Salbutamol (Albuterol),
Fenoterol, Terbutaline, Metaproterenol, Clenbuterol,
Pirbuterol, Procaterol;
- long-acting β2-agonists (12 h): Salmeterol, Formoterol;
- extra-long-acting β2-agonists (24 h): Bambuterol;
- Indicated in premature labour: Salbutamol, Ritodrine, Isoetharine,
Isoxuprine.
1.2. Dopaminergic agonists
D, α and β agonists - non-selective agonist: Dopamine;
- selective D1 and α agonist: Ibopamine
D agonists - selective D1 agonist: Fenoldopam
- Dopamine precursor: Levodopa (L-Dopa) associated or not with:
- inhibitors of dopa-decarboxylase: Carbidopa, Benserazide
- inhibitors of type B monoaminooxidase (MAOB): Selegilline,
Rasagiline, Lazabemide, Mofegiline
- inhibitors of cathecol-O-methyltransferase (COMT):
Entacapone, Tolcapone, Nitecapone
- non-selective dopamine agonists:
- Ergopeptine: Bromocriptine, Lisuride, Pergolide, Cabergoline
- Non-ergopeptine: Piribedil; Ropinirole; Apomorphine;
Pramipexole; Talipexole
2.Mixed acting (direct and indirect acting)
- Ephedrine;
3.Indirect acting
3.1. Stimulants of - amphetamines (Amphetamine, Dextroamphetamine,
catecholamine Methamphetamine, Methylphenidate, Dexmethylphenidate, Pemoline,
release Phenmetrazine, methylen-dioxi-metamfetamina),

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 - Amantadine,
- tyramine.
3.2.Inhibitors of 3.2.1. Inhibitors of cathecolamines reuptake: Cocaine,
transmitter 3.2.2. Selective NE reuptake inhibitors indicated in the treatment of
reuptake depressive disorder: Reboxetine
3.2.3. Non-selective NE and serotonine reuptake inhibitors and other
mechanism of action indicated in the treatment of depressive disorder
3.2.3.1. Tricyclic antidepressants (1st generation) are divided into 3
structural-related groups:
- Imipramine; Desipramine; Clomipramine; Trimipramine.
- Amitriptyline; Nortriptyline; Butriptiline.
- Doxepin; Protriptyline.
3.2.3.2. Heterocyclic antidepressants (2nd and 3rd generation):
- Non selective on amine neutrotransmitters (NE and serotonine):
- With cholinergic effects: Maprotiline, Nomifensine, Amoxapine
- Without cholinergic effects: Venlafaxine, Bupropione
- Antagonists on 5-HT2A/5-HT2C receptors: Trazodone, Nefazodone,
Mirtazapine.
3.3. Inhibitors of IMAO indicated in the treatment of depressive disorder
monoamine oxidase - Non-selective: - Hydrazines: Phenelzine, Isocarboxazid
(IMAO) - Nonhydrazines: Tranylcypromine, Dextroamphetamine
- Isoenzyme MAOA selective: Moclobemide, Brofaromine, Toloxatone

1. Adrenergic agonists with direct and mixed action

1.1. AGONISTS ON α, β-ADRENERGIC RECEPTORS, ± DOPAMINE

RECEPTORS
1.1.1. Direct acting agonists:
 natural catecholamines: ADRENALINE (Epinefrine),
NORADRENALINE (Norepinefrine), DOPAMINE,
 synthetic derivatives: Ibopamine, Fenoldopam.
Mechanisms of action:
 Adrenaline (Epinefrine): agonist on α1≈α2, β1≈β2≈β3 – adrenergic receptors;
 Noradrenaline (Norepinefrine): agonist on α1≈α2, β1 – adrenergic receptors
(it is considered almost no effect on β2 receptors);
 Dopamine  dose – depending effect:
o agonist on dopamine receptors (low doses stimulates dopamine
receptors):
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  stimulation of D1 receptors determine vasodilation;
 stimulation of D2 receptors inhibits the release of NE;
o agonist on β receptors (mild doses stimulates β receptors);
o agonist on α receptors (high doses stimulates α receptors).
Pharmacodynamic effects: see physiological effects of catecholamines.
Indications:
 Adrenaline (Epinefrine):
o anaphylactic shock (drug of choice) – systemic administration;
o cardiac arrest (to restore cardiac rhythm) – systemic administration;
o glaucoma (local administration in open-angle glaucoma);
o associated with local anesthetics (to prolong their action);
o topical hemostatic agent on bleeding surfaces;
o acute bronchial asthma, especially with mucosal edema (to relieve
respiratory distress due to bronchospasm): inhalatory.
 Noradrenaline (Norepinefrine):
o associated with local anesthetics (to prolong their action);
o topical hemostatic agent on bleeding surfaces;
o refractory hypotension in septic shock: intravenous;
o anaphylactic shock as alternative to adrenaline: intravenous.
 Dopamine:
o cardiogenic shock: first-line vasopressor drug;
o decreased cardiac output and hypotension associated with shock (severe
congestive heart failure, cardiogenic and septic shock), septic shock.
 Ibopamine is a synthetic derivative of Dopamine, used experimentally (for
the diagnostic of glaucoma because it increases intraoccular pressure).
 Fenoldopam is a dopamine D1 agonist and with with moderate affinity to α2
presynaptic receptors, with rapidly acting vasodilator effect, indicated as
intravenous treatment for severe hypertension in-hospital for short-term (it
was equivalent to nitroprusside in lowering blood pressure).
Adverse effects:
 Adrenaline (Epinefrine), Noradrenaline (Norepinefrine):
o anxiety, fear, restlessness;
o palpitations, tachyarrhythmia, anginal pain;
o increase blood pressure after high doses (risk of pulmonary edema,
ventricular fibrilation, stroke), cold extremities, headache;
o hyperglycemia.
93
 Dopamine:
o anginal pain,
o headache,
o nausea, vomiting.
Contraindications:
 Adrenaline (Epinefrine), Noradrenaline (Norepinefrine):
o tachyarrhythmia;
o angina pectoris, coronary atherosclerosis;
o arterial hypertension;
o angle-closed glaucoma;
o hyperthyroidia.
o Administration of Adrenaline is contraindicated concomitant with:
 calcium-containing drugs;
 local anesthetics used for anesthesia in extremities (nose,
ears, fingers, penis).
 Dopamine:
o tachyarrhythmia;
o angina pectoris;
o arterial hypertension;
o glaucoma;
o migraine.

1.1.2. Indirect and direct acting agonists (Mixed acting):

EPHEDRINE
It is a natural catecholamine occurring in plants.
Mechanisms of action:
 displacement of stored catecholamines from the adrenergic nerve ending;
 agonist on α1, α2, β1 and β2 – adrenergic receptors.
Pharmacodynamic effects:
1. Cardiovascular System:
 Heart: stimulation of ß1, ß2 receptors  increase force of contraction
(positive inotropic effect), increase pacemaker activity (positive chronotropic
effect), increase conduction velocity (positive dromotropic effect). The
increase of force of contraction and heart rate determine the increase of
myocardial oxygen consumption.
Because of these effects, Ephedrine is used as alternative in atrio-ventricular block and

94
 it is contraindicated in tachyarrhythmias, angina pectoris.
 Blood Vessels (α1 > ß2): stimulation of α1 receptors  vasoconstriction
These effects will result in increase in systemic arterial blood pressure. For this reason,
Ephedrine is indicated as alternative in the treatment of chronic hypotension. Due to
intense vasoconstrictor effect Ephedrine is used in alergies.
Due to vasoconstrictor effect, Ephedrine is used in nasal administration as
decongestant. Pseudoephedrine, a stereoisomer of ephedrine, with similar action, it is
also used as decongestant, because it has less pressor activity and fewer CNS effects.
2. Smooth muscle:
 Respiratory Tract: stimulation of ß2 receptors  powerful bronchodilation
For this effect Ephedrine is used to rapidly relieve the symptoms of acute asthma.
Epinephrine inhibits the release of allergy mediators (e.g., histamine) from mast cells.
 Eye: stimulation of α1 receptors  constriction of pupillary radial muscle 
mydriasis.
 Gastrointestinal and Genitourinary Tract: stimulation of ß2 receptors 
relaxation of smooth muscle; stimulation of α1 receptors  increase
sphyncters tone.
3. Metabolic Effects: hyperglycemia and increased release of free fatty acids
and glycerol into the circulation ( hyperlipidemia).
4. Central Nervous System
 restlessness, anxiety, headache, dizziness, tremor, insomnia, nervousness,
stimulate respiratory center, increase attention, reduce tiredness, increase
capacity of effort, appetite suppressant.
Ephedrine is used as drug of abuse because it increases attention, reduces tiredness,
increases the capacity of physical effort. It is contraindicated in mania, schizophrenia.
Pharmacokinetics
Ephedrine has longer duration of action than other catecholamines; passes
physiologic barriers(including blood brain barrier). Administration: orally or iv.
Indications:
 nasal decongestant;
 atrio-ventricular block (as alternative);
 acute bronchial asthma (as alternative);
 chronic orthostatic hypotension (it was the traditional therapy, now it is as
alternative);
 alergies.
It is also used for non-medical purpose (for weight loss, to increase energy, and
to enhance athletic performance).

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Contraindications: ● arterial hypertension, tachyarrhythmia, angina pectoris;
● endogenous psychoses (mania, schizophrenia).
Adverse effects:
 tachyarrhythmia, anginal pain, increase of blood pressure, anxiety,
 tachyphylaxis,
 anorexia, insomnia, restlessness, phsychological dependence.

1.2. AGONISTS ON α-ADRENERGIC RECEPTORS

1.2.1. Agonists on α-adrenergic receptors with systemic effect
This group includes: Phenylephrine, Metaraminol, Midodrine, Methoxamine,
Etylephrine, Ethylephrine, Mephentermine.
Mechanisms of action:
 direct action as agonist on α-receptors (mainly on α1);
 indirect action through the release of NE from nerve ending – this
mechanism is present only for Phenylephrine, Metaraminol, Mephentermine.
Pharmacodynamic effects:
 vasoconstriction;
Due to the marked systemic vasoconstriction (total peripheral resistance is increased;
increase both systolic and diastolic blood pressure), Phenylephrine and Metaraminol
are used to raise blood pressure in acute orthostatic hypotension23 and as alternative in
paroxysmal supraventricular tachycardia only in patients with hypotension or shock.
The marked vasoconstriction produces reflex bradycardia (increased vagal activity
occurring as a reflex to increased arterial blood pressure) if they are administered iv.
Phenylephrine, Metaraminol, Mephentermine have prolonged effect.
Due to local vasoconstriction, Phenylephrine is used as nasal decongestant and to
prolong the action of local anesthetics after infiltration into tissues.
 mydriasis;
Due to this effect, Phenylephrine is used in ophthalmology to provide optimal dilation
of the pupil with minimal systemic side effects.
 CNS stimulation: nervousness, restlessness, anxiety, dizziness, tremor  in
some patients.
Pharmacokinetics:
Phenylephrine it is not inactivated by COMT and has a much longer duration of
action than the catecholamines.
Midodrine is well absorbed from the gastrointestinal tract. It is a prodrug that

23
Orthostatic (postural) hypotension is an excessive fall in blood pressure when an upright position. It may cause
dizziness, weakness and other signs of cerebral ischemia.

96
undergoes enzymatic hydrolysis in the systemic circulation. The duration of
action is about 4 - 6 h. It does not cross the blood-brain barrier.
Indications:
 symptomatic orthostatic hypotension is the principal use for agonists on α-
adrenergic receptors with systemic effects.
o Midodrine: symptomatic chronic orthostatic hypotension (including L-
Dopa induced hypotension) – preferred for maintenance treatment;
o Methoxamine, Etylephrine, Mephentermine: as alternative;
o Phenylephrine and Metaraminol: acute orthostatic hypotension;
 nasal decongestant: Phenylephrine;
 to prolong the action of local anesthetics: Phenylephrine;
 diagnostic mydriasis (to facilitate fundoscopy): Phenylephrine;
 paroxysmal supraventricular tachycardia (as alternative, intravenous):
Phenylephrine, Metaraminol;
 priapism24: Phenylephrine, Metaraminol.
Adverse effects:
 supine hypertension (this can be minimized by avoiding dosing prior to
bedtime and elevating the head of the bed);
 tachyarrhythmia, anginal pain, increase of blood pressure;
 tachyphylaxis (only for the drugs with indirect mechanism of action).
Contraindications: ● arterial hypertension, tachyarrhythmia, angina pectoris,
● acute renal disease, urinary retention;
● hyperthyroidia.

1.2.2. Agonists on α-adrenergic receptors with local effect

This group includes25: Naphazoline, Xylometazoline, Oxymetazoline,
Tetryzoline.
Mechanisms of action:
 Naphazoline: ● direct action as agonist on α-receptors;
● indirect action through the release of NE from nerve ending;

24
Priapism is a persistent, usually painful, erection that lasts for more than 4 h and occurs without sexual stimulation. It
is an emergency. Intracavernosal Phenylephrine or Metaraminol may result in detumescence due to α-agonist effects.
25
Over-the-counter brand names:
- Naphazoline: - naphazoline nasal: Privine®, Rinofug®; - naphazoline ophthalmic: Naphcon®, AK-Con®, Albalon®,
Vasocon®, Proculin®;
- Xylometazoline: - xylometazoline nasal: Otrivin®, Olynth®;
- Oxymetazoline: - oxymetazoline nasal: Nazivin®; - oxymetazoline ophthalmic: OcuClear®, Visine Long Lasting®.

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 Xylometazoline, Oxymetazoline, Tetryzoline: direct action on α-receptors.
Indications: topical decongestant (nasal mucosa, conjunctival mucosa)
Adverse effects:
 Naphazoline: - tachyphylaxis;
- nasal mucosa atrophy, atrophic rhinitis;
- large doses in children, may cause hypotension, presumably
because of a central Clonidine-like effect;
- large doses in adults, may cause increase in blood pressure,
increase conductivity in excitoconductor tissue (up to
ventricular fibrilation).
 Oxymetazoline: when taken in large doses, may cause hypotension,
presumably because of a central Clonidine-like effect.
Contraindications: ● Naphazoline: children < 3 years old.
● Xylometazoline, Oxymetazoline: children < 4 months old.

1.3. AGONISTS ON β-ADRENERGIC RECEPTORS

1.3.1. Semiselective agonists (β1, β2-receptor agonists):
ISOPRENALINE
Mechanism of action: very potent -receptor agonist and low effect on -
receptors.

Pharmacodynamic effects (short duration of action):

 positive chronotropic and inotropic effects;
 potent vasodilatory effect (lowers peripheral vascular resistance, primarily in
skeletal muscle but also in renal and mesenteric vessels).
Indications: ● complete heart block and cardiac arrest;
● cardiogenic shock (rarely used because of adverse effects);
● severe bradycardia unresponsive to Atropine;
● bronchial asthma (rarely used because of adverse effects).
Adverse effects: ● palpitations, tachycardia, headache, and flushing
● angina pectoris and arrhythmias in patients with coronary
artery disease.
ORCIPRENALINE
Mechanism of action: -receptor agonist (β2 >> β1).
Pharmacodynamic effects: ● low positive chronotropic and inotropic actions;

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 ● potent vasodilatory effect.
Longer duration of action.
Indications: bronchial asthma (rarely used because of adverse effects).

BUFENINE, BAMETHAN
Mechanism of action: -receptor agonist (β2 >> β1).
Pharmacodynamic effects: potent vasodilatory effect
Indications: Raynaud syndrome26; intermittent claudication27.

Contraindications of beta-adrenergic agonists:

 glaucoma;
 migraine and other headache;
 angina pectoris;
 arrhythmias;
 oscillatory hypertension;
 hyperthyroidia;
 endogenous psychosis.

1.3.2. Selective β1-receptor agonists: Dobutamine, Prenalterol

Mechanism of action: β1-receptor agonist.
DOBUTAMINE
Pharmacodynamic effects:
 potent positive inotropic actions, without influence on chronotropic actions;
 minor effects on blood pressure;
 enhancement of atrioventricular and intraventricular conduction.
There is evidence for the development of tolerance to Dobutamine (similar to
tachyphylaxis).
Indications:
 cardiogenic shock;
 short-term treatment of cardiac decompensation (after cardiac surgery,
congestive heart failure, acute myocardial infarction).

26
Raynaud syndrome is characterized by arterial and arteriolar cyanosis of the fingers due to vasoconstriction of
uncertain cause; caused by cold or emotion. Raynaud phenomenon is spasm of the digital arteries, with blanching and
numbness or pain of the fingers, often precipitated by cold.
27
Intermittent claudication is caused by ischemia of the leg muscles due to sclerosis and narrowing of the arteries,
characterized by pain in the leg that a person experiences when walking or exercising; the pain is intermittent and goes
away when the person rests.

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Adverse effects:
 palpitations, tachyarrythmias (sometimes ventricular tachycardia);
 increase of oxygen consumption;
 exaggerated pressor response in patients with a history of hypertension.

PRENALTEROL
Indication: cardiogenic shock.

1.3.3. Selective β2-receptor agonists:

This β2-agonists include drugs:
 indicated in bronchial asthma:
o short-/intermediate-acting (3-4 h): Salbutamol (Albuterol), Fenoterol,
Terbutaline, Metaproterenol, Clenbuterol, Pirbuterol, Procaterol;
o long-acting (12 h): Salmeterol, Formoterol;
o extra-long-acting (24 h): Bambuterol;
 indicated in premature labour: Salbutamol, Ritodrine, Isoetharine,Isoxuprine.
Mechanism of action: β2-receptor agonist.
Pharmacodynamic effects:
 effects of β2-adrenergic agonists on airways:
o bronchodilatatory effect (relaxation of airway smooth muscle);
o inhibition of mast cell mediator release;
o inhibition of plasma exudation and airway edema;
o increased mucociliary clearance and mucus secretion;
o decreased cough;
 other effects of β2-adrenergic agonists:
o immunosuppresory effects;
o antiinflammatory activity.
Indications:
 bronchial asthma:
o acute asthma: Salbutamol (Albuterol), Fenoterol, Terbutaline,
o maintenance treatment:
 intermediate-acting β2-agonists: Salbutamol (Albuterol),
Fenoterol, Terbutaline, Metaproterenol, Clenbuterol,
Pirbuterol, Procaterol, Bitolterol;
 long-acting β2-agonists: Salmeterol, Formoterol;

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  extra-long-acting β2-agonists: Bambuterol;
 premature labour: Salbutamol, Ritodrine, Isoetharine, Isoxuprine.
Adverse effects of β-receptor agonists:
 tremor of the hands – relatively common adverse;
 restlesness, anxiety;
 tachycardia;
 headache;
 peripheral vasodilation;
 hypokaliemia after large doses.
Contraindications of β-receptor agonists: status asthmaticus.
Caution: Beta-blockers may decrease of β-receptor agonist's effectiveness
(competitive antagonism).

2. Stimulants of release of catecholamines

2.1. AMPHETAMINES
This group include: Amphetamine, Dextroamphetamine, Methamphetamine,
Phenmetrazine, Dexmethylphenidate, Pemoline, Methylphenidate, methylen-
dioxi-metamfetamina (MDMA or „Ecstacy”).
Mechanism of action:
 releases of catecholamines (dopamine, serotonin etc) from nerve ending 
increase in the concentration of neuromediators in the synapse;
 inhibits dopamine metabolism by inhibiting MAO in the nerve ending.
Pharmacodynamic effects:
 Central Nervous System: the release of cathecolamines  marked stimulant
effect on mood, locomotor actions and a depressant effect on appetite.
o Higher doses of amphetamine induce stereotyped behavior (like in
schizophrenia, probably due to dopamine), disturbances of perception
and paranoid behavior (due to release of serotonin and dopamine).
o Metamphetamine in small doses has prominent central stimulant effects
without significant peripheral actions.
o Methylphenidate is a mild CNS stimulant with more prominent effects
on mental than on motor activities.
o Phenylpropanolamine determines less effects on mental behaviour.

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 o Methylen-dioxi-metamfetamine (MDMA or „Ecstacy”)  determines
euphoria, hallucinations, stereotyped behavior.
Pharmacokinetic effects:
Amphetamines enter the CNS more readily compared to Ephedrine.
Dexmethylphenidate is an active metabolite of Methylphenidate.
Indications:
 attention-deficit/hyperactivity disorder (in children): Methylphenidate,
Dextroamphetamine, Methamphetamine, Pemoline, Dexmethylphenidate;
 narcolepsy28: Methylphenidate, Dextroamphetamine, Methamphetamine,
Pemoline;
 anorectant: Amphetamine, Phenmetrazine;
 other indications: ● Amphetamine  for the treatment of enurezis, adjunct
treatment in Parkinson disease and in petit mal epilepsy;
● Hydroxiamphetamine  alternative in Horner
syndrome with preganglionar lesions.
Non-medical use for amphetamines: misused as a CNS stimulant.
Adverse effects: Amphetamines have high potential for abuse. Pemoline
determines severe hepatic failure.

2.2. AMANTADINE
Mechanism of action:
 mechanisms of action in parkinsonism:
o potentiate dopaminergic function by stimulating the release of dopamine
in the CNS and inhibition of dopamine degradation;
o block NMDA glutamate receptors (which inhibits the release of Ach in
the CNS);
 mechanisms of antiviral (virus) action:
o inhibit viral uncoating (an early step in viral replication);
o inhibit viral assembly (a late step in viral replication).
Indications: ● adjunct therapy in Parkinson disease;
● influenza A.

2.3. TIRAMINE

28
Narcolepsy is a disorder marked by excessive daytime sleepiness, uncontrollable sleep attacks, and cataplexy (a
sudden loss of muscle tone, usually lasting up to half an hour).

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Tiramine is a product of tyrosine metabolism in the body and it is also found in
high concentrations in some fermented foods (cheese, beer). When taken orally,
it is rapidly metabolized by MAO in the liver.
Mechanism of action: ● inhibition of NE reuptake;
● enhance release of stored catecholamines.
Pharmacodynamic effects: similar to NE.
Contraindications: in patients treated with MAO inhibitors (because it
determines increase in blood pressure), hypertensive patients.

3. Inhibitors of transmitter reuptake

COCAINE
Mechanism of action: inhibition of cathecolamines reuptake (NE and
dopamine).
Pharmacodynamic effects:
 CNS effects: mydriasis, tachyarrhythmia, increase blood pressure;
 local vasoconstriction (in chronic administration determines perforation of
nasal septum);
 blocks nerve transmission, due to its local anesthetic properties;
 euphoric properties due to inhibition of catecholamine uptake, particularly
dopamine, into neurons in the "pleasure centers" of the brain;
 very rapid and potent abuse potential (psychological dependency with
psychological deterioration).
Indications: ● local anesthetic in otorhinolaryngology and ophthalmology.
Non-medical use for euphoric effect.

4. Other drugs activating sympathetic system

4.1. Drugs affecting brain dopaminergic system (indicated in the treatment of

Parkinson disease)
4.1.1. Dopamine precursor: Levodopa (L-Dopa) associated or not with:
o inhibitors of peripheral decarboxylase: Carbidopa, Benserazide;
o inhibitors of type B monoaminooxidase (MAOB): Selegilline,

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 Rasagiline, Lazabemide, Mofegiline;
o inhibitors of cathecolortomethyltransferase (COMT): Entacapone,
Tolcapone, Nitecapone;
4.1.2. Dopamine agonists:
 Ergopeptine: Bromocriptine, Lisuride, Pergolide, Cabergoline;
 Non-ergopeptine: Piribedil; Ropinirole; Apomorphine; Pramipexole;
Talipexole;
4.1.3. Drugs facilitating dopamine transmition: Amantadine, amphetamines;
4.2. Inhibitors of monoamine oxidase (IMAO) (indicated in the treatment of
depressive disorder):
 Non selective: ● Hydrazines: Phenelzine, Isocarboxazid;
● Nonhydrazines: Tranylcypromine, Dextroamphetamine;
 Isoenzyme MAOA selective: Moclobemide, Brofaromine, Toloxatone;
4.3. Selective noradrenaline reuptake inhibitors (indicated in the treatment of
depressive disorder): Reboxetine;
4.4. Non-selective noradrenaline and serotonine reuptake inhibitors and
other mechanism of action (indicated in the treatment of depressive disorder):
4.4.1. Tricyclic antidepressants (1st generation) are divided into 3 structural-
related groups:
 Imipramine; Desipramine; Clomipramine; Trimipramine;
 Amitriptyline; Nortriptyline; Butriptiline;
 Doxepin; Protriptyline;
4.4.2. Heterocyclic antidepressants (2nd and 3rd generation):
 Non selective on amine neutrotransmitters (noradrenaline and serotonine):
o With cholinergic effects: Maprotiline, Nomifensine, Amoxapine;
o Without cholinergic effects: Venlafaxine, Bupropione;
 Antagonists on 5-HT2A/5-HT2C receptors: Trazodone, Nefazodone,
Mirtazapine.

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 Lecture 6
Adrenoceptor-blocking drugs and other sympatholytic
drugs

Learning Objectives:
 Discuss the pharmacological effects of blocking of different adrenergic receptors.
 Explain the differences between the pharmacological effects and indications of
semiselective and selective α-blockers.
 Explain the differences between the pharmacological effects and indications of
semiselective and selective β-blockers. Differentiate between the pharmacological
actions and clinical uses of β-blockers without or with ISA.
 Differentiate between different centrally acting sympatholytic drugs.

Classification of substances blocking sympathetic system activity:

1. Competitive antagonists on adrenergic and / or dopamine receptors
1.1. Antagonists on alpha adrenergic postsynaptic receptors (α-blockers)
Semiselective - Phentolamine,
α-blockers - Ergot derivatives: Dihydroergotoxine, Dihydroergocristine
Selective - block α1–receptors (α1-blockers): Phenoxybenzamine, Prazosin, Terazosin,
Doxazosin, Trimazosin, Indoramin, Tamsulosin, Alfuzosin
- block α2 postsynaptic receptors: Yohimbine, Tolazoline, Rauwolscine
- block α1 postsynaptic receptors and stimulate α2 presynaptic receptors:
Urapidil
1.2. Antagonists on beta receptors (β-blockers)
semiselective β– - without intrinsic sympathomimetic activity (ISA): Propranolol,
blockers (block β1 = β2 Timolol, Sotalol, Nadolol, Bupranolol
–receptors) - with ISA: Oxprenolol, Alprenolol, Pindolol, Penbutolol, Carteolol
selective β1–blockers - without ISA: Metoprolol, Atenolol, Bisoprolol, Esmolol,
Betaxolol, Nebivolol
- with ISA: Acebutolol, Celiprolol
selective β2 –blockers Butoxamine
1.3. Antagonists on alpha and beta receptors (α,β-blockers)
Labetalol, Carvedilol, Medroxolol, Bucindolol
1.4. Antagonists on alpha and / or dopamine receptors
non-selective α1 α2 - phenothiazines:
blockers plus / minus - aliphatic side chain: Chlorpromazine, Levomepromazine;
of dopamine D1, D2, D4 - piperidine derivatives: Thioridazine;

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receptors (± M receptor - piperazine derivatives: Fluphenazine, Perphenazine,
competitive antagonists, Trifluoperazine;
± H1 antagonists, ± 5- - thioxanthenes: thiothixene, Chlorprothixene;
HT2 antagonists) - butyrophenones: haloperidol, trifluperidol, Droperidol
- other structures: Risperidone, Clozapine, Olanzapine, Quetiapine,
Sertindole, Molindone, Sulpiride, Loxapine, remoxipride,
Ziprasidone, Aripiprazole, Paliperidone, Iloperidone, Asenapine,
and Lurasidone.
selective blocker of - diphenylbutylamine derivatives: Pimozide.
dopamine D2 receptors
2.Inhibitors of cathecolamine synthesis
- Metyrosine (competitive inhibitor of tyrozin-hydroxilase)
3.Centrally acting sympatholytic agents
Acting mainly on CNS - Agonists on α2 presinaptic adrenergic receptors and I1
imidazoline receptors: Clonidine, Apraclonidine,
Brimonidine, Tizanidine, Dexmedetomidine
- Selective agonists on I1 imidazoline receptors:
Moxonidine, Rilmenidine
- Other mecanisms of action: Methyldopa, Guanabenz,
Guanfacine
Acting on CNS and peripherally Reserpine
Acting mainly peripherally Guanetidine, Guanadrel, Bethanidine, Debrisoquin.

1. Competitive antagonists on adrenergic receptors

1.1. Antagonists on alpha adrenergic postsynaptic

receptors (α-blockers)

SEMI-SELECTIVE α-BLOCKERS
PHENTOLAMINE
Mechanisms of action:
 competitive antagonist on α1 = α2 – adrenergic receptors;
 competitive antagonist on 5HT2 receptors;
 agonist on muscarinic receptors;
 agonist on histamine H1 and H2 receptors;
 direct action on vascular smooth muscle.
Pharmacodynamic effects:

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 vasodilation with a decrease in blood pressure by:
o postsynaptic α1 receptor blockade (due to compensatory mechanism,
occurs decrease in peripheral resistance and increase in venous return);
o histamine H1 receptor agonist effect;
o direct action on vascular smooth muscle;
 blocking presynaptic α2 receptors → disinhibition of noradrenaline release in
the CNS → positive inotropic effect and increased cardiac output;
 agonist on M receptors determine parasympathomymetic effects: stimulation
of digestive peristalsis, bronchoconstriction (these effects are antagonized
with Atropine);
 stimulation of gastric acid secretion (due to the action as agonist on M and
H1 receptors).
Indications:
 pheochromocytomas (diagnosis of pheochromocytoma; pre- and intra-
operative treatment; inoperable cases of pheochromocytoma);
 impotence (in conjunction with papaverine as intracavernous injection).
Adverse effects:
 tachycardia, tachyarrhythmias (ventricular fibrillation, in high doses),
 orthostatic hypotension;
 abdominal pain, vomiting, diarrhea, gastric ulcer;
 local fibrotic reactions in the penis after local administration for a long time.
Contraindications: peptic ulcers with acid hypersecretion; hypovolemia.

DIHYDROERGOTOXINE
Dihydroergotoxine is a mixture of Dihydroergocornine, Dihydroergocristine,
and Dihydroergocryptine. These ergot alkaloids are derivatives extracted from
Claviceps purpurea, a fungus that infects grain, especially rye, under damp
growing or storage conditions.
Mechanisms of action: ● partial antagonist receptor α1 = α2 - adrenergic;
● competitive antagonist on 5HT2.
Pharmacodynamic effects: vasodilation with hypotension and bradycardia by a
central mechanism.
Indications: ● as an adjunct in the treatment of hypertension;
● disorders of irrigation of the brain, in Alzheimer's disease;
● disorders of peripheral perfusion.

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Adverse effects: ● nausea, vomiting, diarrhea;
● vascular endothelial toxicity (because it is an ergot
derivative); high doses determine ergotism: insomnia,
hallucinations, nightmares, delirium;
● severe arterial hypotension, which is accentuated by the
orthostatic position;
● drowsiness;
● in large doses or for long-term treatment: nephrotoxicity;
● hepatotoxicity.
Contraindications: ● endogenous psychoses;
● pregnancy, breastfeeding, perinatal period;
● young children;
● low blood pressure;
● bradycardia;
● liver failure; kidney failure.

SELECTIVE α1-BLOCKERS
PHENOXYBENZAMINE
Mechanisms of action:
 competitive antagonist α1 >>>> α2 adrenergic (between the receptor and the
ligand is a covalent binding → explains the long-term effect);
 competitive antagonist on 5HT2 receptors;
 muscarinic receptor antagonist;
 histamine H1 receptor antagonist;
 stimulates the release of norepinephrine and inhibit norepinephrine reuptake;
 blocks the renal tubular transport of organic bases.
Pharmacodynamic effects:
 because it blocks α1-receptors, this determine severe arterial hypotension,
reduced peripheral resistance → increase of heart rate and cardiac output
(due to a reflex mechanism);
 stimulation of the release and inhibition of the reuptake of norepinephrine →
determine increase frequency and cardiac output, positive inotropic effect.

Indications:

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 pheochromocytomas (diagnosis of pheochromocytoma; pre- and intra-
operative treatment; inoperable cases of pheochromocytoma);
 phlebitis, thrombophlebitis;
 trauma associated with circulatory disorders;
 obstructive arterial disease; Raynaud syndrome;
 alternative, in acute heart failure, some cases of acute myocardial infarction.
Adverse effects
 severe orthostatic arterial hypotension, accentuated by effort, postprandial;
 anginal pain; tachycardia, arrhythmias; palpitations after consuming alcohol;
 myosis;
 congestion of the nasal mucosa, dry mouth;
 inhibition of ejaculation;
 nausea, vomiting;
 sedation, loss of sense of time, in high doses → convulsions.
Contraindications: ● hypovolemia; angina pectoris; arrhythmias;
● peptic ulcers with acid hypersecretion;
● benign prostate;
● glaucoma.

PRAZOSIN, TERAZOSIN, DOXAZOSIN, TRIMAZOSIN, INDORAMIN

Mechanism of action: competitive antagonists receptor α1 >>>> α2 adrenergic.
Pharmacodynamic effects:
 relaxation of arterial and venous smooth muscle (decreases peripheral
vascular resistance and venous return with a resultant decrease in systemic
arterial blood pressure);
 moderate compensatory tachycardia.
Indications: ● treatment of essential hypertension;
● benign prostatic hypertrophy.
Adverse effects: severe orthostatic hypotension and first dose syncope.
TAMSULOSIN, ALFUZOSIN
Mechanism of action: competitive antagonists receptor α1 >>>> α2 adrenergic.
Pharmacodynamic effects: are relatively selective on vascular α1-receptors in
the prostate; Tamsulosin blocks α1-receptors in ureters → relaxation.
Indications: benign prostatic hypertrophy.
SELECTIVE α2-BLOCKERS
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Mechanism of action: competitive antagonist α2 >>>> α1 adrenergic.
YOHIMBINE
Source: Corynanthe yohimbe (a plant).
Indications: ● analgesic for diabetic neuropathy from diabetes mellitus type 2;
● to determine improvement in sexual function (this effect is
limited in humans).
TOLAZOLINE
Indications: ● persistent pulmonary hypertension of the newborn (in
respiratory distress syndrome of the newborn);
● peripheral vasospastic disease, Raynaud syndrome (alternative
therapy).

SELECTIVE POSTSYNAPTIC α1-BLOCKER AND PRESYNAPTIC α2

STIMULANT
URAPIDIL
Mechanism of action: ● competitive antagonist α1 - adrenergic postsynaptic;
● α2 receptor agonist - adrenergic presynaptic;
● 5HT1A receptor agonist.
Pharmacodynamic effects: decrease blood pressure; anxiolytic effects.
Indications: treatment of hypertension (in Europe).

1.2. Antagonists on beta receptors (β-blockers)

Classification of β-blockers:
- semiselective β-blockers (β1β2-blockers)
 without intrinsec sympathomimetic activity (ISA): Propranolol,
Timolol, Sotalol, Nadolol, Bupranolol;
 with ISA: Oxprenolol, Alprenolol, Pindolol, Penbutolol, Carteolol;
- selective β1–blockers
 without ISA: Metoprolol, Atenolol, Bisoprolol, Esmolol, Betaxolol,
Nebivolol;
 with ISA: Acebutolol, Celiprolol;
- selective β2–blockers: Butoxamine.
β1β2-BLOCKERS

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 Semi-selective blockers of receptors β1=β2 without sympathomimetic
activity (ISA) include PROPRANOLOL, TIMOLOL, SOTALOL,
NADOLOL, BUPRANOLOL
Mechanism of action: semi-selective antagonists of β1=β2-adrenergic receptors.

PROPRANOLOL
Pharmacodynamic effects of Propranolol:
 in experimental dose (low doses) → local anesthetic effect (by the
mechanism of membrane stabilization);
 in therapeutic doses → effects on cardiovascular system, respiratory system,
ocular, CNS, metabolic effects;
 in overdose → effects similar to Quinidine.
1.cardiovascular effects:
 in the heart:
o negative inotropic effect (reduction in force of contraction of the heart);
o negative chronotropic effect (reduction in heart rate);
o negative dromotropic effect (depresses sinoatrial and atrioventricular
conduction);
o reduction in cardiac output;
o reduction in myocardial oxygen consumption (due to decrease of force
of contraction and of heart rate);
 in the vessels:
o reduces systolic and diastolic blood pressures;
o increases peripheral vascular resistance by a compensatory reflex
mechanism (this decline over time).
2.renin-angiotensin-aldosterone system: reduce the plasma renin level (by
blocking the receptors β1 - adrenergic presynaptic renal juxtaglomerular cells).
3.respiratory system: determines bronchoconstriction.
4.in the eye: reduces the aqueous secretion from ciliary epithelium (by blocking
the presynaptic β1-receptors) → determines reduction of intraocular pressure.
5.CNS: anxiolytic effect by a central mechanism (by blocking the presynaptic
β1-receptor) or by reducing circulatory effects (reduction of tachycardia induced
by stress, cold, emotions).
6.metabolic effects: ● inhibition of the glycogenolytic and lipolytic effects of
catecholamines;

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 ● increase in plasma levels of triglycerides and decrease
levels of HDL cholesterol → increase atherogenesis.
Pharmacokinetics of Propranolol:
Propranolol is well absorbed from the gastrointestinal tract. It does not bind
significantly to plasma proteins. Cmax occurs at 1 – 2 h after administration,
when the effect is maximal. Propranolol is metabolized in the liver.
Indications of Propranolol:
 hypertension;
 chronic stable angina pectoris (with normal blood pressure or hypertensive
patients);
 myocardial infarction associated with hypertension;
 supraventricular/ventricular tachyarrhythmia (class II antiarrhythmic drugs);
 pheochromocytomas (only in combination with α - blockers);
 anxiety;
 migraine ( for prophylaxis);
 benign essential tremor or tremor induced by lithium treatment in bipolar
psychoses;
 as the adjuvant treatment of following diseases:
o Parkinson's disease;
o withdrawal syndrome in chronic alcoholics, opiate dependence,
dependence caused by hallucinogens;
o hyperthyroidism, thyrotoxicosis;
o schizophrenia, mania;
 portal hypertension – it is treatment of choice to prevent gastrointestinal
bleeding caused by rupture of esophageal varices.
Adverse effects of Propranolol:
 bradyarrhythmias, atrioventricular block;
 worsening congestive heart failure;
 mask the hypoglycemic effect of insulin and oral hypoglycemic agents
(makes a diabetic less sensitive to changes in blood sugar levels because
reduces the intensity of symptoms of hypoglycemia: light-colored skin,
sweat, tachycardia);
 bronchospasm;
 neuropsychiatric disorders: depression, fatigue, insomnia, hallucinations,
nightmares;

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 chronic administration → deafness, loss of sexual potency (impotence);
 rarely: digestive symptoms (nausea, vomiting, diarrhea/constipation),
immunological reactions type II (lupus-like syndrome) and type I (fever,
purpura, skin erythema).
 sudden withdrawal of Propranolol after chronic administration causes
withdrawal syndrome: significant increase in blood pressure, angina,
myocardial infarction, cardiac arrhythmias up to atrial fibrillation /
ventricular fibrillation, insomnia, nervousness.
Contraindications of Propranolol
 bronchial asthma, spastic bronchitis, chronic obstructive pulmonary disease;
 bradyarrhythmias; AV block;
 diabetes mellitus;
 severe dyslipidemia;
 peripheral vascular insufficiency; Raynaud syndrome;
 depressions;
 pregnancy (Propranolol may cause slower growth in utero, neonatal
hypoglycemia, bradycardia).

TIMOLOL
Indications: glaucoma, hypertension, and chronic stable angina pectoris.
SOTALOL
Mechanism of action:
 semi-selective antagonist effect on β1 = β2 - adrenergic receptors
 potassium channel blockade (the latter explains the class III antiarrhythmic
effects, but also a strong arrhythmogenic effect).
Indications: only for arrhythmias.
The pharmacodynamic effects, adverse effects, contraindications of Timolol
and Sotalol are similar to Propranolol.

 Semi-selective blockers of receptors β1 = β2 with intrinsec

sympathomimetic activity (ISA) include OXPRENOLOL, ALPRENOLOL,
PINDOLOL, PENBUTOLOL, CARTEOLOL
Mechanism of action: semi-selective antagonists of receptors β1 = β2, with
intrinsic sympathomimetic activity (are partial antagonists).
These drugs have the same indications, contraindications and adverse effects

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like β1,β2-blockers without ISA, but the depressant action in the heart is weaker.
Therefore, these drugs may be administered in patients with bradycardia.

β1-BLOCKERS
 Selective β1-blockers without intrinsec sympathomimetic activity (ISA)
include METOPROLOL, ATENOLOL, BISOPROLOL, ESMOLOL,
BETAXOLOL, NEBIVOLOL
These drugs have similar indications, contraindications and adverse effects like
β1,β2-blockers without ISA, but they are selective on β1-receptors and therefore,
these drugs are contraindicated only in patients with severe asthma or COPD.
ATENOLOL is indicated for hypertension, angina pectoris, arrhythmias, and
after myocardial infarction.
METOPROLOL, BISOPROLOL are indicated for hypertension, angina
pectoris, arrhythmias and after myocardial infarction, Metoprolol, Bisoprolol
are indicated also for the treatment of heart failure (because they inhibit
neurohormonal activation). Bisoprolol is metabolized 50% in the liver and 50%
in the kidney and may be indicated in patients with hepatic or renal failure.
BETAXOLOL administered locally is preferred for the treatment of glaucoma;
administered systemic is preferred for the treatment of angina pectoris, arterial
hypertension and arrhythmias.
NEBIVOLOL is a β1-blocker without SIA and which determines also the
release of nitric oxide. It is indicated in patients with angina pectoris, arterial
hypertension. It is contraindicated in patients with glaucoma.

 Selective receptor β1-blockers with intrinsec sympathomimetic activity

(ISA) include ACEBUTOLOL, CELIPROLOL
These drugs have similar indications, contraindications and adverse effects like
β1-blockers without ISA, but their effects on the heart are weaker. Therefore,
these drugs may be indicated in patients suffering of hepatic or renal failure.

1.3. Antagonists on alpha and beta receptors (α,β-

blockers)

This group include LABETALOL, CARVEDILOL, MEDROXOLOL,

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BUCINDOLOL. In some classifications, these drugs are included in the group
of non-selective β-blockers with the special mention that they present also α -
blocker activity.
Mechanisms of action: ● Labetalol: antagonist on α1=α2=β1=β2–receptors;
● Carvedilol: antagonist on α2=β1=β2–receptors;
● capture of oxygen free radicals.
Indications: ● post-myocardial infarction therapy;
● Labetalol: pheochromocytoma, hypertension crises;
● Carvedilol: heart failure, hypertension, angina pectoris.
Adverse effects: orthostatic hypotension; moderate reflex tachycardia.
Contraindications: similar to β-blockers; heart failure (except Carvedilol).

2. Inhibitors of cathecolamine synthesis

Inhibitors of tyrosine hydroxylase: METYROSINE.
Mechanism of action: inhibit tyrosine hydroxylase → inhibitor of dopamine
synthesis.
Indications: treatment of pheochromocytomas (inoperable or metastatic); it is
associated with Phenoxybenzamine.

3. Centrally acting sympatholytic agents

Classification of centrally acting sympatholytic agents
3.1. Acting mainly on CNS:
o Agonists on presinaptic α2-receptors and imidazoline I1 receptors:
Clonidine, Apraclonidine, Brimonidine, Tizanidine,Dexmedetomidine;
o Selective agonists on imidazoline I1 receptors:Moxonidine,Rilmenidine;
o Other mecanisms of action: Methyldopa, Guanabenz, Guanfacine;
3.2. Acting on CNS and peripherally: Reserpine
3.3. Acting mainly peripherally: Guanethidine, Guanadrel, Bethanidine,
Debrisoquin.

AGONISTS ON PRESINAPTIC α2-RECEPTORS AND IMIDAZOLINE

I1 RECEPTORS
This group include CLONIDINE, APRACLONIDINE, BRIMONIDINE,
TIZANIDINE, DEXMEDETOMIDINE.
Mechanisms of action

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 agonist on α2-presynaptic receptors and partial agonists of α1 and α2-
postsynaptic receptors;
 agonist on imidazoline I1 receptors (Clonidine binds to both α and
imidazoline receptors with equal affinity).
Pharmacodynamic effects
 because it is agonist on presynaptic α2–receptors determines:
o inhibition of sympathetic tone (decrease in systolic and diastolic blood
pressure) and increase in parasympathetic tone;
o orthostatic hypotension induced by Clonidine is rare and low,
 iv administration of Clonidine determines first a short
period of increase (by stimulating α1 postsynaptic
receptors), which is followed by a decrease in systolic
and diastolic blood pressure;
 at therapeutic doses (orally), Clonidine does not
determine the pressor effects;
 in overdose, Clonidine can induce severe hypertension;
o sudden interruption of the administration of Clonidine (or missing 1-2
doses) → withdrawal syndrome: increase blood pressure, tachycardia,
headache, nervousness, sweating;
o decrease in renal vascular resistance;
o in the eye: reduction of aqueous secretion of ciliary processes
 this effect is stronger for Clonidine derivatives
(Apraclonidine, Brimonidine, Dexmedetomidine), so
they are indicated for closed angle glaucoma;
o in renal juxtaglomerular cells: inhibition of the synthesis and release of
renin;
o in exocrine glands: reduction of salivary glands secretion (dry mouth)
and gastrointestinal glands (constipation);
 other effects on the CNS:
o sedative - hypnotic, indifference to the environment (Dexmedetomidine
determines the most powerful hypnotic effect);
o inhibition pre - and postsynaptic spinal receptors determine a muscle
relaxant effect important for the treatment of localized spasm of
skeletal muscle and treatment of spasm produced by the pyramidal
lesions (Tizanidine, Dexmedetomidine);

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 o block the release of norepinephrine → depressions;
o inhibition of the symptoms produced by abrupt cessation of opiates;
o inhibition of nausea and vomiting;
o anorectic effect by stimulation of α1 and α2 postsynaptic adrenergic
receptors;
 other pharmacodynamic effects:
o by stimulation of presynaptic α2-receptors (and due to the effect of
partial antagonist on postsynaptic α2-receptors) → determine inhibition
of nociception in the spinal dorsal horn and analgesic effect
(Tizanidine, Dexmedetomidine);
o by stimulation of presynaptic α2-receptors (and due to the effect of
partial antagonist on postsynaptic α1-receptors) → determine inhibition
of ejaculation;
o by presynaptic α2-receptor stimulation → inhibition of release of insulin,
inhibition of the glycogenolytic and lipolytic effects of catecholamines,
increase in plasma levels of triglycerides and decrease in levels of high
density lipids (HDL cholesterol) → increase atherogenesis;
o by partial stimulation of α1-receptors → stimulation of gluconeogenesis;
o by partial stimulation of vascular cerebral postsynaptic α1-receptors →
moderate vasoconstriction.
Indications:
 Clonidine:
o first indication is hypertension with renal failure;
o alternative in the treatment of severe hypertension which does not
respond to other therapies;
o alternative in the treatment of glaucoma;
o migraine, other pulsatile headaches;
o opiate dependence (reduce withdrawal syndrome from alcohol
dependence, nicotine dependence, opiate dependence);
o as an alternative in the treatment of diarrhea (experimentally).
 Apraclonidine: glaucoma (preoperatively and after laser therapy).
 Brimonidine: glaucoma (which does not require surgery ).
 Tizanidine: ● muscle relaxant for the treatment of localized spasm of
skeletal muscle and of spasm produced by the pyramidal lesions;
● analgesic.

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 Dexmedetomidine: ● glaucoma;
● analgesic;
● sedative - hypnotic;
● muscle relaxant.
Adverse effects: ● hypotension (rarely, low intensity), bradycardia;
● dry mouth; constipation; loss of appetite;
● sedation, drowsiness (are reduced for transdermal
administration);
● depression, indifference to environment;
● metabolic disorders (increase in blood glucose,
triglycerides);
● sexual disfunction;
● withdrawal syndrome with abrupt discontinuation of
administration;
● local reactions at the transdermal delivery.
Contraindications: ● endogenous depression;
● pregnancy;
● severe renal failure; severe heart failure;
● bradyarrhythmias, AV block;
● diabetes mellitus;
● severe dyslipidemia;
● peripheral vascular insufficiency, Raynaud syndrome;
● pheochromocytomas;
● association with tricyclic antidepressants.

SELECTIVE AGONISTS ON IMIDAZOLINE I1 RECEPTORS

MOXONIDINE, RILMENIDINE
Mechanism of action: ● selective agonists on I1 imidazoline receptors;
● block sodium influx in renal juxtaglomerular cells.
Pharmacodynamic effects:
 central effects: reduce sympathetic tone and noradrenaline release (less
sedation than Clonidine);
 peripheral effects:
o reduce the release of peripheral NE → reduce blood pressure;
o block sodium influx in renal juxtaglomerular cells → natriuretic effect.

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Selective agonists on imidazoline I1 receptors cause immediate effects, which
gradually increases (the maximum intensity is after 3-4 weeks of treatment); are
administered once daily, as monotherapy or in combination with diuretics,
calcium channel blockers or inhibitors of angiotensin converting enzyme.
Indications: hypertension (mild/moderate).
Rilmenidine is preferred for hypertension in diabetic patients, elderly,
patients with renal failure (when creatinine clearance > 15ml/min),
patients with left ventricular hypertrophy, patients with cerebral
atherosclerosis, patients with hepatic failure.
Adverse reactions (rare): dry mouth; nausea, constipation; at high doses:
decrease libido, headache, depression.
Contraindications: severe depression; severe renal failure (creatinine clearance
<15 ml/min); Raynaud syndrome.
 association with alcohol, neuroleptics, barbiturates, tricyclic antidepressants.
Benefits: They do not cause metabolic effects. They are not hepatotoxic /
nephrotoxic. They do not cause marked hypotension. Cardiac dynamics is not
affected. They do not cause sedation. They do not influence intellectual activity.
They do not cause depression. They do not influence sexual activity.

CENTRALLY ACTING SYMPATHOLYTIC AGENTS WITH OTHER

MECHANISMS OF ACTION
METHYLDOPA
Mechanisms of action:
 It is an analogue of L-Dopa, which crosses the blood-brain barrier, then it is
transformed into metabolites (alpha-methyl-noradrenaline and alpha-methyl-
Dopamine), which are stored in the vesicles of adrenergic neurons, where
replace norepinephrine and are released by nerve endings with role of false
mediator (cannot interact with postsynaptic adrenergic receptors);
 agonist on presynaptic α2- receptors and on postsynaptic α1-receptors;
 agonist on dopamine receptors (including D2).
Pharmacodynamic effects:
 decrease in blood pressure (higher in the patients with hypertension);
 moderate increase in peripheral vascular resistance;
 decrease in heart rate and cardiac output (less than the effect of Clonidine);
 reduction in plasma renin;

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 block drainage of aqueous humor in the eye;
 pseudoparkinsonism, tardive dyskinesia29.
Pharmacokinetics:
 bioavailability → 25%, it has extensive first pass metabolism. After oral
administration, the maximum effect is reached after 4-6 h and lasts longer
than 24 h (the action persists even after the disappearance from circulation).
 it crosses the blood-brain barrier; it does not cross the placenta.
Indications: hypertension in pregnancy - as drug of choice for the chronic
treatment (because does not affect the fetus).
For acute treatment of severe hypertension or pre-eclampsia in
pregnancy is preferred Labetalol.
Adverse effects:
 sedation and tiredness are the most frequent;
 drowsiness, reduction of ability to concentrate, of attention – these can
interphere with skilled motor tasks such as driving),
 slowness in ideation (after long administration), reduction of initiative, sleep,
nightmares, depression, dizziness;
 dry mouth (because of inhibition of salivary secretion), but also inhibition of
nausea and vomiting;
 interphere with cross-matching of blood, positive Coombs test;
 rare: hepatotoxicity (frequent during first 4 months of treatment),
autoimmune hepatitis; lupus-like syndrome; extrapyramidal symptoms;
hyperprolactinemia (females and males); autoimmune hemolytic anemia,
fever, granulocytopenia, thrombocytopenia; loss of appetite; edema.
Do not stop suddenly because it cause rebound hypertension.
Contraindications: depression, liver disease; Parkinson's disease;
pheochromocytoma; glaucoma.
Benefits: the orthostatic hypotension is minimal; the hypotension during effort
is rare.

GUANABENZ, GUANFACINE
Mechanism of action: adrenergic agonists α2 - presynaptic (α2 >>> α1).
Pharmacodynamic effects:

29
Dyskinesia is an impairment in the ability to control voluntary movements, characterized by spasmodic or repetitive
motions or lack of coordination.

120
 decrease blood pressure, decrease peripheral vascular resistance;
 decrease cardiac output;
 reduction of plasma renin.
Pharmacokinetics: cross the blood-brain barrier, cross the placenta, filtered
during dialysis.
Indications: hypertension in patients with coronary artery lesions or myocardial
infarction or left ventricular hypertrophy or with increased plasma renin, in
young adults.
Contraindications: pregnancy; depressions; pheochromocytoma; children
under 12 years.
Benefits: reduction in plasma renin and in circulating catecholamines; are not
nephrotoxic; sexual dynamics is not affected;
 No interference with digitalis, oral antidiabetics, oral anticoagulants, anti-
inflammatory drugs.

CENTRALLY ACTING SYMPATHOLYTIC AGENTS WITH

PREDOMINANT CENTRAL ACTION
RESERPINE
Source: Rauwolfia sandwicensis (plant)
Mechanism of action: block the reuptake and storage of catecholamines in
vesicles from terminal nerve ending of adrenergic neurons → depletion of
norepinephrine, dopamine and serotonin;
Pharmacodynamic effects:
 in the CNS: sedation, mental depression, reduce the aggression,
pseudoparkinsonism;
 periphery: decrease blood pressure, decrease peripheral vascular resistance,
decrease cardiac output, bradycardia, depression of vascular sympathetic
reflexes.
The optimal effects are achieved after 2-3 weeks of treatment.
Pharmacokinetics: drug rapidly crosses the blood-brain barrier.
Indications: hypertension (as an alternative, it is rarely used).
Adverse effects:
 marked orthostatic hypotension;
 asthenia, sedation, mental depression, pseudoparkinsonism, anxiety,
nightmares;

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 stimulate the release of gastrin → gastric hypersecretion,
 stimulate the appetite; weight gain; digestive spasms; diarrhea;
 congestion of the nasal mucosa;
 salt and water retention;
 sexual impotence; menstrual disorders; risk of breast cancer.
Contraindications: depression, peptic ulcer, acute gastroenteritis, acute colitis,
epilepsy, Parkinson's disease, pseudoparkinsonism, pregnancy, young adults.

CENTRALLY ACTING SYMPATHOLYTIC AGENTS WITH

PREDOMINANT PERIPHERAL ACTION
GUANETIDINE, rarely used: GUANADREL, BETHANIDINE,
DEBRISOQUIN
Mechanism of action:
 inhibition of noradrenaline release from sympathetic nerve endings:
Guanethidine is captured in the nerve endings (the same mechanism as for
NE), form covalent bonds with the storage granules, replacing NE → a
progressive depletion of NE from nerve endings.
Pharmacodynamic effects:
 reduction in systolic and diastolic blood presure;
 reduce the force of contraction of the heart; decrease in cardiac output;
 severe bradycardia;
 local anesthetic effect.
Pharmacokinetics: variable bioavailability (3-50%); renal elimination (50%);
half-life=5days.
Indications: hypertension (as an alternative, it is rarely used).
Adverse effects:
 orthostatic hypotension (increased during exercise, heat, alcohol intake),
which can determine cerebral or myocardial ischemia; bradycardia;
 salt and water retention; edema; diarrhea;
 inhibition of ejaculation;
 weakness.
Contraindications: pheochromocytoma; association with tricyclic
antidepressants, phenothiazine antipsychotics, cocaine, amphetamines.
Guanadrel: has properties similar to Guanethidine; the drug is indicated for the
treatment of hypertension (as an alternative, rarely used).

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 Lecture 7
Pharmacological influence of smooth
muscle activity

Learning Objectives:
 Describe aspects of absorption, distribution, metabolism and excretion of a drug;
 List the principal routes of drug administration and their advantages and
disadvantages;
 List examples of drugs concentrated in different tissues or liquids of the body;
 Name the phases in hepatic metabolism;
 Describe the terms “bound” and “unbound” drug to plasma proteins;
 Describe the term “first pass effect”;
 Describe the terms drug metabolism “enzyme induction” and “enzyme inhibition”;
 List the principal routes of drug elimination;
 Explain concept and significance of pharmacokinetic parameters
 Explain concept and significance of steady state concentration.

There are drugs that:

1. inhibit constriction of smooth muscle (= smooth muscle relaxants);
2. stimulate constriction of smooth muscle.

Classification:
I. Drugs that inhibit constriction of smooth muscle (smooth muscle relaxants):
I.1. Non-selective (on different types of smooth muscle):
I.1.1. Calcium channels antagonists (Calcium channels blockers):
- Action on Calcium channels from blood vessels and heart:
- Dihydropyridine: Nifedipine, Amlodipine, Nicardipine, Nitrendipine;
- Phenylalkylamine: Verapamil ;
- Benzothiazepine: Diltiazem;
- Specific action on Calcium channels from blood vessels:
- Dihydropyridine: Felodipine, Isradipine, Nisoldipine, Lacidipine,
Lercanidipine;
- Specific action on Calcium channels from cerebral blood vessels:
- Dihydropyridine: Nimodipine;
- Piperazine: Cinnarizine;
- Specific action on Calcium channels from heart: Bepridil;
I.1.2. Isoquinoline derivatives from opium: Papaverine, Eupaverina, Moxaverine, Ethaverine,
Proxyfylline;

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I.1.3. Methylxanthines:
- Natural sources: Theophylline (1,3,dimethylxanthine), Theobromine
(3,7,dimethylxanthine), Caffeine (1,3,7,trimethylxanthine);
- Synthetic: Pentoxiphylline, Dyphylline, Propentophylline, Pentiphylline.
I.1.4. Substances acting on autonomic nervous system
I.2. Selective on vessels (vasodilatation drugs)
I.2.1. Substances acting on autonomic nervous system
I.2.2. Substances with other mechanisms of action except acting on nervous vegetative
system:
a) Nonspecific mechanism:
- Nonselective (arteriolar and venous):
- Nitrites and nitrates: Nitroglycerine, Isosorbide mononitrate (ISMN),
Isosorbide dinitrate (ISDN), Penta erythroil tetranitrate (PETN), Amyl nitrite, Sodium
nitroprusside
- Other structures: Nicorandil, Molsidomine
- Selective (arteriolar): Hydralazine, Minoxidil, Diazoxide
b) Specific mechanisms:
- Inhibitors of 5-phosphodiesterase: Sildenafil, Tadalafil, Vardenafil
- Prostaglandine derivatives of:
- PGE1 analogs: Alprostadil, Prostin
- PGI 2 analogs: Eproprostenol, Iloprost.
- Antagonists of histamine receptors H1 and stimulants of release of PGE1 and PGI2:
Cicletamine
- Other vasodilatation drugs: ethanol, nicotinic acid
II. Drugs that stimulate constriction of smooth muscle
II.1. Substances stimulating visceral smooth muscle:
II.1.1. Uro-genital tract:
a) Nonselective:
- Substances acting on vegetative nervous system;
- Substances acting on histamine receptors: Histamine;
b) Selective:
- Hormones: Oxytocin;
- Prostaglandine derivatives of:
- PGE2: Dinoprostone;
- PGF2α: Dinoprost, Carboprost;
- Other derivatives: Gemeprost (PGE1), Mifepristone.
- Amino-alcohol ergot derivatives: Ergometrine, Methylergometrine;
II.1.2. Gastro-intestinal tract:
- Bulk forming: dietary fibers; colloidal hydrophilic derivatives;
- Stimulant purgatives: castor oil; antraquinones.
II.1.3. Gallbladder: cholecystokinin; food cholecystokinine-like substances.
II.2. Substances stimulating vascular smooth muscle (vasoconstrictors)
- Substances acting on autonomic nervous system;

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 - Polypeptide ergot derivatives: Ergotamine, Dihydroergotamine;
- Amine ergot derivatives: Methysergid;
- Agonists of serotonine receptors 5-HT1D and 5-HT1B: Sumatriptan, Naratriptan,
Rizatriptan, Zolmitriptan;
- Hormones and synthetic derivatives: Vasopressin, Terlipressin, Desmopressin.
II.3. Contrast agents in radiology: barium salts.

1. Drugs that inhibit constriction of smooth muscle

(smooth muscle relaxants)
I.1. Non-selective (on different types of smooth muscle):
I.1.1. Calcium channels blockers (Calcium channels antagonists)
These are drugs that can inhibit the transfer of membrane calcium in cardiac
muscle cells and vascular.
The calcium channels blockers have different effects on the heart and peripheral
vasculature depending on their chemical structure (fig).

Classification:
- Action on Calcium channels from blood vessels and heart:
- Dihydropyridine: Nifedipine, Amlodipine, Nitrendipine, Nicardipine
- Phenylalkylamine: Verapamil
- Benzothiazepine: Diltiazem
- Specific action on Calcium channels from blood vessels:
- Dihydropyridine: Felodipine, Isradipine, Nisoldipine, Lacidipine,
Lercanidipine
- Specific action on Calcium channels from cerebral blood vessels:
- Dihydropyridine: Nimodipine
- Piperazine: Cinnarizine
- Specific action on calcium channels from heart: Bepridil
Mechanism of action:

125
- Block of voltage sensitive L-type Ca2+ channels30 (reducing Ca2+ flux through
the channel):
- Inhibition of calcium entry into the cell:
- in myocardial cells  decreased myocardial contractility,
slowed AV conduction, decreased heart rate, decreased myocardial
oxygen consumption
- in smooth muscle cells of artery walls  decrease in arteriolar
resistance
- in bronchial cells  bronchodilatation.
- Inhibition to form complexes calcium – calmodulin;
- Stimulation of the kinase inactivation of myosin light chain
- Low intensity inhibition of Ca2+ channels: Verapamil, Diltiazem
- Nifedipine block also Na+ channels.
Pharmacodynamic effects:
Are due to reduction of calcium entry:
- long-lasting relaxation of vascular smooth muscle (very important effect):
- peripheral vessels (explains the decrease of blood pressure -
reduction of systolic and diastolic BP except for selective calcium
channel blockers on the heart), explains the decrease in peripheral
vascular resistance;
This reduction in blood pressure causes a reflex sympathetic stimulation
and stimulation of the renin angiotensin system (by compensatory
mechanisms).
- coronary vessels;
- cerebral vessels (explains the reduction of cerebral ischemic lesions):
Nimodipine, Cinnarizine;
- heart muscle (very important effect):
- inotrop negative effect (reduction in contractility throughout the
heart);
- cronotrop negative effect (decreases in sinus node pacemaker rate);
- dromotrop negative effect (decreases in atrioventricular node

30
Types of voltage-dependent calcium channels (depending on location and electrophysiological characteristics):
- Type L ("Long-lasting"): in smooth muscle and cardiac muscle; have higher conductance and long open time: eg:
couplation excitation – contraction;
- Types N, P, Q and R: at the neural level (neurotransmitter release)
- Type T ("Transient"): in smooth muscle, cardiac muscle and neurons; have low conductance and short open time: eg:
automation of sinoatrial-node.

126
 conduction velocity);
- reduction in myocardial oxygen consumption due to negative
chronotropic and inotropic effects (= anti-ischemic effect).
- bronchial muscle: relaxation (bronchodilatation): Verapamil and Diltiazem
- low analgesic effects: Verapamil, Diltiazem, Nifedipine
- for Verapamil:
- inhibit insulin release in humans;
- block the P-glycoprotein responsible for the transport of many
foreign drugs out of cancer (and other) cells (explains the loss of
resistance to anticancer agents)
- may attenuate the atherosclerotic process: reduce storage of calcium
in vascular wall, increase HDL cholesterol;
- can be effective in decreasing left ventricular hypertrophy.
The calcium channel blockers are agents of Class IV antiarrhythmics
(exception: calcium channel blockers selective on the vessels)  are effective
in supraventricular and ventricular tachyarrhythmias.
Pharmacokinetics:
- Absorption (after oral administration): 50% for Nifedipine and Diltiazem,
80% for Verapamil.
- Binding on plasma proteins: more than 90%.
- Cross blood-brain barrier.
- Metabolism: hepatic (by conjugation). Norverapamil is the active metabolite
of Verapamil, with stronger vasodilatatory effects.
- First pass effect is stronger for Verapamil and Diltiazem, but not present for
Isradipine.
- Elimination is mailnly renal (Nifedipine, Verapamil) or through feces
(Diltiazem).
Indications:
- hypertension (except Nimodipine, Cinnarizine); Nifedipine is an appropriate
second-line antihypertensive medication in pregnancy;
- angina pectoris;
- arrhythmias (calcium channels antagonists are class IV antiarrhythmic agents):
- supraventricular tachyarrhythmia, atrial fibrillation or flutter:
Verapamil, Diltiazem,
- Raynaud syndrome: Nifedipine, Felodipine, Isradipine, Nicardipine;
- prevention of ischemic sequelae in cerebral vasospasm associated with
127
subarachnoid hemorrhage, vertigo: Nimodipine, Cinnarizine;
- hypertrophic cardiomyopathy: Verapamil;
- migraine prophylaxis: Verapamil;
- adjuvant to reverse the resistance of cancer cells to chemotherapeutic drugs:
Verapamil.
Adverse effects:
- excessive vasodilatation (especially with short-acting dihydropyridines):
- orthostatic hypotension (except: Bepridil, Nimodipine, Cinnarizine);
- dizziness, headache,
- flushing,
- peripheral edema (oedema of the lower limbs / ankle edema)
unresponsive to diuretics and occurs after several weeks of treatment,
- reflex tachycardia (due to this effect, the administration of sublingual
nifedipine should be avoided – risk of ventricular fibrilation).
- allergic reaction type I: facial flushing, hot flashes
- cardiac effects:
- bradycardia (which aggravates atrioventricular blocks) (except for
Felodipine, Isradipine, Nisoldipine, Lacidipine, Lercanidipine);
- inotrop negative effects (except for: Felodipine, Isradipine,
Nisoldipine, Lacidipine, Lercanidipine),
- torsade de pointes: Bepridil;
- gingival hyperplasia;
- hiperglicemia: Verapamil;
- sedation: Cinnarizine;
- constipation (due to intestinal relaxant effect), nausea.
Contraindications:
- heart failure (except for Felodipine, Isradipine, Nisoldipine, Lacidipine,
Lercanidipine);
- bradycardia, AV block;
- acute myocardial infarction;
- severe arterial hypotension;
- association with beta-adrenergic blockers.

I.1.2. Isoquinoline derivatives from opium: Papaverine, Eupaverine,

Moxaverine, Ethaverine, Proxifylline
Mechanism of action:
128
- inhibits phosphodiesterases in smooth muscle cells, which produces increased
tissue levels of cyclic adenosine monophosphate and cyclic guanosine 3,5-
monophosphate (also inhibits phosphodiesterase-5 or PDE-5);
- block calcium ion channels in cell membranes, resulting in a reduction of
release of calcium from the intracellular spaces.
Papaverine does not act on opioid receptors (does not determine analgesia and
euforia, does not determine addiction).
Pharmacodynamic effects: relaxation of smooth muscle  vasodilatation and
relaxation of other smooth muscles.
Pharmacokinetics: Papaverine is rapidly absorbed from the gastrointestinal
tract, t1/2 = 1-2 h, plasma protein binding is 90%. It is metabolized in the liver to
inactive metabolites, which are excreted in the urine.
Indications:
- antispasmodic (intestinal, biliary, genito-urinary colicative pain);
- ischemic conditions associated with arterial vasospasm (pre-eclampsia,
eclampsia, cerebral and peripheral ischemia associated with arterial spasm and
without vascular injuries);
- erectile dysfunction (alone, or in combination with phentolamine, or with
phentolamine plus alprostadil).
Adverse effects:
- “arterial steal” in arterial obstructions;
- quinidine-like effects: QT prolongation, ventricular arrhythmias, and torsade
de pointes;
- hepatotoxicity (after high doses / administration prolonguee);
- after intracavernosal injection of papaverine: local administration by injections
into the corpus cavernosum  may lead to the development of injection site
reaction: local penile fibrosis (loss of elasticity of the tissue), transient penile
pain, ecchymosis, and priapism (painful prolonged erection).
Contraindications:
- chronic arterial obstructions;
- atrioventricular block, bradicardia;
- heart failure;
- pregnancy, breast-feeding.

I.1.3. Methylxantines
Classification:
129
 - Natural sources: Theophylline (1,3,dimethylxanthine), Theobromine
(3,7,dimethylxanthine) and Caffeine (1,3,7,trimethylxanthine)
Tea contains caffeine and small amounts of Theophylline and theobromine
when it is prepared from leaves of Thea sinensis, a bush native to southern
China and now cultivated also in other countries. Coffee contains caffeine
and it is extracted from fruits of Coffea Arabica. Cocoa and chocolate
contains theobromine and some caffeine and it is extracted from seeds of
Theobroma cacao. Cola-flavored drinks contain considerable amounts of
caffeine added during their production and extracted from nuts of Cola
acuminate.
- Synthetic: Pentoxiphylline, Propentophylline, Pentiphylline,
Dyphylline
Theophylline is among the least expensive drugs used to treat asthma.
Mechanism of action:
- competitive antagonists at adenozine receptors A1 and A2;
- non-selective inhibition of phosphodiesterases (PDE) – the enzymes that
degrades cyclic 3’,5’-adenosine monophosphate (cAMP). (also inhibit
phosphodiesterase-4 or PDE-4)
Pharmacodynamic effects:
- CNS effects (central stimulant effects):
- vasoconstriction of cerebral vessels (hence the anti-migraine
properties of caffeine);
- psychoanaleptic effect (especially caffeine cause mild cortical arousal
with increased alertness and decrease of fatigue, and stimulate
intellectual work);
- psychic dependency (especially caffeine);
- larger doses cause nervousness, insomnia and fine tremor of hands,
anxiogenic effect and in high doses, convulsant effect;
- very high doses cause medullary stimulation and convulsions;
- peripheral effects:
- cardiovascular system:
- positive chronotropic and inotropic effects, increase in cardiac
output, increase in peripheral resistance (in sensitive individuals,
consumption of a few cups of coffee may result in arrhythmias);
- large doses relax vascular smooth muscle (except in cerebral
blood vessels, where they cause contraction): reduction of
systolic and diastolic BP; dilates coronary, pulmonary, renal, and

130
 general systemic arterioles and veins;
- Pentoxifylline: reduction of platelet aggregation and thrombus
formation, decrease blood viscosity, increase the deformability
of red blood cells;
- pulmonary system:
- bronchodilating effect (due to adenosine receptor antagonism
and PDE inhibition) – Theophylline is the most effective
bronchodilator;
- strengthen the contractions of diaphragmatic muscle (improve
the ventilatory response to hypoxia and diminish dyspnea);
- stimulation of mucociliary transport (increase clearance
mucociliare);
- renal system: weak diuretic efect (vasodilatation determines the
increase in glomerular filtration rate and decrease in tubular
reabsorption of sodium and chloride in proximal tubule);
- antiinflammatory action (inhibits synthesis and secretion of
inflammatory mediators from numerous cell types, including mast cells
and basophils, due to PDE inhibition);
- digestive system: stimulate secretion of both gastric acid and
digestive enzymes;
- immunosupressory effects;
- antialergic effect due to decrease of pre- and post- capillary
permeability;
- analgesic effect.
Theophylline has narrow therapeutic index and requires monitoring of drug
levels.
Pharmacokinetics:
- Absorption: readily after oral or parenteral administration (caffeine is
absorbed more rapidly, food slows the rate of absorption of Theophylline).
- Distribution: into all body compartments, cross the placenta and pass into
breast milk.
- Metabolism: hepatic.
- Elimination: a small part is eliminated renally unchanged.
Indications:
- Theophylline is used as Aminophylline (which is a 2:1 complex of
Theophylline and Ethylenediamine):
131
 - asthma (in emergencies and for maintenance treatment);
- chronic obstructive pulmonary disease;
- apnea of premature infants;
- Pentoxiphylline:
- intermittent claudication (arterial obstructive disease, Raynaud
syndrome) – symptomatic treatment, drug of choice;
- stasis ulcer, phlebitis, thrombophlebitis, hemorrhoidal disease;
- vascular disorder of inner ear;
- multiple myeloma, polycythemia, hyperlipidemia
- Caffeine:
- psychostimulant (reduces fatigue, increases alertness).
Adverse effects:
- cardiovascular effects:
- tachycardia (palpitations);
- there is a coronary vasodilation, but the tachycardia increases the
oxygen needs of the heart  chest pain (angina);
- Pentoxifilline determines vascular steal phenomenon in arteriosclerotic
arteries31.
- CNS effects (related to excessive consumption): tremor, iritability, insomnia,
headache, anxiety, nervousness, convulsive effect;
- for caffeine: chronic consumption determines phenomenon of
tolerance and dependence
- withdrawal symptoms: headache, dizziness, fatigue, irritability,
depressive ideas.
- digestive effects: anorexia, nausea, vomiting, abdominal discomfort,
aggravation of peptic ulcer, gastro-esofagian reflux;
- respiratory effects: tachypnea;
- immunosupressory effects (during prolonged treatment).
Theophylline administration by rapid intravenous  hypotension,
tachyarrhythmias, convulsant effect.
Toxic doses of Theophylline:
- concentrations of 20–40 mg/L in blood determine: agitated maniacal
behavior, frequent vomiting, extreme thirst, slight fever, tinnitus,
palpitation, and arrhythmias;
31
Vascular steal phenomenon is induced by vasodilators in most arteriopathic patients, due to the shunting of blood
from the ischemic to the normally perfused areas.

132
 - concentrations > 40 mg/L in blood determine: seizures, arrhythmias,
death.
Contraindications:
- angina pectoris or acute myocardial infarction, tachyarrhythmias;
- seizure disorders, insomnia, epilepsy, people with mental labile;
- active peptic ulcer;
- liver failure;
- immunosuppressory diseases, herpes disease;
- children;
- association with platelets antiagregant drugs, psychostimulant drugs,
fluoroquinolones.
For children and elderly doses must be adjusted.

