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MCQ:
Subjects
Chapter
1-General Pharmacology
2-A.N.S.
3-C.V.S.
4-Diuretics
5-Respiration
6-Autacoids
7-Blood
8-G.I.T.
9-C.N.S.
10-Endocrine
11-Chemotherapy
MCQ
:
Subjects
Chapter
1-Pharmacokinetics:
-Transmembrane movement of drugs.
-Factors affecting absorption.
-Metabolism (Biotransformation).
-Excretion.
2-Pharmacodynamics.
1-General:
1-Parasympathomimetics:
Choline esters-Pilocarpine.
2-Parasympatholytics: Atropine-Atropine substitutes-Hyoscine.
3-Sympatomimetics: Noradrenaline-Isoprenaline-Ephedrine-Vasopressors-Nasal
decongestants-B2 agonists
4-Sympatholytics: Non-selective alpha blockers-Yohimbine.
Cough therapy.
Histamine-Leukotrienes-Ergot alkaloids and Migraine.
--------------------------------------------------------------------------------------------------Anti-arrhythmic drugs.
1-Fibrinolytics.
2-Drugs used to treat bleeding (hemostatics and coagulants).
1-Bz receptor agonists-Buspirone-Chloral hydrate.
2-Opioid analgesics: Semisynthetic-Methadone-Propoxyphene-Mixed agonist antagonists.
3-NSAIDs other than Salicylates and Paracetamol.
4-Antiepileptic drugs: Ethosuximide.
5-Antiparkinsonian drugs: MAO-B inhibitors-COMT inhibitors-Amantadine-AnticholinergicsDrugs contraindicated in Parkinsonism.
6-Antidepressants and Lithium
7-Antipsychotics.
8-CNS stimulants: Methylxanthines.
1-Other purgatives.
2-Emetics.
3-Treatment of: Ulcerative colitis-Diarrhea-Colics.
1-Mineralocorticoids-Adrenostatics.
2-Calcium homeostasis.
3-Glucagon.
4-Sex hormones (Estrogen-Progestogens)-Antiestrogens (SERMs).
5-Thyroid hormones.
1-Vancomycin. 2-Teicoplanin.
3-Sulfonamides-Trimethoprim-CoTrimoxazole.
4-Anti-T.B. drugs. 5-Antiviral drugs. 5-Antifungal drugs. 6-Praziquantel.
2-A.N.S.:
3-Respiration:
4-Autacoids:
5-Diuretics:
6-C.V.S.:
7-Blood:
8-C.N.S.:
9-G.I.T.:
10-Hormones:
11-Antibiotics:
:
Day 1 (4 June): General Pharmacology Clinical Pharmacology.
Day 2 (5 June): CNS.
Day 3 (6 June): Hormones.
Day 4 (7 June): Antibiotics.
3
Important notes:
1-This is not an obligatory schedule, you can make your own schedule.
2-In any schedule you should leave the last 2-3 days for revision.
3-The most important chapters in the final ESSAY AND MCQ exams-according to the marks are
CNS, CVS, CHEMOTHERAPY, and ENDOCRINE.
4-Do not forget that there will be a 10 mark question about GENERAL PHARMACOLOGY in
paper 1 (essay exam).
5-Try to READ the MCQs in the departments book after studying each chapter, especially in
second term chapters (about 70-80% of MCQs will be about second term chapters; mainly on
CNS, Chemotherapy, and Endocrine).
6- Please DO NOT TEST YOURSELF, JUST READ AND UNDERSTAND THE ANSWERS.
7-In paper (1) take good care of the time, each of the 8 questions should not take more than 15
minutes.
8-The form of your exam is very similar to the exams of the last 3 years, so please take a look
at these exams in the department book of MCQ (Question Bank).
.
General Pharmacology
1-Effect of pH on oral absorption and renal excretion
The presence of acidic drugs as salicylates and barbiturates- in acidic medium as the stomach
and urine increases the unionized form of the drug which is lipid soluble (lipohilic), but the
presence of acidic drugs in alkaline medium as the small intestine increases the ionized form
which is lipid insoluble (hydrophilic) leading to "ion trapping".
On the other hand; the presence of basic drugs as ephedrine and amphetamine- in acidic
medium increases the ionized form (ion trapping) and their presence in alkaline medium
increases the unionized form.
1-Gastric acidity increases oral absorption of acidic drugs as salicylates (aspirin) and barbiturates
(phenobarbitone).
2-Intestinal alkalinity increases oral absorption of basic drugs as ephedrine and amphetamine.
3-Acidifation of urine (e.g. by ammonium chloride or vitamin C) increases excretion of basic
drugs (ion trapping) but reduces excretion of acidic drugs.
4-Alkalinization of urine (e.g. by sodium bicarbonate) increases excretion of acidic drugs (ion
trapping) but reduces excretion of basic drugs.
7-Saturation of enzymes or carriers responsible for 7-No saturation of enzymes or carriers responsible for
drug elimination.
drug elimination.
8-Examples: large doses of aspirin, phenytoin, and
alcohol.
3-Valency: Ferrous salts are better absorbed than the Ferric salts.
4-Nature of the drug: inorganic drugs are better absorbed than organic.
5-Drug formulation: Paracetamol has a rapid rate of dissolution and is rapidly absorbed.
4-Bioavailability:
Definition: the fraction (percent or proportion) reaching the systemic circulation
chemically unchanged following administration by any route.
Factors affecting oral bioavailability: = Factors affecting oral absorption.
Calculation of oral bioavailability:
AUCoral
Oral Bioavailability=
X 100
AUCIV
7-Types of Antagonism
See Drug Interactions ((DI) in Applied Medical Pharmacology book, volume I.
Causes:
1-Occupational: inhalation or skin contamination during spraying insecticides as parathion and
malathion by farmers.
2-Accidental ingestion of insecticides or contaminated fruits and vegetables.
3-Suicidal ingestion of insecticides.
4-Exposure to war gases as sarin, tabun, and soman.
Mechanism of OPC:
OPC bind to the esteratic site of acetylcholinesterase, first by a loose bond, but soon the bond
becomes covalent causing irreversible inhibition of the enzyme (aging of the enzyme), leading to
accumulation of endogenous acetylcholine. Acetylcholine over-activates cholinergic receptors
(Muscarinic and Nicotinic) both peripherally and centrally.
Clinical Manifestations:
1-Muscarinic effects: bradycardia-hypotension-increased bronchial secretion-bronchospasmsalivation-lacrimation-excessive sweating-miosis-abdominal cramps, colics, diarrhea-involuntary
passage of stools and urine.
2-Nicotinic effects: twitches and fasciculations of skeletal muscles followed by flaccid paralysis
of skeletal muscles which may cause death due peripheral respiratory failure.
(N.B.: stimulation of sympathetic ganglia may lead to tachycardia and hypertension in some
cases).
3-CNS effects: headache, dizziness, tremors, anxiety, confusions, convulsions, coma, and death
due to depression of R.C. (central respiratory failure).
Treatment:
A-General supportive treatment:
1-Endotracheal intubation and oxygen.
2-Position: comatose patient is kept in lateral position, head down, and neck extension.
3-Decontamination:
In case of skin contamination: remove contaminated clothes and wash the skin with soap and
water.
In case of oral ingestion: gastric lavage within 1-2 hours of ingestion, and activated charcoal to
adsorb the poson and reduce systemic absorption.
N.B.: decontamination is performed after the patient is fully stabilized and not immediately after
admission.
B-Specific antidotal treatment:
1-AtropineIV (bolus followed by infusion):
Atropine is a competitive antagonist with acetylcholine at M-receptors (not N-receptors) both
peripherally and centrally. Atropine is given until the following
target end-points are achieved:
Tachycardia: heart rate over 80 beats / minute.
Mydriasis (dilted pupils).
Sweating (dry axillae).
A.B.P. (diastolic BP over 80 mmHg.).
Bronchial secretions (clear chest with absence of wheezes).
2-Oximes (cholinesterase reactivators):
Pralidoxime is the most commonly used oxime.
Oximes bind to the anionic site of cholinesterase and attract OPC leading to free enzyme.
Oximes should be given early before aging of the enzyme.
The main advantage over atropine is restoration of skeletal muscle strength and improvement
of diaphragmatic weakness.
3-Benzodiazepines:
Diazepam IV and other benzodiazepines are given to control CNS stimulation as convulsions
(seizures) due to OPC or sometimes due to atropine therapy.
1- Physostigmine
Synthetic.
Carbamate-quaternary ammonium.
1-Source:
2-Chemistry:
3-Pharmacokinetics
-Absorption:
-Distribution:
-Fate:
4-Mechanism of action:
5-Pharmacological
actions:
6-Therapeutic uses:
As physostigmine.
Bradycardia-hypotension
-bronchospasm and bronchial
secretion- HCl secretion.-CNS
stimulation (convulsions).
7-Adverse effects:
As physostigmine (except
parkinsonism).
Bradycardia-hypotension-bronchial
asthma-peptic ulcer-hyperthyroidismparkinsonism.
8-Contraindications:
Manifestations: as physostigmine
except CNS Treatment: stomach
wash and atropine.
Manifestations:
-Muscarinic: bradycardia-hypotension,
bronchospasm, miosis.
-Nicotinic: twitches of skeletal muscles.
-CNS: convulsions, coma, death to
depression of R.C
Treatment:
1-Stomach wash.
2-Artificial respiration.
3-Specific antidote= atropine.
4-Anticonvulsants.
9-Acute toxicity:
Sympathomimetics
1-Adrenaline (Epinephrine)
*Mechanism of action:
Direct agonist that stimulates (activates) all types of adrenergic receptors: all receptors (1, 2,
3), and all receptors (1, 2).
*Pharmacological actions:
A-Local actions:
1-Eye: decongestion and reduction of IOP (1), but no mydriasis except in cases of
supersensitivity as glaucoma, pancreatitis.
2-Bronchi: bronchodilatation (2) and decongestion (1).
3-Skin and mucous membranes: decongestion, hemostatsis, and prolongation of the duration of
local anesthesia and decrease of systemic effects. All these actions are due to V.C. (1).
B-Systemic actions:
I-CVS:
1-Heart: adrenaline increases all cardiac properties (1) including: heart rate (positive
chronotropic)-conductivity (positive dromotropic)-contractility (positive inotropic)excitability-rhythmicity. Adrenaline also increases cardiac output and myocardial oxygen
demands.
2-Blood vessels: V.C. of blood vessels of skin and mucous membranes (1) but vasodilatation of
coronary blood vessels and skeletal muscle blood vessels (2)
3-Arterial blood pressure (ABP): adrenaline elevates ABP (pressor effect)
elevates systolic BP due to increase in cardiac output mainly-the effect on diastolic BP is
variable: in small doses there is reduction in DBP due to vasodilatation of skeletal muscle
blood vessels, but with higher doses there is vasoconstriction especially in skin and
mucous membrane blood vessels and DBP may rise-finally adrenaline markedly increase
pulse pressure.
Adrenaline reversal: adrenaline elevates ABP but when given after alpha blockers as
phentolamine, adrenaline decreases ABP. This is due to the unopposed action of
adrenaline on 2 receptors leading to vasodilatation and hypotension.
II-Smooth muscle fibers:
1-Bloov vessels: see before.
2-Eye: active mydriasis due to stimulation of 1 receptors in dilator pupillae muscle.
3-Bronchi: bronchodilatation (2).
4-GIT: relaxation of the wall ( and ) and contraction of sphincter (1).
5-Urinary bladder: relaxation of the wall=detrusor muscle (2) and contraction of the sphincter
and trigone (1) leading to urine retention.
6-Male sex organs: ejaculation of semen (1).
7-Uterus: variable action but adrenaline relaxes the uterus in human females in late pregnancy
and during labor (2).
8-Pili-erector muscle: contraction (1).
9-Nictitating membrane in cats: contraction (1).
III-Exocrine glands:
1-Salivary glands: thick viscid saliva.
2-Sweat glands: adrenaline increases sweating from apocrine (non-thermoregulatory) sweat
glands in palm and sole (1), but has no effect on eccrine (thermoregulatory) sweat glands
which contain M3 receptors and not 1.
IV-CNS: adrenaline poorly penetrates BBB so it causes mild CNS stimulation causing tremors,
irritability, and anxiety (1).
V-Metabolic actions:
1-Calorigenic action: adrenaline increases BMR, oxygen consumption, and heat production.
11
*Drug interactions:
1-With general anesthesia as halothane sensitization of the heart to catecholamines
arrhythmias (treated by -blockers).
2-With LA as procaine prolongation of action of L.A., reduction of systemic toxicity of LA as
convulsions, and hemostasis.
3-With cocaine severe V.C. which may lead to gangrene.
4-With LA in fingers, toes, and circumscision gangrene.
2-DOPAMINE.
*Pharmacokinetics:
1-Absorption: not absorbed orally, given by I.V. drip.
2-Distribution: poor passage across B.B.B.
3-Fate: metabolized by COMT and MAO (mainly) into homovanilic acid (HVA) which is
excreted in urine.
*Pharmacodynamics:
-Mechanism of action: direct stimulation of specific dopaminergic (D1) receptors, 1-receptors,
and 1-receptors according to the rate of infusion.
- Pharmacological actions: depend on the rate of infusion as follows:
1-Slow rate of infusion (2.5-5 g/kg/minute): dopamine stimulates D1-receptors in blood vessels
leading to V.D. especially renal, mesenteric, and coronary blood vessels, which increases blood
flow to the vital organs as the kidney.
2-Moderate rate of infusion (5-10 g/kg/minute): dopamine stimulates cardiac 1-receptors
leading to increase in COP.
3-Rapid rate of infusion (> 10 g/kg/minute): dopamine stimulates 1-receptors leading to V.C.,
increase in TPR and ABP.
(Renal V.C. leads to acute renal failure and death).
