1. What'is'pharmacology.

'Subdivisions'of'pharmacology;'
Pharmacology!is!a!branch!in!medicine!or!biology!that!concern!to!the!study!of!
drugs!and!its!interactions!within!a!biological!system!to!affect!its!function.!A!drug!
can!be!defined!as!a!man7made!(synthetic)!or!naturally!occurring!substance!that!
excretes!a!biochemical!and/or!physiological!over!a!cell,!tissue,!organ!or!the!
organism!as!a!whole.!More!specifically!it!can!be!defined!as!the!study!of!
interactions!between!a!living!organism!and!a!chemical!substance!that!affects!
normal!or!abnormal!functions.!!
!
There!are!2!main!areas!in!pharmacology:!!
Pharmacokinetics:!is!the!study!of!the!fate!of!the!drug,!or!the!
effects!of!the!organism!over!the!!drug,!composed!of!absorption,!
distribution,-metabolism!and!excretion!(last!2!are!called!also!
!elimination).!!
Pharmacodynamics:!it!is!the!effect!of!the!drug!over!the!
organism,!or!the!drug!action,!!mechanism!of!drug!action.!!
!
Medicine!7!is!a!plant!or!animal!substance!or!even!a!synthetic!substance!or!a!
mixture!of!drugs!!combined!with!other!substances!(vehicle)!to!make!it!stable,!
edible!and!useful!for!therapy.!!
!
Agent!!is!a!collective!name!for!group!of!drugs!(antihypertensive,!antipyretics,!
etc.).!!
!
Subdivisions!in!pharmacology:!!
Clinical'pharmacology:!medication!effects!on!humans!and!animals.!!
Neuropharmacology:!effects!of!a!drug!over!the!nervous!system.!!
Psychoparmacology:!effects!of!a!drug!over!the!human!brain.!!
Toxicology:!study!the!harmful!or!toxic!effects!of!a!given!drug.!!
Theoretical'pharmacology:!study!theories!in!pharmacology.!!
Environmental'pharmacology:!gene7environment!interactions.!
Posology:!also!can!be!called!doseology,!is!a!branch!studying!how!
medicine!is!dosed.!!
!
Adrenergic'agonists'(sympathomimetics);'
Sympathomimetics!by!definition!are!drugs!that!mimic!the!reactions!of!the!
endogenous!noradrenaline!(NA),!either!by!directly!binding!to!the!receptor!or!by!
indirectly!acting,!thus!influencing!the!levels!of!endogenous!NA!
'
Synthesis,'release'and'metabolism'of'NA:'
The!process!involves!5!steps:!synthesis,!storage,!release,!receptor!binding,!
metabolism.!
Synthesis:*Tyrosine!is!transported!to!the!cell!where!it!is!!
Hydroxylated!to!DOPA!(rate!!limiting!step),!which!is!then!
decarboxylated!to!form!dopamine.!!
Storage:*Dopamine!enters!a!vesicle!and!converted!to!NA!
Release:*Calcium!influx!after!an!action!potential,!leading!to!vesicular!
fusion!and!release!of!!NA.!!

!
Agents:!

Receptor*binding:*binds!to!either!post!synaptic!receptor!(1,!1,2)!or!
presynaptic!(2),!thus!!to!formation!of!second!messengers!(cAMP,!
IP3)!or!negative!feedback.!!
Metabolism:*NA!can!be!removed!and!diffuse!into!general!circulation,!
reuptaken!into!the!!neuron,!methylated!by!COMT!(cathecol!O!
methyl!transferase)!or!oxidized!by!MAO!(mono7amino!oxidaze).!!
a. Direct:!act!on!receptor:!!catecholamines,!noncatecholamines!
b. Indirect:!enhance!release!of!NA!from!vesicle:!amphetamines!and!
cocaine!
c. Mixed:!ephedrine,!pseudoephedrine!