I.2. Substances acting selective on the vessels (vasodilatation drugs)

I.2.1. Vasodilatation drugs acting by nonspecific mode of action
I.2.1.1. Nonselective action (on both arteries and veins)
Nitrates and nitrite (collectively termed nitrovasodilators)
Nitroglycerin is the prototype of the group and was used in the manufacture of
dynamite
Mechanism of action:
- NO release (these agents are prodrugs that are sources of NO). NO react with
sulfhydryl groups to form thiol-nitroso groups which activate guanylyl cyclase,
thereby increasing intracellular levels of cyclic GMP. In turn, this promotes the
dephosphorylation of the myosin light chain and the reduction of cystolic
(Ca2+), which leads to the relaxation of smooth muscle cells.
- stimulate production of prostacyclin (PGI2) which leads to the relaxation of
smooth muscle cells. The antiplatelet effect of nitrates is due to stimulation of
prostacyclin (PGI2).
Pharmacodynamic effects:
- hemodynamic effects: vasodilation (preferentially dilate the veins more than
the arterioles),
- dilatation of large veins diminishes preload and reduces work of the
heart (decrease O2 demand);
- dilation of coronary vessels increase blood supply in the heart
muscle;
- relaxation of smooth muscle form other levels: bronchodilation, gastro-
133
intestinal tract relaxation.

Nitroglycerin, Isosorbide mononitrate (ISMN), Isosorbide dinitrate

(ISDN), Penta erythritol tetranitrate (PETN), Amyl nitrite
Pharmacokinetics:
- Absorption:
- Nitroglycerin and Isosorbide dinitrate have very low oral
bioavailability, for this reason it is preferred sublingual route (which
avoids the first-pass effect and achieves a therapeutic blood level
rapidly within a few minutes). Sublingually administered nitroglycerin
has the most rapid onset of antianginal and hemodynamic effects
compared to the other organic nitrates. Sublingual or buccal
nitroglycerin and sublingual or chewable isosorbide dinitrate have a
more rapid onset of action than when given orally or topically.
- Nitroglycerin is well absorbed with delay through intact skin when
applied topically as an ointment or transdermal system.
- Amyl nitrite is a highly volatile liquid (the ampule can be crushed with
the fingers, resulting in rapid release of inhalable vapors and very rapid
absorbed), with unpleasant odor and short duration of action.
- Distribution: highly lipophilic nitrates (nitroglycerin, isosorbide dinitrate) are
widely distributed into vascular and other peripheral tissues, less lipophilic
nitrates (isosorbide mononitrate) are not widely distributed
- Metabolism: liver (isosorbide dinitrate is metabolized to an active metabolite
named isosorbid-mononitrate, used also in therapy).
- Elimination: kidney.
Indications:
- angina pectoris:
- acute angina: Nitroglycerin (sublingual);
- maintenance treatment: Isosorbide mononitrate (ISMN), Isosorbide
dinitrate (ISDN), Nitroglycerin, Penta erythritol tetranitrate (PETN);
- nitroglycerin i.v. for hypertensive crisis (controls blood pressure in
perioperative hypertension, in patients with severe hypertension or crises,
patients with coronary complications such as acute myocardial infarction or
pulmonary edema associated with acute myocardial infarction);
- nitroglycerin i.v. for acute decompensated heart failure;
- Amyl nitrate is a volatile, flammable liquid administered by inhalation as a
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diagnostic aid in tests of reserve cardiac function and diagnosis of certain heart
murmurs and for the treatment of cyanide poisoning (because produce
methemoglobin which binds cyanide). It is used as drug of abuse to produce
euphoria or sexual stimulation.
Adverse effects:
- orthostatic hypotension (may cause dizziness, weakness and other signs of
cerebral ischemia), followed by tachycardia due to excessive stimulation of
baro-reflex;
- sometime nitrate syncope;
- cutaneous vasodilation with facial flushing
- pulsatile bitemporal headache (at the beginning of the treatment);
- tachyphylaxis;
- methemoglobinemia, anemia;
- increase intraocular pressure (acute attack of glaucoma).
Contraindications:
- arterial hypotension, hypovolemia;
- obstructive cardiomyopathy;
- closed angle glaucoma;
- increased intracranial pressure (head trauma, cerebral hemorrhage);
- pregnancy.
Association with inhibitors of phosphodiesterase 5 (Sildefanil, Tadalafil,
Vardenafil) ⇒ increase NO (severe hypotension, sometimes fatal).

Nitroprusside (Sodium nitroprusside)

Pharmacokinetics:
- sodium nitroprusside molecule is unstable (decomposes under strongly
alkaline conditions or when exposed to light). The drug must be given by
continuous intravenous infusion to be effective. Onset of action is immediate
and when the infusion of the drug is stopped, the effect disappears within few
minutes (because the half life is very short) and blood pressure returns to initial
level.
- rapidly metabolized by liver to thiocyanate, which is eliminated almost
entirely in the urine.
Indications:
- hypertensive crisis – in iv administration;
- to induce controlled hypotension during certain surgical procedures;
135
- acute congestive heart failure.
Adverse effects:
- excessive hypotension (determines headache, retrosternal discomfort due to
coronary blood stealing phenomenon, palpitation);
- cyanogenic effects;
- methemoglobinemia;
- thiocyanate accumulation;
- others: anxiety, nausea.

Other structures: Nicorandil, Molsidomine

Mechanisms of action:
Nicorandil: NO release + potassium channel-opening action (additional
mechanism for causing vasodilation).
Molsidomine: direct activation of guanylyl cyclase + NO release.
Pharmacodynamic effects: vasodilation.
Indications: angina pectoris (maintenance treatment).
Adverse effects: headache.
Advantage: don’t determine tachyphylaxis because have multiple mechanisms
of action.

I.2.1.2. Selective (arteriolar) vasodilators: Hydralazine, Minoxidil, Diazoxide

Hydralazine
Mechanism of action:
- powerful direct vasodilatory effect on arteriolar smooth muscle;
- may stimulate the release of norepinephrine from sympathetic nerve terminals;
- direct action on myocardial muscle..
Pharmacodynamic effects:
- direct vasodilation  reduces blood pressure, reduces peripheral resistance
and it is associated with reflexes stimulation of the sympathetic nervous system
 results in increased heart rate and contractility, increased cardiac output,
increased plasma renin activity, and fluid and sodium retention;
- augment myocardial contractility directly: inotrop, cronotrop, dromotrop
positive effects.
Pharmacokinetics:
- Absorption: readily after oral.
- It is concentrated into arteriolar smooth muscle.
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- Metabolism: liver (by acetylation), has important first pass effect, entero-
hepatic cycle.
- Elimination: kidney.
Indications: moderate or severe hypertension not controlled by first-line drugs
(maintenance treatment).
Adverse effects:
- after first doses: headache, flushing, orthostatic hypotension, tachycardia,
allergic reactions (skin rash, fever);
- long-term administration:
- drug-induced lupus syndrome (autoimmune-like reactions – after at
least 6 months of continuous treatment);
- polyneuropathy (paresthesia) due to the ability of hydralazine to
combine with pyridoxine;
- hematologic effects: hemolytic anemia, leukopenia,
agranulocytosis, thrombocytopenia;
- other Adverse effects: fluid retention and edema, headache,
dizziness, tachycardia may precipitate angina pectoris, nasal
congestion, lacrimation, conjunctivitis, diarrhea.
Contraindications:
- renal failure, pregnancy, breastfeeding, seizures, polyneuropathy, peptic ulcer,
anemia
- careful administration: coronary artery disease, tachycardia.

Minoxidil
Mechanism of action:
- direct vasodilating effect on arterial smooth muscle by opening K+- channels.
Pharmacodynamic effects:
- direct vasodilation  reduces peripheral resistance and blood pressure and it
is associated with reflexes stimulation of the sympathetic nervous system
(results in increased heart rate and contractility, increased cardiac output,
increased plasma renin activity, and fluid and sodium retention);
- stimulate regrowth of hair in patients with androgenetic alopecia (by dilating
blood vessels).
Indications:
- systemic administration: severe hypertension (maintenance treatment) – not
controlled by first-line drugs;
137
- local administration: to combat hair loss (androgenic alopecia).
Adverse effects:
- fluid and sodium retention, edema;
- cardiovascular effects: tachycardia, angina pectoris, myocardial infarction in
patients with very severe hypertension, pericardial effusion;
- hypertrichosis (elongation, thickening, and increased pigmentation of fine
body hair on the face, back, arms and legs) - within 3-6 weeks after initiating
minoxidil therapy.

Diazoxide
Mechanism of action:
- direct vasodilating effect on arterial smooth muscle by opening K+- channels;
- direct relaxation effect on uterine muscle;
- inhibits pancreatic insulin secretion.
Pharmacodynamic effects:
- direct vasodilation – reduces peripheral resistance and blood pressure and it is
associated with reflexes stimulation of the sympathetic nervous system (results
in increased heart rate and contractility, increased cardiac output, increased
plasma renin activity, and fluid and sodium retention);
- inhibition of contractions in both the term uterus during labor and the
nongravid uterus;
- increase blood glucose concentration and it has low capacity to inhibit
peripheral glucose utilization by muscle and to stimulate hepatic
gluconeogenesis.
Indications:
- hypertensive crises for emergency (not effective in pheochromocytoma
crises).
Adverse effects:
- fluid and sodium retention, edema;
- hyperglycemia (transient after the first dose, high long-term administration);
- hirsutism (= hypertrichosis = overabundance of hair in women and children,
especially on the forehead, the back and limbs) after prolonged oral therapy.

I.2.2. Vasodilatation drugs acting by specific mode of action

Inhibitors of 5-phosphodiesterase: Sildenafil, Tadalafil, Vardenafil
Mechanism of action:
138
- selective inhibition of phosphodiesterase type 5 (PDE5 from the corpora
cavernosa)  determines increase of cGMP
- additionally inhibits phosphodiesterase type 6 (PDE6).
Pharmacodynamic effects:
- inhibition of PDE5 determines:
- relaxation of the nonvascular smooth muscle of the corpora
cavernosa (which result in the achieve and maintain penile erection);
- low intensity systemic vasodilatory effects (transient modest
reductions in systolic and diastolic blood pressure is usually clinically
unimportant when the drug is taken alone);
- reduction in lower esophageal sphincter tone;
- inhibition of PDE6 in the retina determines consecutive visual disturbances
(e.g., blue/green vision, changes in light sensitivity).
Indications:
- erectile dysfunction;
- pulmonary arterial hypertension;
- Raynaud syndrome;
- non-medical use: aphrodisiac.
Adverse effects:
- moderate Adverse effects:
- cardiovascular effects: headache, flushing, palpitations
- photophobia, sudden vision loss or visual disturbances (blue/green
vision, changes in light sensitivity);
- sudden decrease or loss of hearing;
- adverse GI effects (e.g., reflux-induced dyspepsia and heartburn,
nausea, vomiting);
- myalgia.
- severe Adverse effects:
- prolonged erection (> 4 h) and priapism (painful erection > 6 h) are
medical emergencies;
- orthostatic hypotension, myocardial ischemia and infarction,
ventricular arrhythmia, sudden cardiac death;
- transient ischemic attack, cerebrovascular hemorrhage.
Contraindications:
- cardiovascular diseases: myocardial infarction or active coronary ischemia,
with congestive heart failure, with borderline low blood pressure or low blood
139
volume;
- hepatic or renal severe impairement;
- degenerative diseases of the retina (retinitis pigmentosa);
- anatomical deformation of the penis;
- association with HIV protease inhibitors;
- association with nitrates (because induce severe hypotension).

Prostaglandin analogues
• PGE1 analogs: Alprostadil, Prostin
• PGI 2 analogs: Eproprostenol, Iloprost.
Indications:
• Alprostadil: patent ductus arteriosus, peripheral arterial disease (leg), Raynaud
syndrome;
• Prostin: the erectile dysfunction;
• Epoprostenol: peripheral arterial disease;
• Iloprost: peripheral arterial disease, Raynaud syndrome.

2. Drugs that stimulate constriction of smooth muscle

II.1. Substances stimulating visceral smooth muscle
II.2. Substances stimulating vascular smooth muscle (vasoconstrictors)
Oxytocin
Oxytocin is a nonapeptide hormone secreted by the neurons of the supraoptic
and paraventricular nuclei of the hypothalamus and stored in the posterior
pituitary gland.
Mechanism of action:
- agonist on Oxytocin receptors  increase influx and concentration of
intracellular Ca2+ in the myometrium and the myo-epithelial cells.
Pharmacodynamic effects:
- contraction of uterine smooth muscle  induction and augmentation of labor;
- contraction of myoepithelium that surrounds alveolar channels in mammary
gland  milk ejection;
- weak antidiuretic effect in high doses.
Oxytocin effects on uterus is influenced by other hormones:
- estrogens stimulate Oxytocin activity;
- progesteron inhibits Oxytocin activity .

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During the second half of pregnancy, uterine smooth muscle shows an increase
in the expression of Oxytocin receptors and becomes increasingly sensitive to
the stimulant action of endogenous Oxytocin.
Oxytocin activity is:
- absent  in non-pregnant women;
- maximum  near-term uterus.
Pharmacokinetics:
- Administration: iv or im to initiate or enhance rhythmic uterine contractions
for induction and augmentation of labor and for control postpartum
hemorrhage, spray in both nostrils 2–3 min before feeding to promote milk
letdown in lactating women. It is rapidly inactivated by digestive enzymes.
- Distribution: no plasma protein binding; t1/2 = 5 min.
- Metabolism: rapidly destroyed in the liver.
- Elimination: in urine.
Indications:
- antepartum uses:
- induction of labor in term or near-term pregnancies (when it does
not occur spontaneously),
- augmentation of labor during the first and second stages of labor;
- sometimes used during second-trimester abortions;
- postpartum uses
- control postpartum hemorrhage (stimulate immediate contractions
of the uterus and control uterine bleeding);
- stimulation of milk ejection in lactating women (nasal spray, 3-5
min before nursing);
- prevention of mastitis.
Uterine contractions induced by Oxytocin may be antagonized by:
- beta2-adrenergic agonists,
- inhalatory volatile liquid general anesthetics,
- magnesium sulphate i.v.
Adverse effects:
- uterine rupture, prolonged uterine contractions;
- maternal or fetal death;
- excessive fluid retention (water intoxication) and hyponatremia;
- Oxytocin-induced thrombocytopenia, afibrinogenemia, and
hypoprothrombinemia.
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Contraindications32:
- cephalopelvic disproportion;
- abnormal fetal presentation;
- predispositions for uterine rupture (uterine or cervical scarring from previous
cesarean section or major cervical or uterine surgery);
- placenta previa;
- premature labour;
- fetal distress;
- severe hypertension (preeclampsia or eclampsia);
- impaired hepatic or renal function.

Ergometrine (Ergonovine) and Methylergometrine (Methylergonovine)

Ergometrine (Ergonovine) is a amino-alcohol ergot alkaloid.
Methylergometrine (Methylergonovine) is a semisynthetic derivative of
Ergometrine.
Mechanism of action:
- directly strong stimulation of uterine smooth muscle;
- agonist of α-adrenergic receptors;
- agonist of dopamine receptors;
- partial antagonist of 5-HT2 receptors.
Pharmacodynamic effects:
- intense uterine contractions (increases the basal tone, frequency and amplitude
of contractions), followed by periods of relaxation;
- low vasopressor effects;
- prokinetic effects;
- hallucinatory effects.
Indications:
- subinvolution or atony of the uterus after expulsion of the child
- postpartum hemorrhage (prevention and treatment of postpartum or
postabortion hemorrhage caused by uterine atony or involution)  drug of
choice because produce more sustained contractions and higher uterine tonus
than does Oxytocin.
If the placenta was not expelled, it is necessary to give Oxytocin. Do not give
ergometrine because it causes tonic uterine contractions that could delay

32
Are the indications for cesarean delivery.

142
delivery of the placenta.
- Test the Ergometrine (=Ergonovine): performed during coronary angiography,
which allows to lift the coronary spasm in variant Prinzmetal angina.
Adverse effects (of ergot derivatives):
- nausea and vomiting, abdominal pain, diarrhea;
- vasoconstriction (mainly of capacitance vessels: coronary insufficiency with
precipitation or aggravation of angina pectoris and possibly myocardial
infarction, cold, numb, painful extremities with or without paresthesia,
weakness in the legs, muscle pain or stiffness in the extremities, neck or
shoulders, numbness and tingling of fingers and toes)
- hypertension may occur less frequently with methylergonovine than
with ergonovine;
- endothelial toxicity: vascular stasis, thrombosis, gangrene of extremities;
- hepatotoxicity, nephrotoxicity;
- acute ergot toxicity (ergotism) in high doses: arterial spasm (may affect any
blood vessel) and ischemia of the extremities, hallucinations.
Contraindications:
- pregnancy, breastfeeding;
- severe hypertension, peripheral vascular disease, coronary artery disease, heart
failure;
- impaired hepatic or renal function,
- mental diseases;
- collagen diseases;
- sepsis.

II.2. Substances stimulating vascular smooth muscle (vasoconstrictors)

Ergotamine and Dihydroergotamine
Ergotamine is a naturally occurring peptide ergot alkaloid. Dihydroergotamine
is a semisynthetic peptide ergot alkaloid that is structurally and
pharmacologically related to ergotamine.
Mechanism of action:
- partial agonist of α-adrenergic receptors from vessels (and partial agonist of α-
adrenergic receptors pre- and post-synaptic);
- Ergotamine: partial antagonist of 5-HT2 receptors, Dihydroergotamine:
agonist of 5-HT1D receptors;
- stimulation of uterine smooth muscle (oxytocic activity).
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Pharmacodynamic effects:
- vasoconstrictor effects (may affect any blood vessel): vasoconstriction of
peripheral and cranial arteries, increase in venous tone.
Indications:
- to prevent or abort vascular headaches (including migraine and cluster
headaches).
Ergotamine is associated with Caffeine for the enhancement of Ergotamine
absorption and for the augmentation of vasoconstrictor effect in cerebral
vessels.
Dihydroergotamine effectiveness is lower than that of Ergotamine.
Adverse effects:
- nausea and vomiting, abdominal pain, diarrhea;
- due to vasoconstriction: intermittent claudication, paresthesia, cramps and
pain phenomena, high blood pressure;
- endothelial toxicity: vascular stasis, thrombosis, gangrene of extremities;
- hepatotoxicity, nephrotoxicity;
- acute ergot toxicity (ergotism) in high doses;
- mental depression, fatigue and increased frequency of headache (after
prolonged use).
Contraindications (similar to Ergometrine):
- pregnancy, breastfeeding;
- severe hypertension, peripheral vascular disease, coronary artery disease;
- impaired hepatic or renal function,
- mental diseases;
- collagen diseases;
- sepsis.

Methysergid
Methysergid is an amine ergot alkaloid.
Mechanism of action:
- strong partial antagonist of 5-HT2 receptors;
- weak partial agonist of α1 and α2-adrenergic receptors;
- weak partial antagonist of dopamine receptors;
- weak stimulation of uterine smooth muscle.
Indications:
- migraines resistant to other treatments (prevent or abort vascular headaches
144
including migraine and cluster headaches)
- alternative for carcinoid tumors that secrete serotonin.
Adverse effects:
- chronic administration: retroperitoneal fibrosis, pleural fibrosis, endocardial
fibrosis; it can be reduced this risk if the treatments do not exceed six months
and is repeated after intervals of 3 to 4 weeks;
- occasional CNS stimulation and hallucinations (it was used as a substitute for
LSD);
- nausea and vomiting, abdominal pain, diarrhea;
- high blood pressure;
- endothelial toxicity: vascular stasis, thrombosis, gangrene of extremities;
- hepatotoxicity, nephrotoxicity;
- acute ergot toxicity (ergotism) in high doses.
Contraindications: similar to Ergotamine.

Vasopressin (antidiuretic hormone), Terlipressin, Desmopressin

Vasopressin (antidiuretic hormone) is a polypeptide hormone secreted by the
neurons of the supraoptic and paraventricular nuclei of the hypothalamus and
stored in the posterior pituitary gland.
Terlipressin is a synthetic vasopressin analog with similar efficacy to
vasopressin, but with fewer adverse effects.
Desmopressin is a synthetic polypeptide structurally related to vasopressin.
Vasopressin receptors: V1 (mediate vasoconstriction), V2 (mediate antidiuretic
effect) and V2-like (=V3, stimulate release of coagulation factor VIII and von
Willebrand factor)
Mechanism of action:
- Vasopressin and Terlipressin: agonist of vasopressin receptors V1, V2 and
V2-like.
- Desmopressin: agonist of vasopressin receptors V2 and V2-like.
Pharmacodynamic effects:
- Vasopressin and Terlipressin
- intense vasoconstriction (particularly of capillaries and of small
arterioles, mediated by V1 receptors); Terlipressin has preferential
splanchnic vasoconstrictor; the vasopressor effects are less
pronounced than those of vasopressin.
- antidiuretic effect (maintain serum osmolality within a normal
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 range, mediated by V2 receptors);
- Desmopressin
- potent antidiuretic effect;
- stimulation of release of coagulation factor VIII (antihemophilic
factor) and von Willebrand factor (mediated by V2-like receptors).
Pharmacokinetics:
- Absorption:
- Vasopressin is administered intranasal (very good absorption) or
parenteral.
- Desmopressin (used as acetate salt) is administered intranasally,
orally, by subcutaneous injection, direct IV injection, or slow IV
infusion.
- Distribution: in extracellular fluid, but no plasma protein binding.
- Metabolism: rapidly destroyed in the liver and kidneys.
- Elimination: small quantity  unchanged in urine.
- Vasopressin t1/2 = 10-20 min, Desmopressin t1/2: 8 - 24 h.
Indications:
- Vasopressin and Terlipressin
- diabetes insipidus (it is drug of choice) caused by a deficiency of
endogenous posterior pituitary antidiuretic hormone;
- gastro-intestinal hemorrhage: esophageal variceal hemorrhage,
colonic diverticulosis hemorrhage, intestinal perforation;
- cardiac arrest (may replace the first or second dose of epinephrine in
the treatment of ventricular fibrillation arrest, pulseless ventricular
tachycardia, asystole, or pulseless electrical activity in advanced
cardiovascular life support);
- Desmopressin
- diabetes insipidus caused by a deficiency of endogenous posterior
pituitary antidiuretic hormone (drug of choice);
- primary nocturnal enurezis;
- to evaluate the ability of the kidneys to concentrate urine;
- hemophilia A and von Willebrand disease.
Adverse effects:
- Vasopressin and Terlipressin
- skin pallor;
- increased blood pressure (can lead to hypertension, myocardial
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 ischemia or infarction, mesenteric infarction), bradycardia, minor
arrhythmias;
- nausea, vomiting, abdominal cramps;
- severe hyponatremia (“water intoxication” = overhydration  in
infants and children): headache, confusion, anuria, and weight gain;
- type I alergic reactions (urticaria, angioedema, bronchoconstriction,
fever, rash, wheezing, dyspnea, circulatory collapse, cardiac arrest,
and anaphylaxis).
- Desmopressin
- severe hyponatremia;
- unlike Vasopressin, usual doses of Desmopressin do not cause skin
pallor, vasoconstriction or abdominal cramps.
Contraindications:
- Vasopressin and Terlipressin
- hypertensive disease,
- coronary arteries diseases;
- pregnancy;
- renal failure.
- Desmopressin
- pregnancy;
- renal failure.

3. Drugs used to treat asthma and chronic pulmonary

obstructive disease
1. Substances with stimulatory action on the sympathetic nervous system:
1.1. non-selective: α,β-adrenergic receptor agonists
- direct action (adrenergic receptor agonists): Adrenaline (Epinephrine).
- indirect action (release of norepinephrine cell deposits): Ephedrine.
1.2. semi-selective β1, β2-adrenergic receptor agonists: Isoprenaline
(Isoproterenol), Orciprenaline
1.3. selective β2-adrenergic receptor agonists:
- with medium duration of action and rapid effect: Salbutamol (= Albuterol33),

33
Salbutamol, which is the World Health Organization recommended name for the medication. In the US this
same drug is called Albuterol. In some books it is written that Albuterol has short action, in other books it is
written that Salbuutamol has medium duration of action. I consider that Salbutamol (= Albuterol) has medium
duration of action, to avoid endless confusion.

147
Terbutaline, Fenoterol, Clenbuterol, Pirbuterol, Procaterol;
- with long duration of action and late effect: Salmeterol, Formoterol;
- with super-long duration of action: Bambuterol.
2. Methylxanthines: Theophylline
- used as Aminophylline (a combination of Theophylline and ethylenediamine).
3. Antimuscarinic drugs:
- The natural alkaloids: Atropine;
- synthetic substances:
• with short duration of action: Ipratropium, Oxitropium
• with long duration of action: Tiotropium.
4. Leukotriene receptor antagonists: Montelukast, Zafirlukast, Pranlukast.
5. Inhibitor of 5-lipoxygenase: Zileuton.
6. Inhibitors of histamine release: Cromolyn (cromoglicate), Nedocromil.
7. Glucocorticoids: Betamethasone, Budesonide, Fluticasone, Flunisolide,
Mometazona, Triamcinolone, Prednisone, Prednisolone, Methylprednisolone.
8. Calcium channel blockers: Nifedipine Verapamil.
9. Anti-histamine H1 receptor: Ketotifen.
10. Humanized monoclonal antibody: Omalizumab.

148
 Lecture 8
Autacoids

Learning Objectives:
 List some of the therapeutic uses and adverse effects of H1 agonists and antagonists;
 List the principal routes of drug administration and their advantages and
disadvantages;
 List examples of drugs concentrated in different tissues or liquids of the body;
 Name the phases in hepatic metabolism;
 3. Describe the major pharmacological actions of prostaglandins E and F

Autacoids (Greek, "self-remedy") or local hormones are biologically active

substances (fig) that are are often released locally and have complex
physiologic and pathologic effects through multiple receptor subtypes.

Fig. Autacoids classification

149
 1.Pharmacologic influence of Histamine

Histamine Mechanism of action: on histamine receptor agonist (H), located

transmembrane or on the surface of the membrane of target cells.
Histamine receptors:
- histamine 1 receptor (H1) → in smooth muscle, endothelium and to the brain,
they transmit the biological signal post-receptor stimulating the formation of
IP3 and DAG;
- histamine 2 receptor (H2) → in the gastric mucosa, heart muscle, and brain to
mast cells, they transmit the biological signal post-receptor stimulating the
formation of cAMP;
- histamine 3 receptor (H3) → in the brain, plexus mesenteric and other
neurons, they decrease the release of histamine from histaminergic neurons,
- histamine 3 receptor (H3) → in the brain.

Classification
1. HISTAMINE AGONISTS
 Histamine receptor agonists
- H1 receptors agonists: Histaprodifen
- H2 receptors agonists: Amthamine
- H3 receptors agonists: R-Methylhistamine, imetit, immepip
- H4 receptors agonists: Clobenpropit, imetit, clozapine
 Factors that stimulate histamine release:
- physical factors: trauma, burns;
- chemical factors (including drugs that release histamine):
- opiates;
- Quinine;
- Hydralazine;
- natural and semi-synthetic penicillins, cephalosporins,
aminoglycosides;
- pachycurares: D-tubocurarine, Atracurium, Pipecuronium,
Pancuronium, Rocuronium, Vecuronium, Gallamine;
- barbiturates;
- bradykinin;
- snake venom, insect bites, allergens from pollens.

150
2. HISTAMINE ANTAGONISTS
 Physiologic antagonists: Adrenaline, Noradrenaline (NA)
 Histamine release inhibitors:
- Cromolyn (Disodium cromoglycate)
- Nedocromil
- others: Amlexanox; Lodoxamide; Pemirolast; Reprinast;
Methylxantine; Flavonoids.
 Histamine receptor antagonists:
- H1 receptor antagonists:
- 1st generation (cross the blood-brain barrier):
- Alkylamines: Chlorpheniramine, Brompheniramine;
- Phenothiazines: Promethazine, Prochlorperazine,
Thiethylperazine, Alimemazine;
- Tricyclic dibenzoxepins: Doxepin
- Ethanolamines: Diphenhydramine, Carbinoxamine,
Doxylamine, Dimenhydrinate;
- Imidazolines: Antazoline;
- Ethylaminediamines: Pyrilamine, Tripelenamine;
- Ethylendiamines: Chloropiramine;
- Piperazines: Hydroxyzine, Cyclizine, Meclizine;
- Miscellaneous: Cyproheptadine (also a 5-HT
antagonist), Phenindamine, Clemastine, Clorfenoxamine,
Dimetinden, Bamipine, Ketotifen;
- 2nd generation (do not cross the blood-brain barrier):
- Piperidines: Loratadine, Desloratadine, Fexofenadine,
- withdrawn from market: Astemizol,
Terfenadine;
- Piperazines: Cetirizine, Levocetirizine, Mequitazine;
- Miscellaneous: Ebastine, Levocabastine, Azelastine,
Mizolastine, Acrivastine.
- H2 receptor antagonists: Cimetidine, Ranitidine, Nizatidine,
Famotidine.
- H3 receptor antagonists: Thioperamide, Clobenpropit
- H4 receptor antagonists: Thioperamide.

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1. HISTAMINE AGONISTS
Cromolyn (Disodium cromoglycate)
Mechanism of action:
- inhibition of the release of histamine and leukotrienes from sensitized mast
cells;
- block the transmembrane calcium influx caused by the interaction of
immunoglobulin E to the antigen on the surface of mast cells;
- inhibition of phosphodiesterase;
- alteration of channel function of chlorine channels in cell membranes;
- interference effects of platelet factor.
Indications (prophylaxis only):
- bronchial asthma;
- allergic rhinitis;
- allergic conjunctivitis;
- food allergies.
Adverse effects:
- dermatitis, urticaria (rarely);
- myositis;
- pulmonary infiltrates with eosinophilia;
- arthralgia;
- dysuria, nausea, bad taste;
- transient bronchospasm, coughing, wheezing (rarely).
Nedocromil: effects similar to Cromolyn (Disodium cromoglycate), in
addition, it inhibits the cough.

2. HISTAMINE ANTAGONISTS
H1 receptor antagonists
Pharmacodynamic effects:
- anti-allergic effects;
- sedative effects  anti-H1 1st generation
- phenothiazines: Promethazine, Prochlorperazine, Thiethylperazine,
Alimemazine,
- piperazine derivatives: Hydroxyzine, Cyclizine, Meclizine,
- ethylenediamines: Chloropiramine,
- ethanolamines: Diphenhydramine, Carbinoxamine, Doxylamine,
Dimenhydrinate;
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- antiemetic effects:
- phenothiazines: Promethazine, Prochlorperazine, Tiethylperazine,
Alimemazine,
- piperazine derivatives: Hydroxyzine, Cyclizine, Meclizine,
- ethanolamines: Diphenhydramine, Carbinoxamine, Doxylamine,
Dimenhydrinate;
- anticholinergic effects:
- phenothiazines: Promethazine, Prochlorperazine, Thiethylperazine,
Alimemazine,
- ethylenediamines: Chloropiramine,
- ethanolamines: Diphenhydramine, Carbinoxamine, Doxylamine,
Dimenhydrinate;
- alkylamines: Chlorpheniramine, Brompheniramine;
- antiparkinsonian effects
- ethanolamines: Diphenhydramine, Carbinoxamine, Doxylamine,
Dimenhydrinate;
- ethylenediamines: Chloropiramine,
- α1 adrenergic receptor blockade (especially phenothiazines, alkylamines);
- phenothiazines: Promethazine, Prochlorperazine, Tiethylperazine,
Alimemazine,
- alkylamines: Chlorpheniramine, Brompheniramine;
- antiserotoninergic effects (Cyproheptadine);
- the local anesthetic (piperidine derivatives, ethanolamines, ethylenediamines);
- anti-inflammatory effect  anti-H1 2nd generation;
- Hydroxyzine: inhibits release of substance P, serotonin, prostaglandins.
Indications:
- prevention and treatment of allergic reactions (bronchial asthma, allergic
rhinitis, allergic conjunctivitis, allergic dermatitis);
- as antiemetics and for the treatment of motion sickness (phenothiazines,
ethanolamines, piperazines);
- nausea and vomiting (Doxylamine);
- Meniere’s disease (Prochlorperazine);
- anxiolytics, sedative-hypnotics (ethanolamines, ethylenediamine,
phenothiazines, piperazines);
- as antipsychotics (Chlorpromazine);
- stimulation of appetite (Cyproheptadine);
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- Parkinson’s disease (ethanolamines);
- interstitial cystitis syndrome (Hydroxyzine).
Adverse effects:
- sedative effects: anti-histaminics anti-H1; in children determine paradoxical
excitement, nervousness, euphoria;
- anticholinergic effects;
- stimulation of appetite and weight gain (Cyproheptadine);
- lethal tachyarrhythmias (torsade de pointes) when aadminsiterred with
grapefruit juice: Terfenadine, Astemizol.

H2 receptor antagonists
Mechanism of action: - antagonism on H2 receptors;
- Nizatidine: also it is acetylcholinesterase inhibitor.
Pharmacodynamic effects: inhibition of basal gastric secretion of HCl.
Pharmacokinetics:
o Cimetidine: is inhibitor of drug metabolism.
Indications:
- peptic ulcer;
- Zollinger-Ellison syndrome;
- gastroesophageal reflux;
- non-ulcer dyspepsia;
- prevention of gastritis induced by stress;
- hypersecretory conditions (systemic mastocytosis, leukemia, basophilia).
Adverse effects:
- Cimetidine:
- in the CNS: confusional states, hallucinations, delusions, agitation;
- endocrine effects: gynecomastia, galactorrhea, decreased
spermatogenesis, libido;
- hematological effects: granulocytopenia, aplastic anemia;
- effects on the liver: the elevation of transaminases, cholestatic
jaundice, acute hepatitis;
- Ranitidine: elevation of transaminases, cholestatic jaundice, acute hepatitis;
- Famotidine: headache, transient elevation of transaminases;
- Nizatidine: headache; transient elevation of transaminases, prokinetic effect,
reduction in heart rate, reducing the force of contraction of the heart.
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 2.Pharmacologic influence of Serotonin (5-
hydroxytryptamine)

These biologically active amines.

Classification:
1. SEROTONIN AGONISTS:
 Serotonin receptor agonists
- 5HT1A agonists: Buspirone, Ipsapirone, Gepirone, Tandospirone;
- 5-HT1D and 5-HT1B agonists: Sumatriptan, Naratriptan, Rizatriptan, Zolmitriptan;
- 5HT4 and 5HT2A agonists: Cisaprid, Norcisaprid,
- partial 5HT4 agonists: Tegaserod;
- 5HT1 and 5HT2 partial agonists: ergot alcaloids.
 Release stimulators:Dexphenfluramine, Phenfluramine.
2. SEROTONIN ANTAGONISTS:
 Serotonin receptor antagonists
- 5-HT2A/5-HT2C antagonists: Trazodone, Nefazodone, Mirtazapine.
- 5-HT3 antagonists:
- antiemetic effect: Ondansetron, Granisetron, Dolasetron, Tropisetron;
- prokinetic effect: Alosetron, Cilansetron.
- 5-HT2 antagonists:
- antiplatelet effect: Ritanserine;
- indicated in migraine headache profilaxy: Methysergid;
- indicated in schizophrenia:
- phenothiazines with piperazine side chain:
Fluphenazine,Trifluoperazine, Perphenazine;
- phenothiazines with aliphatic side chain: Chlorpromazine,
Levomepromazine;
- phenothiazines with piperidine side chain: Thioridazine;
- butyrophenones: Haloperidol, Droperidol;
- atypical antipsychotics: Risperidone, Clozapine, Olanzapine,
Quetiapine, Sertindole, Paliperidone, Iloperidone, Asenapine, and
Lurasidone.
- 5-HT1C and 5HT2 antagonists: Ketanserin.
- 5-HT antagonist and H1 antagonist: Cyproheptadine.
 Release inhibitors
- Selective inhibitors of serotonin reuptake: Fluoxetine, Sertraline, Paroxetine,
Fluvoxamine, Citalopram, Escitalopram
- Inhibitors of serotonin reuptake and norepinephrine: Venlafaxine, Bupropion.

1. SEROTONIN AGONISTS
1.1. 5HT1A agonists: Buspirone, Ipsapirone, Gepirone, Tandospirone

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Pharmacodynamic effects: anxiolytic effects without sedation.
Pharmacokinetics:
- have important hepatic first-pass effect;
- form active metabolites;
- have short time of action.
Indications: as anxiolytics (they are not effective for panic attacks).
Adverse effects:
- tachycardias;
- nervousness;
- paresthesias;
- confusion;
- gastrointestinal disorders;
- miosis (dose dependent);
- increase in blood pressure (when are associated with MAO inhibitors);
- they do not cause addiction.
Contraindications: arrhythmias.
1.2. 5-HT1D and 5-HT1B agonists: Sumatriptan, Naratriptan, Rizatriptan,
Zolmitriptan
Indications: treatment and prophylaxis of migraine and other vascular
headaches.
Adverse effects:
- altered sensitivity (paresthesia);
- angina pain;
- tachycardias.
Contraindications: angina, severe atheromatous coronary lesions.

1.3. 5HT4 and 5HT2A agonists: Cisaprid, Norcisaprid

Mechanism of action:
- agonists of 5-HT4 receptors;
- release of acetylcholine in the enteric nervous system.
Pharmacodynamic effects:
- stimulate gastrointestinal function;
- relax the pylorus;
- determine the increase in tone of the cardia.
Indications: as prokinetics (hypo-gastrointestinal motility, gastro-esophageal
reflux, gastroparesis in patients with diabetes mellitus).
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Adverse effects:
- diarrhea, abdominal cramps;
- headache;
- severe arrhythmias.
1.4. Partial 5HT4 agonists: Tegaserod
Indications: irritable bowel syndrome.
1.5. Stimulators of the release of serotonin: Dexfenfluramine, Fenfluramine
Pharmacodynamic effects: anorexia.
Indications: treatment of obesity.
Adverse effects:
- sleeplessness, headache;
- retroperitoneal and endocardial fibroplasia;
- pulmonary hypertension, sometimes fatal.

2. SEROTONIN ANTAGONISTS
2.1. 5-HT3 antagonists with antiemetic effect: Ondansetron, Granisetron,
Dolasetron, Tropisetron
Pharmacodynamic effects:
- antiemetic effects;
- antidepressant effects.
Indications: nausea and vomiting (including nausea and vomiting determined
by cytostatics).
Adverse effects:
- headache;
- constipation / diarrhea, abdominal cramps;
- severe arrhythmias.
Contraindications: pregnancy.
It is necessary to reduce the dose in patients with impaired liver and kidney.
2.2. 5-HT3 antagonists with prokinetic effect: Alosetron, Cilansetron
Indications: irritable bowel syndrome.
2.3. 5-HT2 antagonists with antiplatelet effect: Ritanserin
Pharmacodynamic effects:
- alter bleeding time;
- reduce the formation of thromboxane;
- affect platelet function.
Indications: as platelet aggregation inhibitor.
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2.4. 5-HT1C and 5HT2 antagonists with antihypertensive effects:
Ketanserin
Mechanism of action:
- antagonist of 5-HT1C and 5-HT2;
- α1 receptor antagonist.
Pharmacodynamic effects:
- antiplatelet effect;
- vasodilation.
Indications: hypertension.
2.5. 5-HT antagonist and H1 antagonist: Cyproheptadine
Mechanism of action:
- antagonist of 5-HT2 receptors;
- H1-receptor antagonist.
Pharmacodynamic effects:
- antiallergic effect;
- sedative effect;
- increase in weight because of stimulation of appetite.
Indications:
- allergy;
- stimulation of appetite;
- carcinoid tumors secreting serotonin;
- dumping syndrome, post-gastrectomy.
Adverse effects:
- drowsiness;
- confusion;
- headache.
Contraindications:
- glaucoma;
- urinary retention;
- drivers and people who perform precision work.

3.Pharmacologic influence of Angiotensin and renin-

angiotensin-aldosteron system
Classification
1. Stimulants of angiotensin and renin-angiotensin-aldosteron system

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 - Stimulation of aldosteron: synthetic angiotensin, hormones
(glucocorticoids, estrogens, thyroid hormones);
- Stimulation of renine: Minoxidil, Hydralazine, Diazoxid, thiazide or
loop diuretics.
2. Inhibitors of angiotensin and renin-angiotensin-aldosteron system
- angiotensin converting enzyme inhibitors (ACEI):
- sulphydrile: Captopril, Zofenopril;
- dicarboxilate: Lisinopril, Enalapril, Ramipril, Quinapril,
Perindopril, Benazepril;
- phosphonate: Fosinopril;
- miscellanous: Moexipril, Spirapril, Trandolapril, Cilazapril,
Alacepril, Altiopril, Fentiapril, Pivalopril, Delapril, Imidapril;
- angiotensin receptors blockers (competitive antagonists on angiotensin
receptorsAT-R):
- nonselective: Saralazin;
- selective on AT1 receptors from vessels: Valsartan, Losartan,
Candesartan, Telmisartan, Irbesartan, Eprosartan;
- inhibitors of renine activity: Enalkiren, Remikiren, Aliskiren.
- inhibitors of renine release: Clonidine, Methyldopa, Guanfacine,
Guanabenz, Rilmenidine, Moxonidine, beta-antagonists;

Biological effects induced by the angiotensin receptor (AT receptors):

- AT1 receptor:
- increase in systolic and diastolic blood pressure (they determine the
stimulation of the synthesis and release of aldosterone, dipsogenic effect
and stimulate sodium reabsorption in the proximal tubule, determine
arteriolar vasoconstriction, especially in coronaries, cerebral and renal
vessels and increase the release of norepinephrine from sympathetic
nerve endings);
- cellular hypertrophy and hyperplasia (they determine the increase in
the expression of collagen and fibronectin in cardiac fibroblasts,
involved in the remodeling of the cardiac tissue interstitial),
- increase the expression of receptors for lipoproteins density (low
density lipoproteins - LDL) - oxidized lipoproteins in the coronary
arteries;
- AT2 receptors:
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 - adjusting the blood pressure, modulation of ion channels (Ca2+ / K+);
- suppress the growth of cells and tissues, and modulate neuronal
differentiation,
- initiate apoptosis,
- modulate the behavior;
- AT3 receptors: the least studied;
- AT4 receptors: memory; inhibition of renal tubular reabsorption; cardiac
hypertrophy; angiogenesis.

Synthetic angiotensin
Indications: shock without hypovolemia (as an alternative to norepinephrine).
Advantage: it does not promote tachyarrhythmias, it does not cause
hyperlactataemia.

Angiotensin converting enzyme inhibitors (ACEI)

Classification:
- sulphydrile: Captopril, Zofenopril;
- dicarboxilate: Lisinopril, Enalapril, Ramipril, Quinapril, Perindopril,
Benazepril;
- phosphonate: Fosinopril;
- miscellanous: Moexipril, Spirapril, Trandolapril, Cilazapril, Alacepril,
Altiopril, Fentiapril, Pivalopril, Delapril, Imidapril;
Mechanism of action:
- inhibition of the enzyme angiotensin converting  inhibition of the
conversion of angiotensin I to angiotensin II;
- inhibition of the degradation of bradykinin, substance P and enkephalins.
Pharmacodynamic effects:
- block the production of aldosterone  increase in serum potassium, inhibition
of water and sodium retention;
- reduction of myocardial and vascular remodeling;
- stimulate the release of vasodilator prostaglandins PGE1 and PGI2;
- reduction of afterload;
ACE inhibitors, by removing the vasoconstrictor effect of angiotensin II
on the efferent arteriole of the glomerulus, may decrease glomerular
filtration and shall fix the decrease in pressure within the renal
glomerular and the importance of this effect depends on the degree
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 dependence of glomerular filtration with respect to the presence of
angiotensin II, which explains that in some cases, kidney failure can
occur after institution of therapy with ACEI, this reduction in
glomerular filtration rate by the ACEI was used to protect kidney
function and reduce proteinuria in some patients with diabetes;
- reduce the level of plasma renin;
- reduce the plasma level of collagen;
- reducing the secretion of endothelin I;
- inhibit the degradation of bradykinin  increase bradikinin concentration 
explains cough, angioedema;
- IEC does not influence the force of contraction of the heart;
- the hypotensive effect is not accompanied by reflex tachycardia because:
- induced hypotension is moderate
- the suppression of the presynaptic effect of angiotensin II increases the
release of norepinephrine;
- during chronic treatment, ACE inhibitors are opposed to the process of cardiac
hypertrophy by inhibiting the trophic effects of angiotensin II, this action also
explains the anti-atherosclerotic effects observed experimentally.
Pharmacokinetics:
- The absorption is reduced in the presence of food (Captopril, Lisinopril,
Moexipril).
- Fosinopril, Moexipril, Zofenopril present entero-hepatic circulation.
- They are:
- active drugs: Captopril, Lisinopril;
- prodrugs: the other ACE inhibitors.
- Metabolism is in the liver: inactivation of active drugs, the activation of
prodrugs.
- They easily pass physiological barriers, with the exception of the blood-brain
barrier.
- They are concentrated in the smooth muscle, myocardial cells, milk, bile.
- The elimination is particularly in the kidney (with the exception of Moexipril
and Fosinopril, which are eliminated mainly via the bile).
Indications:
- high blood pressure (the preferred treatment for hypertension in patients with
diabetes mellitus, hypertension in patients with heart failure, high blood
pressure in patients with acute coronary events; hypertension in patients with
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left ventricular hypertrophy, arterial hypertension in the elderly);
- congestive heart failure (the treatment of choice);
- after a myocardial infarction (to prevent left ventricular remodeling);
- prevention of diabetic nephropathy (they are renoprotective in type II
diabetes).
Maximum efficiency of treatment is found after two weeks of treatment.
Adverse effects:
- common to all ACEI group:
- hypotension (it is pronounced after the first dose);
- dry cough, irritating (less for Fosinopril, Moexipril);
- angioedema (less severe for Fosinopril, Moexipril);
- hyperkalemia;
- increase in uric acid concentration;
- hypoglycemia;
- nausea, diarrhea;
- nephrotoxicity (less severe for Fosinopril, Moexipril);
- teratogenicity.
- specific Adverse effects:
- Captopril, Alacepril, Zofenopril: - taste disturbances;
- type I immunological reactions
(rash, fever);
- neutropenia;
- increase transaminases;
- proteinuria;
- pancreatitis.
- Captopril: - effects like Addison's disease (by reducing the action
of 11-beta-hydroxy steroid dehydrogenase).
- Enalapril: - syncope;
- muscle cramps;
- glossitis;
- increase transaminases;
- visual disturbances;
- tinnitus.
Contraindications:
- absolute Contraindications:
- renal artery stenosis (bilateral artery stenosis or renal artery stenosis of
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 unique kidney),
- angioedema in anamnesis;
- pregnancy (because ACEI are teratogenic),
- allergy to ACEI
- relative contraindications
- hypotension (<90 mm Hg; exposed to dizziness and falls in the
elderly);
- serum creatinine > 3 mg/dL,
- hyperkalemia > 5.5 mEq/l;
- hypernatremia < 130 mEq/l;
- association with potassium-sparing diuretics, cardiac glycosides, anti-
inflammatory drugs (NSAIDs).

Angiotensin receptors blockers (competitive antagonists on angiotensin

receptors AT-R)
Classification:
- nonselective (non-selective antagonists of AT1 and AT2 receptors):
Saralazin;
- selective on AT1 receptors from vessels: Valsartan, Losartan,
Candesartan, Telmisartan, Irbesartan, Eprosartan;
Mechanism of action: - competitive antagonists of AT1 ± AT2;
- Losartan: uricosuric effect.
Pharmacodynamic effects: similar to ACEI, except inhibition of the catabolism
of bradykinin  explains that they don’t induce cough or angioedema.
Pharmacokinetics:
- Their oral bioavailability is sufficient for oral administration.
- Losartan is metabolized to an active metabolite.
- Telmisartan has the longest duration of action.
Indications: - essential hypertension;
- congestive heart failure;
- nephropathy – renoprotective in Type II diabetes.
The dose should be increased gradually.
Adverse effects: similar to ACEI, except inhibition of the catabolism of
bradykinin  so, they don’t induce cough or angioedema.
Contraindications:
- pregnancy;
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- renal failure, renal artery stenosis (bilateral artery stenosis or renal artery
stenosis of unique kidney),

Inhibitors of renine activity: Enalkiren, Remikiren, Aliskiren

Pharmacodynamic effects: decrease blood pressure.
Inhibitors of renin activity have similar efficacy to ACEI, but it is necessary to
improve their bioavailability for oral administration.

4.Pharmacologic influence of Kallikrein–kininogen–kinin

system
Kinins are a group of very strong vasodilator peptides, which are formed by the
enzymatic action of kallikrein.
Biological effects of kinins:
- arteriolar vasodilator effect by:
- direct action;
- action mediated by nitric oxide or prostaglandins PGE1, PGI2;
- contraction of smooth muscles of the intestine, uterus, bronchial smooth
muscle, endothelial cells;
- stimulation of nociceptors;
- modulating the tone of the canal pancreatic and salivary glands;
- modulating the symptoms of inflammation;
- the influence of maturation and sperm motility.
Kallikrein–kininogen–kinin system stimulation:
- ACEI
- kallikrein
Indications: diabetic gangrene; frostbite; healing difficult
wounds; acute vascular occlusions.
Kallikrein–kininogen–kinin system inhibition:
- kallikrein inhibitor: Aprotinine
Aprotinine inhibit kallikrein, trypsin and has antifibrinolytic
effects.
Indications: acute hemorrhagic pancreatitis; hemorrhagic shock;
as antifibrinolytic.
- bradykinin B2 receptor antagonists: Icatibant
- Icatibant Mechanism of action: selective competitive

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 antagonists of bradykinin B2 receptors
- Icatibant: angioedema (acute attacks of hereditary angioedema
or ACEI-induced angioedema in adults).

5.Pharmacologic influence of other endogenous peptides

1. Natriuretic peptide (ANP, BNP, CNP):
Natriuretic peptides, atrial natriuretic peptide (ANP), brain natriuretic peptide
(BNP), and C-type natriuretic peptide (CNP) are a family of endogenous
polypeptide mediators mainly of cardiac origin with natriuretic and vasodilator
effects, inhibition of renin secretion, angiotensin II and aldosterone and
sympatholytic effect. They act on specific natriuretic peptide receptors.

Therapeutic application: synthetic derivative of BNP  Nesiritide

Indications: congestive heart failure acutely decompensated (iv).
Adverse effects:
- hypotension, ventricular tachycardia, ventricular extrasystoles, angina
pectoris.
- headache, insomnia, dizziness, anxiety
- abdominal pain, nausea, vomiting.
- increases in serum creatinine.
2. Endothelins
Endothelins are polypeptides found in vascular endothelium (which explains
their denomination), but also in brain, kidney, intestine, adrenal gland. There
are three endothelins, endothelin I (ET-1), endothelin II (ET-2) and endothelin
III (ET-3), different only by some amino acids. Endothelin I is considered as
the most active and determines vasoactive effects, proarrhythmia, stimulation of
the proliferation of vascular smooth muscle cells, pro-inflammatory effects,
pro-platelet effects. Endothelin II determines vasoactive effects. These act on
endotheline receptors called ETA and ETB. Endothelins, by activating ETA and
ETB receptors, determine a general vasoconstriction.
Therapeutic application: antagonist of endothelin ETA and ETB receptors
 Bosentan
Mechanism of action: inhibits vasoconstriction.
Indications: pulmonary hypertension (oral administration).
Adverse effects:

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- increases in aminotransferases and in total bilirubin.
Contraindications:
- liver impairment
- pregnancy.

6.Pharmacologic influence of Lipid-derived autacoids

(eicosanoids)
The eicosanoids (prostaglandins or PGs, leukotrienes ot LTs, and related
compounds) are oxygenation products of polyunsaturated long chain fatty acids.
Arachidonic acid from membrane phospholipids is the most important
precursors of the eicosanoids and it is released from tissue by the action of
phospholipase A2 and other acyl hydrolases. The eicosanoids are:
- Cyclooxygenases products: - Prostaglandins: PGA  PGJ;
- Tromboxans: TXA, TXB.
- Lipoxygenase products: - Leukotrienes: LTA  LTE;
- Lipoxins;
- Hepoxilins.
- Epoxygenase products: - Epoxyprostaglandins;
- Dioli.
- Products of other pathways: - Isoprostanes.
Prostaglandins are products of arachidonic acid metabolism. They are
synthesised in the tissues and stimulate contractility of the uterine and other
smooth muscle and have the ability to lower blood pressure, regulate acid
secretion of the stomach, regulate body temperature and platelet aggregation,
and control inflammation and vascular permeability.
Leukotrienes are products of arachidonic acid metabolism. Leukotrienes
(LTC4, LTD4 and LTE4) are synthesized by eosinophils, mast cells, and
monocytes. They act on leukotrienes receptors and determine increased
vascular permeability, edema formation, mucus production, contraction of
airway smooth muscle, inflammatory cell chemotaxis.
1. Prostaglandine analogues indicated in obstetric-gynecology:
 PGE1 derivatives: Gemeprost;
 PGE2 derivatives: Dinoprostone, Sulprostone;
 PGF2alfa derivatives: Carboprost, Dinoprost.
Indications:

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- to induce abortion in the first and second trimester of pregnancy;
- prevention of postpartum hemorrhage (PGF2alfa derivatives).
Adverse effects:
- nausea and vomiting;
- diarrhea, abdominal cramps;
- analogues of PGE → hypotension, tachyarrhythmias;
- analogues of PGF2α → hypertension, bronchoconstriction.
2. Prostaglandine analogues indicated in peptic ulcer:
 PGE1 derivatives: Misoprostol;
 PGE2 derivatives: Enprostil, Arbaprostil, Rioprostil.
Mechanism of action:
- agonists on PGE1 or PGE2 receptors;
- stimulate the gastric secretion of mucus, bicarbonate and decrease pepsin
secretion.
Pharmacodynamic effects:
- cytoprotective effect (because stimulate the gastric secretion of mucus and
bicarbonate);
- inhibition of gastric acid secretion (=antisecretory effect because decrease
pepsin secretion);
- produces uterine contractions.
Indications:
- prevention of NSAID-induced ulcers or stress-induced ulcers.
- peptic ulcers.
- Misoprostol is indicated also for prevention of postpartum hemorrhage.
Adverse effects:
- Misoprostol: diarrhea, abdominal cramps, stimulate uterine contractions;
- Enprostil: diarrhea.
Contraindications: pregnancy.
3. Prostaglandine analogues indicated intravenous in cardiovascular
diseases:
 PGE1 derivatives: Alprostadil;
 PGI2 (prostacyclin) derivatives: Eproprostenol, Iloprost.
Indications:
- Alprostadil:
- iv: patent ductus arteriosus; severe peripheral vascular disease

167
 (including Raynaud syndrome),
- intracavernous or intraurethral: erectile dysfunction;
- Epoprostenol: pulmonary hypertension; severe peripheral vascular disease
(including Raynaud syndrome);
- Iloprost: severe peripheral vascular disease (including Raynaud syndrome).
Adverse effects: analogues of PGE → hypotension, tachyarrhythmias.
4. Prostaglandine analogues indicated in glaucoma:
 PGF2 derivatives: Latanoprost, Travoprost, Bimatoprost.
Pharmacodynamic effects: lower intraocular pressure.
Indications: glaucoma (firstline therapy in patients who are intolerant or have
insufficient responses to other intraocular pressure lowering medications).
5. Leukotriene antagonists:
 5-lipoxigenase inhibitors: Zileuton;
 LTD4 antagonists: Montelukast, Zafirlukast, Pranlukast.
Mechanism of action:
- Zileuton: inhibition of 5-lipoxygenase  inhibit the production of LTC4 and
LTD4 (which determine bronchospasm), LTB4 (which has role in chemotactic
effects and leukocyte activation in the bronchial mucosa);
- Montelukast, Zafirlukast, Pranlukast: antagonists on leukotriene LTD4
receptors.
Indications:
- long-term treatment of bronchial asthma, including asthma induced by aspirin,
bronchial asthma induced by effort or bronchial asthma induced by antigens.
- Zafirlukast is also indicated for asthma with concomittant allergic rhinitis.
Adverse effects:
- Montelukast, Zafirlukast, Pranlukast: allergic reactions, insomnia, headache;
gastrointestinal disorders, asymptomatic elevations of serum aminotransferase.
- Zileuton: asymptomatic elevations of serum aminotransferase.

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 Lecture 9
Pharmacological influence of cardio-
vascular system

Learning Objectives:
 Describe aspects of absorption, distribution, metabolism and excretion of a drug;
 List the principal routes of drug administration and their advantages and
disadvantages;
 List examples of drugs concentrated in different tissues or liquids of the body;
 Name the phases in hepatic metabolism;
 Describe the terms “bound” and “unbound” drug to plasma proteins;
 Describe the term “first pass effect”;
 Describe the terms drug metabolism “enzyme induction” and “enzyme inhibition”;

1. Cardiac glycosides and drugs for chronic heart failure

Classification of inotrop positive agents:

1.1. Cardiac glycosides
- short and rapid onset action:
- Digoxin,
- rare used: Lanatoside C, Ouabain (Strophanthin G), Methyldigoxin, Acetyldigoxin,
Deslanoside
- long and slow onset action: Digitoxin.
1.2. Other positive inotropic agents
- stimulants of beta-adrenergic receptors:
- beta1-adrenergic agonists: Dobutamine, Prenalterol
- beta1,beta2-adrenergic agonists: Isoproterenol (Isoprenaline)
- dopamine and alpha,beta-adrenergic agonists: Dopamine
- phosphodiesterase inhibitors:
- bipyridines: Milrinone, Amrinone (Inamrinone),
- imidazoles: Enoximone
- calcium-sensitising agents:
- benzimidazoles: Levosimendan, Pimobendan,
- glucagon (pancreatic hormone)
- non-selective inhibitors of phosphodiesterase: Theophylline, Caffeine.

1.1. Cardiac glycosides

Sources
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The major cardiac glycosides were obtained from the foxglove, Digitalis purpurea,
Scrofulariacee for digitoxin (Digitalis formerly discovered by Nativelle). The digoxin,
acetyldigoxin, the lanatoside C and deslanoside were obtained from woolly foxglove, Digitalis
lanata, Scrofulariacee. Strophanthin (ouabain) was obtained from various Strophanthus,
Apocynaceae.
Some toads glands of the skin produce bufadienolides, similar to cardenolides. Based on highly
sensitive immunochemical techniques it was demonstrated that ouabain is synthesized by the
adrenal glands and perhaps by the brain in humans and other mammals. Ouabain is released as
an endocrine and paracrine agent in certain circumstances, such as high salt intake and heart
failure. In congestive heart failure, plasma concentrations of ouabain are positively correlated
with the severity of the deficiency. There are chemical and physiological reasons to question
whether ouabain is indeed synthesized in patients with heart failure, progression of the disease
continues to the point of requiring treatment with exogenous glycosides are an insufficient
supply of endogenous and the development of tolerance or another alternate? Meanwhile, it
seems surprising that one can have more than one endogenous ligand for the receptor. This case
may demonstrate convergent evolution in plants, frogs and mammals.
Structure of cardiac glycosides:
- a steroid nucleus containing an unsaturated lactone ring at the C17 position,
and one or more glycosidic (sugar) residues at C3:
- unsaturated lactone ring is esential for pharmacodynamic properties
- steroid nucleus explains endocrine effects
- glycosidic (sugar) residues are essential for pharmacokinetic properties
(absorption, half-life and metabolism) and for specificity of action, are bound
by steroid nucleus through a very reactive hydroxil group which is necessary
for the activity.

Mechanism of action of cardiac glycosides

- inhibition of Na+/K+-ATPase (membrane-bound transporter called sodium
pump) from the membrane of myocardial cells and other excitable cells
(neurons, smooth muscle);
- activation of voltage-dependent calcium channels;
- increasing the release of calcium from the sarcoplasmic reticulum.
The pharmacodynamic effects of cardiac glycosides

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A. The cardiac effects
- Mechanical effects: the positive inotropic effects; tonotropes positive effects.
- The electrical effects:
1. direct electrical effects:
 to the top: a short extension of the action potential, followed by
reduction thereof, especially during the plateau reduction of the action
potential is determined, probably by increasing the potassium
conductance (which is produced by the increase in intracellular calcium)
→ an action similar to that produced by stimulation of cardiac M2
receptors (negative chronotropic effect and the negative dromotropic
effect);
2. the indirect electrical effects:
 therapeutic doses: parasympathomimetic effects - the negative
chronotropic effect (slower pace), the negative dromotropic effect
(slowed conduction), but the effect bathmotropic positive;
 toxic doses: sympathomimetic effects (ventricular extrasystoles,
atrioventricular block, ventricular fibrillation.
B. Extracardiac effects:
- weak diuretic effects;
- modulatory effect on blood pressure.
Pharmacokinetics
- absorption after oral administration: Lanatoside C - very low; Digoxin - 50%;
Digitoxin - 90%; strophanthin G is only administered intravenously;
concomitant administration of Digoxin with antibacterial agents (e.g.,
Erythromycin) → toxic effects by increasing the bioavailability; administration
concomitant cholestyramine or antacids determines the decrease of absorption
of Digoxin;
o distribution: liver, kidney, skeletal muscle, only 1% accumulates at heart;
o the plasma protein binding: strophanthin G is not connected; Lanatoside C -
the small proportion; Digoxin - 50%; Digitoxin - the high proportion;
o hepatic metabolism: Digoxin - 10%; Digitoxin - 90%;
o digitalis to slow-acting and long-term, after oral administration, enterohepatic
circulation;
o elimination: in the kidney → Digoxin - 90%; Digitoxin - 10%;
o digitalis exhibit the phenomenon of accumulation: after the last dose, the

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effect persists → very little, strophanthin G and C Lanatoside; 6 to 7 days,
Digoxin, 14 days for Digitoxin.
Indications:
 heart failure, especially associated with atrial fibrillation or with tachycardia;
 chronic atrial fibrillation, atrial flutter.
Adverse effects:
- cardiac effects (are based on an ion imbalance: hypokalemia,
hypomagnesemia, hypercalcemia):
- in therapeutic doses: the early late depolarization, the bigeminy, sinus
bradycardia, atrioventricular extrasystoles, tachycardias (atrial or
ventricular) conduction disorders (atrioventricular block, the
lengthening of the PR on ECG or block type II or III);
- in toxic doses → atrial tachycardia with block, ventricular tachycardia,
ventricular fibrillation;
- digestive effects: anorexia, nausea, vomiting, abdominal pain, diarrhea due to
prokinetic effect (by direct action, but also by stimulation of the area postrema
of the fourth ventricle - "trigger area");
- renal effects: oliguria, anuria;
- endocrine effects: gynecomastia, amenorrhea-galactorrhea syndrome;
- adverse effects in the CNS (more rarely):
- sedation, headache, dizziness, disorientation,
- visual disturbances with a yellow hallou around objects, bright wavy
lines, aberrations of color perception, hallucinations,
- agitation and convulsions are occasionally reported.
Contraindications
- hypokaliemia;
- bradycardia, ventricular tachycardia, atrioventricular block;
- hepatic or renal impairment;
- acute myocarditis;
- constrictive pericarditis;
- severe mitral stenosis;
- association with drugs:
- Erythromycin (by destroying the intestinal flora, Erythromycin
increase digoxin bioavailability by reducing the catabolism normally
performed by the intestinal flora);
- drugs that reduce absorption: cholestyramine, antacids;
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 - drugs that determine negative inotropic effects: β-adrenergic blockers
and calcium channel blockers;
- drugs that determine hypokalemia: thiazide diuretics (potentiate
digitalis effects);
- antiarrhythmics: Amiodarone, Propafenone;
- compounds with calcium (hypercalcemia potentiate digitalis effects).
If overdose of digoxin, the antidote is represented by the specific anti-digoxin
(Fab fragments).

1.2. Other positive inotropic agents

1.2.1. Phosphodiesterase inhibitors: Milrinone, Inamrinone (previous name
Amrinone), Enoximone
Chemical structure:
 bipyridines: Milrinone, Inamrinone (previous name Amrinone),
 imidazoles: Enoximone
Mechanism of action:
 inhibits phosphodiesterase 3 (PDE3) in cardiac and vascular muscle;
 increased calcium influx during the action potential;
 inhibition of Na+/K+-ATP-ase.
Pharmacodynamic effects:
 positive inotropic activity by direct stimulation of myocardial
contractility, with minimal chronotropic activity;
 vasodilatory activity arterial and venous dilation with a consequent fall
in systemic and pulmonary vascular resistances, and left and right heart
filling pressures and an increase in renal blood flow and glomerular
filtration.
Pharmacokinetics: intravenous administration. Milrinone has a shorter half-life
than Inamrinone and is less likely to cause thrombocytopenia. Metabolism:
hepatic, elimination: renal (40% unchanged).
Indication: acute congestive heart failure (short-term treatment)
Adverse effects: ectopic beats, hypotension, thrombocytopenia, reversible
hepatotoxicity, nephrotoxicity, reduce the sense of taste and olfactory
sensitivity.
Contraindications: stenotic or obstructive valvular disease,
Precautions: dosage adjustments may be necessary in patients with hepatic

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impairment or with severe renal impairment.
Milrinone is the agent of choice among currently available PDE inhibitors for
short-term, parenteral inotropic support.

1.2.2. Calcium-sensitising agents: Levosimendan, Pimobendan

Levosimendan and Pimobendan are novel calcium-sensitising agents (= agents
that produce inotropic effect by stabilizing the calcium–troponin C complex and
facilitate myocardial cross-bridging).
Chemical structure: benzimidazoles.
Mechanism of action:
 sensitize myofibrils to Ca2+, binds to troponin-C in cardiomyocytes, reduce
the Ca2+ sensitivity of contractile proteins in vascular smooth muscle;
 inhibition of PDE3 (low for Levosimendan compared to Pimobendan);
 for Levosimendan also opening of ATP-sensitive K+ channels.
Pharmacodynamic effects:
 inotropic positive effect and enhances cardiac output;
 vasodilation of peripheral arteries and venes, reduces systemic vascular
resistance and lowers pulmonary capillary wedge pressure;
 anti-inflammatory effect.
These drug don’t influence myocardial oxygen consumption.
Indication: acute congestive heart failure
Adverse effects: hypotension, dose-related increase in heart rate, headache.

2. Antiarrhythmic drugs
Vaughan-Williams Classification of Antiarrhythmic Drugs:
2.1. Class 1 (Sodium Channel-Blocking Drugs)
2.1.1. Subgroup 1A: Quinidine, Procainamide, Disopyramide, Ajmaline;
Aprindine;
2.1.2. Subgroup 1B: Lidocaine; Phenytoin; Mexyletin; Tocainide;
2.1.3. Subgroup 1C: Propafenone; Flecainide; Encainide; Lorcainide;
Indecainide; Moricizine; Cibenzoline;
2.2. Class 2 (Beta-Adrenoceptor–Blocking Drugs): Propranolol; Atenolol,
Metoprolol; Bisoprolol, Betaxolol, Nebivolol, Nadolol; Esmolol, Acebutolol;
Sotalol (has also class III mecanism);
2.3. Class 3 (Drugs That Prolong Effective Refractory Period by Prolonging

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Action Potential): Amiodarone; Dronedarone; Sotalol, Ibutilide; Dofetilide;
Bretylium; Clofilium; Pranolium;
2.4. Class 4 (Calcium Channel–Blocking Drugs): Verapamil; Diltiazem;
2.5. Class 5 (other antiarrhythmic agents): Adenozine; Magnezium sulphate;
Cardiac glycosides.
For antiarrhythmic drugs: a drug concentration that is therapeutic
(antiarrhythmic) under the initial circumstances of treatment may become
"proarrhythmic" (arrhythmogenic) in special conditions such as acidosis,
hyperkalemia, or ischemia.

CLASS 1 (SODIUM CHANNEL-BLOCKING DRUGS)

Subgroup 1A: Quinidine, Procainamide, Disopyramide, Ajmaline;
Aprindine
Antiarrhythmics subgroup IA are called "quinidine" group; prolong the QT
interval.
Mechanism of action:
 block voltage - dependent sodium channel (they combine with fast sodium
channels open and in their inactive state and thereby inhibit recovery after
repolarization in a time- and voltage-dependent manner which is associated
with subsequent dissociation of the drug from the sodium channels)  are
effective to inhibit ectopic arrhythmias;
 Quinidine also blocks potassium channels; it is a weak alpha blocker and has
anticholinergic effects;
 Procainamide also blocks potassium channels; it is a weak alpha blocker.
Electrophysiological effects:
 moderate phase 0 depression;
 prolong the action potential duration by blocking outward potassium current;
 prolong refractoriness;
 slows the upstroke of the action potential, slows atrio-ventricular and
intraventricular conduction and prolongs the QRS duration of the ECG
(increase QT interval);
 increase of ectopic automaticity (tertiary centers);
 depress myocardial contractility  negative inotropic effect.
Indications:
 atrial tachyarrhythmias (=supraventricular arrhythmias): atrial fibrillation,

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 atrial flutter;
 ventricular arrhythmias: ventricular tachycardia, ventricular ectopic activity;
 Quinidine has also antimalarial effects, alpha-adrenergic blocking effect and
Atropine-like effect.
Adverse effects:
 risk of arrhythmias (due to increase of ectopic automaticity);
 Quinidine iv administration determines hypotension and sinus tachycardia
(due to alpha-adrenergic blocking effects and Atropine-like effects);
 Quinidine cardiac toxicity:
o torsade de pointes due to the prolongation of QT interval; this
may evoluate to ventricular fibrillation;
o atrioventricular block, syncope, asystole;
o depression of myocardial contractility (can aggravate heart
failure);
 Quinidine digestive symptoms (in 1/3 to 1/2 of patients): diarrhea (may
induce hypokaliemia which potentiate torsades de points), nausea, and
vomiting;
 Quinidine intoxication = cinconism (blurred vision, dizziness, headache,
tinnitus, psychosis);
 Procainamide: antinuclear antibodies (to 1/2 of patients), systemic
eritematosus lupus (to 1/5 of patients).

Subgroup 1b: Lidocaine (Lignocaine); Phenytoin; Tocainide; Mexiletine;

Antiarrhythmics subgroup IB are "lidocaine" group; shortening of the QT
interval.
Mechanism of action: voltage - dependent sodium channel blockade (they act
on sodium inactivated channels)  suppression of ectopic automatism.
Electrophysiological effects:
 shorten the action potential duration;
 negligible effect on repolarization, on QT interval, on atrio-ventricular
conduction (but in ischemic myocardium reduce conduction of impulses)
and on myocardial contractility;
 minimal effect on phase 0 upstroke;
 shorten refractoriness;
 reduction of ectopic automaticity (tertiary centers).

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Indications:
 ventricular arrhythmias: ventricular tachycardia, ventricular ectopic activity;
o Lidocaine i.v. is drug of choice for ventricular arrhythmias.
o Phenytoin i.v. is drug of choice for tachyarrhythmias due to
digoxin intoxication.
Adverse effects of Lidocaine:
 low toxicity on CNS system: drowsiness, confusion, convulsions – in high
doses;
 hypotension.
Lidocaine is one of the least cardiotoxic antiarrhythmics.

Subgroup 1c: Propafenone; Flecainide; Encainide; Lorcainide;

Indecainide; Moricizine; Cibenzoline
Antiarrhythmics subgroup IC doesn’t change the QT interval.
Mechanism of action: voltage - dependent sodium channel blockade (on open
state);
 Propafenone, Flecainide  also blocks potassium channels.
Electrophysiological effects:
 no effects on the action potential duration, on QT interval, on repolarization;
 depression of phase 0 of the action potential;
 slows atrio-ventricular conduction;
 prolong refractoriness;
 depress myocardial contractility  negative inotropic effect;
 reduction of ectopic automaticity (tertiary centers).
Indications:
 ventricular arrhythmias (prophylaxis and treatment);
 some supraventricular arrhythmias: atrial fibrillation, atrial flutter;
o Propafenone is drug of choice for paroxysmal supraventricular
tachycardia.
 pharmacological cardioversion (Propafenone, Flecainide).
Adverse effects: proarrhythmic effects such as ventricular tachycardia and
torsade des points.
Contraindications: Propafenone has also weak beta-blocking activity, therefore
caution is needed in obstructive airways disease.

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2.2. CLASS 2 (BETA-ADRENOCEPTOR–BLOCKING DRUGS):
Propranolol; Metoprolol; Nadolol; Atenolol; Esmolol, Acebutolol; Sotalol
(with aditional mechanism of class 3);
Electrophysiological effects:
 shorten the action potential duration;
 slows atrio-ventricular conduction;
 no effects on QT interval;
 depress myocardial contractility  mild negative inotropic effect;
 reduction of the automatism of the sinus node;
 prolong refractoriness;
 reduction of ectopic automaticity (tertiary centers).
Indications:
 sinus tachycardia;
 ventricular arrhythmias: premature ventricular contractions, prevention of
ventricular fibrillation.