*Therapeutic uses:
1-Shock (hypovolemic, cardiogenic, and endotoxic): dopamine is given at a slow-moderate rate
to increase tissue perfusion and blood flow to vital organs as the kidney, and to increase COP and
accordingly urine output and ABP especially systolic - increase.
13
Blood volume should be corrected, e.g. by blood transfusion, before administration of dopamine
"fill up then open up".
2-Heart failure: especially acute and resistant heart failure, dopamine is given in a moderate
infusion rate.
*Adverse effects:
1-Tachycardia, palpitation, arrhythmias (ventricular), and anginal pains due to direct and reflex
1-stimulation (treated by 1- blockers).
2-Hypertension if given with MAO inhibitors or in rapid infusion rate due to 1-stimulation
(treated by 1- blockers).
3-Nausea and vomiting (due to stimulation of D2-receptors in C.T.Z.)
4-weak CNS actions as headache and anxiety.
*Important notes:
1-Dopamine is not effective in treatment of Parkinsonism as it cannot pass B.B.B., but its
precursor L-dopa can pass easily and is converted into dopamine by dopa decarboxylase in CNS.
2-Dopamine receptor subtypes are D1, D2, D3, D4, and D5 (see CNS).
3-To antagonize the pharmacological actions of dopamine we have to block the following
receptors:
-D1- receptors: by dopaminergic antagonists as "haloperidol".
-1- receptors by: 1-blockers as" propranolol".
-1- blockers by: 1-blockers as "phentolamine".
4-The dose of dopamine should be reduced in patients treated with MAO inhibitors to avoid
elevation of ABP (explain).
5-Precautions during infusion: monitor heart rate by ECG -monitor ABP and urine volume
-replace fluids before dopamine -avoid extravasation-stop infusion gradually.
3-Dobutamine
Source: synthetic.
Chemistry: catecholamine.
Pharmacokinetics: Given by I.V.infusion-Does not cross BBB-metabolized by MAO.
Pharmacodynamics:
1-Direct selective B1 agonist.
2-Positive inotropic with much less increase in heart rate (more inotropic than chronotropic).
3-Almost no effect on T.P.R., i.e. no vasoconstriction (no action on alpha1) or vasodilatation (no
effect on D1).
Therapeutic uses:
1-Cardiogenic shock as due to acute myocardial infarction.
2-Acute heart failure (especially with hypotension).
Adverse effects:
1-Tachycardia, palpitation, arrhythmia, angina pains if given in large doses (less than dopamine).
2-Nausea and vomiting.
Isoprenaline
Dobutamine
Dopamine
Synthetic.
Synthetic.
Natural.
Summary of Catecholamines:
Noradrenalin
Adrenaline
e
Natural.
Natural.
Source:
as adrenaline.
as adrenaline.
as adrenaline.
as adrenaline.
as adrenaline.
as adrenaline.
as adrenaline.
as adrenaline.
1-S.L.
2-Inhalation.
3- I.V. infusion
(drip).
I.V. infusion
(drip).
I.V. infusion
(drip).
I.V. infusion
(drip).
1,2,3 no
selective 1
no D or .
Minimal effect
(more ino- than
chrono- and no
effect on blood
vessels).
H.R.both
directly and
reflexly-A.B.P.
(diastolicvariable effect
on systolicpulse
pressure).
1-AV block.
2-Asthma.
1-Cardiogenic
shock (due to
myocardial
infarction).
2-Heart failure.
, 1.D1,
Mainly 1 weak
1 no 2.
H.R. (slowH.R. (reflex)moderate rate)A.B.P. (both
A.B.P (rapid
systolic and
rate).
diastolic-no
effect on pulse
pressureabolished after blockers).
1-Shock. To elevate A.B.P.
2-Heart failure.
in severe
hypotension.
1
*Catechol.
*L-isomer is
more active.
*Unstable.
*Not absorbed.
*Poor passage
across BBB.
*Metabolism by
MAO and
COMT-uptake.
1-S.C.
2-Inhalation.
3-Eye drops.
4-Nasal pack.
5-Intracardiac.
All and .
Chemistry
Kinetics:
Route(s):
Agonist on:
H.R. -A.B.P.
(systolicvariable effect on
diastolic-pulse
pressure-reversed
after -blockers).
Action on
H.R. and
A.B.P.:
1-Anaphylactic
shock.
2-Cardiac
resuscitation.
3-With L.A.
4-Decongestant
5-Hemostatic.
6-Asthma.
7-Glaucoma.
8-Contraction
ring of uterus.
Uses:
Adrenaline
Chemistry: Catecholamine.
Mechanism of action:
Direct acting sympathomimetic by stimulation of all adrenergic receptors
(Beta1,2,3 and Alpha1,2).
*Therapeutic Uses (Indications):
15
Contraindications:
As adrenaline + CNS symptoms as insomnia, anxiety,
psychosis, and anorexia.
A-Local uses:
1-With LA: to prolong the action and reduce systemic toxicity of LA (except
in fingers, toes, and circumscision).
2-Open angle glaucoma: adrenaline is given as eye drops to reduce I.O.P.,
but Dipivefrin (prodrug converted into adrenaline) is preferred as it
more lipophilic, more diffusible, and less toxic.
3-Hemostatic as in cases of epistaxis, given as nasal pack (except in
hypertension).
4-Decongestion of mucous membranes of eyes and nose.
B-Systemic uses:
1-Anaphylactic shock: SC adrenaline is life-saving and the drug of choice
due to its anti-allergic action (adrenaline is the physiological
antagonist of histamine).
2-Cardiac arrest: adrenaline is given intra-cardiac for cardiac resuscitation.
3-Contraction ring of the uterus (B2 agonists as Ritodrine and Isoxsuprine
are preferred).
4-Acute bronchial asthma: adrenaline is given S.C. (SABA as Salbutamol
and Terbutaline are preferred).
5-Hypoglycemic coma: adrenaline is given S.C. (I.V. glucose 50 mL 50% is
preferred).
Adverse effects:
1-Elevation of arterial blood pressure which may lead to cerebral
hemorrhage in hypertensive patients.
2-Gangrene if given with L.A. in fingers and toes, and during circumscision.
3-Cardiac manifestations: tachycardia, arrhythmia, palpitations, and angina
pains in patients with ischemic heart disease.
4-Cardiac arrhythmias (ventricular arrhythmia up to V.F.) if given with
general anesthesia (G.A.) as halothane (treated by beta blockers).
5-Weak CNS manifestations as irritability, tremors and insomnia.
6-Exaggerated action if given in thyrotoxic patients, with MAO inhibitors or
sympatholytics.
Contraindications:1-Hypertension.2-Angina pectoris
3Arrhythmia.4-Thyrotoxicosis.5-With: L.A. in fingers, toes,
circumscision- halothane-sympatholytics-MAOIs.
sympathetic outflow from CNS V.D. (and decrease in TPR) and bradycardia (and decreased
C.O.P.) and accordingly decrease ABP.
2- Stimulation of presynaptic 2-receptors release of noradrenaline from adrenergic
neurons V.D. and decrease in TPR, Heart rate and COP (bradycardia is due to reduced
sympathetic tone and predominance of vagal tone).
3-Stimulation of 2 receptors in kidneyRenin release.
Both central and peripheral actions decrease A.B.P.
4-blocks postsynaptic 1 receptors on blood vessels V.D.
5-Anti-serotonin action.
*Therapeutic uses:
1- Treatment of hypertension, including hypertension with renal impairment (clonidine increases
renal blood flow) and high renin hypertesion.
2- Prophylaxis of migraine headache.
3- Control of withdrawal symptoms in morphine and nicotine addicts.
4- Analgesic (given intrathecal).
*Adverse effects:
1- Rebound hypertension if clonidine is stopped suddenly. This is due to upregulation of 1receptors with chronic use of clonidine, it may be accompanied by tachycardia (due to
upregulation of 1-receptors). Rebound hypertension can be treated by re-administration of
clonidine (to reduce noradrenaline release) or by 1-blockers -blockers but never use nonselective -blockers without 1-blockers to avoid more hypertension by unopposed 1stimulation.
2- Sedation and drowsiness due to decreased sympathetic activity.
3- Dry mouth (may be due decreased acetylcholine release from cholinergic neurons to salivary
glands).
4-Bradycardia (see before).
*Drug interaction:
Tricyclic antidepressants (TCAs) inhibit neuronal reuptake of noradrenaline (cocaine-like action)
and antagonize the effect of clonidine.
N.B. Apraclonidine and brimonidine are 2 agonists used in treatment of glaucoma (as eye
drops), whereas tizanidine is a central 2 agonist used as central skeletal muscle relaxant.
2-Alpha-Methyl Dopa
*Pharmacodynamics:
Mechanism of action:
1-Alpha-methyl dopa competitively inhibits dopa decarboxylase enzyme leading to inhibition of
synthesis of noradrenaline (from dopamine) in adrenergic neurons.
2-Alpha- methyl dopa itself is converted-by dopa decarboxylase-into alpha-methyl dopamine
then into alpha-methyl noradrenaline. Alpha-methyl noradrenaline acts as 2-agonist,
stimulating 2-receptors both centrally and peripherally.
Pharmacological actions:
I-CVS:
1-Stimulation of central 2-receptors decreases sympathetic discharge from CNS leading to
vasodilatation and TPR (due to inhibition of VMC), bradycardia and COP, both
actions ABP.
17
2-Inhibits phosphodiesterase enzyme (PDE) both c-AMP (which causes V.D. and
tachycardia) and c-GMP (which causes V.D. and bradycardia).
Pharmacological actions:
1- V.D. of both arteries (TPR= afterload) and veins (venous return= preload) by blocking postsynaptic 1 receptors, and increase c-AMP and c-GMP. V.D. leads to A.B.P.
2- No (or minimal) reflex tachycardia because:
-No 2-blocking action and no increase in noradrenaline release from adrenergic neurons
innervating the heart.
-Inhibition of PDE leading to increase in both c-AMP ( heart rate) and c-GMP (heart rate).
3- Relaxation of urinary bladder sphincter.
Therapeutic uses:
1-Treatment of essential (primary) hypertension (a diuretic may be added on prolonged use).
2-Treatment of congestive heart failure (CHF) as it reduces both preload due to venodilatation
and afterload due to arteriodilatation. This increases COP in these patients.
3- P.V.D. as Raynaud's disease.
4- Secondary hypertension due to pheochromocytoma (beta blockers may be added)..
5- BPH (Tamsulosin is better because it is a selective 1A blocker ).
6-Other use: Rebound hypertension after sudden clonidine cessationHypertensive crisis in depressed patients treated by MAO inhibitors (cheese reaction)-Severe
V.C. if extravasation of noradrenaline occurs during IV infusion.
Adverse effects:
1-"First dose phenomenon": severe postural hypotension after the first dose due to potent
venodilatation. It can be prevented by starting treatment with a small dose given at bed time, and
then the dose is gradually increased.
2- Nasal congestion.
3- Failure of ejaculation.
4- Na+ and water retention due to decreased RBF, corrected by adding a diuretic.
5-Headache and dizziness (due to cerebral V.D.).
Question: How to correct hypotension induced by -blockers as phentolamine?
Answer: Angiotensin II given by IV infusion (physiological antagonism). Alpha agonists as
phenylephrine and noradrenaline will not effective because alpha receptors are blocked, whereas
adrenaline is dangerous because it will stimulate 2-receptors leading to V.D. and more
hypotension.
2-Distribution:
3-Plasma protein
binding:
4-Fate:
PROPRANOLOL
*Pharmacodynamics:
A-Mechanism of action:
Competitive non-selective -antagonist. Propranolol is a pure antagonist (no ISA).
Propranolol also blocks Na+ channels = MSA = L.A. action and antiarrhythmic action
(quinidine-like action).
B-Pharmacological actions:
1-CVS:
Heart: blocking of 1-receptors leads to:
- automaticity= negative chronotropic action (heart rate and may cause bradycardia). The
effect of -blockers on heart rate is more marked during exercise than during rest.
-conductivity=negative dromotropic action (conductivity all over the heart including AV
conduction).
-excitability.
- myocardial contractility= negative inotropic action.
-COP.
-myocardial O2 requirements.
-The anti-arrhythmic action of propranolol is due to: 1-blocking action (decreases excitability,
automaticity, and conductivity) + membrane stabilizing activity (MSA) due to Na+-channel block
(quinidine-like).
Blood vessels: blocking of 2-receptors in blood vessels leads to initial V.C. especially in
skeletal muscles, coronary, and hepatic blood vessels.
ABP:
-At the start of treatment of hypertensive patients with propranolol; ABP is not reduced although
propranolol COP, because it causes initial V.C. especially in skeletal muscle blood vessels by
blocking 2-receptors.
-After continous treatment with propranolol (at least for 4 weeks); ABP is reduced due to the
following mechanisms:
1- COP.
2- renin release by blocking 1-receptors in juxta-glomerular apparatus in kidney.
3- noradrenaline release from adrenergic neurons by blocking pre-synaptic -receptors.
4- sympathetic outflow from CNS by blocking central 1-receptors (propranolol is "lipophilic").
5- Re-setting of baroreceptors.
6- Stimulation of synthesis of vasodilator prostaglandins, as prostacyclin (PGI2) and PGE2.
N.B.: Propranolol and all non-selective -blockers "abolish" the hypotensive action of
isoprenaline and "augment" the hypertensive (pressor) action of adrenaline (they have no effect
on the hypertensive action of noradrenaline).
2-Bronchi:
Propranolol and all non-selective -blockers induce bronchospasm by blocking 2-receptors in
bronchial smooth muscles. This is very dangerous in asthmatic patients as it may precipitate
attacks of asthma.
Cardio-selective -blockers are less dangerous but remember that "selectivity is not absolute".
3-Metabolic actions:
- lipolysis by blocking 1and 3-receptors and reduces free fatty acids.
21
- glycogenolysis by blocking 2-receptors in liver and skeletal muscles. This may be dangerous
in case of insulin-induced hypoglycemia.
-Long-term (chronic) use of propranolol may induce atherosclerotic changes as it increases
VLDL and LDL and decreases HDL (this is less marked with -blockers having ISA, and with
cardio-selective -blockers).
+
- uptake of K by skeletal muscles, and may lead to "hyperkalemia", by blocking 2-receptors in
skeletal muscles.
Important Notes:
1- Hypoglycemia=stress sympathetic activity tachycardia and palpitation (1-stimulation),
Glycogenolysis and increased blood glucose (2-stimulation), and increased sweating (M3stimulation in thermoregulatory sweat glands).
2-Propranolol will mask the symptoms of hypoglycemia except sweating (why?). This may lead
to "silent hypoglycemia" and coma in diabetic patients receiving overdoses of insulin or oral
hypoglycemic drugs.
4-Eye:
- Formation of aqueous humor by blocking -receptors (2 mainly) in ciliary body, and
accordingly decrease IOP.
- No change in the size of the pupil and no action on the ciliary muscle.
- Local application of timolol may lead to systemic actions as bradycardia and bronchospasm
(how?).
5-CNS actions:
- Reduces anxiety by blocking 1-receptors in CNS.
- Reduces tremors mainly by blocking 2-receptors in skeletal muscles and mainly by CNS
action (propranolol is lipophilic).
6- Liver:
-V.C. of hepatic blood vessels and decreases portal pressure in cases of portal hypertension due
to liver cirrhosis.
-Reduction of hepatic blood flow reduces HME activity leading to "non-specific" or "indirect"
HME inhibition which may decrease hepatic metabolism of drugs.
*Thearpeutic Uses of -Blockers:
CVS:
1- Prophylaxis of angina pectoris (ischemic heart disease), useful in stable angina and in unstable
angina as it decreases cardiac work and myocardial oxygen requirements, but it is
contraindicated in variant=Prinzmetal angina=vasospastic angina which is due to sudden
coronary V.C. (due to supersensitive 1-receptors in coronary blood vessels) as it leads to more
V.C. due to "unopposed 1 effect.
2-Treatment of essential hypertension (propranolol decreases ABP after prolonged use).
3-Treatment of supra-ventricular tachycardia (as PAT) and ventricular arrhythmias (due to
general anaesthesia, digitalis, 1agonists as adrenaline and isoprenaline, acute myocardial
infarction, thyrotoxicosis, and cardiac surgery).
(-blockers are "Class II" antiarrhythmic drugs).
4-After acute myocardial infarction (AMI) to decrease size of infarction, treat arrhythmias,
decrease cardiac work and myocardial oxygen requirements, and increase survival (decrease
mortality rate).
5-Acute dissecting aortic aneurism (with sodium nitroprusside).
Contraindications
Adverse Effects
1-Bradycardia (treated by atropine).
1-Bradycardia.
4-Bronchial asthma.
10-Severe depression.
-and -Blockers:
1-Labetalol:
Blocks - and 1-receptors in a ratio of 3:1.
Less potent than propranolol as -blocker, and less potent than phentolamine as 1-blocker.
Decreases ABP by decreasing both COP and TPR.
It causes V.D. and hypotension without reflex tachycardia (why?).
Used in: 1-Essential hypertension, including emergency hypertension.
2-Pheochromocytoma (it is used alone).
2-Carvedilol:
As labetalol: and 1 blocker + Antioxidant.
25
Autacoids: Antihistaminics
Non-Sedating
(2nd generation)
Loratadine-Fexofenadine-Cetrizine
Poor passage across BBB.
As sedating antihistaminics.
Sedating Antihistaminics
(1st generation)
Diphenhydramine-Promethazine-DimenhydrinateCyclizine-Meclizine-Clemastine-HydroxyzineCyproheptadine
Pass BBB.
Competitive antagonists with histamine at
H1 receptors.
3-Duration:
4-Pharmacological
actions:
4-Therapeutic uses:
5-Adverse effects:
BPH-Glaucoma-Pregnancy-Driving.
6-Contraindications:
NSAIDs
1-CNS: Analgesic-Antipyretics
2-Anti-inflammatory.
3-Iatrogenic Peptic ulcer.
4- RBF Na+ and water retention,
and may lead to nephropathy.
5-Antiplatelet action by Aspirin
(pediatric dose) by inhibition of
TXA2 synthase.
Prostaglandins (PGs)
1-CNS: Algesia-Pyrexia.
2-Inflammation.
3-GIT: protect the stomach and duodenum by HCl,
mucus, HCO3 (PGE2).
4-Renal V.D. and RBF.
5-V.D. by PGI2 and PGE2 or V.C. by PGF2 and
TXA2.
6- Platelet aggregation by PGI2 or platelet
aggregation by TXA2.
7-Oxytocic action (PGF2 and PGE2).
27
Actions:
6-Tocolytic action.
7-Bronchoconstriction due to shift of
arachidonic acid into LT pathway.
8-Premature closure of DA if given
in late pregnancy.
1-Analgesic in superficial pains
2-Antipyretic (non-specific).
3-Antiinflammatory in acute gouty
arthritis, rheumatic fever, rheumatoid
arthritis.
4-Prophylaxis of thrombo-embolism
by aspirin.
5-Tocolytics in premature labor and
dysmenorrhea.
6-Obliteration of patent ductus
arteriosus (by Indomethacin).
1-Allergy.
2-Peptic ulcer (iatrogenic).
3-Asthmatic attacks in bronchial
asthma.
4-Bleeding.
5-Teratogenicity.
6-Premature closure of ductus
arteriosus.
7-Delayed labor and increase postpartum hemorrhage.
1-Allergy.
2-Peptic ulcer.
3-Bronchial asthma.
4-Bleeding disorders.
5-Pregnancy (early and late).
Therapeutic uses:
Adverse effects:
Contraindications:
Serotonin agonists
1-Buspirone:
5-HT1A agonist.
Non-Benzodiazepine anxiolytic (anxio-selective).
Used in generalized anxiety disorder, but has slow onset of action.
2-Triptans: Sumatriptan-Zolmitriptan:
5-HT1D agonists,
Cause vasoconstriction of cranial, coronary, and systemic blood
vessels.
29
Respiration
*Drug Therapy in Bronchial Asthma:
A-Bronchodilators (Short-term asthma relievers):
1-Sympathomimetic 2-Agonists.
2-Methylxanthines.
3-Antimuscarinic drugs (Anticholinergic drugs-Muscarinic antagonists).
A-Bronchodilators:
I-2-Agonists:
Pharmacodynamics:
Stimulation of 2-receptors activation of adenylate cyclase synthesis of c-AMP
bronchodilatation + mast cell stabilization and inhibition of release of bronchoconstrictor
mediatorsfrom mast cells + reduction of mucus secretion + increase muco-ciliary clearance +
decrease microvascular leakage (capillary permeability).
Classification:
A-Selective 2-Agonists: They are the most important drugs in treatment of bronchial asthma,
they include:
1-Short-acting 2-agonists=Asthma relievers:
Salbutamol and Terbutaline given by inhalation in acute attacks duration 3-4 hours.
2-Long-acting 2-agonists=Asthma controllers:
Salmeterol, Formoterol by inhalation, and Bambuterol given orally-duration 12 hours.
Role in bronchial asthma:
1-The drugs of choice in acute attacks: SABA are given by inhalation.
2-LABA are given for long-term prophylaxis with inhaled steroids.
3-Salbutamol is given by inhalation (nebulizer) or IV in severe acute asthma (status asthmaticus).
Adverse effects:
1-Tremors of the skeletal muscles.
2-Tachycardia (mostly reflex due to V.D. and hypotension, but may be due to direct stimulation
of cardiac 1 receptors especially with repeated doses because selectivity is not absolute).
3-Tolerance (due to down-regulation of 2-receptors, corrected by corticosteroids).
4-Nervousness Tension.
5-Hypokalemia.
6-Hypotension-Headache-Flushing.
7-LABA increase the risk of asthma-related death if used alone in patients with ischemic heart
disease or arrhythmia, that is why they should be combined with inhaled corticosteroids (ICS).
B-Non-Selective -Agonists:
They are not commonly used because of cardiac adverse effects as tachycardia,
palpitation,arrhhythmia and anginal pains due to 1-stimulation. Examples:
1-Adrenaline (inhalation and S.C.).
2-Isoprenaline (inhalation and S.L.).
II- Methylxanthines:
Theophylline and Aminophylline (theophylline ethylene diamine).
Pharmacodynamics:
Mechanism of action:
1-Inhibit phosphdiesterase type 4 intracellular c-AMP bronchodilatation + mast cell
stabilization and inhibition of release of bronchoconstrictor mediatorsfrom mast cells + reduction
of mucus secretion + increase muco-ciliary clearance + decrease microvascular leakage
(capillary permeability) .
2-Block of adenosine receptors bronchodilatation + decrease histamine release..
3-Improve diaphragmatic contractions.
4-Inhibition of PDE-4 in inflammatory cells reduces the release of cytokines and reduces cell
migration.
The Role of Methylxanthines in Bronchial asthma:
31
1-Aminophylline may be given very slowly IV (250-500 mg.) in acute attacks (asthma reliever)
if there is no response to inhaled selective 2- agonists. This may be dangerous especially if
aminophylline is rapidly injection as it may lead to arrhythmia and severe hypotension (velocity
reaction).
2-Theophylline is given as sustained release tablets or capsules in prophylaxis of bronchial
asthma (asthma controller).
Aminophylline may be also given as rectal suppositories (500 mg.).
3-Aminophylline is given by IV infusion in life-threatening asthma (status asthmaticus =severe
acute asthma).
Adverse effects:
-Theophylline and Aminophylline have low therapeutic index and the plasma level should be
measured to avoid toxicity.
-Therapeutic plasma concentration of theophylline: 5-20 mg / L (5-20 g / mL) and the toxic
level > 20 mg / L.
-Adverse effects include:
1-CNS manifestations: nervousnss, insomnia, headache, and seizures (convulsions).
2-CVS manifestations: tachycardia, palpitations, arrhythmias, anginal pains, and hypotension.
3-GIT manifestations: anorexia, nausea, vomiting, ulceration, and proctitis (rectal suppository).
4-Thrombophlebitis (IV injection).
Symptoms of toxicity may start at plasma level of 15 mg/L.
Seizures and arrhythmia occur at plasma levels above 40 mg/L.
Drug interactions:
A-The clearance of theophylline is reduced by:
1-HME inhibitors as: Erythromycin (Macrolide antibiotics)-Fluroquinolones-ChloramphenicolCimetidine-Contraceptive pills.
2-Hepatic cirrhosis.
3-Heart failure (decreases COP and so decreases hepatic blood flow).
In these conditions the dose of theophylline should be reduced to avoid toxicity.
2-The clearance theophylline is increased by:
-HME inducers as: Phenobarbitone- Phenytoin-Rifampicin Cigarette smoking (nicotine).
The dose of theophylline should be increased in these conditions to achieve therapeutic levels.
2-They are used as alternatives to LABA patients who are intolerant to LABA as in cases of
arrhythmia or ischemic heart diseases.
3-They may be added to LABA to achieve synergism.
4-They are the drugs of choice in asthmatic attacks precipitated by non-selective beta antagonists
as propranolol.
5-Chronic obstructive pulmonary disease (COPD).
Advantages of Synthetic substitutes:
Advantages of Ipratropium
Disadvantages of Atropine
1-Quaternary ammonium-given by inhalation.
1-Tertiary amine-given orally-Passes BBB.
2-Minimal systemic anticholinergic actions. 2-Systemic anticholinergic actions: dry mouth
constipation-urine retention-tachycardia-blurred
vision and elevation of IOP.
3-No CNS (cannot penetrate BBB).
3-CNS actions.
4-Little effect on bronchial secretion. 4-Causes dryness of bronchial secretion leading
to thick viscid sputum.
5-No effect on muco-ciliary clearance.
5-Decreases muco-ciliary clearance.
B-Anti-inflammatory Drugs:
I- Corticosteroids (Glucocorticoids):
Mechanism of action:
1-Anti-inflammatory action by inhibition of phospholipase A2 leading to inhibition of synthesis
of arachidonic acid, leukotrienes and prostaglandins.
2-Anti-inflammatory action by inhibition of synthesis of cytokines as interleukins (IL1,2,3,4) and
tumor necrosis factor (TNF).
3-Potentiate the effects of 2-agonists (by upregulation of receptors) thus prevent tolerance.
4-Inhibit IgE antibody synthesis and antigen-antibody reaction.
Corticosteroids are not bronchodilators and are not used in acute attacks.
The Role of Corticosteroids in Bronchial asthma:
1-Inhaled corticosteroids (ICS) as Beclomethasone, Fluticasone, Triamcinolon, Budesonide,
are used in prophylaxis of bronchial asthma. This is the preferred route to avoid the serious
adverse effects of systemic steroids (immunosuppression-osteoporosis-edema-hypertensionulcer).
2-Systemic steroids as Hydrocortisone sodium succinate or methylprednisolone IV is the drug
of choice in status asthmaticus (200 mg. / 4-6 hours for 24 hours).
This is followed by oral prednisolone for 7-10 days then gradually withdrawn to avoid acute
adrenocortical insufficiency.
33
3-Systemic steroids as predisolone orally are used only in severe persistent asthma not
responding to other anti-asthmatic drugs (see later).
Adverse effects of Inhaled steroids:
1-Oro-pharyngeal candidiasis (moniliasis): prevented by mouth wash after corticosteroid
inhalation, and treated by oral Nystatin.
2-Dysphonia (voice abnormality, e.g. weakness and hoarseness).
3-Systemic adverse effects may occur on prolonged use, e.g. growth retardation in children and
osteoporosis in females
Cough Therapy
Acetylcysteine:
Pharmacodynamics:
1-Mucolytic: by splitting the disulfide bonds of mucoproteins of respiratory secretion. This leads
to reduced viscosity and tenacity of mucus.