2.3. CLASS 3 (DRUGS THAT SLOW THE OUTWARD POTASSIUM

CURRENT): Amiodarone; Dronedarone; Sotalol, Ibutilide; Dofetilide;
Bretylium; Clofilium; Pranolium; Vernakalant.
Mechanism of action: block potassium channels (Kr and Ks) and sodium
channel fast voltage - dependent (inactive during repolarization).
 Amiodarone: also block beta receptors, has L-type calcium channel blocking
actions and has antithyroid action.
o Amiodarone has properties of all four classes of antiarrhythmic
drugs (Amiodarone inhibits sodium channels, L-type calcium
channels, several types of potassium channels, and the sodium-
calcium exchanger, and is a noncompetitive blocker of α- and β-
adrenoceptors) therefore it is indicated for a wide range of
arrhythmias.
 Because of its efficacy and safety, Amiodarone is currently one of the most
used antiarrhythmic agents.
Electrophysiological effects:
 prolong the action potential duration;
 slows sino-atrial automatism and atrio-ventricular conduction; no effect on
intraventricular conduction;

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 prolongs the QRS duration on the ECG (increase QT interval);
 no effect on myocardial contractility;
 reduction of ectopic automaticity (tertiary centers);
 prolong refractoriness;
 prolong repolarization.
Pharmacokinetics:
 can be administered iv or oral (food enhance absorption);
 onset of action: 2 days – 2 weeks even with loading;
 it is stored in many tissues (cumulation phenomenon)  explain the adverse
effects;
 leaves body very slow; very long half-life (25-60 days).
Indications:
 Amiodarone  ventricular and atrial arrhythmias refractory to other
treatments (e.g., paroxysmal supraventricular tachycardia, paroxysmal
tachycardia ventricular, atrial fibrillation, atrial flutter);
 pharmacological cardioversion;
o Amiodarone is the most effective drug for maintenance of sinus
rhythm in patients with atrial fibrillation and for decreasing risk
of ventricular tachyarrythmias.
 Bretylium  used iv in life-threatening ventricular tachycardia and
fibrillation;
 Ibutilide  used iv for acute conversion of atrial flutter/fibrillation to sinus
rhythm.
Advantages of Amiodarone:
 Low incidence of pro-arrhythmogenic effects;
 Has little effect on contractility and is of choice in arrhythmias from heart
failure;
 It reduces mortality in nonischemic cardiomyopathy patients at risk of
sudden death.
Adverse effects:
 Amiodarone:
o In acute administration:
 atrio-ventricular block;
 hypotension;
o In chronic administration:

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  Dose-independent adverse effects:
 thyroid dysfunction (the most frequent): hypo or hyper
(because Amiodarone contains iodine and thus may
interfere with iodine uptake);
 interstitial pulmonary fibrosis (can be rapidly progressive
and fatal);
 toxicity in pregnancy and breastfeeding;
 Dose-dependent adverse effects:
 corneal microdeposits and optic neuropathy (optic neuritis
may progress to blindness);
 photosensitivity (skin deposits result in a photodermatitis
and a gray-blue skin discoloration in sun-exposed areas);
 hepatotoxicity (transaminases increase at doses higher than
600mg/day);
 sinus bradicardia, proarrythmogenic effect;
 CNS (tremor, ataxia, dizziness).
o raise levels of Digoxin, Warfarin, Cyclosporine, Quinidine,
Procainamide, Phenytoin.
 Bretylium: hypotension;
 Sotalol: see adverse effects of β-blockers; prolongation of QT interval is the
most severe.
Contraindications of Amiodarone:
 sinus bradycardia, thyroid dysfunction; pregnancy and breast-feeding;
 association with Digoxin, Quinidine, Procainamide, Sotalol (are relative
contraindications).

2.4. CLASS 4 (CALCIUM CHANNEL–BLOCKING DRUGS): Verapamil;

Diltiazem;
Mechanism of action: calcium channel type L blockade.
Electrophysiological effects:
 shorten the action potential duration;
 no effects on QT interval;
 reduction of the automatism of the sinus node;
 slows atrio-ventricular conduction; no effect on intraventricular conduction;
 depress myocardial contractility  negative inotropic effect;

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 prolong refractoriness;
 no influence on ectopic automaticity (tertiary centers).
Indications: atrial arrhythmias (= supraventricular arrhythmias): atrial
fibrillation, atrial flutter;
o Verapamil is i.v. alternative for paroxysmal supraventricular
tachycardia.

2.5. CLASS 5 (OTHER ANTIARRHYTHMIC AGENTS): Adenozine;

Magnezium sulphate; Cardiac glycosides
ADENOZINE
 It is a nucleoside that occurs naturally in the body (half life is 10-15
seconds).
 Mechanism of action: agonist on purinergic receptors:
o from heart: negative chronotrope and dromotrope effects;
o from vessels: vasodilation.
 Indications: drug of choice for paroxismal supraventricular arrhythmias
(conversion to sinus rhythm).
 Adverse effects: asystole (the most severe), dyspneea, chest pain, headache,
flushing.
MAGNEZIUM SULPHATE
 Indications: drug of choice for torsades de points and digoxin-induced
arrhythmias.
 Adverse effects: bradycardia, headache, flushing.

3. Lipid-regulating drugs

Classification
3.1. Cholesterol absorption inhibitors:
3.1.1. Bile acid sequestrants: Cholestyramine and colestipol;
3.1.2. Inhibitors of intestinal absorption of cholesterol and plant sterols:
Ezetimibe.
3.2. Inhibitors of cholesterol biosynthesis:
3.2.1. HMG-CoA reductase inhibitors (statins): Lovastatin, Simvastatin,
Atorvastatin, Rosuvastatin, Fluvastatin, Pravastatin, Cerivastatin, Mevastatin,
Pitavastatin;

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3.2.2. fibrates: Clofibrate, Fenofibrate, Bezafibrate, Gemfibrozil, Ciprofibrate,
Tocofibrate, Pirifibrate, Simfibrate;
3.2.3. niacin group: niacin (nicotinic acid), Nicotinamide, Xantinol nicotinate,
Acipimox.
3. Other substances: Probucol; Omega-3-acid ethyl esters; Neomicine;
estrogens; Dextrotiroxine.

1. Cholesterol absorption inhibitors

1.1. Bile acid sequestrants: Cholestyramine and colestipol
Cholestyramine and colestipol are anion-exchange resin, capable of binding to a
number of drugs in the GI tract and may delay or reduce their absorption.
Mechanism of action: inhibits cholesterol absorption because releases chloride
ions and adsorbs bile acids in the intestine  forming a nonabsorbable complex
that is excreted along with unchanged resin in the feces. Cholestyramine must
be taken in 2 or 3 times daily with meals, setting resins bile salts taken between
meals have no effect.
Pharmacodynamic effects:
- partial removal of bile acids from the enterohepatic circulation;
- decrease in plasma total cholesterol and low-density lipoprotein (LDL)
concentrations;
- moderate increases in plasma triglyceride concentrations, due to moderate
increases in very low-density lipoprotein (VLDL) concentrations
- modest increase (less than 10%) in the high-density lipoprotein (HDL)-
cholesterol fraction in patients with type II hyperlipoproteinemia
Pharmacokinetics: are not absorbed from gastro-intestinal tract, are not
metabolised by digestive enzymes.
Indications:
- primary hypercholesterolemia as adjunct to dietary therapy to decrease
elevated serum total and LDL-cholesterol concentrations (hyperlipidemia type
IIa and IIb);
- pruritus associated with partial cholestasis;
- cardiac glycoside toxicity as adjunct in the treatment (to reduce initial
absorption of the glycoside).
Adverse effects:
- gastro-intestinal effects: constipation (most frequent), abdominal discomfort
and/or pain, abdominal distention, bloating, flatulence, nausea, vomiting,
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anorexia, heartburn, biliary colic, steatorrhea, indigestion
- dose-related increases in serum triglyceride concentrations.
Contraindications:
- asociation with cardiac glycosides, thiazide diuretics, Warfarin, Tetracycline,
Vancomycin, Tiroxine, fer salts, Folic acid, Phenylbutazone, Acethylsalicilic
acid.
- pregnancy.
1.2. Ezetimibe
Pharmacodynamic effects: cholesterol and plant sterols absorption inhibitor
This results in decreased delivery of intestinal cholesterol to the liver,
which causes a reduction in hepatic cholesterol stores, a compensatory
increase in hepatic uptake of cholesterol from systemic circulation, and
consequently, an increase in systemic clearance of cholesterol.
Ezetimibe does not appear to inhibit the absorption of triglycerides, fatty
acids, bile acids, progesterone, ethyl estradiol.
Pharmacokinetics: More than 90 % of Ezetimibe is absorbed systemically.
Ezetimibe is rapidly and extensively metabolized in the small intestine and liver
to a pharmacologically active metabolite. Ezetimibe is excreted mainly in feces,
less in urine.
Indications: hypercholesterolemia in association with statins
Ezetimibe is adjunct to dietary therapy in the treatment of primary
hypercholesterolemia and mixed dyslipidemia, homozygous familial
hypercholesterolemia, homozygous familial sitosterolemia.
Ezetimibe/Simvastatin combination therapy is useful for the
management of primary hypercholesterolemia or mixed dyslipidemia in
adults.
Adverse effects:
- elevations in serum aminotransferase (transaminase) concentrations
- elevations of serum creatine kinase
- diarrhea, abdominal pain, fatigue.
Contraindications: active liver disease, pregnant or nursing women.
2.1. Hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors
(statins):
Lovastatin, Simvastatin, Atorvastatin, Rosuvastatin, Fluvastatin,
Pravastatin, Cerivastatin, Mevastatin, Pitavastatin.
Mechanism of action: inhibit HMG-CoA reductase, the enzyme that catalyzes
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the conversion of HMG-CoA to mevalonic acid, an early precursor of
cholesterol
Pharmacodynamic effects:
- antilipemic action  decrease elevated cholesterol concentrations
- reduce serum concentrations of low-density lipoprotein (LDL)-
cholesterol,
- reduce serum concentrations of very low-density lipoprotein (VLDL)-
cholesterol,
- reduce serum concentrations of apolipoprotein B (apo B),
- moderate decrease in serum concentrations of triglycerides
- slight increase in HDL-cholesterol concentrations
- antiatherogenic effects (slow the progression of and/or induce regression of
atherosclerotic lesions)
- anti-inflammatory activity
Pharmacokinetics:
- rapidly absorbed following oral administration
- food reduce the systemic bioavailability of lovastatin, fluvastatin, pravastatin,
atorvastatin
- evening administration of atorvastatin and pravastatin was associated with a
decrease in peak plasma concentrations and areas under the plasma-
concentration time curve
- undergo extensive first-pass metabolism in the liver
- metabolized: principally in the liver (lovastatin, simvastatin, atorvastatin and
rosuvastatin have active metabolites, while the principal metabolites of
fluvastatin and pravastatin are
pharmacologically inactive); Lovastatin and simvastatin are inactive lactone
prodrugs.
- half-lives: long for atorvastatin and rosuvastatin (14 and 19 h, respectively),
the other statins have relatively short half-lives (between 0.5 - 3 h)
- eliminaton: in urine and feces.
Indications:
- dyslipidemias: primary hypercholesterolemia and mixed dyslipidemia,
homozygous familial hypercholesterolemia, primary dysbetalipoproteinemia,
and/or hypertriglyceridemia
- coronary heart disease for the prevention of cardiovascular events
Adverse effects:
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- gastro-intestinal tract effects: diarrhea, abdominal pain, flatulence, anorexia,
nausea
- hepatotoxicity (dose dependent increases in serum aminotransferase
concentrations);
- myopathy and/or rhabdomyolysis - after higher dosages of statins or after
concomitant use of statins and macrolide antibiotics, Cyclosporine, niacin,
fibric acid derivatives, certain antifungal azoles (i.e., Itraconazole,
Ketoconazole), alcohol
- skin rash, pruritus;
- CNS effects: headache, asthenia, fatigue, dizziness
Contraindications:
- active liver disease
- pregnant or lactating women, women of childbearing age
- children
2.2. Fibrates (fibric acid derivatives): Clofibrate, Fenofibrate, Bezafibrate,
Gemfibrozil, Ciprofibrate, Tocofibrate, Pirifibrate, Simfibrate.
Mechanism of action:
- stimulation of activity of lipoprotein-lipase;
- inhibition of hepatic synthesis of VLDL.
Pharmacodynamic effects:
- antilipemic effects  decrease elevated triglyceride and cholesterol
concentrations
- decreases serum concentrations of:
- total cholesterol,
- low-density lipoprotein (LDL)-cholesterol,
- apolipoprotein B (apo B),
- very low-density lipoprotein (VLDL)-cholesterol,
- triglycerides,
- increases serum concentrations of:
- high-density lipoprotein (HDL)-cholesterol,
- apolipoprotein A-I (apo A-I),
- apolipoprotein A-II (apo A-II).
- antiatherogenic effects
- decreases platelet adhesiveness.
Fenofibrate has been shown to reduce serum uric acid concentrations.
Pharmacokinetics:
185
- rapidly and completely absorbed from the GI tract
- high percentage is protein bound (mainly albumin)
- metabolized: in the liver
- excreted: mainly in urine.
Indications:
- primary hypercholesterolemia and mixed dyslipidemia
- hypertriglyceridemia
- coronary heart disease for the prevention of cardiovascular events
Adverse effects:
- gastro-intestinal tract effects: epigastric pain or dyspepsia
- hepatotoxicity (increases in serum aminotransferase concentrations)
- slight decreases in hemoglobin, hematocrit and in leukocyte count
- cholelithiasis (due to increase cholesterol excretion in bile)
- myositis, myopathy, and/or rhabdomyolysis
Contraindications:
- hepatic impairment, including primary biliary cirrhosis
- severe renal impairment;
- preexisting gallbladder disease
- pregnant or lactating women,
- children
- alcohol.
2.3. Niacin group: niacin (nicotinic acid), Nicotinamide, Xantinol
nicotinate, Acipimox.
Niacin and niacinamide are water-soluble, B complex vitamins.
Mechanism of action: partial inhibition of free fatty acid release from adipose
tissue, a decreased delivery of free fatty acids to the liver, and a decrease in
triglyceride synthesis and VLDL-triglyceride transport.
Pharmacodynamic effects:
- antilipemic action  reductions in cholesterol and triglyceride concentrations
- reduce serum concentrations of low-density lipoprotein (LDL)-
cholesterol and and very-low-density lipoprotein (VLDL)-cholesterol,
- reduce in serum concentrations of triglycerides
- increase in HDL-cholesterol concentrations
- antiatherogenic effects
- cutaneous vasodilation
- activates the fibrinolytic system
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Indications:
- dyslipidemias: hypercholesterolemia and/or hypertriglyceridemia, type V
hyperlipoproteinemia
- coronary heart disease for the prevention of cardiovascular events
- pellagra
Niacin in combination with:
- a bile acid sequestrant, is used as an adjunct to dietary therapy to
decrease elevated serum total and LDL-cholesterol concentrations,
- lovastatin is used in the treatment of primary hypercholesterolemia
(heterozygous familial and nonfamilial) and mixed dyslipidemia
- an HMG-CoA reductase inhibitor is considered drug of choice for
hypercholesterolemia in adults with increased LDL-cholesterol.
Adverse effects:
- gastro-intestinal tract effects: diarrhea, nausea, vomiting, abdominal pain,
dyspepsia, anorexia
- flushing, pruritus, headache
- hepatotoxicity (dose dependent increases in serum aminotransferase
concentrations)
- elevation in blood glucose concentrations
- elevation in blood uric acid concentrations
Contraindications:
- active liver disease
- pregnant or lactating women,
- gout
- active peptic ulcer disease
- arterial bleeding
Acipimox has lower frequency of adverse effects, but it is less efficient as
antilipemic drug.
3. Other antilipemic drugs
3.1. Probucol
Probucol is used to lower levels of cholesterol from blood.
Pharmacodynamic effects:
- antilipemic action  reductions in cholesterol concentrations
- reduce serum concentrations of low-density lipoprotein (LDL)-
cholesterol and and high-density lipoprotein (HDL)-cholesterol,
- does not influence serum concentrations of triglycerides
187
- antioxidant effects (reduce oxidation of fatty acids)
Pharmacokinetics: Probucol remains in the body few months after stopping the
treatment
Indications: pure hypercholesterolemia
Adverse effects:
- gastro-intestinal tract effects: nausea, abdominal pain;
- alergic reactions;
- QT prolongation with risk of arrhythmias.
Contraindications:
- pregnant or lactating women,
- children.
3.2. Omega-3-acid ethyl esters
Omega-3 fatty acids (n-3 fatty acids) are long-chain, polyunsaturated fatty acids
(PUFAs), that are obtained mainly from marine sources such as fatty fish.
Mechanism of action:
- inhibit diacylglycerol O-acyltransferase;
- increase peroxisomal b-oxidation;
Pharmacodynamic effects:
- antilipemic action:
- reduce in serum concentrations of triglycerides;
- reduce serum concentrations of very-low-density lipoprotein (VLDL)-
cholesterol.
Indications:
- hypertriglyceridemia;
- coronary heart disease for the prevention of cardiovascular events.
Adverse effects:
- hepatotoxicity (increases in serum aminotransferase concentrations);
- increases in LDL-cholesterol concentrations;
- prolongation of bleeding time.
3.3. Neomicine reduces serum concentrations of LDL-cholesterol.

4. Pharmacological influence of cardio-vascular system

disorders
4.1. Antianginal and other anti-ischemic drugs
4.1. Anginal attacks: Nitroglycerin (sublingual), Amyl nitrite (only inhalatory as drug test);
4.2. Maintenance treatment:

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- Basic treatment:
- Nitrates: Nitroglycerine, Isosorbide mononitrate (ISMN), Isosorbide dinitrate (ISDN), Penta
erythroil tetranitrate (PETN);
- compounds with similar action to nitrates: Nicorandil, Molsidomin;
- β-adrenergic blockers;
- Ca2+-channel blockers: Nifedipine; Amlodipine; Felodipine; Isradipine, Nicardipine,
Nisoldipine; Verapamil; Diltiazem;
- metabolic modulators (partial inhibitors of the fatty acid oxidation pathway in myocardium or
pFOX inhibitors): Trimetazidine, Ranolazine;
- selective If sodium channel blockers: Ivabradine;
- Adjunct treatment:
- antiplatelet drugs: Acethylsalicilic acid (75-325 mg/day); Clopidogrel, Ticlopidine;
Abciximab, Eptifibatide; Dipiridamol;
- lipid-lowering drugs;
- ACE-inhibitor drugs;
- other coronarodilatators (no more used): Carbocromen; Methylcromone.
Trimetazidine and Ranolazine
Are metabolic modulators.
Mechanisms of action:
 shift myocardial metabolism from free fatty acid oxidation to glucose metabolism,
resulting in reduced myocardial O2 consumption.
 block non-selective voltage - dependent sodium channel;
 reduce the production of free radicals;
 reduce the level of the Cu-Zn superoxide dismutase.
Pharmacodynamic effects:
 reduction of fatty acid oxidation;
 increase in the oxidation of glucose;
 reduced myocardial O2 consumption.
Indications:
 prophylaxis of angina pectoris;
 the symptomatic treatment of vertigo, Meniere's syndrome;
 corio-retinal vascular disease.
Adverse effects (rarely, <1%): epigastric pain, nausea, pruritus, headache.
Ivabradine
Mechanisms of action:
 selective and specific inhibitor of the cardiac pacemaker If current of sodium channel
in the sino-atrial node (it inhibits the If current in a dose-dependant manner).
Pharmacodynamic effects:
 decrease heart rate
 decrease myocardial oxygen demand at rest and during exercise.
Indications:
 symptomatic treatment of chronic stable angina pectoris in patients with normal sinus

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 rhythm who have a contra-indication or intolerance to ß-blockers.

4.2. Antihypertensive drugs

5.1. Drugs for maintenance treatment of hypertension
- diuretics
- thiazide diuretics (sulfonamide diuretics):
- thiazides: Hydrochlorothiazide, Chlorothiazide, Methyclothiazide, Polythiazide,
Hydroflumethiazide, Bendroflumethiazide, Cyclopenthiazide, Benzthiazide
- analogues of thyazides: Indapamide, Chlorthalidone, Quinethazone, Metolazone,
Clopamide, Xipamide
- loop diuretics:
- sulfonamide loop diuretics: Furosemide and its analogues (Bumetanide, Piretanide),
Torsemide
+
- K sparing diuretics:
- physiologically antagonists (direct acting): Amiloride, Triamterene
- aldosterone antagonists (mineralocorticoid receptor antagonists):
- nonselective on steroidal hormone receptors: Spironolactone,
Prorenone
- selective on aldosterone receptors: Eplerenone
- carbonic anhydrase inhibitors: Acetazolamide
- calcium channels blockers
- Action on Calcium channels from blood vessels and heart: Nifedipine, Amlodipine,
Nitrendipine, Nicardipine; Verapamil; Diltiazem
- Specific action on Calcium channels from blood vessels: Felodipine, Isradipine,
Nisoldipine, Lacidipine, Lercanidipine, Nimodipine
- Angiotensin and renin-angiotensin-aldosteron system inhibition
- angiotensin receptors blockers (= ARB, selective antagonists on angiotensin AT1
receptors from vessels): Losartan, Valsartan, Candesartan, Telmisartan, Irbesartan,
Eprosartan.
- angiotensin converting enzyme inhibitors (ACEI): Captopril; Enalapril, Ramipril,
Quinapril, Perindopril, Lisinopril, Benazepril; Fosinopril; Moexipril, Spirapril,
Trandolapril, Cilazapril, Alacepril, Altiopril, Fentiapril, Pivalopril, Zofenopril,
Delapril, Imidapril.
- Substances blocking sympathetic system activity
- Antagonists on beta receptors
WITHOUT intrinsic with ISA
sympathomimetic activity (ISA)
semiselective Propranolol, Sotalol, Timolol, Oxprenolol, Alprenolol, Pindolol,
β1,β2–blockers Nadolol, Bupranolol Penbutolol, Carteolol
selective β1– Metoprolol, Atenolol, Bisoprolol, Acebutolol, Celiprolol
blockers Betaxolol, Nebivolol, Esmolol
- Antagonists on alpha receptors: Phenoxybenzamine, Prazosin, Terazosin,
Doxazosin, Indoramin

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 - block α1 presynaptic receptors and stimulate α2 postsynaptic adrenergic
receptors: Urapidil
- centrally acting sympatholytic agents
- Acting mainly on CNS:
- Selective agonists on I1 imidazoline receptors: Moxonidine,
Rilmenidine
- Agonists on α2 presinaptic adrenergic receptors and I1
imidazoline receptors: Clonidine
- Other mecanism of action: Methyldopa, Guanabenz, Guanfacine
- Acting on CNS and peripherally: Reserpine
- Acting mainly peripherally: Guanetidine, Guanadrel, Bethanidine,
Debrisoquin
- direct acting vasodilatation drugs: Hydralazine, Minoxidil, Diazoxide
- 5-HT1C and 5HT2 antagonists: Ketanserin
5.2. Drugs for treatment of hypertensive emergencies
- parenteral agents for hypertensive emergencies:
- Furosemide (action onset in 15 min);
- Nitroglycerine (action onset in 2-5 min, duration 5-10 min);
- Metoprolol (action onset in 1-2 min);
- Enalapril (action onset in 15 min, duration 6 h);
- Labetalol (action onset in 5 min, duration 4-8 h);
- Esmolol (action onset in 5-30 min, duration 30 min);
- Nicardipine (action onset in 15-30 min, duration 40 min);
- Sodium nitroprusside (action onset in seconds, duration 3-5 min);
- Diazoxide (action onset in 1-5 min);
- Fentolamine (action onset in 1-2 min);
- Ketanserine (action onset in 10 min);
- Fenoldopam (action onset in 4 min, duration 8-10 min);
- Urapidil (action onset in 10-20 min, duration 4-6 h);
- Other drugs: Hydralazine (action onset in 10-20 min, duration 4-6 h); Trimetaphan
(action starts in 1-5 min, duration 10 min), Clonidine, Methyldopa, Reserpine;
- oral agents for hypertensive emergencies:
- Furosemide (action onset in 30 min);
- Nitroglycerin (action onset in 1-2 min, duration 5-10 min) – also sublingual;
- Captopril (action onset in 15-30 min, duration 4-6 h) – also sublingual;
- Nifedipine (action onset in 5-15 min, duration 3-6 h);
- Others:
- Losartan (action onset in 60 min, duration 12-24 h);
- Labetalol (action onset in 30-120 min, duration 6-12 h);
- Clonidine (action onset in 30-60 min, duration 6-8 h).

4.3. Pharmacological Treatment of Heart Failure

Heart failure is viewed as a consequence of disordered circulatory dynamics and pathologic

191
cardiac remodeling.
Chronic heart failure (CHF) is typically a chronic illness during which episodic, acute
decompensation may occur. Chronic heart failure is a pathological state characterized by
abnormal cardiac function which is responsible for the failure of heart to pump blood in the
body.
Acute heart failure (AHF) is characterized by low arterial pressure (cardiogenic shock) and
dyspnoea (pulmonary edema).
6.1. Pharmacological therapy for CHF
6.1.1. Beta-blockers  under specialist care
- beta1-blockers: Metoprolol, Bisoprolol
- alpha,beta-blockers: Carvedilol
6.1.2. Vasodilator drugs:
- angiotensin converting enzyme inhibitors (ACEI)  drugs of choice
- sulphydrile: Captopril;
- dicarboxilate: Enalapril, Ramipril, Quinapril, Perindopril, Lisinopril, Benazepril;
- phosphonate: Fosinopril;
- miscellanous: Trandolapril, Cilazapril;
- angiotensin II receptor antagonists  for patients who not tolerate ACEI
- selective on AT1 receptors from vessels: Valsartan, Losartan, Candesartan,
Telmisartan, Irbesartan, Eprosartan;
- direct acting vasodilators:
- nitrates: Nitroglycerine, Isosorbide dinitrate, Isosorbide mononitrate, Nitroprusside
- arteriolar vasodilator: Hydralazine
- Vasopressin receptor antagonists:
- V1,V2-receptor antagonist: Conivaptan,
- V2-receptor antagonist: Tolvaptan, Lixivaptan, Satavaptan
6.1.3. Diuretic agents  essential for symptomatic treatment
- loop diuretics - thiazide diuretics - K+ sparing diuretics
6.1.4. Positive inotropic agents
- cardiac glycosides - Ivabradine
6.2. Pharmacological therapy for AHF: positive inotropic agents
- beta1-blockers: Dobutamine, Prenalterol
- dopamine,alpha,beta-adrenergic agonists: Dopamine
- calcium-sensitising agents: - benzimidazoles: Levosimendan, Pimobendan,
- phosphodiesterase inhibitors:
- bipyridines: Milrinone, Amrinone,
- imidazoles: Enoximone
- beta1,beta2-adrenergic agonists: Isoproterenol
- Glucagon (pancreatic hormone).

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 Lecture 10

Learning Objectives:
 Describe aspects of absorption, distribution, metabolism and excretion of a
drug;
 List the principal routes of drug administration and their advantages and
disadvantages;
 List examples of drugs concentrated in different tissues or liquids of the body;
 Name the phases in hepatic metabolism;
 Describe the terms “bound” and “unbound” drug to plasma proteins;
 Describe the term “first pass effect”;
 Describe the terms drug metabolism “enzyme induction” and “enzyme
inhibition”;
 Explain concept and significance of steady state concentration.

1. Diuretics and antidiuretics

1.1. Diuretics
Diuretics are agents that increase diuresis (increase urine volume due to
increase of the rate of urine flow) and excretion of electrolytes and water.

Diuretics classification:
1. Thiazide diuretics (sulfonamide diuretics):
- benzothiazines (thyazides): Hydrochlorothiazide, Chlorothiazide,
Methyclothiazide, Polythiazide, Hydroflumethiazide,
Bendroflumethiazide, Cyclopenthiazide, Benzthiazide
- thiazide-like diuretics (analogues of thyazides): Indapamide,
Chlorthalidone, Quinethazone, Metolazone, Clopamide, Xipamide
2. Loop diuretics:
- sulfonamide loop diuretics:
- Furosemide and its analogues (Bumetanide, Piretanide)
- Torsemide (sulfonylurea derivative)
- phenoxiacetic acid derivative:
- Ethacrynic acid and its analogues (Indacrinone, Ticrinafen)
- mercurial diuretics: no longer used
193
3. K+ sparing diuretics:
- aldosterone antagonists (mineralocorticoid receptor antagonists):
- nonselective: Spironolactone, Prorenone
- selective: Eplerenone
- physiologically antagonists (direct acting): Amiloride, Triamterene
4. Carbonic anhydrase inhibitors: Acetazolamide, Dorzolamide,
Methazolamide, Brinzolamide,
5. Osmotic diuretics: Mannitol, Glycerin, isosorbide, urea
6. Other substances with low diuretic effect:
- antagonists of antidiuretic hormone: Lithium salts, Demeclocycline
(tetracycline derivative)
- methylxanthines: Theophylline, Caffeine
- cardiac glycosides.

1. THIAZIDE DIURETICS
Classification of thiazide diuretics
 benzothiazines (thyazides):
o Hydrochlorothiazide,
o Others: Chlorothiazide, Methyclothiazide, Polythiazide,
Hydroflumethiazide, Bendroflumethiazide, Cyclopenthiazide,
Benzthiazide
 thiazide-like diuretics (analogues of thyazides):
o Indapamide,
o Clopamide,
o Chlorthalidone, Quinethazone, Metolazone, Xipamide
Structure
All thiazides have an unsubstituted sulfonamide group:
 benzothiadiazines derivatives have unsubstituted sulfonamide group and
benzothiadiazine nucleus;
 analogs and variants are derivatives that only unsubstituted sulfonamide
group.
Mechanism of action:
- inhibit the cotransporter Na+/Cl- from the proximal segment of the distal
convoluted tubule (probably also in the ascending limb of Henle and the last
segment of the proximal tubule).

194
- Indapamide stimulate production of vasodilatory prostaglandins (PGE1,
PGE2, PGI2)
 the increas in renal blood flow causes a redistribution of blood flow
within the renal cortex  stimulation of cyclooxygenase  production
of PGE1, PGE2 and PGI2 (vasodilator prostaglandins)  reduction in
blood pressure  chronic administration, stimulating the production of
renin, then, the drug inhibits the cotransporter Na+/Cl- at the proximal
segments of the distal convoluted tubule (probably also in the ascending
limb of Henle and last segment of the proximal convoluted tubule).
Pharmacodynamic effects of thiazide diuretics are of medium intensity:
- diuretic effect: increase the excretion of Na+, Cl-, K+ and water;
- retention of uric acid, Ca2+;
- metabolic effects:
 hyperglycemia (reduce peripheral glucose utilization),
 hyperlipidemia: increas total plasma cholesterol and LDL-cholesterol;
- Indapamide has vasodilator effect (at doses lower than doses with diuretic
effect).
Duration of pharmacodynamic effects of thiazide diuretics:
 medium: Hydrochlorothiazide,Chlorothiazide, Bendroflumethiazide,
Hydroflumethiazide, Benzthiazide, Cyclothiazide, Cyclopenthiazide,
Méthyclothiazide, Buthiazide;
 long: Indapamide, Clopamide, Polythiazide, Chlortalidone.
Pharmacokinetics
- absorption: for Hydrochlorothiazide  incomplete , for Indapamide  very
good absorption;
 Chlorothiazide  low fat solubility, the drug is administered only
parenterally;
- plasma protein binding: for Hydrochlorothiazide  58%;
- metabolism: Indapamide  hepatic metabolism, and presents first pass effect;
- elimination: Hydrochlorothiazide  renal elimination, unmetabolized, by
tubular secretion; Indapamide  elimination by biliary secretion.
Indications
- hypertension;
- chronic heart failure;
- renal failure (renal clearance > 30 ml / min);

195
- kidney stones due to idiopathic hypercalciuria;
- nephrogenic diabetes insipidus induced by lithium (doses are adjusted, as
thiazides decrease lithium elimination).
Adverse effects
- hypokalemic metabolic alkalosis;
- due to ions excretion:
 blood: hyponatremia, hypokalemia, hypercalcemia
 urine: hyperphosphaturia;
- hyperuricemia;
- uric lithiasis;
- hyperglycemia, glycosuria (in patients with diabetes mellitus);
- the increase in insulin resistance;
- hyperlipidemia (increased total plasma cholesterol and LDL - cholesterol
plasma); o mental fatigue, physical fatigue, paresthesias;
- sexual impotence;
- Type I immunological reactions (rash, pruritus), type II (hemolytic anemia,
thrombocytopenia) and type III (Stevens-Johnson syndrome)  cross-reactivity
to other sulfonamides;
- other adverse effects (rare): acute pancreatitis, cholestatic jaundice, acute
pulmonary edema.
Contraindications
- diabetes mellitus;
- dyslipidemia;
- liver cirrhosis, heart failure associated with renal failure (except, indapamide),
heart failure associated with liver cirrhosis;
- gout;
- sarcoidosis.

2. LOOP DIURETICS (or High-Ceiling Diuretics)

Classification of loop diuretics
 sulfonamide loop diuretics:
o Furosemide and its analogues (Bumetanide, Piretanide)
o Torsemide (= Torasemide) (sulfonylurea derivative)
 phenoxiacetic acid derivative:
o Ethacrynic acid and its analogues (Indacrinone, Ticrinafen)

196
  mercurial diuretics: no longer used
Mechanism of action:
- inhibition of the cotransporter Na+/K+/2Cl- in the ascending limb of Henle;
- increase the production of vasodilatory prostaglandins (PGE1, PGE2, PGI2).
Pharmacodynamic effects of loop diuretics are fast, very intense and short-
term (after iv administration):
- vasodilator effect appears before the diuretic effect;
 Furosemide acutely increase systemic venous capacitance and thereby
decrease left ventricular filling pressure
 the increase in renal blood flow cause a redistribution of blood flow
within the renal cortex  increase of renal blood flow stimulate
cyclooxygenase  increase production of vasodilatory prostaglandins
 reduction in blood pressure  if volume deppletion occurs it is
stimuled the production of renin.
- increase in glomerular filtration rate;
- diuretic effect: increase the excretion of Na+, K+, Ca2+, Mg2+, Cl-, water and
phosphates.
Pharmacokinetics
- absorption is rapid (after oral administration);
- protein binding: for Furosemide  99%;
- metabolism: liver;
- rapid renal elimination by tubular secretion (in the proximal convoluted
tubule) and glomerular filtration.
Indications
- Furosemide
 hypertensive crisis;
 edema of various etiologies:
o acute heart failure (acute pulmonary edema, cardiac asthma);
o chronic heart failure (edema refractory to diuretic therapy with
other groups and salt restricted diets);
o liver cirrhosis (complicated with ascites);
o nephrotic syndrome, acute or chronic renal failure (but are
contraindicated in patients with renal failure associated with
cirrhosis);
 hyperkalaemia;

197
  hypercalcemia (these drugs are contraindicated in massive dehydration
or in lung cancer).
- Torsemide, Bumetanide, Piretanide  similar to Furosemide;
- Ethacrynic acid  glaucoma;
- Indacrinone and Ticrinafen  gout.
Adverse effects
- hypokalemia, hyponatremia, hypocalcemia, hypomagnesemia
 hypomagnesemia induced by Furosemide increase the ototoxic effects
of aminoglycosides and fluoroquinolones;
- hypokalemic metabolic alkalosis;
- urine: hypercalciuria, moderate hypophosphaturia;
- hyperglycemia and hyperuricemia are weaker than those caused by thiazide
diuretics;
- hypovolemia determines:
 hypotension;
 extracellular dehydration,
- nausea, vomiting;
- Type I immunological reactions (rashes), type II (thrombocytopenic purpura)
and type III (acute interstitial nephropathy)  cross-reactivity to other
sulfonamides;
- increase in plasma renin.
Contraindications
- hypersensitivity to sulfonamides;
- massive dehydration;
- lung neoplasms.
Precautions: administration of Furosemide, Bumetanide and Torsemide in
patients with liver cirrhosis associated with kidney failure or heart failure 
electrolyte imbalances.

3. K+ SPARING DIURETICS
Classification of K+ sparing diuretics
 aldosterone antagonists (mineralocorticoid receptor antagonists):
o nonselective (act on both aldosterone and steroidal hormone
receptors):
 Spironolactone,

198
  Prorenone
o selective (act only on aldosterone receptors): Eplerenone
 physiologically antagonists (direct acting):
o Amiloride,
o Triamterene
Mechanisms of Action
- competitive antagonists of aldosterone receptors from the distal convoluted
tubule  block Na+/K+ -ATPase in the membrane of target cells  block Na+
reabsorption and the secretion of K+ and H+,
- physiological antagonists of aldosterone  block Na+ channels in collecting
duct of the nephron  block Na+ /K+ exchange (not dependent of the presence
of aldosterone).
Pharmacodynamic effects  are of low intensity
- stimulate the reabsorption of H+ and K +;
- increase elimination of Na+, Cl-, bicarbonates and water;
- block myocardial remodeling (anti-fibrosis effect);
- antiandrogenic effects (only for non-selective competitive antagonists).
Duration of pharmacodynamic effects of potassium-sparing:
 medium: Amiloride, Triamterene;
 long: Spironolactone, Prorenone, Eplerenone.
Pharmacokinetics
- absorption: for Spironolactone and Triamterene  good absorption; for
Amiloride  reduced absorption;
- metabolism: hepatic (Spironolactone is biotransformed in active metabolites);
Spironolactone and Triamterene  present first pass effect;
- elimination: renal.
Indications
- as diuretic in combination with a thiazide or loop diuretic (to prevent the K+
excretion induced by these drugs);
- in hypokalemia
- refractory oedema (from hepatic cirrhosis, heart failure because preserve
potassium);
- Spironolactone: congestive heart failure;
- Spironolactone: primary and secondary hyperaldosteronism.
Adverse effects

199
- hyperkalemia, hyponatremia;
- hyperkalemic metabolic acidosis, especially in cases of renal failure which is a
cons-indication for their use;
- Spironolactone determines endocrine adverse effects (because has an
antiandrogenic effect): gynecomastia, menstrual disorders, impotence, and
benign prostatic hypertrophy;
- Triamterene: megaloblastic anemia in patients with liver cirrhosis, renal
failure when it is associated with Indomethacin, kidney stones;
- Amiloride: hyperammonemia, impaired glucose tolerance.
Contraindications
- hyperkalemia with or without clinical symptoms (disorders of atrioventricular
conduction);
- acidosis of various etiologies;
- chronic renal failure;
- hepatorenal syndrome;
- breastfeeding.

4. CARBONIC ANHYDRASE INHIBITORS

Classification of carbonic anhydrase inhibitors diuretics
 Acetazolamide,
 Dorzolamide,
 Methazolamide,
 Brinzolamide
Mechanism of action
- inhibition of carbonic anhydrase → block the formation of bicarbonates and
H+ ions
There is carbonic anhydrase in the eye, kidneys (predominantly in the
proximal convoluted tubule), CNS, gastric mucosa, pancreas,
erythrocytes.
Pharmacodynamic effects  are of low intensity and short duration
- renal: inhibition of carbonic anhydrase activity depresses bicarbonate
reabsorption in the proximal tubule and inhibit the exchange of H+ ions with
Na+ ions:
 in urine are eliminated: Na+, K+, bicarbonate, phosphate, water (increase
diuresis);

200
  in blood increase H+ and Cl-
- eye: reduce intraocular pressure in glaucoma (because decreases the rate of
formation of aqueous humor);
- CNS: local acidosis induced by inhibitors of carbonic anhydrase determine
 anticonvulsant effects, reduce cerebral edema and regulate nerve
impulses in the cortical and subcortical areas;
 reduce hypercapnia;
- gastric mucosa: reduce gastric acidity;
Pharmacokinetics
- absorption: good for Acetazolamide, slow for Metazolamide;
- plasma protein binding: 90%;
- renal elimination as unchanged drugs.
Indications
- glaucoma
 Acetazolamide is used by mouth for open angle and for closed angle
glaucoma;
 Dorzolamide is drug of choice – used as 2% topical drops;
- diuretic
 for urinary alkalinization (to increase renal excretion of weak acids);
 increase urinary phosphate excretion during severe hyperphosphatemia;
- acute mountain sickness (= high-altitude disorders)
 Symptoms: weakness, dizziness, insomnia, headache and nausea may
occur in mountain travelers who ascend rapidly to above 3000 m →
pulmonary or cerebral edema;
 prophylaxis can be obtained after oral administration, starting 24 h
before the ascent;
- epilepsy  as an alternative or adjunct to first-line drugs;
- peptic disease;
- to correct metabolic alkalosis.
Adverse effects:
- rapid development of tolerance;
- hyperchloremic metabolic acidosis;
- kidney stones;
- renal elimination of potassium;
- dizziness, fatigue, drowsiness, CNS depression and paraesthesia at high doses;

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- bone marrow depression (rare);
- hypersensitivity reactions (fever, pruritus, interstitial nephritis).
Contraindications:
- liver cirrhosis.

5. OSMOTIC DIURETICS
Classification of osmotic diuretics
 Mannitol,
 Others: Glycerin, isosorbide, urea
Mechanisms of action
- increase the osmotic pressure (physical action) in the lumen of vessels and of
nephrons;
 act in the nephron segments highly permeable to water: the proximal
convoluted tubule, the collecting tubule, the descending limb of Henle.
Pharmacodynamic effects  are of moderate intensity and short duration
- increase the glomerular filtration rate;
- diuretic effect: increase the elimination of water, K+, bicarbonates, phosphate,
Ca2+, Mg2+.
Pharmacokinetics
- administration: only iv;
- distribution: in extracellular fluid;
- metabolism: hepatic (Mannitol is metabolised 10%);
- elimination: glomerular filtration.
Indications
- intracranial hypertension: to reduce intracranial pressure;
- before ophthalmic surgery: to reduce intraocular pressure;
- to increase in urine volume, when renal hemodynamics is compromised (e.g.,
renal failure);
- syndromes with hypersecretion of antidiuretic hormone.
Adverse effects
- transient increase in extracellular volume;
- transient severe hypernatremia;
- cellular dehydration.

6. OTHER SUBSTANCES WITH LOW DIURETIC EFFECT

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 - antagonists of antidiuretic hormone: Lithium salts, Demeclocycline
(tetracycline derivative)
- methylxanthines: Theophylline, Caffeine
- cardiac glycosides.

1.2. Antidiuretics

Antidiuretics are agents that reduce urine volume, particularly in diabetes

insipidus. They have also other effects.
Classification
1. Antidiuretic hormone (peptides):
- natural: Vasopressin (ADH)
- synthetic: Desmopressin, Terlipressin
2. Drugs that potentiate the antidiuretic effects of antidiuretic hormone:
- Chlorpropamide,
- Carbamazepine,
- Clofibrate

VASOPRESSIN (ANTIDIURETIC HORMONE), TERLIPRESSIN,

DESMOPRESSIN
 Vasopressin (antidiuretic hormone) is a polypeptide hormone secreted
by the neurons of the supraoptic and paraventricular nuclei of the
hypothalamus and stored in the posterior pituitary gland.
 Terlipressin is a synthetic Vasopressin analog with similar efficacy to
Vasopressin, but with fewer adverse effects.
 Desmopressin is a synthetic polypeptide structurally related to
Vasopressin.
Vasopressin receptors:
 V1 (mediate vasoconstriction),
 V2 (mediate antidiuretic effect)
 V2-like (=V3, stimulate release of coagulation factor VIII and von
Willebrand factor)
Mechanism of action
- Vasopressin and Terlipressin: agonist of vasopressin receptors V1, V2 and
V2-like.

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- Desmopressin: agonist of vasopressin receptors V2 and V2-like.
Pharmacodynamic effects
- Vasopressin and Terlipressin
- intense vasoconstriction (particularly of capillaries and of small
arterioles, mediated by V1 receptors); Terlipressin has preferential
splanchnic vasoconstrictor; the vasopressor effects are less
pronounced than those of Vasopressin.
- antidiuretic effect (maintain serum osmolality within a normal
range, mediated by V2 receptors);
- Desmopressin
- potent antidiuretic effect;
- stimulation of release of coagulation factor VIII (antihemophilic
factor) and von Willebrand factor (mediated by V2-like receptors).
Pharmacokinetics
- Absorption:
- Vasopressin is administered intranasal (very good absorption) or
parenteral.
- Desmopressin (used as acetate salt) is administered intranasally,
orally, by subcutaneous injection, direct IV injection, or slow IV
infusion.
- Distribution: in extracellular fluid, but no plasma protein binding.
- Metabolism: rapidly destroyed in the liver and kidneys.
- Elimination: small quantity  unchanged in urine.
- T1/2 = Vasopressin: 10-20 min, Desmopressin: 8 - 24 h.
Indications
- Vasopressin and Terlipressin
- diabetes insipidus (it is drug of choice) caused by a deficiency of
endogenous posterior pituitary antidiuretic hormone;
- gastro-intestinal hemorrhage: esophageal variceal hemorrhage,
colonic diverticulosis hemorrhage, intestinal perforation;
- cardiac arrest (may replace the first or second dose of epinephrine in
the treatment of ventricular fibrillation arrest, pulseless ventricular
tachycardia, asystole, or pulseless electrical activity in advanced
cardiovascular life support);
- Desmopressin
- diabetes insipidus caused by a deficiency of endogenous posterior
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 pituitary antidiuretic hormone (drug of choice);
- primary nocturnal enurezis;
- to evaluate the ability of the kidneys to concentrate urine;
- hemophilia A and von Willebrand disease.
Adverse effects
- Vasopressin and Terlipressin
- skin pallor;
- increased blood pressure (can lead to hypertension, myocardial
ischemia or infarction, mesenteric infarction), bradycardia, minor
arrhythmias;
- nausea, vomiting, abdominal cramps;
- severe hyponatremia (“water intoxication” = overhydration  in
infants and children): headache, confusion, anuria, and weight gain;
- type I alergic reactions (urticaria, angioedema, bronchoconstriction,
fever, rash, wheezing, dyspnea, circulatory collapse, cardiac arrest,
and anaphylaxis).
- Desmopressin
- severe hyponatremia;
- unlike vasopressin, usual doses of Desmopressin do not cause skin
pallor, vasoconstriction or abdominal cramps.
Contraindications
- Vasopressin and Terlipressin
- hypertensive disease,
- coronary arteries diseases;
- pregnancy;
- renal failure.
- Desmopressin
- pregnancy;
- renal failure.

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 2. Agents Used in Anemias and Hematopoietic Growth
Factors

AGENTS USED IN ANEMIAS

Classification of agents used for the treatment of anemia due to deficiency
of iron, vitamin B12, or folic acid:
1. Iron salts: - oral administration: Ferrous sulfate
Ferrous fumarate
Ferrous gluconate
Polysaccharide–iron complex
- parenteral administration iron dextran
sodium ferric gluconate complex
in sucrose
iron sucrose
2. Vitamin B12: Cyanocobalamin, Hydroxocobalamin
3. Folic acid

Iron salts
These compounds contain divalent or trivalent iron. The necessary daily intake
of iron is 50mg.
Pharmacokinetics
- administration: p.o. or parenteral (i.m. or i.v.).
- absorbtion: the compounds containing divalent iron are better absorbed in the
duodenal mucosa and they are less irritating than the digestive compounds
containing trivalent iron. Organic iron compounds present are better digestive
tolerance.
Indications
- treatment of iron deficiency anemia;
- prophylaxis of iron deficiency anemia (the necessary daily intake of iron is 30
mg): during pregnancy, lactation, blood donors, infants, young children,
puberty, elderly, vegetarians.
- parenteral administration is indicated if:
 oral intake is inadequate or the oral route can not be used;
 gastrointestinal bleeding (is continuous or intermittent and rainfall
associated with lower intake tract);

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  after gastrectomy;
 anterior resection of the small intestine;
 inflammatory bowel disease involving the proximal small intestine;
 malabsorption syndromes.
 gastrointestinal bleeding.
Adverse effects
- when administered po: nausea, vomiting, gastrointestinal irritation, abdominal
cramps, constipation / diarrhea, dark stool.
- when parenteral administration: - headache, flushing, intense sweating,
fever, arthralgia;
- pigmentation at the injection site;
- hemochromatosis (high dose).
Contraindications: - hemochromatosis;
- haemosiderosis;
- hemolytic anemia;
- thalassemia;
- peptic ulcer;
- colitis.
Specific treatment in poisoning with iron: deferoxamine, EDTA.
Drug interactions
- drugs which decrease iron absorption: antacids; Cimetidine; caffeine;
cholestyramine; dairy products; citric acid;
- drugs which increase iron absorption: ascorbic acid, fructose, cysteine,
alcohol.

Vitamin B12
The necessary daily intake of vitamin B12  2 to 2.5 mcg / day.
Pharmacodynamic effects
- Vitamin B12 is essential for the activity of two enzymes:
 deoxy-adenosyl-cobalamin enzyme which determine the conversion of
the enzyme methylmalonyl-CoA to succinyl-CoA;
 5-methyltetrahydrofolate-homocysteine-methyltransferase enzyme
which determine:
o conversion of the inactive form of tetrahydrofolate (the
methyltetrahydrofolate) to active (formyltetrahydrofolate);

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 o conversion of homocysteine to methionine.
Pharmacokinetics:
- administration: only parenteral route (im or sc);
- absorption: in the stomach, vitamin B12 binds to a glycoprotein (Castle
intrinsic factor) forming a complex that is absorbed in the ileum; it has
enterohepatic circuit;
- transport in the blood: it is linked to transcobalamin; there are storage reserves
in the liver;
- elimination: renal and biliary.
Indications: treatment of megaloblastic anemia.
Adverse effects: allergy (rare).
Contraindications: malignant tumors; polycythemia.

Folic acid
The necessary daily intake of folic acid  100 mg / day (food sources far
exceed this amount).
Pharmacodynamic effects
- cofactor in the synthesis of purines and pyrimidines  folic acid has role in
DNA synthesis.
- involved in cell maturation.
Indications: - treatment of megaloblastic anemia;
- prophylaxis in pregnancy (to prevent neural tube defects).
Contraindications: - malignant tumors.
- association with drugs that inhibit folic acid synthesis
(Sulfonamides, Trimethoprim, Methotrexate, Phenytoin,
Isoniazid, oral contraceptives).

HEMATOPOIETIC GROWTH FACTORS

Classification of hematopoietic growth factors used to treat anemia,
thrombocytopenia, and neutropenia, and to support stem cell
transplantation.
1. erythropoietin;
2. myeloid growth factors: - granulocyte colony-stimulating factor (G-CSF)
- granulocyte-macrophage colony-stimulating
factor (GM-CSF)
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 - interleukin-3 (IL-3),
3. thrombopoetic growth factors (Megakaryocyte Growth Factors):
- interleukin-11 (IL-11)
- thrombopoietin
Hematopoietic growth factors are administered only i.v.
Erythropoietin
Mechanism of action: bind on erythropoietin receptors from erythroblasts (red
cell progenitors) in bone marrow
Pharmacodynamic effects:
- stimulates erythroid proliferation and differentiation
- induces release of reticulocytes from the bone marrow.
Indications:
- anemia in patients with chronic renal failure, chronic inflammatory diseases,
myelodysplasia, myelofibrosis, multiple myeloma, phlebotomy;
- anemia induced by zidovudine therapy.
Available preparations:
- epoetin alfa and epoetin beta (recombinant human erythropoietin),
- Darbepoetin alfa (glycosylated form of erythropoietin).
Adverse effects: - hypertension;
- headache, vomiting, visual disturbances, convulsions;
- thrombosis;
- immunological reactions: skin rash, chills, flu-like
symptoms.
Contraindications: - hypertension,
- treatment with iron.

Myeloid growth factors G-CSF, GM-CSF

Indications:
- neutropenia: - neutropenia after chemotherapy or after bone marrow
transplantation;
- congenital neutropenia;
- neutropenia induced by treatment with zidovudine;
- neutropenia more aplastic anemia;
- myelodysplasia;
- pancytopenia (in combination with other growth factors, because G-CSF, GM-
CSF does not determine the stimulation of the formation of erythrocytes and
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platelets).
Available preparations:
- granulocyte colony-stimulating factor (G-CSF): - filgrastim;
- pegilated compound:
pegfilgrastim;
- lenograstim;
- granulocyte-macrophage colony-stimulating factor (GM-CSF):
- sargramostim;
- molgramostim.
Adverse effects: fever; arthralgia; syndrome of capillary infiltration.

Interleukin-3 (IL-3)
Pharmacodynamic effects: stimulates production of platelets and erythrocytes.
Indications: bone marrow failure.
The toxicity is high.
Interleukin-11 (IL-11)
Indications: thrombocytopenia (as secondary prophylaxis after chemotherapy
in non-myeloid cancers).
Adverse effects
- fatigue, headache, dizziness;
- anemia (due to hemodilution);
- dyspnea;
- supraventricular arrhythmias (transient);
- hypokalemia (rarely).

Thrombopoietin
Mechanism of action: bind on thrombopoietin receptors.
Pharmacodynamic effects
- stimulate the growth of lymphoid and myeloid cells  stimulate the growth of
primitive megakaryocytic progenitors  increases the number of peripheral
platelets and neutrophils.
Indications: thrombocytopenia after chemotherapy or after bone marrow
transplant (it is also given to donors).
Available preparations
- recombinant human thrombopoietin.

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 3. Drugs Used in Disorders of Coagulation

Classification
1. Hemostatic drugs
2. Antitrombotic drugs
- Anticoagulants
- Antiplatelet drugs
- Fibrinolytic drugs

1. HEMOSTATIC DRUGS
Hemostasis is the cessation of blood loss from a damaged vessel.
Classification of hemostatic products
1.1. Topical products to treat active compressible, localised bleeding
1.2. Infusible products to treat non-compressible, internal bleeding or prevent
bleeding
Indications: mild to moderate bleeding from capillaries and small venules

1.1. Topical products to treat active compressible, localised bleeding

(hemostatic drugs with local effect):
 Mechanical haemostatics (passive haemostats):
o Mechanism of action: mechanisms of absorption, pressure,
vasoconstriction
 vasoconstrictor effects: Adrenaline, Noradrenaline,
 absorbable hemostatic drugs: Gelatin (can absorb many
times its weight of blood)
o Indications:
 Adrenaline: haemostatic in superficial hemorrhages of
the skin or mucosa
 Gelatin: haemostatic in surgical procedures (as an
absorbable film/sponge)
 Haemostatics inductors of coagulation
o Mechanism of action:
 Biotransformation of fibrinogen in fibrin (accelerate
fibrin formation through exogenous thrombin and

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 fibrinogen): Trombin, Fibrin
 Matrix for coagulation: Celulose (applied to a bleeding
surface, they swell to form a gelatinous mass which aids
in the formation of a clot)
o Indications: to control haemorrhage from capillaries and small
venules during surgical procedures
 Others: Hydrogen peroxide
o Mechanism of action: it is an oxidising agent which release
oxygen when applied to tissues (the effect lasts only as long as
the oxygen is released) = short duration of action. The
antimicrobial effect of the liberated oxygen is reduced in the
presence of organic matter.
o Pharmacodynamic effets:
 antiseptic, disinfectant, and deodorant.
 antibacterial activity and is also effective against viruses,
including HIV.
 mild haemostatic action. It owes its antiseptic action to
its ready; in addition. The mechanical effect of
effervescence is probably more useful for wound
cleansing than the antimicrobial action.
o Indications
 to cleanse wounds and ulcers in concentrations of up to
6%;
 adhering and blood-soaked dressings may be
released by the application of a solution of
hydrogen peroxide.
 mouthwash in the treatment of acute stomatitis and as a
deodorant gargle as a 1.5% solution
 removal of wax from ears
 disinfect soft contact lenses
 for bleaching hair.
o Adverse effects
 irritating 'burns' on the skin and mucous membranes with
a white eschar,
 mouth ulceration if used as hydrogen peroxide 3%.

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1.2. Infusible products to treat non-compressible, internal bleeding or prevent
bleeding (hemostatic drugs with systemic effect)
Classification
 hemostatic drugs efficient for the coagulation of blood:
o Vitamin K,
o Protamin sulfate,
o factor VIII fraction, factor IX fraction, factor I fraction
(fibrinogen), factor XIII fraction (stabilizating fibrine);
 hemostatic drugs that increase blood capilary resistance: - Etamsylate,
-
Carbazocrome,
- calcium;
 antifibrinolytic drugs (inhibit fibrin disolution): - Tranexamic acid,
- epsilon-aminocaproic
acid,
- Aprotinin.
Vitamin K
Sources: - plant sources: vitamin K1 (phytomenadione);
- intestinal flora: Vitamin K2 (menaquinone);
- synthetic: vitamin K3 (menadione).
Mechanism of action: Vitamin K is reduced to vitamin K-epoxide that acts as a
cofactor in the hepatic synthesis of factors II (prothrombin), VII
(proconvertină), IX (B antihemofilică globulin) and X (Stuart-Prower factor)
coagulation . Subsequently, the action of epoxide reductase, vitamin K is
regenerated.
Pharmacokinetics
- absorption: vitamin K1 and K2 are fat soluble vitamins requires bile salts for
absorption from the gastro-intestinal; vitamin K3 is water soluble it is absorbed
easily.
- metabolism: in the liver;
- elimination: renal.
Indications
- deficit of vitamin K (bowel resection, malabsorption syndromes, prolonged
antibiotic therapy etc).

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- prevention of bleeding in premature infants;
- as an antidote to overdose of oral anticoagulants (only vitamins K1 and K2).
Adverse effects: - hemolysis (in patients with deficiency of glucose - 6 -
phosphate dehydrogenase, G6PDH);
- kernicterus in neonates;
- dyspnea, retrosternal pain;
- methemoglobinemia.
Contraindications: - thrombophlebitis;
- thromboembolism.
Protamine sulfate
Mechanism of action: the physico-chemical mechanism the basic molecule of
protamine sulfate determines the inactivation of heparin.
Indications: - antidote to the overdose of heparin;
- surgery using cardiopulmonary bypass.
Adverse effects: - dyspnea;
- bradycardia;
- hypotension.
Coagulation factors
Representatives of:
- factor I (human fibrinogen);
- factor VIII;
- factor IX;
- factor XIII (fibrin stabilizing).
Administration: i.v. infusion
Indications:
- hemophilia: factor VIII, factor IX, factor XIII;
- hypo-or afibrinogenemii: factor I.
Adverse effects:
- factor VIII: allergies, antibody formation, risk of transmission of viral
infections (hepatitis, HIV);
- factor IX: fever, nausea, vomiting, headache, changes in blood pressure.
- stimulating factor VIII activity: Desmopressin, Danazol.
Etamsylate
Mechanism of action: - increase in resistance by reducing capillary
permeability.
Indications: - bleeding by capillary fragility;
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 - menorrhagia, metrorrhagia.
Adverse effects: transient hypotension, headache, rash.
Epsilon-aminocaproic acid (EACA)
Mechanisms of action: - inhibition of the plasminogen activator;
- anti-inflammatory effect.
Administration: parenteral route.
Indications: - adjuvant treatment in hemophilia;
- bleeding by hyperfibrinolysis;
- prophylaxis: bleeding after dental extractions, bleeding in
intracranial aneurysms;
- after prostatectomy;
- liver disease.
Adverse effects: hypotension, abdominal pain, diarrhea, arrhythmias.

2. ANTITROMBOTIC DRUGS
2.1. Anticoagulants:
Classification of anticoagulant drugs:
 indirect thrombin inhibitors
o Parenteral anticoagulants:
 Unfractioned heparin:
 Heparin Calciparin
 Low molecular weight heparins:
 Enoxaparin, Dalteparin, Nadroparin, Tinzaparin,
Fondaparinux, Others: Ardeparin, Reviparin, Parnaparin,
Certoparin, Idraparinux
 Heparinoids and hirudins:
 Danaparoid, Lepirudin, Hyaluronidase Others:
Bivalirudin, Argatroban, Drotrecogin alfa, Desirudin,
o Oral anticoagulants:
 4-hydroxycoumarin:
 Warfarin, Acenocoumarol, Others: Bisdihydroxicumarin,
Ethyl biscumacetat, Tioclomarol, Cyclocumarol,
Phenprocoumon;
 indan-1,3-dione:
 Phenindione, Others: Difenadione, Anisindione,
Bromindione, Fluindionone;
o In vitro anticoagulants:
 Sodium oxalate, Sodium Fluoride, Sodium citrate, Sodium edetate
 direct thrombin inhibitors:

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 o iv
 Lepirudin (recombinant hirudin) Bivalirudin, Argatroban,
o sc
 Desirudin (recombinant hirudin) Melagatran,
o p.o.
 Dabigatran Ximelagatran

Heparin
Heparin anticoagulant activity is in international units (IU).
Heparin has anticoagulant activity both in vivo and in vitro.
Mechanisms of action
- heparin binds to antithrombin III  results a complex that inhibits factors II,
IX, X, XI, XIII of coagulation;
- activation of lipoprotein lipase;
- inhibition of hyaluronidase;
- inhibition of serum complement;
- inhibition of the production of aldosterone;
- decrease activity of antithrombin III (in chronic administration).
Pharmacokinetics
- Heparin does not cross the blood-brain barrier, it does not cross the placental
barrier and it does not pass into the milk.
- administraton: Heparin: iv/sc, Calciparin: sc
Indications: - treatment of choice in deep vein thrombosis, pulmonary
embolism, arterial embolism, myocardial infarction;
- prophylaxis: postoperative (prevention of venous thrombosis).
Adverse effects: - bleeding by overdose;
- thrombocytopenia by the anti-heparin (frequently, IgG-
like);
- stimulation of platelet aggregation;
- osteoporosis, spontaneous fractures;
- transient reversible alopecia;
- rarely, allergic reactions (rhinitis, conjunctivitis,
bronchospasm, urticaria, anaphylactic shock).
During treatment  evaluation of aPTT (activated partial thromboplastin
time).
In overdose  heparin antidote is protamine sulfate.
Contraindications
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- i.m. administration;
- hemophilia, thrombocytopenia, purpura;
- high blood pressure, intracranial hypertension;
- endocarditis;
- active tuberculosis;
- liver carcinoma, liver failure;
- gastrointestinal ulcerative lesions.

Low molecular weight heparins

Mechanisms of action: - inhibit only activated factor X clotting.
Pharmacokinetics: - administration: s.c. only;
- the time for action is long;
- elimination: renal excretion.
Indications, contraindications, adverse effects  are similar to those of
Heparin.
Advantages: - time for action is long,
- low risk for osteoporosis,
- allergic reactions are rare.
Not require monitoring by aPTT monitoring.

Oral anticoagulants
Mechanisms of action
- inhibition of the epoxide reductase (enzyme involved in regeneration of
vitamin K)  results in production of inactive coagulation factors;
The anticoagulant effect occurs after a latency period of at least 8-12 h, but the
therapeutic effect is achieved after 36 h of charging.
During treatment: necessary evaluation of INR (= prothrombin index).
Pharmacokinetics:
- digestive absorption: very good;
- plasma protein binding of Warfarin: 99%;
- cross the placenta;
- metabolism: hepatic;
- elimination: renal.
Indications:
- prosthetic valves;
- chronic pulmonary embolism;
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- embolism in chronic atrial fibrillation;
- post-thrombotic syndromes;
- secondary prevention of stroke and atrial fibrillation;
- postoperative immobilization;
- cancers.
Adverse effects:
- bleeding due to overdose;
- rash;
- teratogenic effects;
- Warfarin: bronchodilation, alopecia;
- bis-dihydroxycoumarin: capillary damage, increase transaminases;
- Phenindione: liver damage; kidney damage;
- Anisindione: agranulocytosis, proteinuria.
In overdose  oral anticoagulants antidote is vitamin K1 or K2.
Contraindications
- pregnancy;
- breastfeeding;
- hemophilia;
- severe hypertension;
- acute hemorrhagic stroke.
Drug Interactions
- increase the anticoagulant effect:
 Phenylbutazone (and other NSAIDs), vitamin E  because of removing
them from plasma proteins;
 Cimetidine, Ketoconazole, Erythromycin  because inhibit their
metabolism;
 platelet agregants  because of potentiating synergism;
- reduce the effect of anticoagulant:
 Cholestyramine: decreases absorption;
 barbiturates, carbamazepine, Rifampicin  enzyme induction.

2.2. Antiplatelet drugs

Classification of antiplatelet drugs:
 antiagregant effect depending on dose or as secondary effect:
o Acethylsalycilic acid,

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 o Dipyridamole,
o Flurbiprofen, Sulfinpyrasone,
o prostaglandine derivatives
 PGI2 derivatives: Epoprostenol
 PGE1 derivatives: Alprostadil
 antagonists on platelets receptors for fibrinogen:
o Ticlopidine,
o Clopidogrel;
 glycoprotein IIb/IIIa antagonists:
o Abciximab,
o Eptifibatide,
o Tirofiban,
o Optifiban;
 5HT2 receptor antagonists:
o Ritanserine.
Mechanism of action
- Acetylsalicylic acid: inhibition of thromboxane synthase (this will inhibit the
release of thromboxane A2);
 antiplatelet effect occurs only at low doses (80-325 mg / day),
increasing the dose is lost, hold 5-7 days after the last dose.
- Dipyridamole: inhibition of platelet accession to thrombogenic surfaces,
inhibiting phosphodiesterase activity.
- platelet fibrinogen receptor blockers: block the platelet receptor for fibrinogen
by inhibiting binding of ADP-dependent type.
- GP-IIb/IIIa of platelet receptor antagonists: block platelet integrin receptors
and other proagregante substances.
Pharmacodynamic effects: decrease platelet agregability.
Indications: prevention of thromboembolic accidents or transient ischemic
attacks in patients with increased thrombotic risk (myocardial infarction,
unstable angina, stroke etc).
Adverse effects:
- promote bleeding.
- for Ticlopidine: blood dyscrasias (leukopenia, agranulocytosis, aplastic
anemia), increase in transaminases and alkaline phosphatase,
hypercholesterolemia, hypertriglyceridemia, skin reactions

219
Contraindications: in acute hemorrhagic stroke, thrombocytopenia.

2.3. Fibrinolytic drugs

Classification of fibrinolytic drugs:
 proteolytic enzyme produced by beta haemolytic Streptococcus:
Streptokinase,
 enzyme synthesized in the human kidney: Urokinase,
 tissue-type plasminogen activators
o Alteplase,
o Reteplase,
o Tenecteplase,
 complex of streptokinase plasminogen activator: Anistreplase
(anisoylated plasminogen streptokinase activator complex; APSAC).
Indications (fibrinolytics are effective within the first 6 h of thrombus
formation):
- acute myocardial infarction;
- multiple pulmonary thromboembolism;
- peripheral vascular disease;
- syndrome of superior vena cava.
Adverse effects:
- bleeding;
- allergic reactions, fever;
- mobilization of thrombus lysed fragments;
- reperfusion arrhythmias;
- streptokinase has high antigenic properties.
Contraindications: history of allergies.
Overdose: In the fibrinolytic overdose epsilon-aminocaproic acid is
administered.

4. Fluids and electrolytes

Classification
1. Oral preparations for fluid and electrolyte imbalance (oral rehydration therapy)
- oral potassium, oral sodium and water, oral bicarbonate
3. Parenteral preparations for fluid and electrolyte imbalance
- electrolyte solutions (micromolecular solutions)

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 Single electrolyte:
Sodium chloride,
Glucose (Dextrose monohydrate),
Potassium chloride,
Sodium bicarbonate,
Sodium lactate,
Mixtures of electrolytes:
Sodium chloride and glucose,
Ringer solution (contains Ca2+, K+, Na+, Cl-),
Ringer lactate (contains Ca2+, K+, Na+, Cl-, HCO3-)
- plasma substitutes (macromolecular solutions):
Dextrans (Dextran-40 and Dextran-70 are polysaccharides)
Polygeline (gelatin-derived polymer)
Etherified starch: hetastarch, hexastarch, and pentastarch
High-molecular-weight hetastarch (average molecular weight
450000 to 480000) and medium-molecular-weight pentastarch
(average molecular weight 200000 to 250000). Other etherified
starches are low-molecular-weight pentastarch and medium-
molecular-weight hexastarch, with a degree of etherification between
that of pentastarch and hetastarch.
Pharmacodynamic effects
- electrolyte solutions (micromolecular solutions)
 provide osmotic pressure;
 recover fluid for a short time as soon leave the vascular bed;
- plasma substitutes (macromolecular solutions)
 ensure the colloid-osmotic and oncotic pressure;
 are removed from the body in more than 24 h (partially degraded,
partially eliminated in urine)  restore circulating mass and BP for long
interval;
- other effects for Dextran 40:
 antithrombotic action by inhibiting platelet aggregation;
 prevent erythrocyte aggregation.
Indications
- restoring volume expansion after excessive loss through diarrhea, vomiting,
bleeding, burns etc.
Adverse effects
- electrolyte solutions (micromolecular solutions)
 Sodium chloride: Hypernatraemia, hyperchloraemic;
 in overdosage: nausea, vomiting, headache, fever, abdominal cramps,
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 tachycardia, peripheral and pulmonary edema, convulsions, respiratory
arrest.
 plasma substitutes (macromolecular solutions)
- Dextran 70: type I immunological reactions, increased bleeding time, interfere
with the determination of glucose, total protein and bilirubin.
- Gelofusine, hydroxyethyl starch: rash (rare).
Contraindications: hypertension, edema.
 Venosta
- Mechanism of action: transforms fibrinogen into fibrin.
- Administration: injection.
- Indications: postsurgical bleeding, bleeding prevention of various types.
- Contra thromboembolism, thrombocytopenia.
With systemic hemostatic action:
 Carbazocroma
- Mechanism of action: increasing resistance by reducing capillary permeability.
- Indications: • treatment of bleeding capillaries;
• prophylaxis prior to surgery (low efficiency).
 calcium preparations.
- Tranexamic acid action is 10 times stronger than epsilon-aminocaproic acid.
- Aprotinin
 Mechanisms of action: o the inhibition of the plasminogen activator;
o inhibition of kallikrein, trypsin.
 Indications: o Acute hemorrhagic pancreatitis;
o hemorrhagic shock;
o septic peritonitis;
o Prophylaxis: surgical procedures using cardiopulmonary bypass.
 Adverse effects: allergic reactions.
Heparinoids
 sulfonesterice are polysaccharides containing groups, as heparin, is the active molecule.
 containing the active substances in preparations: Lasonil ®, Lioton ®, Hirudoid ®,
Hepatrombin ®, Lipoveni ®.
 Pharmacodynamic effects:
- anticoagulant effect is much weaker than heparin, but are useful in clarifying the action of
serum;
- not affect clotting.
 Indications: - local treatment in superficial phlebitis, thrombophlebitis, varicose veins,
hemorrhoids, bruising.

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 CHEMOTHERAPEUTIC DRUGS
Lecture 11

Learning Objectives:
 Describe the general mechanisms of action of antimirobial drugs.
 List examples of drugs concentrated in different tissues or liquids of the body.
 Classify antiseptic and disinfectant drugs.
 Explain the indications, and adverse effects of frequently used antiseptic and
disinfectants.
 Classify antibacterial drugs.
 Explain the indications, and adverse effects of frequently used antibiotics.

1.Pharmacokinetic and pharmacodynamic particularities

of chemotherapeutic drugs

History
1928: Alexander Fleming, a Scottish biologist, descovered the antibiotic effect of Penicillum.
He observed that Penicillium notatum, a common mold, had destroyed staphylococcus bacteria
in culture. Fleming received Nobel price for this discovery.
S. A. Waksman (1941): an antibiotic is a substance produced by a micro-organisme and has the
capacity to inhibit the development of other micro-organismes and even to destroy them.
1946: started the industrial production of antibiotics.
Definitions
Antibiotic is a natural substance produced by a micro-organism to kill another.
Antiinfectives/Anti-microbrial is any agent (natural or synthetic) that kills pathogens
(microbes). There are antibacterial chemotherapeutics, antiviral chemotherapeutics, antifungal
chemotherapeutics, antiparasitic chemotherapeutics.
Key: it needs to kill the microbial cell and not be toxic to normal healthy human cells. Many
bacteria are now resistant to antibiotics and some are resistant to all known agents. New drugs
are continually being introduced to combat evolving patterns of resistance.
“Biocide” is a chemical agent (usually broad spectrum), that inactivates microorganisms.
Because biocides range in antimicrobial activity, other terms may be more specific:
“-static” is an agent which inhibit growth (e.g., bacteriostatic, fungistatic, and sporistatic)
“-cidal” is an agent which kill the target organism (e.g., sporicidal, virucidal, and bactericidal).
Bacteriostatic vs Bactericidal
Bacteriostatic allows for natural immunity to deal with the microbe (antibodies, phagocytosis

223
etc). Bactericidial may lead to release of toxins and microbial contents leading to subsequent
illness and inflammatory responses.
Bacteriostatic Bactericides
- tetracyclines; - betalactams (penicillins, cephalosporins, carbapenems,monobactams);
- fenicoli; - glycopeptides (Vancomycin) or polypeptides (bacitracin);
- macrolides*; - polymyxins;
- lincosamides*; - aminoglycosides;
- sulfonamides, - ketolides;
- trimethoprim. - quinolones;
- Rifampicin; Isoniazid.
* According to the dose may be bactericidal for some organisms
Spectrum of Activity
 Relates to the number of microbes that are sensitive to the action of the drug
 Narrow (limited number) / Broad (wide)
o Oxacillin is a narrow spectrum drug because it is only effective against
Staphylococcus spp.
o Tetracyclines are broad spectrum drugs because they are effective against
gram-positive and gram-negative microbes.
Note: Never confusion these terms with potency levels of the drugs or efficacy (Never
confusion: Narrow are weak, Broad are strong)

Indications for antibiotics

Absolute indications:
- in children, the elderly;
- before surgery (e.g., gastrointestinal surgery, joint replacement) or
antibacterial protection during surgery;
- people with valvular heart disease: to prevent bacterial endocarditis with S.
aureus;
- person with severe chronic diseases or immunocompromised;
- prophylaxis of rheumatic fever.
Relative indications:
- prophylaxis of scarlet fever in contacts;
- prevention of meningococcal meningitis;
- the incubation period of some bacterial diseases (pertussis, tuberculosis,
syphilis).

Associations of chemotherapics
- Theoretically: the treatment of bacterial infections should be in accordance
with the culture and sensitivity testing or (second best) knowledge of these

224
agents.
- Practically: the treatment of bacterial infections is empirical in:
 mixed infections;
 serious infection of unknown origin;
 when there is the possibility of microbial resistance to chemotherapic
groups;
 long term traitementes.
- The benefits:
 widening the antibacterial spectrum;
 increase efficiency;
 delay emergence of resistance
- No associations are allowed between:
 bacteriostatic with bactericidal;
 aminoglycosides with polymyxins;
 penicillins in high doses with nephrotoxic cephalosporins (generation I
and II) or with aminoglycosides (gentamicin, kanamycin and others).

Criteria for the choice of chemotherapy

• The pharmacokinetic characteristics:
 Absorption: depends on type of chemotherapy, gastrointestinal tract;
 serum: absorption depends on the dose, the rate of administration,
distribution in the tissue removal;
 half-life and rate of administration;
 diffusion in tissues (access to the site of infection, local conditions of
infected tissue) is best in the inflamed organs by increasing blood flow,
better chemotherapeutic diffuse low molecular weight, soluble and
ionized;
 metabolism: the liver and functional status and maturation;
 excretion (renal / liver) and elimination of the form (active / inactive).
• The characteristics of chemotherapy:
 spectrum of action, resistance, in vitro tests,
 bactericidal / bacteriostatic chemotherapy.
• Particular physiological states: the newborn, adult, pregnancy, old.

Pharmacokinetic particularities
225
- Administration:
 Oral administration is the most advantageous.
 Food may affect the absorption.
 iv: prefered in severe infections to reach higher concentrations in the
body.
- Protein binding: Tetracyclines and lincomycin are highly bound to plasma
proteins, this is why they are not used in patients on hemodialysis.
- Duration of treatment:
 single dose:
o for lower urinary primoinfections requiring a single dose of
Ampicillin,
o gonococcal primary infection requiring a single dose of
streptomycin.
 long treatment: staphylococcal endocarditis (4 weeks) etc.
- Dose depends on many factors: the nature and severity of infection, weight,
age, renal function and liver function of the patient.
- In severe liver disease
 Reduce the dose or contraindicate: Chloramphenicol, Rifampicin.
 No risk of acute toxicity: clindamycin, lincomycin, Ampicillin, nafcillin,
isoniazid.
- In case of severe renal impairment:
 Reduce dose or contraindicate: aminoglycosides, polymyxin,
Vancomycin.
 Tetracyclines: are contraindicated.
- During pregnancy: penicillins and cephalosporins reach high concentrations in
the fetus, but no fetal toxicity problem.
- The active concentrations in the tissues:
 There are necessary lower concentrations when the local immune
mechanisms have a normal function
 There are required high concentrations when the local immune
mechanisms are deficient.
- Entry into cells:
 Possible when the cell has no cell wall. Required to destroy bacteria that
survive in different cells, e.g., phagocytes (Koch, Brucella, Legionella).
Rifampicin or quinolones of the third generation are active on

226
 intracellular pathogens.
- The access of active substances to the site of infection
 Infections in poorly perfused tissues are difficult to treat, when defense
mechanisms are deficient, higher concentrations are needed.
 penetration into the brain, eye, prostate, bone:
- The classical cephalosporins can not reach bactericidal concentrations in
cerebrospinal fluid (CSF), but Chloramphenicol penetrates through the
meninges (faster when the meninges are inflamed);
- staphylococcal osteomyelitis responds well to clindamycin (concentrated in
the bones).

Chimioterapics concentrate in:

 Bronchial secretions: Ampiciline, Cefalotin, Gentamicin;
 Liver: Dapsone (against leprosy);
 Bile: antibiotics (aminopenicillins, antistaphylococcal penicillins, macrolides, tetracyclines,
Cyclosporine, Rifampicin, quinolones 3rd generation, cephalosporins III-rd and IV-th
generation, aminoglycosides),.
 salivary glands: Minocycline, quinolines (Chlorquinaldol)
 tears: Rifampicin, Minocycline;
 sweat: Rifampicin;
 milk: Penicillin G, aminoglycosidestetracyclines;
 hair: quinolones 3rd generation (Temafloxacin, Ofloxacin, Norfloxacin, Ciprofloxacin);
 nails: antifungal drugs (Ketoconazole, Terbinafine, Itraconazole, Griseofulvin), droguri
(Metamphetamine, Cocaine);
 peritoneal liquid: Gentamicin, Vancomycin, Cefoxitin;
 prostate: quinolones 3rd generation, sulfonamides, Trimetoprim, Spectinomycin
 seminal fluid: cefalosporins, macrolides, quinolones.
 vaginal fluid: quinolones 3rd generation, sulfonamide, Trimetoprim
 Bone, cartilages: tetracyclines, lincosamides, quinolones 3rd generation, heavy metals.
 Phagocyte cells: Rifampicin, quinolones 3rd generation,
 Thyroid gland: quinolines (Clioquinol, Chlorquinaldol)
 fetal blood and amniotic liquid: Ampicillin, Azlociline.

A bacterial cell structure

- the cell wall (cell maintains the structure) compound of peptidoglycan, a
polymer of sugars and amino acids
- flagella (structures used for locomotion)
- plasma membrane (phospholipid bilayer surrounding the cell) contains

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proteins that play a role in the transport of ions, nutrients and waste
- nucleus
 DNA (single double-stranded circular chromosome)
 Plasmid (small circular chromosome) - can carry a gene for antibiotic
resistance
- Ribosomes (site of protein synthesis)

Some characteristics of infectious bacteria

- Virulence factors: molecules produced by a pathogen that aid in its survival in
a host
- capsule: surrounds the bacterial cell wall, protects the bacteria from
phagocytosis
- pili: allows bacteria to attach and invade other cells in spite of mucus and cell
turnover
- Enzymes: breaking the matrix between cells allows bacteria to spread into the
tissues
- Toxins
 Exotoxins: lysis of host cells because of some
 enterotoxins: cause fluid secretion in the small intestine leads to
vomiting and diarrhea
 Endotoxin o: cell-bound lipopolysaccharide, fever and inflammation.

Bacterial resistance
- natural resistance:
 relative resistance of Gram (-) to Penicillin G;
 Bacterial resistance to antifungal structure with polienique to
chemotherapy etc.
- acquired resistance to drugs:
 by mutations;
 transfer (plasmid or extracromosomial) R factor (= resistance factor
found in plasmids);
 by the production of lytic enzymes;
 by adaptation during antibacterial chemotherapy;
 by changing the membrane permeability of bacteria.
- It can prevent the emergence of resistance: the fair, adequate doses of

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antibacterial agents, treatment monitoring, avoiding autotratamentelor.

Adverse effects: of antibacterial agents

• Toxic reactions at therapeutic doses:
 aminoglycosides are ototoxic and nephrotoxic
 polimixines, cephalosporins generation I and II are nephrotoxic;
 Rifampicin, Chloramphenicol, macrolides (Erythromycin,
Azithromycin, Roxithromycin) are hepatotoxic;
 Chloramphenicol is medulotoxic;
 penicillins in high doses and polimixines are neurotoxic.
• The immunological reactions:
 Type I (IgE mediated): penicillins, cephalosporins, sulfonamides,
 Type III (mediated by IgG / IgM): penicillins, cephalosporins,
sulfonamides.
• The biological reactions:
 dismicrobism intestinal or superinfection with resistant organisms (after
oral administration of broad-spectrum chemotherapy, long-term):
tetracyclines, quinolones as IIIrd generation.

CLASSIFICATION OF ANTIBIOTICS CAN IN SEVERAL WAYS:

 Depending on their mechanism of action against the infecting
organism (the most common criteria). Some antibiotics attack the cell
wall, some disrupt the cell membrane, the majority inhibit the synthesis
of nucleic acids and proteins etc.
1. Inhibitors of bacterial cell wall synthesis
2. Inhibitors of the function of the bacterial cell wall (disruption
of the cell membrane)
3. Inhibitors of bacterial protein synthesis
4. Inhibitors of nucleic acid synthesis
5. Inhibitors of the synthesis of other structures bactérienes
(interference with metabolic processes).
 According to which bacterial strains they affect: staphylococcus,
streptococcus, E. coli etc.
 Based on the chemical structure: penicillins, cephalosporins,
aminoglycosides, tetracyclines, macrolides, sulfonamides etc.

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 2.Antiseptic and disinfectant drugs

Classification
1. Alcohols 9. Surface-active agents (surfactants)
2. Aldehydes 10. Antiseptics and disin-fectants from
3. Acids the group of dyes
4. Halogen-releasing agents 11. Quinoleine derivatives
5. Peroxygens 12. Metenamine derivatives
6. Heavy metal compounds 13. Nitrofurans
7. Phenols 14. Gases.
8. Other structures

2.1. Antiseptic and disinfectant drugs with local administration

1. ALCOHOLS
Mechanism of action: precipitation of cellular proteins.
Bactericidal. Weakly fungicidal, virucidal variably. Not sporicidal.
ETHANOL: The concentration of 70% is bactericidal in 1-2 min at 30°C;
lower or higher concentrations are less effective. The hydration facilitates
penetration into bacterial cells. Its effectiveness is reduced in the presence of
organic matter. Do not apply to mucous membranes, wounds, infants.
 Indications: antisepsis of healthy skin before injection and blood
samples (except: blood culture, or procedures requiring surgical
asepsis). As spray with 70% alcohol: disinfect equipment for artificial
respiration.
PROPYLENE GLYCOL and other glycols: for disinfection of the air.

2. ALDEHYDES
Mechanism of action: precipitation of cellular proteins. They are irritating for
the tissues.
Bactericidal at high concentrations and more effective on G (-) bacteria,
sporicidal (if prolonged contact time), fungicidal, virucidal, ineffective on
prions.
FORMALDEHYDE (or formalin): the concentration of 1-10% destroy

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microorganisms and spores in 1-6 h. Uses: disinfection of the rooms in
notifiable diseases, disinfection of surfaces, conservation of anatomical
specimens.
GLUTARALDEHYDE (2% alkaline solution in 70% isopropanol and pH =
7.5 to 8.5): destroy microorganisms in 10 min and spores in 3-10 h. Uses:
disinfection of heat-sensitive medical devices and soil surfaces.

3. ACIDS
INORGANIC ACIDS are used for cauterization of tissues.
BORIC ACID: 5% solution or powder is applied to skin lesions (antimicrobial
effects). May have toxic effects, especially in children: pain, hypotension,
hyperthermia, convulsions.
BENZOIC ACID: 0.1% solution is used as food preservative. Esters of
benzoic acid ("parabens"): preserve some drugs.
ACETIC ACID: 1% solution is used in surgery (local antimicrobial agent),
0.25% solution to irrigate ear and lower urinary tract. Active against G (-)
bacteria (e.g., Pseudomonas spp).
SALICYLIC ACID: keratolitic action (for the treatment of horn, also known
as clavus) and fungicide: in dermatophytosis.

4. HALOGEN-RELEASING AGENTS
Classification
- chlorine-releasing agents: Hypochlorous acid, Sodium hypochlorite,
Chloramine;
- iodine and iodophors: - alcoholic solutions of iodine
- iodophors ("iodine carriers" or "iodine-releasing
agents"): povidone-iodine and poloxamer-iodine.
Chlorine may be presented as:
 HYPOCHLOROUS ACID: highly bactericidal for many organisms,
including M.tuberculosis; in the presence of damaged proteins, the
activity is greatly reduced;
 SODIUM HYPOCHLORITE 0.5% (Dakin solution): disinfect
wounds, sputum, pus, urine, blood and premises;
 CHLORAMINE and chlorine: disinfection of water.
Iodine and iodophors are the most effective germicidal (solution 1/20000

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destroys bacteria and spores in up to 15min).
 ALCOHOL SOLUTION OF IODINE (2% iodine, sodium iodide
2.4% in alcohol 47%): very good skin antiseptic.
o Disadvantage: onset of dermatitis in hypersensitive individuals;
accidental poisoning: collapse, renal failure; treated with sodium
thiosulfate (p.o./iv).
 POVIDONE-IODINE (polyvinylpyrrolidone iodine bound, Betadine):
preoperative antiseptic for skin, hair, mucosa etc. In aqueous medium:
free iodine is released. Advantage: no hypersensitivity reactions.

5. PEROXYGENS (oxidizing agents)

Mechanism of action: the release of atomic oxygen, which blocks the enzyme
systems of microbial germs. Antibacterial activity and is also effective against
viruses, including HIV.
Oxidizing agents have short action.
HYDROGEN PEROXIDE (H2O2): hydrogen peroxide 30%, of hydrogen
peroxide at 3% (hydrogen peroxide). Hydrogen peroxide has the following
properties:
 disinfectant and antiseptic to cleanse wounds and ulcers;
 haemostatic action (epistaxis and bleeding gums);
 release adhering and blood-soaked dressings.
POTASSIUM PERMANGANATE 1/5000: to wash wounds, disinfectant and
deodorizer.

6. HEAVY METAL COMPOUNDS (external use only)

6.1. MERCURY SALTS
Mechanism of action: block "-SH" groups both in bacteria and in the host:
precipitate proteins and inhibit sulfhydryl enzymes.
PHENYLMERCURBORATE: disinfection of mucous membranes and
instruments with metal and rubber.
THIOMERSAL (THIOMEROSAL): disinfection of mucosa, instruments,
preservation of serum and vaccines.
6.2. SILVER SALTS
Mechanism of action: protein precipitation.
SILVER NITRATE (concentration of 1/100000): eye drops in newborn to

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avoid gonorrhea.
SILVER SULFADIAZINE: to treat burns.
6.3. OTHER METALS SALTS: copper salts and zinc, bismuth salts.

7. PHENOLS: Phenol, Hexachlorophene, Triclosan, Chloroxylenol, Cresols,

Resorcinol;
PHENOL Mechanism of action: a high concentration has a lethal effect by
penetration into the cell and precipitation of cellular proteins, a low
concentration inhibit cell multiplication by inactivation of enzyme systems and
alteration of the cytoplasmic membrane. Bacteriostatic at low concentration
(0.2%) and bactericidal at a concentration higher than 1%. Not virucidal,
sporicidal not, inactive in prion. Indications: disinfection of instruments, of
rooms. Disadvantages: smell is unbearable, it is corrosive to metals and many
materials.
PHENOL DERIVATIVES (have a broader spectrum of action, less toxic to
the skin and mucousa).
 HEXACHLOROPHENE (phenolic index increased to 7.5) is 10 times
more active than phenol, it is insoluble in water but soluble in organic
solvents and soaps. Indications: surgery (including liquid soaps),
cosmetics (soaps, shaving creams, shampoos), the newborn after bath
powder (3% concentration).
 CRESOLS (phenolic index greater than 3 times) Indications: in
dentistry.
 CREOLINE (mixture of cresols,aromatic hydrocarbons, soap):
disinfection of rooms.
 RESORCINOL (1-5% solution): in dermatitis (as antipruritic,
keratolytic), oral antiseptic.

8. OTHER STRUCTURES: Chlorhexidine, Lindane;

LINDANE (gamma benzene hexaclorit) Indications: 1% solution (lotions,
shampoos, creams) in scabies, pediculosis. Solution>10% are absorbed through
skin and induce toxicity.
CHLORHEXIDINE is an antiseptic bisdiguanide. Mechanism of action:
disruption of the cytoplasmic membrane of microorganisms. Indications:
0.02% solution as a bladder irrigation in some urinary-tract infections (less

233
effective against strains of Pseudomonas, Serratia, coliforms and G(+)
bacteria); 0.1% solution: disinfection of instruments, catheters; 0.1% - 0.2%
solution: antiseptic to the oral mucosa.

9. Surface-active agents (surfactants): cationic agents (cationic detergents),

soaps (anionic surfactants) are salts of sodium or potassium with fatty acid);
Mechanism of action: change the surface tension existing at the surface of the
cell membrane. Bacteriostatic action, effective against spores, fungi and M.
tuberculosis.
Indications: antiseptic to mucous membranes and skin, to disinfect instruments
and membranes, for cleaning or washing.

10. Antiseptics and disinfectants from the group of dyes: Methylen blue,
Rivanol, Gentian violet, Crystal violet, Methyl violet, Acridine;
GENTIAN VIOLET, METHYL VIOLET AND CRYSTAL VIOLET:
dilutions of 1/1000000 destroy streptococci, staphylococci, diphtheria bacilli
etc.
RIVANOL: disinfect the wound and instrumentation, has low antifungal
properties.
METHYLENE BLUE: phenothiazine derivative, antiseptic and antifungal for
external use.

11. QUINOLEINE DERIVATIVES: Clioquinol, Chlorquinaldol,

Mexaform®;
12. METENAMINE DERIVATIVES: methenamine mandelate, methenamine
hippurate;
13. NITROFURANS: Nitrofurazon, Furazolidone, Nitrofurantoin.
14. GASES:
- oxidizing agents: ozone (O3), chlorine gas (Cl2), chlorine dioxide (ClO2)
- alkylating agents: ethylene oxide (C2H4O), formaldehyde, propylene
(C3H6O).

2.2. Antiseptic drugs with systemic administration

Urinary antiseptics and other drugs used for the treatment of urinary
infections
- Nitrofurans: Nitrofurantoin;
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- Quinolones;
- Methenamine: methenamine mandelate, methenamine hippurate;
- Acidifiant agents:Amonium chloride,Ascorbic acid,Mandelic
acid,Methionine,Hipuric acid
- Sistemic administration: sulfonamides (Sulfisoxazol, Trisulfapirimidine),
Penicillins (Ampicillin, Carbenicillin), aminoglycozide (Gentamicin,
Kanamycin, Amikacin), Cycloserin
- Local administration: Amphotericin B, Polymyxins, Neomycin.

3.Antibacterial drugs
3.1.Inhibitors of bacterial cell wall synthesis

Most bacteria possess a cell wall to protect from osmotic pressures. When
microbe divides, they need to create a new cell wall. Interrupttion of this leads
to new microbes being susceptible to external influences. Cell ruptures
determines microbe death.

Classification
1. Inhibitors of bacterial cell wall synthesis
1.1. Betalactam antibiotics:
1.1.1. Penicillins:
- Natural penicillins: Benzylpenicillin (Penicillin G); Procainpenicillin; Benzathinpenicillin;
Phenoxymethylpenicillin (Penicillin V).
- Semisynthetic penicillins:
- Antistaphylococcal penicillins:
- izoxazolylpenicillins: Oxacillin, ClOxacillin, DiclOxacillin;
- Methycillin;
- Nafcillin.
- Extended spectrum penicillins:
- Aminopenicillins: Ampicillin, Amoxicillin;
- Carboxipenicillins: Carbenicillin, Ticarcillin;
- Ureidopenicillins: Piperacillin, Mezlocillin, Azlocillin;
- Amidinopenicillins: Pivmecillinam, Furazlocilin.
Beta-lactamase inhibitors: Clavulanic acid; Sulbactam; Tazobactam.
Combinations: Augmentin® = Amoxicillin + Clavulanic acid;
Timentin® = Ticarcillin + Clavulanic acid;
Zosyn® = Piperacillin + Tazobactam;
Unasyn® = Ampicillin + Sulbactam.

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1.1.2. Cephalosporins
Cephalosporins 1st generation:
- oral administration: Cephradine, Cephalexin, Cefadroxil;
- parenteral administration: Cephradine, Cefazolin, Cephalotin, Cephapirin.
Cephalosporins 2nd generation:
- oral administration: Cefuroxime, Cefaclor, Loracarbef, Cefotiam;
- parenteral administration: Cefuroxime, Cefamandole, Cefmetazole, Cefotetan, Cefoxitin,
Cefonicid, Ceforanid.
Cephalosporins 3rd generation:
- oral administration: Cefixime, Cefpodoxime;
- parenteral administration: Ceftriaxone, Ceftazidime, Cefotaxime, Cefoperazone, Moxalactam,
Ceftizoxime, Ceftibuten, Proxetil.
Cephalosporins 4th generation:
- parenteral administration: Cefepime, Cefpirome.
Cephalosporins 5th generation:
- parenteral administration: Ceftaroline, Ceftobiprole.
1.1.3. Carbapenems: Imipenem, Meropenem, Ertapenem;
Combinations: Tienam® = Imipenem + Cilastatin
1.1.4. Monobactams: Aztreonam;
1.2. Glycopeptide antibacterials: Vancomycin, Teicoplanin;
1.3. Phosphomycins: Phosphomycin;
1.4. Cycloserin;
1.5. Polypeptide antibacterials: Bacitracin, Gramicidin, Tyrothricin;
1.6. Ristocetin;
1.7. Daptomycin.

Structure
Betalactams are the most important family (derived from 6-aminopenicillanic
acid) with the structure:
- betalactam cycle
- tiazolidine cycle
- a second group R (which determines the antibacterial activity).
If the betalactam ring is enzymatically cleaved by bacterial beta-lactamases,
results penicilloic acid, which lacks antibacterial activity, but determine allergic
reactions.

PENICILLINS
Sources
- Are derived from Penicillium chrysogenum.
- Penicillin G and Penicillin V are unaltered products of Penicillium
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fermentation.
- Semi-synthetic penicillins are formed by addition of R groups to the main 6-
aminopenicillanic acid ring.
The activity of Penicillin G was originally defined in units. Semisynthetic
penicillins are prescribed by weight rather than units.
Mechanism of action: inhibition of the synthesis of bacterial cell wall in three
steps:
- covalent bind to specific receptors: penicillin binding proteins (PBP);
- inhibits transpeptidation;
- activation of autolisines.
Bactericidal effect.
 Effective only against rapidly growing organisms that synthesize
peptidoglycan. (Ineffective against mycobacteria.)
Penicillins bacterial resistance
- formation of a barrier that prevents access to receptors PBP - Gram (-);
- alteration of PBP receptors;
- inactivation under the action of beta-lactamases;
- lack bacterial cell wall.
Pharmacokinetics
- Administration:
 only parenteral:
o Benzylpenicillin (=Penicillin G) – administered i.v./i.m.;
o Procainpenicillin; Benzathinpenicillin – administered i.m.
because are depot penicillins,
o Methycillin, carboxipenicilins, ureidopenicilins, Furazlocilin;
 only oral: Penicillin V (because it is acid resistant), Pivmecilinam
 the others are administered either parenteral or oral.
- Protein binding: high to nafcillin, Oxacillin very low. T1/2 increases in renal
failure.
- crosses the blood-brain barrier:
 The penicillins: cross very difficult through normal meninges, but very
easily through inflamed meninges;
 High concentrations in CSF are neurotoxic (determine seizures, tremors,
restlessness, nervousness).
- Do not enter the host cell.

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- Presents enterohepatic cycle: Oxacillin, ClOxacillin, Dicloxacilin, Nafcillin,
Ampicillin, Amoxicillin.
- Concentrated in: breast milk; sputum.
- Elimination: 90% is unchanged,
 eliminated mainly renal (natural penicillins, carboxipeniciline,
ureidopeniciline, methicillin):
o Dosage adjustment in renal impairment;
o There is competition between Penicillin G and Probenecid for
the mechanism of renal tubular secretion;
 mainly biliary (Izoxazolilpenicilline, Nafcillin, Aminopenicilins)
o no adjustment of dosage in renal failure.

NATURAL PENICILLINS
Classification
 Benzylpenicillin (= Penicillin G);
 Procainpenicillin (is a natural penicillin composed of procaine and
Penicillin G);
 Benzathinpenicillin;
 Phenoxymethylpenicillin (= Penicilina V).
Antibacterial spectrum of the natural penicillins:
- most effective against Gram-positive bacteria, and less effective against
Gram-negative organisms and ineffective against fungi:
 G(+) cocci: streptococci (including Streptococcus beta-hemolytic group
A, pneumococcus, enterococcus, peptostreptococcus);
 G(+) bacilli: Lysteria monocytyogenes, Corynebacterium;
 G(-) cocci: Neisseria meningitidis, Neisseria gonorrhoeae;
 G(-) bacilli: Bacteroides (without Bacteroides fragilis);
 spirochetes: Treponema pallidum, Leptospira;
 Actinomyces.
Indications
- Penicillin G:
 Drugs of choice for:
o pneumococcal pneumonia or bacteremia;
o beta hemolytic streptococcal infection (pharyngitis, septicemia);
o infections of the upper respiratory tract, skin and soft-tissue

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 infections, scarlet fever, and erysipelas due to susceptible
streptococci;
o meningococcal meningitis or pneumonia;
o syphilis;
o leptospirosis;
o bacteroides infections (oropharyngeal, other G(-) anaerobic),
infections with Actynomyces or Clostridium (tetanus, gangrene);
o meningitis, septicemia, endocarditis in combination with other
chemotherapeutic antibacterial.
o anaerobic infections, gonorrhea, ear infections, sinusitis.
NOTE: Reports indicate an increasing number of strains of
staphylococci resistant to Penicillin G.
- Procainpenicillin: treatment of infections due to Penicillin G-sensitive
microorganisms;
- Benzathinpenicillin (retard type Penicillins):
 prophylaxis of rheumatic fever
 treatment of mild/moderate infections in the upper respiratory tract
caused by Streptococcus sp.
 treatment of syphilis.
- Penicillin V: minor infections of the respiratory tract.

SEMISYNTHETIC PENICILLINS
Classification
 Antistaphylococcal penicillins (= narrow spectrum penicillins):
o izoxazolylpenicillins: Oxacillin, ClOxacillin, DiclOxacillin;
o Methycillin;
o Nafcillin.
 Extended spectrum penicillins:
o Aminopenicillins: Ampicillin, Amoxicillin;
o Carboxipenicillins: Carbenicillin, Ticarcillin;
o Ureidopenicillins: Piperacillin, Mezlocillin, Azlocillin;
o Amidinopenicillins: Pivmecillinam, Mecillinam, Furazlocilin.
 Beta-lactamase inhibitors: Clavulanic acid; Sulbactam; Tazobactam.
 Combinations: Augmentin® = Amoxicillin + Clavulanic acid;
Timentin® = Ticarcillin + Clavulanic acid;

239
 Zosyn® = Piperacillin + Tazobactam;
Unasyn® = Ampicillin + Sulbactam.
Antibacterial spectrum of:
 Antistaphylococcal penicillins: G(+) cocci (staphylococci and
streptococci)
o are resistant to staphylococcal lactamases, resist degradation by
penicillinase, useful for treating S. aureus infections.
 Broad and Extended spectrum penicillins
o Aminopenicilins (Broad spectrum):
 G(+) cocci: streptococci (including beta-hemolytic group
A streptococcus, pneumococcus, enterococcus);
 G(+) bacilli: Lysteria monocytyogenes, some species of
Chlamydia, Corynebacterium;
 G (-) cocci: Neisseria meningitidis, Neisseria
gonorrhoeae;
 G (-) aerobic bacilli: H. influenzae, E. coli, Salmonella,
Shigella, H. pylori etc.
o Carboxipenicilins (Extended spectrum penicillins):
 They are less active bacteria G (+).
 active against more G (-) aerobic bacilli, including
Pseudomonas, Proteus, Serratia, Enterobacter.
o Ureidopenicilins (Extended spectrum penicillins): spectrum
similar carboxypenicilins, but are more active on Klebsiella
pneumoniae.
o Carboxipenicilins and ureidopenicilins are also called anti-
Pseudomonal penicillins. Often used with aminoglycosides
when treating Pseudomonal infections.
Indications
- Antistaphylococcal penicillins34:
 Drugs of choice for beta-lactamase staphylococcal infections;
 infection with strains of streptococci (S. pneumoniae).
- Aminopenicilins:
 respiratory tract infection (drugs of choice for pneumococcal

34
Dicloxacillin: highest serum levels after oral administration; Nafcillin: preferred for parenteral administration;
Methicillin: rarely used due to toxicity.

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 pneumonia),
 infection of the bile or urinary infections (E. coli, Proteus),
 typhoid infections (Salmonella);
 severe infections (septicemia, meningitis etc.);
 drugs of choice for infections with Lysteria, H. influenzae, gonococcal;
 treatment for eradication H. pylory infection.
- Carboxipenicilins, ureidopenicilins:
 Drugs of choice for nosocomial infections, particularly determined by
Pseudomonas.
- Amidinopenicillins:
 Pivmecillinam: acute uncomplicated cystitis, chronic or recurrent
bacteruria and salmonellosis.
 Mecillinam: severe infections due to Gram negative enteric bacteria.
Adverse reactions of penicillins
- hypersensitivity reactions (due to penicilloic acid in 1-10% of patients):
 Type I: rash (most common), fever, pruritus, urticaria, angioedema,
anaphylactic shock (rare, but very severe);
 Type II: hemolytic anemia;
 Type III: Stevens-Johnson syndrome.
 Rashes - most common reaction. 50% do not have a recurrent rash.
- Herxheimer reaction: Penicillin G (administered at high doses in syphilis);
- dysmicrobism, nausea, vomiting: for extended spectrum penicillins;
- pseudomembranous colitis: to Ampicillin.
- neurotoxicity: penicillin (intrarahidian or high dose). In patients with renal
failure, high doses cause convulsions.
- hepatotoxicity: for Oxacillin, carboxipeniciline.
- nephrotoxicity: for methicillin, carboxipeniciline.
- medulotoxicity (leukopenia, neutropenia, thrombocytopenia, hemolytic
anemia and injuries in those with severe renal impairment): for
carboxipeniciline;
- severe granulocytopenia: for methicillin.
- systemic hypokalemic alkalosis: for Carbeniciline.
- bleeding disorders: for Carbeniciline.
Contraindications
- hypersensitivity reactions to penicillins

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- Penicillin G sodium is contraindicated in heart failure, arrhythmias;
- Penicillin G potassium is contraindicated in renal failure and arrhythmias (risk
of arrhythmias).
BETA-LACTAMASE INHIBITORS
Classification:
 Clavulanic acid: produced by Streptomyces clavuligerus;
 Sulbactam;
 Tazobactam.
Mechanism of action: inhibitors of many (but not all bacterial lactamases) and
protect penicillins from inactivation by these enzymes.
Bactericidal effect.
Indications:
- drug of choice for gonorrhea, infections with bacteria that produce beta-
lactamase;
- infection to other susceptible organisms.
CEPHALOSPORINS
Are chemical similar to penicillins (semisynthetic beta-lactams with 7-
aminocephalosporanic acid ring). Generally, are more resistant to beta-
lactamases.
Classification of cephalosporins is by generations:
 Cephalosporins 1st generation:
o oral administration: Cephradine, Cephalexin, Cefadroxil;
o parenteral administration: Cephradine, Cefazolin, Cephalotin,
Cephapirin.
 Cephalosporins 2nd generation:
o oral administration: Cefuroxime, Cefaclor, Loracarbef,
Cefotiam;
o parenteral administration: Cefuroxime, Cefamandole,
Cefmetazole, Cefotetan, Cefoxitin, Cefonicid, Ceforanid.
 Cephalosporins 3rd generation:
o oral administration: Cefixime, Cefpodoxime;
o parenteral administration: Ceftriaxone, Ceftazidime, Cefotaxime,
Cefoperazone, Moxalactam, Ceftizoxime, Ceftibuten, Proxetil.
 Cephalosporins 4th generation:
o parenteral administration: Cefepime, Cefpirome.

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  Cephalosporins 5th generation:
o parenteral administration: Ceftaroline, Ceftobiprole.
Mechanism of action: inhibition of the synthesis of bacterial cell wall in three
steps:
Antibacterial spectrum:
first-generation compounds have better activity against G(+)
organisms and the later generation have improved activity
against beta-lactamase-producing strains and against G(-)
aerobic organisms.
 first-generation cephalosporins: good activity against G(+) bacteria
and relatively modest activity against G(-)bacteria (active on
Escherichia coli, Klebsiella);
 2nd generation cephalosporins: some activity against G(+) bacteria
and somewhat increased activity against G(-) bacteria (E. coli,
Klebsiella, Proteus, Haemophilus influenzae);
 3rd generation cephalosporins: less active than first-generation agents
against G(+) cocci, but are much more active against G(-) bacteria (E.
coli, Klebsiella, Proteus, H. influenzae, Serratia), including beta-
lactamase-producing strains;
 4th generation cephalosporins: extended activity spectrum (E. coli,
Klebsiella, Proteus, H. influenzae, Serratia, Pseudomonas); resist
hydrolysis by beta-lactamases.
 5th generation cephalosporins: extended antibacterial activity on
bacteria resistant to other antibacterial drugs.
Pharmacokinetics
- 1st generation cephalosporins:
 do not cross the blood-brain barrier.
 not effective systemic concentrations.
 are highly nephrotoxic.
nd
- 2 generation cephalosporins:
 do not cross the blood-brain barrier (except cefuroxime).
 determine effective systemic concentrations.
 are highly nephrotoxic.
 cefamandole is the only compound that is concentrated in bile.
- cephalosporins 3rd, 4th and 5th generation:

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  crosses the blood-brain barrier.
 are hepatotoxic
 are concentrated in bile, present enterohepatic cycle.
Indications
- 1st-generation cephalosporins: excellent agents for skin and soft tissue
infections (especially S. aureus and S. pyogenes), surgical profilaxis for skin
infections.
- 2nd-generation cephalosporins are used to treat respiratory tract infections,
intra-abdominal infections, pelvic inflammatory disease, diabetic foot infection
and are preferred for prophylaxis for intestinal anaerobes (e.g., colorectal
surgery).
- 3rd-generation cephalosporins are the drugs of choice for serious infections
caused by Klebsiella, Enterobacter, Proteus, Providencia, Serratia, and
Haemophilus spp, for treatment of community-acquired pneumonia, for initial
treatment of meningitis in immunodepressed patients. Ceftriaxone is the drug of
choice for all forms of gonorrhea. Ceftazidime is active against Pseudomonas.
- 4th- and 5th-generation cephalosporins are indicated for the empirical
treatment of nosocomial infections where there is resistance to other antibiotics.
Adverse effects:
- hypersensitivity reactions (15% of patients):
 Type I: urticaria angioedema, anaphylaxis;
 Type III: Stevens-Johnson syndrome.
- intestinal dysmicrobism (after oral administration);
- disulfiram-like reactions: Moxalactam, Cefamandole, Cefotetan,
Cefoperazone;
- anticoagulant-like effect (risk of bleeding): Cefamandole, Cefoperazone;
- hepatotoxicity: III and IV generation cephalosporins;
- nephrotoxicity: I and II generation cephalosporins.
CARBAPENEMS
Carbapenems: Imipenem, Meropenem, Ertapenem
Association: imipenem + cilastatin (dehydropeptidase inhibitor) = Primaxin ®.
Are resistant to beta-lactamases, but are inactivated by metallo-beta-lactamase
or dehidropeptidases from renal tubules.
Mechanism of action: inhibition of the synthesis of bacterial cell wall.
Bactericidal effect.

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Antibacterial spectrum - very large (very active on anaerobes):
- G (+) cocci: except for Methicillin-resistant staphylococci;
- G (+) bacilli: Lysteria; G (-) bacilli: Pseudomonas, Enterobacter, H. influenze
etc.
Indications: polymicrobial infections or bacteria resistant to beta-lactams.
Adverse effects:
- type I immunological reactions (allergies), local reactions (phlebitis,
thrombophlebitis, erythema), nausea, vomiting, hypotension, sweating,
dizziness, nephrotoxicity,
- convulsions (neurotoxicity) in the elderly, in alcoholics and in chronic renal
failure.
MONOBACTAMS
Monobactams: Aztreonam
They are resistant to beta-lactamases.
Bactericidal effect.
Mechanism of action: inhibition of the synthesis of bacterial cell wall.
Antibacterial spectrum is narrow: only aerobic G (-) bacteria (including
Pseudomonas, Serratia, Enterobacter, Haemophilus influenzae etc).
 Ineffective against gram positive and anaerobic organisms.
Indications:
- infections by G(-) bacteria resistant to other antibacterial chemotherapy
(respiratory tract, skin, osteomyelitis);
- alternative for patients allergic to penicillins or cephalosporins.
Adverse effects:
- nephrotoxicity;
- neurotoxicity;
- increase of serum transaminases;
- suprainfection with staphylococci, enterococci etc.

GLYCOPEPTIDES
Glycopeptides: Vancomycin, Teicoplanin
Mechanism of action: inhibition of the synthesis of bacterial cell wall.
Antibacterial spectrum: G (+) bacteria: staphylococci (including S. aureus
and S. epidermidis resistant to methicillin), streptococci, enterococci, Clostridia.
Bactericidal effect.

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Pharmacokinetics: Low concentrations in the CNS (only when the meninges
are inflamed). It is excretion by glomerular filtration.
Synergy with aminoglycosides.
Indications:
- drug of choice for staphylococcal infections resistant to methicillin or and
highly resistant to Streptoccocus species.;
- drug of choice for pseudocolite membranous Clostridium difficile;
- infections with G(+) bacteria resistant to other antibacterial chemotherapics;
- Staphilococcal infections in persons with allergies to penicillins and
cephalosporins.
Adverse effects:
- erythema on the neck (or red neck syndrome "red man"),
- nephrotoxicity,
- ototoxicity – may potentiate known ototoxic agents,
- phlebitis at the injection site.
FOSFOMYCINES
Fosfomycines: Fosfomycin
Bactericidal effect.
Mechanism of action: inhibition of the synthesis of bacterial cell wall in three
steps:
Antibacterial spectrum: broad spectrum G (+) and G (-) bacteria.
Indications: lower urinary tract infection without complications, ENT
infections.
Contraindication: renal failure, breastfeeding.

CYCLOSERINE
Chemotherapeutic antibacterial produced by Streptomyces orchidaeus.
Bactericidal effect.
Mechanism of action: inhibition of the synthesis of bacterial cell wall.
Antibacterial spectrum: M. tuberculosis, G (+) and G (-) bacteria.
Pharmacokinetics
- widely distributed in tissues;
- most of the administered dose is excreted in the urine as active metabolite.
Indications: treatment of tuberculosis (in case of resistance to first-line
antituberculosis treatment).

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Adverse effects: neurotoxicity (dose): headache, tremor, acute psychosis,
seizures.
Note: therapeutic dose is 0.5 to 1 g/24 h, divided into 2-3 partial doses. Doses of 0.75
g/24 h prevents the effects on the central nervous system.
BACITRACIN
Produced by Bacillus subtillis.
Antibacterial polypeptides: Bacitracin, Gramicidin, Tyrothricin
Bactericidal effect.
Mechanism of action: inhibition of the synthesis of bacterial cell wall in three
steps:
Antibacterial spectrum: bacteria G (+) and G (-), including Neisseria.
Topical appliquation (because of increased toxicity when administered
systemically).
Indications only in topical use:
- skin lesions or mucous membranes, suprainfected (as ointments, in
combination with neomycin or polymyxin);
- irrigation of joints, wounds or pleural cavity (saline with bacitracin 100-200
units / ml).
Adverse effects: nephrotoxicity (proteinuria, hematuria, nitrogen retention),
immunological reactions of type I.

3.2.Inhibitors of bacterial cell function

Essentially, affect cell membrane transport: increasing the permeability of the
membrane.Note: These agents are more toxic than systemic agents that inhibit
cell wall synthesis.
Classification of polymyxins: Colistin; Polymyxin B.
Bactericidal effect.
Antibacterial spectrum: G (-)bacteria (including Pseudomonas).
 Resistant to polymyxin: G (+) bacteria, Proteus, Neisseria.
Mechanism of action:
- as cationic detergents on bacterial cell membranes  blocks the
transmembrane transport.
Pharmacokinetics:
- not absorbed through the intestinal cells, do not enter the liver.
Indications: uncomplicated skin lesions, superficial infected skin lesions.
Contraindications: renal failure, lactation.

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 Lecture 12

Learning Objectives:
 Describe the general mechanisms of action of antimirobial drugs;
 Classify antibacterial drugs.
 Explain the indications, and adverse effects of frequently used antibiotics.
 Describe the mechanims of action and the adverse effects of antituberculois
drugs.
 List drugs used to treat leprosy

3.3.Inhibitors of bacterial protein synthesis

Mechanism of action:
- inhibition of bacterial protein synthesis by the coupling with the 30S or 50S
subunit of bacterial ribosomes:
 enter the bacterial cell by passive or active mechanisms;
 inhibit bacterial protein synthesis by:
o inhibition of protein synthesis initiation complex bacterial
o determine "misreading" of the genetic code of the bacterium;
o destruction of polysomes and formation of ineffective
monosomes.
- target: the bacterial ribosome.
 Bacterial – 70S (50S/30S)
o 50S binders - Macrolides, Clindamycin, Chloramphenicol,
Streptogramins.
o 30S binders - Aminoglycosides, Tetracyclines, Mupirocin
 Mammalian – 80S (60S/40S)
o High levels may interact with mammalian ribosomes.

Classification
3. Inhibitors of bacterial protein synthesis
3.1. Aminoglycosides: Streptomycin; Gentamicin; Tobramycin; Amikacin;

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Kanamycin; Neomycin; Netilmycin; Paromomycin; Isepamycin; Framycetin,
Sisomicin.
3.2. Aminocyclitols: Spectinomycin
3.3. Macrolides: Erythromycin; Clarithromycin; Azithromycin;
Roxithromycin; Rovamycine; Josamycin; Diritromycin; Spiramycin.
3.4. Ketolides: Telithromycin
3.5. Streptogramine: Quinupristin (streptogramin B); Dalfopristin
(streptogramin A); Pristinamycin.
3.6. Tetracyclines:
- short acting: Tetracycline, Oxitetracycline, Chlortetracycline,
Rolitetracycline;
- intermediate acting: Demeclocycline, Metacycline, Lymecycline;
- long acting: Doxicycline, Minocycline.
3.7. Phenicols: Chloramphenicol, Tiamphenicol
3.8. Oxazolidinone: Linezolid, Eperozolid
3.9. Lincosamide: Lincomycin, Clindamycin
3.10. Nitrofurani: Nitrofurazon; Furazolidon; Nitrofuranoin.
3.11. Fusidic acid.

AMINOGLYCOSIDES
 STREPTOMYCIN; GENTAMICIN; TOBRAMYCIN;
AMIKACIN; KANAMYCIN; NEOMYCIN; NETILMYCIN;
PAROMOMYCIN; ISEPAMYCIN; FRAMYCETIN, SISOMICIN
Sources: Some aminoglycosides are produced naturally by bacteria of the
genus Streptomyces and Micromonospora.
Structure: hexose ring to which various amino sugars are attached by
glycosidic linkages.
Mechanism of action: inhibition of bacterial protein synthesis by irreversible
coupling with the 30S subunit of bacterial ribosomes
Antibacterial spectrum:
- aerobic G(-) bacilli: Enterobacter, Pseudomonas, E. coli, Klebsiella, Proteus,
Serratia, Salmonella, Francisella tularensis, Vibrio cholerae, Yersinia pestis;
- G(+) cocci: streptococci, staphylococci (including S. aureus);
- Mycobacterium tuberculosis (for streptomycin, amikacin).
Bactericidal effect.

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  The action is inhibited by polymyxins and by anionic detergents.
Pharmacokinetics
- Absorption: no intestinal absorption (are absorbed in the intestine in the
presence of ulceration).
- Administration:
 im/iv in systemic infections; intrarahidian in meningitis;
 orally (neomycin, streptomycin) in:
o treatment of intestinal infections,
o preparation in the digestive tract before surgery
o to reduce the intestinal flora in hepatic coma
 topically (skin, mucous membranes): Neomycin, Gentamicin,
Kanamycin, Tobramycin;
 aerosols (better focus in the lungs).
- Distribution: aminoglycosides are very polar; this is why they do not readily
penetrate cells and in the CNS, not penetrate physiological barriers (intestinal,
blood-brain), EXCEPT the placenta. Good distribution in the renal cortex,
pleural or synovial fluid. Concentrated in milk, kidney and bile.
- Elimination: renal. Are removed by hemodialysis.
Indications:
- the therapy of choice for empirical therapy of serious infections with
unidentified bacteria;
- tuberculosis (streptomycin, amikacin)
 Tobramycin: is the only aminoglycoside ineffective in tuberculosis;
- Gentamicin: in osteomyelitis (it is administered directly into the infected bone
cavity in the form of "pearls" of porous material impregnated with gentamicin);
- neomycin: for the preoperative preparation of the colon, encephalopathy.
Contraindications:
- pregnancy,
- myasthenia,
- perioperative period to avoid interference with nondepolarizing skeletal
muscle relaxants.
Adverse effects:
- nephrotoxicity;
- ototoxicity (hearing loss) and vestibulotoxicity (= loss of balance, dizziness,
ataxia);

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  toxicity is cumulative and irreversible
- currare-like effects (skeletal muscle relaxation similar to currare);
- immunological reactions of type I and III;
- pain at the injection site.

AMINOCYCLITOLS
 SPECTINOMYCIN
It is structurally related to aminoglycosides: from aminociclitol.
Bacteriostatic (bactericidal only on N. gonorrhea).
Antibacterial spectrum: some G(+) and G(-) bacteria: Enterobacteriaceae, N.
gonorrhea.
Mechanism of action: inhibition of bacterial protein synthesis by the coupling
on the 30S subunit of bacterial ribosomes.
Administration: i.m. only
Indications: alternative treatment for gonorrhea in women.
Adverse effects: nephrotoxicity, anemia, pain at the injection site.

MACROLIDES
 ERYTHROMYCIN; CLARITHROMYCIN; AZITHROMYCIN;
ROXITHROMYCIN; ROVAMYCINE; SPIRAMYCIN;
JOSAMYCIN; DIRITROMYCIN.
Macrolides have a macrocyclic lactone ring. Erythromycin was obtained from
Streptomyces erythreus.
Mechanism of action: inhibition of bacterial protein synthesis by coupling of
50S ribosomal bacterial subunit.
Binding site is in the close proximity of the binding sites of lincomycin,
clindamycin and Chloramphenicol  occurs competition for the same
sites.
Bacteriostatic. May be bactericidal particularly at higher concentrations and
for susceptible strains of bacteria.
Antibacterial spectrum
- for Erythromycin:
 G (+) and G (-) cocci;
 G (+) or (+) bacteria: Legionella pneumoniae, H. pylori etc;
 spirochete (Treponema pallidum),

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  Rickettsia, Chlamydia, Mycoplasma, Bordetella, Bartonella.
- for Clarithromycin:
 spectrum of Erythromycin, extended with H. influenzae, Moraxella
catarrhalis, Mycobacterium avium, Toxoplasma gondii.
- for Azithromycin:
 spectrum of Erythromycin, extended with H. influenzae, Moraxella
catarrhalis, M. leprae, Toxoplasma gondii. It is less active on the G (+)
cocci.
- for Spiramycin: Toxoplasma gondii.
Antibacterial resistance appears in:
- production of esterases by Enterobaceriacee;
- change of the ribosome binding site;
- production of methylases;
- transfer of plasmids.
Pharmacokinetics
- Absorption:
 the absorption of Erythromycin and Azithromycin decrease in the
presence of food
 Erythromycin base is destroyed by gastric juices, Erythromycin stearate
and Erythromycin esters are resistant to acidic pH.
 clarithromycin is stable in acid;
- Do not cross the blood-brain barrier, but crosses the placenta. Good tissue
distribution EXCEPT CSF.
- Strong intracellular concentration in macrophages and neutrophils.
- Concentration in bile, breast milk.
- Metabolism:
 Liver: Erythromycin, clarithromycin;
 Azithromycin is not metabolized.
Clarithromycin and Azithromycin are metabolized to active compounds.
Erythromycin and Clarithromycin are inhibitors of metabolising
enzymes (inhibitors of cytochrome P450).
- enterohepatic cycle.
- elimination: bile and kidney.
Indications
- drug of choice in people allergic to penicillin;

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- respiratory infections, ENT, skin, urethritis, prostatitis, diphtheria, acne;
- eradication of infection with H. pylori;
- toxoplasmosis: Spiramycin;
- periodontal disease: Rovamycine.
Adverse effects
- prokinetic effects (due to the stimulation of motilin receptors): diarrhea,
nausea, vomiting, abdominal pain;
- hepatotoxicity (cholestatic hepatitis);
- nephrotoxicity induced by the active metabolite of clarithromycin;
- Erythromycin: prolong QT interval.
- Allergic reactions are rare.
Contraindications
- chronic hepatitis,
- chronic renal failure with a creatinine clearance <30 ml / min for
clarithromycin.
Drug Interactions
- Erythromycin and clarithromycin are inhibitors of drug metabolism 
increased plasma concentrations of Theophylline, methylprednisolone,
Cycloserine, coumarin oral anticoagulants.
- Erythromycin increases serum levels of digoxin (destroying the intestinal flora
that inactivates some oral digoxin), so, it increases the bioavailability of oral
anticoagulants.

KETOLIDES
 TELITHROMYCIN
It is a semisynthetic derivative of Erythromycin.
Mechanism of action: bind to the 50S subunit of bacterial ribosomes and
suppresses bacterial protein synthesis (similar to macrolides).
Antibacterial spectrum (it is similar to Azythromycin): staphylococci,
streptococci (including S. Pneumoniae), Haemophilus influenza, Moraxella
catarrhalis, mycoplasma, chlamydia, and Legionella
Bactericide.
Indications: mild-to-moderate severity pneumonia, bronchitis, sinusitis,
pharyngitis.
Adverse effects:

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- nausea, vomiting, diarrhea;
- hepatotoxicity (increases levels of transaminases);
- significant QT interval prolongation (increase risk of ventricular arrhythmia).

STREPTOGRAMINS
 QUINUPRISTIN (STREPTOGRAMIN B); DALFOPRISTIN
(STREPTOGRAMIN A); PRISTINAMYCIN.
Quinupristin is a streptogramin B, Dalfopristin is a streptogramin A. They are
derivatives of Pristinamycin.
Mechanism of action: bind to the 50S subunit of bacterial ribosomes and
suppresses bacterial protein synthesis.
Antibacterial spectrum: G(+) cocci, including those resistant to other
antibiotics (not effective on Enterococcus faecalis)
Bacteriostatic, but the combination Quinupristin + Dalfopristin is
bactericidal.
The antibacterial resistance appears in the production of metilases.
Administration: iv.
Indications: infections with streptococci, staphylococci, enterococci multidrug
resistant.
Adverse effects:
- pain at the infusion site;
- arthralgia and myalgia.

TETRACYCLINES
Classification
 short acting: TETRACYCLINE, OXITETRACYCLINE,
CHLORTETRACYCLINE, ROLITETRACYCLINE;
 intermediate acting: DEMECLOCYCLINE, METACYCLINE,
LYMECYCLINE;
 long acting: DOXYCYCLINE, MINOCYCLINE.
Mechanism of action: bind to the 30S subunit of bacterial ribosomes and
suppresses bacterial protein synthesis.
Pharmacodynamic effects
- antibacterials,
- immunosuppression by direct cytotoxic effects on T and B lymphocytes;

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- Demeclocycline inhibits the action of ADH in the renal tubule.
Antibacterial spectrum: very wide
- G (+) and G (-) aerobic and anaerobic bacteria
- intracellular microorganisms: rickettsiae; Chlamydia; Mycoplasma;
- spirochetes (Treponema pallidum);
- Actinomyces;
- amoeba;
- Minocycline is only active in Neisseria meningitidis.
Bacterial resistance occurs by:
- mutations;
- transfer of plasmids.
Bacteriostatic.
Pharmacokinetics
- Absorption: intracellular concentrations
 is reduced by food, dairy products, antacids, preparations with Fe2 + or
other divalent or trivalent metal ions;
 to Minocycline, Doxycycline, Lymecicline: absorption is not affected by
food.
- wide tissue distribution.
- enter into cells;
- cross the placenta.
- Metabolism: hepatic; enterohepatic cycle.
- Concentrated in all body tissues:
 liver, kidney, breast milk, bronchial epithelium, tissues that become
calcified tissues (bone, teeth), carcinoid tumors with high calcium
content.
 Minocycline concentrates in saliva and tears.
 Enter the phagocytes, pleural fluid, peritoneal fluid, sputum, synovial.
- Elimination: renal, bile (Doxycycline is entirely eliminated by bile, so it is
considered the safest tetracycline in renal failure), milk.
Indications:
- Treatment choices for:
 ricketsiosis;
 Mycoplasma pneumoniae;
 chlamydia;

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  cholera;
 spirochetes (Treponema pallidum, Borrelia burgdorferi).
- Treatment of:
 the bacterial exacerbations of bronchitis;
 acne (vulgaris, rosacea);
 malabsorption;
 Periodontal disease;
 Minocyclne: menigococal carriers state in saliva;
 Demeclocicline: syndrome of inappropriate secretion of ADH;
 Doxycycline: prostatitis, sinusitis, malaria.
 Meningites;
 Alternative for pelvic infection, brucellosis, leptospirosis, eradication of
ulcers with H.pylori.
Adverse effects
- gastrointestinal: nausea, vomiting, diarrhea, gastric irritation, intestinal
dysmicrobisme, Clostridium difficile pseudomembranous enterocolitis;
- oral or vaginal candidiasis (superinfection with Candida);
- determination of calcium ions from the bone: brown-yellow teeth, dental
hypoplasia, dysplasia of dental enamel, distortion or inhibition of bone growth;
- hepatotoxicity;
- Fanconi syndrome (renal tubular acidosis): Doxycycline;
- irritation of tissues: venous thrombosis, muscle irritation;
- vestibular toxicity: Minocycline, Doxycycline;
- photosensitization: Tetracycline, Doxycycline, Demeclocycline;
- Type I immunological reactions (rash, fever) very rare;
- immunosuppressive effect.
Contraindications
- children under 8 years (12 years);
- pregnancy, breastfeeding;
- renal failure (EXCEPT Doxycycline);
- liver failure;
- lupus erythematosus;
- people with immunosuppression;
- patients receiving a reduced calorie diet.

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PHENICOLS
 CHLORAMPHENICOL, TIAMPHENICOL
Mechanism of action: inhibition of bacterial protein synthesis by coupling of
50S ribosomal bacterial subunit.
Antibacterial spectrum: very wide
- G (+) and G (-) aerobic and anaerobic bacteria
- intracellular microorganisms: rickettsiae. Not active on Chlamydia. Not active
on Pseudomonas.
Bactericidal or bacteriostatic, depending on the organism.
Pharmacokinetics
- metabolized by hepatic glucuronidation;
- widely distributed in all tissues and body fluids, pass the physiological
barieres,
- concentrated in milk, eyes, urine;
- elimination: in urine and in bile;
- they are inhibitors of drug metabolism (increase plasma concentrations of
phenytoin, coumarin anticoagulants, oral antidiabetics type sulfonylurea).
Indications: life-threatening infections because of the severe adverse effects
- infection with H. influenzae resistant to other antibacterial chemotherapy;
- treatment of choice for typhoid fever;
- meningitis;
- topical (conjunctivitis, vaginitis).
Adverse effects
- gastrointestinal disturbances (nausea, vomiting, diarrhea);
- medulotoxicity:
 anemia and reticulocytopenia (are dose-related);
 aplastic anemia (idiosyncratic);
 hemolytic anemia in G6PD deficient individuals.
- hepatotoxicity;
- Herxheimer reaction (during treatment with high doses of Salmonella);
- gray syndrome of the neonates:
 Clinical: vomiting, hypothermia, cardiovascular collapse with
irreversible gray coloration of the skin, shock  death.
 Cause: low capacity of the liver to metabolize the antibiotic.
- immunosuppression.

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Contraindications: G6PD deficiency, hepatic failure, renal failure.

OXAZOLIDINONES
 LINEZOLID, EPEROZOLID
Mechanism of action: bind to the 50S subunit of bacterial ribosomes and
suppresses bacterial protein synthesis.
The antibacterial resistance appears in: blocking the active transport into the
bacterial cell; mutations; transfer of plasmids.
Antibacterial spectrum: G(+) organisms resistant to other antibiotics
(staphylococci, streptococci, enterococci, anaerobic cocci, and G(+) rods such
as corynebacteria and Listeria monocytogenes).
Bacteriostatic, EXCEPT for streptococci for which it is bactericidal.
Indications: pulmonary infections, enterococcal infections.
Adverse effects: - thrombocitypenia (if administered more than 2 weeks),
neutropenia;
- nausea, vomiting, diarrhea.

LINCOSAMIDES
 LINCOMYCIN, CLINDAMYCIN
Mechanism of action: bind to the 50S subunit of bacterial ribosomes and
suppresses bacterial protein synthesis.
Antibacterial spectrum: G (+) cocci (including penicillin-resistant strains) and
anaerobes (including Bacteroides fragilis). Not active on Clostridium difficile.
Bacteriostatic on enterococci, bactericidal on pneumococci.
Pharmacokinetics:
- well distributed in the body, but not pass physiological barriers (not pass even
the meninge is inflamed);
- metabolism: liver;
- concentrated in leukocytes, bone, joints, urine. Penetration into bone occurs
even in the absence of inflammation.
- elimination: bile, urine.
Indications:
- drug of choice for staphylococcal bone infections (osteomyelitis), peritonitis;
- severe infections: deep neck space infections, chronic tonsillo-pharyngitis,
odontogenic abscesses, and surgical prophylaxis in contaminated wounds.

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Adverse effects
- pseudomembranous colitis can be fatal (more frequent to clindamycin >
compared to cephalosporins (Ceftin) and > aminopenicillins.
Clinically: abdominal pain, fever, leukocytosis, bloody stool… Diarrhea
commonly develops on days 4-9 of treatment. Symptoms typically
resolve 14 days after stopping the antibiotic. Treatment is with
Metronidazole. Life threatening cases can be treated with
Vancomycin.
- hepatotoxicity;
- medulotoxicitate (severe);
- rash (rash).

FUSIDIC ACID
Mechanism of action: inhibition of bacterial protein synthesis.
Antibacterial spectrum: G (+) cocci including methicillin-resistant
staphylococci; some G (+) bacteria (Clostridia).
Pharmacokinetics: good diffusion into bone, synovial membrane, the
bronchial tubes. Good intracellular diffusion. Only biliary elimination.
Indications: staphiloccocus infections resistant to penicillin (skin infections,
osteomyelitis, endocarditis).
Adverse effects: - nausea, vomiting;
- rash;
- hepatotoxicity, jaundice;
- nephrotoxicity.

NITROFURANS
 NITROFURAZONE; FURAZOLIDONE; NITROFURANOIN
Nitrofurans should be used with caution in those with G6PD deficiency, during
pregnancy and lactation, in infants less than 3 months old. Contraindications:
hypersensitive to nitrofurans; for Nitrofurantoin also renal failure.

NITROFURAZONE (skin antiseptic)

Antibacterial spectrum: broad spectrum, but with little activity against
Pseudomonas.
Indications: wounds, burns, ulcers, and skin infections, before skin grafting.

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Adverse effects: may cause sensitization.

FURAZOLIDONE (intestinal antiseptic)

Antibacterial spectrum: antibacterial (against enteric bacteria) and
antiprotozoal (against Giardia intestinalis). Bactericidal.
Indications: enteritis (acute or subacute) caused by pathogenic enteric bacteria.

NITROFURANTOIN (urinary antiseptic)

Antibacterial spectrum: antibacterial (against urinary-tract bacteria); no
activity against Pseudomonas aeruginosa and most strains of Proteus.
Antibiotic activity is greater in acidic urine (urinary pH increased to about
5.5).
Indications: urinary antiseptics (lower urinary tract infections).
Adverse effects for Furazolidone and Nitrofurantoin
- anorexia, nausea, vomiting,
- allergic reactions (skin rashes, hypersensitivity reactions),
- hemolytic anemia (in G6PD deficiency),
- disulfiram-like reactions, hepatotoxicity;
- colors the urine: Furazolidone in yellow, Nitrofurantoin in brown;
- for Nitrofurantoin also: acute pneumonitis, neuropathies.
Drug interactions:
- Nitrofurantoin antagonizes the action of quinolones.
- Furazolidone and Nitrofurantoin: should not be associated with monoamine
oxidase inhibitors, antipsychotic drugs, alcohol and foods containing tyramine.

3.4.Inhibitors of bacterial nucleic acid synthesis

Classification
4.1. Rifampicin;
4.2. Quinolones:
 1st generation: Nalidixic acid  only for lower urinary infections;
particular for intestinal shigellosis;
 2nd generation: Oxolinic acid, Pipemidinic acid, Cinoxacin  not used
today in therapy;
 3rd generation (fluoroquinolones): Ciprofloxacin, Pefloxacin,

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 Norfloxacin, Ofloxacin, Temafloxacin, Sparfloxacin, Quinafloxacin,
Levofloxacin, Trovafloxacin, Lomefloxacin, Moxifloxacin,
Acrosoxacin, Enoxacin, Grepafloxacin, Gatifloxacin, Moxifloxacin.

QUINOLONES (are called DNA gyrase inhibitors)

Mechanism of action: block bacterial DNA replication by inhibiting bacterial
DNA gyrase (topoisomerase II) and topoisomerase IV.
Antibacterial spectrum
- Nalidixic acid: G(-) bacteria (E. coli, Proteus, Enterobacter, Salmonella,
Shigella etc)
- fluoroquinolones (greatly improved antibacterial spectrum compared with
nalidixic acid):
 G(-): E. coli, Proteus, Enterobacter, Klebsiella, Haemophilus,
Pseudomonas aeruginosa, Neisseria etc;
 G(+): Legionella, S. aureus (not those resistant to methicillin),
streptococci (including pneumococci) etc;
 Mycoplasma, Rickettsia, Chlamydia;
 Mycobacterium tuberculosis.
Bactericidal.

NALIDIXIC ACID
Indications: only for lower urinary tract infections; particular: for intestinal
shigellosis.
Adverse effects: false positive glucose tolerance test, hyperglycemia,
glycosuria; gastro-intestinal disorders; rash; photosensitivity; blurred vision;
CNS stimulation (convulsions if overdose).

FLUOROQUINOLONES
Pharmacokinetics
- absorption: reduced in the presence of antacids;
- distribution: wide (EXCEPT Norfloxacin that doesn’t achieve systemic
antibacterial levels);
- concentrated in the urine, kidney, lungs, prostate, bone, bile, CSF.
- good concentrations in neutrophils and macrophages;
- metabolism: in the liver.

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- enterohepatic cycle;
- elimination: renal (glomerular filtration and tubular secretion), bile (20%), in
milk.
 Dose adjustment is required for patients with renal failure (EXCEPT
Moxifloxacin).
Indications (infections including those caused by multidrug-resistant bacteria
such as pseudomonas and enterobacter)
- urinary tract infections
- respiratory tract infections (acute exacerbation of chronic bronchitis,
Pneumocystis carinii pneumonia in immunocompromised individuals);
 fluoroquinolones have poor activity against S. pneumoniae and
anaerobic bacteria, EXCEPT newer fluoroquinolones (such as
Gatifloxacin and Moxifloxacin).
- infections of soft tissues, bones, and joints;
- gastrointestinal infections (diarrhea, including traveler’s diarrhea) and
abdominal infections;
- septicemia, endocarditis;
- gonorrhea;
- antrax prophylaxis;
- typhoid fever;
- multidrug-resistant tuberculosis and atypical mycobacterial infections.
Adverse effects
- nausea, vomiting, diarrhea;
- headache, dizziness, insomnia;
- increase in liver enzymes;
- superinfection with Candida and streptococci;
- rash and pruritus, hypersensitivity-type reactions;
- hyperglycemia in diabetic patients and those agents who receive oral:
Gatifloxacin;
- photosensitivity: Pefloxacin, Lomefloxacin;
- prolong the QT interval on ECG (risk of arrhythmia);
- articular cartilage erosion (=arthropathy) in children, risk of tendinitis or
rupture of achilles tendon in adults.
Contraindications:
- children under 18 years,
- severe renal impairment,
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- pregnancy, lactation.
- co-administration with
 Theophylline because of increase in serum Theophylline levels (risk of
toxic effects, especially seizures).
 antiarrhythmics or other drugs known to prolong the QTc interval (e.g.,
Erythromycin, tricyclic antidepressants) because of increase of risk of
arrhythmias.

3.5.Inhibitors of the synthesis of other bacterial structures synthesis

Classification
5.1. Sulfonamides:
 oral administration, but not absorbed from digestive tract: Sulfizoxazol,
Sulfamethylthiazol, Sulfamethoxazole, Sulfadiazine, Sulfadoxine;
 oral administration and absorbed from digestive tract: Sulfasalazine,
Ftalylsulfatiazol;
 with topic administration: Mafenid, Sulfadiazine, Sulfacetamide.
5.2. Trimethoprim.

Bacteria require extracellular p-aminobenzoic acid (PABA) in order to form

dihydrofolic acid, an essential step in the synthesis of nucleic acids.
Mechanism of action
- Sulfonamides (are structural analogs of PABA): compete with PABA,
inhibiting the dihydropteroate synthase (enzyme involved in the synthesis of
folic acid);
- Trimethoprim: inhibits dihydrofolate reductase (enzyme involved in the
synthesis of folic acid).
Both sulfonamides and Trimetoprim are bacteriostatic, but their combination
Trimethoprim + Sulfamethoxazole is bactericidal (has a potentiating
synergistic effect).
Antibacterial spectrum
- sulfonamides (antibacterial spectrum varies from one community to another):
 some G(-) bacteria: Proteus, E. coli, Klebsiella pneumoniae, Shigella,
Salmonella, Enterobacter, Vibrio cholerae etc;
 some G(+) cocci: streptococci, staphylococci, Nocardia etc;

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  Chlamydia;
 Actinomyces;
 Protozoa: Plasmodium falciparum, Pneumocystis carinii, Toxoplasma
gondii.
- Trimethoprim: similar to sulfonamides.
Pharmacokinetics
- Sulfonamides:
 oral administration and systemic absorption:
o cross the blood-brain barrier in the absence of inflammation,
cross placenta, pass into breast milk;
o metabolism: hepatic via acetylation, elimination: renal and
biliary;
o concentrates in milk, saliva, sweat, bile (enterohepatic cycle).
 oral nonabsorbable from digestive tract: Sulfasalazine is split into 5-
aminosalicylates and sulfapiridine in intestine (with anti-inflammatory
and immunosuppressive effect).
- Trimethoprim:
 cross the physiological barriers;
 concentrate in the prostate and vaginal secretions;
 hepatic metabolism, renal elimination.
Indications
- sulfonamides:
 Sulfasalazine: ulcerative colitis (Crohn's disease);
 Ftalilsulfatiazol: intestinal infections (dysentery).
 Mafenid, sulfadiazine: burns;
 eye infections: sulfacetamide.
- trimethoprim alone or in combination with sulfamethoxazole:
 urinary tract infections, prostatitis,
 respiratory infections (including Pneumocystis carinii infection),
 gastro-intestinal infections.
Adverse effects
- Sulfonamides:
 gastrointestinal: nausea, vomiting, diarrhea;
 immunological reactions:
o Type I: rash, pruritus, angioedema, urticaria, anaphylactic shock;

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 o Type III: arthritis, fever, interstitial nephritis, Stevens Johnson
syndrome;
 crystalluria can result in nephrotoxicity;
 hepatotoxicity; inhibition of vitamin K;
 hemolytic anemia in patients with G6PD deficiency,
 agranulocytosis, thrombocytopenia, aplastic anemia, leukemoid
reaction;
 kernicterus in neonates;
 photosensitivity, CNS disorders, psychosis.
- Trimethoprim:
 gastrointestinal (nausea, vomiting),
 folic acid deficiency;
 type I immunological reactions: rash;
 increase the concentration of serum creatinine.
Contraindications:
- pregnancy, lactation, infants less than two months;
- renal failure;
- also:
 for sulfonamides: association with oral anticoagulants, antidiabetics,
methotrexate, phenytoin.
 for Trimethoprim: blood dyscrasias.

3.6. Drugs used to treat tuberculosis

Classification
 First line drugs:- Isoniasid (hydrazide of isonicotinic acid or HIN);
- Rifampicin;
- Ethambutol;
- Pyrazinamide;
- Streptomicin.
 Second line drugs: Etionamide; Paraaminosalicilic acid (PAS);
Amikacin; Capreomycin; Tetraciclines; Rifabutin; Rifapentine;
Fluoroquinolones (Ciprofloxacin, Ofloxacin, Levofloxacin);
Clofazimine; Cycloserine.
o Fluoroquinolones are effective and well tolerated, but to be

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 reserved for resistant strains.

FIRST LINE ANTITUBERCULOSIS

ISONIAZID
Isoniazid (the hydrazide of isonicotinic acid) is a synthetic analog of pyridoxine
(vitamine B6).
Mechanism of action: inhibits synthesis of mycolic acids (essential
components of the wall of Mycobacterium tuberculosis).
Antibacterial narrow spectrum: Mycobacterium tuberculosis (M
tuberculosis).
Bactericidal on intra- and extracellular bacilli.
Pharmacokinetics
- good intestinal absorption.
- distribution good and rapid in all tissues and body fluids. In the CNS and CSF
concentrations are 20-100% of serum concentrations.
- hepatic metabolism: inactivation by acetylation (acetylators are genetically
"slow", "intermediate" and "fast"). In rapid acetylators, hepatotoxic reactions
occur quickly.
Isoniazid is an enzyme inhibitor of hepatic metabolism of drugs
(carbamazepine, phenytoin, primidone, phenobarbital ...) and can
therefore, in combination, increase the plasma concentrations with risk
of overdose by blocking their hepatic catabolism.
- elimination: in urine.
Indications: treatment of tuberculosis.
Adverse effects
- hepatotoxicity: elevated transaminases, acute hepatitis (sometimes fatal),
 Symptoms: right upper quadrant pain, fatigue, loss of appetite, nausea,
vomiting, jaundice;
- peripheral neuropathy (due to pyridoxine deficiency) and CNS toxicity
(insomnia, psychomotor agitation, seizures, convulsions, mental disorders),
- immunological reactions type I (rash, fever) and type II (jaundice by
autoimmune hepatitis, myalgia, arthralgia, lupus erythematosus induced by
isoniazid);
- digestive disturbances: nausea, vomiting, epigastric pain;
- various: algoneurodystrophy, hemolytic anemia in G6PD deficient

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individuals.

RIFAMPICIN
It is a semi-synthetic derivative of rifamycin (antibiotic produced by
Streptomyces mediterranei).
Mechanism of action inhibits the activity of RNA polymerase-DNA-
dependent.
Antibacterial broad spectrum: G(+) and G(-) cocci, some G (-) bacilli,
Chlamydia, M. tuberculosis and atypical mycobacteria, Legionella species,
Brucella sp.
 Prolonged post-antibiotic effect in vivo.
Bactericidal on intra- and extra-cellular bacilli (eliminate semi-dormant or
persisting organisms).
Pharmacokinetics
- very good absorption (bioavailability = 100%), foods inhibit the absorption.
- distribution: good cellular and tissue penetration, low diffusion in CSF
(EXCEPT in cases of inflammation). It concentrates in bile, phagocytes,
sputum.
- Hepatic metabolism. Biliary excretion.
- powerful enzyme inducer (induction of cytochrome P450) which explains
drug interactions:
 increase the elimination of methadone, oral anticoagulants,
anticonvulsants, contraceptives;
 reduce plasma concentrations of Ketoconazole, Cyclosporine,
Chloramphenicol;
 blood levels of Rifampicin are decreased by Ketoconazole.
Indications
- infections caused by sensitive bacteria;
- tuberculosis.
Adverse effects
- orange color (red to brown) of fluids: urine, saliva, sweat, tears (note: color
contact lenses);
- increase in transaminases, cholestatic jaundice, hepatitis.
- interstitial nephritis (proteinuria, cylinder in the urine);
- thrombocytopenia, with or without purpura;

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- immunological reactions (hypersensitivity reactions): rash, vasomotor
reactions, pruritus, urticaria, rare;
- gastrointestinal disturbances: anorexia, nausea, vomiting, abdominal pain,
meteorism, diarrhea;
- flu-like symptoms (fever, chills, headache, dizziness, arthralgia).

ETHAMBUTOL
Mechanism of action: inhibition of the synthesis of arabino-galactan = wall
component of M. tuberculosis
 Promotes penetration of other lipophilic antituberculosis drugs
(Rifampicin, ofloxacin) and increase their activities.
Antibacterial spectrum: M. tuberculosis and atypical mycobacteria.
Bacteriostatic on extracellular bacilli.
Pharmacokinetics: Absorption: good. Good tissue distribution (lung, CSF) and
through the inflamed meninges. Renal elimination (80%) and feces (20%).
Indications: tuberculosis.
Adverse effects:
- decrease in visual acuity, optic retrobulbar neuritis, sometimes retinal lesions
(necessary monitoring of the visual field, color vision);
- very rare: hypersensitivity (skin rash).

PYRAZINAMIDE
It is related to the nicotinamide.
Antibacterial spectrum: M. tuberculosis.
Bactericidal on intracellular bacilli (in macrophages), known as
"quiescent" and bacilli with slow metabolism.
Pharmacokinetics: easily diffuse into the tissue and macrophages and, through
inflamed meninges.
To be active, pyrazinamide requires an acid pH.
Indications: tuberculosis.
Adverse effects:
- hepatotoxicity;
- digestive disorders: anorexia, nausea, vomiting, abdominal pain;
- hyperuricemia (very common cause of arthralgia; is cons-indicated in acute
attack of gout).

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SECOND-LINE ANTITUBERCULOSIS
Other RIFAMYCINS: rifabutin, rifapentine
- Rifabutin: fewer drug interactions
- orange color (red to brown) fluids.
ETHIONAMIDE (not marketed in some countries)
- Bacteriostatic on intra-and extracellular bacilli
- dissemination in the CSF.
- Adverse effects: gastric irritation, neurological symptoms (neurotoxicity
prevented by pyridoxine), hepatotoxicity.
PARA-AMINOSALICILIC ACID
- The same mechanism of action and adverse effects like salicylates.
CAPREOMYCIN
- Antibiotic polypeptide, cross-resistance with aminoglycosides (kanamycin,
amikacin).
- Adverse reactions (similar to aminoglycosides): nephrotoxicity, ototoxicity.
CYCLOSERINE: risk of seizures

3.7. Drugs used to treat leprosy

Classification
 Dapsone;  Rifampicin;
 Acedapsone (derived from Dapsone)  Clofazimine;
 alternative in patients intolerant  Amithiozon.
to dapsone;
 Thiambutosin (derived from
Dapsone);

DAPSONE
Indications:
- leprosy
- malaria
- dermatitis herpetiformis
- prevention and treatment of Pneumocystis carinii and Toxoplasma gondii
infections.
Adverse effects: methaemoglobinaemia, haemolysis, agranulocytosis.

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 Lecture 13

Learning Objectives:
 Classify antifungal drugs.
 Explain the indications, and adverse effects of frequently used antifungals.
 Classify antiviral drugs.
 Explain the indications, and adverse effects of frequently used antivirals.
 Classify antiparasitic drugs
 Explain the indications, and adverse effects of frequently used antiparasitic
drugs.
 Classify anticancer drugs.
 Explain the common adverse effects of anticancer drugs.
 List drugs influencing immune system.