2-Acetaminophen (Paracetamol) antidote: by normalizing hepatic glutathione (SH donor) which
binds to the hepatotoxic metabolite of acetaminophen (NABQ) and protects liver cells.
3-Antioxidant.
Therapeutic uses:
1-Mucolytic: used as adjuvant in treatment of acute and chronic respiratory diseases as bronchial
asthma, T.B., pneumonia, cystic fibrosis-also used to clear the airways as in bronchoscopy.
2-Treatment of acute acetaminophen toxicity, considered as its antidote
Diuretics
+
K Sparing diuretics
(Spironolactone)
Loop diuretics
Oral only.
Very slow.
Long.
Distal part of DCT.
Weak.
Oral only.
Delayed.
Long.
Proximal segment of DCT.
Moderate.
1-Routes:
2-Onset:
3-Duration:
4-Site of action:
5-Potency:
1-Diuretic.
2-Spironolactone and Eplerenone
reduce mortality in Heart failure.
1-Diuretic.
2- RBF.
3-Antihypertensive.
4-Hyperuricemia.
5-Hyperglycemia.
6-Actions:
35
7-Uses:
1-Hyperkalemia.
2-Acidosis.
3-Gynecomastia and sexual
disturbances (by Spironolactone due to
steroid structure).
4-Gut upset.
5-CNS disturbances.
6-Allergy.
7-Hypocalcemia.
1-Hypokalemia.
2-Hyponatremia.
3-Hypomagnesemia.
4-Hypochloremic alkalosis.
5-Hypovolemia and
dehydration.
6-Hypotension.
7-Hypocalcemia.
8-Hypersensitivity.
9-Hyperuricemia.
10-Hyperglycemia.
11-Ototoxicity.
12-Teratogenicity.
1-Allergy.
2-Digitalis toxicity.
3-With Lithium lithium
toxicity.
4-With Aminoglycosides.
5-Diabetes mellitus.
6-Gout.
7-With Steroids.
8-Pregnancy.
Frusemide-BumetanideTorsemide-Ethacrynic acid.
Aldosterone antagonists:
Spironolactone, Eplerenone. Nonaldosterone antagonists: AmilorideTriamterene.
1-Hypokalemia.
2-Hyponatremia.
3-Hypomagnesemia.
4-Hypochloremic alkalosis.
5-Hypovolemia and dehydration.
6-Hypotension.
7-Hypocalcemia.
8-Hypersensitivity.
9-Hyperuricemia.
10-Hyperglycemia.
11-Hyperlipidemia.
12-Teratogenicity.
8-Adverse effects:
1-Allergy.
2-Digitalis toxicity.
3-Renal insufficiency.
4-Hepatic insufficiency.
5-Diabetes mellitus.
6-Gout.
7-With Steroids.
8-Pregnancy.
9-Contraindications:
Thiazides: ChlorothiazideHydrochlorothiazide.
Thiazide-like: IndapamideChlorthalidone-Metolazone.
10-Examples:
K-sparing diuretics
(Spironolactone)
1-Hyperkalemia antagonizes
1-Hypokalemia induced by thiazide may
the action of digoxin.
precipitate digoxin toxicity.
2-Spirnolactone + Thiazide
2-Thiazides + loop diuretics severe
synergism and correction
hypokalemia.
+
+
of serum K .
3-Frusemide + K sparing diuretics as
3-Spironolactone + loop spironolactone, amiloride, or triamterene
diuretics synergism and
synergism and correction of serum K+.
+
correction of serum K .
4-Frusemide + ACEIs as captopril
4-Spironolactone + ACEIs
synergism in treatment of HF and
severe hyperkalemia.
hypertension and correction of serum K+.
5- Spironolactone + ARBs
5- Frusemide + ARBs as losartan
severe hyperkalemia.
CVS
Anti-Anginal Drugs
Summary of anti-anginal drugs:
CCBs: Verapami and
Diltiazem
(non DHP)
CCBs: Nifedipine
(DHP)
Nitrates
Atreriodilatation and
afterload (much less than
nifedipine).
Potent
arteriodilatation and
afterload.
Arteiodilatation and
afterload.
No vasodilatation.
Almost no
venodilatation.
Almost no
venodilatation.
Potent venodilatation
and preload.
No venodilatation.
Non-selective BB may
cause V.C. due to
unopposed effect.
Bradycardia.
Reflex tachycardia.
Reflex tachycardia.
37
Beta Blockers
Decrease.
Decrease.
Decrease by cardiac
properties (mainly) +
afterload.
Decrease by
afterload.
Beneficial in long-term
prophylaxis.
1-Beneficial in acute
attacks (S.L.).
2-Beneficial in
immediate prophylaxis
(S.L.).
3-Beneficial in longterm prophylaxis (SR
oral preparations).
Beneficial.
Beneficial.
Beneficial.
Beneficial.
Beneficial.
Bradycardia.
Decrease.
5-Effect on ABP:
Decrease by cardiac
properties and ABP.
Beneficial in long-term
prophylaxis.
Contraindicated.
Beneficial.
1--Blockers:
All -blockers both selective and non-selective- are useful in prophylaxis of stable angina
because they decrease heart rate, contractility, and ABP leading to decreased cardiac work and
myocardial oxygen demands.
Non-selective -blockers are contraindicated in variant angina because they lead to
"unopposed 1-action" causing more vasospasm.
Cardio-selective -blockers are used with great caution and are better avoided in variant angina
because selectivity is not absolute.
In unstable angina: -blockers without ISA are used (in addition to
I.V. nitroglycerin, nifedipine(CCB), heparin and antiplatelet drugs as aspirin).
Adverse effects and contraindications: see ANS,
But remember that they should never be stopped suddenly.
N.B.:
1-The dose of -blockers is adjusted according to the heart rate, which should not exceed 50-60
beats/minute at rest, and 100-120 beats/minute during exercise.
2--blockers decrease heart rate prolongation of diastole increased end-diastolic volume
(EDV) and ejection time increased cardiac work and oxygen consumption which partially
antagonizes their beneficial effect in angina. This can be corrected by co-administration of
nitrates (nitrates increase heart rate reflexly and shorten diastole).
acute attacks and immediate prophylaxis, and are given orally, as skin ointment, and as
transdermal patch for long-term prophylaxis. Nitroglycerin is given by IV infusion in unstable
angina.
2-Heart failure: they reduce pre-load mainly and after-load to a lesser extent. Nitroglycerin is
given by IV infusion in acute heart failure. Reduction of pre-load in patients with heart failure
improves myocardial contractility and increases COP (but in patients without heart failure COP
is reduced due to reduction of venous return and EDV).
3-Emergency hypertension: nitroglycerin IV infusion is used.
4-Acute myocardial infarction: nitroglycerin IV infusion decreases cardiac work, dilates the
coronaries, and decreases pulmonary congestion. It may also reduce the size of infarction.
5-Nitrites as amyl nitrite (inhalation) and sodium nitrite (IV) are used in cyanide poisoning
because they cause methemoglobinemia.
6-Treatment of acute bronchial asthma, colics (intestinal, biliary, or renal colics), and contraction
ring of uterus.
*Precautions (Instructions to the patient):
1-Instruct the patient to sit after S.L. administration to avoid postural hypotension.
2-Instruct the patient to get rid of the pellet-by swallowing or spitting- as soon as pain is relieved
to avoid adverse effects.
3-Never stop nitrates suddenly after long use which may lead to rebound ischemia and infarction
(nitrate dependence).
4-Never double the dose: if a dose is missed wait for the next dose.
5-Nitrate-free interval is essential to avoid nitrate tolerance.
6-Do not use after expiry date (drug is ineffective).
7-Never combine with sildenafil.
*Adverse effects:
1-Reflex tachycardia (due to hypotension. It is avoided by adding -blockers or verapamil to
nitrates).
2-Postural hypotension and dizziness, and may cause syncopal attacks (nitrate syncope). This
can be prevented by asking the patient to take S.L. pills when sitting - not in the standing
position- and to get rid of the pill after relief of pain, either by swallowing or spitting.
3-Throbbing (pulsating) headache.
4-Flushing.
5-Methemoglobinemia and cyanosis especially with nitrites.
6-Allergic reactions as skin rash.
7-GIT disturbances.
8-Nitrate Tolerance: it is due to depletion of tissue SH group required for de-nitration of nitrates.
It is prevented by allowance of "nitrate-free" intervals of 8-10 hours or by alternative use with
other anti-anginal drugs as CCBs and -blockers.
9-Nitrate dependence.
10-Carcinogenicity due to formation of nitrosamines.
N.B.:
1-In factory workers exposed to nitrates it has been noticed that headache and dizziness occur
rapidly after 1-2 days of exposure but rapidly disappear due to the development of nitrate
tolerance. However the symptoms recur at the beginning of the week (after the week-end) and
then disappear again and so on.
2-Nitrate dependence has been observed after prolonged exposure to nitrates if the workers
spend 1-2 days away from nitrates and is manifested as "variant angina".
*Drug Interactions:
1-Nitrates + -blockers (propranolol) = beneficial combination.
2-Nitrates + Verapamil = beneficial combination.
3-Nitrates + Nifedipine = unfavorable combination.
4-Nitrates + Sildenafil (Viagra)) = very dangerous combination because sildenafil causes V.D.,
hypotension, and reflex tachycardia through inhibition of phosphodiesterase 5 leading to
increased intracellular
c-GMP. They are given at least 6-hours apart.
(All are pharmacodynamic interactions)
41
1-Angina pectoris: Prophylaxis of all types of angina. Verapamil is usually used in stable angina
as it reduces cardiac work and myocardial oxygen requirements. Nifedipine is usually used in
variant and unstable angina, due to its potent vasodilator effect.
2-Hypertension: all CCBs are useful in treatment of hypertension. Nicardipine I.V. is useful in
emergency hypertrension.
3-Arrhythmias: verapamil and diltiazem are used in supraventricular arrhythmia and are
classified as class IV antiarrhythmic drugs.
(Dihydropyridines as nifedipine are contraindicated in tachyarrhythmias as they lead to reflex
cardiac stimulation).
4-Hypertrophic obstructive cardiomyopathy (verapamil).
5-Cardioprotective in acute myocardial infarction.
6-PVDs as Raynaud's disease (nifedipine).
7-Prophylaxis of migraine headache (flunarizine and verapamil).
8-Premature labor (tocolytic action) and toxemia of pregnency.
9-Nimodipine is used to prevent cerebral vasospasm after subarachnoid hemorrhage.
10-Acute bronchial asthma.
11-Acute and chronic renal failure (to increase RBF).
(N.B. Nifedipine is given S.L. in acute anginal attacks and in emergency hypertension).
*Adverse effects:
A-Common Adverse effects:
1-Hypotension.
2-Constipation (more with verapamil).
3-Headache, flushing, and ankle edema (due to V.D., so they are more marked with
dihydropyridines as nifedipine).
B-Specific adverse effects of verapamil:
1-Bradycardia.
2-Reduction of AV conduction.
3-Decreases myocardial contractility.
C-Specific adverse effects of nifedipine:
1-Reflex tachycardia.
2-"Coronary Steal Phenomenon": nifedipine dilates normal coronaries and not atherosclerotic
vessels so the normal myocardium "steals" the blood from the ischemic myocardium.
*Contraindications:
1-Hypotension.
2-Verapamil is contraindicated in: Bradycardia- AV block Congestive heart failure.
3-Nifedipine is contraindicated in tachyarrhythmias.
*Drug interactions:
A-Pharmacokinetic interactions:
1-CCBs especially verapamil displace digitalis from plasma proteins.
2-CCBs especially verapamil decrease renal excretion of digitalis (digoxin).
B-Pharmacodynamic interaction:
1-Verapamil + -blockers = severe bradycardia, AV block, and diminished contractility and may
cause cardiac arrest.
4-Antiplatelet Drugs:
They inhibit platelet aggregation and are used in stable and unstable angina. They include:
1-Aspirin (pediatric dose=75-150 mg. /day) and Dazoxiben. They inhibit TXA2 synthesis.
2-Dipyridamole: inhibits phosphodiesterase c-AMP in platelets, blood vessels, and heart
inhibition of platelet aggregation, V.D., and myocardial stimulation (also reflexly due to
hypotension). It is used in stable angina and in thrombo-embolic diseases.
3-Ticlopidine and Clopidogrel: inhibit ADP-dependent platelet aggregation.
4-Sulphinpyrazone: inhibits COX.
5-PGI2 analogues as Epoprostenol.
Anti-Hypertensive Drugs
1-ACE inhibitors (as Captopril) and Angiotensin receptor antagonists (as Losartan).
2-Sympathetic Depressants:
a-Central 2-agonists (as Clonidine and alpha- methyldopa).
b- Competitive ganglion blockers (they are obsolete except Trimetaphan).
c- Adrenergic neuron depressants: Guanethidine-Reserpine (rarely used).
d- Adrenoceptor antagonists: -blockers (as Propranolol) selective 1-blockers (as Prazosin) drugs that block and -receptors(as Labetalol).
3- Calcium channel blockers (as Verapamil and Nifedipine).
4- Diuretics: Thiazide diuretics (as Hydrochlorothiazide)- Loop diuretics (as Frusemide) K+sparing diuretics (Spironolactone- Amiloride- Triamterene).
5-Vasodilators:
a- Arteriodilators:
43
Summary of vasodilators:
3-Diazoxide
2-Minoxidil
1-Hydralazine
Oral.
Route:
Acetylation.
Fate:
Mechanism of
action:
1-Arteriodilatation
TPR ABP (diastolic > systolic).
2- Arteriodilatation
TPR
AfterloadCOP in heart failure.
1-Arteriodilatation
TPR ABP (diastolic > systolic).
2- Arteriodilatation
TPR
AfterloadCOP in heart failure.
Actions:
1-Emergency hypertension.
(IV as before).