4.Antifungal drugs

Classification of antifungals
1. Polienes: Arnfothericin B*; Natamycin; Nystatin**;
2. Benzofuranones: Griseofulvin*;
3. Azoles:
3.1. Imidazoles: Ketoconazole, Miconazole, Econazole, Clotrimazole; Isoconasole**;
3.2. Triazoles: Fluconazole*, Itraconazole*, Voriconazole*; Bifonazole**,
Fenticonazole**, Sertaconazole**, F1utrimazole*;
4. Alylamines: Terbinafine; Naftifine**;
5. Other structures: Flucytosine*; Hydroxistilbamidine*; Cyc1opiroxol-amine*;
Caspofilngin*, Tolnaftat**; Tolciclat**; Haloprogin**; Cyclopirox**; Candicidin**;
Clordantoine*.
* - only systemic; ** - only local

1. Polienes
AMPHOTERICIN B
Mechanism of action: bind to sterols in the fungal membrane → pore
formation → membrane loss of cell contents.
Antifungal spectrum (broad): Candida albicans, Cryptococcus neoformans,
Blastomyces dermatidis, Histoplasma capsulatum, Sporotrix schenckii,
Coccidioides immitis, Paracoccioides brasiliensis, Aspergillus fumigatus,
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Penicillium marneffrei
- it is not effective against the bacteria, but it is active in Naegleria
meningoencephalitis
- fungal resistance: produced by the decrease in ergosterol or by modifications
of the fungal membrane.
Pharmacokinetics:
- the absorption is low, after oral administration
- distribution: broad; does not penetrate physiological barriers (produces low
concentrations in cerebrospinal fluid and is administered intrathecally to
patients with fungal meningitis).
Indications: systemic mycoses, fungal meningitis.
Adverse effects:
- immediate adverse effects (after iv administration): fever, chills, muscle
spasms, nausea, headache, hypotension
- late Adverse effects: hepatotoxicity, nephrotoxicity (renal tubular acidosis,
disturbances in serum potassium levels, disruptions in the plasma levels of
magnesium), neurotoxicity after intrathecal administration (seizures,
arachnoiditis), anemia.

NATAMYCIN
The drug is with systemic and local administration.
Antifungal spectrum (broad): yeasts, dermatophytes, Aspergillus spp.,
Trichomonas spp.
Indications:
- candidiasis
- trichomoniasis
- fungal keratitis
- respiratory mycoses.
Adverse effects: nausea, vomiting, diarrhea, irritation.

NYSTATIN
Mechanism of action: bind to sterols in the fungal membrane → determine
pore formation → membrane loss of cell contents.
Antifungal spectrum (narrow spectrum): Candida albicans, Cryptococcus
neoformans, Histoplasma capsulatum, Microsporum audouini, Epidermophyton
spp., Trichophyton spp.
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- fungal resistance: it has not been described.
Pharmacokinetics:
- after oral administration, the drug does not determine effective therapeutic
blood levels
- after cutaneous or mucosal administration → the drug is not absorbed
- the drug is not inactivated in the digestive tract
- excreted unchanged in feces.
Indications: skin and mucosal fungal infections (vaginal mucosa, intestinal
mucosa).
Adverse effects: the drug is highly hepatotoxic → it is administered only
topically.

2. Benzofuranones: GRISEOFULVIN
The drug is administered only systemically.
Mechanism of action: bind to the microtubule forming the mitotic spindle →
block fungal mitosis (block the polymerization of microtubule).
Antifungal spectrum (narrow spectrum):
- Microsporum spp., Epidermophyton spp., Trichophyton spp.
- fungal resistance: absence of the system dependent energy to penetrate the
fungal cell.
Pharmacokinetics:
- the absorption is increased in the presence of fat meals
- distribution is wide, the drug is stored in the keratin layer of the skin or in the
stratum corneum of the nail, in the horny layer of hair, skin
- the elimination is renal, partly as unchanged.
Indications:
- fungal infections of the hair (→ treatment is for few weeks)
- onychomycosis (treatment of the hands: 3 to 5 months; of the legs: 8 -12
months)
- skin fungal infections (treatment is for few weeks).
Adverse effects:
- direct toxic reactions: headache, nausea, vomiting, diarrhea, hepatotoxicity,
photosensitization, confusion
- immunological reactions (rash, leukopenia)
- teratogenicity, carcinogenicity
- disulfiram-like effect.
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Interactions:
- enzyme induction: drug decreases the action of oral anticoagulants,
contraceptives
- barbiturates decrease the action of griseofulvin by enzyme induction.

3. Azoles
Mechanism of action: the inhibition of C-14 alfa steroid methylase → block
the conversion of lanosterol to ergosterol (the essential steroid of the fungal
membrane). The azoles are fungistatic or fungicidal, dose-dependent.
Antifungal spectrum (broad):- Candida (albicans, tropicalis, glabrata,
neoformans), Blastomyces dermatidis, Histoplasma capsulatum, Coccidioides
immitis, Pracoccioides brasiliensis, Trichophyton spp., Malassezia
(Microsporum) furfur, Epidermophyton spp., Corynebacterium minutissium
- less sensitive: Aspergillus fumigatus, Spirotrichum schenckii
- Miconazole, Econazole, Clotrimazole → bacteria G (+)
- fungal resistance: by multiple mechanisms.
Pharmacokinetics:
- azoles are inhibitors of drug metabolism enzymes (cytochrome P450)
- drugs penetrate the corneum stratum where they remain few days.
Derivatives of imidazole: KETOCONAZOLE, MICONAZOLE,
ECONAZOLE, CLOTRIMAZOLE, ISOCONAZOLE
Pharmacokinetics:
- the absorption of Ketoconazole is increased in acidic pH, it decreases in the
presence of food, antacids
- limited distribution: does not pass into the cerebrospinal fluid (it is not
effective in cases of fungal meningitis), it produces high concentrations in
vaginal secretions
- hepatic metabolism
- elimination is primarily biliary; also a small proportion is eliminated to the
kidney.
Indications:
- systemic mycoses
- oropharyngeal candidiasis and gastrointestinal candidiasis
- fungal skin infections (Ketoconazole is also effective in seborrheic dermatitis;
Miconazole and Econazole are also effective for G + bacteria), mucous
membranes, hair fungal infections
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- Clotrimazole: epidermo-mycoses, oropharyngeal candidiasis and vaginal
candidiasis.
Adverse effects:
- Ketoconazole:
 hepatotoxicity
 allergic reactions
 digestive disturbances (nausea, vomiting, abdominal pain)
 gynecomastia, impotence, menstrual irregularities;
- Miconazole and Econazole: local erythema, pruritus;
- Miconazole: nausea, diarrhea;
- Miconazole (iv): anginal pain, hyperlipidemia, inhibition of platelet
aggregation;
- Clotrimazole: local irritation, rash.
Contraindications: pregnancy, breastfeeding, hepatic failure.
Interactions:
- Ketoconazole increases plasma concentrations of oral anticoagulants, oral
antidiabetics
- Ketoconazole increases the toxicity of Cyclosporine, phenytoin, terfenadine,
astemizole
- Rifampicin reduces the plasma concentration of Ketoconazole
- Cimetidine and antacids decrease the absorption of Ketoconazole.
Triazole derivatives: FLUCONAZOLE, ITRACONAZOLE,
VORICONAZOLE, BIFONAZOLE, FENTICONAZOLE,
SERTACONAZOLE, FLUTRIMAZOLE
Pharmacokinetics:
- Fluconazole absorption is not affected by food / antacids
- the absorption of Itraconazole capsules is increased in the presence of food,
the absorption of Itraconazole solutions is reduced in the presence of food,
antacids, inhibitors of gastric secretion
- distribution is wide:
 Fluconazole determines high concentrations in cerebrospinal fluid,
saliva, sputum, vaginal fluid;
 Itraconazole does not realize active concentrations in cerebrospinal fluid
- elimination is renal
- Fluconazole does not inhibit cytochrome P450. Fluconazole does not depress

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the immune system.
Indications:
- Fluconazole:
 meningitis with Coccidioides spp. (it is the treatment of choice)
 digestive candidiasis, vaginal
 prophylaxis reduced fungal infections in immunocompromised
individuals;
- Itraconazole:
 cryptococcal meningitis
 dermatophytosis and onychomycosis (the treatment of choice)
 infection with Aspergillus spp., Histoplasma spp., Blastomyces spp.,
Sporothrix spp.
Adverse effects of antifungal triazole derivatives:
- nausea, vomiting, diarrhea, abdominal pain
- increase in transaminases
- Stevens-Johnson syndrome
- alopecia
- Fluconazole: rash
- Itraconazole: peripheral neuritis.

4. Alylamines
TERBINAFINE
The drug has systemic and topical administration.
Mechanism of action: inhibition of squalene 2,3 - fungal epoxidase which
determines the inhibition of fungal ergosterol synthesis.
Antifungal spectrum: highly active against dermatophytes, less active against
Candida spp.
Pharmacokinetics:
- easy absorption after oral administration
- intense first-pass effect
- concentrated into: skin, sebum, sweat, nails
- hepatic metabolism
- renal elimination.
Indications: dermatophytes, pityriasis versicolor, cutaneous candidiasis.
Adverse effects:

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- digestive disorders
- headache
- rash
- rare: liver toxicity, severe neutropenia,Stevens-Johnson syndrome, toxic
epidermal necrosis.

5. Other structures
FLUCYTOSINE
Mechanism of action: drug penetrate into the fungal cell and determine
deamination of the drug to 5-fluorouracil, which acts as an anti-metabolite.
Antifungal spectrum: Cryptococcus neoformans, Candida spp., Aspergillus
spp., Clodosporium spp., Phialophora spp.
- fungal resistance: alteration of drug metabolism.
Pharmacokinetics:
- easy absorption after oral administration
- weak binding to plasma proteins
- concentrated in cerebrospinal fluid
- renal elimination (80% in unchanged form).
Indications: candidiasis, cryptococcosis, aspergillosis, chromoblastomycosis.
Adverse effects:
- myelotoxicity (anemia, leukopenia, thrombocytopenia)
- gastrointestinal disturbances (nausea, vomiting, toxic enterocolitis)
- hepatotoxicity (increase serum transaminases and alkaline phosphatase)
- rash.

5.Antiviral drugs

Classification of antiviral drugs

1. Inhibitors of viral entry into cells
1.1. Inhibitors of the absorption and penetration into the cells
- Gamma globulin
- Amantadine
- Rimantadine
- Disoxaviril
1.2. Inhibitors of penetration into the host cell → fusion inhibitors:
- Enfuvirtide
- Docosanol

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2. Inhibitors of intracellular viral protein synthesis
2.1. Inhibitors of early regulatory protein synthesis:
- Guanidine
- Hydroxybenzyl-benzimidazole
2.2. Inhibitors of the synthesis of viral nucleic acids
2.2.1. Nucleosidic analogues:
- inhibitors of the viral RNA polymerase / viral DNA polymerase: Ribavirin,
Sorivudine, Trifluridine, Bromvinyledeoxyuridine;
- nucleosidic inhibitors of retroviral revers-transcriptase: Zidovudine
(AZT), Didanosine (ddI), Zalcitabine (ddC), Lamivudine(3TC),
Stavudine(d4T), Abacavir (ABC), Emtricitabine, Adefovir dipivoxil (POM-
PMEA);
- other nucleosidic analogues: Acyclovir, Valacyclovir, Pencyclovir,
Famcyclovir, Cidofovir, Brivudine, Ganciclovir, Valgancyclovir, Vidarabine,
Idoxuridine, Cytarabine, 5 - fluorouracil, 5 - bromouracil;
- other inhibitors of the viral nucleic acids synthesis: Foscarnet, interferons
(Interferon alpha, Interferon beta, Interferon gamma).
2.2.2. Nucleotidic inhibitors of revers-transcriptase: Tenofovir, Cidofovir.
2.2.3. Non-nucleosidic inhibitors of retroviral revers-transcriptase: Nevirapine,
Efavirenz, Delavirdine, Atevirdine, Alfa-anilino-phenyl-acetamide.
2.2.4. Inhibitors of retroviral proteases: Saquinavir, Ritonavir, Indinavir, Nelfinavir,
Amprenavir, Fosamprenavir, Atazanavir, Lopinavir.
2.3. Inhibitors of the late regulatory protein synthesis: Fluorophenylalanine, Puromycine,
Thiosemicarbazone, Methisazone, 2-Deoxy-2-glucose.
2.4. Other inhibitors of the synthesis of nucleic acids: Fosfonoacetic acid, Azidothymidine.
3. Inhibitors of assembly(maturation) of viral particles and release of virus from the cell
3.1. Neuraminidase inhibitors: Zanamivir, Oseltamivir
3.2. Other inhibitors: 5-Fluoro-2-deoxyuridine, Puromycin, Rifampicin
3.3. Chemokine receptor inhibitors
3.4. Anti-integrases

1. Inhibitors of viral entry into cells

1.1. Inhibitors of the absorption and penetration into the cells
GAMMA GLOBULIN
Mechanism of action: the drug has anti-surface antigens antiviral → block the
penetration of the viral particle to the host cell.
Indications:
- hepatitis;
- rabies;
- polio;
- varicella-zoster.
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The protective effect is for 2-3 weeks.

AMANTADINE, RIMANTADINE, DISOXAVIRIL

Mechanisms of action:
- inhibition of the M2 protein at the surface of the viral capsid → prevent
penetration of viral genetic material into the core → prevent viral assembly and
the release of new virions;
- Amantadine also determines the release of central dopamine and the inhibition
of dopamine reuptake → postsynaptic dopaminergic effects;
- Amantadine also determines the inhibition of NMDA receptors.
Antiviral spectrum:
- Amantadine, Rimantadine → influenza A (but not influenza B virus);
- Disoxaviril → poliovirus, coxsackievirus, rhinoviruses.
Indications:
- antiviral prophylaxis and treatment of influenza;
- Amantadine also for the treatment of Parkinson’s disease.
Adverse effects: digestive intolerance, disturbances in the CNS (nervousness,
difficulty in concentration, bright dots in the visual field).
The adverse effects are less obvious to Rimantadine.

1.2. Inhibitors of penetration into the host cell → fusion inhibitors:

ENFUVIRTIDE
Mechanism of action: block the action of glycoprotein gp41 to anchor to the
target cell membrane to initiate fusion between the viral lipid layer and the lipid
cell membrane layer.
Antiviral spectrum: HIV
Indications: HIV infections with multidrug-resistant strains.
Adverse effects:
- local Adverse effects: pain at the injection site, rash, nodules;
- systemic Adverse effects: nausea, vomiting, diarrhea, rash, eosinophilia.

DOCOSANOL
Mechanism of action: block the fusion of the viral lipid layer and the lipid cell
membrane.
Antiviral spectrum: herpes virus HSV-1.
Indications: herpes infections recurrent oro-labial.
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2. Inhibitors of intracellular viral protein synthesis
Inhibitors of the viral RNA polymerase / viral DNA polymerase
- RIBAVIRIN (the nucleoside analogue of guanosine),
- SORIVUDINE (the pyrimidine nucleoside analogue),
- TRIFLURIDINE (the nucleoside analogue fluorinated pyrimidine),
- BROMVINYLEDEOXYURIDINE
Mechanism of action:
- penetration into the host cell → the enzymes of the host cell determine the
phosphorylation of drugs into active forms → drug inhibition of viral DNA
dependent RNA polymerase → inhibition of viral synthesis;
- Ribavirin blocks the conversion of GTP to dGTP;
- Trifluridine blocks the conversion of dUMP to dTMP.
Antiviral spectrum:
- Ribavirin: influenza A and influenza B virus, parainfluenza virus, respiratory
syncytial virus, paramyxoviruses, the hepatitis viruses, HIV-1;
- Sorivudine: varicella-zoster virus, herpes virus HSV-1, Epstein-Barr virus;
- Trifluridine: herpes virus HSV-1 and herpes virus HSV-2.
Indications:
- Ribavirin:
- bronchiolytis or pneumonia with respiratory syncytial virus;
- chronic hepatitis (treatment with Ribavirin is associated with
interferon α-2alpha in patients with hepatitis C virus);
- in immunocompromised patients with severe infections with the
influenza virus, parainfluenza virus or other adenoviruses;
- Trifluridine: only topical administration→skin infections with herpes virus,
herpes keratitis.
Adverse effects:
- Ribavirin:
- administration in aerosols → conjunctival irritation or bronchial
irritation;
- systemic administration → anemia, bone marrow depression;
- Sorivudine: bone marrow depression;
- Trifluridine: ocular discomfort, eyelid edema.
Contraindications: pregnancy.

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Nucleosidic inhibitors of retroviral revers-transcriptase: ZIDOVUDINE
(AZT), DIDANOSINE (ddI), ZALCITABINE (ddC), LAMIVUDINE (3TC),
STAVUDINE (d4T), ABACAVIR (ABC), EMTRICITABINE, ADEFOVIR
dipivoxil (POM-PMEA);
Mechanism of action: three consecutive phosphorylations (determine the
formation of monophosphate → formation of diphosphate → formation of
triphosphate); 5-triphosphate is active → inhibition of reverse transcriptase of
retroviruses → inhibition of viral synthesis.
Antiviral spectrum: HIV-1 and HIV-2
- Zidovudine (AZT) → also active on other viruses with tropism to human
lymphocytes; the action is low on herpes viruses and Epstein-Barr virus;
- Adefovir dipivoxil (POM-PMEA) → also active in other virus tropism to
human lymphocytes, herpes viruses and hepatitis B virus.
Pharmacokinetics:
- variable absorption after oral administration;
- distribution in all tissues and fluids (Zidovudine accumulates in cells in the
form of monophosphate; Zidovudine determines high concentrations in CSF);
- drugs are excreted in milk, they cross the placental barrier;
- hepatic metabolism;
- renal elimination.
Indications: HIV infections (adults and children).
Adverse effects:
- Zidovudine:
- early Adverse effects: headache, myalgia, tiredness, nausea, difficulty
in concentration, dyspepsia, insomnia;
- later adverse effects (are very severe): anemia, leukopenia,
thrombocytopenia, confusion, dementia, nail pigmentation, Stevens-
Johnson syndrome, increase in transaminases, cardiomyopathy,
ulcerations of the esophagus, lactic acidosis;
- Didanosine:
- peripheral neuropathy, insomnia, increase in plasma uric acid;
- rarely: acute pancreatitis, hepatitis, lactic acidosis;
- children: retinitis, optic neuritis;
- very rare: suppressive effects on bone marrow;
- Zalcitabine (ddC):
- after the start of the treatment: transient symptoms such as stomatitis,
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 mucosal ulcerations, rash, fever;
- later Adverse effects: pancreatitis, oesophageal ulcer, cardiomyopathy,
leukopenia, thrombocytopenia, edema, diarrhea, peripheral neuropathy;
- Stavudine (d4T): peripheral neuropathy, hepatotoxicity, headache, confusion,
asthenia, increased levels of creatine kinase;
- Abacavir (ABC): peripheral neuropathy, gastrointestinal disturbances,
hypersensitivity reactions.

Other nucleosidic analogues: ACYCLOVIR, VALACYCLOVIR,

PENCYCLOVIR, FAMCYCLOVIR, CIDOFOVIR, BRIVUDINE,
GANCICLOVIR, VALGANCYCLOVIR, VIDARABINE,
IDOXURIDINE, CYTARABINE, 5 - FLUOROURACIL, 5 –
BROMOURACIL
Mechanism of action: penetration into the host cell → viral thymidine kinases
determine the phosphorylation of drug into an active forms → active form
inhibit the viral DNA polymerase → inhibition of viral synthesis.
Antiviral spectrum:
- Acyclovir, Valacyclovir: herpes virus HSV-1 and HSV-2 (during replication),
varicella-zoster, Epstein-Barr virus, cytomegalovirus (CMV);
- Penciclovir, Famciclovir: herpes virus HSV-1 and HSV-2; varicella-zoster
virus; Epstein-Barr virus, hepatitis B virus;
- Ganciclovir, Valganciclovir: cytomegalovirus; herpes virus HSV-1 and HSV-
2;
- Vidarabine: herpes virus HSV-1 and HSV-2, varicella-zoster,
cytomegalovirus, rhabdoviruses, poxviruses, hepatitis B virus oncogenes;
- Idoxuridine: herpes virus HSV-1 and HSV-2; poxvirus;
- Estriol: herpes virus HSV-1 and varicella-zoster virus.
Indications:
- herpes virus infections:
a) topical administration: Acyclovir, Penciclovir, Ganciclovir,
Vidarabine, Cidofovir, Estriol, Idoxuridine;
b) systemic administration: Acyclovir, Valacyclovir, Penciclovir,
Famciclovir, Ganciclovir, Valganciclovir, Vidarabine, Cidofovir,
Estriol;
- varicella-zoster infections: Acyclovir, Valacyclovir, Penciclovir,
Famciclovir, Vidarabine, Estriol;
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- cytomegalovirus (CMV) infections: Ganciclovir, Valganciclovir → CMV
retinitis in immunocompromised patients, the infection with CMV in organ
transplantats; drugs are ineffective as monotherapy in patients CMV with
pneumonia;
- hepatitis B infections → Ganciclovir, Valganciclovir.
Contraindications: pregnancy → Acyclovir, Valacyclovir, Vidarabine,
Cidofovir.
Adverse effects:
- Acyclovir, Valacyclovir:
- after topical administration: local irritation, erythema;
- after systemic administration of Acyclovir: nausea, diarrhea, headache,
rash;
- high doses: neurotoxicity (tremors, delirium);
- nephrotoxicity (to renal failure);
- in immunocompromised patients: sometimes lethal thrombocytopenia,
hemolytic uremic syndrome;
- Penciclovir, Famciclovir: nausea, diarrhea, headache, hallucinations in the
elderly;
- Ganciclovir, Valganciclovir: myelosuppression (neutropenia,
thrombocytopenia and rarely, anemia), neurotoxicity (headache, confusional
states, behavioral disorders), rarely: liver and kidney failure;
- Vidarabine: teratogenicity, myelotoxicity (anemia, leukopenia,
thrombocytopenia), gastrointestinal effects, neurological effects (confusional
states, myoclonus, seizures), nephrotoxicity, hepatotoxicity, myelosuppression;
- Idoxuridine: corneal toxicity, allergic contact dermatitis.

Other inhibitors of the viral nucleic acids synthesis: FOSCARNET,

INTERFERONS (Interferon alpha, Interferon beta, Interferon gamma).
FOSCARNET
Mechanism of action: the drug interacts with DNA polymerase and herpes
virus reverse transcriptase of the retrovirus determining irreversible block and
non-competitive pyrophosphate binding of the enzyme.
Antiviral spectrum: herpes virus HSV-1 and HSV-2, HIV, varicella-zoster
virus, cytomegalovirus, Epstein-Barr virus, hepatitis B virus.
Indications: herpes virus infections, cytomegalovirus retinitis, cytomegalovirus
colitis and cytomegalovirus esophagitis.
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Adverse events: nephrotoxicity (kidney failure); hydro-electrolyte disorders
(hypocalcemia / hypercalcemia, hypophosphatemia / hyperphosphatemia),
genital ulcers, neurotoxicity (headache, irritability, hallucinations and
convulsions).

INTERFERONS (α, β, γ): IFN-α, IFN-β, IFN-γ

Mechanism of action: action on specific membrane receptors.
Pharmacodynamic effects:
- interferons have a role in viral replication at the protein level:
- inhibit the transcription and translation;
- block glycosylation of proteins
- inhibit the maturation of the virus;
- interferons increase the expression of major histocompatibility antigens and
have antiproliferative properties and fix the upregulation ("up-regulation") of
MHC class I and are immunomodulators of humoral and cellular immunity.
Indications:
- chronic hepatitis B → IFNα-2a, IFNα-2b;
- chronic hepatitis C → IFNα-2a, PEG-IFN α-2a, PEG-IFN α-2b;
- prevention of spread of varicella-zoster infection in people with cancer;
- prevention of cytomegalovirus infection in people with organ transplants;
- human papiloma virus infections, multiple sclerosis, rabies, haemorrhagic
fever;
- Kaposi’s sarcoma in patients with HIV infection, other malignancies (chronic
myelogenous leukemia, lymphomas, multiple myeloma).
Adverse effects:
- flu-like symptoms (a few hours after administration);
- neurotoxicity (somnolence, confusional states, anxiety, behavioral disorders,
memory disorders, sleep disorders, convulsions);
- myelosuppression (granulocytopenia, thrombocytopenia);
- myalgia, rash, autoimmune thyroiditis;
- rarely: heart failure, renal failure, pulmonary fibrosis, hepatotoxicity,
retinopathy, formation of antibodies against IFNα-2a.

Nucleotidic inhibitors of revers-transcriptase: TENOFOVIR, CIDOFOVIR.

CIDOFOVIR
Antiviral spectrum: herpes virus HSV-1 and HSV-2, varicella-zoster,
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cytomegalovirus, poxvirus, hepatitis B virus, human papillomavirus, poliovirus,
adenovirus.
Indications: infections with herpes virus HSV-1 and HSV-2, varicella-zoster
virus, cytomegalovirus retinitis; papillomavirus skin and laryngeal lesions;
adenovirus keratoconjunctivitis.
Adverse effects: nephrotoxicity, neutropenia, proteinuria.
TENOFOVIR
Antiviral spectrum: HIV-1, HIV-2; other retroviruses, hepatitis B virus.
Indications: infections with HIV.

Non-nucleosidic inhibitors of retroviral revers-transcriptase: NEVIRAPINE,

EFAVIRENZ, DELAVIRDINE, ATEVIRDINE, ALFA-ANILINO-
PHENYL-ACETAMIDE
Mechanism of action: allosteric binding to reverse transcriptase of the
retrovirus.
Antiviral spectrum: HIV (selectively).
Indications: HIV infections in adults.
Adverse effects: skin rash, headache, nausea, increase in transaminases.

Inhibitors of retroviral proteases: SAQUINAVIR, RITONAVIR,

INDINAVIR, NELFINAVIR, AMPRENAVIR, FOSAMPRENAVIR,
ATAZANAVIR, LOPINAVIR
Antiviral spectrum: HIV-1, HIV-2.
Indications: HIV infections in adults and children.
Adverse effects:
- Saquinavir: headache, nausea, abdominal pain, diarrhea, fever;
- Ritonavir: headache, nausea, abdominal pain, taste changes, altered tactile
sensations, dizziness, peripheral and central paresthesias, increased
transaminases, hypertriglyceridemia;
- Indinavir: crystalluria, nephrolithiasis, insomnia, pharyngeal pain, increase in
transaminases, bilirubin, thrombocytopenia, hair loss;
- Nelfinavir: fecal incontinence, diarrhea, fatigue, carbohydrate intolerance,
high cholesterol;
- Amprenavir: headache, nausea, flatulence, diarrhea, lipodystrophy, oral
paraesthesia.

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3. Inhibitors of assembly(maturation) of viral particles and release of virus
from the cell
Neuraminidase inhibitors: ZANAMIVIR, OSELTAMIVIR
Antiviral spectrum: influenza A and B.
Indications: prevention and treatment of influenza.
Adverse effects: rarely, nausea, diarrhea, headache, insomnia, vertigo.
Contraindications: kidney failure.

6.Antiprotozoal and antihelminthic drugs

3.1. Treatment of protosoal infections:

3.1.1. Amoebiaze:
 Dicloroacetamide derivative: Diloxanid-furoate, lodoquinole;
 nitroimidazoles: Metronidazole, Tinidazole, Ornidazole, Secondizole;
 other structures: Emetine, Dihydroemetine, Paromomicine, Chlorquinaldol, Clioquinol,
Diiodohydroxyquinoline, Chloroquine.
3.1.2. Leishmanioses:
 Pentamidine;
 Sodium stibogluconate;
 Meglumine antimoniate;
 other structures: Amphotericin B, Metronidazole, Cycloguanil embonate,
 Dehydroemethyn-resinate, Allopurinol ± Sodium stibogluconate.
3.1.3. Malaria:
 4-aminoquinoline: Chloroquine; Hedroxichioroquhine; Amodiaquine;
 Quinoline-methanol: Quinine; Mefloquine;
 Fenantrilcarbinol: Halofantrine;
 Diaminopirimidine: Pirimethamine;
 8-aminoquinoline: Primaquine
 Biguanide derivatives: Proguanil
 From plants: Artemisinin, Artemether, Artesunate.
3.1.4. Pneumocistosis: Atovaquone.
3.1.5. Toxoplasmoses:
 Sulfonamide + Pirimethamine  of choice,
 Spiramicine, Azitromicine, Cotrimoxazol, Pentamidine.
3.1.6. Trichomoniases:
 nitroimidazoles: Metronidazol, Tinidazol, Ornidazol, Secondizole.
3.1.7. Tripanosomiases:
 aromatic diamide: Pentamidine, Stilbamidine, Propamidine;
 Melarsaprol;

285
 other structures: Alpha-difluoro-methyl-omitine, Nifurtimox, Suramine.
3.2. Treatment of helminthiases:
 benzimidazole derivatives: Albendazole, Mebendazole, Thiabendazole;
 other structures: Bithionol, Diethylcarbamazine cytrate, Emetine, Ivermectin, Levamisole,
Metrifonate, Niclosamide, Oxamniquine, Oxantel, Paromomicine, Piperazine, Praziquantel,
Pyrantel, Quinacrine, Suramine, Tetrachiorethylene.

Nitroimidazoles: METRONIDAZOLE, TINIDAZOLE, ORNIDAZOLE,

SECONDIZOLE
Mechanism of action: the prodrug is activated by reducing the band "Nitro" by
ferredoxin to sensitive compounds that react with different macromolecules
inside anaerobic bacteria or protozoa → effect "cid ";
- Metronidazole has also anti-inflammatory effect.
Spectrum of activity:
- protozoa: Entamoeba histolytica (only trophozoites) Trichomonas vaginalis,
Giardia lamblia
- bacilli G (-) anaerobes: Bacteroides spp., H. pylori
- cocci G (-) anaerobes: Peptostreptococcus spp., Clostridium.
Pharmacokinetics:
- absorption is rapid after oral administration;
- weak binding to plasma proteins;
- distribution is broad in tissues: cerebrospinal fluid, brain, bile, seminal fluid,
vaginal secretions, bone, saliva, liver abscesses; the drug passes into breast
milk;
- hepatic metabolism;
- renal elimination.
- Metronidazole is an inhibitor of enzymatic metabolism of other drugs.
Indications:
- extraintestinal and intestinal amebiasis, trichomoniasis → it is the treatment of
choice
- giardiasis,
- infections with anaerobes: Clostridium difficile diarrhea, balantidioses,
Gardenella vaginalis infections, Fusobacterium spp. → as alternative treatment.
Adverse effects:
- metallic taste, glossitis, oral candidiasis, nausea, vomiting, headache, diarrhea
- red-brown urine
- disulfiram-like effect
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- paresthesia, peripheral neuritis, ataxia, mental disorders, convulsions,
peripheral neuropathy
- pancreatitis, leukopenia
- mutagenic, carcinogenic.
Contraindications: pregnancy, breastfeeding, young children.
Precautions: severe hepatic impairment, organic brain disorders, blood
dyscrasias.
Interactions:
- Metronidazole increases the effects of oral coumarin anticoagulants; increases
the toxicity of lithium
- phenytoin and phenobarbital accelerate the elimination of Metronidazole
- Cimetidine decreases the plasma clearance of Metronidazole.

7.Cancer chemotherapy

Indications for antineoplastic chemotherapy (curative treatment):

- testicular cancer
- diffuse histiocytic lymphoma, Hodgkin’s disease, Burkitt’s lymphoma
- choriocarcinoma
- acute lymphoblastic leukemia
- Wilms tumor
- embryonal rhabdomyosarcoma.
Common adverse effects of antineoplastic chemotherapy:
- digestive disturbances: nausea, vomiting, gastrointestinal bleeding, ulcers
- myelosuppression
- alopecia
- nephrotoxicity
- teratogenicity
- immunosuppression
- carcinogenicity.

Cytotoxic drugs can be classified as either:

• Cell cycle nonspecific: these kill cells whether resting or actively cycling (as
in a low growth fraction cancer such as solid tumours, e.g. alkylating agents,
doxorubicin and allied

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anthracyclines)
• Cell cycle (phase) specific: these kill only cells that are actively cycling (often
because their site of action is confined to one phase of the cell cycle, e.g.
antimetabolite drugs).

Classification
1. Antitumor drugs with specific action on the cell cycle
- Antimetabolites
 Folic acid antagonis: Methotrexate
 Purine antagonists: Mercaptopurine, Azathioprine, Thioguanine,
Pentostatin, Fludarabine, Cladribine
 Pyrimidine antagonists: 5-Fluorouracil, Floxuridine, Azacitidine,
Cytarabine, Capecitabine, Gemcitabine
- Antitumor peptide: Bleomycin
- Alkaloids of podophyllotoxin: Etoposide (VP-16), Teniposide (VM-26)
- Vinca alkaloids: Vincristine, Vinblastine, Vinorelbine
- Taxanes: Paclitaxel, Docetaxel
2. Antitumor drugs with non-specific action on the cell cycle
- Alkylating agents
 nitrogen mustards derivatives: Cyclophosphamide, Ifosfamide,
Chlorambucil, Melphalan, Mechloretamine
 Alkyl sulfones: Busulfan, Treosulfan
 Ethylenimines: Thiotepa
 Nitrosourea derivatives: Carmustine, Lomustine, Semustine,
Estramustine
 Other structures: Mechlorethamine, Dacarbazine, Temozolomide
- Cytotoxic antitumor drugs:
 Anthracyclines: Doxorubicin, Daunorubicin, Epirubicin, Idarubicin,
Aclarubicin, Mitoxantrone, Valrubicin
 Other structures: Dactinomycin, Mitomycin, Mithramycin
- Platinum compounds: Cisplatin, Carboplatin, Oxaliplatin
- Camptothecins: Topotecan, Irinotecan
- Other structures: Procarbazine, Altretamine
3. Other antitumor agents
- Hormonal agents

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- Aromatase inhibitors: Aminoglutethimide, Anastrozole, Exemestane,
Letrozole
- Other structures: asparaginase, hydroxyurea, mitotane, retinoic acid
derivatives, growth factors from bone marrow
- Monoclonal antibodies:
 monoclonal antibodies indicated for the release of isotopes:
Arcitumomab, Ibritumomab Tiuxetan, Tositumomab;
 monoclonal antibodies indicated as antitumor agents: Trastuzumab,
Rituximab, Bevacizumab, Cetuximab, Gemtuzumab, Alemtuzumab.

Monoclonal antibodies identified as antitumor agents

Mechanisms of action:
- Trastuzumab, Cetuximab: receptor blockade of human epidermal growth
factor (HER2);
- Bevacizumab: binds to vascular endothelial growth factor → inhibition of
angiogenesis;
- Rituximab: lysis of complement mediated cytotoxicity and antibody-
dependent cell → stimulation of apoptosis.
Indications:
- Bevacizumab, Cetuximab: metastatic colorectal cancer;
- Trastuzumab: metastatic breast cancer in HER2 amplified cells;
- Gemtuzumab: acute myeloid leukemia;
- Rituximab: lymphoma.
Adverse effects:
- Cetuximab: myelosuppression (neutropenia, anemia, thrombocytopenia,
opportunistic infections);
- Gemtuzumab: myelosuppression (particularly neutropenia), hepatotoxicity,
hypersensitivity reactions.

Monoclonal antibodies indicated for the release of isotopes:

- release of technetium 99m (99mTc):
 Arcitumomab → Indications: gastrointestinal carcinoma;
- release of indium (111In):
 ibritumomab tiuxetan → Indications: non-Hodkin’s lymphoma;
- release of iodine 131 (131I):

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  Tositumomab → Indications: non-Hodkin’s lymphoma.

8.Immunopharmacology

Classification:
 Specific immunosupressor drugs: monoclonal and policlonal
antilymphocyte antibodies, immuneglobulin.
 Non-specific immunosupresors drugs:
o Physical agents: X and gamma radiations;
o Chemical agents:
 alchilants: Cyclophosphamide, Clorambucil,
Dacarbazine, Procarbazine;
 purine antagonists: Mercaptopurine, Azathioprine,
Thioguanine, Fludarabin-phosphat, Cladribine;
 pirimidinic antagonists: Fluorouracil, Cytarabine,
Azacitidine;
 antimetabolits: Metotrexat;
 nonsteroidal antiinflammatory drugs;
 disease-modifying antirheumatic drugs;
 other agents: Hydroxiureea, Dapsone,
Tetraclordecaoxygen;
o viral agents;
o Natural drugs and analogues:
 Alcaloids: Vinblastine, Vincristine, Podofilotoxine;
 Colchicine;
 Dextran;
 Bucillamine;
 Cyclosporine and other immunosupressor drugs;
 Glucocorticosteroids and their analogues;
 Antibodies and circulatory immune complexes;
 Gamma globuline;
 Prostaglandinee and leukotrienes;
o Other immunosupressors: Mycophenolate mofetil, Mizoribine,
Brequinar sodic, 15-Deoxyspergualin, Sirolimus, Talidomida,
Leflunomid.

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 Lecture 14
Drugs used in the treatment of
gastrointestinal diseases

Learning Objectives:
 Describe aspects of absorption, distribution, metabolism and excretion of a
drug;
 List the principal routes of drug administration and their advantages and
disadvantages;
 List examples of drugs concentrated in different tissues or liquids of the body;
 Name the phases in hepatic metabolism;
 Describe the terms “bound” and “unbound” drug to plasma proteins;
 Describe the term “first pass effect”;
 Describe the terms drug metabolism “enzyme induction” and “enzyme
inhibition”;
 List the principal routes of drug elimination;
 Explain concept and significance of pharmacokinetic parameters
 Explain concept and significance of steady state concentration.

1. Drugs used in gastric ulcer disease

Classification
1. Drugs that reduce intragastric acidity
 Antiacids
 Inhibitors of acidity secretion
o H2-receptor antagonists: Cimetidine, Ranitidine, Famotidine,
Nizatidine
o Proton pump inhibitors (inhibitors of Na+/K+-ATP-ase):
Omeprazole, Lansoprazole, Pantoprazole, Rabeprazole,
Esomeprazole
o Inhibitor of gastrine (somatostain analogue): Octreotide
o Cholecystokinin antagonists: Proglumid.
o Inhibitors of carbon anhidrase: Acetazolamide
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 o Antimuscarinic drugs with antispasmodic effect: Pirenzepine
Telenzepine, Propantheline;
2. Mucosal protective agents
 Colloidal bismuth compounds: Bismuth subsalicylate, bismuth
subcitrate, bismuth dinitrate
 Sucralfate
 Carbenoxolone
 Prostaglandin E1 analog: Misoprostol
3. Drugs with anti Helicobacter pylori activity:
 Aminopenicillines (Ampicillin, Amoxicillin),
 Macrolides (Erythromycin, Clarithromycin, Azithromycin),
 Ciprofloxacin,
 Tetracycline,
 Metronidazole,
 Colloidal bismuth compounds.
Combinations used to treat peptic disease associated with H. pylori:
Amoxicillin
or proton pump inhibitor
Ampicillin (omeprazole)
or
clarithromycin or
or + Metronidazole +
Azithromycin Misoprostol
or
Erythromycin

1. DRUGS THAT REDUCE INTRAGASTRIC ACIDITY

1.1. ANTACIDS
Classification
 Neutralising agents: Calcium carbonate, Magnesium hydroxide,
Magnesium oxyde, Magnesium peroxyde, Magnesium trisilicate,
Aluminium hydroxide, Aluminium phosphate
 Alkalising agents: Sodium bicarbonate (baking soda)
Mechanism of action: reaction with HCl determines neutralization or
alkalinisation of gastric pH.
Pharmacodynamic effects:
- neutralizing / alkalinity of the gastric juice;

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- inactivation of pepsin.
Indications:
- ulcer disease
- gastroesophageal reflux, esophagitis;
- other indications:
 Sodium bicarbonate is indicated for metabolic acidosis (iv), for alkaline
urine (oral);
 Calcium carbonate is indicated as calcium supplementation, for
treatment of hyperphosphatemia in chronic renal failure;
 magnesium compounds are used as laxatives;
 aluminum compounds are indicated to treat hyperphosphatemia in
chronic renal failure, as vaccines adjuvant.
Adverse effects
- Sodium bicarbonate:
 metabolic alkalosis,
 acid rebound effect,
 in the digestive tract: abdominal cramps, flatulence;
- Calcium carbonate:
 constipation, flatulence,
 acid rebound effect,
 hypercalcemia, hypophosphatemia, milk - alkaline syndrome;
- Magnesium compounds:
 diarrhea,
 hypermagnesemia in patients with renal insufficiency;
- Aluminum compounds:
 constipation,
 hypercalcemia, hypophosphatemia.
Contraindications
- renal failure;
- also for:
 Sodium bicarbonate: heart failure, hypertension;
 Calcium carbonate: hypercalcemia, hypophosphatemia,
hypomagnesemia, recent upper gastrointestinal bleeding;
 Compounds containing magnesium: neuromuscular
disorders,cardiovascular diseases.

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  Aluminium compounds: hypercalcemia, hypophosphatemia.
Drug Interactions:
- Antacids lower gastrointestinal absorption of: digoxin, tetracyclines,
quinolones, Ketoconazole, Itraconazole, iron compounds, ursodeoxycholic acid.

1.2. INHIBITORS OF ACIDITY SECRETION

 H2-receptor antagonists: Cimetidine, Ranitidine, Famotidine,
Nizatidine;
 Proton pump inhibitors (inhibitors of Na+/K+-ATP-ase):
o 1st generation: Omeprazole, Lansoprazole, Pantoprazole,
o 2nd generation: Rabeprazole, Esomeprazole;
 Inhibitors of carbon anhidrase: Acetazolamide;
 Cholecystokinin antagonists: Proglumid;
 Antimuscarinic drugs with antispasmodic effect: Pirenzepine
Telenzepine, Propantheline.

H2 RECEPTOR ANTAGONISTS: Cimetidine, Ranitidine, Nizatidine,

Famotidine
Mechanism of action:
- antagonism on H2 receptors;
- Nizatidine: also it is acetylcholinesterase inhibitor.
Pharmacodynamic effects: inhibition of basal gastric secretion of HCl.
Pharmacokinetics: Cimetidine: is inhibitor of drug metabolism.
Indications:
- peptic ulcer;
- Zollinger-Ellison syndrome;
- gastroesophageal reflux;
- non-ulcer dyspepsia;
- prevention of gastritis induced by stress;
- hypersecretory conditions (systemic mastocytosis, leukemia, basophilia).
Adverse effects:
- Cimetidine:
 in the CNS: confusional states, hallucinations, delusions, agitation;
 endocrine effects: gynecomastia, galactorrhea, decreased

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 spermatogenesis, libido;
 hematological effects: granulocytopenia, aplastic anemia;
 effects on the liver: increase of transaminases, cholestatic jaundice,
acute hepatitis;
- Ranitidine: elevation of transaminases, cholestatic jaundice, acute hepatitis;
- Famotidine: headache, transient elevation of transaminases;
- Nizatidine: headache; transient elevation of transaminases, prokinetic effect,
reduction in heart rate, reducing the force of contraction of the heart.
Drug Interactions:
- reduce the absorption of Ketoconazole,
- inactivate sucralfate,
- inhibit renal clearance of basic drugs secreted by the renal tubules
(procainamide)
- Cimetidine is an inhibitor of drug metabolism:
 Beta-blockers,
 Diazepam, Clordiazepoxid, alprazolam,
 Phenytoin,
 Quinidine,
 Theophylline,
 tricyclic and heterocyclic antidepressive
 Warfarin.

PROTON PUMP INHIBITORS (INHIBITORS OF NA+/K+-ATP-ASE)

Classification
 1st generation: Omeprazole, Lansoprazole, Pantoprazole,
 2nd generation: Rabeprazole, Esomeprazole
They are prodrugs.
Mechanism of action: inhibition of H+/K+-ATPase.
Pharmacodynamic effects: inhibition of basal gastric secretion of HCl.
Indications:
- ulcer disease (including NSAID induced);
- Zollinger Ellison syndrome or other gastrinomas (tumour that secretes the
hormone gastrin);
- gastroesophageal reflux;
- non-ulcerative dyspepsia;

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- prevent stress-induced gastritis;
- in associations to eradicate the infection with H. pylori.
The advantages of second generation (Rabeprazol, Esomeprazole):
- faster onset of pharmacodynamic effect;
- lowest doses determine maximal suppression of acidity;
- completely inhibits acid secretion for 24 h.
Adverse effects
- hypochlorhidria that promotes enteric infections (Salmonella, Shigella);
- atrophic gastritis;
- intestinal metaplasia;
- hypergastrinemia;
- rare: diarrhea/constipation, headache, flatulence, risk of gastric carcinoid
tumors.
Contraindications: pregnancy, lactation.

CARBONIC ANHYDRASE INHIBITORS: Acetazolamide

Mechanism of action
- inhibition of carbonic anhydrase → block the formation of bicarbonates and
H+ ions.
There is carbonic anhydrase in the gastric mucosa, eye, kidneys
(predominantly in the proximal convoluted tubule), CNS, pancreas,
erythrocytes.
Pharmacodynamic effects  are of low intensity and short duration
- gastric mucosa: reduce gastric acidity;
- renal: inhibition of carbonic anhydrase activity depresses bicarbonate
reabsorption in the proximal tubule and inhibit the exchange of H+ ions with
Na+ ions:
 in urine are eliminated: Na+, K+, bicarbonate, phosphate, water
(increase diuresis);
 in blood increase H+ and Cl-;
- eye: reduce intraocular pressure in glaucoma (because decreases the rate of
formation of aqueous humor);
- CNS: local acidosis induced by inhibitors of carbonic anhydrase determine
anticonvulsant effects, reduce cerebral edema and regulate nerve impulses in
the cortical and subcortical areas; reduce hypercapnia;
Pharmacokinetics: absorption: good for Acetazolamide; plasma protein
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binding: 90%; renal elimination as unchanged drugs.
Indications:
- peptic disease;
- gastroesophageal reflux;
- other indications:
 glaucoma (Acetazolamide p.o. for open angle and for closed angle
glaucoma);
 acute mountain sickness (= high-altitude disorders)
o symptoms: weakness, dizziness, insomnia, headache and nausea
may occur in mountain travelers who ascend rapidly to above
3000 m → pulmonary or cerebral edema;
o prophylaxis can be obtained after oral administration, starting 24
h before the ascent;
 diuretic (for urinary alkalinization and to increase urinary phosphate
excretion);
 epilepsy  as an alternative or adjunct to first-line drugs;
 to correct metabolic alkalosis.
Adverse effects:
- rapid development of tolerance;
- hyperchloremic metabolic acidosis;
- kidney stones;
- renal elimination of potassium (hypokaliemia);
- dizziness, fatigue, drowsiness, CNS depression and paraesthesia at high doses;
- bone marrow depression (rare);
- hypersensitivity reactions (fever, pruritus, interstitial nephritis).
Contraindications: liver cirrhosis, renal failure, pregnancy.

CHOLECYSTOKININ ANTAGONISTS: Proglumid.

- used for the treatment of peptic ulcer.

2. MUCOSAL PROTECTIVE AGENTS

 Colloidal bismuth compounds: Bismuth subsalicylate, bismuth
subcitrate, bismuth dinitrate
 Sucralfate
 Carbenoxolone

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  Prostaglandin E1 analog: Misoprostol

COLLOIDAL BISMUTH COMPOUNDS: Bismuth subsalicylate, bismuth

subcitrate, bismuth dinitrate
Mechanism of action: selective binding to ulcerated tissue, stimulating the
secretion of mucus, bicarbonate and prostaglandins; inhibits the activity of
pepsin.
Pharmacodynamic effects:
- cytoprotective effect because stimulate stimulating the secretion of mucus,
bicarbonate and prostaglandins, inhibits the activity of pepsin;
- anti-Helicobacter pylori.
Indications: Peptic ulcer and gastritis with H.pylori.
Adverse effects:
- black coloration of the stool, darkening of the tongue,
- risk of hepatic encephalopathy (bismuth toxicity in prolonged use).
Contraindications: hepatic and renal failure.

SUCRALFATE
It is a salt of sucrose complexed with aluminum hydroxide; is a prodrug.
Mechanism of action:
- turns into a viscous substance capable of binding to the mucosal
gastroduodenal and creates a protective film (selective binding to ulcerated
tissue is carried out only in acid),
- promotes the secretion of mucus, bicarbonate and prostaglandins,
- inhibits the action of pepsin and bile salts.
Pharmacodynamic effects: cytoprotective effect.
Indications: Peptic disease, prevent ulcers induced by stress / NSAIDs.
Adverse effects: constipation.
Contraindications: severe renal impairment.
Drug interactions: there are required 2 h between administration of sucralfate
(which is active only in acid environment and binds to other drugs) and
antacids, H2 blockers, antihistamines, digitalis, anticoagulants, Ketoconazole,
fluoroquinolones, tetracyclines.

CARBENOXOLONE
It is a synthetic derivative of glycyrrhizinic acid.
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Mechanism of action: increased production, secretion and viscosity of mucus.
Pharmacodynamic effects: cytoprotective effect.
Indications:
- gastroesophageal reflux,
- peptic diseases.
Adverse effects: the effects hyperaldosteronism type (water retention resulting
in blood pressure, hypokalemia).
Contraindications:
- absolute: hypokalemia, pregnancy, seniors, children;
- relative: cardiovascular diseases (hypertension, heart failure), liver failure,
renal failure.
- association with digoxin (increase risk of hypokaliemia) or Spironolactone
(antagonize the effects).

PROSTAGLANDIN E1 ANALOG: Misoprostol

Mechanism of action:
- agonist on PGE1 receptors;
- stimulate the gastric secretion of mucus, bicarbonate and decrease pepsin
secretion.
Pharmacodynamic effects:
- cytoprotective effect (because stimulate the gastric secretion of mucus and
bicarbonate);
- inhibition of gastric acid secretion (=antisecretory effect because decrease
pepsin secretion);
- produces uterine contractions.
Indications:
- prevention of NSAID-induced ulcers or stress-induced ulcers.
- peptic ulcers.
- prevention of postpartum hemorrhage.
Adverse effects: diarrhea, abdominal cramps, stimulate uterine contractions;
Contraindications: pregnancy.

2. Antiemetic drugs

Classification

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  H1-receptor antagonists 1st generation:
o Phenothiazines: Promethazine, Prochlorperazine,
Tiethylperazine;
o Ethanolamines: Diphenhydramine, Carbinoxamine, Doxylamine;
o Piperazines: Hydroxyzine, Cyclizine;
 Antimuscarinic drugs: Scopolamine, Atropine, Butilscopolamine
 Cholinomimetic and antidopaminergic drugs: Metoclopramide,
 Antidopaminergic drugs: Domperidone
 Neuroleptic drugs (phenothiazine structure): Chlorpromazine
 Antagonists on 5HT3 receptors: Ondansetron, Granisetron,
Dolasetron, Tropisetron
 Antagonists on neurokinin NK-1 receptors: Aprepitant, Fosaprepitant
(Indications: cytotoxic chemotherapy induced nausea and vomiting)
 Marijuana derivatives: Tetrahydrocanabinol (THC), Dronabinol,
Nabilone (Indications: cytotoxic chemotherapy induced nausea and
vomiting)
 Corticosteroids: Dexamethasone, Methylprednisolon (Indications:
alternative for cytotoxic chemotherapy induced nausea and vomiting)
 Other substances: benzodiazepines, Procaine, benzocaine, sodas, tea
(mint, melissa, chamomile, aniseed).

METOCLOPRAMIDE
Mechanism of action:
- acetylcholine release in the enteric nervous system,
- competitive antagonist of central and peripheral dopamine D1 and D2
receptors.
Pharmacodynamic effects:
- stimulates eso-gastro-intestinal peristalsis, accelerates gastric emptying,
- relaxes the pyloric sphincter
- increase the tone of the cardia;
- antiemetic effects.
Pharmacokinetics: crosses the blood-brain barrier (causes extrapiramidal
effects, pseudo-parkinsonism, effects of prolactin stimulation).
Indications:
- prokinetic (gastrointestinal hypomotility, diabetes mellitus gastropareses,

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gastroesophageal reflux, pyloric spasm);
- anti-emetic (nausea / vomiting of various etiologies);
- migraine (as an antiemetic);
- hiccups.
Adverse effects
- diarrhea, abdominal cramps;
- neurovegetative dystonia (extrapyramidal symptoms);
- pseudoparkinsonism (tardive dyskinesia),
- gynecomastia, galactorrhea, menstrual disorders (due to stimulation of
prolactin secretion).
Should not be associated with:
- drugs that cause extrapyramidal effects (neuroleptic phenothiazines);
- antimuscarinic drugs (they antagonize the effects of Metoclopramide).

DOMPERIDONE
Mechanism of action: competitive antagonist of dopamine D2 receptors.
Pharmacodynamic effects:
- stimulates esophageal, stomach and gastrointestinal peristalsis,
- relaxes the pylorus;
- increase the tone of the cardia;
- antiemetic effects.
Pharmacokinetics: does not cross the blood-brain barrier.
Indications:
- prokinetic (gastrointestinal hypomotility, gastroesophageal reflux disease);
- antiemetic for short term treatment (nausea / vomiting of various etiologies).
Adverse effects
- diarrhea, abdominal cramps;
- reduced: hyperprolactinemia, neurovegetative dystonia.

5-HT3 ANTAGONISTS: Ondansetron, Granisetron, Dolasetron, Tropisetron

Pharmacodynamic effects: antiemetic effects; antidepressant effects.
Indications:
- drugs of choice for cytotoxic chemotherapy or radiotherapy induced nausea
and vomiting,
- prevention and treatment of postoperative vomiting.
Adverse effects:
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- headache;
- constipation / diarrhea, abdominal cramps;
- increase in transaminases;
- severe arrhythmias (prolongation of QT interval in rapid i.v. administration).
Contraindications: pregnancy.
It is necessary to reduce the dose in patients with impaired liver and kidney.

ANTAGONISTS ON NEUROKININ NK-1 RECEPTORS: Aprepitant,

Fosaprepitant
Mechanism of action: antagonists on neurokinin NK-1 receptors;
Indications: antiemetics for cytotoxic chemotherapy-induced vomiting.
Adverse effects: headache, constipation / diarrhea, abdominal cramps, increase
in transaminases.

3. Antispasmodic drugs

Classification
1. Antimuscarinic:
 natural alkaloids: Atropine, Scopolamine;
 synthetic or semi-synthetic derivatives:
o quaternary amines:
 Antispasmodic and antiemetic: Butilscopolamine;
 Antispasmodics: Propantheline, Glycopyrrolate,
Clidinium, Tridihexethyl, Anisotropine, Isopropamide,
Methantheline, Oxyphenonium, Methylscopolamine,
Hexociclium;
o tertiary amines:
 Antispasmodics: Oxyphencyclimine, Mebeverine;
 Antispasmodics in irritable bowel: Dicyclomine
(Dicycloverine).
2. Isoquinoline derivatives from opium: Papaverine, Drotaverine (No-Spa®)
3. Antimuscarinic and calcium channel blockers: Mebeverine, Rociverine
4. Others: Alverine.

ISOQUINOLINE DERIVATIVES FROM OPIUM: Papaverine, Drotaverine

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PAPAVERINE
Mechanism of action:
- inhibits phosphodiesterases in smooth muscle cells, which produces increased
tissue levels of cyclic AMP and cyclic GMP (also inhibits phosphodiesterase-5
or PDE-5);
- block calcium ion channels in cell membranes, resulting in a reduction of
release of calcium from the intracellular spaces.
Papaverine does not act on opioid receptors (does not determine analgesia and
euforia, does not determine addiction).
Pharmacodynamic effects: relaxation of smooth muscle  vasodilatation and
relaxation of other smooth muscles.
Pharmacokinetics: Papaverine is rapidly absorbed from the gastro-intestinal,
t1/2 = 1 - 2 h, plasma protein binding is 90%. It is metabolized in the liver to
inactive metabolites, which are excreted in the urine.
Indications:
- antispasmodic (intestinal, biliary, genito-urinary colicative pain);
- ischemic conditions associated with arterial vasospasm (pre-eclampsia,
eclampsia, cerebral and peripheral ischemia associated with arterial spasm and
without vascular injuries);
- erectile dysfunction (alone or in combinations: + phentolamine, or
+ phentolamine + alprostadil).
Adverse effects:
- “arterial steal” in arterial obstructions;
- quinidine-like effects: QT prolongation, ventricular arrhythmias, and torsade
de pointes;
- hepatotoxicity (after high doses / administration prolonguee);
- after intracavernosal injection of papaverine: local administration by injections
into the corpus cavernosum  local penile fibrosis (loss of elasticity of the
tissue), transient penile pain, ecchymosis, and priapism (painful prolonged
erection).
Contraindications:
- chronic arterial obstructions;
- atrioventricular block, bradicardia;
- heart failure;
- pregnancy, breast-feeding.
DROTAVERINE
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Mechanism of action: inhibition of phosphodiesterase-IV, rapid and direct
relaxation effect on the smooth muscle.
Indications: antispasmodic (biliary-tract, urinary-tract and gastrointestinal
spasm).

ANTIMUSCARINIC AND CALCIUM CHANNEL BLOCKERS:

Mebeverine, Rociverine
Mechanism of action: antimuscarinic, direct relaxation effect on the intestine
smooth muscles, inhibitor of calcium-depot replenishment.
Indications: antispasmodic (irritable bowel syndrome, gastric and duodenal
ulcers).

ALVERINE
Mechanism of action: direct relaxation effect on the intestine and uterine
smooth muscles.
Indications: antispasmodic.

4. Drugs stimulating gastrointestinal motility.

Classification
1. Cholinomimetic drugs
 direct acting parasympathetic drugs: Betanechol (indication:
postoperative in abdominal distention, in gastric atony or gastroparesis)
 indirect acting parasympathetic drugs: Neostigmine, Pyridostigmine
(indication: therapy of paralitic ileus);
2. Cholinomimetic and antidopaminergic drugs: Metoclopramide,
3. Antidopaminergic drugs: Domperidone
4. Cholinomimetic and agonist on 5HT4 receptors: Cisapride, Norcisapride,
Renzipride, Mosapride (Indications: as prokinetics)
5. Antagonists on 5HT3 receptors: Alosetron (indication: irritable bowel
syndrome)
6. Partial agonists on 5HT4 receptors: Tegaserod (indication: irritable bowel
syndrome)
7. Macrolides (stimulate motilin receptors): Erythromycin, Clarithromycin,

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Azithromycin
8. Inhibitor of gastrine (somatostatin analogue): Octreotide.

Contraindications: in the presence of mechanical obstruction of the

gastrointestinal tract.

5. Laxatives

Laxatives are agents which promote bowel evacuation.

Classification
4.1. Stool softeners:
 Surfactant agents: docusate (p.o./intrarectal), glycerin suppositories
(intrarectal),
 Lubricants: mineral oil p.o. (liquid paraffin, olive oil, sunflower oil etc),
4.2. Bulk-forming laxatives:
 Colloids:
o hydrophilic colloids: natural products form plants
(methylcellulose, ispaghula, psyllium), extracts from marine
algae or synthetic products (polycarbophil)
o indigestible fiber: polysaccharides, cellulose, wheat bran or other
fiber (Psylla seeds, flax seeds)
 Osmotic laxatives:
o Lactulose (it is a disaccharide)
o Macrogol (it is a polyethylene glycol)
o Sorbitol (it is a polyhydric sugar alcohol)
o glycol (mixture of polymers, for example, Forlax ®)
o Salts: magnesium hydroxide (milk of magnesia), magnesium
sulfate, sodium sulfate, sodium phosphate, sodium potassium
tartrate, magnesium citrate
4.3. Irritant laxatives (non-specific stimulants of the gut):
 antraquinone derivatives from plants p.o. (aloe, senna, cascara),
 castor oil (p.o.),
 Bisacodyl (p.o./intrarectal).

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Indications:
- food poisoning or other intoxication with substances administered orally;
- diseases where consistency should be soft (hemorrhoids, for example) or
diseases in which defecation effort should be avoided (eg heart failure, inguinal
hernia etc.);
- habitual constipation (with caution not to make a habit);
- to clean the intestine before surgical or diagnostic procedures (oral or enema);
- as adjunctive therapy (some cases of anthelminthic treatment).
Contraindications:
- hepatic or renal failure;
- undiagnosed abdominal pain (e.g., acute appendicitis);
- dehydrated (avoid to children because of the risk of rapid dehydration);
- threatened abortion (= imminent abortion), breastfeeding.

Stool softeners (docusate, glycerin suppositories, mineral oil)

- Surfactant agents: docusate (p.o./intrarectal), glycerin suppositories
(intrarectal)
 Mechanism of action: soften stools by promoting water and fats in the
stool, making it more bulky and easier to move along the intestine.
Onset of action: 12 - 72 h.
- Lubricants: mineral oil p.o. (liquid paraffin, olive oil, sunflower oil etc)
 Mechanism of action: oil lubricates fecal material in colon and decrease
absorption of water from stools, making the stool softness and slippery
to move through the intestine. Onset of action: 6 - 8 h. Adverse effect:
long term administration reduces absorption of fat soluble vitamins.

Colloids ((methylcellulose, ispaghula, psyllium, extracts from marine algae

polycarbophil, polysaccharides, cellulose, Psylla seeds, flax seeds etc)
Mechanism of action: taken with water form a bulky gel, thus increasing the
bulk of the stool and stimulating peristalsis. Onset of action: 12-72 h. Adverse
effects: abdominal distension due to digestion of plant fibers by the colon
bacteria. These should be administered with plenty of water to avoid intestinal
obstruction.

Osmotic laxatives (Lactulose, Macrogol, Sorbitol, glycol, magnesium

hydroxide and other salts)
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Mechanism of action: are soluble non-absorbable compounds with a high
osmotic tension that increase the osmotic pressure within the intestinal tract and
cause more water to enter the intestines; this result in the distention of the
bowel, increase of intestinal peristalsis and produce defecation in few hours.
Onset of action: 0.5 - 3 h. Adverse effects: liquid depletion and electrolyte
disturbances; lactulose is metabolized by colonic bacteria producing distension
and cramps.
Lactulose is also used for the treatment of hepatic encephalopathy (it is
metabolized by intestinal bacteria, to form lactic acid, acetic acid and
other organic acids that increase the elimination of ammonia and other
toxins to CNS, prevent absorption of NH3 and thus lowers circulating
ammonia levels.
Magnesium sulfate is also used as drug of choice in eclampsia to
decrease blood pressure, for torsades de points and digoxin-induced
arrhythmias.

Irritant laxatives (antraquinone derivatives, castor oil, Bisacodyl)

Mechanism of action: stimulate directly the enteric nervous system and
increase the permeability of the intestinal mucosa, which increase colonic
electrolyte and fluid secretion, thus increasing intestinal motility. Onset of
action: 6 - 12 h when given orally and within 2 h when given rectally. Adverse
effect: abdominal cramps, hepatotoxicity.

6. Antidiarrheal agents

Classification
 Opioid agonists: Loperamide, Diphenoxylate, Diphenoxyn
 Others:
o kaolin, pectin
o Inhibitor of gastrine (somatostatin analogue): Octreotide
o In clinical trial: presynaptic receptor agonists central alpha2
(Clonidine).

OPIOID AGONISTS: Loperamide, Diphenoxylate, Diphenoxyn

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Does not pass the blood-brain barrier.
Indications:
- acute nonspecific diarrhea,
- chronic diarrhea of inflammatory bowel disease.
Contraindications:
- ulcerative colitis (may induce toxic megacolon)
- infection by Shigella, Salmonella.

INHIBITOR OF GASTRINE (SOMATOSTATIN ANALOGUE):

Octreotide
Mechanism of action: selectively inhibits the release of growth hormone,
insulin, glucagon, gastrin, serotonin, vasoactive intestinal peptide (VIP),
secretin, motilin, and pancreatic polypeptide, TSH, decreases splanchnic blood
flow.
Pharmacodynamic effects:
- inhibition of the release of growth hormone (GH)  it is indicated in
acromegaly,
- selectively inhibition of the release of glucagon, gastrin, serotonin, VIP,
secretin, motilin, and pancreatic polypeptide  it is indicated in diarrheas from
carcinoid tumors and other secretory diarrhea, in acute pancreatitis, in
complications after pancreatic surgery;
- direct constriction of the splanchnic arterioles (decreases of splanchnic blood
flow) and inhibition of the release of intestinal peptides involved in the
circulatory syndrome of portal hypertension  it is indicated in esophageal
bleeding varices, in bleeding peptic ulcer;
- inhibition of the release of insulin,
- suppresses secretion of thyroid stimulating hormone (TSH);
- inhibit gallbladder contractility and decrease bile secretion.
Indications:
- diarrheas associated with carcinoid tumors and other secretory diarrhea (such
as chemotherapy-induced diarrhea, diarrhea associated with human
immunodeficiency virus (HIV), and diabetes-associated diarrhea).
 Watery diarrhea, hypokalemia and achlorhydria (WDHA) syndrome is
caused by VIP-producing tumor;
- acromegaly;
- esophageal bleeding varices; bleeding peptic ulcer;
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- acute pancreatitis, complications after pancreatic surgery.
Adverse effects
- nausea, vomiting, abdominal cramps, flatulence, steatorrhea;
- cholelithiasis (after 6 months of treatment);
- transient changes in glucose tolerance test, hyperglycemia, hypothyroidism.

Drugs causing constipation:

 Morphine and its analogues  Anti-parkinsonism drugs
 Barium Sulphate  Anti-histamine drugs
 Al(OH)3  NSAID
 Anticholinergic drugs  Ganglion blockers
 Calcium channel blockers  MAO inhibitors

7. Pancreatic enzyme substituents

Classification
 pancreatic enzymes (tripsine, lipase, amylase): Digestin®, Mexaze®,
Mexaform®, Triferment®, Kreon®
 pancreatic enzymes combined with bile (Panzcebil®, Festal®, Digestal
forte®) or with Dehydrocolic acid (Zymogen®)
Indications:
- secretory exocrine pancreas insufficiency (chronic pancreatitis, cystic fibrosis
of the pancreas);
- dyspeptic disorders (fermentation / putrefaction dyspepsia).
Contraindication: bile gallstone disease.

8. Drugs stimulating bile and therapy for gallstones

Terminology
- choleretic = enhances the formation of the bile;
- cholagogue (colecistokinetic) = stimulates the discharge of bile from the
gallblader (stimulates gallbladder motility);
- colespasmolytic = relaxes the gallblader and the sphincter of Oddi.
Classification of substances stimulating bile
- choleretic (stimulate bile secretion):

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  Animal: salts and bile acids;
 Vegetable: Anghirol(+) (Cinar Scolimus extract), extract / infusion of
Boldo (Pneumus boldus), volatile or ethereal oils (menthol, borneol,
pinene, cineol): Rowachol® (combination of essential oils), Boldocholin
® (salicylate + menthol + magnesium carbonate + extract of Boldo).
 Synthetic: sodium salicylate, Propilbenzen.
- cholagogue (stimulate bile elimination):
 food: olive oil, sunflower, egg yolk, cream;
 Magnesium sulphate (alone or in combination with peptone
(Peptocolin(+)).
Indications
- choleretic:
 malabsorption of lipids and fat soluble vitamins;
 chronic cholecystitis;
 cholelithiasis;
 atherosclerosis;
 constipation due to insufficient quantity of bile;
 flatulence;
 myigrenoide syndromes.
- cholagogue:
 hypotonia gallbladder, gallbladder hypokinesia;
 nonlithiazic chronic cholecystitis.
Contraindications: obstructive jaundice, acute hepatitis.
Colagogues are contraindicated also in cholelithiasis (gallstone disease).

DRUGS USED AS THERAPY FOR GALLSTONES: Ursodeoxycholic acid,

Chenodeoxycholic acid, Dehidrocolic acid; Monooctanoin.
ACID CHENODEOXICOLIC
Mechanism of action: inhibition hidroximetilglutaril-coenzyme A reductase.
Indications: cholesterol stones in gallbladder.
Adverse effects: diarrhea, elevated transaminases, increased LDL-cholesterol in
the blood.
Contraindications: obstructive jaundice, frequently biliary colics, cholestasis,
cholecystitis, angiocolitis, severe gastrointestinal disease, liver and renal failure,
pregnancy.

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Drug interactions: absorption is reduced in the presence of aluminum antacids,
colestipol, cholestyramine.
URSODEOXYCHOLIC ACID
Mechanism of action: decreases biliary lipid secretion, quickly and strongly
decreases cholesterol content of the bile so that it is less lithogenic,
cytoprotective effects on hepatocytes.
Indications: cholesterol gallstones, chronic cholestatic liver disease (primary
biliary cirrhosis).
Adverse effects: diarrhea, nausea, vomiting, elevated transaminases.
Stopping suddenly determine risk of gallstones formation.

9. Drugs to treat inflammatory bowel disease

Classification
 Corticosteroids
 Aminosalycilates:
o 5-aminosalycilic acid
o Azo compounds: Sulfasalasine, Olsalazine, Balsalazine,
o Mesalamine compounds: Mesalamine

Indications: inflammatory bowel disease (ulcerative colitis, Crohn's disease).

Adverse effects: nausea, abdominal discomfort, headache, inhibiting the
absorption of folic acid, allergic reactions, severe depression of the
hematopoietic marrow.

11. Drugs with hepatoprotector effect

Classification
1. Drugs with hepatoprotector effect:
 Classification:
o Choline (is synthesized by the liver),
o Methionine (is an essential amino acid),
o Aspartic acid (is one of 20 amino acids constituting the protein),
o Phospholipids
 Indications:

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 o steatosis, chronic hepatitis, cirrhosis, liver failure
o Choline is also indicated in diabetic retinopathy and neuropathy
 Aspartic acid has a hepatoprotective effect by: participation in the
biosynthesis of pyrimidine nucleotides; improvement of the synthesis of
coenzymes uridiniques, which explains the increase in bilirubin
conjugation; restores oxidative phosphorylation and energy metabolism;
inhibition of the deconjugation of bilirubin; ammonia is determined by
one of its carboxyl groups, stimulate ureopoese, remove excess
ammonia by converting it to urea.
2. Drugs decreasing hyperamoniemia:
 Classification:
o Arginine,
o Glutamic acid,
o Ornitine
 Indications: states of hyperammonemia, conditions of hunger, pre-coma
or hepatic coma, hepatic encephalopathy
 Arginine is important in the urea cycle and decreases the concentration
of ammonia in the bloodstream arginine sorbitol serves as a substrate for
use of energy.
 Contraindication: hyperchloremic acidosis.
 Glutamic acid and sodium, potassium and calcium glutamate act as
detoxifying the setting of ammonia.
 Ornithine decreases hyperammonemia.
 Contraindications: severe renal impairment. Attention in
the first trimester of pregnancy. Do not associate in the
same infusion with penicillin, rifampin, Meprobamat,
diazepam, Phytomenadione.
3. Treatment of hepatic encephalopathy: Glutamic acid, Lactulose,
Neomycine.
 Neomycin (nonabsorbable aminoglycoside antibiotic) Indications:
hepatic coma (the removal of coliform flora for a long time - reduces
ammonia poisoning, by capturing the protein).

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 PHARMACOLOGICAL INFLUENCE OF THE
CENTRAL NERVOUS SYSTEM
Lecture 15

Learning Objectives:
 Describe aspects of absorption, distribution, metabolism and excretion of a
drug;
 List the principal routes of drug administration and their advantages and
disadvantages;
 List examples of drugs concentrated in different tissues or liquids of the body;
 List the principal routes of drug elimination;
 Explain concept and significance of pharmacokinetic parameters
 Explain concept and significance of steady state concentration.

1.Opioids

Terminology
 Opioid is an endogenous or exogenous substance causing effects similar to
Morphine.
 Opiate (old term) is a drug extracted from the exudate of the poppy.
 Narcotic analgesics or morfiniques act on the CNS depression of the
conduction path of the somatosensory pathways, thalamic and medullary
crosslinked. They are addictive and create drug. They are producing opiate
narcotic sleep.
 Opiod peptides (endogenous opioid peptides) are endogenous substances that
act as agonists at opioid receptors; endogenous opioid peptides are included
in the enkephalins – endorphins system. Opioid peptides that are produced in
the body include: endorphins, enkephalins, dynorphins, endoMorphines.

History of Opioids
 Opium is extracted from the juice of poppy seeds (Papaver somniferum). The name “opium”
is a Greek word meaning “juice,” or the liquid extracted from the poppy seeds.
 Papaver somniferum properties have been known for thousands of years and the accounts of
its use can be found in ancient Egypt, Greece and documents novels. Smoke "by burning
poppy and hemp especially on the rocks" was also known by the ancestors of the

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 Romanians, the Geto-Dacian.
 Opium is obtained from the opium poppy by incision of the seed pod after the petals have
fallen. The white latex flowing turns brown and hardens on contact with air. This gum is
sticky brown opium.
o It contains approximately 20 alkaloids, including phénanthrèniques alkaloids such as
Morphine (10%), codeine (0.5%), thebaine (0.2%) and isoquinoline derivatives such
as papaverine and noscapine. Thebaine, papaverine and noscapine are not analgesics.
Thebaine is the precursor of several receptor agonist opioids, semi-synthetic
derivatives (e.g., etorphine, a veterinary officer of 500 -1000 times more potent than
Morphine, which is more toxic than Morphine) and antagonists (naloxone).
 Opium was used alone or combined with alcohol (laudanum is the name of opium combined
with alcohol) were used to treat almost all known diseases because it produces relief of pain,
sedation, relief from diarrhea and cough suppression. It produces also euphoria.
 Morphine was isolated from opium in 1804 by Serturner.
o Friedrich Wilhelm Adam Sertürner (1783-1841) was one of the most outstanding
chemists which greatly influenced the transformation of pharmaceutical chemistry
from alchemy to the status of a recognized branch of science, at the end of 18th
century. At the age of twenty-one, in 1803, Sertürner was the first to report some
results concerning the substance that was thought to be responsible as "sleep-agent."
This substance was isolated by him from the poppy. When other chemists did not
accept the report indicating the discovery of Morphine, Sertürner turned to
experimenting on himself and three friends of him to prove that the substance he
isolated was responsible for specific actions of opium. He called the new substance
“Morphine”, after Morpheus, “the god of sleep and dreams” of the ancient Greeks.
o Sir William Osler (1849-1919) called Morphine "God's own medicine" ("The medicine
of God"). His contributions to urology are significant and include descriptions of his
own episodes of colic and the use of Morphine. Morphine remains nowadays the
standard of comparison for drugs with a strong analgesic action.
 Morphine and its derivatived are considered the most effective treatment for severe pain.
 For more than 100 years, there were few useful therapeutic agents for analgesia. Morphine
has been known to reduce pain with remarkable efficiency and has become the standard
drug for treatment.
Natural opioids occur:
1) In the juice of the opium poppy (Morphine and codeine)
2) As endogenous endorphins
All other opioids are prepared from either Morphine (semisynthetic opioids such as heroin)
or they are synthesized from precursor compounds (synthetic opioids such as fentanyl).