2-Treatment of insulinoma (given orally).
Indications:
Adverse effects:
1-Angina.
2-Arrhythmia.
3-D.M. 4-Gout. 5-Allergy.
1-Angina.
2-Arrhythmia.
1-Angina.
2-Arrhythmia.
Contraindications:
4- Fenoldopam:
Selective D1-agonist V.D. of arterioles.
Given by IV infusion.
Used in emergency hypertension.
Adverse effects: Reflex tachycardia- Headache Flushing Elevation of IOP.
1-Vagal action: digitalis stimulates vagal C.I.C. both directly and reflexly through stimulation of
baroreceptors, and sensitizes SAN to acetylcholine. This vagal action is the mechanism of
bradycardia in the beginning of treatment by digitalis (early digitalization).
2-Direct action (extra-vagal action): digitalis decreases SAN automaticity directly and decreases
sensitivity of SAN to catecholamines (anti-adrenergic action). This action occurs after full
digitalization.
Very important note: the earliest objective manifestation of digitalis toxicity is
"BRADYCARDIA 60 beats / minute.
Give reason: Atropine can cause tachycardia if given in early digitalization but cannot produce
tachycardia in fully digitalized patients?
6- Refractory Period (R.P.):
Net effect
Shortening.
Prolongation.
Shortening.
Direct Action
Prolongs.
Prolongs.
Shortens.
Vagal Action
Shortens.
Prolongs.
No effect.
1-Atrial R.P.
2-AV R.P.
3-Ventricular R.P.
7- Conductivity:
Net Effect
Accelerates.
Direct Action
Slows.
Vagal Action
Accelerates.
Slows.
Slows.
Slows.
Accelerates.
Accelerates.
No effect.
1-Atrial Conductivity.
2-AV Conductivity.
3-Ventricular
Conductivity.
8-Automaticity:
- SAN: digitalis decreases SAN automaticity leading to heart rate (negative chronotropic).
-AV system: digitalis decreases AV conduction (negative dromotropic). This may lead to AV
block, but it is beneficial in supra-ventricular arrhythmias as it protects the ventricles.
-Purkinje fibres: in therapeutic levels, digitalis has no effect but in digitalis toxicity there is
increased automaticity leading to ectopic pace-makers and ventricular arrhythmias.
Very important note:
Digitalis is useful in treatment of supra-ventricular arrhythmias but is contraindicated in
ventricular arrhythmias.
9-Excitability:
-In therapeutic levels digitalis increases excitability due to increased intra-cellular Na+ which
causes partial depolarization.
-In cases of digitalis toxicity; excitability may be reduced due to inactivation of fast Na+channels.
10-ABP:
-Digitalis "normalizes" ABP if it was low as it increases COP. However; it may increase ABP in
case of toxicity by V.C. (direct action and by stimulation of VMC).
-Digitalis can be used in patients suffering from hypertensive heart failure.
11-Diuretic Action:
Digitalis has a diuretic action only in cases of congestive heart failure as it increases COP
renal blood flow (RBF) GFR. In addition; improvement of COP reduces sympathetic
activity renin-angiotensin-aldosterone system.
12-Blood Volume:
Diuretic action of digitalis in heart failure decreases blood volume.
13-Coronary vessels:
-Therapeutic levels of digitalis have no effect on coronary circulation and it can be used in
patients with angina and heart failure.
-In digitalis toxicity coronary vasospasm may occur.
14- E.C.G.
Prolongation of P-R interval: due to delay in AV conduction.
Short QRS and Q-T segment due to strong short systole and rapid repolarization.
Depressed S-T segment (especially in case of toxicity).
Flat or inverted T-wave. Bradycardia.
Ventricular arrhythmias (extrasystole-Pulsus Bigeminus or Trigeminus-Ventricular tachycardiaVentricular Fibrillation=V.F.).
Therapeutic uses:
1-Congestive heart failure, especially left ventricular systolic dysfunction. Digitoxin and digoxin
can be used in chronic cases whereas digoxin and ouabain can be used in acute heart failure
(acute L.V.F.).
2-Atrial Fibrillation (A.F.): digitalis is useful in A.F. with or without heart failure. It has the
following advantages:
After Digitalis
Before Digitalis
1-Worsens atrial arrhythmia (due to
1-Atrial rate: 400 or more-irregular.
atrial conductivity).
2-Slows ventricular rate to normal by
2-Ventricular rate: about 150-irregular.
AV conduction (protects the ventricle).
3-Eliminates pulse deficit.
3-Pulse deficit present.
4-Restores mechanical efficiency.
3-Atrial Flutter: digitalis protects the ventricles by reducing AV conduction but it may convert
atrial flutter into A.F.
After stopping digitalis one of the following may occur:
-Normal sinus rhythm is restored and the patient is cured.
-A.F. persists.
-The condition reverses into atrial flutter.
If A.F. persists or atrial flutter recurs; Quinidine is given to restore normal sinus rhythm. It
should be noted that quinidine should never be given before digitalis because quinidine may
increase AV conduction due to atropine-like action leading to ventricular arrhythmia which may
be fatal. In addition; quinidine should never be given with digitalis to avoid serious drug
interactions (see later).
4-Paroxysmal Atrial Tachycardia (PAT) and Nodal Tachycardia: digitalis decreases SAN
automaticity and AV conductivity.
N.B. PAT is also treated by -blockers, verapamil, and M2-agonists as edrophonium and
neostigmine.
49
B-Pharmacodynamic interactions:
1-K+-losing diuretics as thiazides and loop diuretics cause hypokalemia and hypomagnesemia
which predispose to digitalis toxicity.
2-K+-sparing diuretics cause hyperkalemia which antagonizes digitalis.
3--blockers and verapamil antagonize inotropic action of digitalis but augment bradycardia and
AV block.
4-Sympathomimetics acting as 1-agonists as adrenaline may lead to ventricular arrhythmia.
5-Ca2+ salts increase the action of digitalis and may lead to toxicity.
*Digitalis Toxicity:
Cardiac glycosides have low therapeutic index (narrow safety margin).
The earliest manifestations of toxicity: nausea and vomiting, and bradycardia below 60
beats /minute. Other manifestations of toxicity: see before.
Digitalis toxicity is usually chronic (digitalis is a cumulative drug) and rarely acute due to high
loading dose especially in old age.
Factors predisposing to digitalis toxicity:
1-Hypokalemia and hypomagnesemia due to concurrent use of thiazides or loop diuretics with
digitalis in treatment of heart failure. Corticosteroids and carbenoxolone (aldosterone-like) also
cause hypokalemia.
2-Hypercalcemia.
3-Sympathomimetics.
4-HME inhibitors (see before).
5-Drugs that displace digitalis from plasma proteins (see before).
6-Drugs that reduce renal clearance of digoxin (see before).
7-Acidosis, hypoxia, and ischemia: decrease activity of Na+/K+ ATPase and increase the effect of
digitalis.
8-Hypothyroidism decreases elimination of digitalis.
9-Old age: dimished liver and kidney functions reduce elimination of digitalis.
10-Hepatic insufficiency reduces metabolism of digitoxin and renal impairment reduce renal
excretion of digoxin.
*Prevention of digitalis toxicity:
1-Avoid and correct predisposing factors.
2-Monitoring plasma level of digoxin (therapeutic level: 0.5-2ng./mL.) and digitoxin (therapeutic
level: 10-25 ng./mL).
*Treatment of digitalis toxicity:
1-Stop digitalis.
2-In case of hypokalemia: stop K+-losing diuretics and give KCl (syrup, sustained release tablets,
or slowliy IV infusion) except in case of renal impairment and AV block.
3-In case of hypercalcemia: give Ca2+ chelating agent as disodium edetate IV.
4- To treat AV block use atropine.
5- To treat ventricular arrhythmias With AV block: Phenytoin.
To treat ventricular arrhythmias Without AV block: Lidocaine or -blockers.
51
6- In case of acute toxicity: Digoxin antibodies (Fab fragments) are given, and cholestyramine to
decrease oral absorption of digitoxin.
Very important notes:
1-DC shock (electric cardioversion) is contraindicated in digitalis toxicity as it may lead to V.F.
2-Quinidine is contraindicated in treatment of arrhythmias due to digitalis toxicity (why?).
CNS Pharmacology
Sedative/ Hypnotics and Anxiolytics:
Bz1 Agonists
Non-benzodiazepines
Well absorbed orally.
Benzodiazepines
Benzodiazepines.
Chemistry:
well absorbed orally. Pharmacokinetics:
1-Sedation.
2-Hypnotic action (little REM
and minimal hangover).
Minimal:
Anticonvulsant-AntispasticityTolerance and dependence.
Given IV.
Irregular absorption after IM injection due to
binding to muscle proteins, except Lorazepam.
Highly bound to plasma proteins.
Pass BBB.
Pass placental barrier.
Fate: most Bz are activated in the liver-some Bz
are inactivated by the liver (Lorazepam and
Oxazepam)-Clorazepate is a prodrug activated by
HCl.
Bz are Agonists that stimulate specific Bz 1,2
(omega) receptors opening of chloride channels
hyperpolarization and post-synaptic neuronal
inhibition , i.e. facilitate GABA transmission.
1-Sedation.
2-Anxiolytic action.
3-Hypnotic action (little REM and minimal
hangover).
4-Anesthetic action.
5-Amnesia.
6-Anticonvulsant and Antiepileptic action.
7-Antispasticity action.
8-Taming action in wild animals.
9-Alprazolam has anti-depressant action.
NO: Autonomic-Extrapyramidal-HME inductionCVS or Respiratory actions in therapeutic doses.
Benzodiazepines
Mechanism of
action:
Actions:
Bz1 Agonists
Insomnia.
1-Anxiety disorders.
2-Insomnia (Flurazepam-Temazepam-Triazolam).
3-Epilepsy (Diazepam-Clonazepam-Lorazepam).
4-Convulsions (DiazepamIV
5-Skeletal muscle spasticity (Clonazepam).
6-Pre-anesthetic medication and IV anesthesia
(Midazolam).
7-Depression and anxiety (Alprazolam).
8-Alcohol withdrawal.
9-Diagnostic aids in Psychiatry.
1-Amnesia, Ataxia.
2-Day-time Sedation (with long acting Bz),
rebound insomnia and anxiety (with short acting
Bz).
53
Therapeutic Uses:
Adverse effects;
Zolpidem-Zaleplon-Zopiclone.
Flumazenil.
3-Allergy.
4-Increased appetite and weight gain.
5-Sexual dysfunction.
6-Thrombophlebitis.
7-Gut upset.
8-Tolerance and dependence (addiction).
9-Teratogenic.
10-Mental confusion and hypotension in old age.
11-Acute toxicity: if given with other CNS
depressants as alcohol.
Short acting: Triazolam-Midazolam.
Intermediate acting: Lorazepam-OxazepamAlprazolam-Temazepam-Clonazepam-Estazolam.
Long acting: Diazepam-FlurazepamChlordiazepoxide-Clorazepate-QuazepamPrazepam.
Flumazenil: selective Bz competitive antagonist.
Examples:
Antidote:
Buspirone:
Pharmacodynamics:
1- Agonist (or partial agonist) on 5-HT1A receptors.
2-Anxioselective.
Therapeutic uses:
Generalized Anxiety Disorders (GAD).
Advantages over Benzodiazepines:
1-No: sedation, drowsiness, hypnosis, amnesia, ataxia, no effect on driving skills.
2-Little tolerance, dependence, and additive effect with alcohol.
3-No cross tolerance with barbiturates or benzodiazepines.
Disadvantages:
1- Delayed onset of action.
2-No anticonvulsant, antiepileptic, skeletal muscle relaxant actions.
3-Adverse effects: nervousness, tachycardia, GIT distress (nausea mainly).
Analgesics
Aspirin
Less potent-relieves mainly low intensity
pain (superficial pain).
Irreversible non-selective inhibition of all
1-Potency:
2-Mechanism of action:
Meperidine
3-Analgesic action:
4-Other actions:
5-Analgesic in:
Synthetic.
Not an opium alkaloid.
50%.
Into normeperidine (active) and
meperidinic acid (inactive).
Rapid onset and short duration.
Agonist on opiate receptors (mainly
).
Potent.
Narcotic.
Potent.
Potent.
Potent.
In some human females and some animals.
In large and toxic doses due to inhibition of GABA
release.
No atropine-like action.
Miosis (central).
Potent.
Less addictive.
Highly addictive.
1-Source:
2-Chemistry:
3-Oral
bioavailability:
4-Metabolism:
5-Onset and duration:
6-Mechanism of
action:
7-Actions:
Analgesic:
Narcosis:
R.C .depression:
Antitussive:
Euphoria:
Excitation:
Convulsions:
Atropine-like action:
Pupil:
55
Emetic action
(nausea, vomiting):
Spasmogenic action
on GIT and
constipation:
Addiction:
Uses:
-Neurogenic shock.
-Insomnia due to pain.
Allergy to acetaminophen.
*Chemistry:
*Pharmacokinetics:
-Pharmacological
actions:
*Indications:
*Adverse effects:
*Contraindications:
Anti-epileptic drugs
Valproic acid and Sodium valproate Phenytoin (Diphenylhydantoin)
1-Blocks sodium channels (as phenytoin)
2-Blocks T-type calcium channels (as
Ethosuximide).
3-Inhibits GABA transaminase so increases GABA
Mechanism of
action:
level.
4-Antagonizes excitatory transmitters as aspartate.
All types of epilepsy (broad-spectrum antiepileptic)
including petit-mal, but:
1-Not the drug of choice in petit-mal epilepsy as it
may cause sedation and hepatotoxicity
(Ethosuximide is the drug of choice).
2-The drug of choice in mixed epilepsy (petit-mal +
grand-mal) and in myoclonic epilepsy.
1-Grand-mal epilepsy.
2-Partial epilepsy (seizures).
3-Status epilepticus (given slow I.V.).
Not in petit-mal epilepsy as it may worsen
it.
Uses in Epilepsy:
Other uses:
1-GIT irritation.
1-CNS: confusion-hallucinations2-Transient alopecia.
cerebellovestibular dysfunction (ataxia,
3-Teratogenicity (spina bifida).
vertigo, diplopia, nystagmus).
4-Bone marrow depression (thrombocytopenia).
2-Gut upset: anorexia,nausea,vomiting
5-CNS: ataxia and sedation.
(irritant due to high alkalinity, so it is given
6-Cholestatic hepatitis (and may lead to
after meals).
hepatotoxicity).
3-Hirsutism due to its androgenic effect.
7-Drug interactions:
4-Hepatotoxicity.
-HME inhibition leading to decreased metabolism of
5-Gum hyperplasia which is irreversible
phenytoin. 6-Allergy and lymphadenopathy which may
-Displaces phenytoin from plasma protein binding
be mis-diagnosed as Hodgkins lymphoma.
sites and increases its plasma level. 7-During pregnancy:cleft palate and hare lip
(fetal hydantoin syndrome) if given in first
trimester, and hypoprothrombinemia and
bleeding of newborn if given before labor
due to increased metabolism o vitamin K
(prevented and treated by vitamin K).
8-Blood: hypoprothrombinemia (see
before), and folic acid deficiency leading to
megaloblastic anemia due to increased
metabolism of folic acid (prevented and
treated by folic acid).
9-Osteomalacia of bones due to increased
metabolism of vitamin D (prevented and
treated by vitamin d and calcium).
10-Decreased release of ADH and insulin
(may cause hyperglycemia).
11-Drug interactions:
-Induces its own metabolism tolerance to
the anti-epileptic action.
57
Carbamazepine:
Chemistry:
Related to tricyclic antidepressants (cross allergy).
Mechanism of Action: as phenytoin.
Pharmacological actions:
1-Antiepileptic.
2-Mood stabilizer.
Therapeutic uses:
1-Treatment of epilepsy: grand-mal and partial seizures.
2-Manic-depressive illness.
4-Trigeminal neuralgia.
4-Diabetic neuropathy.
Adverse effects and Drug interactions:
As phenytoin except: gum hyperplasia-hirsutism-increases ADH release causing fluid retention.
Anti-depressants
SSRIs
TCAs
Mechanism of action:
1-Sedation.
2-Lowering of seizure threshold.
3-Increased appetite and weight gain.
4-Atropine-like manifestations: dry
mouth-tachycardia-constipation-urine
retention-blurred vision and elevation of
IOP.
5-Cardiotoxicity: ventricular arrhythmias
which may be fatal.
6-Alpha blocking actions: Postural
hypotension, reflex tachycardia, and
delayed ejaculation.
7-Allergy: agranulocytosis and
cholestatic hepatitis (jaundice).
8-Acute toxicity: TCAs have low
therapeutic index and toxicity occurs with
large doses, manifested by: Coma,
Cardiotoxicity, Convulsions, and
atropine-like signs as red hot dry skin and
passive mydriasis.
1-BPH.
59
Pharmacological actions:
Therapeutic uses:
Adverse effects:
2-Glaucoma.
3-Allergy.
4-Epilepsy.
5-Hypotension.
6-Tachyarrhythmias.
7-With MAOIs Atropine-like toxicity.
Fluoxetine-Fluvoxamine-SertralineParoxetine-Citalopram-Escitalopram.
Contraindications:
Examples:
Adverse effects
1-Sedation.
2-Seizures.
3-Extrapyramidal
manifestations
Indications
1-Treatment of
Psychosis as
Schizophrenia. It
improves mainly
Actions
A-Receptor Blocker:
1-Potent D2 blocker in: limbic
system-CTZ-basal gangliahypothalamus.
Mechanism
Blocks D
receptorsmainly D2-in
the limbic
3-Hypotension and
cardiac diseases as
angina and
arrhythmia.
4-BPH.
5-Glaucoma.
6-Allergy.
7-Liver diseases.
8-Pregnancy.
9-Idiosyncracy.
(Akathisia, dystonia,
tremors) and
iatrogenic
Parkinsonism
(prevented and
treated the dose
and by
antimuscarinics as
Benztropine).
4-Tardive
dyskinesia.
5Hyperprolactinemia
(gynecomastia,
impotence and loss
of libido in malesgalactorrhea and
amenorrhea in
females).
6-Postural
hypotension.
7-Atropine-like
manifestations.
8-Allergy:
obstructive hepatitis
and jaundice.
9-Increased appetite
and weight gain.
10-Corneal and lens
opacities.
11-Teratogenicity.
12-Idiosyncracy:
Neuroleptic
malignant
syndrome.
positive signs as
hallucinations.
2-Antiemetic, but not
effective in motion
sickness and
contraindicated in
pregnancy.
3-Severe persistent
hiccough.
4-Pre-anesthetic
medication.
5-Hypothermic agent
during GA.
6-Severe itching
(pruritus).
2-Potent 1 blockerpostural
hypotension, reflex tachycardia,
delayed ejaculation.
3-Potent 5-HT blocker.
4-Weak M-blocker (atropinelike).
5-Weak H1-blocker
(antihistaminic).
6-Weak ganglion blocker.
7-Weak NM blocker (curare-like
action).
B-CNS:
1-Antipsychotic.
2-Antiemetic not motion
sickness.
3-Extrapyramidal manifestations
and Parkinsonism.
4-Hyperprolactinemia.
5- Appetite.
6-Hypothermia.
7-Sedation.
8-Lowers seizure threshold.
9-Potentiates CNS depressants
as morphine, barbiturates,
alcohol.
C-Autonomic actions:
1-Alpha blocking action.
2-Atropine-like action.
3-Ganglion blocking action.
4-Inhibits neuronal reuptake.
D-CVS:
1-Heart: tachycardia (reflex +
G.B. + atropine-like)Myocardial depression
(quinidine-like action).
2-B.V.: V.D. (alpha block mainly
+ GB + direct).
3-ABP: hypotension (postural).
E-Othe actions:
Na+-channel blocker L.A.
GIT Pharmacology
PEPTIC ULCER
Treatment:
61
system.
The aim of treatment of peptic ulcer is to restore the balance between the mucosal offensive
agents (HCl, pepsin, and H.pylori) and the mucosal protective agents (PGs mainly) by the
following drugs:
I-Anti-secretory drugs: they reduce HCl secretion, and are used for "healing of the ulcer".
II-Anti-microbial drugs: to eradicate H.pylori.
III-Mucosal protective agents.
IV-Antacids: to relieve pain and hyperacidity, i.e they are used only for "symptomatic treatment"
and not for healing of the ulcer.
N.B.: Corticosteroids and NSAIDs except paracetamol- cause peptic ulcer by inhibition of PG
synthesis; this is known as Iatrogenic ulcer and is best prevented and treated by PG analogues as
Misoprostol.
I- Anti-secretory Drugs:
These drugs reduce HCl secretion from the parietal cell of the stomach and are classified
according to the mechanism of action into:
1-H2-Antagonists: Cimetidine, Ranitidine, Nizatidine, Famotidine.
2-Proton Pump Inhibitors (PPIs): Omeprazole, Esomeprazole, Lansoprazole, Pantoprazole,
Rabeprazole.
3-Anti-Muscarinic Drugs (Anticholinergic drugs = Muscarinic antagonists): Pirenzepine,
Telenzepine, Dicyclomine (selective M1-blockers), Propantheline, Oxphenonium, Atropine
methyl nitrate, Hyoscine butyl bromide (quaternary ammonium compounds).
They decrease HCl secretion and also reduce pain by decreasing motility of GIT.
4-Prostaglandin Analogues: e.g. Misoprostol.
It is a prostaglandin E1 analogue.
It acts both as anti-secretory drug and mucosal protective agent.
It is the drug of choice in prophylaxis and treatment of iatrogenic ulcers caused by cortisol and
NSAIDs.
It causes abdominal cramps and diarrhea.
It is contraindicated in pregnancy because it is a powerful oxytocic and may lead to abortion.
1-H2-Antagonists:
Cimetidine Ranitidine Nizatidine Famotidine.
*Pharmacokinetics:
Absorption:
Absorbed orally and can also be given by IV injection.
Distribution:
-Pass BBB and may cause CNS adverse effects especially in old age and in renal impairment.
-Pass placental barrier and may cause teratogenicity.
-Bound to plasma proteins.
Fate:
Partly metabolized by the liver and excreted in urine (unchanged mainly and as metabolites).
They are also excreted in breast milk.
*Pharmacodynamics:
-Mechanism of action:
Competitive antagonists with histamine released from enterochromaffin-like cells (ECL) at H2receptors in gastric parietal cells.
-Pharmacological actions:
1-Reduction of HCl secretion (basal, nocturnal, stimulated by histamine, food, gastrin, vagus,
insulin, and drugs as methylxanthines and muscarinic agonists).
2-Reduction of both volume and H+ ion concentration of gastric juice.
3-Reduction in pepsin secretion.
4-Mild reduction of intrinsic factor without impairment of vitamin B12 absorption, so no
incidence of pernicious anemia.
5-No effect of gastric emptying or GIT motility (in contrast to antimuscarinic drugs).
*Therapeutic uses:
1-Peptic ulcer; both gastric and duodenal ulcers. They are given in a dose of 2 tablets / day for 68 weeks until healing of the ulcer, then given in a maintenance dose of 1 tablet / day for 6 months
to prevent recurrence of the ulcer.
2-Zollinger Ellison syndrome: gastrin-secreting tumor of the pancreas accompanied with peptic
ulcers.
3-Gastro-Esophageal Reflux Disease (GERD) = Reflux esophagitis.
4-Prevention and treatment of upper GIT bleeding following severe trauma, burns, and acute
renal failure. They are given IV.
5-Treatment of stress ulcers and iatrogenic ulcers.
6-Treatment of hiatus hernia.
7-Other uses: Combined with H1-blockers (antihistaminics) and NSAIDs in treatment of
symptoms of systemic mastocytosis Combined with antihistaminics in treatment of resistant
urticaria.
*Adverse effects:
1-Recurrence of the ulcer in case of sudden stoppage of H2-antagonists.
2-Allergic reactions: skin rash.
3-GIT disturbances: diarrhea.
4-Blood dyscrasias: bone marrow depression as aplastic anemia and granulocytopenia.
5-Cholestatic hepatitis and jaundice.
6-CNS disturbances: drowsiness, confusion, tremors, slurred speech, delirium and hallucinations.
They are more common in old age and in renal impairment (dose should be adjusted according to
renal function).
7-Teratogenicity and affect nursing babies.
8-Rarely CVS manifestations as bradycardia and hypotension.
9-Cimetidine causes sexual dysfunctions in males (gynecomastia, impotence, loss of libido and
decreased sperm count causing infertility), and in females (galactorrhea and breast tenderness).
This is probably due to hyperprolactinemia in both sexes and due to anti-androgenic effect in
males.
*Drug interactions:
1-Cimetidine is a hepatic microsomal enzyme inhibitor (inhibitor of CYP 450) and decreases
clearance of theophylline, warfarin, phenytoin, digitoxin, and propranolol and may cause serious
adverse effects by these drugs.
2-Decreased gastric acidity may decrease the effect of clorazepate (prodrug activated by gastric
acid) and sucralfate (see later), and may decrease absorption of Ca2+, iron, and some drugs as
digoxin, and ketoconazole (antifungal).
63
III- Antacids:
Antacids are drugs that neutralize excess HCL.
65
Antacids are used for symptomatic treatment to relieve ulcer pain and hyperacidity and are not
useful for healing of ulcers.
Antacids are classified into:
A-Physical antacids: they adsorb HCl and pepsin.
B-Chemical antacids: they chemically antagonize HCl and are further subdivided into:
1-Systemic antacids: NaHCO3 which causes "systemic alkalosis".
2-Local (non-systemic) antacids: Aluminium and magnesium salts which do not cause systemic
alkalosis.
Sodium Bicarbonate
Magnesium
Salts
Aluminium Salts
Advantages:
1-Rapid onset.
2-No diarrhea or constipation.
3--Alkalinize the urine in:
treatment of acute toxicity by
acidic drugs as salicylates
with uricosuric drugs in
prophylaxis of gout
prevention of crystalluria
caused by some drugs as
sulphonamides.
Disadvantages:
1-Systemic alkalosis.
2-Releases CO2 leading to
distension, discomfort,
rebound acidity, and may be
rupture (perforation).
3-Hypernatremia which may
cause edema, elevate ABP,
and heart failure.
4-Short duration.
5-Alkalinization of urine may
precipitate phosphate stones
and decreases renal excretion
of basic drugs as ephedrine
and amphetamine.
1-Delayed onset.
2-Diarrhea.
3-Decreases oral
absorption of
quinolones,
tetracyclines, warfarin,
digoxin, ketoconazole,
theophylline, ranitidine.
1-Delayed onset.
2-Constipation.
3-Decreases oral absorption of
quinolones, tetracyclines,
warfarin, digoxin, ketoconazole,
theophylline, ranitidine.
4-Hypophosphatemia (except Al
phosphate gel).
Important Notes:
1-NaHCO3 is also used:
-To alkalinize the urine in: treatment of acute toxicity by acidic drugs as salicylates with
uricosuric drugs in prophylaxis of gout prevention of crystalluria caused by some drugs as
sulphonamides.
-To treat systemic acidosis.
PURGATIVES
I-Physical (Luminal)Purgatives
II-Irritant (Chemical)
A-Bulk forming B-Lubricant C-Surfactant
A-Mild
B-Moderate
1-Bran (food).
Liquid paraffin. Dioctyl sodium Castor oil. 1-Anthracenes:
2-Methylcellulose.
Sulphosuccinate.
Aloe-Senna3-Agar.
Cascara.
4-Plantago seeds.
2-Phenolphthal.
5-Osmotic purgatives=
3-Bisacodyl. Saline
purgatives as Magnesium sulphate.