ENDOGENOUS OPIOID PEPTIDES (enkephalin - endorphin system)

The endogenous opioid system includes a large number of opioid peptides that are ligands for
numerous types of opioid receptors. Three distinct families of classical endogenous opioid
peptides have been described: enkephalins, endorphins, and dynorphins. Each family derives
from a distinct precursor protein, which is subject to complex cleavages and posttranslational

314
modifications that result in the synthesis of multiple active peptides.
 Enkefalins family:
 The precursor protein is preproenkephalin (which includes 6 copies of methionine-
enkephalin and a copy of the leucine-enkephalin).
 The active products are methionine-enkephalin (met-enkephalin) and leucine-enkephalin
(leu-enkephalin), which possess analgesic activity. Met-enkephalin and leu-enkephalin are
pentapeptides,
 Endorphins family:
 The precursor protein is prepro-opiomelanocortin (POMC).
 The active products are:
o beta-endorphins (are tetrapeptides) which possess analgesic activity,
o nonopioid peptides such as adrenocorticotropic hormone (ACTH), melanocyte-
stimulating hormone (MSH), and beta-lipotropin (beta-LPH).
 Dynorphins family:
 The precursor protein is preprodynorphin (alternatively termed prepro-enkephalin B
includes copies of leucine-enkephalin).
 The active products are:
o dynorphin A (alternatively termed nociceptin or orphanin FQ) which possess
behavioral and pain modulatory properties, has high affinity on opioid receptors and
also acts as an agonist at the NMDA receptor. It determines hyperalgesia in a very
long time, in case of an inflammatory process. Also acts on the receptor ORL
("orphanin opioid-like subtype reptor-1"), which interferes with the learning process
of memory and it opposes the analgesia mediated by μ receptors.
o dynorphin B,
o alpha and beta neoendorphins.
More recently were identified 2 additional short peptides, endoMorphine-1 and
endoMorphine-2, which possess a high affinity and selectivity for µ opioid receptors and
produce analgesia.

The biological role of endogenous opioid peptides. Endogenous opioid peptides have action as
neurotransmitters, neurohormones, immunomodulatory substances:
 regulate the activity of SNV;
 control the emotional tone;
 regulate central integration and interpretation of pain;
 are involved in the process of memorization;
 regulate the GABA system;
 are involved in the mechanism of traumatic shock and septic shock;
 regulate endocrine activity:
 stimulate the release of ADH, STH, prolactin;
 inhibit the release of LH;
 regulate the activity of the immune system: they determine cell proliferation, chemotaxis,
production of antibodies Ig.

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The structure – effect relationship:
 Morphine (agonist with high-affinity on μ opioid receptors) → codeine
(agonist with low affinity on μ opioid receptors) → nalbuphine (the μ opioid
receptor antagonist and agonist opioids k) ;
 Hydromorphone (agonist with high-affinity on μ opioid receptors) →
oxycodone (agonist with low affinity on μ opioid receptors) →
buprenorphine (partial agonist of opioid receptors μ) → naloxone (antagonist
on μ opioid receptor).
 The antagonist property is obtained from the replacement of a methyl group
to the nitrogen atom by a allyl radical.

OPIOID RECEPTORS
Classification
 Specific receptors:  Nonspecific receptors:
o presynaptic receptors: o σ (sigma);
 μ (mu): μ1, μ2; o ԑ (epsilon).
 δ (delta): δ1, δ2;
 k (kappa): k1, k2, k3;
o postsynaptic receptors:
 μ (mu): μ1, μ2.
Receptors μ, δ and k are also localized at the spinal level (neurons of the spinal
dorsal horn). Agonists of these receptors determine analgesia without the effects
mediated supra-spinal (nausea and vomiting, respiratory depression, sedation).
On opioid receptors bind:
 Pure Agonist: has affinity for binding and determine a biological effect.
 Pure Antagonist: has affinity for binding but no biological effect; blocks
action of endogenous and exogenous ligands.
 Mixed Agonist-Antagonist: produces an agonist effect at one opioid receptor
and an antagonist effect at another opioid receptor.
 Partial Agonist: has affinity for binding but low biological effect.
Biological effects mediated by opioid receptors:
 μ receptors (mu): spinal and supra-spinal analgesia, euphoria, miosis
(constricted pupils), respiratory depression, constipation, physical
dependence, sedation, modulation of the release of hormones and

316
 neurotransmitters.
 receptors k (kappa) spinal and supra-spinal analgesia, dysphoria, miosis,
constipation, physical dependence, sedation.
 receptors δ (delta): spinal and supra-spinal analgesia, modulation of the
release of hormones and neurotransmitters.
 receptors σ (sigma): dysphoria, mydriasis, respiratory stimulation, visual
hallucinations and auditory hallucinations.
 receptors ԑ (epsilon) analgesia.
Opioid Receptor Signaling
 Activation of peripheral nociceptive fibers causes release of substance P and
other pain-signaling neurotransmitters from nerve terminals in the dorsal
horn of the spinal cord. Release of pain-signaling neurotransmitters is
regulated by endogenous endorphins or by exogenous opioid agonists by
acting presynaptically to inhibit substance P release, causing analgesia.
 Opioid receptors are coupled to the Gi protein which is coupled to adenylate
cyclase → receptor stimulation determines the decrease in the intracellular
concentration of cyclic AMP.
 The stimulation of presynaptic μ (mu), k (kappa) and δ (delta) receptors:
o block and inactivate voltage-dependent calcium channels → block the
release of excitatory neurotransmitters (acetylcholine, norepinephrine,
glutamate, substance P, serotonin);
o decrease sensitivity of 5-HT3 receptors for serotonin.
 The stimulation of postsynaptic μ (mu) receptors:
o activate potassium channels → determines the postsynaptic neuronal
membrane hyperpolarization.

The molecular mechanism of opiate dependence

 Chronic administration of opioids leads to the need of gradually increase of
the dose, because it determines tolerance and addiction. Tolerance and
addiction involve changing the system of second messengers (cAMP) and
changes in intracellular calcium concentrations.
 Acute administration of opioids determines the decrease of the level of
intracellular calcium.
 Chronic administration of opiates determines the increase of the level of
intracellular calcium. Chronic administration of opiates thus determines the

317
 decrease in the activity of adenylate cyclase → cAMP → decrease the
phosphorylation of intracellular proteins → modification of DNA →
stimulation of early genes, c-fos and c-jun → gene transcription → syntheses
of proteins (e.g., the synthesis of G protein coupling) → "up - regulation" of
opioid receptors → the need to increase the dose. On the other hand,
increasing the concentration of agonist determines "down - regulation"
opioid receptors → decrease in the number of receptors → the need to
increase the dose.
 In young and healthy persons, addiction is quick due to activation gene c-fos
and c-jun (genes involved in transcription of certain proteins such as protein
G). In people with chronic pain dependence does not occur or occurs late
during the regular administration due to impaired production and impaired
activity of mediators for genes c-fos and c-jun.

CLASSIFICATION OF OPIOIDS
 agonists of opioid receptors:
 natural alcaloids:
o strong agonists: Morphine;
o mild to moderate agonists: Codeine (Methylmorphine);
 semisynthetic derivatives:
o strong agonists: Heroine (DiaMorphine), Hydromorphone,
Oximorfon, EthylMorphine, Etorphine;
o mild to moderate agonists: Dihydrocodeine, Oxycodone,
Hydrocodone;
 synthetic derivatives:
o strong agonists:
 Meperidine,
 Methadone, Levometadil (Levacetylmethadol),
 Fentanyl, Alfentanyl, Sufentanyl, Remifentanyl,
Levorfanol;
o mild to moderate agonists:
 Dextromoramide;
 Levopropoxyphene, Propoxyphene35
 Dextropropoxyphene36,

35
Used as cough suppressant; was recently withdrawn from market in some countries.

318
  Loperamide, Difenoxilate, Difenoxin,
 partial agonists of opioid receptors: Buprenorphine, Tramadol;
 agonists-antagonists of opioid receptors:
 Pentazocine, Dezocine,
 Nalorphine, Nalbufine,
 Butorphanol;
 competitive antagonists of opioid receptors:
 central acting: Naloxone, Naltrexone, Nalmefene;
 periferal acting: Alvimopan.

PHARMACOKINETICS
 Routes of administration of opioids
 Natural Morphine and semi-synthetic opiates are administered only by
injection: s.c. or i.v.
 Synthetic opiates:
o parenteral route – s.c., i.v.;
o oral - capsules, tablets, coated tablets (e.g., MS Contin ®);
o transdermal patches (e.g., MST);
o intrarectally;
o epidural;
o nasal (nasal spray);
o sublingual;
o as subcutaneous pump = PCA ("patient - controlled -
analgesia").
The maximum initial partial dose of Morphine is 20 mg; the daily dose is 60 mg
per day.
 Absorption:
 the effect of a given dose is less after oral than after parenteral
administration for natural and semi-synthetic opiates because they
present a significant first-pass metabolism in the liver (first pass effect),
this is why natural (Morphine) and semi-synthetic opiates are
administered only by injection (sc or iv).
 Codeine and oxycodone are drugs partially protected against the first

36
Used as analgesic, some combinations containing Dextropropoxifen were withdrawn from market because of dose-
related cardiac conduction abnormalities.

319
 pass effect, due to the methyl of aromatic hydroxyl at C3.
 Distribution:
 Opioids cross the blood-brain barrier (for heroin is faster) and the
placental barrier.
 Opiates are concentrated in the milk and gall bladder.
 Metabolism in the liver:
 Morphine is metabolized to:
o Morphine - 6 - glucuronide (the metabolite has stronger
analgesic effect than Morphine);
o Morphine - 3 - glucuronide (the metabolite has a toxic effect on
the CNS).
 Codeine is metabolized to Morphine in a ratio of 10%.
 Heroin is metabolized to Morphine in a ratio of 100%.
 Types of reactions:
o opiates with free hydroxyl groups (e.g., Morphine, levorphanol)
are metabolized by conjugation with glucuronic acid.
o esters (e.g., heroin, remifentanil) are metabolized by tissue
esterases.
o hepatic oxidative metabolism is the metabolic pathway for
alfentanil, sufentanil, fentanyl.
 Elimination: mainly through kidney and partially in bile (natural opiates and
semi-synthetic).

PHARMACODYNAMIC EFFECTS OF MORPHINE AND OTHER

OPIOIDS
 Effects on CNS:
 analgesia - opioids affect two components of pain37 (Morphine
determines a more powerful effect on the continues, spinoreticular
chronic pain and determines less effect on acute, intermittent
spinothalamic pain);
 euphoria, tranquility (due to the action on μ receptors from
diencephalon and frontal cortex)
o sometimes may occur dysphoria;
37
Pain is subjective and it is defined as a sensory and emotional experience. The first component of pain is the sensory
input to the central nervous system (CNS) that results in recognition of the sensation of pain. The second component is
the reactive (subjective) component with role in the interpretation of the pain.

320
  sedation (especially the elderly);
 miosis;
 truncal rigidity (due to the action on μ receptors from spinal cord);
 respiratory depression and decrease sensitivity of the respiratory
centers to variations of carbon dioxide concentrations;
 inhibition of cough center (→ explains the indication for dry cough and
contraindications in productive cough);
 induction of nausea and vomiting (these effects are more pronounced
for patients which are moving).
 Peripheral effects:
 cardiovascular system: bradycardia, hypotension (the effects are more
pronounced in patients with these symptoms before treatment);
 increase of intracranial pressure;
 respiratory tract: increase bronchial muscle tone, reduce bronchial
secretions;
 digestive tract: increase gastrointestinal muscle tone, decrease
gastrointestinal peristalsis (→ explains constipation), spasm of Oddi
sphincter (→ explains the pancreatic reflux;
 urogenital: increase urogenital muscle tone and decrease urogenital
peristalsis, spasm of the sphincter of the urinary bladder, inhibition of
uterine contractions (→ explains the contraindications during labor);
 stimulate histamine release (cause bronchospasm → explains the
contraindication in bronchial asthma or COPD; cause hypotension →
explains the contraindication in low blood pressure; anaphylactic shock
or other allergic reactions);
 endocrine system: stimulate the release of ADH, STH, prolactin,
inhibition of LH release;
 immune system: chemotaxis of PMN, T cell proliferation, production of
Ig.

Miosis, truncal rigidity and constipation are pharmacodynamic effects of

opioids for which no tolerance develop in chronic administration. These
effects are pathognomonic signs in chronic opiates consumers.

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INDICATIONS, CONTRAINDICATIONS, ADVERSE EFFECTS OF
OPIOIDS
 MORPHINE
Indications:
 analgesia:
o cancer pain,
o other chronic pain (degenerative rheumatic disease, rheumatoid
arthritis),
o visceral pain (renal / ureteral / biliary colicative pain -
Meperidine is preferred because of its Atropine-like effects →
Meperidine does not cause nausea, vomiting, spasm of the
sphincter of Oddi)
o pain in myocardial infarction (Meperidine is preferred because
of its Atropine-like effects → Meperidine does not cause nausea,
vomiting, spasm of the sphincter of Oddi, bradycardia, marked
hypotension);
 acute pulmonary edema38;
 pre-anesthesia, intraoperatory (general anesthesia), post-operatory,
neuroleptanalgesia(Fentanyl is preferred, associated with
Droperidol/Haloperidol).
Adverse effects:
 respiratory depression;
 bradycardia, hypotension;
 nausea, vomiting;
 constipation;
 spasm of Oddi sphincter and pancreatic and bile reflux;
 acute retention of urine;
 immunological reactions type I;
 addiction.
Contraindications:
 absolute Contraindications:
o bronchial asthma;

38
Furosemide, morphine, and nitroglycerin have historically been the baseline standard for drug therapy in CPE
management. Most current textbooks and official guidelines advise the use of morphine as one of the first-line
treatments for patients in acute cardiogenic pulmonary oedema.

322
 o chronic obstructive pulmonary disease (COPD);
o labor, pregnancy, breastfeeding;
o acute abdominal pain;
o severe heart failure,cardiac
arrhythmias,bradycardia,atrioventricular block;
o intracranial hypertension;
 relative Contraindications: kidney failure, liver failure.
 CODEINE
Indications:
 cough suppressant (the treatment of choice for dry cough and itchy);
 analgesia: dentistry, oral surgery, maxillofacial surgery eyc.
The drug has addictive potential.
Contraindications: productive cough.
 DIHYDROCODEINE
Indications: analgesia (treatment of choice).
The drug has the addictive potential higher than Morphine.
 MEPERIDINE
This drug also has Atropine effects → does not cause nausea, vomiting, spasm
of the sphincter of Oddi, bradycardia, marked hypotension.
Indications: analgesic
 visceral pain (renal colic, ureteral colic, biliary colic),
 chronic degenerative rheumatism,
 rheumatoid arthritis,
 pain in myocardial infarction (particularly in myocardial infarction with
hypotension or bradycardia).
 METHADONE
Methadone has a longer duration of action than Morphine, it determines low
euphoric effects and lower intensity abstinence syndrome compared to
Morphine.
Indications: treatment of opiate dependence (replace opiates that caused the
addiction).
 FENTANYL AND ITS DERIVATIVES (ALFENTANIL,
SUFENTANIL, REMIFENTANIL)
Fentanyl determine analgesic effect of 80-100 times more potent than
Morphine, but it is also more toxic than Morphine.

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 These derivatives have rapid and short duration action.
Remifentanil is very effective in rectal administration or in the form of
transdermal patches.
Indications:
 neuroleptanalgesia (Fentanyl is associated with Droperidol or
Haloperidol);
 general anesthesia.
 DEXTROMORAMIDE
It is an analgesic for oral administration, more powerful and shorter
action than Morphine. It can cause orthostatic hypotension.
 LEVOPROPOXYPHENE
Indications: cough suppressant (dry and itchy cough).
Contraindications: productive cough.
 LOPERAMIDE, DIPHENOXYLATE, DIFENOXIN
These drugs are partial agonists of μ-opioid receptors and don’t cross the blood-
brain barrier at antidiarrheal doses.
Indications: diarrhea (acute nonspecific or chronic inflammatory diarrhea).
Contraindications:
 ulcerative colitis (treatment may induce toxic megacolon);
 intestinal infections with Shigella spp., Salmonella spp.
 BUPRENORPHINE
Indications:
 acute intoxication with opioids in addicted persons;
 chronic intoxication with opioids (restore the opioid receptor sensitivity
to endogenous opioid peptides after treatment of withdrawal syndrome).
 TRAMADOL
It is an partial agonist on opioid receptors, with low Adverse effects:.
Indications: analgesia
 PENTAZOCINE, NALBUPHINE
These are agonists – antagonists on opioid receptors (agonists on k
receptors and antagonists on μ receptors). Pentazocine is also agonist on σ
opioid receptors.
Indications:
 Pentazocine → analgesia;
 Nalorphine → acute intoxication in addicted persons.

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Pentazocine and nalbuphine are good analgesics, but they cause dysphoria, they
determine lower addiction.

 COMPETITIVE ANTAGONISTS OF OPIOID RECEPTORS

(NALOXONE, NALTREXONE, NALMEFENE)
Indications:
 antidote in acute opiate intoxication for people which are not addicted;
 post-traumatic spinal cord injury.

2.Cough suppressants and expectorant drugs

COUGH SUPPRESSANTS
Classification:
 Opioids: Codeine; Propoxyphen, Levopropoxyphen;
 Nonopioids:
 Oxeladine;
 Clobutinol;
 Butamirat;
 Pentoxiverine, Prenoxdiazine, Levodropropizine; Clofedanol.
Mechanism of action: inhibition of the cough center (non-opioid drugs do not
act on opioid receptors); also determines bronchodilator effects.
Indications: as cough suppressant (treatment of dry and itchy cough).
Contraindications:
 productive cough (is common for all cough suppresants);
 other Contraindications:
o Oxeladin: children under 16;
o Clobutinol: kidney failure, liver failure, respiratory failure,
bronchial asthma, neuropsychological disorders, pregnancy (first
trimester).

EXPECTORANTS
Classification:
 fluidifiants:
 from plants: Liquiritia extracts, Primula roof; Ipeca;

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  Guiafenesin;
 amonium salts (e.g., Amonium chloride), Sodium benzoate;
 sweet juices, tea, candies.
 mucolytics: Acethylcisteine, Carbocisteine, Dornaze alfa
(Desoxiribonuclease), Erdosteine;
 mixt mechanism (fluidifiants and mucolytics): Bromhexin, Ambroxol
(active metabolite of Bromhexin).

Expectorants which increas the fluidity of bronchial secretions

 Mechanism of action: increasing the proportion of water bronchial
secretions.
 Indications: acute and chronic bronchitis.
 Guaifenesin
o Pharmacodynamic effects: expectorant, skeletal muscle
relaxant, sedative, antiseptic, local anesthetic effect.
o Adverse effects:
 gastrointestinal irritation, sedation,
 false-positive reaction for 5-hydroxyindoleacetic acid in
the urine (marker for the diagnosis of carcinoma).
o Contraindications: persons performing precise movements.
Mucolytic expectorant drugs
 Mechanism of action: cleavage of the mucin molecule → decrease the
viscosity of bronchial secretions.
 Indications: acute and chronic bronchitis, bronchiectasis, pneumonia,
amyloidosis, cystic fibrosis.
 Adverse effects:
o excessive stimulation of bronchial secretions;
o Acetylcysteine:
 determines rhinorrhea, stomatitis, nausea;
 acetylcysteine inactivates penicillins and cephalosporins
→ these drugs should not be mixed in vitro;
 metals inactivate acetylcysteine.

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 Lecture 16

Learning Objectives:
 Describe aspects of absorption, distribution, metabolism and excretion of a
drug;
 List the principal routes of drug administration and their advantages and
disadvantages;
 List examples of drugs concentrated in different tissues or liquids of the body;
 Name the phases in hepatic metabolism;
 Describe the terms “bound” and “unbound” drug to plasma proteins;
 Describe the term “first pass effect”;
 Describe the terms drug metabolism “enzyme induction” and “enzyme
inhibition”;
 List the principal routes of drug elimination;
 Explain concept and significance of pharmacokinetic parameters
 Explain concept and significance of steady state concentration.

1.Anxiolytic – sedative – hypnotic drugs

Terminology
 Anxiety, an emotional state in which fear dominates a person's life, is defined as appre-
hensive anticipation of future danger or misfortune, accompanied by a feeling of dysphoria or
somatic symptoms of tension39. It is thus a future-oriented state, motivating the person to avoid
the perceived danger40; worry may be seen as a cognitive manifestation of anxiety.
o Fear, by contrast, is a basic emotion that is associated with a “fight or flight” response
to an immediate danger, whereas anxiety is apprehension over a potential future
danger.
 Anxiety disorders are relatively evident: the patient appears apprehensive, sweats, and
complains of nervousness, palpitations, and faintness; somatic signs include rapid breathing,
tachycardia, and labile blood pressure.
 Anxiolytic drugs are pharmacologically active substances that reduce anxiety (stress or
tension) without reducing mental clarity and improve the capacity of the individual to adapt.
 Sedative drugs are pharmacologically active substances that exert a calming effect and
reduce anxiety with minimal effect on motor function or mentally. The degree of CNS
depression caused by a sedative drug should be the minimum consistent with therapeutic
efficacy.

39
Definition of The Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), American Psychiatric
Association. Washington, DC, 1994
40
Anxiety need not be negative: it may increase vigilance and arousal, and thereby enhance performance and learning.

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 Hypnotic drugs are pharmacologically active substances that cause drowsiness and
promote the onset and maintenance of a state of sleep. Hypnotic effects involve more
pronounced depression of the CNS than sedation.
 Antiseizure Drugs (antiepileptic drugs) are pharmacologically active substances indicated
in the treatment of epilepsy and of seizures of various etiologies (intoxication, metabolic
disorders, injuries of the CNS etc).

History
 The first benzodiazepine, chlordiazepoxide, was discovered in 1955 by Leo Sternbach and
introduced in therapeutics in 1960 under the name of Librium (Hoffmann-La Roche), with
anxiolytic properties.
 The first barbiturate, barbituric acid, was discovered in 1863 by Adolf von Baeyer (1835-
1917), the Nobel Prize winner in chemistry (1905). In 1913, the second barbiturate,
Phenobarbital, was introduced into medical practice

THE GABA SYSTEM

Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the CNS and
acts on three groups of receptors: GABAA, GABAB and GABAC.
 GABAA and GABAC receptors are ionotropic receptors or ligand-gated ion channels
receptors (attached to a chlorine channel),
 GABAB receptors are metabotropic receptors that are G-protein coupled (that act via second
messengers).
GABAA receptor has five specific bindings sites (see the mechanism of action on page XXX:
opening of chloride channel → inhibitory influx of Cl - in the CNS → resulting in anxiolytic,
sedative, hypnotic, skeletal muscle relaxant effects and anticonvulsant effects):
 GABA site
 Agonist is GABA → direct opening of Cl- channel;
 Benzodiazepine site functions as benzodiazepine receptor. There are two subtypes of
benzodiazepine receptor: BDZ1 receptors (named also omega Ω1) and BDZ2 receptors (Ω2).
Three types of ligands act on benzodiazepine receptors: agonists, competitive antagonists,
inverse agonists.
 Agonists (act by indirect opening of chloride channel because inhibit Gi, the inhibitory
protein that bind the mediator GABA on the GABA site → more molecules of GABA
will be bound on GABA site → increase in the frequency of Cl- channel opening):
o non-selective agonists (act on both BZD1 and BZD2 receptors and produce
anxiolytic, sedative, hypnotic, skeletal muscle relaxant and anticonvulsant
effects):
 endogenous (e.g., endozepines)
 exogenous (e.g., 1,4–benzodiazepines, triazolobenzodiazepines);
o selective agonists on BDZ1 receptors (produce anxiolytic, sedative, hypnotic
effects): imidazopyridines.
 Competitive antagonists: Flumazenil (it is an imidazobenzodiazepine which blocks

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 only the actions of benzodiazepines, therefore it is used as antidote in benzodiazepine
intoxication).
 Inverse agonists: betacarboline (act as negative allosteric modulator of GABA
receptor function and produce anxiety and seizures).
 Barbiturate site
 agonists are GABA-mimetic substances such as barbiturates and ethanol; they act by
direct opening of chloride channel → prolong the opening of the Cl- channel.
 Anesthetic steroids site
 agonists are general anesthetics volatile liquids, general anesthetics with intravenous
administration → indirect opening of chloride channel (similar to benzodiazepines).
 Picrotoxinic site
 competitive antagonist is picrotoxin → determines excitatory effects in the CNS.

Suvorexant (trade name Belsomra) is a selective dual orexin receptor antagonist

Orexin-A and -B (also known as hypocretin-1 and -2) are neuropeptides produced in
the lateral hypothalamus that promote many aspects of arousal through the OX1 and
OX2 receptors. In fact, they are necessary for normal wakefulness, as loss of the
orexin-producing neurons causes narcolepsy in humans and rodents. This has
generated considerable interest in developing small-molecule orexin receptor
antagonists as a novel therapy for the treatment of insomnia.

CLASSIFICATION OF ANXIOLYTIC – SEDATIVE – HYPNOTIC

DRUGS
1. Drugs with Anxiolytic – sedative – hypnotic effect41:
 Barbiturates:
 Oxibarbiturates (classification acording to the duration of action):
o long-acting (8-12 h): Phenobarbital;
o intermediate-acting (4-6 h): Amobarbital, Butabarbital;
o short-acting (3 h): Cyclobarbital, Pentobarbital, Secobarbital;
 Thiobarbiturates (very short-acting 10-20 min): Hexobarbital, Thiopental,
Methohexital, Thiamilal;
 Benzodiazepines:
 1-4 benzodiazepines (classification according to half-life):
o long-acting t1/2: Diazepam, Chlordiazepoxide, Clorazepate, Prazepam,
Flurazepam;
o intermediate-acting t1/2: Nitrazepam, Flunitrazepam, Temazepam,
Clonazepam, Halazepam, Quazepam;
o short-acting: Oxazepam, Lorazepam;
 triazolobenzodiazepines (classification according to half-life):
o intermediate-acting: Alprazolam, Estazolam;

41
Drugs with anti-anxiety effect (anxiolytics), calming effect (sedatives), sleep-inducing effect (hypnotics).

329
 o short-acting: Midazolam. Triazolam;
 Imidazopiridines: Alpidem, Zolpidem, Zaleplon, Zoplicone, Eszoplicone;
 Alcohols / aldehydes: Chloral hydrate, Trichloroethanol, Paraldehyde;
 Quinazolones: Methaqualone;
 Carbamates: Ethinamate, Meprobamate;
 Piperidindiones: Glutethimide, Methyprilon;
 Acyclic ureides: Bromisoval, Carbromal;
 Bromides: salts of sodium, potasium, amonium, calcium (in monotherapy/association);
 Other structures:
 L-Tryptophane;
 H1 receptor antagonists 1st generation:
o Ethanolamines:Diphenhydramine,Doxylamine;
o Ethylaminediamines: Pyrilamine;
o Phenothiazines: Promethazine;
o Piperazines: Hydroxyzine;
 Antagonists on H1 and 5-HT receptors: Cyproheptadine;
 Ethchlorvynol;
 products from plants.
2. Anxiolytic drugs without sedative effect:
 Serotonin receptor 5HT1A agonists: Buspirone, Ipsapirone, Gepirone, Tandospirone
3. Treatment of psychomotor agitation:
 Diazepam,
 Scopolamine,
 Neuroleptic drugs,
 Magnezium sulfate (parenteral administration)

BARBITURATES
Classification
 Oxibarbiturates (classification acording to the duration of action):
o long-acting (8-12 h): Phenobarbital;
o intermediate-acting (4-6 h): Amobarbital, Butabarbital;
o short-acting (3 h): Secobarbital, Cyclobarbital, Pentobarbital;
 Thiobarbiturates (very short-acting 10-20 min): Hexobarbital,
Thiopental, Methohexital, Thiamilal.
Mechanism of action:
 agonists on barbituric segment of the GABAA;
 increase the release of GABA;
 inhibit the GABA reuptake;
 reduce the release of excitatory neurotransmitters: norepinephrine,

330
 acetylcholine;
 interfere with calcium entry into brain synaptosomes;
 increase the permeability of neuronal membranes;
 inhibit the pyruvate oxidation;
 determine the uncoupling of oxidative phosphorylation.
Pharmacodynamic effects
 CNS (cortex, hypothalamus, thalamus, limbic system)
o influence both stages of the sleep (particularly the slow wave
sleep and determine residual somnolence after waking).
o reduce the oxygen consumption in the brain (10% during sleep
and 50% during the narcosis).
o determine anticonvulsant effects.
o determine adiction.
 Autonomic nervous System: depress ganglionic transmission, determine
currara-like effects in the neuromuscular synapse.
 Respiratory tract
o decrease the respiratory rate (which is similar to the
physiological sleep).
o high doses → respiratory depression and suppress the sensitivity
of the respiratory centers to changes in the concentration of
carbon dioxide.
 Cardiovascular system
o decrease cardiac activity (similar to the physiological sleep).
o high doses → depression of vasomotor center (vasodilation,
hypotension).
 Digestive system: decrease the motility and secretory activity.
 Urogenital tract: decrease the motility of the urinary bladder and the
frequency of uterine contractions.
 Stimulate the release of ADH.
Pharmacokinetics
 Barbiturates are lipophilic drugs that readily cross blood-brain barrier.
 Absorption: mainly duodeno-jejunal, but also in the stomac.
 Distribution → widely throughout the body; binding to plasma proteins
is variable (e.g., Phenobarbital - 98% Thiamylal <5%). Thiobarbiturates
are highly lipophilic → pass very quickly blood-brain barrier → very

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 rapid distribution into the brain → hypnotic effect → followed by
distribution to other organs (adipose tissue, muscles, heart, kidney,
liver) → decrease the plasma concentration. This is called redistribution
of the drug; redistribution accounts for the short duration of action of
these drugs, a feature useful in recovery from anesthesia.
 Metabolism: for oxybarbiturates → in the liver; for thiobarbiturates →
in the liver, kidneys, brain etc.; barbiturates are enzyme inducers of drug
metabolism of other drugs and of their metabolism (autoinduction).
 Elimination: mainly through kidneys, but also in milk, saliva, urine.
 Alkalinization of urine determines the acceleration of renal elimination.
Indications:
 oxybarbituriques (indications are dose-dependent):
o sedatives;
o hypnotic;
o anticonvulsants (tonic-clonic epilepsy, partial epilepsy, juvenile
myoclonic epilepsy, status epilepticus);
o Phenobarbital is indicated also in neonatal jaundice (because
accelerate bilirubin metabolism);
 thiobarbiturates: intravenous general anesthetics.
Adverse effects:
 adiction and withdrawal syndrome;
 residual drowsiness in the morning, after waking;
 increased reaction time (determine stimulation of motor incoordination);
 reduce the capacity of concentration and learning;
 phenomenon of paradoxical excitement;
 decrease respiratory rate;
 decrease cardiac activity (decrease cardiac output, arrhythmias,
hypotension);
 decrease digestive secretory activity and digestive and urinary bladder
motility;
 reduce the frequency of uterine contractions;
 immunological reactions type I;
 acute crisis of porphyrinuria;
 hemolysis in patients with G6PDH deficiency.
Contraindications:

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  absolute Contraindications:
o heart failure, angina, hypovolemia, shock;
o status asthmaticus;
o G6PDH deficiency42; acute intermittent porphyria43;
 relative Contraindications:
o severe renal failure;
o severe liver failure;
o pregnancy, breastfeeding;
o children with psychomotor agitation;
o Parkinson's disease;
o acute adrenal insufficiency; valvular lesions; sepsis.
Warning: doses of barbiturates should be reduced in old patients and
children, in patients suffering from bronchial asthma, hypotension.
BENZODIAZEPINES
Classification
 1-4 benzodiazepines (classification according to half-life):
o long-acting: Diazepam, Chlordiazepoxide, Clorazepate,
Flurazepam
o intermediate-acting: Nitrazepam, Flunitrazepam, Temazepam,
Clonazepam, Halazepam, Quazepam
o short-acting: Oxazepam, Lorazepam
 triazolobenzodiazepines (classification according to half-life):
o intermediate-acting: Alprazolam, Estazolam
o short-acting: Midazolam. Triazolam
Mechanism of action:
 nonselective agonists segments BZD1 = BZD2;
 inhibition of the release of serotonin in the synapse.
Differences between various benzodiazepines exist based on:
 pharmacodynamic characteristics: certain molecules have a dominating
effect (e.g., anticonvulsive effect) relatively more important than other
effects.
42
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymatic disorder of red blood cells in
humans. The G6PD enzyme catalyzes the first step in the pentose phosphate pathway, leading to antioxidants that
protect cells against oxidative damage. A G6PD-deficient patient lacks the protection against oxidative stresses from
certain drugs, metabolic conditions, infections, and ingestion of fava beans.
43
Porphyria is a hereditary disorder due to reduction in enzyme activity of heme synthesis system, resulting in
accumulation of heme precursors.Acute intermittent porphyria is characterized by a hereditary deficiency of hepatic
porphobilinogen deaminase (PBGD) activity.

333
  pharmacokinetic characteristics: onset and duration of action explain
differences between their therapeutic uses44.
Pharmacodynamic effects
 CNS (cortex, hypothalamus, limbic system, the cerebellar cortex, spinal)
o influence both phases of sleep (no residual somnolence).
o anticonvulsant effects.
o skeletal muscle relaxant effects.
o addiction.
 Respiratory tract: only large doses decrease respiratory rate (it is not
influenced the sensitivity of the respiratory center to CO2 variations),
respiratory acidosis.
 Cardiovascular system: decrease the force of contraction of the left
ventricle → decrease cardiac output. Only large doses → depression
vasomotor of center (hypotension, reflex increase in peripheral
resistance and heart rate).
o The cardiocvascular effects are not significant in
triazolobenzodiazepines.
 Digestive system: only large doses → decrease in gastrointestinal
motility.
Pharmacokinetics
 Benzodiazepines are lipophilic drugs that readily cross the physiological
barriers.
 Absorption: duodeno-jejunal.
 Metabolism: in the liver. Some benzodiazepines are biotransformed into
active metabolites(e.g., Diazepam is metabolized to nordiazepam,
oxazepam, temazepam).
 Benzodiazepines present enterohepatic circuit, effect of first-pass
metabolism.
 Elimination: mainly in the kidneys, but also in milk and in bile.
Indications:
 anxiolytics;
 sedatives;

44
Long-acting benzodiazepines are associated with daytime sedation, cognitive and psychomotor impairment
particularly in the elderly [explains increase of falls, hip fractures]; prefered when need of daytime sedation.
Intermediate and short-acting benzodiazepines are more efficacious in inducing sleep during the first night of
administration.

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  hypnotic;
 anticonvulsants;
 skeletal muscle relaxants.
Adverse effects:
 adiction and withdrawal syndrome (short-acting benzodiazepines have
an earlier onset of withdrawal symptoms, long-acting benzodiazepines
have a later onset);
 increased reaction time determine exogenous stimulation of motor
incoordination;
 phenomenon of paradoxical excitement;
 decrease the force of contraction of the left ventricle → decrease cardiac
output, and the heart rate, arterial hypotension (for 1,4 -
benzodiazepines);
 decrease the gastrointestinal motility;
 immunological reactions type I;
 hepatotoxicity.
The antidote in acute intoxication with benzodiazepines is Flumazenil.
Contraindications:
 severe heart failure;
 severe renal insufficiency;
 severe hepatic insufficiency;
 pregnancy, breastfeeding.
 myasthenia gravis;
Benzodiazepines should be administered with caution in old patients (doses are
reduced).
IMIDAZOPYRIDINES: ALPIDEM, ZOLPIDEM, ZALEPLON,
ZOPLICONE, ESZOPLICONE
Mechanism of action: selective agonists on the BZD1 (Ω1) receptor (from
GABAA receptor).
Pharmacodynamic effects: anxiolytic, sedative, hypnotic.
Indications: anxiolytics; sedatives; hypnotics.
Adverse effects: severe hepatotoxicity.
Contraindications are similar to those of benzodiazepines.
ALCOHOLS / ALDEHYDES: CHLORAL HYDRATE
Pharmacodynamic effects: anxiolytic, sedative, hypnotic.

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Indications: anxiolytics; sedatives; hypnotics.
Adverse effects and contraindications are similar to those of barbiturates.
THE QUINAZOLINONES: METHAQUALONE
Indications: anxiolytics; sedative; hypnotic.
Adverse effects and contraindications are similar to those of barbiturates.
These drugs determine adiction.
CARBAMATES: ETHINAMATE, MEPROBAMATE
Pharmacodynamic effects: effects anxiolytics, sedatives, hypnotics, these
drugs do not affect REM sleep.
Indications: anxiolytics; sedatives; hypnotics.
Adverse effects and contraindications are similar to those of barbiturates.
These drugs determine adiction.
PIPERIDINEDIONES: GLUTETHIMIDE, METHYPRYLON
Pharmacodynamic effects: effects anxiolytics, sedatives, hypnotics (these
medications do not determine the residual sleepiness), anticonvulsant,
anticholinergic effects.
These drugs are enzyme inducers metabolism of vitamin D, Warfarin and
barbiturates.
These drugs are concentrated in milk and bile. They present enterohepatic
circulation.
Indications: anxiolytics; sedatives; hypnotics.
Adverse effects and contraindications are similar to those of barbiturates.
These drugs determine adiction.
ACYCLIC UREIDES: BROMISOVAL, CARBROMAL
Indications: sedative. Adverse effects: bromism. These drugs have low
therapeutic index. Contraindications are similar to those of barbiturates.
BROMIDES: SALTS WITH SODIUM, POTASSIUM, AMMONIUM,
CALCIUM
Mechanism of action: replacement of the chloride from the extracellular fluid.
Pharmacodynamic effects: sedative effects, hypnotics, anticonvulsants.
Indications:
 sedatives;
 hypnotic;
 anticonvulsants in patients with G6PDH deficiency (it is treatment of
choice).

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Adverse effects:
 bromism: digestive symptoms (nausea, vomiting), CNS symptoms
(drowsiness, irritability, tremors, ataxia, hallucinations, mania, delirium,
psychoses, slurred speech, memory impairment), conjunctivitis, skin
rashes and folliculitis/ toxic epidermal necrolysis (particularly after
long-term treatment);
 immunological reactions type I ("rash").

NON-SEDATING ANXIOLYTICS: Buspirone, Ipsapirone, Gepirone,

Tandospirone
Mechanism of action: partial agonists of the 5 HT1A.
Pharmacodynamic effects: anxiolytic effects without sedation.
Pharmacokinetics: have short-term action, present enterohepatic circulation
and first-pass effect.
Indications: anxiolytic (not efficient for panic attacks).
Adverse effects: tachycardia, nervousness, paresthesia, confusional states,
gastro-intestinal, miosis (dose-dependent), increase blood pressure when are
associated with MAO inhibitors.
These drugs do not determine adiction.
Contraindications: heart rhythm disorders.

THE TREATMENT OF AGITATION: Diazepam; Scopolamine;

Neuroleptics; Magnesium sulfate
Parenteral Magnesium sulfate
Indications: arrhythmias (torsade de pointes, arrhythmias associated with
hypokalaemia), eclampsia, premature labor, hypertensive encephalopathy,
seizures, tetanus.
Adverse effects: flushing of the skin, hypotension (due to vasodilation),
respiratory depression and loss of deep tendon reflexes (both due to
neuromuscular blockade).

2. Local anesthetics
Local anesthetics are pharmacologically active substances that are applied
locally and block temporarily and reversibly the transmission of action
potentials in the membranes of excitable cells (neurons, muscle cells, gustatory

337
corpuscles etc.).
Types of local anesthesia
 1. Topical anesthesia (surface anesthesia) is anesthesia of mucous membranes (nose,
mouth, throat, tracheobronchial, esophagus, genitourinary tract) or skin, produced by direct
application of local anesthetics.
 2. Infiltration anesthesia is the injection of a local anesthetic directly into tissue (superficial
as to include only the skin, profound to include deeper structures) without taking into
consideration the course of cutaneous nerves.
 3. Nerve Block Anesthesia is the injection of a local anesthetic into or around individual
peripheral nerves or nerve plexuses; produces greater areas of anesthesia than previous
techniques.
 4. Intravenous Regional Anesthesia is the injection of a local anesthetic into a cannulated
vein of an extremity which was exsanguinated with an elastic bandage and with a
proximally located tourniquet inflated to 100–150 mm Hg above the systolic blood pressure.
Complete anesthesia of the limb ensues within 5–10 min.
 5. Spinal Anesthesia (intrathecal anesthesia) is one of the most popular forms of anesthesia
and is the injection of local anesthetic in the subarachnoid space into the cerebrospinal fluid
(CSF), by penetration of the spinal dura from the lumbar space under the second lumbar
vertebra.
 6. Epidural Anesthesia is the injection of a local anesthetic into the epidural space (also
known as "extradural space" or "peridural space", is the space outside the dura mater
enveloping the spinal cord45).
Classification depending on the structure of local anesthetics:
 1. Esters:
- Natural sources: Cocaine
- Synthetic: Benzocaine, Tetracaine, Procaine (Novocain), Chloroprocaine,
Proparacaine
 2. Amides: Lidocaine (Xylocaine), Mepivacaine, Articaine, Ropivacaine,
Bupivicaine, Levobupivicaine, Prilocaine, Etidocaine
 3. Other structures: Ethylchloride.
Classification depending on the duration of action46,47:
- short acting (20-60 min): Benzocaine, Procaine, Chloroprocaine,
Proparacaine;
- intermediate acting (1-2 h): Lidocaine (Xylocaine), Mepivacaine, Prilocaine,

45
The membrane that covers the spinal cord and nerve roots in the spine is called the dura membrane. The space
surrounding the dura is the epidural space. Epidural space is the space bounded by the ligamentum flavum posteriorly,
the spinal periosteum laterally, and the dura anteriorly.
46
The anesthetic effect of short and intermediate acting local anesthetics can be prolonged by increasing the dose or by
adding a vasoconstrictor.
47
The onset of local anesthesia can be accelerated by the use of solutions saturated with CO2 which results in
intracellular acidosis favourable for the intracellular accumulation of the cationic form of the anesthetic.

338
Cocaine;
- long acting (> 3 h): Articaine, Ropivacaine, Bupivacaine, Levobupivacaine,
Etidocaine, Tetracaine, Ethylchloride.

Mechanism of action:
 Local anaesthetics act as Na+ channel-blocking agents: bind on the inner
gate of voltage-gated Na+ channels → block Na+ movement through the
channels, and thus block the action potential and neural conduction →
no new depolarization can be produced = “membrane stabilization”.
 At higher concentrations of drug → local anesthetics can block K+
channels.
There is a differential sensitivity of nerve fibers to local anesthetics: small
unmyelinated fibers (mediating pain and temperature sensations) are blocked
before the larger myelinated fibers (mediating postural, touch, pressure, and
motor information).
Local anesthetics are not water soluble, but their salts with acids are water-
soluble and can be injected. Solutions dissociate rapidly after injection →
"onium" structure prevents the passage of solutions through physiological
membranes, but it is necessary to pass through the membrane to reach the inner
gate of sodium channels where the molecules must complete blockage. local
anaesthetics penetrate the nerve membrane in the uncharged form and
block the action potential from inside the membrane in the charged form, with
"N" trivalent. After the passage, the molecules pass again in the form of
"onium" to block the inner door of sodium channels. The following factors
influence this transformation:
 tissue pH (alkaline pH tissue is favorable) → in inflamed tissue, the
acidic pH reduce the effectiveness of anesthetic;
 pH of the substance.

Pharmacodynamic effects
 Local anesthetic effect
 Antiaarhythmic effect (Lidocaine is class Ib antiarrhythmic drug)
 Vasodilatatory effect
o All local anesthetics (except cocaine) are vasodilators →
necessary the association of local anesthetics with

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 vasoconstrictor agents. The vasoconstrictors are: Adrenaline,
Norepinephrine, Phenylephrine. The synthetic derivative
vasopressin is used in patients with contraindications for
sympathomimetics.
o Mepivacaine has the lowest vasodilatatory effect.
o Advantages of the association of local anesthetics with
vasoconstrictors:
 prolong the effect of local anesthetics because delays the
removal of drug from the injection site;
 reduce the bleeding and congestion of the mucosa →
operatory field is clear;
 prevent the systemic absorption → decrease the
probability of CNS toxicity because the blood level of
local anesthetic is low;
o Contraindications of the association with vasoconstrictors:
hypertension, tachyarrhythmias, local anesthesia of the
extremities such as nose, ears, fingers, penis (because may
determine the ischemic tissue necrosis).
Pharmacokinetics:
 Bupivacaine passes the feto-placental barrier.
 Metabolism:
o Local anesthetics with ester structure are hydrolyzed and
inactivated primarily by plasma esterases and by hepatic
enzymes.
o Local anesthetics with amide structure are degraded by the
hepatic enzymes.
Indications:
 local anesthetic for surgery (eye, ear, nose, throat, and cosmetic
surgery);
o Tetracaine is indicated only for topical (surface) anesthesia;
o Lidocaine is indicated in:
 topical anesthesia, infiltration anesthesia, nerve block
anesthesia, spinal anesthesia, epidural anesthesia;
 ventricular arrhythmias;
o Articaine is prefered in dentistry (has a good concentration in

340
 bones);
o Prilocaine is used intravenous regional anesthesia;
o Ropivacaine, Bupivacaine are used in obstetrics.
 neuropathic pain syndromes (interruption of pathological reflexes);
Adverse effects:
 tachyphylaxis (loss of effectiveness) because the repeated injections of a
local anesthetic deplete the buffering capacity of the local tissues,
especially in areas of limited buffer reserve, such as the cerebrospinal
fluid, and induce extracellular acidosis which limit the diffusion of local
anesthetic into cells (for local anesthetics with long duration are
preferred bupivacaine, ropivacaine, etidocaine).
 irreversible spinal injuries (in spinal anesthesia)
 cardiovascular effects (related to the free concentration of drug)
o Cocaine: vasoconstrictor effects, hypertension; positive inotropic
effect; tachyarrhythmias;
o Other local anesthetics: arterial hypotension; negative inotropic
effect; atrioventricular block; tachyarrhythmias to ventricular
fibrillation;
o Bupivacaine has the highest cardiotoxicity (QRS shortening,
myocardial depression, ventricular arrhythmia), Ropivacaine is
less cardiotoxic.
 CNS effects are related to the free concentration of drug: drowsiness
(most common), restlessness, tremor, tonic-clonic seizures;
 immunological reactions of type I for local anesthetics with ester
structure;
 depress contractions of intestine, vascular, and bronchial smooth
muscle;
 methemoglobinemia (is a rare but serious complication of local
anesthetic prilocaine iv administration).
 Adverse effects: caused by stimulants sympathetic vasoconstrictor.

3. General anesthetic agents

General anesthetics are pharmacologycally active substances that suppress

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temporarily and reversibly the state of consciousness, sensitivity to pain,
somatic, autonomic reflexes.
Stages of general anesthesia using a single general anesthetic:
 1. Stage of analgesia:
 depression of certain cortical and spinal cord areas, of spinothalamic tract;
 initially analgesia without amnesia (state of consciousness is maintained), later are
produced both analgesia and amnesia;
 2. Stage of excitement:
 depression of small inhibitory circuits and amnesia (no consciousness);
 hyperexcitability (delirium, excitation, vomiting, irregular respirations);
 3. Stage of Surgical Anesthesia:
 depression of ascending reticular activation system (but with the maintainance of the
sensitivity of bulbar vegetative centers) and skeletal muscle relaxation;
 Four stages represent the increasing depth of anesthesia:
o changes in ocular movements,
o reduced eye reflexes,
o changes in pupil size,
o respiratory depression.
 4. Stage of Medullary Depression
 toxic paralysis of bulbar centers (severe depression of the vasomotor and respiratory
center) → death rapidly ensues.
Recovery from general anesthesia follows the same stages, in reversed order.

A good general anesthesia is characterized by:

 good muscle relaxation.
 the depth of general anesthesia is continuously monitored at all time
frames.
 installation and recovery of anesthesia must be quick, with fewer
adverse effects.
 the general anesthetic should have a high index narcotic.

Classification of general anesthetics

 1. Inhalational general anesthetics:
 gases: Nitrous oxide, Cyclopropane
 volatile liquides: Halothane, Isoflurane, Enflurane, Desflurane,
Sevoflurane, Methoxyflurane, Ethilic ether, Chloroform
 2. Intravenous general anesthetics:
 Thiobarbiturates (very short acting barbiturates): Hexobarbital,

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 Thiopental, Methohexital, Thiamilal, Thiobutabarbital;
 benzodiazepines (as adjuncts in anesthesia): Midazolam, Diazepam,
Lorazepam;
 imidazoles: Etomidate
 steroid structure: Althesin
 opioid analgesics: Morphine, Fentanyl, Sufentanil, Alfentanil,
Remifentanil
 others: Propofol, Ketamine, Dexmedetomidine, Propanidid.

Preanesthetic medication
 cholinoreceptor-bloking drugs (anticholinergic drugs)  reduce salivary
and bronchial secretion, prevent vagal bradycardia and reflex
hypotension.
 antihistaminic drugs  antialergic and antiemetic effects, 1st generation
has also sedative effects
 benzodiazepines  anxiolytic-sedative-hypnotic effects
 opioids are analgesic drugs that potentiate analgesic effect of general
anesthetics
 neuroleptic drugs
 antiplatelet drugs: Abciximab, Eptifibatide  prevent venous
thrombosis.

Depth of anesthesia is dependent upon the concentration of anesthetic in the

CNS, the lipophilicity of the general anesthetic and the reactivity of the patient.
Achievement of an adequate brain concentration of an inhaled anesthetic
requires transfer of that anesthetic from the alveolar air to blood and then to
brain. The transfer of an anesthetic from the lungs to the arterial blood depends
on its solubility, evaluated by the blood:gas partition coefficient (the relative
affinity of an anesthetic for the blood compared to air). There is an inverse
relationship between the blood solubility of an anesthetic and the onset of
action. E.g., nitrous oxide has low solubility in blood (low blood:gas partition
coefficient), so, little of the anesthetic dissolves in the blood, which in turn
results in rapid equilibration between the inhaled anesthetic and arterial blood,
respectively rapid equilibration with the brain and fast onset of action.
Potency of an inhalational anesthetic agent depends on the minimum alveolar

343
concentration (MAC), with 1 MAC defined as the minimum alveolar
concentration that results in immobility (loss of response) in 50% of patients in
response to surgical incision. MAC is usually expressed as the percentage of
gas in a mixture required to achieve the effect (MAC is small for potent
anesthetics).
Potency of an intravenous anesthetic agent depends on the free plasma drug
concentration that results in immobility (loss of response) to surgical incision in
50% of subjects.

1. INHALATIONAL GENERAL ANESTHETICS

1.1. GASES
 NITROUS OXIDE (N2O) (“laughing gas”)
 It is a gas, non-explosive, colorless, odorless, tasteless. The blood:gas
partition coefficient is low. It is a potent analgesic, but it has a very low
narcotic effect.
Indications:
 general anesthesia (only in association with general anesthetics volatile
liquids);
 analgesia in obstetrics (for labor).
Adverse effects:
 sensitivity to cathecolamines, depression of the myocardium;
 increase in cerebral perfusion and increase in intracranial pressure.
Contraindications:
 pneumothorax;
 pneumopericardium;
 renal cysts, lung cysts;
 bowel obstruction (= intestinal occlusion);
 first two trimesters of pregnancy (because of its effects on DNA
production).
1.2. VOLATILE LIQUIDS
These drugs have a high narcotic effect, but low analgesic effect.
Mechanisms of action:
 reduce time of opening of Ach-dependent Na+ channels;
 agonists on GABAA receptors;
 agonists on α2 presynaptic receptors; activate K+ channels and block

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 Ca2+ channels associated with α2 presynaptic receptors.
Pharmacokinetics: metabolism in the liver: Halothane >40%, Isoflurane <2%,
Enflurane = 8%, Desflurane = 0.05%, Sevoflurane = 2-5%, Methoxyflurane
>70%.
Indications: induction or maintenance of general anesthesia
Adverse effects:
 HALOTHANE
o hepatotoxicity (hepatic failure appears to be greatly increased by
repeated exposure to halothane; toxicity to halothane is rare and
not severe in children);
o high cardiac sensitivity to cathecolamines, resulting in an
increased incidence of cardiac arrhythmias due to myocardial
excitability;
o depression of the myocardium (this drug does not allow
compensatory sympathetic response) → reduce cardiac output
and hypotension;
o respiratory depression;
o increase intracranial pressure.
 ISOFLURANE, ENFLURANE, SEVOFLURANE
o moderate sensitivity to cathecolamines;
o decrease blood pressure and determine a compensatory
tachycardia → these drugs are contraindicated in coronary artery
disease.
 METHOXIFLURANE
o hepatotoxicity
o high cardiac sensibility to cathecolamines
 ETHYL ETHER (is flammable in contact with oxygen or air; irritates
the respiratory tract → stimulates bronchial secretion, salivation,
coughing, laryngeal spasm; nausea and vomiting; increase levels of
circulating catecholamines).

2. INTRAVENOUS GENERAL ANESTHETICS

These drugs have a very high narcotic effects, but with very low/absent
analgesic effects.
Indications: induction or maintenance of general anesthesia.

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 THIOBARBITURATES (narcotics barbiturates) see Chapter Sedative-
hypnotic drugs.
 determines narcotic sleep in a few seconds, duration of 10-20 min;
 PROPOFOL (2,6-DIISOPROPYLPHENOL) is similar to barbiturates
narcotics.
 determines narcotic sleep in 40 seconds;
 is widely used because it produces an euphoric feeling in the patient and
does not cause postanesthetic nausea and vomiting.
 Indications: induction or maintenance of general anesthesia.
 ETOMIDATE is a derivative of imidazole
 determines narcotic sleep in a few seconds, a duration of 7-14 min;
 metabolism in the liver and plasma (esterases);
 Indications: induction of general anesthesia in patients with coronary
artery disease or cardiovascular dysfunction (because don’t influence
heart activity).
 Disadvantages: pain at the site of injection, myoclonus; rarely: apnea.
 PROPANIDID:
 very short duration of action (2-5 min); metabolism: by plasma pseudo-
cholinesterases → increase the duration of action of succinylcholine;
Adverse effects: vasodilation, decrease blood pressure, negative
inotropic effect, hyperventilation, apnea, phlebitis, allergy, vomiting,
tonic-clonic seizures, death.
 ALTHESIN48 (has steroid structure, but does not determine endocrine
adverse effects).
 BENZODIAZEPINES (DIAZEPAM, MIDAZOLAM, LORAZEPAM).

 DISSOCIATIVE ANESTHESIA (realised with Ketamine)

Characteristics of dissociative anesthesia: catalepsy (immobility), amnesia and
low visceral analgesia (“the patient feels dissociated from the environment”).
Latency = few seconds (iv administration) or minutes (im administration);
duration of action=12-25 min.
Mechanisms of action of KETAMINE:
 allosteric antagonist of the NMDA glutamate receptors;
 inhibit the reuptake of norepinephrine and dopamine.
48
It is now withdrawn from the market of different countries due to severe drug reactions.

346
Indications:
 pediatric surgery;
 induction of general anesthesia;
 orthopedic maneuvers;
 laryngoscopy;
 transport of patients from the accident site;
 burn wound dressing in adult patients.
Adverse effects: psychomotor agitation, hallucinations, the stupor, disorders of
consciousness, adiction and effects of sympathetic stimulation.
Contraindications:
 patients with cardiovascular disease;
 neurosurgery (due to intracranial hypertension syndrome);
 ophthalmic surgery;
 pregnancy.
Disadvantage: Ketamine does not produce skeletal muscle relaxation and does
not influence pharyngeal and laryngeal reflexes.

 NEUROLEPTANALGESIA (Fentanyl combined with

Droperidol/Haloperidol)
The characteristics of neuroleptanalgesia: preserve consciousness, the patient
answers to questions (useful in surgery of the inner ear, thyroid, neurosurgery;
insensitivity to pain is achieved with fentanyl, complete disinterest is achieved
with droperidol (neuroleptic).
Indications:
 preoperatory preparation;
 endoscopies; neuro-radiological explorations;
 potentiation of regional anesthesia;
 burn wound dressing in adult patients;
 cardiac surgery; elderly;
 neurosurgery (neuroleptanalgesia not determine the syndrome of
intracranial hypertension); surgery of the inner ear; thyroid surgery.
Neuroleptanesthesia = neuroleptanalgesia + nitrous oxide + skeletal
muscle relaxant.

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 Lecture 17
Antiseizure Drugs (antiepileptic drugs)

Learning Objectives:
 Describe aspects of absorption, distribution, metabolism and excretion of a
drug;
 List the principal routes of drug administration and their advantages and
disadvantages;
 List examples of drugs concentrated in different tissues or liquids of the body;
 List the principal routes of drug elimination;
 Explain concept and significance of pharmacokinetic parameters
 Explain concept and significance of steady state concentration.

Antiseizure Drugs (antiepileptic drugs) are pharmacologically active

substances indicated in the treatment of epilepsy and of seizures of various
etiologies (intoxication, metabolic disorders, injuries of the CNS etc).
Epilepsy is a disease characterized by abnormal and excessive electrical activity in the CNS,
which result in symptoms of limited duration (involuntary contractions of skeletal muscles, loss
of consciousness, abnormal movements, behavioral manifestations, distorted perceptions).
Classification of epileptic seizures:
 Partial seizures (originate in localized area of cortex)
o simple partial seizures is associated with motor, sensory, autonomic or psychic
symptoms; there is preservation of consciousness.
 Particular form: Jacksonian seizure is characterized by motor seizures which
begin in a restricted region such as fingers and gradually progress to a larger
portion of the extremity.
o complex partial seizures is associated with automatisms (purposeless movements such
as lip smacking, chewing, hand wringing, aimless walking etc) associated with
impairment of consciousness.
o simple partial seizures with secondarily generalized tonic-clonic seizures is a
particular form characterized by symptoms of partial epilepsy (simple or complex),
followed by symptoms of grand mal epilepsy (tonic-clonic seizures).
 Generalized seizures (involve diffuse regions of the brain in both hemispheres)
o Tonic-clonic seizures (grand mal epilepsy) is characterized by sudden loss of
consciousness and loss of postural control, muscular contractions (evoluate in two
phases: initial is a tonic phase characterized by continuous contraction with teeth-
clenching and rigidity in extension, followed by clonic phase characterized by rapid

348
 rhythmic muscular contraction and relaxation). Tongue-biting and incontinence may
occur during the seizure. Recovery of consciousness is typically gradual over many
minutes to hours. Headache and confusion are common postictal phenomena.
o Absence seizures (petit mal epilepsy) is characterized by abrupt onset of impairment of
consciousness, with staring and cessation of ongoing activities, but without loss of
postural control, typically lasting <30 seconds.
o Myoclonic seizures are characterized by brief (shock-like) contractions lasting for few
seconds/minutes and may be restricted to part of one extremity or may be generalized.
o Febrile seizures are characterized by seizures induced by high fever between the age
of 6 months and 3-4(5) years
o Status epilepticus is life-threatening disordes characterized by continuous seizures
(>15–30 min) or repetitive, with impaired consciousness (without recovery of full
consciousness between episodes).
Particular forms of epilepsy:
 Infantile spasms (West syndrome) is a severe form of epilepsy characterized by
sudden muscular contractions followed by stiffening, developmental regression
(mental retardation) and a specific pattern on electroencephalography testing called
hypsarrhythmia (chaotic brain waves).
 Lennox-Gastaut syndrome is a severe form of epilepsy characterized by mental
retardation or regression and multiple types of seizures (tonic-clonic, tonic, atonic,
myoclonic, and atypical absence seizures).

History of Antiepileptic Drug Therapy

 1857 – Bromides  1974 – Carbamazepine,  1995 – Lamotrigine,
 1912 – Phenobarbitone Oxcarbazepine Levetiracetam
 1937 – Phenytoin  1975 – Clonazepam  1997 – Topiramate,
 1944 – Trimethadione  1978 – Valproate Tiagabine
 1954 – Primidone  1993 – Felbamate,
 1960 – Ethosuximide Gabapentin

The objectives of antiseizure therapy:

 to reduce the frequency of attacks;
 to normalize EEG between seizures of epilepsy;
 social integration between seizures of epilepsy.
Classification of Antiseizure Drugs (antiepileptic drugs)
I.1. Barbiturates: Phenobarbital and congeners (Primidone)
I.2. Hidantoines: Phenytoin, Fosphenytoin, Mephenytoin, Ethotoin,
Phenacemide
I.3. Tricyclic compounds: Carbamazepine
I.4. Succinimides: Ethosuximide, Phensuximide, Methsuximide

349
I.5. Carboxilic acids: Valproic Acid, Sodium valproate
I.6. Oxazolidinediones: Trimethadione, Paramethadione, Dimethadione
I.7. Benzodiazepines used as anticonvulsant therapy: Diazepam, Lorazepam,
Clonazepam, Nitrazepam, Clorazepate, Clobazam
I.8. Bromides
I.9. Carbonic anhydrase inhibitors: Acetazolamide
I.10. Other structures: Vigabatrin, Lamotrigine, Felbamate, Gabapentin,
Topiramate, Tiagabine, Zonisamide, Levetiracetam.

All antiseizure drugs have a narrow therapeutic index (with the exception of
benzodiazepines) and duration of treatment is all life (it is necesssary periodic
clinical, biochemical and haematological evaluation).
Replacement with an antiseizure drug another antiseizure drug is progressively:
the dose of the former antiseizure drug is progressively reduced and the new
dose of antiseizure drug is gradually increased until complete replacement.
Abrupt discontinuation of the administration of antiseizure drug determine
withdrawal syndrome called status epilepticus.
The treatment of status epilepticus (regardless of the origin of epilepsy) is with
benzodiazepines (particularly Clonazepam or Diazepam iv).
Common adverse effects: of antiseizure drugs (antiepileptic drugs) include
somnolence, fatigue, ataxia, dizziness, gastrointestinal upset. Patients should be
counseled that these effects could impair driving and the ability to safely
operate complex machinery. Use of alcohol can magnify these effects.

1. Barbiturates and related substances

Classification: Phenobarbital; related substances: Primidone.
Particularities:
 Primidone is a prodrug, which is metabolised to Phenobarbital.
 The anticonvulsant doses of barbiturates do not produce excessive sedation.
 Barbiturates do not determine tolerance to anticonvulsant effect.
 Primidone is indicated only as anticonvulsant drug.
Mechanisms of action, pharmacodynamic effects, pharmacokinetics,
indications, contraindications, Adverse effects: → see in Chapter "anxiolytic-
sedative-hypnotics".

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2. Hydantoins
This group includes49: Phenytoin, Phosphenytoine and structural analogues
such as Mephenytoin and Ethotoin.
Phenytoin (diphenylhydantoin) is the oldest non-sedating anticonvulsant,
introduced in therapy in 1938.
Mechanisms of action:
 block the voltage-gated sodium channels (selectively bind to the channel
in the inactive state and reduce the ability of the channel to recover from
inactivation);
 inhibition of transmembrane calcium flux;
 inhibition of bone marrow post-tetanic potential;
 stimulation of Na + / K + - ATP - ase glial cell membrane;
 inhibition of release of noradrenaline and serotonin;
 stimulation of dopamine uptake and inhibition of MAO activity;
 stimulation of acetylcholine cleavage;
 antagonise the effects of glutamate;
 inhibition of the release of excitatory aminoacids;
 inhibition of GABA reuptake;
 stimulation of the proliferation and expression of GABA receptors;
 inhibition of the synthesis of folic acid;
 interference with metabolism of vitamin D;
 interference with activity of sexual hormones;
 interference with membrane lipids → produce membrane stabilization.
Pharmacodynamic effects:
 anticonvulsant effects (hydantoins control partial epilepsy and generalised
tonic-clonic epilepsy; are used as part of the emergency treatment of status
epilepticus);
 antiarrhythmic effects (Phenytoin is a class Ib antiarrhythmic drug);
 antifolate effects.
Pharmacokinetics:
 Phenytoin is 90% bound to plasma proteins. Hypoalbuminemia increases the
concentration of unbound fractions. Plasma protein binding is reduced in
renal disease.

49
Phenacemide (has been withdrawn from the market).

351
 Hydantoins are metabolic enzyme inducers (stimulate hepatic metabolism of
other drugs and even its metabolism).
 Phenytoin has saturable kinetics (saturable enzyme metabolism).
Indications:
 anticonvulsant for:
o tonic-clonic seizures (grand mal epilepsy),
o partial epilepsy,
o status epilepticus (phenytoin iv and / or phenobarbital im are part
of the status epilepticus treatment: they are administered after
benzodiazepines);
 ventricular arrhythmias (it is used particularly for the treatment of acute
intoxication with digitalis).
Adverse effects:
 nausea, diplopia, nystagmus, tremor, ataxia, headache, lethargy;
 hyperkinesia, choreoathetosis50 symptoms, paradoxical increase in seizure
frequency;
 gingival hyperplasia;
 osteomalacia;
 megaloblastic anemia, agranulocytosis;
 immunological (alergic) reactions: fever, rash, exfoliative dermatitis;
 hirsutism (by modifying the metabolism of sex hormones);
 keloid formation;
 lymphadenopathy (a possible causal relationship to Hodgkin's disease);
 sedation at high doses;
 peripheral neuropathy, decreased deep tendon reflexes in the legs;
 coarsening of facial features;
 hepatotoxicity.
Drug interactions:
 Phenylbutazone and sulfonamides displace Phenytoin from plasma proteins
→ increase the plasma concentration of free fractions of Phenytoin;
 Carbamazepine and Phenobarbital (are metabolic enzyme inducers)
determine the decrease in Phenytoin steady-state concentration;
 Isoniazid (metabolic enzyme inhibitor) increase Phenytoin steady-state
50
Athetosis is a repetitive involuntary, slow, sinuous, writhing movement of the fingers and hands (and
sometimes of the toes and feet), usually caused by an extrapyramidal lesion.

352
 concentration.
 Phenytoin has a high affinity for thyroid-binding globulin → false results in
tests of thyroid function (evaluation of thyroid function in patients treated
with Phenytoin is only by measurement of plasma concentrations of TSH).
 Hypoalbuminemia increases the concentration of free fractions of phenytoin,
reduced total plasma concentrations of phenytoin → increasing the dose
determines toxic concentrations of phenytoin.
Phosphenytoine is a prodrug, which is rapidly converted into Phenytoin in
plasma; the administration is parenteral.
Ethotoin may be recommended for patients hypersensitive to Phenytoin, but
the adverse effects are more severe than those of Phenytoin.
Mephenytoin is metabolized to nirvanol (an active metabolite); the adverse
effects (dermatitis, agranulocytosis, hepatitis) are more severe than those of
Phenytoin.

3. Tricyclic compounds: Carbamazepine, Oxcarbazepine

Carbamazepine was initially marketed for the treatment of trigeminal
neuralgia but later proved efficacy for treating epilepsy.
Carbamazepine is considered first generation antiseizure drugs.
Oxcarbazepine is considered second generation antiseizure drugs.
Mechanisms of action:
 block the voltage-gated sodium channels (selectively bind to the channel
in the inactive state and reduce the ability of the channel to recover from
inactivation);
 inhibit the release and reuptake of norepinephrine;
 interfere with adenosine receptors;
 possible potentiate the postsynaptic action of GABA.
Pharmacodynamic effects:
 anticonvulsant effects,
 antipsychotic effects,
 analgesic effects only for Carbamazepine.
Pharmacokinetics:
 Carbamazepine is metabolic enzyme inducer (stimulate hepatic metabolism
of other drugs and even its metabolism).
 Oxcarbazepine is a prodrug; it has a longer duration of action through its

353
 active metabolite. Oxcarbazepine is less potent enzyme inducer than is
Carbamazepine.
Indications:
 anticonvulsant for:
o partial epilepsy simple and complex (Carbamazepine is first-
choice drug);
o tonic-clonic seizures (grand mal epilepsy),
 alternative treatment for bipolar psychoses(when lack of response to lithium
salts);
 analgesic: trigeminal neuralgia (Carmamazepine is first-choice drug).
Adverse effects:
 the most common in initial therapy are:
o ataxia51, diplopia,
o gastro-intestinal symptoms: nausea, vomiting, anorexia,
abdominal pain;
o CNS effects: dizziness, drowsiness, headache;
 immunological reactions type I (rash, skin erythema, urticaria) or type II
 hyponatremia, sometimes edema;
o Oxcarbazepine determines a more severe hyponatremia.
 very severe: idiosyncratic blood dyscrasias: agranulocytosis, aplastic anemia;
 rare: abnormalities of liver and kidney function, hepatitis, cholestatic
jaundice.
Drug interactions
 Carbamazepine and Phenobarbital decreases steady-state concentration
of Phenytoin by inducing CYP3A4.
 Phenytoin and Phenobarbital decrease steady-state concentrations of
Carbamazepine by inducing CYP3A4.

4. Succinimides: Ethosuximide, Phensuximide, Methsuximide

Mechanisms of action:
 inhibit T-type calcium channels (in thalamic neurons);
 inhibit Na+/K+-ATP-ase;
 inhibit GABA – transaminase52 (GABA - T).

51
Ataxia is the inability to coordinate muscle activity during voluntary movement.

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Pharmacodynamic effects: anticonvulsant effects.

Ethosuximide
Indications: absence seizures as first-choice drugs.
Adverse effects:
 gastro-intestinal symptoms: nausea, vomiting, anorexia, gastric upset,
abdominal pain,
 CNS effects: drowsiness, dizziness, headache, transient lethargy, fatigue,
mild euphoria, hiccups, behavioral changes,
 abnormalities of liver and kidney function,
 others: rash, thrombocytopenia (→pancytopenia), eosinophilia; lupus
erythematosus.
Methsuximide
Indications:
 absence seizures (treatment of choice),
 partial epilepsy (alternative treatment because of the high toxicity).

5. Carboxylic acids: Valproic acid, Sodium valproate,

Divalproex (Divalproex is a combination of Sodium valproate and Valproic
acid)
Mechanisms of action:
 block the voltage-gated sodium channels (selectively bind to the channel in
the inactive state and reduce the ability of the channel to recover from
inactivation);
 increase levels of GABA in brain:
o inhibit GABA - transaminase;
o inhibition of GABA transporter GAT-1, involved in the uptake
of GABA;
o increase the activity of glutamic acid decarboxylase (GAD), the
enzyme responsible for GABA synthesis;
 block NMDA receptor-mediated excitation;
 decrease the concentration of aspartate in the brain;
 open and activate potassium channels in the neuronal membrane, which

52
GABA – transaminase is the short name of GABA aminotransferase, the enzyme involved in the degradation of
GABA.

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 increase membrane potassium conductance determining membrane
hyperpolarisation.
Pharmacodynamic effects: anticonvulsant effects.
Indications:
 as anticonvulsants:
o absence seizures (drug of choice),
o juvenile myoclonic epilepsy (as first-choice drug),
o tonic-clonic seizures (grand mal epilepsy),
o partial epilepsy, simple and complex;
 migraine prophylaxis;
 alternative treatment for bipolar psychoses.
Adverse effects:
 gastro-intestinal symptoms: nausea, vomiting, abdominal pain, "heartburn",
increased apetite (has as consequence weight gain);
 transient alopecia (hair loss);
 tremors;
 sedation at high doses;
 hepatotoxicity: increase serum transaminases, hepatic necrosis, increase
serum alkaline phosphatase; pancreatitis;
 thrombocytopenia → may cause abnormal bleeding;
 teratogenic effects (administered during pregnancy increase the incidence of
spina bifida, cardiovascular anomalies, orofacial and digital anomalies).

6. Oxazolidinediones: Trimethadione, Paramethadione, Dimethadione

Their use is limited today.
Mechanisms of action: inhibit T-type calcium channels (in thalamic neurons)
Pharmacokinetics: Trimethadione is metabolized to an active metabolite which
exert major antiseizure activity and has long half-life.
Pharmacodynamic effects: anticonvulsant effects.
Indications: absence epilepsy.
Adverse effects:
 most common: sedation;
 metabolic acidosis;
 immunological effects type I (rash, exfoliative dermatitis) or type II
(autoimmune nephrotic syndrome, myasthenia gravis);

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 pancytopenia, night blindness, disorders of visual accommodation.

7. Benzodiazepines used as antiseizure drugs: Diazepam, Clorazepate,

Nitrazepam, Clonazepam, Lorazepam, Clobazam.
Indications:
 myoclonic epilepsy;
 infantile spasm;
 status epilepticus (benzodiazepines may be associated with ACTH or
dexamethasone).
Mechanisms of action, pharmacodynamic effects, pharmacokinetics,
indications, contraindications, adverse effects → see in Chapter "anxiolytic-
sedative-hypnotics".

8. Bromides
Mechanisms of action, pharmacodynamic effects, pharmacokinetics,
indications, contraindications, adverse effects → see in Chapter "anxiolytic-
sedative-hypnotics".