6-Lactulose.
I-Physical (Luminal)Purgatives
A-Bulk forming Purgatives:
They increase bulk of gastric and intestinal contents stretch of wall reflex peristalsis.
They act on BOTH small and large intestine.
Onset of action: 1-3 hours taken in the morning.
1-Food: contains bran and methylcellulose (undigested fibers in vegetables) and is suitable and
safe for chronic constipation in elderly.
2-Plantago seeds and agar: imbibe water.
3-Osmotic (Saline) purgatives:
Examples: Magnesium sulphate (Epsom salt) Sodium sulphate- Mg oxide + Mg hydroxide
(Milk of Magnesia).
Given orally in the morning on empty stomach (15 g. isotonic solution).
Non-absorbable osmotic salts retain water in bowel
increase bulk of gastric and intestinal contents stretch of wall reflex peristalsis.
Release cholecystokinin evacuation of bile from gall bladder into small intestine
peristalsis.
4-Lactulose:
Synthetic disaccharide made up of Galactose + Fructose.
Non-digested Non-absorbed osmotic laxative retain water in bowelincrease bulk of
gastric and intestinal contents stretch of wall reflex peristalsis.
Split in the colon by colonic bacteria into Lactic acid and other acids which lower pH of
colon inhibition of proteolytic bacteria (ammonia-forming bacteria).
Uses:
1-Constipation.
2-Hepatic (ammonia) encephalopathy given with Neomycin to reduce synthesis of ammonia in
colon.
B-Lubricant purgatives: Paraffin oil (Liquid paraffin):
Non-absorbable synthetic mineral oil.
Softens and lubricates hard stools and mucosa of large intestine.
Onset of action: 8-10 hours; so given at night.
Useful in chronic habitual constipation.
Adverse effects (disadvantages);
3-Liver damage.
4-Cumulation.
3-Bisacodyl:
Chemically related to phenolphthalein but no entero-hepatic circulation and so short duration.
Given orally and rectally (suppository).
Sodium Picosulphate is related to Bisacodyl.
Severe Irritant Purgatives (as croton oil and colocynth) are obsolete due to severe colics,
diarrhea, dehydration, and GIT perforation.
Therapeutic uses of Intestinal evacuants (Purgatives):
1-Treatment of constipation.
2-Before abdominal surgery, radiology, and endoscopy.
3-Drug and food poisoning: e.g after morphine poisoning.
4-To prevent straining in heart failure, hernia, after eye and neurological operations.
5-Before and after treatment of Helminthes as Tinea solium.
Stool softeners: Glycerin suppository-Liquid paraffin-Dioctyl sodium sulphosuccinate. They are
useful in chronic (habitual) constipation.
Endocrine Pharmacology
Anti-Diabetic drugs
GLP-1 receptor agonists
Examples:
DPP-IV inhibitors
1-Sitagliptin.
2-Vildagliptin.
3-Saxagliptin.
Amylin analogues
Pramlintide.
Route:
Mechanism and
actions:
S.C. injection.
Stimulate Glucagon-Like
Peptide-1 (GLP-1) receptors
leading to:
1-Stimulation of insulin release
from B-cells.
2-Decrease glucagon release
from A-cells.
3-Delay gastric emptying (to
prevent sudden elevation of
blood glucose after meals).
4-Suppress appetite (CNS
action).
Oral.
Inhibit Di-PeptidylPeptidase-4 (DPP-IV)
enzyme endogenous
GLP-1 stimulation of
GLP-1 receptors leading to:
1-Stimulation of insulin
release from B-cells.
2-Decrease glucagon release
from A-cells.
3-Delay gastric emptying (to
prevent sudden elevation of
blood glucose after meals).
4-Suppress appetite (CNS
action).
Indications:
Type II D.M.step 4.
Adverse effects
(Disadvantages):
1-Hypoglycemia (when
combined with SU).
2-Nausea is very common.
3-Decreased absorption of
some drugs as paracetamol due
to delayed gastric emptying.
4-Given only by injection.
INSULIN
*Source:
1-Animal insulin: from animal pancreatic extracts and is either:
71
S.C. injection.
Stimulates amylin
receptors leading to:
1-Decrease glucagon
release from A-cells.
2-Delay gastric emptying
(to prevent sudden
elevation of blood
glucose after meals).
3-Suppress appetite
(CNS action).
N.B. amylin does not
stimulate insulin release
(it may even reduce
insulin release but this is
insignificant).
Type I and Type II D.M.
to prevent post-prandial
hyperglycemia.
-Bovine: differs from human insulin in 3 amino acids and is highly antigenic.
-Porcine: differs from human insulin in 1 amino acid and is less antigenic than bovine insulin.
2-Human insulin: obtained by 2 different techniques:
-Synthesis by recombinant DNA technology (Bio-synthetic insulin).
-Enzymatic modification of animal insulins (Semi-synthetic insulin).
Human insulin is the least antigenic but is much more expensive.
*Chemistry:
Insulin is composed of 2 polypeptide chains: A chain made up of 21 amino acids, and B chain
made up of 30 amino acids. Both chains are connected by 2 disulphide links which are essential
for the biological activity of insulin.
*Factors Affecting Insulin Release:
Factors Stimulating Insulin Release
Factors Inhibiting Insulin Release
1-Glucose (the most potent stimulus): glucose
1-Fasting and starvation: increase sympathetic
enters B-cells by GLUT 2 and undergoes
activity leading to release of adrenaline and
glycolysis to form ATP, which in turn blocks
noradrenaline which stimulate 2-receptors thus
ATP-sensitive K+ channels depolarization inhibit insulin release.
opening to voltage-dependent Ca2+ channels 2-Somatostatin (inhibits glucagon release more
influx of Ca2+ insulin release.
than its inhibitory action on insulin).
2-Amino acids (leucine and arginine) and fatty
2-PG E1.
acids in diet.
3-Autonomic innervation and receptors:
3-GIT hormones (incretins) as Glucagon-like
2 stimulation, 2 block, and muscarinic block.
peptide 1 (GLP-1) and Gastrin inhibitory
4-Drugs:
peptide (GIP).
Thiazides, Loop diuretics, and Diazoxide:
4-Systemic Hormones: Glucagon and growth
open ATP-sensitive K+ channels in B-cells
hormone (secondary to increased blood
leading to hyperpolarization.
glucose).
Phenytoin (Na+ channel blocker).
5-Autonomic innervation and receptors:
CCBs as Verapamil.
Muscarinic stimulation, 2 stimulation, and 2
block increase insulin release.
6-Insulin secretagogues (Oral hypoglycemic
drugs, e.g. sulfonylureas and meglitinides).
*Pharmacokinetics:
-Insulin is never given orally because it is a polypeptide; i.e. it is destroyed by proteolytic
enzymes in GIT.
-All insulin preparations are given by S.C. injection.
-Only regular (soluble) insulin is given IV Only in case of diabetic ketoacidosis (D.K.A.).
-Insulin is distributed to all tissues.
-Fate: insulin is metabolized by glutathione insulin transhydrogenase (insulinase) in liver and
kidney which breaks the disulphide links, then the polypeptide chains are degraded by
polypeptidases.
*Pharmacodynamics:
-Mechanism of action:
Insulin acts by stimulation of specific insulin receptors.
Insulin receptors are "Tyrosine Kinase linked".
Each receptor is composed of 2 -subunits on the cell membrane, and 2 -subunits that transfix
the cell membrane (partly extracellular and partly intracellular). These subunits are linked by
disulphide links.
Insulin molecule binds to -subunits of insulin receptors which then activate -subunits leading
to activation of tyrosine kinase and phosphorylation of different enzymes which initiate the
biological actions of insulin; e.g. glucose transporters (GLUT) which glucose uptake.
The insulin receptor then undergoes "conformational change" and "internalization", then it is
either degraded or "recycled" to the cell membrane.
-Pharmacological actions:
"Remember that insulin is an anabolic hormone".
1-Action on Carbohydrate Metabolism:
Insulin tends to reduce blood glucose by the following mechanisms:
-Stimulation of glucose uptake by formation of "glucose transporters" as GLUT 4 which is
responsible for glucose uptake into skeletal muscles and adipose tissue.
-Stimulation of glucose utilization by glycolysis (glucose by glucokinase glucose 6 phosphate
ATP).
-Stimulation of glycogenesis and inhibition of hepatic glycogenolysis.
-Inhibits gluconeogenesis.
2-Action on Protein metabolism:
-Amino acid transport and stimulates synthesis of proteins.
-Inhibits gluconeogenesis ( protein degradation).
3-Action on Fat Metabolism:
-Stimulates lipogenesis by stimulating lipoprotein lipase andadipocyte fat storage.
-Inhibits lipolysis by inhibition of triglyceride lipase.
-Free fatty acids in blood.
-Fatty acid oxidation and inhibits ketone bodies synthesis (inhibits ketogenesis).
4-Stimulates transport of K+, Mg2+, and phosphate and decreases their plasma level.
Insulin deficiency in D.M. is characterized by:
1-Hyperglycemia and glucosuria due to:
-Glucose uptake and utilization.
-Glycogenesis.
-Glycogenolysis.
-Gluconeogenesis.
2-Free fatty acids in blood due to:
-Lipolysis.
-Lipogenesis.
3-Oxidation of free fatty acids and formation of ketone bodies (ketogenesis).
4-Amino acid uptake and protein synthesis and protein catabolism.
5-Weakness, immunocompromization and recurrent infections.
*Indications of insulin:
A-Diabetic indications:
1-Treatment of Type I (IDDM): replacement therapy from the time of diagnosis and throughout
life.
2-Treatment of Diabetic Keto-Acidosis (DKA) by soluble insulin IV.
73
3-Temporarily in Type II (NIDDM) in cases of "stress" due to: infections surgery pregnancy
-trauma.
4-Permanently in Type II (NIDDM) in cases of:
-Failure to control hyperglycemia by diet + exercise + oral anti-diabetics.
-Development of renal or hepatic impairment.
-After recovery from DKA.
B-Indications of insulin in "non-diabetic cases":
-Treatment of hyperkalemia due to renal impairment (glucose should be given with insulin to
avoid hypoglycemia).
*Adverse effects:
A-Local Adverse Effects:
1-Lipodystrophy: either hypertrophy (more common due to insulin-induced lipogenesis) or
atrophy of subcutaneous fats. It is prevented by changing (rotating) the site of injection.
2-Local allergic reactions; they are rare nowadays due to the use of human insulin instead of
animal insulin.
3-Localized infections.
B-Systemic Adverse Effects:
1-HYPOGLYCEMIA:
Hypoglycemia is the most dangerous adverse effect of insulin therapy.
Causes:
1-Insulin overdose (too much insulin).
2-Ommission of meals (too little food).
3-Exhaustive physical exercise (too much exercise).
Manifestations:
-Sympathetic stimulation: tachycardia and palpitations (the most important warning symptoms)
tremors sweating pallor.
-Neuroglycopenia: headache blurred vision and diplopia confusion coma and may end in
death.
Tretment:
-If the patient is conscious: treatment by oral glucose or sweeting agents (juice, chocolate, etc.).
-If the patient is comatosed: treatment by IV glucose (50 mL. of 50% glucose) or by glucagon
(1mg.) given IM or SC followed by oral glucose.
2-Systemic allergic reactions (uncommon because human insulin has largely replaced animal
insulins).
3-Insulin resistance (daily insulin requirements exceed 200 Units, common in obese nonexercising patients, and may improve by adding insulin sensitizers as glitazones).
4-Hypokalemia may occur especially with insulin therapy in DKA.
Biguanides (Metformin)
-Mechanism of action: unclear but may act
Pharmacodynamics:
through:
1-Increases insulin sensitivity by stimulation
of binding to its receptors.
2-Decreases oral absorption of glucose from
GIT.
3-Decreases glucagon release from pancreas.
4-Increases action of insulin in peripheral
tissues and thus stimulates glucose uptake and
utilization by skeletal muscles and adipose
tissues.
5-Stimulates anaerobic glycolysis.
6-Inhibits hepatic gluconeogenesis ( hepatic
glucose output).
7-Decreases appetite leading to weight
reduction.
(Remember that metformin does not stimulate
insulin release, this is why it is euglycemic not
hypoglycemic).
Indications:
Adverse effects:
Pharmacokinetic interactions:
1-Sulphonylureas displace oral anticoagulants
as warfarin from plasma proteins leading to
bleeding.
2-Sulphonylureas are displaced by NSAIDs as
aspirin and phenylbutazone, and
sulphonamides from plasma proteins and may
augment the hypoglycemic effect of
sulphonylureas.
3-Probenecid decreases renal excretion of
sulphonylureas and may augment their
hypoglycemic effect.
4-Alcohol hypoglycemia.
Pharmacodynamic interactions:
1-Thiazide diuretics, loop diuretics,
diazoxide, and phenytoin antagonize the
hypoglycemic effect of sulphonylureas
because they inhibit insulin
release (thiazides, loop diuretics, and
diazoxide open ATP-sensitive K+-channels
and phenytoin blocks Na+-channels).
2-Corticosteroids and oral contraceptives
cause hyperglycemia and antagonize the
hypoglycemic effect of sulphonylureas.
Contraindications:
Drug interactions:
Examples:
Glucocorticoids
Mechanism of action: see Applied Medical Pharmacology book, page 286.
77
Contraindications
1-Sudden withdrawal of
glucocorticoids after
prolonged use.
2-Peptic ulcer.
3-Diabetes mellitus.
4-Hypertension.
5-CHF.
Adverse effects
Toxic effects from
sudden withdrawal:
1-Suppression of HPA
axis and adrenal atrophy
which leads to acute
adrenocortical
insufficiency if
exogenous steroids are
suddenly stopped after
prolonged therapy.
2-Corticosterone
withdrawal syndrome:
fever, myalgia, arthralgia,
and malaise.