9. Carbonic anhydrase inhibitors: Acetazolamide

Mechanisms of action:
 inhibition of carbonic anhydrase in the brain determine metabolic acidosis;
 inhibition of carbonic anhydrase in the eye;
 inhibition of carbonic anhydrase in the proximal convoluted tubule;
 inhibition of carbonic anhydrase in the gastric mucosa.
Pharmacodynamic effects:
 in the CNS → antiseizure and antiemetic effect;
 reduction of intraocular pressure;
 increased diuresis (alkaline diuresis);
 inhibiting the production of HCl.
Indications:
 anticonvulsant as alternative treatment for all types of epilepsy (tolerance to
this effect appears after 4 weeks of treatment), it is the treatment of choice in
women with seizure exacerbations at the time of menses;
 other indications: glaucoma; altitude sickness; metabolic alkalosis; as
diuretic to alkalinization of urine; ulcer disease.
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Contraindications: renal failure and severe hepatic impairment, pregnancy.
Adverse effects:
 hyperchloremic metabolic acidosis;
 immunological reactions of type I and type III;
 hypokalemia;
 phosphaturia, hypercalciuria, hyperbicarbonaturia, formation of kidney
stones;
 paresthesias in the limbs, disorders of the CNS in patients with renal
insufficiency.

10. Other structures (second generation antiseizure drugs)

With the exception of felbamate and vigabatrin, second generation antiseizure
drugs (e.g., gabapentin, lamotrigine, topiramate, levetiracetam, pregabalin,
lacosamide, zonisamide) have a number of potential advantages over older
antiseizure drugs (e.g., phenobarbital, phenytoin, carbamazepine, valproate):
 lower side-effect rates,
 little or no need for serum monitoring,
 once or twice daily dosing for some,
 fewer drug interactions.
Vigabatrin
The drug is a derivative of gamma-vinyl-GABA.
Mechanism of action: irreversible inhibition of GABA-T.
Pharmacodynamic effects: anticonvulsant effects.
Pharmacokinetics: saturable kinetics; bioavailability = 60%; the drug is not
significantly related to plasma proteins; t1/2 = 6 - 8 h; renal elimination.
Indications:
 partial epilepsy;
 West syndrome.
Adverse effects:
 weight gain;
 drowsiness, dizziness;
 rarely, psychomotor agitation, states of confusion, psychoses (the drug
is contraindicated in patients with psychiatric disorders);
 visual field defects (1/3 of patients) – irreversible retinal toxicity;
 teratogenic.
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Tiagabine
The drug is a derivative of nipecotic acid.
Mechanisms of action: inhibition of GABA transporter GAT-1, involved in the
uptake of GABA in the neurons and glial cells → increased levels of GABA in
the forebrain and the hypothalamus.
Pharmacokinetics: bioavailability = 100%; t1/2 = 5 - 8 h (t1/2 is decreased in the
presence of other antiepileptic drugs); foods decrease plasma concentrations;
liver failure determines a decrease in clearance.
Indications:
 partial epilepsy;
 tonic-clonic seizures (grand mal epilepsy).
Adverse effects: dizziness; drowsiness; asthenia; ataxia; confusional state;
nervousness; tremors; difficulties in concentrating; depressive states; emotional
lability; psychoses; rash.
Gabapentin
The drug is an analogue of GABA.
Mechanism of action: modulation of synaptic release and metabolism of
GABA or GABA reuptake by GABA transporters.
Pharmacokinetics: the drug is not metabolized; linear elimination kinetics;
renal elimination; t1/2 = 5 - 8 h.
Indications:
 partial epilepsy;
 epilepsy grand mal;
 as an analgesic in neuropathic pain (includin postherpetic neuralgia).
Adverse effects: somnolence, drowsiness, dizziness, headache, fatigue, tremor,
ataxia. The adverse effects usually are mild and dissapear within 2 weeks after
start of treatment.
Lamotrigine
The drug is a derivative of phenyltriazine.
Mechanism of action: block the voltage-gated sodium channels (selectively
bind to the channel in the inactive state and reduce the ability of the channel to
recover from inactivation).
Pharmacokinetics: the plasma protein binding is approximately 55%;
metabolism is in the liver by glucuronidation; elimination is renal; it presents
saturable kinetics; t1/2 = 24 h (it is 13 - 15 h in the presence of metabolic

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enzyme inducers).
Indications: ● partial epilepsy;
● juvenile myoclonic epilepsy;
● absence seizures (probably, the drug also acts on calcium
channels).
Adverse effects: nausea; headache; drowsiness, dizziness; diplopia; rash;
dermatitis (1-2%).
Topiramate The drug is a substituted monosaccharide.
Mechanisms of action:
 block the voltage-gated sodium channels (selectively bind to the channel
in the inactive state and reduce the ability of the channel to recover from
inactivation);
 potentiation of the inhibitory effect of GABA at other sites than the
barbiturate or benzodiazepine site;
 inhibit the action of kainate on AMPA receptors.
Pharmacokinetics: saturable kinetics; bioavailability = 80%; the drug is bound
to plasma proteins → 15%; t1/2 = 20 - 30 h; metabolism = 20 - 50%; the drug
decreased plasma concentrations of estrogens.
Indications (monotherapy):
 partial epilepsy;
 tonic-clonic seizures (grand mal epilepsy).
Adverse effects: drowsiness; dizziness; fatigue; decreased cognitive function;
paresthesia; nervousness; confusional state; urolithiasis (15%); teratogenicity.
Zonisamide The drug is a sulfonamide derivative.
Mechanisms of action:
 block the voltage-gated sodium channels (selectively bind to the channel
in the inactive state and reduce the ability of the channel to recover from
inactivation);
 block voltage-dependent calcium channels.
Pharmacokinetics: the kinetics is linear. Good bioavailability. T1/2 = 1 - 3 days.
Indications:
 partial epilepsy;
 tonic-clonic seizures (grand mal epilepsy);
 infantile spasm;
 myoclonus.

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Adverse effects: drowsiness; damage cognitive function; kidney stones; rash.
Pregabalin
Mechanisms of action: block the voltage-gated sodium channels.
Indications:
 partial epilepsy;
 neuropathic pain (associated with diabetic peripheral neuropathy,
postherpetic neuralgia, and fibromyalgia);
 generalised anxiety disorder.
Adverse effects: drowsiness; blurred vision, weight gain, peripheral edema.
Felbamate
Mechanism of action:
 block NMDA receptors;
 block voltage-dependent sodium channels;
 block calcium channels;
 potentiate GABA actions.
Pharmacokinetics: metabolism in the liver by hydroxylation and
glucuronidation.
Indications:
 Lennox-Gastaut syndrome;
 partial epilepsy (the third line of treatment due to toxicity).
Adverse effects: severe hepatitis; aplastic anemia.
Drug interactions:
 Felbamate determines the increase in plasma levels of Phenytoin and
Valproic acid,
 Felbamate determines the decrease in plasma levels of carbamazepine.
Levetiracetam The drug is an analogue of Piracetam.
Mechanisms of action:
 allosteric modulation of GABA receptor,
 modulation of high-voltage activated Ca2+ channels and some K+
channels.
Pharmacokinetics: the kinetics is linear. T1/2 = 6 – 8 h, approximately. It is
prolonged in the elderly.
Indications: adjunct therapy of partial seizures, myoclonic seizures, and
generalized tonic-clonic seizures.
Adverse effects: drowsiness, fatigue, dizziness

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 Lecture 18
1.Drugs used in mental illness

Learning Objectives:
 Describe aspects of absorption, distribution, metabolism and excretion of a
drug;
 List the principal routes of drug administration and their advantages and
disadvantages;
 List examples of drugs concentrated in different tissues or liquids of the body;
 Name the phases in hepatic metabolism;
 Describe the terms “bound” and “unbound” drug to plasma proteins;
 Describe the term “first pass effect”;
 Describe the terms drug metabolism “enzyme induction” and “enzyme
inhibition”;
 List the principal routes of drug elimination;
 Explain concept and significance of pharmacokinetic parameters
 Explain concept and significance of steady state concentration.

Neuroleptic drugs (antipsychotic drugs) are a group of drugs that have been
used mainly for treating schizophrenia but are also effective in some other
psychoses and conditions marked by severe agitation.
The term "psychosis" denotes a variety of mental disorders in which a person has lost some
contact with reality. Specific psychotic symptoms include delusions, hallucinations, ideas of
reference, and disorders of thought.
 Schizophrenia is a disorder usually present between late adolescence and the third
decade, in which patients have psychotic symptoms that persists for at least 6 months.
It is characterized by delusions, hallucinations (often in the form of voices), marked
thinking or language disturbances, inappropriate affect and bizarre disorganized
behavior.
 Paranoia (chronic systematized delusions) is a personality disorder characterized by
systematized delusions of persecution or grandeur usually without hallucinations, with
exaggerated self-reference, a tendency to construe independent events and acts as
pertaining to him- or herself. Paranoia was formerly classified as a distinct psychosis,
but is now considered as one of several varieties of schizophrenia or of personality
disorder.
 Bipolar disorder (manic depressive illness) is a mood disorder in which episodes of
major depression are interspersed with episodes of mania or hypomania. Mania is

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 characterized by increased motor activity and restlessness, unusual talkativeness, flight
of ideas and racing thoughts, decreased need for sleep and appetite, excessive
involvement in risky activities. Hypomania is characterized by attenuated manic
symptoms.

1. NEUROLEPTIC DRUGS (ANTIPSYCHOTIC AGENTS)

Classification and mechanisms of action of neuroleptics:
1.1.Phenothiazines:
- Aliphatic side chain [ α1 = M =H1 =5HT2 ≥ D2 >D1]: Chlorpromazine,
Levomepromazine
- Piperidine side chain [ α1 = M =H1 =5HT2 ≥ D2 >D1]: Thioridazine
- Piperazine side chain [ D2>D1 = D4 >α1 > 5HT2]: Fluphenazine,
Trifluoperazine, Perphenazine
1.2. Thioxanthenes: Thiothixene, Chlorprothixene
1.3. Butyrophenones [ D2>D1=D4> α1 >5HT2]: Haloperidol, Droperidol
1.4. Diphenylbutilpiperidine [ D2]: Pimozide
1.5. Other structures atipical neuroleptics: Risperidone [ D2 = 5HT2],
Clozapine [ D4 = H1 = α1 > 5HT2 > D2 > D1], Quetiapine [ D2 = α1 = α2 =
H1 = 5HT2], Olanzapine [ 5HT2 = H1 > α1 = D2 = D1], Sertindole [ 5HT2
>> D2 = α1], Molindone, Sulpiride, Loxapine, Remoxipride, Ziprasidone,
Paliperidone, Iloperidone, Asenapine, and Lurasidone.
Effects of blocking dopamine receptors:
 from the mesolimbic area → improvement in symptoms of
schizophrenia;
 from the nigrostriatal area → pseudoparkinsonism;
 from the tuberoinfundibular area → hyperprolactinemia.
Antipsychotic drugs that selectively block dopamine receptors does not cause
ataxia, dysarthria, narcosis.
Pharmacodynamic effects of Antipsychotics (neuroleptics) in mental illness:
 reduction of hostility, of aggression, of anxiety;
 attenuation of the dynamics of mental processes;
 inhibition of autism, the delusional ideation, hallucinations.
Pharmacodynamic effects of Antipsychotics (neuroleptics) in healthy
humans:
 discomfort; drowsiness;

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  anxiety, psychomotor agitation;
 vegetative effects (particularly phenothiazines);
 answers correctly to questions;
 decreased physical ability and intellectual capacity;
 indifference to the environment;
 inhibition of conditioned reflexes and unconditioned reflexes
maintenance.

Indications common for all neuroleptics:

 psychotic disorders
o schizophrenia;
o mania;
o chronic systematized delusions;
o manic periods of bipolar psychosis;
o Alzheimer dementia
o behavioral disorders in psychomotor agitation.
 Other particular indications for some neuroleptics:
o Chlorpromazine:
 antiallergic (hay fever, pruritus, rash);
 antiemetic and treatment of motion sickness;
 anxiolytic-sedative-hypnotic;
o Haloperidol: neuroleptanalgesia
Adverse reactions common to all antipsychotics:
 neuropsychiatric disorders:
o "pseudodepressions" because akinesia;
o pseudoparkinsonism;
o tardive dyskinesia;
o confusional state (with antimuscarinic effects);
o ataxia (with the exception of selective antidopaminergic
neuroleptics);
 hyperprolactinemia: syndrom amenorrhea – galactorrhea, infertility,
decreased libido, impotence;
 hypotension, the inhibition of ejaculation (anti-adrenergic α1 effects);
 antimuscarinic effects;
 immunological reactions → agranulocytosis, cholestatic jaundice,

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 rashes;
 neurovegetative dystonia;
 teratogenic effects;
 weight gain (probably by blocking H1 receptors and 5-HT2) → mild for
ziprasidone and aripiprazole and severe for olanzapine;
 hyperglycemia and diabetes mellitus (secondary to dyslipidemic
syndrome associated with insulin resistance) → more common for
clozapine and olanzapine.
 The neuroleptic malignant syndrome occurs in patients chronically
treated with neuroleptics. The syndrome is characterized by muscle
rigidity which results in a dangerous increase in body temperature and
leukocytosis (the latter two effects require a differential diagnosis with
infectious processes). Other symtoms are alterations in blood pressure
and pulse; increase the creatine kinase (reflecting muscle injuries). The
treatment of neuroleptic malignant syndrome is with:
o antiparkinsonian drugs → dopamine receptor agonists
(Bromocriptine);
o skeletal muscle relaxants → Dantrolene, Diazepam
o treatment of fever.
 Other particular adverse effects for some neuroleptics:
o Chlorpromazine: accumulation of pigment in the anterior
chamber (cornea, crystalline);
o Thioridazine accumulation of pigment in the retina;
o Thioridazine determines quinidine-like effects (in large doses
determines arrhythmias, T wave changes in the EKG, ventricular
fibrillation).
o Ziprasidone: cardiotoxicity.

Pharmacological characteristics of different groups of neuroleptics

 Phenothiazines with aliphatic side chain (Chlorpromazine,
Levomepromazine) and the side chain piperidine (Thioridazine)
 Pharmacodynamic effects:
o weak antipsychotic effects;
o powerful sedative effects;
 These phenothiazines determine mild antipsychotic

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 effects and strong sedative effects. These drugs have the
advantage of much lower incidence pseudoparkinsonism
and hyperprolactinemia.
o Thioridazine has also thymoleptic effect (favorably modifies
mood in serious affective disorders such as depression or
mania);
o Chlorpromazine has also anti-allergic, anti-inflammatory,
anxiolytic-sedative-hypnotics, anti-emetic effects.
 Pharmacokinetics:
 Chlorpromazine and Thioridazine are liposoluble; are bound to plasma
proteins (92%-99%); after oral administration present intense first-pass
hepatic and enterohepatic circulation; they are metabolized to active
metabolites → chlorpromazine metabolites are eliminated through urine,
several weeks after administration; thioridazine metabolite
(mesoridazine) is very active and determines concentrations with
significant antipsychotic effects.
 Indications:
o Chlorpromazine:
 antiallergic (hay fever, pruritus, the hives, rash);
 antiemetic and treatment of motion sickness;
 anxiolytic-sedative-hypnotic;
 antipsychotic (schizophrenia, mania, manic periods of
bipolar psychoses, dementia from Alzheimer,
psychomotor restlessness);
o Levomepromazine: antipsychotic (schizophrenia);
o Thioridazine: antipsychotic (schizophrenia, mania, psychomotor
agitation).
 Contraindications:
o Similar to antimuscarinic drugs (glaucoma; angina; heart failure,
arrhythmias; peptic ulcer; prostate hyperplasia; children under
12 years; sun exposure;
o combination with tricyclic antidepressants (particularly for
thioridazine, which has quinidine-like effects);
o old persons.
 Adverse effects:

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 o excessive sedation;
o the confusional state;
o antimuscarinic effects: dry mouth (dryness of mucousa);
difficulty for urination (acute retention of urine), constipation,
and unclear view;
o hypotension, inhibition of ejaculation (by blocking adrenergic
α1);
o the level of eye:
 Chlorpromazine: accumulation of pigment in the anterior
chamber (cornea, crystalline);
 Thioridazine accumulation of pigment in the retina;
o Thioridazine determines quinidine-like effects (in large doses
determines arrhythmias, T wave changes in the EKG, ventricular
fibrillation).
 Phenothiazines piperazine side chains and butyrophenone
 Pharmacodynamic effects:
o strong antipsychotic effects(these drugs are called "major
antipsychotics").
 These drugs determine pseudoparkinsonism and they
have the advantage of lower sedative effects.
 Pharmacokinetics → Haloperidol has important hepatic first pass
effect.
 Indications:
o antipsychotic (schizophrenia, mania, manic periods of bipolar
psychoses, behavioral disturbances in psychomotor restlessness);
o neuroleptanalgesia (Droperidol/Haloperidol in association with
Fentanyl).
 Adverse effects:
o orthostatic hypotension;
o reduced sedation;
o extrapyramidal Adverse effects:;
o teratogenic effects (especially the piperazine phenothiazines).
 Diphenylbutylpiperidines (Pimozide)
 Pharmacodynamic effects: antipsychotic effects are very strong.
 Adverse effects: pseudoparkinsonism; tardive dyskinesia.

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 Thioxanthenes (Thiothixene, Chlorprothixene)
 high clinical efficacy;
 extrapyramidal effects; they have also sedative effects; moderate
hypotension;
 these drugs also have antidepressant effect.
 Other structures (atipical neuroleptics)
o Antipsychotics from this group are called "atypical
antipsychotics" because of their partial action on dopamine
receptors and stronger action on receptors other than dopamine
receptors.
 Risperidone
 Pharmacodynamic effects: antipsychotic effects are very strong.
 Adverse effects: reduced sedation; reduced extrapyramidal Adverse
effects:; hypotension with low intensity.
 Clozapine
 Pharmacodynamic effects: moderate antipsychotic effects.
 Adverse effects: reduced extrapyramidal Adverse effects:; reduced
sedative effects; agranulocytosis; marked weight gain; increased
frequency syndrome dyslipidemia and diabetes mellitus.
 Quetiapine
 Pharmacodynamic effects: antipsychotic effects very strong.
 Adverse effects: pseudoparkinsonism drug; tardive dyskinesia; moderate
sedative effects;
 Olanzapine
 Pharmacodynamic effects: antipsychotic effects very strong.
 Adverse effects: moderate sedative effects; mild hypotension; marked
weight gain; increased frequency of dyslipidemic syndrome and
diabetes mellitus.
 Sertindole
 Pharmacodynamic effects: antipsychotic effects very strong.
 Adverse effects: reduced extrapyramidal Adverse effects:; reduced
sedative effects; hypotension in very low intensity.
 Ziprasidone, Aripiprazole, Molindone, Sulpiride, Loxapine,
Remoxipride
 Pharmacodynamic effects: moderate antipsychotic effects.

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  Adverse effects: moderate extrapyramidal effects; moderate sedative
effects; moderate hypotension; Ziprasidone → cardiotoxicity;
Ziprasidone, Aripiprazole → reduced frequency of weight gain,
dyslipidemia syndrome and diabetes mellitus.

2. LITHIUM AND OTHER MOOD STABILIZING DRUGS (antimaniac

drugs)
Classification of mood stabilizing agents
2.1. Lithium salts: Lithium acetate, Lithium carbonate
2.2. Tricyclic compounds: Carbamazepine
2.3. Carboxilic acids: Valproic Acid, Sodium valproate

 Pharmacodynamic effects of lithium:

 increase intervals between periods of mania, sometimes complete;
 effect is installed after 2-3 weeks of administration (during this period,
lithium salts are associated with neuroleptics). Determine lethargy,
cyanosis, hepatomegaly, Moro reflex in the newborn.
 The therapeutic index is low.
 Pharmacokinetics of lithium salts: good absorption after oral
administration; lithium is not bound to plasma proteins; Lithium is not
metabolized; elimination through urine (elimination is reduced by dietary salt
restriction, thiazide administration); cross the placenta, are concentrated in the
milk;
 Indications of lithium salts: manic periods (treatment of choice).
 Adverse effects of lithium salts:
 hematological effects: leukocytosis;
 neurological effects: tremors of the extremities, dizziness, confusional
states, choreoathetoid crises, convulsions;
 renal effects: polyuria and polydipsia (decrease the ability of the
collector tube to retain water, which is followed by dehydration = the
nephrogenic diabetes insipidus, which is resistant to treatment with
vasopressin), interstitial nephritis chronic lesions in the glomeruli in
nephrotic syndrome decreased glomerular filtration with increasing
azotemia, edema with sodium retention;

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  cardiovascular effects: sick sinus syndrome (bradycardia/tachycardia
syndrome), flattening of the T wave on ECG;
 teratogenic effects (cardiac dysmorphogenesis);
 diarrhea;
 decreased thyroid function;
 more rarely, acneiform eruptions (early treatment).
 Contraindications of lithium salts:
 pregnancy; breastfeeding;
 renal failure;
 heart failure; coronary artery disease; hypotension;
 organic diseases of the brain;
 sodium diet / salt-free diet;
 treatment with thiazides (thiazides reduce the elimination of lithium).

3. ANTIDEPRESSANT DRUGS
Classification of antidepressant drugs
3.1. Tricyclic antidepressants (1st generation)
3.2. Heterocyclic antidepressants (2nd and 3rd generation)
3.3. Selective serotonin reuptake inhibitors (SSRI)
3.4. Inhibitors of monoamine oxidase (IMAO):
3.5. Selective noradrenaline reuptake inhibitors: Reboxetine

 Indications for antidepressants

 depression;
 enuresis (for tricyclic antidepressants);
 chronic pain.

 TRICYCLIC ANTIDEPRESSANTS (first generation of

antidepressants)
 These drugs are divided into 3 structural-related groups:
o Imipramine; Desipramine; Clomipramine; Trimipramine.
o Amitriptyline; Nortriptyline; Butriptiline.
o Doxepin; Protriptyline.
 Mechanisms of action:

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 o block the reuptake of noradrenaline and serotonin;
o block muscarinic receptors;
 Pharmacokinetics: these drugs are highly lipophilic; prsent hepatic
first-pass effect; strong binding to plasma proteins; the volume of
distribution is high; metabolism by hydroxylation and then by
glucuronoconjugatoin, demethylation; desipramine and nortriptyline are
metabolized to active substances.
 Adverse effects:
o antimuscarinic effects;
o sedation / insomnia;
o negative inotropic effect (prolongaton of PR and QRS on ECG),
conduction disorders, arrhythmias;
o orthostatic arterial hypotension;
o tremors, convulsions;
o endocrine effects: weight gain, disorders of sexual function.
 Contraindications:
o ischemic heart disease, congestive heart failure;
o hyperthyroidism;
o antimuscarinic contraindications.

 HETEROCYCLIC ANTIDEPRESSANTS (second and third

generation)
 Classification
o Non selective (block noradrenaline and serotonine reuptake):

 With cholinergic effects: Maprotiline, Amoxapine,

Nomifensine
 Without cholinergic effects: Venlafaxine, Bupropione
o Antagonsts on 5-HT2A/5-HT2C receptors: Trazodone,
Nefazodone, Mirtazapine
 Mechanisms of action:
o Heterocyclic Antidepressants with antimuscarinic effects:
 block the reuptake of noradrenaline and serotonin;
 block muscarinic receptors;
 amoxapine also determines the blocking of dopamine

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 receptors and block the reuptake of dopamine;
 maprotiline selective block the reuptake of noradrenaline;
o Heterocyclic Antidepressants without antimuscarinic effects:
 venlafaxine block the reuptake of serotonin,
norepinephrine and low block of the reuptake of
dopamine;
 bupropion block the reuptake of serotonin,
norepinephrine;
 antagonists on receptor 5-HT2A / 5-HT2C.
 Pharmacokinetics is similar to that of tricyclic antidepressants.
 Adverse effects:
o antimuscarinic effects for Heterocyclic Antidepressants with
antimuscarinic effects:
o venlafaxine: nausea, drowsiness, sweating, sexual dysfunction,
hypertension, anxiety;
o bupropion: dizziness, dry mouth, sweating, tremors, convulsions;
o receptor antagonists 5-HT2A / 5-HT2C: sleepiness / insomnia,
dizziness, nausea, psychomotor agitation;
o mirtazapine: drowsiness, increased appetite, weight gain,
dizziness.

 SELECTIVE INHIBITORS OF SEROTONIN REUPTAKE

INHIBITORS (SSRIs): Fluoxetine, Sertraline, Paroxetine, Fluvoxamine,
Citalopram, Escitalopram
 Mechanisms of action: selective blockade of serotonin reuptake.
 Pharmacokinetics: these drugs are enzyme inhibitors of hepatic
metabolism of drugs. Paroxetine and Sertraline have short t1/2,
Fluoxetine has an active metabolite, and t1/2 is 7 - 9 days.
 Adverse effects:
o gastrointestinal symptoms; decreased libido; acute anxiety;
insomnia; tremors;
o association of selective inhibitors of serotonin reuptake with
MAOIs can determine serotoninergic syndrome (hyperthermia,
muscle rigidity, myoclonus, rapid changes in the mental state ±
vital signs).

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 MAO inhibitors
 Classification
o Non selective: - Hydrazines: Phenelzine, Isocarboxazid
- Nonhydrazines: Tranylcypromine,
Dextroamphetamine
o Isoenzyme MAOA selective: Moclobemide, Brofaromine,
Toloxatone
 Mechanisms of action:
o non-selective MAO → inhibition of both MAOA and MAOB;
o selective MAOA → selective inhibition of MAOA.
 Pharmacokinetics: rapid absorption; metabolism by acetylation (there
are rapid acetylators / intermediate acetylators / slow acetylators);
determine the accumulation of tyramine and the decrease in hepatic
first-pass effect → hypertension in case of consumption of foods
containing tyramine. The pharmacodynamic effect persists 7 days after
the last dose of tranylcypromine and 2-3 weeks after the last dose of
phenelzine.
 Adverse effects: sleep disorders; weight gain; orthostatic arterial
hypotension; Phenelzine → sexual disorders.
 Contraindications: arterial hypertension; tachyarrhythmias.

4. ANXIOLYTIC DRUGS
- Benzodiazepines
- Antidepressant drugs
- Anxiolytic drugs without sedative effects (Serotonin receptor 5HT1A
agonists: Buspirone, Ipsapirone, Gepirone, Tandospirone)
- ß-blocking drugs

5. PSYCHOMOTOR STIMULANTS: Methylxanthines (Caffeine),

Amphetamine, Cocaine

6. RESPIRATORY STIMULANTS: Doxapram

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  Indications:
o lung disease (including respiratory failure, accompanied of
hypoxemia and hypercapnia);
o resuscitation after general anesthesia.
 Adverse effects: cough, nausea, vomiting, agitation, hypertension,
tachycardia, arrhythmias, headache, sensation of heat, sweating, tremor,
muscle hypertonia, clonic convulsions.
 Contraindications:
o epilepsy;
o bronchial asthma;
o recent stroke.

7. NOOTROPE DRUGS: Meclofenoxat, Meclosulfonat, Piracetam, Piritinol,

Gingko Biloba, Lecitine
 Mechanisms of action: increase glucose metabolism promoting the use
of glucose by neurons.
 Indications:
o sequelae after stroke, post-traumatic syndromes;
o precoma, coma;
o behavior disorders in epileptics;
o encephalopathies, dizziness;
o neuropsychiatric disorders in chronic alcoholism;
o delay in the psychic development in children.
 Adverse effects:
o Piracetam: at the beginning of treatment → agitation, anxiety;
for people with mental illness → aggressiveness, agitation; for
people with epilepsy → decrease seizure threshold;
o pyritinol: irritability, anxiety, insomnia, headache, "burns"
epigastric; nausea, rash (blistering rashes in people with
rheumatoid arthritis → interruption of treatment); rarely,
agranulocytosis, proteinuria.
 Contraindications nootropics: epilepsy and renal failure.

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8. NON-SELECTIVE AND SELECTIVE ß-BLOCKING DRUGS USED
IN PSYCHIATRY AND NEUROLOGY: Propranolol, Oxprenolol, Sotalol,
Metoprolol.

9. IMMUNOMODULATOR DRUGS USED IN SCHIZOPHRENIA:

Levamisole.

2. Drugs of abuse inducing euforia and

psychotomimetics

1. Drugs of abuse inducing euforia

1.1. CNS depressants: opioids (natural or synthetic sources), benzodiazepines,
barbiturates, ethanol and other structures (Meprobamate, Glutethimide,
Methyprilon, Methaqualone, Chloral hydrate, Paraldehyde)
1.2. CNS stimulants: Caffeine, Nicotine, Amphetamines, Cocaine
1.3. Inhalants: inhalatory general anesthetics (nitrous oxide, ether,
chlorophorm), industrial solvents (gasoline, toluene, benzene,
trichloroethylene), aerosol propellants.
2. Psychotomimetics (Hallucinogens, Psychodysleptics)
2.1. Lysergic acid diethylamide (LSD) and related compounds
(Dimethyltriptamine, Diethyltriptamine, Dipropiltriptamine, Para-clor-
phenylalanine)
2.2. Mescaline and related compounds (Methylenedioximetamphetamine =
MDMA = “Ecstasy”)
2.3. Psilocybin and related compounds
2.4. Phencyclidine (PCP)
2.5. Cannabinoids: Marijuana, Hashis, tetrahydrocannabinol (THC)
2.6. Anticholinergic hallucinogens (natural or synthetic sources).

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 Lecture 19
Learning Objectives:
 Describe aspects of absorption, distribution, metabolism and excretion of a
drug;
 List the principal routes of drug administration and their advantages and
disadvantages;
 List examples of drugs concentrated in different tissues or liquids of the body;
 Name the phases in hepatic metabolism;
 Explain concept and significance of steady state concentration.

1.Skeletal muscle relaxants

Skeletal muscle relaxants are pharmacologically active substances which

determine the relaxation of skeletal muscles. These drugs are used for skeletal
muscle paralysis required for surgical procedures (e.g., neuromuscular
blockers), to reduce muscle spasms or to reduce spasticity53 in neurologic
diseases (e.g., spasmolytic).

Classification of skeletal muscle relaxants based on the site of action

(skeletal muscle, neuromuscular end plate or CNS):
1. Directly acting skeletal muscle relaxants: Dantrolene;
2. Neuromuscular blockers (antagonists of Nm receptors or curare-like
substances)
2.1. nondepolarizing neuromuscular blocking drugs:
- long acting: - isoquinoline derivatives: D-tubocurarine, Doxacurium,
Metocurine;
- steroid derivatives: Pancuronium, Pipecuronium;
- other structure: Gallamine;
- intermediate acting: - isoquinoline derivatives: Atracurium, Cisatracurium;
- steroid derivatives: Rocuronium, Vecuronium;
- short acting: Mivacurium;
2.2. depolarizing neuromuscular blocking drugs:

53
Spasticity is a form of muscular hypertonicity with increased resistance to stretch (increase of tonicity in
the flexor muscles of the arms or the extensors of the legs together with muscle weakness), associated with
cerebral palsy, multiple sclerosis or stroke.

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- ultrashort acting: Succinylcholine.
3. Centrally acting skeletal muscle relaxants
3.1. GABAA receptor agonists (agonists on benzodiazepine BZD1 and BZD2
receptors): Diazepam, Clonazepam;
3.2. GABAB receptor agonist: Baclofen;
3.3. GABAA and GABAB receptor agonists: Glycine, Progabide;
3.4. Inhibitor of glutamatergic transmiters: Riluzole;
3.5. Agonists on α2 presynaptic receptors: Tizanidine, Dexmedetomidine;
3.6. Antimuscarinic drugs: Chlorzoxazone, Cyclobenzaprine, Carisoprodol,
Metaxolone, Methocarbamol, Orphenadrine, Chlorphenesin, Mephenesin;
3.7. Inhibitor of release of acetylcholine: Botulinum toxin;
3.8. Other skeletal muscle relaxants: Gabapentin, Progabalin, Idrocilamide.

1. DIRECTLY ACTING SKELETAL MUSCLE RELAXANTS:

DANTROLENE
Mechanism of action: blocks ryanodine receptors54 from the calcium channels
of sarcoplasmic reticulum in the skeletal muscle fibers, which inhibits the
release of calcium from the sarcoplasmic reticulum of skeletal muscle.
Pharmacodynamic effects: inhibition of calcium release in sarcoplasmic
reticulum interfere with excitation-contraction coupling in the muscle fibers, so
that it determines skeletal muscle relaxation.
Pharmacokinetics: administration oral or intravenous (in case of emergency).
Indications:
 spasticity (the spasticity is an adaptation to pyramidal tract injury in
diseases such as hemiplegia, multiple sclerosis etc.).
 malignant hyperthermia (the syndrome is due to a genetic defect in the
sequestration of calcium in the sarcoplasmic reticulum and it is
characterized by generalized skeletal muscle contracture, rigidity, severe
hyperthermia resulting from skeletal muscle contraction which produce
heat, accelerated muscle metabolism, endogenous accumulation of lactic
acid metabolic acidosis, and tachycardia).
Adverse effects:
 hepatitis (abnormal liver function tests in chronic administration): 1-
10% of cases are lethal after 60 days of treatment);
54
Ryanodine receptors mediate the release of calcium ions from the sarcoplasmic reticulum, an essential step in skeletal
muscle contraction.

377
  generalized muscle weakness and fatigue;
 Sedation.

2. NEUROMUSCULAR BLOCKERS (curare-like substances)

The mechanisms of action, pharmacodynamic effects, pharmacokinetics,
indications, contraindications, Adverse effects: → See chapter on the
pharmacology of autonomic nervous system (curare-like substances).

3. CENTRALLY ACTING SKELETAL MUSCLE RELAXANTS

3.1. GABAA receptor agonists (agonists on benzodiazepine BZD1 and BZD2
receptors): DIAZEPAM, CLONAZEPAM → See chapter on the
benzodiazepines.
Mechanism of action: agonist on GABA-A receptors;
Particularly, benzodiazepines cause relaxation of skeletal muscles flexors
(Clonazepam → in non sedative doses).
Indications: reduce muscle spasms.
3.2. GABAB receptor agonist: BACLOFEN
It is an analog of GABA.
Mechanisms of action:
 agonist on GABAB receptors;
 inhibition of the release of substance P → analgesic effect.
Pharmacodynamic effects:
 skeletal muscle relaxation;
 analgesia.
Indications: spasticity in diseases with lesions of the pyramidal tract
(hemiplegia, paresis, multiple sclerosis etc.).
Adverse effects:
 muscular hypotonia;
 rarely, sedative effect; increase the frequency of seizures in patients with
epilepsy; in intrathecal administration → fever, drowsiness, respiratory
depression, tolerance (after several months of therapy).
3.3. GABAA and GABAB receptor agonists: GLYCINE, PROGABID
Mechanisms of action: agonist on GABAA and GABAB receptors;
Indications: reduce spasticity of the skeletal muscles.

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3.7. INHIBITOR OF GLUTAMATERGIC TRANSMITERS: RILUZOLE
Mechanism of action: inhibition of glutamatergic transmission.
Pharmacodynamic effects: reduce spasticity of the skeletal muscles.
Indications: amyotrophic lateral sclerosis (drug of choice).
3.5. AGONISTS ON ALPHA2 PRESYNAPTIC RECEPTORS:
TIZANIDINE, DEXMEDETOMIDINE - See chapter on medication acting
on vegetative system.
Mechanism of action: inhibition of presynaptic a2 adrenergic receptors from
spinal motor neurons
Indications: reduce spasticity of the skeletal muscles.
Adverse effects: hepatotoxicity (Tizanidine).
3.6. ANTIMUSCARINIC DRUGS: CHLORZOXAZONE,
CYCLOBENZAPRINE, CHLORPHENESIN, MEPHENESIN,
METAXOLONE, METHOCARBAMOL, ORPHENADRINE,
CARISOPRODOL - See chapter on medication acting on vegetative system.
Mechanism of action: inhibition of cholinergic receptors from spinal motor
neurons
Indications: reduce muscle spasms.
Adverse effects: increase liver transaminases (Chlorzoxazone, Metaxalone),
hematologic abnormalities and tachycardia (Orphenadrine), transient neurologic
changes (Carisoprodol).
3.7. INHIBITOR OF RELEASE OF ACETYLCHOLINE: BOTULINUM
TOXIN - See chapter on medication acting on vegetative system.
Mechanism of action: inhibition of the release of acetylcholine from nerve
endings
Indications: reduce spasticity of the skeletal muscles.
3.8. OTHER SKELETAL MUSCLE RELAXANTS: GABAPENTIN,
PROGABALIN, IDROCILAMIDE.
 Gabapentin and Pregabalin are antiepileptic drugs with skeletal muscle
relaxant effect, indicated for the treatment of spasticity;
 Idrocilamide is indicated in amyotrophic lateral sclerosis.

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 2. Pharmacologic management of parkinsonism

Classification of drugs indicated for the treatment of Parkinson's disease

(anti-Parkinson drugs)
1. Drugs affecting brain dopaminergic system
1.1. Dopamine precursor: Levodopa (L-Dopa)
associated or not with:
- inhibitors of peripheral decarboxylase: Carbidopa, Benserazide
- inhibitors of type B monoaminooxidase (MAOB): Selegilline,
Rasagiline, Lazabemide, Mofegiline
- inhibitors of cathecolortomethyltransferase (COMT):
Entacapone, Tolcapone, Nitecapone
1.2. Dopamine agonists:
- Ergopeptine: Bromocriptine, Lisuride, Pergolide, Cabergoline
- Non-ergopeptine: Piribedil; Ropinirole; Apomorphine; Pramipexole;
Talipexole.
1.3. Drugs facilitating dopamine transmition: Amantadine, amphetamines
2. Drugs affecting cholinergic system
2.1. Antimuscarinic drugs:
- Centrally and peripherally acting: Natural: Atropine, Scopolamine,
synthetic derivative: Benztropine
- Centrally acting: Trihexyphenidyl, Orphenadrine, Biperiden,
Procyclidine
2.2. 1st generation H1 receptor antagonists: Diphenhydramine
4. Other drug therapies: Vitamin E, neurotrophic factors.
ANTIPARKINSONIAN DRUGS AFFECTING BRAIN DOPAMINERGIC
SYSTEM
1. SUBSTITUTION OF THE DOPAMINE DEFICIENCY
 LEVODOPA
Mechanisms of action:
 Levodopa enters the CNS where it enters in the nerve endings of
nigrostriatal neurons (functional neurons), where it is converted into
dopamine, which acts as an agonist of dopamine receptors.
Pharmacodynamic effects (Levodopa determine these effects in patients with
Parkinson's disease. Levodopa does not affect muscle tone or motility in healthy

380
man):
 improvement of akinesia, bradykinesia;
 improve the muscle stiffness;
 improvement of motor function (the facial expression, speech, writing,
reading etc).
 improve the mental functions;
 remove the apathy, depression;
 it renews the interest of patients for themselves and for the environment.
Pharmacokinetics:
 Levodopa crosses the blood-brain barrier; dopamine does not cross the
blood-brain barrier;
 approximately 95% of the administered L-Dopa is decarboxylated and
converted to dopamine in periphery → only 1% of the administered
dose enters the brain → it is needed association with inhibitors of
enzymes involved in the metabolism of dopamine.
Adverse effects:
 early onset adverse effects:
o anorexia, nausea, vomiting → nausea and vomiting are treated
with domperidone (peripheral D2 receptor antagonist), which
does not cross the blood-brain barrier;
o orthostatic hypotension → treated with midodrine (a α1
adrenergic stimulant), which does not cross the blood-brain
barrier;
o transient tachyarrhythmias → treated with β1-blockers;
o hypertension → occurs in the presence of MAOI, in patients
treated with sympathomimetics or in patients with Parkinson's
disease treated with high doses of Levodopa;
o taste changes.
 late onset adverse effects:
o after 3-4 months of treatment → abnormal involuntary
movements (in 80% of patients after one year of treatment);
o fluctuations of effect → "on - off effect";
o neurovegetative dystonia;
o psychiatric disturbances (hallucinations, nightmares, delirium,
mania, depression);

381
 o insomnia;
o sexual excitation (due to the action on the diencephalic region).
 Sudden interruption of the administration of Levodopa → withdrawal
syndrome which is equivalent to the neuroleptic malignant syndrome:
o Initial: muscle rigidity, high fever, leukocytosis (the lattest two
effects require a differential diagnosis with infectious diseases);
o Late: autonomic nervous system instability with changes in
blood pressure and pulse rate, increase in creatine kinase
(reflecting muscle damage).
 INHIBITORS OF PERIPHERAL DECARBOXYLASE (DDC
INHIBITOR): BENSERAZIDE, CARBIDOPA
Mechanisms of action: inhibition of dopa decarboxylase in periphery.
Pharmacokinetics: do not cross the blood-brain barrier → these drugs
determine efficient concentration of L-Dopa in the brain.
Indications: association to L-Dopa treatment.
 INHIBITORS OF TYPE B MONOAMINOOXIDASE (MAOB):
SELEGILINE, RASAGILINE, LAZABEMIDE, MOFEGILINE
Mechanisms of action: inhibition of MAOB.
Pharmacodynamic effects: MAOB effectively prolong the duration of action of
L-Dopa. The advantage of MAOB → do not determine hypertensive accidents
when administered with foods containing tyramine.
Pharmacological characteristics of Selegiline
 Pharmacokinetics → the drug rapidly crosses the blood-brain barrier,
t1/2 = 40 h, but the therapeutic effect is being extended in relation to the
"turnover" of MAO.
 Pharmacodynamic effects → determines a reduced antiparkinsonian
effect and effectively prolongs the duration of action of L-Dopa;
 Contraindications → association with antidepressants inhibiting
serotonin reuptake, because the association may determine the serotonin
syndrome.
 Some studies indicate a high risk of mortality after administration of
selegiline.
 INHIBITORS OF CATECHOL-O-METHYLTRANSFERASE
(ICOMT): TOLCAPONE, NITECAPONE, ENTACAPONE
Mechanisms of action: inhibition of catechol-O-methyltransferase.

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  Entacapone and nitecapone act exclusively at the peripheral level (at the
COMT from digestive tract, liver, and plasma);
 Tolcapone is the only ICOMT that crosses the blood-brain barrier → the
drug also determines the inhibition of peripheral and central COMT.
Pharmacokinetics:
 increase the bioavailability of L-Dopa;
 T1/2 of elimination increases without increasing plasma concentration;
 highly bound on plasma proteins; metabolism in the liver by
glucuronidation;
Indications → reduce the symptoms of "on - off effect" of Levodopa.
Adverse effects: similar to those caused by L-Dopa (nausea, orthostatic
hypotension, dyskinesias);
 other Adverse effects: diarrhea, abdominal pain, discoloration of urine.
2. DOPAMINE AGONISTS
Mechanisms of action:
 ERGOPEPTINES
o Bromocriptine → agonist on D2 receptor and antagonist on
α=D1=5-HT2;
o Pergolide → agonist on D2 = D1 receptor;
o Lisuride → agonist on D2 receptor, partial agonist on D1,
interfere with 5-HT2 receptors;
o Cabergoline → agonist on D2 receptor;
 NON ERGOPEPTINES:
o Piribedil → agonist on D2 receptor and low agonist on D3 = D1
receptors;
o Ropinirole → agonist on D2 = D3 = D4 receptors;
o ApoMorphine → agonist on D2 = D3 = D4 receptors;
o Talipexole → agonist on D2 = D3 = D4 receptors;
o Pramipexole → agonist on D2 = D3 = D4 receptors.
The benefits of dopamine agonists:
 stimulation of dopamine receptors is more stable compared to the L-
Dopa;
 there is a good relationship between dose and effect;
 reduce the severity of "off" periods.
Contraindications of agonists on dopamine receptors:

383
  psychoses;
 glaucoma;
 breastfeeding;
 melanoma and other pigmented skin lesions;
 pseudoparkinsonism caused by neuroleptics;
 pregnancy;
 cardiovascular disease;
 peptic ulcer;
 liver failure;
 kidney failure.
Adverse effects of agonists of dopamine receptors:
 psychiatric disorders (hallucinations, nightmares, delirium, mania,
depression);
 "dopaminergic psychosis" (hallucinations, particularly visual
hallucinations), due to the excessive stimulation of mesolimbic
dopamine receptors, these effects are also caused by interfering with
serotonergic transmission.
Particularities of some dopamine agonists
 BROMOCRIPTINE Adverse effects:
 hallucinations;
 hypotension;
 circulatory disorders induced by cold;
 rarely dyskinesias.
 Lisuride, Terguride determine less frequently tardive dyskinesia.
 Pergolide Adverse effects: → induce "on - off effect".
 Cabergoline determine a very stable dopaminergic stimulation.

ANTIPARKINSONIAN DRUGS AFFECTING CHOLINERGIC

SYSTEM
1. ANTIMUSCARINIC DRUGS improve salivation.
Indications:
 adjuvant treatment of Parkinson's disease;
 the centrally acting anticholinergic drugs are the only effective treatment
of pseudoparkinsonism.
The mechanisms of action, pharmacodynamic effects, pharmacokinetics,
384
indications, cons-indications, Adverse effects: → See in the chapter on the
pharmacology of SNV.
The central anticholinergic drugs may determine the onset of "dopaminergic
psychosis" (particularly visual hallucinations).
2. 1ST GENERATION H1 RECEPTOR ANTAGONISTS
The mechanisms of action, pharmacodynamic effects, pharmacokinetics,
indications, contra-indications, Adverse effects: → See in the chapter of
autacoids.
3. The treatment of tremor and other movement disorders
Tremor consists of a rhythmic oscillatory movement around a joint. Types of
tremor:
 postural tremor occurs during maintenance of sustained posture
 intention tremor occur during movement.
1. Treatment of postural tremor (physiological): Propranolol
2. Treatment of essential tremor: Propranolol, Metoprolol
3. Other treatments:
 anticonvulsants → Primidone;
 small amounts of alcohol;
 benzodiazepines:
o 1,4 – benzodiazepines: Diazepam, Chlordiazepoxide;
o Triazolobenzodiazepines: Alprazolam.
3. Treating intention tremor → blockers semi-selective β1 = β2 receptors -
adrenergic blockers and selective β1 receptor - adrenergic as adjuvant therapy
in chronic alcoholism.
C. Treatment of Huntington's disease (the treatment of dyskinesia):
 Sympatholytic with central and peripheral action: Reserpine
 Antipsychotics butyrophenone derivatives: Haloperidol
D. The treatment of athetosis and dystonia: Diazepam, Amantadine,
antimuscarinics, Levodopa, Carbamazepine, Baclofen, Haloperidol,
phenothiazine derivatives.
E. The treatment of Wilson's diseas: D-penicillamine, Trientine
F. The treatment of tics55: Haloperidol, Fluphenazine, Clonazepam, Clonidine,
Carbamazepine.

55
Tic is a sudden, repetitive, stereotyped, nonrhythmic movement (motor tic) or sound (phonic tic) involving discrete
muscle groups.

385
 Lecture 20
Analgesics, antipyretic and antiiflammatory
drugs

Learning Objectives:
 Describe aspects of absorption, distribution, metabolism and excretion of a
drug;
 List the principal routes of drug administration and their advantages and
disadvantages;
 List examples of drugs concentrated in different tissues or liquids of the body;
 Name the phases in hepatic metabolism;
 List the principal routes of drug elimination;
 Explain concept and significance of pharmacokinetic parameters
 Explain concept and significance of steady state concentration.

1. Nonsteroidal antiinflammatory drugs (NSAIDS)

Classification
 Salycilate derivatives:
o Acethylsalycilic acid
o Other salycilates: Diflunisal, Sodium salycilate
 Propionic acid derivatives: Ibuprofen, Ketoprofen, Naproxen,
Fenoprofen, Pirprofen, Carprofen, Oxaprozin, Tiaprofen;
 Phenylalkanoic acid derivatives: Flurbiprofen
 Acetic acid derivatives: Etodolac;
 Phenyl acetic acid derivatives: Diclofenac;
 Pirolacetic acid derivatives: Tolmetin;
 Sulfoxides: Sulindac;
 Indol derivatives: Indomethacin;
 Ketones: Nabumetone;
 Pirazolone derivatives: Phenylbutazone, OxiPhenylbutazone,
Azapropazone;
 Oxicams: Piroxicam, Ampiroxicam, Meloxicam, Tenoxicam, Droxicam;

386
  Fenamates: Mefenamic acid, Meclofenamate, Flufenamic acid,
Tolfenamic acid, Niflumicacid;
 Other structures: Pirfenidone; Tenidap; Nimesulid; COX-2 inhibitors
(Celecoxib, Parecoxib, Valdecoxib, Etoricoxib).

SALICYLATE DERIVATIVES: ACETYLSALICYLIC ACID

Molecular mechanisms of action
 Anti-inflammatory:
 prostaglandin-mediated mechanisms:
o irreversibly inhibition of COX-1, COX-2 and COX-3;
o competitive antagonist of receptors for PGE1 and PGF2alfa;
 non-prostaglandin mechanisms:
o inhibits migration of neutrophils and macrophages into
inflammatory site;
o inhibit the adhesion of PMN to endothelial cells and between
them;
o inhibits the synthesis and release of oxygen free-radicals (in
particular, superoxide anion) from the PMN;
o inhibit the proteolytic enzymes from the monocytes;
o inhibits the activation of lysosomes and the release of lysosomal
enzymes from the monocytes;
o inhibits the synthesis of collagenases from the monocytes;
o inhibits the synthesis and the release of osteoclast activating
factor;
o inhibits the rheumatoid factor;
o inhibits the kinins;
o inhibits the synthesis of mucopolysaccharides, of proteoglycans
and of glycosaminoglycans;
o inhibits the release of proinflammatory cytokines from synovial
cells;
o stimulates suppressor T lymphocytes.
 Antipyretic:
o central mechanism:
 inhibit COX in the CNS;
 inhibits the synthesis and the release of IL-1 from the

387
 hypothalamus;
o peripheral mechanism:
 vasodilation and sweating which causes heat loss;
 decreases the sensitivity of peripheral receptor for IL-1.
 Analgesic:
o central mechanism: inhibition of subcortical centers of pain;
o peripheral mechanism: pain decreases due to the inflammatory
effect.
 antiplatelet effect:
o inhibit thromboxane synthase (this will inhibit the release of
thromboxane A2) – this effect occurs only at low doses (80-325
mg/day); when the dose increases, the effect is lost; the effect
duration is 5-7 days after the last dose.
Pharmacokinetics
 Absorption is good after oral administration (salicylates are absorbed
from the gastric and duodeno-jejunal mucosa).
 T1/2 is short (15 min) because it is rapidly metabolised by plasma and
tissue esterases resulting acetate and salicylate. Salicylate is the active
metabolite (it has long t1/2), which is metabolized by conjugation and
eliminated unchanged or by renal tubular secretion. Salicylate kinetics is
saturable, readily crosses the physiological barriers (including the
blood-brain barrier and the placenta), it is concentrated into the synovial
liquid.
Indications: - antiplatelet (at doses between 70-80mg/zi and 325mg/zi);
- analgesic;
- antipyretic;
- inflammatory;
- other indications for doses with antiplatelet effect: to slow
cataract development, to reduces the frequency of colon cancer.
Contraindications:
 peptic ulcer;
 young children with viral febrile illness (viral respiratory infections,
measles, chickenpox);
 asthma and other allergies;
 pregnancy, lactation;

388
  severe renal impairment, hepatic impairment;
 haemophilia A;
 endogenous psychoses.
Adverse and toxic effects
 Gastrointestinal (also for doses with antiplatelet effect) from superficial
ulceration and microbleeds, to perforation of the digestive mucosa.
 Liver: acute liver failure (Reye syndrome) in young children with febrile
viral infections, hepatitis in patients with asymptomatic chronic
autoimmune disease (lupus, rheumatoid arthritis).
 Renal: retention of water and NaCl, interstitial tubulopathy.
 Bronchitis: bronchoconstriction (only in people with asthma).
 Hematologic:
o toxic dose: anticoagulant effect (toxic doses inhibit coagulation
factors in the liver);
o those with collagen: autoimmune hemolytic anemia.
 Cardiovascular: toxic dose determine vasodilation (hypotension) and
myocardial depression.
 CNS
o low doses: discrete euphoric effect;
o high doses: stimulate the respiratory center (hypercapnie),
salicylism (deafness, tinnitus, vertigo);
o Toxic dose: inhibition of the respiratory center (causes metabolic
acidosis), hyperthermia, hallucinations, delirium, coma.
 immunosuppression on the cellular components (suppressor T
lymphocytes are stimulated).
 immunological reactions type I and type III.
 worsening of articular cartilage lesions.
 Other effects:
o inhibition of respiratory enzymes tissue, inhibition of ATP-
dependent reaction (produc uncoupling of oxidative
phosphorylation);
o at doses ≤ 2 g / day increase uricemia;
o at ≥ 4 g / day decrease uricemia.
Interactions
o Do not associate acetylsalicylic acid:

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 o in antiplatelet doses with nitrite/nitrate because increase the risk
of bleeding (can be done under the supervision of cardiologist);
o with other NSAIDs, uricosuric drugs (probenecid,
sulfinpyrazone), phenytoin, methotrexate, oral antidiabetic
because they increase plasma concentrations of acetylsalicylic
acid due to displacement from plasma proteins;
o Glucocorticosteroids lowers plasma levels of salicylates;
o Acetylsalicylic acid decrease the diuretic and natriuretic effects of loop
diuretics (decrease also Furosemide antihypertensive effect), reduces the
pharmacological activity of Spironolactone;
o Acetazolamide increase the elimination of salicylates;
o Acetylsalicylic acid competes with Penicillin G for renal tubular
secretion mechanism;
o Ammonium chloride decreases the clearance of salicylates;
o Alcohol aggravates gastrointestinal bleeding caused by salicylates.
OTHER SALICYLATE DERIVATIVES: COLINSALICILAT SODIUM,
SODIUM SALICYLATE, MAGNESIUM SALICYLATE, SODIUM
TIOSALICILAT, SALICILSALICILIC ACID (SALSALATE),
DIFLUNISAL
Mechanism of action: inhibition of COX-1 and COX-2.
Pharmacodynamic effects: weak anti-inflammatory, analgesic and antipyretic
effects of moderate, compared with aspirin.
Advantages: less focus in the synovium, articular cartilage harm less can be
administered to individuals with haematological, renal, bronchial.
Indications: chronic rheumatic inflammatory diseases (rheumatoid arthritis,
osteoarthritis etc.), analgesic (biliary colic, dysmenorrhea etc).
Adverse effects and Contraindications: similar to acetylsalicylic acid.
DIFLUNISAL:
 antipyretic effect is weak than aspirin;
 action is longer; it is less gastric irritative than acetylsalicylic acid; it
forms salicylate and acetate by metabolism.
PROPIONIC ACID DERIVATIVES: IBUPROFEN, KETOPROFEN,
NAPROXEN, FENOPROFEN, PIRPROFEN, CARPROFEN,
OXAPROZIN, TIAPROFEN
Mechanism of action: inhibition of COX-1 and COX-2.
Ketoprofen inhibits also lipoxygenase and leukotriene B4 synthesis.
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Pharmacodynamic effects:
 antiinflammatory effect (medium intensity);
 analgesic (Pirprofen has the strongest analgesic effect from these
derivatives);
 antipyretic effect (medium intensity compared with acetylsalicylic acid);
 antiplatelet effect (independent of dose).
Pharmacokinetics: rapid absorption, t1/2 short (except: Ketoprofen, Naproxen,
Oxaprozin, Carprofen). Ketoprofen is bound on plasma proteins (99%), but
does not interfere with the plasma transport of coumarin oral anticoagulant or
cardiac glycosides.
Indications:
 inflammatory diseases: chronic rheumatic diseases (rheumatoid arthritis,
osteoarthritis etc.), ENT diseases, dentistry, gynecology etc.;
 analgesic in dysmenorrhea, postoperatory, biliary colic etc.
 other Indications:
o Ibuprofen: migraine, antipyretic and analgesic in children;
o Ketoprofen, Naproxen: acute gout; Oxaprozin: chronic therapy
of gout;
o Pirprofen: analgesic in cancer (advantage: does not cause
addiction, does not cause constipation).
Contraindications: peptic ulcer, hemophilia, severe renal failure, hepatic
failure, heart failure, severe hypertension, acute myocardial infarction, asthma
(except ketoprofen), pregnancy, lactation, children (except Ibuprofen).
Adverse effects:
 CNS: tinnitus, hearing loss, vertigo, headache; asymptomatic meningitis
in patients with lupus;
 lower gastrointestinal events compared with aspirin: irritation of the
mucosa, ulceration, bleeding;
 retention of water and NaCl;
 other: medulotoxicity (aplastic anemia, granulocytopenia,
agranulocytosis), nephrotoxicity (interstitial nephritis, nephrotic
syndrome, acute renal failure), hepatotoxicity, immunological reactions
type I, II, III.
Interaction: Ketoprofen is the only NSAID that can be administered to patients
receiving coumarin oral anticoagulants or digitalis.

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FENILALCANOIC ACID DERIVATIVES: FLURBIPROFEN
Mechanism of action: inhibition of COX-1 = COX-2;
Pharmacodynamic effects: moderate anti-inflammatory and analgesic effects,
mild antipyretic effect compared to aspirin.
Pharmacokinetics: enterohepatic circulation, concentrates well in the synovial
liquid.
Indications:
 chronic rheumatic inflammatory diseases (rheumatoid arthritis,
osteoarthritis, ankylosing ankilopoetică, juvenile arthritis etc.);
 analgesic in biliary colic, dysmenorrhea, migraine, surgery etc.
 intraoperatively topic in ophthalmology (to prevent myositis).
Adverse effects: reduced frequency of gastrointestinal symptoms (15-20% of
patients treated po), granulocytopenia, autoimmune haemolytic anemia.
ACETIC ACID DERIVATIVES: ETODOLAC
Mechanism of action: inhibition of COX-1 <COX-2;
Pharmacodynamic effects: anti-inflammatory effect (medium intensity as
compared with aspirin). Advantage: it can greatly reduce acute gastric lesions.
Indications: inflammatory joint diseases (rheumatoid arthritis, osteoarthritis,
ankylosing ankilopoetic etc).
Adverse effects: similar to other NSAIDs; headache, sleepiness / insomnia,
confusion, paraesthesia, tremor, rash.
PHENYLACETIC ACID DERIVATIVES: DICLOFENAC
Mechanism of action: inhibition of COX-1 = COX-2;
Pharmacodynamic effects: strong anti-inflammatory, analgesic.
Advantages: high concentrations in the synovial liquid, cartilage injuries do not
worsen.
Pharmacokinetics: absorption is very good; metabolism is hepatic, present
first-pass effect and enterohepatic circulation; elimination is through kidney
(2/3) and bile (1/3).
Indications:
 inflammatory joint diseases (rheumatoid arthritis, osteoarthritis etc.) and
extraarticular;
 acute gout crisis;
 analgesic in biliary colicative pain, renal surgery, phlebitis,
thrombophlebitis, osteoarticular trauma, dysmenorrhea etc;

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  prophylaxis of myositis in ophthalmology.
Adverse effects:
 gastrointestinal irritation (it is very strong);
 retention of salt and water (it is very strong);
 increase serum transaminases;
 medulotoxic (granulocytopenia) and nephrotoxic – these effects are
weak.
PIROLACETIC ACID DERIVATIVES: TOLMETIN
Mechanism of action: inhibition of COX-1 <COX-2;
Pharmacodynamic effects: anti-inflammatory, analgesic, antipyretic (medium
intensity).
Pharmacokinetics: it present enterohepatic circulation, t1/2 is short.
Advantage: it can greatly reduce acute gastric lesions.
Indications: rheumatoid arthritis, osteoarthritis, ankylosing ankilopoetică,
juvenile arthritis.
Adverse effects: like other NSAIDs; allergic reactions.
SULFOXIDES: SULINDAC
It is a prodrug.
Pharmacokinetics: in the liver it is biotransformed into active metabolite
(sulfide), present enterohepatic circulation.
Indications: - inflammatory joint diseases (rheumatoid arthritis, osteoarthritis
etc.);
- analgesic.
Adverse effects:
 gastrointestinal irritation (ulcers, gastrointestinal bleeding);
 medulotoxicity (aplastic anemia, agranulocytosis);
 nephrotoxicity;
 increase serum transaminases;
 immunological reactions type I and III.
INDOLE DERIVATIVES: INDOMETHACIN
Mechanism of action: inhibition of COX-1 >> COX-2.
Pharmacodynamic effects: strong anti-inflammatory effect, very weak
analgesic effect, medium intensity antipyretic effect.
Pharmacokinetics: very good absorption; elimination through kidneys.
Indications:

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  inflammatory joint diseases (rheumatoid arthritis, osteoarthritis etc.);
 extraarticular inflammatory disorders (pericarditis, pleuritis, pleurisy,
uveitis etc);
 acute gout;
 analgesic in biliary colic, renal surgery, dysmenorrhea etc.
 patent ductus arteriosus in the newborn;
 fever (from Hodgkin's disease, fever refractory to other therapies).
Adverse effects:
 gastrointestinal irritation (it is very strong): abdominal pain, ulcers,
bleeding, diarrhea, hemorrhagic pancreatitis, cholestatic jaundice, acute
toxic hepatitis;
 retention of salt and water (it is very strong);
 CNS: headache, dizziness, mental depression, hallucinations, psychosis,
nightmares, delirium;
 articular cartilage injuries;
 medulotoxicity (aplastic anemia, neutropenia, thrombocytopenia);
 nephrotoxic (it is very strong);
 hyperkalaemia;
 retinal lesions (after chronic administration of high doses);
 immunological reactions type I and III.
KETONES: NABUMETONE
It is a prodrug.
Mechanism of action: inhibition of COX-1 = COX-2.
Pharmacokinetics: the compounds of metabolism are more active than the
parent compound.
Indications: rheumatoid arthritis, osteoarthritis.
Adverse effects: diarrhea, nausea, abdominal pain, headache; rash; increased
serum transaminases.
PYRAZOLONE DERIVATIVES: PHENYLBUTAZONE,
OXIFENILBUTAZONA, AZAPROPAZON
Mechanism of action: inhibition of COX-1> COX-2;
Pharmacodynamic effects: strong anti-inflammatory, analgesic, antipyretic
effects.
Pharmacokinetics: absorption is very good;it is bound to plasma proteins
(>90%); hepatic metabolism to active compounds; elimination through kidney,

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t1/2 long.
Indications: - chronic rheumatic inflammatory diseases (rheumatoid arthritis,
osteoarthritis, ankylosing ankilopoetică etc.);
- thrombophlebitis, thrombosis, muscle pain, frostbite;
- acute gout.
Adverse effects: gastrointestinal irritation (superficial ulcers, gastrointestinal
bleeding) water and salt retention, hepatotoxicity, nephrotoxicity,
medulotoxicity (aplastic anemia, agranulocytosis, granulocytopenia), optic
neuritis, immunological reactions type I and II.
OXICAMS: PIROXICAM, AMPIROXICAM, MELOXICAM,
TENOXICAM, DROXICAM
Mechanism of action: inhibition of COX-1 and COX-2; Piroxicam inhibits
COX-1 >> COX-2; Meloxicam is relatively selective COX-2.
Pharmacodynamic effects: anti-inflammatory and analgesic effects are
stronger.
Pharmacokinetics: absorption is not influenced by food; they are highly bound
to plasma proteins (99%); renal elimination, very long t1/2 (Tenoxicam has the
longest t1/2).
Advantages: high concentrations in the synovial liquid, less articular cartilage
injuries.
Indications: - inflammatory rheumatic joint diseases (rheumatoid arthritis,
osteoarthritis, ankylosing ankilopoetică etc.) and extraarticular
(periarthritis, tendinitis);
- acute gout.
Adverse effects: CNS (headache, vertigo, tinnitus); the gastrointestinal irritation
is uncommon; retention of water and salt; immunological reactions type I and
III.
FENAMATES: MEFENAMIC ACID, MECLOFENAMATE,
FLUFENAMIC ACID, TOLFENAMIC ACID, NIFLUMIC ACID
Mechanism of action: inhibition of COX-1 and COX-2;
Pharmacodynamic effects: strong analgesic effect, weak anti-inflammatory
effect.
Determine severe injuries of:
 articular cartilages (the administration in adults should be for less than 1
week);
 cartilage growth (absolute contraindication for children with less than
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 18 years).
Indications: analgesic in rheumatic diseases, dysmenorrhea, thrombophlebitis,
traumatic pain in ENT, gynecology etc.
Adverse effects:
 meclofenamate, flufenamic acid determine diarrhea;
 mefenamic acid determine diarrhea, rash;
 niflumic acid determine gastrointestinal irritation, prolonged
administration causes impairment in renal and hepatic function,
hematologic disorders.
NIMESULIDE
Mechanism of action: selectively inhibits COX-2, inhibits neutrophil
activation, inactivate oxygen free radicals.
Pharmacokinetics: an active compound is formed by metabolism.
Indications: - articular and extraarticular inflammatory diseases;
- antipyretic;
- analgesic.
Adverse effects: rash, headache, nausea, vomiting, abdominal pain.
SELECTIVE COX-2 INHIBITORS: CELECOXIB, PARECOXIB,
VALDECOXIB, ETORICOXIB
Mechanism of action: selectively inhibits COX-2.
Pharmacodynamic effects: inhibits natriuresis, causes retention of water and
NaCl.
Pharmacokinetics: well absorbed (lipophilic food delays the absorption of
Celecoxib); metabolised in the liver (Parecoxib is transformed into an active
compound: Valdecoxib); renal elimination.
Indications: - inflammatory joint disease (osteoarthritis, rheumatoid arthritis);
- analgesic.
Adverse effects: gastrointestinal effects of low intensity (nausea, diarrhea,
bleeding), edema of lower limbs, hypertension.
Contraindications: renal failure.

2. Analgesic – antipyretic drugs without anti-inflammatory

effect
Classification:
 Pirazolone derivatives: Aminofenasone; Metamizole;

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  Phenacetine and its active metabolite, Acetaminophen;
 Zomepirac.
 Ketorolac.
Mechanism of action: inhibition of COX.
Pharmacodynamic effects: analgesic and antipyretic.
METAMIZOLE (OR DIPYRONE)
Aminofenazone (aminopyrine) is no longer used in therapy. Its derivative,
Metamizole (or Dipyrone) it is used in some countries.
Pharmacodynamic effects of Metamizole: analgesic (very efficient for renal or
biliary colicative pain, dysmenorrhea) and antipyretic.
Adverse effects: allergic reactions, medulotoxicity (aplastic anemia,
granulocytopenia) hepatotoxicity.
ACETAMINOPHEN
Phenacetin is no longer used in therapy. It has powerful analgesic and
antipyretic effect, but no anti-inflammatory effect. It is strongly nephrotoxic.
Pharmacodynamic effects of Acetaminophen: strong analgesic (postpartum in
migraine, dysmenorrhea) and antipyretic.
Pharmacokinetics: Acetaminophen is the active metabolite of phenacetin. It is
metabolized to N-acetyl-p-benzakinone (strong hepato- and nephrotoxic
compound).
Indications: analgesic and antipyretic (it is drug of choice in children with viral
infections).
Adverse effects: hepatotoxicity, haematological (leukopenia, thrombocytopenia,
aplastic anemia, hemolytic anemia in G6PD deficiency), methemoglobinemia.
Acute acetaminophen poisoning: the antidote is N-acetylcysteine.
ZOMEPIRAC
Zomepirac was withdrawn from market in some countries due to its
medulotoxicity.
Pharmacodynamic effects: strong analgesic, moderately antipyretic effect.
KETOROLAC
It is derived from acetic acid.
Pharmacodynamic effects: strong analgesic (preferably postoperative instead
opioids).
Adverse effects: gastrointestinal irritation, nephrotoxicity, abrupt
discontinuation (after 2 weeks of dosing) cause withdrawal effects.

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 3. Disease-modifying antirheumatic drugs
Disease-modifying antirheumatic drugs are drugs that reduce lysosomal
emzyme activity and phagocytosis, which result in reduction of inflammatory
and immune responses.
Classification of disease-modifying antirheumatic drugs (DMARDS):
1. Antimalarial drugs: Chloroquine, Hydroxichloroquine;
2. Gold salts: Sodium aurothiomalate, Aurothioglucose, Auranofin;
3. Penicillamine;
4. Sulfasalazine.
5. Immunosuppressants:
- Cyclosporine;
- alkilating agents: Ciclophosphamide, Chlorambucil;
- purine agonists: Azathioprine, Mercaptopurine;
- antimetabolites: Metothrexate;
- other immunosuppressants: Leflunomide.
- nonselective immunomodulating drugs: Levamisole; Lobenzaride;
6. Biological agents (tumor necrosis factor TNF blocking agents):
- TNF alfa inhibitors: Etanercept (synthetic TNF receptor), Infliximab
(monoclonal antibody), Adalimumab (monoclonal antibody).
- inhibitors of IL-1 receptors: Anakinra;
- inhibitors of IL-6 receptors: Tocilizumab;
- other agents: Abatacept (a soluble fusion protein that consists of the
extracellular domain of human cytotoxic T-lymphocyte-associated
antigen 4 (CTLA-4) linked to the modified Fc (hinge, CH2, and CH3
domains) portion of human immunoglobulin G1 (IgG1)), Rituximab
(anti-CD20 monoclonal antibodies).
Indications: rheumatoid arthritis, juvenile rheumatoid arthritis. These drugs
treat arthritis symptoms, but also can slow down progressive joint distruction.
Some of these medications have been used to treat other conditions, such as
cancer or inflammatory bowel disease, or to reduce the risk of rejection of a
transplanted organ.
Methotrexate is the drug of choice after NSAIDs in rheumatoid arthritis.
Therapeutic effects occurs after: - 1-3 months of treatment for antimalarial
drugs;

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 - 4 months of treatment for organic
compounds with gold;
- 3-4 months for D-penicillamine
treatment.
CHLOROQUINE, HYDROXYCHLOROQUINE
Mechanisms of action:
 stabilize lysosomal membranes by inhibiting lysosomal enzymes;
 block migration of neutrophils and macrophages;
 inhibit the nucleic acid synthesis by inhibiting DNA and RNA
polymerase;
 inhibit phospholipase A2;
 decrease cytokine production by phagocytes.
Indications: - rheumatoid arthritis;
- systemic lupus erythematosus;
- malaria and protozoal infections (against Entamoeba
histolytica)
Adverse effects:
 gastrointestinal symptoms, headache, pruritus, anorexia, clouding
vision, urticaria;
 medulotoxicity (haemolytic anemia in G6PD deficiency);
 CNS symptoms (headache, vertigo, tinnitus, psychosis, convulsions);
 other: skin reactions, alopecia / thinning of hair, hypotension, ECG
changes (changes in T wave, QRS widening).
Contraindications: retinal or visual field changes.

GOLD SALTS: SODIUM AUROTHIOMALATE

AUROTHIOGLUCOSE, AURANOFIN
Mechanisms of action: - stabilize lysosomal membranes by inhibiting
lysosomal enzymes (the compounds are taken up by macrophages and will
suppress phagocytosis and lysosomal enzymes);
- inhibit the formation and release of inflammatory
mediators;
- inhibit the release of oxidizing radicals;
- inactivation of complement;
- Auranofin inhibits PGE2 release from synovial cells.

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They are concentrated into the synovial liquid.
Indications: rheumatoid arthritis, juvenile rheumatoid arthritis.
Adverse effects: skin pigmentation, pancytopenia, nephrotic syndrome,
hepatotoxicity, peripheral neuritis.
Contraindications: association with D-penicillamine, pregnancy, lactation,
severe liver disease, severe kidney disease, porphyria, history of blood
disorders.

D-PENICILLAMINE
It is a metabolite of penicillin.
Mechanisms of action: - chelating agent for gold, copper, mercury, arsenic;
- stabilize lysosomal membranes by inhibiting
lysosomal enzymes;
- inhibit the synthesis of collagen and
mucopolysaccharides;
- inhibit the rheumatoid factor;
- complement inactivation.
Indications: - rheumatoid arthritis unresponsive to treatment with gold
compounds;
- heavy metal poisoning;
- Wilson disease.
Adverse effects: - hematologic: leukopenia, thrombocytopenia, aplastic anemia;
- proteinuria, nephritis;
- autoimmune diseases: myasthenia gravis, lupus, hemolytic
anemia, thyroiditis, Goodpasture's syndrome;
- metallic taste, anorexia, nausea, vomiting;
- alopecia.
Contraindications: pregnancy, lactation, moderate-to-severe kidney disease,
allergy to penicillin.

SULFASALAZINE
It contains a molecule 5-aminosalicylic acid bound to sulfapyridine by a diazo
bond.
Mechanism of action: dose of 2 g/day  in the colon it is split the azo bond
and it is released the active 5- salicylate.
Indications:
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  rheumatoid arthritis, juvenile arthritis, ankylosing ankilopoetică;
 Crohn's disease.
Adverse effects: leukopenia, nausea, vomiting, abdominal discomfort,
headache, inhibit the absorption of folic acid, allergic reactions, severe spinal
marrow depression, neurological or psychiatric disorders.

LEFLUNOMIDE
It is a prodrug (it is rapdly converted to active metabolites).
Mechanisms of action: - relatively selective inhibition of COX-2;
- inhibits the release of inflammatory mediators
(histamine, 5-HETE);
- inhibits T and B lymphocyte proliferation and
antibody response of B cells by blocking dihydro-orotic
dehydrogenase (block pyrimidine synthesis);
- inhibits IL-2 and TGF-alpha;
- inhibit gene expression (granzyme B and perforin)
involved in the rejection of transplanted tissue;
- stimulation of macrophage functions and inhibition
of postreceptor signal transmission biological of IL-4.
Pharmacodynamic effects: immunosuppression, antiinflammatory.
Indications: - rheumatoid arthritis, myasthenia gravis, lupus, autoimmune
nephritis, allergic encephalomyelitis
- prevent acute rejection of allogeneic tissue transplants;
- prevention infestation with Leismania major, with Listeria
monocytogenes.
Adverse effects: increases blood pressure, rash, ulcers, abdominal pain,
diarrhea, increase serum transaminases.
Therapeutic efficiency is equal to or better than cyclophosphamide, adverse
effects are less severe.

LEVAMISOLE
Mechanisms of action:
 promotes differentiation and maturation of T lymphocytes;
 normalizes regulatory functions of T cells;
 stimulates the formation of suppressor T lymphocytes;

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  increases phagocytic activity of macrophages and granulocytes;
 increases circulating immune complexes;
 oxygen free-radical scavenger.
Adverse effects: blood dyscrasias (leukopenia, agranulocytosis,
thrombocytopenia), rash, mucosal ulcers, influenza-like disease, abnormal taste,
nausea, vomiting, reversible immune glomerulonephritis type headache,
dizziness, drowsiness / excitation, hypotension, fever .
Indications:
 rheumatoid arthritis;
 chronic hepatitis (type B, toxic, autoimmune), biliary cirrhosis, chronic
pancreatitis;
 as adjunvant in recent gynecological inflammation, pulmonary
tuberculosis, glomerulonephritis and nephrotic syndrome resistant to
corticosteroids, warts, erosive or ulcerative injuries of the
gastrointestinal tract, oligospermia, Hodgkin's disease, colorectal cancer,
gastrointestinal choriocarcinoma, breast cancer, lung cancer, malignant
melanoma, kidney cancer;
 schizophrenia.
Contraindications: hepatic or renal impairment.
LOBENZARIDE
Mechanisms of action:
 enhances the proliferation and differentiation of helper T cells;
 stimulates NK cell activation;
 stimulates the production of IFN-alpha;
 decreases production of IL-1 in human mast cells;
 increases expression of receptors for the Fc fragment of Ig on human
lymphocytes;
 inhibits T cell proliferation by inhibiting cytokine production by
macrophages.
Indications: rheumatoid arthritis.

4. Drugs used in gout

ACUTE ATTACK OF GOUT:
- Colchicine
- NSAIDs: Indomethacin, Ibuprofen, Ketoprofen, Naproxen,

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Phenylbutazone, Piroxicam, Tenoxicam, Diclofenac
COLCHICINE
Mechanisms of action:
 inhibits tubulin polymerization in macrophages;
 inhibits the movement of macrophages to uric acid crystals (prevents the
phagocytosis of crystals);
 inhibits leukocyte migration into the inflammatory site;
 inhibits release of lysosomal enzymes and proinflammatory mediators;
 inhibits the formation of leukotrienes B4.
Pharmacokinetics: rapid gastrointestinal absorption, wide tissue distribution
(gastro-intestinal mucosa, liver, kidney, intraleucocitar) slow elimination in the
feces (70%) and urine.
Indications: - gout: treatment and prophylaxis of acute crisis (in combination
with uricosurics);
- other indications: amyloidosis, family mediterranean fever.
Adverse effects: - gastrointestinal (diarrhea, nausea, vomiting, abdominal pain);
- rare: blood dyscrasias (leukopenia, neutropenia,
agranulocytosis, aplastic anemia), rash, alopecia, azoospermia,
anovulatory cycles.
Contraindications: severe renal or hepatic impairment, pregnancy, lactation.
LONG-TERM CONTROL OF GOUT
Drugs used for long-term control of gout:
- xanthine-oxidase inhibitors: Allopurinol.
- uricosuric drugs: Probenecid, Oxaprozin, Sulfinpyrazone.
ALLOPURINOL
Mechanism of action: inhibits xanthine oxidase (decrease xanthine and
hypoxanthine oxidation).
Pharmacodynamic effects: decreases uricemia (blood concentrations of uric
acid) and increases elimination of uric acid through urine.
Pharmacokinetics
 rapid gastrointestinal absorption, it is metabolised to an active
compound (aloxantine) with weak action of xanthine oxidase inhibition;
 wide tissue distribution (gastrointestinal mucosa, liver, kidney,
intraleucocitar);
 slow elimination in the feces (70%) and urine.

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Indications: treatment of gout.
Adverse effects: gastrointestinal symptoms (epigastric pain, nausea, diarrhea),
itchy rash, vasculitis, inhibition of hematopoiesis (leukopenia), liver and kidney
damage.
Contraindications: acute gout attacks, pregnancy, lactation, renal or hepatic
impairment.
PROBENECID
Mechanism of action: inhibition of tubular reabsorption of uric acid.
Indications: treatment of gout.
Adverse effects: gastrointestinal irritation, allergic skin reactions, uric kidney
stones.
Contraindications: - acute gout attacks;
- hyperuricaemia secondary to hematologic
malignancies;
- peptic ulcer;
- renal failure;
- deficiecy in G6PD.
Interactions: - delay eliminationof Penicillin G, Indomethacin, sulphonylurea
antidiabetic drugs, methotrexate, iodinated derivatives;
- uricosuric action of is reduced by salicylates or thiazide
diuretics.
SULFINPYRAZONE
Mechanism of action: inhibition of tubular reabsorption of uric acid.
Pharmacodynamic effects: - uricosuric effect stronger than Probenecid, but is
more toxic.
- antiplatelet effect.
Indications: treatment of gout.
Adverse effects: gastrointestinal irritation (ulcer or gastrointestinal bleeding),
allergic skin reactions, bone marrow depression.
Contraindications: peptic ulcer, renal or hepatic impairment, pregnancy.
Interaction:
 decreases the clearance of oral antidiabetic drugs, oral anticoagulants;
 acetylsalicylic acid inhibits its uricosuric effect.

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 DRUGS AFFECTING ENDOCRINE SYSTEM
Lecture 21

Learning Objectives:
 Describe aspects of absorption, distribution, metabolism and excretion of a
drug;
 List the principal routes of drug administration and their advantages and
disadvantages;
 List examples of drugs concentrated in different tissues or liquids of the body;
 Name the phases in hepatic metabolism;
 Describe the terms “bound” and “unbound” drug to plasma proteins;
 Describe the term “first pass effect”;

1.Drugs affecting hypothalamic and pituitary gland

hormones

The hormones secreted by the hypothalamus and the pituitary gland are
peptides that act by binding on specific receptors. In hypothalamus are secreted
releasing factors which control the secretion of anterior pituitary hormones.
Some hypothalamic and pituitary hormones are used for diagnostic or
treatment, whereas other are used as research tools.

1.1. Hypothalamic hormones

1.1.1. Growth hormone-releasing hormone (GHRH or somatorelin)
Natural occurring GHRH exists as 44- and 40-amino-acid peptides (GHRH40
and GHRH44). In therapy are used synthetic analogues such as Sermorelin (a
synthetic peptide corresponding to the 1–29 amino acid sequence of GHRH)
and Hexarelin.
Sermorelin
- Indications: - diagnosis of growth hormone deficiency (to test pituitary GH
reserve),
- treatment of growth hormone deficiency in children.
- Adverse effects are rare: facial flushing, reactions at the injection site (pain,

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erythema, swelling).

1.1.2. Growth hormone inhibiting hormone (Somatostatin)

Somatostatin inhibits growth hormone release in the CNS. Also reduce gastrin
secretion, reduce exocrine secretion by pancreas, reduce secretion of insulin and
glucagon, inhibits mediators of carcinoid tumors (e.g., 5-HT, neurokinin A,
Vasoactive Intestinal Peptide), inhibits thyrotropin (TSH).
Somatostatin has limited therapeutic usefulness because of its short duration of
action (t1/2 = 1-3 min) and its multiple effects on many secretory systems. In
therapy are used Octreotide and Lanreotide (synthetic analogues of
Somatostatin) and Pegvisomant (a growth hormone receptor antagonist).
Octreotide has similar properties to Somatostatin, but a longer duration of
action (t1/2 = 80 min  it is administered every 8 h).
- Indications: - acromegaly;
- carcinoid tumours, VIPomas, glucagonomas, thymic
carcinomas and other neuroendocrine tumors (it is efficient for
the classical symptoms of carcinoid syndrome such as flushing,
watery diarrhoea56, but do not influence the progression of the
disease);
- management of bleeding oesophageal varices;
- prevention of complications after pancreatitis and pancreatic
surgery;
- treatment of nausea and vomiting in paliative care;
- other indications: - AIDS-related diarrhoea, antineoplasic
chemotherapy associated diarrhoea, ileostomy-
related diarrhoea;
- dumping syndrome, intestinal
pseudoobstruction;
- Somatostatin receptor scintigraphy with
Octreotide is the most sensitive method for
imaging lesions in patients with Zollinger-Ellison
syndrome.
- Adverse effects: - visual changes, headache;

56
Watery diarrhea-hypokalemia-achlorhydria syndrome (pancreatic cholera) is characterised by watery diarrhoea,
decreased K+, hypotension and dehydration caused by neuroendocrine tumours of the pancreas, most commonly
VIPoma.

406
 - nausea, vomiting, steatorrhoea, abdominal cramps,
flatulence, malabsorption due to reduction of pancreatic exocrine
function;
- changes in glucose tolerance test (hypo/hyperglycemia),
- changes in thyroid function (hypothyroidism);
- bradicardia;
- acute hepatitis;
- biliary sludge and gallstones (after 6 months of use,
therefore avoid abrupt interruption of the treatment, which can
precipitate biliary colic and pancreatitis).
Lanreotide is indicated for the treatment of acromegaly.
Pegvisomant is indicated for the treatment of acromegaly refractory to other
treatments.

1.1.3. Thyrotropin-releasing hormone (TRH)

Thyrotropin-releasing hormone (TRH) stimulates the release of thyrotrophin
from the anterior lobe of the pituitary. It also has prolactin-releasing activity. In
therapy is used Protirelin (synthetic TRH). It is rare used.
- Indication: for diagnostic  to differentiate between primary and secondary
hypothyroidism.
- Adverse effects: an urge to micturate, flushing, metallic taste, headache,
dizziness, nausea.

1.1.4. Corticotropin-releasing hormone (CRH)

Corticotropin-releasing hormone (CRH) stimulates the release of ACTH from
the anterior lobe of the pituitary. In therapy is used Corticorelin (ovine or
synthetic human CRH). It is rare used.
- Indication: for diagnostic  to differentiate Cushing's syndrome from ectopic
ACTH secretion.
- Adverse effects: flushing of the face, neck and upper chest.

1.1.5. Gonadotropin-releasing hormone (GnRH, LHRH): in therapy are

used
Gonadotropin-releasing hormone GnRH is produced in the arcuate nucleus of
the hypothalamus.
 Pulsatile GnRH secretion is essential to stimulate the gonadotroph cell
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 to produce and release luteinizing hormone (LH) and follicle stimulating
hormone (FSH).
 Continuous administration of GnRH or GnRH analogs inhibits the
release of FSH and LH by the pituitary in both women and men,
resulting in hypogonadism.
In therapy are used: - synthetic gonadotropin: Gonadorelin (synthetic form of
GnRH)
- synthetic gonadotropin analogues: Leuprorelin
(Leuprolide), Nafarelin, Goserelin, Buserelin, Histrelin,
Triptorelin
- GnRH antagonists: Cetrorelix acetate, Ganirelix
Gonadorelin
- is a synthetic polypeptide hormone which stimulate the release of the LH from
the hypothalamus.
- Indications: - diagnosis of hypothalamic-pituitary-gonadal dysfunction
- infertility related to hypogonadotrophic hypogonadism in both
women and men
- cryptorchidism,
- prostate cancer,
- precocious puberty.
- Adverse effects: headache, nausea, flushing, dermatitis, hypersensitivity
reactions (bronchospasm and anaphylaxis).
- Contraindications: pregnancy and breast feeding.
Gonadotropin analogues: Leuprorelin (Leuprolide), Nafarelin, Goserelin,
Buserelin, Histrelin
- Mechanism of action: agonists on GnRH receptors (induce hypogonadism
when given continuously).
- Indications: - breast and prostate cancer,
- endometriosis,
- uterine fibroids,
- polycystic ovarian syndrome,
- precocious puberty.
- Adverse effects: - in women: hot flushes, sweats, headache, diminished libido,
depresssion, ovarian cysts, breast atrophy, osteoporosis.
- in men: serum testosterone levels increase, pain in men with
bone metastases, hot flashes, sweats, edema, gynecomastia, diminished libido,
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decreased hematocrit and asthenia.
- Contraindications: pregnancy and breast feeding.
GnRH antagonists: Cetrorelix acetate, Ganirelix
- Mechanism of action: antagonists on GnRH receptors.
- Indication: ovulation induction.
- Adverse effects: reactions at the injection site (erythema, pruritus, and
swelling).
- Contraindications: moderate to severe renal or hepatic impairment.

1.1.6. Prolactine inhibiting hormone (PIH).

Not used in therapy.

1.2. Hormones of the anterior pituitary gland:

1.2.1. Growth hormone (GH, Somatotropin)
Growth hormone produces growth of skeletal (at open epiphyses), muscular
(produce growth of skeletal muscle), and other tissues, stimulates protein
anabolism, and affects fat and mineral metabolism. It has a diabetogenic action
on carbohydrate metabolism. Secretion is pulsatile and dependent on neural and
hormonal influences: release is stimulated by Growth hormone-releasing
hormone (GH-RH) and inhibited by Growth hormone inhibiting hormone
(Somatostatin).
In therapy are used Somatropin (as recombinant human growth hormone =
rhGH) and its analogue Somatrem.
- Mechanism of action: directly (on target) or indirectly (mediated by
somatomedines)
- Indications: - GH deficiency in children (pituitary dwarfism, Turner's
syndrome, in short children born small for gestational age,
idiopathic short stature etc)
- GH deficiency in adults
- Adverse effects: - intracranial hypertension (headache, nausea, vomiting)
- Creutzfeldt-Jakob disease after the use of GH from
human cadaver pituitary gland
- hypothyroidism
- Contraindications: - patients with closed epiphyses
- active neoplasms or intracranial lesions
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 - hypothyroidism.

1.2.2. Thyrotropin (TSH): recombinant human TSH

Thyrotrophin is an anterior pituitary hormone that stimulates the thyroid to
produce and synthesize
thyroxine (T4), triiodothyronine (T3) and thyroglobulin.
In therapy is used Thyrotropin alpha (synthetic recombinant human TSH).
It is rare used.
- Indication: - diagnostic purpose  diagnosis of hypothyroidism and to
differentiate between primary and secondary hypothyroidism.
- stimulate uptake of radio-iodine for treatment of thyroid
residual tissue after cancer thyroidectomy and metastatic differential thyroid
cancer.
- Adverse effects: headache, dizziness, nausea, flushing, an urge to micturate.
High doses may produce hyperthyroidism (excessive thyroid stimulation
explains angina, tachycardia or arrhythmias, dyspnea, sweating, nervousness
and irritability).

1.2.3. Adrenocorticotropin (ACTH = corticotropin): ACTH

Corticotropin is a naturally occurring hormone of the anterior lobe of the
pituitary gland. It stimulates the adrenal glands to secrete adrenocortical
hormones, especially cortisol (hydrocortisone), some mineralocorticoids such
as corticosterone, and, to a lesser extent, androgens. It has little effect on
aldosterone secretion, which proceeds independently.
In therapy are used: - Corticotropin (animal or synthetic human ACTH) –
it is rare used
- Tetracosactide (synthetic polypeptide with the first 24
residues of human ACTH).
- Indications: - diagnostic purpose  to differentiate between primary
(Addison’s disease) and secondary adrenal insuficiency.
- infantile spasms (West syndrome).
- Adverse effects: similar to corticosteroids. Its mineralocorticoid properties can
produce marked sodium and water retention, considerable potassium loss.
Abrupt withdrawal of corticotropin may result in symptoms of adrenal
insufficiency. Tetracosactide is less immunogenic than Corticotropin.

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1.2.4. Follicle-stimulating hormone (FSH); luteinizing hormone (LH);
human chorionic gonadotropin (hGC)
Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are
produced by gonadotroph cells in the anterior pituitary. FSH and LH regulate
gonadal function.
The principal function of FSH is to stimulate gametogenesis and follicular
development in women and spermatogenesis in men. In ovary, FSH acts on the
immature follicular cells and induces development of the mature follicle and
oocyte. Both LH and FSH are needed for proper ovarian steroidogenesis. LH
stimulates androgen production by these cells, and FSH stimulates androgen
conversion into estrogens by the granulosa cells. In the testes, FSH acts on the
Sertoli cells and stimulates their production of androgen-binding protein.
LH is primarily responsible for regulation of gonadal steroid hormone
production. In men, LH acts on testicular Leydig cells to stimulate testosterone
production. In the ovary, LH acts in concert with FSH to stimulate follicular
development. LH acts on the mature follicle to induce ovulation, and it
stimulates the corpus luteum in the luteal phase of the menstrual cycle to
produce progesterone and androgens.
In therapy are used:
- menotropins (or human menopausal gonadotropin):
- menotropins (hMG) is a purified extract of FSH and LH
- urofollitropine (uFSH) is a purified preparation of human FSH
- follitropin alpha (rFSH) is recombinant FSH
- human chorionic gonadotropin (hGC): Choriogonadotropin alfa is
a recombinant form of chorionic gonadotrophin.
Menotropins (or human menopausal gonadotropin)
- obtained as extract of human postmenopausal urine.
- Indications: infertility treatment (in male and female) due to hypogonadism.
Human menopausal gonadotrophins are given to induce follicular maturation
and are followed by treatment with chorionic gonadotrophin to stimulate
ovulation and corpus luteum formation.
- Adverse effects: - ovarian enlargement (risk of hemoperitoneum due to
rupture of ovarian cysts),
- hypovolaemia,
- multiple births,
- spontaneous abortion,
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 - gynecomastia in men.
- Contraindications: pregnancy, abnormal genital bleeding, hormone sensitive
malignancies (such as those of the breast, uterus, prostate, ovaries or testes),
ovarian cysts or enlargement not caused by the polycystic ovary syndrome.
Human chorionic gonadotropin (hGC)
- is a hormone produced by the placenta and it is obtained from the urine of
pregnant women.
- Indications: - infertility treatment (in male and female) due to hypogonadism
- treatment of prepubertal cryptorchidism
- delayed puberty due to hypogonadotrophic hypogonadism.
- Adverse effects: headache, depression, edema, precocious puberty,
gynecomastia, ovarian enlargement (risk of hemoperitoneum due to rupture of
ovarian cysts), hypovolaemia.
- Contraindications: - carcinoma of the prostate or tumours of the breast,
uterus, ovarian, testicular, hypothalamus, pituitary, thyroid, and adrenal glands
- precocious puberty.

1.2.5. Prolactin
Prolactin amino-acid peptide hormone produced in the anterior pituitary,
responsible for lactation. Prolactin secretion is stimulated by suckling and, for a
few months after delivery, it has an inhibitory effect on the ovaries, acting as a
natural contraceptive. Prolactin secretion may also be stimulated by
Methyldopa, Metoclopramide, Reserpine, opioid analgesics, and phenothiazine
or butyrophenone antipsychotics.
A deficiency of prolactin is manifested by failure to lactate or by a luteal phase
defect.
Prolactin Indications: management of lactation disorders and some forms of
menstrual disturbance.
For patients with symptomatic hyperprolactinemia, inhibition of prolactin
secretion can be achieved with dopamine agonists such as Bromocriptine,
Cabergoline, Pergolide (these are ergot derivatives), Quinagolide (nonergot
drug).
Bromocriptine is an ergot derivative.
Mechanism of action: agonist on dopamine D2-receptors.
Indications: - to inhibit the secretion of prolactin:
 prolactinoma and endocrinological disorders
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 associated with hyperprolactinaemia;
 suppress puerperal lactation for medical reasons
- Parkinson's disease;
- acromegalic patients (adjunct to surgery and radiotherapy to
reduce plasma-growth hormone concentrations).
Adverse effects: - peripheral vasoconstrictor effect (because it is an ergot
derivative): vasospasm, Raynaud syndrome, leg cramps,
- arrhythmias, exacerbation of angina, asymptomatic
hypotension, very rarely hypertension, myocardial infarction,
- psychiatric disorders
- pulmonary and retroperitoneal fibrosis (because it is an
ergot derivative)
Contraindications: - hypertension, coronary artery disease,
- history of serious psychiatric disorders
- pregnancy and breast-feeding.

1.3. Hormones of the posterior pituitary gland:

1.3.1. Oxytocin;
1.3.2. Vasopressin, desmopressin.

2.Drugs affecting thyroid hormones

Thyroid gland synthesize thyroid hormones T3 and T4 following the steps:

- uptake of iodide from blood into thyroid gland (iodide is from ingested food,
water or medication)
- iodide oxidation (oxidation of iodide to iodine by thyroidal peroxidase)
- iodide organification (iodinated thyrosine residues form monoiodothyrosine
[=MIT] and diiodothyrosine [=DIT])
- coupling of iodothyrosines to result of thyroid hormones: T4 (by combination
of 2 molecules of DIT), T3 (by combination of one molecule of DIT and one
molecule of MIT). The thyroid hormones are released from gland into blood.
Transport of thyroid hormones is by thyroxine-binding globulin.

2.1. Treatment of hypothyroidism  thyroid preparations:

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- Liothyronine (T3),
- Levothyroxine (T4),
- Liotrix (a 4:1 ratio of T4:T3),
- thyroid desiccated.
Mechanism of action: thyroid hormones T3 and T4 are dissociated from
thyroid-binding globulin  enter the cells by diffusion or possibly by active
transport  T4 is converted to T3 by 5'-deiodinase, and the T3 enters the
nucleus  in nucleus T3 binds to a specific T3 receptor protein  increased
formation of RNA and subsequent protein synthesis.
Indications: - hypothyroidism (T3 is more active than T4, but has shorter
half-life) – it is preferred Levothyroxine (T4),
- to suppress TSH production in the treatment of thyroid
carcinoma,
- as a diagnostic agent for the differential diagnosis of
hyperthyroidism.
Adverse effects: correspond to symptoms of hyperthyroidism (tachycardia,
palpitations, cardiac arrhythmias, increase in blood pressure, anginal pain,
headache, restlessness, excitability, insomnia, tremors, muscle weakness and
cramps, heat intolerance, sweating, flushing, fever, weight loss, menstrual
irregularities, diarrhoea, and vomiting).
Contraindications: cardiovascular disorders including angina, heart failure,
myocardial infarction, and hypertension. Precaution in elderly patients.

2.2. Prophylaxy of endemic gout: Potassium iodide.

Indications: low doses taken by mouth for:
- prophylaxis and treatment of iodine deficiency disorders (e.g., endemic gout,
to prevent neonatal goitre and cretinism),
- radiation protection (to saturate the thyroid when uptake of radio-iodine by the
gland is not desired),
Adverse effects: iodism (acneiform rash,drug fever, conjunctivitis, rhinorrhea,
metalic taste, mucous membrane ulcerations).
2.3. Treatment of hyperthyroidism  antithyroid agents:
2.3.1. Thioamides: Methimazole (Thiamazole), Carbimazole,
Propylthiouracil.
Mechanism of action: block the production of thyroid hormones by multiple
mechanisms:
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 - block iodide oxidation,
- block iodide organification,
- block coupling of iodothyrosines.
Indications: - hyperthyroidism, including the treatment of Graves' disease,
- preparation of hyperthyroid patients for thyroidectomy,
- as an adjunct to radio-iodine therapy,
- treatment of thyroid storm.
Adverse effects: - skin rashes and fever  most common,
- mild leucopenia with neutropenia  the most frecquent,
agranulocytosis  the most severe.
- cholestatic jaundice, hepatitis,
- rare: limphadenopathy, arthralgia, vasculitis, lupus-like
reactions, hypoprothrombinemia, nausea and vomiting, gastric
discomfort, headache, pruritus,
Propylthiouracil is preferable in pregnancy (preferred to carbimazole or
thiamazole) and in breast-feeding since it enters breast milk less readily.
2.3.2. Iodides: Potassium iodide.
Indications: - high doses for pre-operative management of hyperthyroidism
(reduce vascularity and friability of thyroid gland, increase thyroid firm).
2.3.3. Anion inhibitors: Perchlorate, Pertechnetate, Thiocyanate.
Mechanism of action: block uptake of iodide
Indications: drug induced hyperthyroidism (e.g., Amiodarone-induced
hyperthyroidism)
Adverse effects: aplastic anemia.
2.3.4. Radioactive Iodine (131I).
Mechanism of action: destruction of thyroid parenchima.
Indications: treatment of thyreotoxicosis (hyperthyroidism, thyroid carcinoma).
Adverse effects: hypothyroidism.
Contraindications: pregnancy, breast-feeding, severe thyrotoxic heart disease.
2.3.5. Iodinated contrast media: Ipodate, Iopanoic acid.
Mechanism of action: inhibit the conversion of T4 to T3 in different tissues.
Indications: hyperthyroidism, thyroid storm.
Adverse effects: simmilar to iodides.
2.3.6. Beta-blockers (Propranolol) or neurosympaticolytic drugs
(Guanethidine, Reserpine).

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2.4. Treatment of thyroid cancer:
- Radioactive Iodine (131I),
- anticancer drugs: - cell cycle-specific agents:
- antimetabolites: 5-Fluorouracil,
- antitumor antibiotic: Bleomycin,
- cell cycle-nonspecific agents:
- alkylating agents: Melphalan.
- antracycline(antitumor antibiotic): Doxorubicin.

3.Agents that affect bone mineral homeostasis

3.1. Hormonal agents that influence bone mineral homeostasis:

3.1.1. Vitamin D: cholecalciferol (D3), ergocalciferol (D2), 25(OH)D3
(calcifediol); 1,25-(OH)2-D3 (calcitriol); 24,25-(OH)2-D3 (secalcifediol);
Dyhydrotachysterol (DHT); 1α(OH)D2 (doxercalciferol);
25‑hydroxiisotachysterol; Isotachysterol.
Mechanism of action: stimulation of intestinal calcium and phosphate transport
and bone resorption.
Indications: treatment and prevention of vitamin D deficiency states and
hypocalcaemia in disorders such as hypoparathyroidism and secondary
hyperparathyroidism.
Adverse effects:
- excessive intake of vitamin D  hyperphosphataemia, hypercalcaemia
(hypercalcaemia is associated with hypercalciuria, ectopic calcification, and
renal and cardiovascular damage).
- overdosage of vitamin D  anorexia, nausea and vomiting, constipation or
diarrhoea, polyuria, nocturia, sweating, headache, thirst, somnolence, and
vertigo.
Contraindications: hypercalcaemia, patients with renal impairment or calculi
or heart disease (risk of organ damage if hypercalcaemia occurred). Plasma
phosphate concentrations should be controlled to reduce the risk of ectopic
calcification.

3.1.2. Parathyroid hormone (PTH): Teriparatide (recombinant form of

416
parathyroid hormone).
Indication: treatment of osteoporosis in patients with high risk of fractures (it is
the only drug that stimulate bone formation).

3.1.3. Calcitonin.
Calcitonin is a hormone produced by mammalian thyroid parafollicular cells.
Mechanism of action: lower serum calcium and phosphate due to inhibition of
osteoclastic bone resorption and increase urinary excretion of calcium and
phosphorus
Indications: - osteoporosis (prevention and treatment),
- bone pain due to osteoporotic fractures,
- Paget's disease of bone,
- severe hypercalcaemia, especially that associated with
malignancy.
Adverse effects: - rhinitis (after intranazal administration),
- abdominal pain, skin rashes of head and hands
- antibody formation (after long-term treatment with
salmon /pork calcitonin).

3.1.4. Others:
- Glucocorticoids.
- Selective estrogen receptors modulators (estrogen-like drugs): Raloxifene.
- Thyroid hormones, somatotrop, androgens.

3.2. Non-hormonal agents that influence bone mineral homeostasis:

- Biphosphonates: Etidronate, Alendronate, Pamidronate, Risedronate,
Tiludronate, Zolendronate, Ibandronate, Clodronate.
Mechanism of action: inhibit bone resorption by osteoclasts
Pharmacokinetics: biphosphonates are poorly absorbed after oral
administratiopn (absorption is reduced by food, especially by products
containing calcium or other polyvalent cations). Bioavailability in the fasting
state is less then 10%. About 50% of an absorbed dose is sequestered to bones
and retained in the body for prolonged periods. Excretion is in the urine, as
unchanged drug.
Indications: - osteoporosis (biphosphonates are first choice for prevention
and treatment),
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 - osteoporotic fragility fractures
- Paget's disease of bone,
- treatment of severe hypercalcaemia, especially when associated
with malignancy.
Adverse effects:
- gastrointestinal disturbances: abdominal pain, nausea, vomiting, diarrhoea,
- musculoskeletal pain,
- disturbances in serum electrolytes (hypocalcaemia, hypophosphataemia),
- oesophagitis and esophageal ulcer: low in Etidronate (to minimize this risk,
patients should remain upright for 30 minute after taking Alendronate,
Risedronate, 60 min after taking Ibandronate),
- osteonecrosis of the jaw, osteomalacia after Etidronate administration.
Contraindications: pregnancy.
- Mithramycin (Plicamycin)
Mechanism of action: not well known
Indications: hypercalcemia and Paget disease
- Thiazide diuretics, Loop diuretics, Fluoride.
- Calcium preparations:
- parenteral preparations: - Calcium gluconate (0.45 mEq calcium /
mL = 9% calcium)
- Calcium chloride (0.68-1.36 mEq
calcium/mL= 27%calcium)
- Calcium gluceptate (0.9 mEq calcium /
mL = 8% calcium)
- oral preparations: - Calcium carbonate (40% calcium)
- Calcium lactate (13% calcium)
- Calcium phosphate (25% calcium)
- Calcium citrate (21% calcium)
- Calcium acetate (25% calcium)
- Calcium glubionate (6.5% calcium)
- Tricalcium phosphate (39% calcium)
Indications: - hypocalcaemia and calcium deficiency states (in simple
deficiency states  given by mouth, in severe acute hypocalcaemia or
hypocalcaemic tetany  given parenteral)
- hyperkalaemia (calcium gluconate)
- hypermagnesaemia (calcium gluconate)
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 - hyperphosphataemia (calcium carbonate)
- antiacids (calcium carbonate, calcium silicate)
Adverse effects: - gastrointestinal irritation (calcium chloride is the most
irritant)
- soft-tissue calcification (after parenteral adminstration)
- hypercalcemia.
Contraindications: - renal lithiases, renal impairment,
- diseases associated with hypercalcaemia (sarcoidosis,
some malignancies).
Interactions: - cardiac glycosides (calcium enhances the effects of digitalis
glycosides on the heart and may precipitate digitalis intoxication),
- thiazide diuretics decrease its urinary excretion,
- corticosteroids reduce calcium absorption,
- bisphosphonates, fluoride, some fluoroquinolones, tetracyclines
(calcium salts reduce their absorption; doses should be separated by at
least 3 h).
Treatment of hypocalcemia: Vitamin D + Calcium preparations
Osteoporosis treatment
- Estrogens ± progestins; selective estrogen receptors modulators (estrogen-like
drugs): Raloxifene.
- Biphosphonates: Etidronate, Alendronate, Pamidronate, Risedronate,
Tiludronate, Zolendronate, Ibandronate, Clodronate, Tiludronate.
- Calcitonin.
- Recombinant form of parathyroid hormone (PTH): Teriparatide.
- Fluoride.
Treatment of Paget’s disease of bone
- Calcitonin.
- Biphosphonates: Etidronate, Alendronate, Risedronate, Tiludronate.
- Mithramycin (Plicamycin).
Treatment of hypercalcemia
- Saline diuresis: rehydration with saline ± Furosemide.
- Other drugs: biphosphonates (Etidronate, Pamidronate, Zolendronate),
Calcitonin, Gallium nitrate, Mithramycin (Plicamycin), phosphates (sodium or
potassium salts), Glucocorticoids.

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 Lecture 22

Learning Objectives:
 Understand what is meant by pharmacokinetics and pharmacodynamics. Describe the
mechanisms of action and the main pharmacological actions of glucocorticoid and
mineralocorticoid hormones;
 List the main groups of glucocorticoid hormones;
 Describe the biological effects of glucocorticoid hormones;
 Give the common side effects encountered with these drugs:
 List of therapeutic uses of inhibitors of the synthesis of glucocorticoids and
glucocorticoid antagonists;
 List the inhibitors of the synthesis of glucocorticoids and glucocorticoid antagonists
and their therapeutic uses.

1. Drugs affecting the hormones of the adrenal gland

The hormones of the adrenal gland:

- mineralocorticoid hormones (HMC) → is produced in zona glomerulosa;
- glucocorticoid hormones (hGC) → is produced in zona fasciculata;
- sex hormones → is produced in the zona reticularis.

1.1. Drugs affecting glucocorticoid hormones

Mechanisms of action: free hormones enter the cytosol → hormones cytosolic

receptors couple to target cells (these receptors are related to a type of protein
called "heat shock proteins" - "heat shock proteins" - or "Hsp," that prevent
complexation receptor nuclear sites) → hormones produce conformational
changes of the receiver, the energy releasing, which detaches from the receivers
Hsp proteins (particularly protein Hsp90) → complex form homodimers
entering actively nucleus where it binds to the receptor sites for the
glucocorticoid target gene (GRE) or other receptor sites of gene transcription →
→ syntheses of specific proteins to the role of mediators.
Classification
• The natural glucocorticoids: - Cortisol

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- Hydrocortisone 2.2. medium duration of action:
• The glucocorticoid synthesis: Glucocorticoid hormones
2.1. Short term / medium duration of - Triamcinolone
action: - paramethasone
- hydrocortisone (hemisuccinate or the - fluprednisolone
acetate); 2.3. long duration of action:
- Prednisone; - Betamethasone
- Prednisolone; - Beclomethasone
- Methylprednisolone; - Dexamethasone
- meprednisone;
Inhalatory: Budesonide, Fluticasone, Mometasone, Ciclesonide

Pharmacokinetics
- Administration → to the oral route by spraying the parenteral route, the
topically, as ointments;
- secretion of glucocorticoid hormones → 20 mg / 24 h (without stress)
secretion is minimal after midnight;
- → glucuronidation metabolism;
- the renal elimination.
The biological effects
a) Effects on metabolism:
- effects on carbohydrate metabolism:
- glucocorticoids increases gluconeogenesis from protein;
- glucocorticoids increase the deposition of glycogen in the liver;
- Glucocorticoids increase blood glucose;
- glucocorticoids decrease the utilization of glucose in peripheral
- effects on lipid metabolism:
- Action permissive to the release of fatty acids from adipose tissue by
catecholamines;
- the increase in lipid mobilization → changes in the distribution of adipose
tissue;
- effects on protein metabolism:
- the increase in urogenèse;
- increase in the elimination of nitrogen;
- reduced affinity of insulin to insulin receptors;
- effects electrolyte metabolism:
- the increased sodium retention and the elimination of potassium, hypokalemic

421
alkalosis l;
- channel setting to the elimination of water;
- the increase in renal elimination and reduction of intestinal calcium
absorption.
b) The anti-inflammatory and immunosuppressive:
- the increased synthesis of lipocortin macrocortine and → the inhibition of
phospholipase A2 → the inhibition of lymphocytes, LTB4, others leukotrienes,
prostaglandins, prostacyclins, thromboxanes (effects of the process
inflammatory);
- decrease in the number of circulating eosinophils and lymphocytes,
particularly the number of Lyt;
- the involution of the thymus and lymph nodes.
c) other effects:
- the euphoria;
- behavioral changes;
- lower the threshold for seizures.
Indications:
a) replacement therapy: - Addison's disease;
- the pituitary insufficiency;
- adrenogenital syndrome.
b) therapy at doses large, supra-physiological
collagenosis: - rheumatoid arthritis;
- rheumatic fever;
- polymyositis;
- systemic lupus erythematosus;
- ulcerative colitis;
- polyarteritis nodosa dangerous;
- temporal arteritis etc.
allergic diseases - allergic reactions to drugs;
- contact dermatitis;
- angioedema;
- allergic rhinitis;
- skin rush;
- anaphylactic shock etc.
eye diseases - acute uveitis;

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 - allergic conjunctivitis;
- choroiditis;
- optic neuritis;
gastrointestinal diseases - inflammatory gastrointestinal diseases;
- subacute hepatic necrosis;
kidney disease - nephrotic syndrome;
hematological diseases - idiopathic thrombocytopenic purpura;
- autoimmune hemolytic anemia;
- leukemias;
- multiple myeloma;
pulmonary disease - the aspiration pneumonia;
- the bronchial asthma,
- syndrome respiratory distress in the
newborn;
infections - septicemia with Gram-negative;
osteoarticular inflammation - arthritis;
- bursitis;
- tenosynovitis;
dermatological diseases - atopic dermatitis; dermatitis; seborrheic
dermatitis;
- pemphigus vulgaris;
- psoriasis;
- mycosis fungoides;
- eczema etc.
acute attack of gout;
post-traumatic lesions, cerebral edemas;
cardiogenic shock and endotoxic shock
Hypercalcemia
Contraindications:
- the peptic ulcer;
- diabetes mellitus;
- dyslipidemia;
- the osteoporosis;
- the hypertension ± the heart failure;
- infections (herpetic lesions of the cornea);
- glaucoma;
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- psychoses;
- children that the growth plates are not ossified.
Adverse effects:
- characteristic changes of hyperadrenocorticism: facies as "full moon", the
hirsutism, acne, stretch marks, fatty deposits on the trunk, but not members;
- the osteoporosis, loss of muscle mass;
- the amenorrhea;
- sodium retention, the hypertension, the worsening of heart failure;
- dyslipidemia;
- the necrotizing arteritis rheumatic patients, worsening the damage of cartilage
growth, degeneration of the synovial folds;
- diabetes mellitus (diabetes drug);
- the gastro-intestinal ulcer;
- the immunosuppression;
- psychotic symptoms;
- the atrophy of the adrenal gland;
- the stunting among children.

Inhibitors of the synthesis of glucocorticoids and glucocorticoid antagonists

Classification
• inhibitors of the synthesis of glucocorticoids: - metyrapone
- Aminoglutethimide
- Ketoconazole
- Mitotane
- Amphenone B
- Trilostane
- abiraterone
2. The glucocorticoid receptor antagonists: - Mifepristone

The pharmacological properties of inhibitors of the synthesis of

glucocorticoids and glucocorticoid antagonists
Metyrapone
Mechanisms of action: the inhibition of 11-hydroxylation at the adrenal → the
inhibition of the production of cortisol and cortisone.
Indications:
- diagnostic test for measurement of the ability of the anterior pituitary to the
production of ACTH;

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- Cushing's syndrome;
- pituitary tumors;
- syndrome ectopic ACTH secretion;
- the adrenal hyperplasia;
- the limitation of adverse effects of glucocorticoids;
- the immunosuppression due to surgery or radiation therapy.
Adverse effects: - minor adverse effects: dizziness, transient gastrointestinal
disorders;
- major adverse effects: edema (retention of sodium and
water), the hirsutism.
Aminoglutethimide
Mechanisms of action: inhibition of the synthesis of all steroids.
Indications: - breast carcinoma (to decrease the production of estrogens and
androgens);
- association with Ketoconazole → Cushing's syndrome, adrenal
cancer.
Ketoconazole
The drug is an enzyme inhibitor of drug metabolism.
Indications: - as antifungal;
- as inhibitor of the synthesis of steroids;
- Cushing's syndrome.
Mitotane
Indications: - adrenocortical carcinoma.
Adverse effects: - diarrhea, nausea, vomiting;
- depression, drowsiness;
- rashes.
Amphenone B
Mechanisms of action: the inhibition of hydroxylation at position 11th, 17th
and 21st.
Adverse effects:
- the increased production of ACTH;
- the anterior pituitary hyperplasia;
- depression;
- for gastrointestinal disorders;
- rashes;
- disorders of liver function and thyroid function.
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Trilostane
Mechanisms of action: the inhibition of 3-beta hydroxysteroid dehydrogenase
/ isomerase of 5-4 at the adrenal → the inhibition of the production of
mineralocorticoids and glucocorticoids.
Indications: - Cushing's syndrome;
- the primary aldosteronism.
Adverse effects: - for gastrointestinal disorders;
- drowsiness.
Abiraterone
The drug is the latest inhibitors of steroid synthesis in clinical trials.
Mechanisms of action: the inhibition of the 17 α-hydroxylase (P450c17) and
17,20-lyase → decreased cortisol synthesis and gonadal steroids in steroids
adrenal and gonadal steroids in the gonads.
Indications: - abiraterone is a prodrug that is activated in the oral treatment of
prostate cancer refractory to other treatments.
Mifepristone
Mechanisms of action: the partial agonist for the glucocorticoid receptor and
progesterone.
Indications: - Cushing's syndrome, as antiprogestin drug.

1.2. Drugs affecting mineralocorticoid hormones

Mineralocorticoid hormones are aldosterone and deoxycorticosterone (DOC).
factors that stimulate or regulate the secretion of aldosterone:
- ACTH;
- the hypovolemia by bleeding or dehydration by mass;
- receptor stimulation β1 - adrenergic presynaptic level of the renal
juxtaglomerular cells;
- diet without salt or salt restriction;
- the prolonged administration of diuretics that increase the elimination of Na+
(thiazides, loop diuretics).
All these factors stimulate the synthesis and release of renin → the activation of
the renin - angiotensin - aldosterone l.
Mechanisms of action: it is similar to glucocorticoids acting on cytosolic and
nuclear receptors from target cells (cells of the distal convoluted tubules, the
loop of Henle, the cells of the epithelium carrier the urinary bladder and colon)
→ stimulation of membrane Na+/K+- ATP-ase → the passage of sodium ions in
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renal tubular cells, from the blood to the tubular space, the increased secretion
of H+ ions and K+ in the peritubular space.
The pharmacokinetics of aldosterone: - secretion → daily 100-200 mg / 24 h;
- hepatic metabolism → glucuronidation;
- the renal elimination in a partially unchanged;
- T1/2 = 15 - 20 min.
The excess aldosterone determines the following effects:
- hyponatremia;
- hypokalemia;
- increase in plasma volume;
- increase in blood pressure;
- edema;
- hypokalemic metabolic alkalosis.
DOC:
- The setting is made only of ACTH.
- The substance is not influenced by the diet without salt or salt restriction.
- The substance is released in large quantities in the adrenal carcinoma and
hyperplasia in congenital adrenal.
- T1/2 = 70 min.
In therapy → synthetic derivatives: - deoxycorticosterone acetate (DOCA)
- Fludrocortisone
Indications: - the lack of mineralocorticoid hormones;
- → Fludrocortisone treatment alternative to hypotension.
Adverse effects: - Fludrocortisone → high sodium retention.
mineralocorticoid antagonists
Classification
1. Competitive antagonists of aldosterone receptors
1.1. Non-selective competitive antagonists of aldosterone receptors
- Spironolactone
- Prorenone
Mineralocorticoid antagonists
- Drospirenone
1.2. Competitive antagonists selective for aldosterone receptor: - Eplerenone
2. Physiological antagonists: - Amiloride
- Triamterene
Indications:
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- as potassium-sparing diuretics;
- the primary and secondary hyperaldosteronism;
- Spironolactone → l congestive heart failure;
- drospirenone → as an oral contraceptive.
The mechanisms of action, pharmacodynamic effects, pharmacokinetics,
indications, cons-indications, adverse effects: → See chapter pharmacology of
diuretic - potassium sparing diuretics.

2. Drugs affecting pancreatic hormones

Pancreatic hormones are:

- Insulin - secreted by pancreatic beta cells;
- Glucagon - secreted by pancreatic alpha cells;
- insular amyloid polypeptide (IAPP) - secreted by pancreatic beta cells;
- Somatostatin - secreted by pancreatic delta cells;
- polypeptide hormone - secreted by pancreatic or liver cells.

2.1.Insulin
Table. Factors influencing Insulin release
Insulin release is stimulated by: Insulin release is inhibited by:
- plasma glucose or other sugars; - Somatostatin;
- glucagon; - diazoxide, minoxidil;
- amino acids (leucine, arginine); - phenytoin and other hydantoin;
- fatty acids; - Vinblastine;
- gastrointestinal hormones: gastrin, secretin, - Colchicine;
cholecystokinin, gastric inhibitory polypeptide - presynaptic adrenergic alpha2 receptor
(GIP), enteroglucagon; agonists;
- beta2-adrenergic - alpha1 adrenergic receptor agonists;
- Sulphonylureas; - stimulation of ventro-medial areas of the
- ventrolaterale areas of CNS stimulation. CNS.

Insulin - mechanism of action

Insulin binds to a receptor on the cell surface enzyme to its target (liver, skeletal
muscle, adipose tissue). This receptor is a glycoprotein composed of two
subunits alpha and two beta subunits linked by disulfide bridges.
- alpha subunit coupling insulin activation of a tyrosine kinase receptor beta

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subunit structure portion autophosphorylation increases beta aggregation and
stabilization of alpha and beta heterodimers activated state of the receptor
tyrosine kinase phosphorylation as a result of repeated - it activates a protein
that is second messenger of biological signal transmission postreceptor.
Complex insulin - receptor is then internalized and then you dissolution occurs
with insulin metabolism and recycling of cell surface receptors.
Elevated plasma insulin receptor causes down-regulation.
translocation and expression of glucose transporters to the cell surface is
mediated calcium influx, while glucose transport is accomplished by activating
adenylate cyclase.
glucocorticosteroids decrease its affinity insulin receptors, while growth
hormone increases insulin affinity for these receptors.
There are 5 types of glucose transporters: GLUT-1 to GLUT-5. Defect in
GLUT-4 characterizes type 2 diabetes.
Insulin - biological effects
-Carbohydrate metabolism:
- in the liver cells: decreases gliconeogeneza and glycogenolysis, increased
glycolysis and glicogenogeneza;
- in adipose tissue: increased glucose uptake, increased synthesis of glycerol;
- the muscle tissue: increased glucose uptake, glycolysis, glicogenogeneza.
Lipid metabolism:
- in the liver cells: increased lipogenesis;
- in adipose tissue: increased synthesis of triglycerides and fatty acids;
- in muscle does not work.
Proteic metabolism:
- in the liver cells: cleavage of proteins decreases;
- in adipose tissue does not act;
- the muscle tissue: increased amino acid uptake and protein synthesis.
Other metabolic effects of insulin are:
- increase in cell transport of K+, Ca2 +, nucleosidelor and inorganic phosphate
ion;
- increase nucleic acids.
Insulin Pharmacokinetics
- is degraded by gastric acid;
- circulate free in plasma; t1/2 = 3-5 min;
- metabolized in the liver (predominantly for endogenous insulin) and kidney
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(predominantly for exogenous insulin).
Administration: sc, iv infusion in a closed system, implantable pumps, external
pumps, aerosol.
Types of insulin:
- conventional preparations: beef, pig or mixed (beef + pig)
- human preparations: human insulin (recombinant DNA techniques,
biosynthesis in E. coli), semi-synthetic insulin, human proinsulin (recombinant
DNA techniques).

Classification of insulin preparations

Onset of Effect is Duration Administration
effect maximum
Ultra-fast acting insulin 5-15 min 1h 3-5 h s.c./i.v.
- Insulin lispro;
- Insulin aspart;
- Insulin glulisine;
Rapid acting insulin: 30 min 2-3 h 5-8 h s.c./i.v.
- Insulin Regular
Intermediate-acting insulin: 2-4 h 6-10 h 10-16 h s.c.
- Zinc-Insulin;
- Neutral protamine Hagedorn insulin
(NPH Insulin or Insulin Isophane);
Long-acting Insulin: 1-1,5 h Maintened 24 h s.c.
- Insulin glargine; in platou
- Insulin determir.
insulin mixtures:
- 70% + 30% NPH Insulin Regular Insulin;
- 75% NPL insulin (neutral protamine lispro insulin) + 25% insulin lispro.

Insulin Indications:
- diabetes type 1 (insulin-dependent patient, whose survival depends on
exogenous insulin);
- type 2 diabetes who do not respond to oral agents because INFLUENCE
stress, infection, surgery, pregnancy.
Adverse effects: - hypoglycaemia;
- Type I immunological reactions (urticaria,
anaphylaxis);

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 - insulin resistance (IgG antibodies antiinsulinici);
- Lipodystrophy at the injection site;
- Somogyi effect (nocturnal hyperglycemia);
- Dawn phenomenon (early morning hyperglycemia).
Glucagon
Biological effects:
- hyperglycemia, increased gluconeogenesis and ketogenesis;
- positive chronotropic and inotropic effect;
- intestinal smooth muscle relaxation.
Indications: - in severe hypoglycemic states;
- poisoning with beta-blockers;
- cardiogenic shock;
- functional capacity for diagnosis of pancreatic beta cells and
intestinal seating capacity.
Adverse effects: - immediate-type immunologic reactions;
- abdominal discomfort, nausea, vomiting.
Insular amyloid polypeptide (IAPP)
Pramlintide is an analog of IAPP, suitable in emergencies and, alternatively, in
insulin-resistant diabetes.

2.2.Oral antidiabetic drugs

Classification
4.1. Sulphonylurea:
- 1st generation: Tolbutamide, Chlorpropamide, Tolazamide, Acetohexamide
- 2nd generation: Glyburide, Glipizid, Gliclazide, Glibenclamide, Glibormerid, Glisopexine,
Gliquidone
- 3rd generation: Glimepiride.
4.2. Meglitinides: Repaglinide.
4.3. Phenylalanine derivatives: Nateglinide.
4.4. Biguanides: Metformin, Fenformin, Buformin.
4.5. Alpha-glucosidase inhibitors: Acarbose, Miglitol, Vogliboza.
4.6. Thiazolidinediones: troglitazone, pioglitazone, Englitazone, Ciglitazone, Rosiglitazone.
4.7. Aldozreductaze inhibitors: Tolrestat.
4.8. Glucagon-like peptide agonists (glucagon-like peptide-1) (also called incretinmimetics):
Exenatide.
4.9. Dipeptidyl-peptidase-4 (DPP-4) (inactivates glucose-dependent insulinotropic polypeptide
GIP): Sitagliptin, Valdegliptin, Saxagliptin, Linagliptin.
4.1. Sulphonylurea: 1st generation (Tolbutamide, Chlorpropamide,

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Tolazamide, Acetohexamide), 2nd generation (Glyburide, Glipizid,
Gliclazide, Glibenclamide, Glibormerid, Glisopexine, Gliquidone), 3rd
generation (Glimepiride)
Mechanism of action: block receptor-dependent K+ channels.
Pharmacodynamic effects: - stimulate the release of insulin and somatostatin;
- increase insulin receptor sensitivity in insulin target cells.
1 generation presents a reduced hypoglycemic effect at the high doses, 2nd and
st

3rd generation presents an increased hypoglycemic effect at low doses.

Indications: diabetes mellitus type 2 (treatment "traditional" choice in this type
of diabetes).
Contraindications: - pregnancy;
- renal failure, hepatic impairment.
Adverse effects:- hypoglycemia;
- type I immunological reaction;
- teratogenicity;
- type Disulfiram-like effects;
- the 1st generation: • diuretic effect (except chlorpropamide);
• Chlorpropamide: antidiuretic effect,
hyponatremia, thrombocytopenia, transient
leukopenia, jaundice, redness when combined
with alcohol;
nd
- the 2 generation: hepatotoxicity, nephrotoxicity.
NB: It is assumed that Ca2+ channel blockers could not antagionise the effects
of sulphonylureas. Diazoxide and Minoxidil counteracts the effects of
sulphonylureas.
4.2. Meglitinides: Repaglinide
Mechanisms of action:
- stimulate insulin secretion in a glucose-dependent mechanism;
- blocking K+-ATP channel-dependent membrane cause depolarization, which
open the voltage-dependent Ca2+ channels, resulting in an increase of
intracellular Ca2+ influx, followed by the release of insulin;
- binding to sulfonylurea receptors in pancreatic beta cells (SUR1), but the other
binding site.
Pharmacodynamic effects:
- Repaglinide induced insulin secretion appears early after drug administration
and returned to baseline levels before the next dose.
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Indication:
- Diabetes mellitus type 2 (uncontrolled by diet and exercise).
- type 2 diabetes patients found to failure after treatment with other oral
antidiabetic agents.
Adverse effects: - hypoglycemia;
- weight gain;
- nausea, diarrhea / constipation;
- arthralgia;
- headache;
- upper respiratory tract infections (sinusitis).
1.4. Biguanides: Metformin, Fenformin, Buformin
Are "euglicemiant" more than hypoglycemic.
Mechanism of action: decrease plasma glucose levels (not related to the
presence of functional pancreatic beta cells).
Pharmacodynamic effects:
- slow intestinal glucose resorption;
- increase insulin binding to insulin receptors.
- direct stimulation of glycolysis in tissues with increased glucose utilization in
the periphery;
- decrease hepatic gluconeogenesis;
- reduce the absorption of glucose from the intestine;
- decreased plasma levels of glucagon.
Indications: diabetes mellitus type 2 (treatment "traditional" choice in this type
of diabetes).
Contraindications:- alcoholism;
- anoxic conditions (cardiovascular disease and chronic lung);
- renal or hepatic insuficiency;
- elderly;
- pregnancy.
Adverse effects:- lactic acidosis;
- reduce the absorption of vitamin B12;
- anorexia, nausea, vomiting, abdominal discomfort, diarrhea.
It is associated with first generation sulphonylureas.
1.5. Alpha-glucosidase inhibitors: Acarbose, Miglitol, Vogliboza
Mechanism of action: inhibit alpha-glucosidase which delays the absorption of
carbohydrates (dextrins, maltose, sucrose, lactose not) from intestine, resulting
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a reduced postprandial increase of blood glucose and increases the effect of
insulin.
Adverse effects: due to fermentation of carbohydrats in intestine: flatulence,
abdominal meteorism, diarrhea.
It is associated with biguanides, sulfonylureas, insulin.
1.6. Thiazolidinediones: Troglitazone, Pioglitazone, Englitazone,
Ciglitazone, Rosiglitazone
Mechanism of action: increase sensitivity to insulin receptor target cells.
Pharmacodynamic effects: - potentiates the action of insulin;
- increase glucose uptake and glucose oxidation in
muscle and adipose tissue;
- reduce hepatic gluconeogenesis.
Indications: - type 2 diabetes;
- patients resistant to insulin therapy (usually in patients with
hypertension, hyperlipidemia, atherosclerosis);
- prophylaxis to reduce the recurrence of diabetes in high-risk
women with a history of gestational diabetes.
Adverse effects:
- weight gain;
- decrease in hemoglobin and hematocrit (dose-dependent);
- changes in liver function tests (hepatotoxicity), abdominal pain, nausea,
vomiting, anorexia, fatigue, or dark urine, increases in CPK and LDH are
transient and have no pathological significance;
- haemodilution fluid retention, peripheral edema;
- other adverse effects (2% placebo): respiratory infections (11%), sinusitis,
dental disease, headache, fatigue, dizziness, nausea, flatulence, constipation /
diarrhea, visual disturbances, arthralgia, pain in the back of the chest, myalgia,
muscle cramps, numbness and tingling.
1.7. Inhibitors of aldozreductaze: Tolrestat
Mechanism of action:
- aldozreductaze is inhibited by inhibiting the conversion of glucose to fructose,
and further, so the transformation of fructose into sorbitol, which enhances the
toxic effects of glucose and increases the effect of insulin.
Indications: prevention or reduction of nephropathy, retinopathy, neuropathy in
diabetes mellitus.
Adverse effects: nausea, vomiting.
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 Lecture 23
Drugs affecting sex hormones

Learning Objectives:
 Name the hormones produced by the male and female gonads and describe
their function.
 Classify analogs and inhibitors drugs of sex hormones.
 List main indications and adverse effects of analogs and inhibitors drugs of sex
hormones.
 Describe the major side effects of sex hormone therapy.
 Describe the various types of contraceptives available.

Mechanism of action of drugs affecting sex hormones: bind to specific

nuclear receptors  the complex hormon-receptor binds to DNA 
stimulate specific protein synthesis.

1. Drugs affecting androgens

Natural androgens: testosteron, dihydrotestosteron, androstenedione,
dehydroepiandrosterone.
Natural androgens have anabolic and androgenic properties.
Testosterone is the main androgenic hormone. It is formed in the
interstitial (Leydig) cells of the testes and, in small quantities is derived
from the metabolism of less potent androgens secreted by the adrenal
cortex and ovaries.
Testosterone is converted to dihydrotestosterone by 5-alpha reductase in
many target tissues (dihydrotestosterone is the major active androgen of
these tissues). Some testosterone also undergoes peripheral conversion to
estradiol.
Physiological effects of testosterone:
- normal maturation in men (controls the development of the male sex
organs and secondary sex characteristics),
- stimulate and maintain sexual function in men (stimulate and maintain
spermatogenesis),
- produces systemic anabolic effects: stimulate skeletal growth and

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accelerate epiphysial closure, increase synthesis of muscle proteins,
increase retention of nitrogen, calcium, sodium, potassium, chloride, and
phosphate,
- increases erythropoiesis.
In therapy are used:
1.1. Androgens and anabolic androgens
- Natural androgens: Testosterone (activity of natural testosterone is
improved by esterification propionate, enantate, cypionate, undecanoate)
- for i.m. administration: Testosterone propionate, Testosterone
enantate, Testosterone cypionate, Testosterone undecanoate
- for sublingual administration: Testosterone propionate
- for transdermal administration: Testosterone
Indications:
- androgen replacement therapy in men (caused by testicular [
primary hypogonadism] or pituitary deficiency [ secondary
hypogonadism; treatment should be started in puberty]),
- delayed puberty or growth in boys,
- premenopausal women with breast tumors,
- in combination with estrogens in postmenopausal women
(eliminate endometrial bleeding),
- as anabolic (to reverse protein loss after trauma, surgery, or
prolonged immobilization and in patients with debilitating diseases),
- anemia (in refractory anaemias, such as aplastic anaemia),
- as male contraceptives (high doses reduce spermatogenesis).
Adverse effects:
- retention of sodium and water, hypercalcemia,
- increase LDL-cholesterol, decrease HDL-cholesterol, increase
haematocrit,
- large doses in adult men  suppress spermatogenesis, cause
degenerative changes in the seminiferous tubules, gynaecomastia,
- large doses in adult boys in early puberty  closure of the
epiphyses, stop linear growth, precocious sexual development,
- in women  suppression of ovarian activity and menstruation,
virilism (hirsutism or male-pattern baldness, deepening of the voice,

436
atrophy of the breasts and endometrial tissue, oily skin, acne, increased
libido, suppressed lactation). Masculinisation of the external genitalia of
the female fetus may occur if androgens are given during pregnancy.
Contraindications: - pregnancy,
- neoplasms of the prostate or breast,
- infants and young children.
- Semisynthetic androgens:
- Methyltestosterone, Fluoxymesterone: oral administration, but
have hepatotoxic effects,
- Mesterolone (is not metabolised to estrogens  not inhibit
gonadotrophin secretion or spermatogenesis).
- Androgens with anabolic activity (androgenic anabolic activity is
compared to testosteone):
- Testosterone (1:1)
- Nandrolone phenpropionate (1:3 – 1:6)
- Nandrolone decanoate (1:2.5 – 1:4)
- Ethylestrenol (1:4 – 1:8) (androgenic effect and slight
progestational activity)
- Stanozolol (1:3 – 1:6)
- Drostanolone propionate (Dromostanolone) (1:3 – 1:4)
- Methandienone (Methandrostenolone) (1:3) (anabolic, some
androgenic and little progestational activity)
- Oxymetholone (1:3)
- Oxandrolone (1:13)
Indications: anabolic after debilitating illness
Adverse effects similar to testosterone.
1.2. Androgen suppression and antiandrogens
- Androgen suppression: Gn-RH analogues (Leuprolide, Nafarelin,
Goserelin, Buserelin, Histrelin)
- Antiandrogens: - steroid synthesis inhibitors: Ketoconazole
- 5-alpha reductase inhibitors (inhibits conversion of steroid
precursors to androgens): Finasteride, Dutasteride
- androgen receptors inhibitors:
- Cyproterone acetate,

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 - Flutamide, Bicalutamide, Nilutamide
- Spironolactone.
Ketoconazole
Indications: - antifungic drug.
- for anti-androgenic effects: prostatic cancer, hirsutism,
precociuos puberty.
5-alpha reductase inhibitors: Finasteride, Dutasteride
Mechanism of action: inhibits 5-alpha reductase which convert steroid
precursors to androgens
Indications: - benign prostatic hypertrophy
- alopecia androgenetica in men
Adverse effects: decreased libido, erectile dysfunction, ejaculation
disorders, gynaecomastia.
Cyproterone acetate
Mechanism of action: androgen receptors inhibitor (Cyproterone acetate
has marked progestational effects)
Indications: - hirsutism in women,
- control of libido (in men to decrease excessive sexual
drive),
- hormonal contraceptive.
Flutamide, Bicalutamide, Nilutamide
Mechanism of action: competitive antagonist at the androgen receptors.
Indications: prostatic carcinoma.
Adverse effects: gynecomastia, hepatotoxicity.
Spironolactone
Mechanism of action: competitive antagonist at the aldosterone
receptors.
Indications: - potassium-sparing diuretic,
- refractory oedema associated with liver cirrhosis,
nephrotic syndrome,
- ascites associated with malignancy,
- heart failure,
- primary hyperaldosteronism,
- hirsutism, particularly in the polycystic ovary syndrome.

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 2. Drugs affecting progestins
Natural progestins: progesterone.
Progesterone is the main hormone secreted by the corpus luteum.
Physiological effects of progesterone:
- acts on the endometrium by converting the proliferative phase induced
by oestrogen to a secretory phase thereby preparing the uterus to receive
the fertilised ovum,
- catabolic action
- causes a slight rise in basal body temperature during the secretory phase
of menstruation,
- during pregnancy the placenta produces large quantities of
progesterone, which suppresses uterine motility and is responsible for the
further development of the breasts.
Progestins are synthetic progestogens that have progestogenic effects
similar to those of progesterone.
In therapy are used:
2.1. Natural and synthetic progestins:
- Natural: Progesterone.
- Synthetic progestins:
-21-carbon compounds:
- progesterone derivatives: Hydroxiprogesterone,
Medroxyprogesterone, Megestrol
- 17-ethyniltestosterone derivative: Dimethisterone
-19-carbon compounds: Norgestrel, Desogestrel, Norethindrone
(Noretisterone), Ethynodiol, Lynestrenol (Ethynylestrenol), Noretynodrel
- other compounds: Allylestrenol, Dienogest, Gestodene,
Norgestimate, Ethisterone (Ethynyltestosterone), Norelgestromin,
Etonorgestrel, Danazol
Indications: - replacement therapy (caused by primary hypogonadism),
- contraception (alone or in combination with estrogens),
- test diagnostic of estrogen secretion.
Adverse effects: - headache,
- depression,
- weight gain (for androgen-like progestins:

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 Norgestrel, Norethindrone, Ethynodiol, Levonorgestrel,
Lynestrenol),
- hirsutism (aggravated by the 19-nortestosterone
derivatives: Norgestrel, Desogestrel, Norethindrone,
Ethynodiol, Lynestrenol, Noretynodrel),
- changes in libido.

2.2. Inhibitors and antagonists of progestins:

- antagonist of progesterone and glucocorticoid receptors: Mifepristone.
Mifespristone
Mechanism of action: antagonist of progesterone and glucocorticoid
receptors
Indications: - contraception (emergency contraception),
- abortion,
- endometriosis,
- breast cancer,
- Cushing syndrome.
Adverse effects: prolonged bleeding, incomplete abortion.

3. Drugs affecting estrogens

Natural estrogens: estradiol, estrone, estriol.
Estradiol is the major secretory product of the ovarian follicles. Some
estrone is produced in the ovary. Most estrone and estriol are formed in
the liver from estradiol or in peripheral tissues (adipose tissue) from
androstenedione and other androgens.
Physiological effects of estrogens:
- normal maturation in women (controls the development of the female
sex organs and secondary sex characteristics),
- functions of the uterus and its accessory organs: endometrial
development (proliferation of the endometrium, the development of the
decidua), the cyclic changes in the cervix and vagina,
- induce synthesis of progesterone receptors.
In therapy are used:
3.1. Natural and synthetic estrogens:

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- Natural: Estradiol, Estrone, Estriol.
Oral activity of natural oestrogens is improved by esterification
( estradiol valerate, estriol cypionate) or by conjugation (
estrone sulfate).
- Semisynthetic and synthetic estrogens:
- steroidal structure: Ethinyl-estradiol, Estropipate, Mestranol,
Quinestrol
- nonsteroidal structure: Diethylstilbestrol, Chlorotrianisene,
Dienestrol, Methallenestril, Hexestrol.
Indications: - estrogen replacement therapy (caused by primary
hypogonadism),
- postmenopausal hormone therapy (to reduce „hot
flushes” and vaginal atrophy),
- contraception (in combination with progestins).
Adverse effects: - uterine bleeding.
- risk of endometrial carcinoma,
- Nausea and breast tenderness,
- migraine headaches,
- cholestasis, gallbladder disease,
- hypertension.
Contraindications: - estrogen-dependent neoplasms,
- undiagnosed genital bleeding,
- liver disease,
- history of thromboembolic disorder,
- heavy smokers.
3.2. Inhibitors and antagonists of estrogens:
- Selective estrogen-receptor modulators:
- Estrogen partial antagonist: Tamoxifen, Toremifene
- Estrogen partial agonist-antagonist: Raloxifene
- Estrogen partial agonist and inhibitor of endogenous
estrogens: Clomiphene
- Estrogen receptor antagonist: Fluvestrant
- Inhibitors of aromatase:
- steroidal inhibitors: Testolactone (weak inhibitor),

441
 - nonsteroidal inhibitors: Anastrozole, Letrozole (selective
inhibitors), Exemestane (irreversible inhibitor), Fadrazole
Tamoxifen, Toremifene
Mechanism of action: estrogen partial antagonist
Indications: breast cancer
Adverse effects: hot flushes, nausea, mennstrual irregularities, vaginal
bleeding.
Raloxifene
Mechanism of action: estrogen partial agonist-antagonist
Indications: osteoporosis and prevention of breast cancer in
postmenopausal women.
Adverse effects: hot flushes, thrombosis.
Clomiphene
Mechanism of action: estrogen partial agonist and inhibitor of
endogenous estrogens
Indications: induce ovulation.
Adverse effects: hot flushes, headache, enlargement of ovaries, multiple
pregnancy.
Fluvestrant
Mechanism of action: estrogen receptor antagonist
Indications: breast cancer resistant to Tamoxifen
Inhibitors of aromatase
Classification: - steroidal inhibitors: Testolactone (weak inhibitor),
- nonsteroidal inhibitors: Anastrozole, Letrozole (selective
inhibitors), Exemestane (irreversible inhibitor), Fadrazole
Indications: breast cancer resistant to Tamoxifen
Ovulation-inducing agents:
- estrogen partial agonist and inhibitor of endogenous estrogens:
Clomiphene
- menotropins (or human menopausal gonadotropin):
- menotropins (hMG) is a purified extract of FSH and LH
- urofollitropine (uFSH) is a purified preparation of human FSH
- follitropin alpha (rFSH) is recombinant FSH
- human chorionic gonadotropin (hGC).

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- synthetic gonadotropin: Gonadorelin
- GnRH antagonists: Cetrorelix acetate
Indications: induce ovulation.
Adverse effects: hot flushes, headache, enlargement of ovaries, multiple
pregnancy.

4.Hormonal contraception
Classification of hormonal contraceptives:
1. Chemical contraception in women:
1.1. Combined oral contraceptives (contain two synthetic steroid hormones: an estrogen
and a progestin)
- Oral contraceptives:
- Types of combinations:
- monophasic (constant dosage of estrogens and progestins during the cycle)
- biphasic (dosage of progestins is changed once during the cycle)
- triphasic (dosage of one or both commponents are changed once or twice
during the cycle)
- contain: - Estrogens: Ethynil estradiol, Mestranol
- Progestins:
• First generation:
1) Estranes derived from testosterone: norethindrone,
norethynodrel, norethindrone acetate, ethynodiol
diacetate
2) Pregnanes derived from 17-OH progesterone:
medroxyprogesterone acetate, chlormadinone acetate
• Second generation are Gonanes derived from testosterone:
levonorgestrel, norgestrel, Lynestrenol?
• Third generation are Gonane (Levonorgestrel) derivatives:
desogestrel, gestodene, norgestimate/norelgestromine,
etonorgestrel
• Fourth generation
1) Non ethylated estranes: dienogest, drospirenone
2) Pregnanes (19-norprogesterones): nestorone,
nomegestrol acetate, trimegestone.
- transdermal patch: Ethynyl estradiol + Norelgestromin
- vaginal ring: Ethynyl estradiol + Etonorgestrel
1.2. Progestins only: Norethindrone, Norgestrel, Levonorgestrel.
2. Chemical contraception in men:
- Testosterone, Testosterone enantate

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 - combinations: Testosterone + Danazol, androgens + progestins
(Medroxyprogesterone acetate)
- Cyproterone acetate
- Gossypol
- Gn-RH analogues – in study.
Hormonal contraceptives in women are indicated for:
- contraception,
- endometriosis,
- menstrual disorders (severe dysmenorrhoea, premenstrual syndrome,
menorrhagia),
- polycystic ovary syndrome,
- acne and hirsutism (those containing non-androgenic progestogens).
Progestogen-only oral contraceptives are indicated for women when an
oestrogen component is contra-indicated.
Emergency contraception (postcoital contraception or “morning after
pill”)
- is indicated within 72 h of intercourse.
- prevent implantation, prevent or delay ovulation, disrupt ovum
transport, and alter corpus luteum function
- are used:
- high doses of progestin (Levonorgestrel)
- high doses of estrogens associated with progestins
(Ethynylestradiol + Levonorgestrel)
- Mifepristone (antagonist at progesterone and
glucocorticoid receptors)
Adverse effects of oral contraceptives in women:
- severe Adverse effects:
- vascular effects: venous thromboembolic disease, myocardial
infarction, cerebrovascular disease. This risk appears to be concentrated
in women 35 years of age or older who are heavy smokers.
- gastrointestinal disorders: cholestatic jaundice, gallbladder
disease (including cholecystitis and cholangitis),
- depression,
- cancer: reduce the risk of endometrial and ovarian cancer, but
increase the risk of cervical and breast cancer.

444
- moderate Adverse effects:
- breakthrough bleeding (most common for progestational agents alone),
- breast fulness,
- fluid retention (edema),
- weight gain (common for combination containing androgen-like
progestins: Norgestrel, Norethindrone, Ethynodiol, Levonorgestrel,
Lynestrenol),
- skin pigmentation (especially in dark-skinned women),
- acne may be exacerbated by agents containing androgen-like progestins,
- hirsutism (aggravated by the 19-nortestosterone derivatives: Norgestrel,
Desogestrel, Norethindrone, Ethynodiol, Lynestrenol, Noretynodrel),
- folic acid deficiency anemia,
- vaginal infections,
- amenorrhea (95% of patients  for next few months, some  for
several years).
- mild Adverse effects:
- nausea, mastalgia, breakthrough bleeding, edema (related to the
amount of estrogen),
- headache,
- changes in glucose tolerance,
- oestrogen component increases triglycerides and HDL, but
decreases LDL, whereas the progestogen component decreases HDL and
increases LDL, particularly if it is androgenic.
Contraindications of oral contraceptives in women:
- pregnancy,
- thrombophlebitis, thromboembolic phenomena, cardiovascular and
cerebrovascular disorders,
- estrogen-dependent neoplasm,
- liver disease, asthma, eczema, migraine, diabetes, hypertension, optic
neuritis, retrobulbar neuritis, or convulsive disorders.
Gossypol
Mechanism of action: destroys elements of the seminiferous epithelium
but does not alter the endocrine function of the testis.
Adverse effects: hipokaliemia (may lead to transient paralysis).

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 Index

A D

Acetaminophen · 14 Dactinomycin · 26
acethylsalicylic acid · 25 Deferoxamine · 14
Acetylcholine · 17 Dextran · 13
acetylsalicylic acid · 37 Diazoxide · 26
Acetylsalicylic acid · 34 Digoxin · 14
activated charcoal · 14, 32 Diltiazem · 26
adrenaline · 31 Dimercaprol · 14
Adrenaline · 17, 32 Doxorubicin · 26
Aluminium hydroxide · 14 d-Tubocurrarine · 27
Amiloride · 25
aminoglicozide · 260
aminoglycosides · 26, 34 E
amphetamine · 27
Amphotericin B · 26 ephedrine · 35
atrial natriuretic peptide · 22 Ephedrine · 27
epidermal growth factor · 22
Erythromycin · 26
B Esomeprazole · 18

Benzodiazepines · 24
betacarbolins · 17 F
bromide · 34
Felodipine · 26
Flumazenil · 31
C folic acid · 25

Calcium carbonate · 14
Captopril · 25 G
Carbachol · 27
Carmustine · 26 Gallamine · 18, 32
Chloramphenicol · 26 glucocorticoid · 24
Cholestyramine · 14 Glyburide · 26
Cimetidine · 28 Glycerol · 13
Citalopram · 18
Cyclophosphamide · 26

446
 Nystatin · 27
H

Hetastarch · 13 O
Hidralazine · 34
histamine · 28, 31
Omeprazole · 18
Histamine · 32

P
I
Penicillamine · 14
Ibuprofen · 25
Phenylephrine · 27
Indomethacin · 37
Pindolol · 17
insulin · 22
Polycarbophil · 13
iodine · 34
Polygeline · 13
Isosorbide · 13
Prazosin · 17
Ispaghula · 13
Procainamide · 25
Propafenone · 25
Propranolol · 17
L
Protamine sulfate · 14
Psyllium · 13
Lactulose · 13
Lidocaine · 10, 25
Lignocaine · 10 Q
Lomustine · 26

Quinidine · 25

M
S
magnesim sulphate · 30
Magnesium hydroxide · 13, 14
Sodium bicarbonate · 14
Magnesium sulfate · 13
Sodium phosphate · 13
Mannitol · 13
Sodium potassium tartrate · 13
Methylcellulose · 13
Sodium sulfate · 13
Methyldopa · 34
Sorbitol · 13
Minoxidil · 26
Succinylcholine · 23, 33
Morphine · 27
sulfonamides · 33, 34
Sulfonamides · 25

N
T
Naphazoline · 27
Nifedipine · 26
Tetracicline · 294
Nitroglycerine · 35
tetracyclines · 14
norepinephrine · 27
Tetracyclines · 26

447
titanium dioxide · 14
W
Tolbutamide · 26

Warfarin · 25
V
Z
Vancomycin · 36
Varenicline · 17
zinc oxide · 14
Verapamil · 26
Zolpidem · 30
vitamin K · 25

448
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