Toxic effects due to
continued use of large
doses:
1-Iatrogenic Cushing'
syndrome: moon facebuffalo hump-trunkal
obesity- wasting of
limbs.
2-Iatrogenic peptic ulcer
and acute pancreatitis.
3-Hyperglycemia and
glucosuria.
4-Skeletal muscle
wasting and myopathyosteoporosis-sublaxation
of joints-delayed wound
healinggrowth retardation in
children.
5-Na+ and water retention
leading to edema and
weight gain, elevation of
ABP, and may cause HF.
6-Hypokalemia
(hypokalemic
alkalosis).
7-Hypocalcemia.
Uses
Actions
1-Acute adrenocortical
1-Negative feed-back inhibition of
insufficiency (acute
hypothalamic-pituitary-adrenal
Addisonian crisis) due to
cortex with suppression of
sudden withdrawal of endogenous glucocorticoid synthesis.
exogenous steroid
Atrophy of the adrenal cortex may
therapy, or due to stress
occur due to inhibition of ACTH.
(trauma or infection).
2-Metabolic Actions:
Treatment by
On Carbohydrate metabolism:
Hydrocortisone sodium
-Anti-insulin actions: stimulate
succinate IV +
gluconeogenesis and inhibit glucose
0.9% NaCl IV infusion +
uptake and utilization.
glucose 5% IV infusion.
-Stimulate glycogenesis in liver.
2-Chronic adrenocortical -The net result is Hyperglycemia and
insufficiency (chronic
glucosuria.
Addison's disease):
On Protein metabolism:
treated by oral steroids
Glucocorticoids cause protein
having both gluco- and
catabolism in most tissues except
mineralocorticoid actions
liver- as skeletal muscles, bone,
as cortisol or
lymphoid tissue, and connective
fludrocortisone (see tissue leading to muscle wasting and
preparations).
myopathy, osteoporosis, growth
B-Suppressive Therapy:
retardation in children, and delayed
Suppression of ACTH in
wound healing.
treatment of
On Fat metabolism:
adrenogenital
-Lipolysis of fats in limbs, thighs,
hyperplasia.
and buttocks.
C-Supplementary
-Lipemia.
Therapy: -Lipogenesis in face, back, and trunk
1-Anti-allergic in
leading to "moon face", "buffalo
angioneurotic edema,
hump", and trunkal obesity. This is
dermatitis, allergic
known as Fat Redistribution.
rhinitis, allergic
3-Mineralocorticoid action:
conjunctivitis, glucocorticoids have aldosterone-like
anaphylactic shock.
action causing Na+ and water
2-Anti-inflammatory and
reabsorption and hypokalemia. This
anti-allergic in bronchial may lead to edema, elevation of ABP,
asthma (inhaled steroids
and may dangerous in patients with
as beclomethasone in
CHF. Severe hypokalemia occurs if
prophylaxis, and
given with thiazides and loop
hydrocortisone sodium
diuretics.
succinate IV in status
In addition; they are essential for
asthmaticus).
diuresis of excess water (may be
3-Anti-inflammatory and
through inhibition of ADH).
immunosuppressive in
4-On vitamin D and Ca2+:
7-Uncontrolled infections.
8-Thrombo-embolic
diseases.
8-Immunosuppression
and masking of
inflammation leading to
infection by T.B., viral
and fugal infections (as
candidiasis). Inhaled
steroids cause
oropharyngeal
candidiasis and
dysphonia.
9-Increased blood
coagulability and
thrombo-embolic
manifestations.
10-Catarct and glaucoma.
9-Glaucoma.
11-Hirsutism and
menstrual disturbances.
12-CNS manifestations:
psychosis or mania.
auto-immune diseases
glucocorticoids have anti-vitamin D
(collagen diseases) as
action and decrease Ca2+ absorption
rheumatic carditis, R.A., from GIT and increase Ca2+ excretion
S.L.E., nephrotic
by the kidney, leading to
syndrome, chronic
Hypocalcemia (negative calcium
hepatitis, and ulcerative
balance).
colitis (may be given as
5-Anti-inflammatory action:
retention enema).
-By inhibition of phospholipase A2
4-Anti-inflammatory in:
(through synthesis of lipomodulin
acute gouty arthritis
and macrocortin by neutrophils and
resistant to NSAIDs,
macrophages, respectively) leading
osteoarthritis (may be
to inhibition of synthesis of
given intra-articular), and
inflammatory mediators: PGs,
cerebral edema (avoid
leukotrienes, and platelet activating
glucocorticoids with saltfactor (PAF).
retaining effect).
-Inhibit migration of macrophages.
5-Immunosuppressive
-Decrease circulating lymphocytes,
after organ
eosinophils, monocytes, basophils.
transplantation to prevent -Decrease synthesis of inflammatory
rejection.
cytokines and interleukins.
5-Blood diseases as:
-Stabilize lysosomal membrane and
leukemia (acute inhibit release of lysosomal enzymes.
lymphocytic leukemia),
-Decrease capillary permeability.
thrombocytopenic
6-Immunosuppression and Antipurpura, agranulocytosis,
allergic actions:
and hemolytic anemia.
Through inhibition of antibody
6-Hypercalcemia and formation, antigen-antibody reaction,
hypervitaminosis D
and tissue response to
(vitamin D intoxication).
inflammation.
7-Shock.
7-Action on blood:
-Increased number of RBCs due to
increased release from bone marrow
(polycythemia).
-Increased number of neutrophils due
to inhibition of migration
(neutrophilia).
-Increased number of platelets
(thrombocytosis).
-Increased blood coagulability.
-Decreased number of lymphocytes
due to catabolic effect on lymphoid
tissue (lymphopenia).
-Decreased number of eosinophils
(eosinopenia).
8-Action on Serum Uric Acid:
Uricosuric action and decrease serum
79
uric acid.
9-Action on CNS: cause euphoria
and may lead to psychosis.
10-Action on Respiratory system:
-Anti-inflammatory in bronchial
asthma.
-Increase number of 2-receptors and
prevents down regulation by 2agonists.
-Stimulate production of surfactant in
neonates.
11-Action on GIT: inhibit synthesis
of cytoprotective PGE2 and
PGI2and accordingly increase HCl
and decrease mucus leading to peptic
ulcer. This iatrogenic ulcer is best
prevented and treated by
misoprostol.
12-Anti-stress and Anti-shock: (by
increasing blood volume and BP by
hypernatremia, by increasing blood
sugar, and by CNS action).
Anti-Thyroid drugs
Iodide
Given orally and concentrated in thyroid
follicles.
Thioamides (Thioureas)
Absorption:
Absorbed orally. PTU is incompletely absorbed
and can also be given IV in thyrotoxic crisis.
Distribution:
-Highly bound to plasma proteins.
-Concentrated in thyroid gland.
-Pass BBB.
-Pass placental barrier and may cause fetal
goiter or cretinism. PTU is the safest thioamide
in pregnancy (PTU does not cross placental
barrier).
Fate:
-Carbimazole is a prodrug and is metabolized
into active methimazole.
-Thioamides are metabolized by the liver by
conjugation and metabolites are excreted in
urine. They are excreted in breast milk and
affect suckling infants.
Mechanism of action:
1-Inhibit peroxidase enzyme and accordingly
inhibit oxidation of iodide into iodine.
2-Inhibit organification of iodine and formation
of MIT and DIT.
3-Inhibit coupling of MIT with DIT and DIT
with DIT thus inhibiting synthesis of T3 and T4.
4-PTU also inhibits peripheral de-iodination.
5-Inhibition of iodine absorption from GIT.
Pharmacological actions:
Inhibition of synthesis of "new" thyroid
hormones but no effect on iodide uptake and no
effect on release of already formed and stored
hormones. That is why they have delayed onset
of action (about 2 weeks) until the stored
hormones are depleted and due to long t1/2
of thyroid hormones.
1-Treat mild cases of hyperthyroidism. They
are given until the patient is "euthyroid" then a
smaller maintenance dose is given to prevent
recurrence.
2-Temporary control of hyperthyroidism in
patients treated by radioactive iodine which has
very delayed onset of action (about 2-3
months).
3-Pre-operative preparation before subtotal
thyroidectomy to decrease the stored hormones
81
Pharmacokinetics:
Pharmacodynamics:
Indications:
Allergy to iodide.
Onset of action in
hyperthyroidism:
Adverse effects:
Contraindications:
I131
Given orally-concentrated in thyroid colloid.
Thioamides
See before.
Pharmacokinetics:
Emits destructive beta and gamma particles that destroy thyroid follicular
cells.
Very slow onset after 1-2 months. Maximum response appears after other
2 months.
1-Hyperthyroidism.
2-Thyroid carcinoma.
1-Iatrogenic hypothyroidism (main disadvantage).
2-Thyroid storm (due to excessive release of stored hormones).
3-Cretinism if given during pregnancy or lactation.
4-Very slow onset.
5-Repeated doses may be needed.
6-Leukemia and carcinomas of the neckmay appear after 15-20years?
1-Pregnancy and lactation.
2-Young age.
See before.
Pharmacodynamics:
See before.
Onset of action:
See before.
Indications:
See before.
Adverse effects:
See before.
Contraindications:
83
Contraindications
Adverse effects
3-Diabetes mellitus.
4-Fibroids and endometrial carcinoma (estrogendependent).
5-Pre-menopausal breast carcinoma (estrogendependent).
6--Undiagnosed vaginal bleeding (which may be due to
endometrial or vaginal carcinoma).
7-Thromboembolic diseases.
8-Females over 35 years to avoid thromboembolism,
hypertension, DM, especially in obese and smokers.
Summary of Antibiotics
I- Cell Wall Inhibitors:
Adverse effects (toxicity)
Mechanism of action
Action on
bacteria
Antibiotic
1-Hypersensitivity (allergy).
2-Diarrhea-superinfectioninhibition of floravitamin
K and B synthesis.
3-CNS toxicity (seizures in
large doses).
4-Platelet dysfunction.
5-Methicillinacute
interstitial nephritis.
7-Jarisch-Herxheimer reaction
in syphilis.
1-Hypersensitivity (allergy
and cross allergy with
penicillin).
2-Nephrotoxicity.
3-Diarrhea-superinfectioninhibition of floravitamin
K and B synthesis.
4-Bleeding (platelet
dysfunction + anti-vitamin K).
5-Pain at site of IM injection.
6-Thrombophlebitis.
1-Allergy and cross allergy
with penicillin.
2-Gut upset.
3-Seizures (in large doses).
4-Neutropenia and
esinophilia.
1-Bind to PBPinhibit
transpeptidase inhibit
formation of cross linking
between peptidoglycan
layersinhibition of cell
wall synthesis.
2-Activation of
autolysinscell wall lysis.
Bactericidal.
1-Penicillins:
As Penicillins.
Bactericidal.
2-Cephalosprins:
As Penicillins.
Bactericidal.
3-Carbapenems:
As Penicillins.
Bactericidal.
4-Monobactams:
Bactericidal.
Vancomycin and
Teicoplanin:
85
Mechanism of
action
Action on
bacteria
Antibiotic
Erythromycin mainly:
1-Epigastric pain, diarrhea, and colics.
2-Cholestatic jaundice and hepatitis
(caused by esteolate ester).
3-Allergy (skin rash).
4-Ototoxicity (azithromycin).
5-Erthromycin and clarithromycin are
HME inhibitorstoxicity by warfarin
and phenytoin
1-Pseudomembranous colitis (treated
by oral vancomycin + metronidazole).
2-Liver impairment.
3-Gut upset.
4-Allergy (skin rash).
1-Ototoxicity (deafness-vertigo).
2-Nephrotoxicity.
3-Skeletal muscle weakness
(paralysis).
4-Allergy (contact dermatitis).
Bind irreversibly to
50 S ribosomal
subunitinhibition
of protein synthesis.
Bacteriostatic in low
concen. and
bactericidal in high
concen.
1-Macrolides:
ErthromycinClarithromycinAzithromycin.
As Macrolides.
As Macrolides.
2-Clindamycin:
Bind to 30 S
ribosomal
subunitinhibition
of protein synthesis
(formation of
defective proteins).
Bind to 30 S
ribosomal subunit
inhibition of
protein synthesis.
Bactericidal.
3-Aminoglycosides:
Bacteriostatic.
4-Tetracyclines:
Bacteriostatic and
may be bactericidal.
5-Chloramphenicol:
Bind to 50 S
ribosomal subunit
inhibition of
protein synthesis.
Mechanism of
action
Action on
bacteria
Antibiotic
1-Hypersensitivity.
2-Hemolysis in favism.
3-Bone marrow depression.
4-Crystalluria.
5-Hyperbilirubinemia,
jaundice, and kernicterus
(in neonates).
Megaloblastic anemia (folic
acid deficiency anemia).
Bacteriostatic.
1-Sulphonamides:
Bacteriostatic.
2-Trimethoprim:
As sulpha + trimethoprim.
1-Arthropathy.
2-CNS disturbances.
3-Gut upset.
4-Allergy (skin rash) and
photosensitivity.
5-Hepatotoxicity
(trovafloxacin).
6-HME inhibition.
1-Orange-red discoloration.
2-Flu-like syndrome.
3-Hepatotoxicity.
4-CNS disturbances
(ataxia).
5-Gut upset.
6-HME inducer.
1-Gut upset (metallic taste).
2-CNS disturbances
(vertigo).
3-Teratogenicity and
mutagenicity.
4-Disulfiram-like action in
alcoholics.
5-Leucopenia.
Bactericidal.
3-Cotrimoxazole:
(sulpha+trimethoprim)
Bactericidal.
4-Fluoroquinolones:
Inhibits DNA-dependent
RNA
polymeraseinhibit
RNA synthesis.
Bactericidal.
5-Rifampicin:
Converted inside
organism (bacteria or
protozoa) into active
metabolite Inhibits
DNA synthesis.
Bactericidal and
Amebicidal.
6-Metronidazole:
87