'
Classification'of'agents:''
1. Catecholamines:!rapid!onset,!brief!duration,!no!oral!administration!
2. Noncatecholamines:!longer!duration!of!action,!mostly!B7receptors,!oral!
administration!
3. Selective!drugs:!act!on!alpha!receptors!
4. Act'on'CNS:!ephedrine!and!amphetamine!(alpha!and!beta!receptors)!!
!
Adrenaline:!Increases!systolic!BP!and!tachycardia!
NA:!Increases!diastolic!BP!and!bradycardia!(compensatory!reflex)!
Drug'
Receptor' Therapy'
Acute!asthma,!anaphylactic!shock,!Local!
Adrenaline!
All!
anaesthetic!
A1,!A2,!
NOA!
B1!
Shock!
Isoprenaline!
B1,!B2!
cardiac!stimulant!
Dopamine!
B1!
shock,!Heart!failure!
Dobutamine!
B1!
congestive!heart!failure!
Terbutaline!
B2!
bronchial!asthma!
Salbutamol!
B2!
bronchial!asthma!
Phenylephrine! A1!
supraventricular!tachycardia!
Nafasoline!
A1!
nasal!decongestion,!opthalmology!
Clonidine!
A2!
Hypertension!
!
Direct'acting'adrenergic'agonists:'binds!directly!to!the!receptor.!!!
Epinephrine*(adrenaline):**
A!cathecolamine,!synthesized!from!tyrosine!in!the!adrenal!medulla!
It!has!positive'inotropic!and!chronotropic!on!the!heart!
Bronchodilation!(beta!2)!
Increased!glycogenolysis!(beta!2)!
The!drug!is!used!in!broncospasm,!open!angle!glaucoma!
(vasoconstriction),!anaphylactic'shock,'cardiac'arrest,'anesthetic'
solution!(to!cause!vasodilation).!
Rapid!onset,!brief!duration,!it!is!metabolized!by!COMT!and!MAO.!Can!be!
given!SC,!IV,inhalation!and!topically!
Side'effects:!CNS!disturbances,!arrhythmias,!pulmonary!edema.!

NA:*!

Mostly!alpha!response,!leading!to!vasoconstriction,!thus!leading!to!
increased'BP.!!
Used!to!treat!shock!(only!indication),!given!IV,!similar!metabolism!and!
side!effects!as!adrenaline.!Leads!to!reflex!bradycardia.!

!
Isoproterenol:*predominantly!stimulate!beta!receptors!(1!and!2)!thus!it!is!not!
used!therapeutically,!but!can!be!used!in!emergencies!to!stimulate!the!heart.!!
!
Dopamine:*!
Stimulate!alpha,!beta!and!Dopamine!receptors,!thus!it!acts!on!the!heart!
with!positive!inotropic!and!chronotropic!effects,!vasodilator,!as!well!as!on!
the!renal!and!splanchnic!arteries!leading!to!vasodilation.!!
Used!in!shock!states!by!continuous!infusion.!Short!lived!side!effects.!!
!
Oxymetazoline:*stimulate!alpha!1!and!2!receptors,!used!primarily!as!a!nasal'
decongestant!(otrivin)!or!eye!vasoconstrictor!(stilla)!!rebound!congestion!
with!long!term!use.!!
!
Dobutamine:*beta!1!agonist,!used!in!cardiology!in!congestive'heart'failure!to!
increase!cardiac!output.!!
!
Phenylepherine:*alpha!1!agonist,!used!mainly!as!nasal'decongestant!and!
produce!prolonged!vasoconstriction.!!
!
Albuterol,*Salmeterol:*short!acting!beta!2!agonist,!used!as!bronchodilator.!!
'
Indirect'acting:'cause!NA!release!or!inhibit!uptake.!!
Amphetamine:*marked!CNS!stimulation,!leading!to!inhibition!of!NA!
uptake,!used!to!!treat!narcolepsy!and!hyperactivity!in!children.!!
Cocaine:*block!reuptake!of!NA!by!blocking!Na/K!pump!leading!to!
accumulation!of!NA!!in!the!synaptic!cleft.!!
'
Mixed'action:'induce!release!of!NE!and!activate!adrenegic!receptors.!!
Ephedrine*and*pseudoephedrine:*are!plant!alkaloids!with!long!duration!
of!action,!absorbed!well!orally,!used!for!asthma!treatment!and!as!nasal'
decongestant.'
!
Typical!side'effects!for!all!sympathomimetics!are:!arrhythmias,!headache,!
nausea,!tremor,!insomnia,!hyperactivity.!
!
!
!
!
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!
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Antiviral'and'antifungal'drugs.'
Antiviral:!zidovudine,'acyclovir,'indinavir,'vidarabine,'amantadine,'
interferones!
'
Mechanism'of'actions:''
1.!Block!virus!attaching!to!cell!!
2.!Block!uncoating!of!virus!
3.!Inhibit!viral!protein!synthesis!!
4.!Inhibit!specific!viral!enzymes!!
5.!Inhibit!virus!assembly!!
6.!Inhibit!virus!release!!
7.!Stimulate!host!immune!system!!
!
NB:!viruses!=!no!cell!wall,!no!cell!membrane,!do!not!carry!out!metabolic!
processes!therefore!use!host!cell,!clinical!features!appear!late!after!virus!
replicates!and!budded!!
!
Zidovudine:!inhibit!reverse!transcriptaste!(dRNA!virus),!incorporates!
into!viral!DNA,!AIDS!therapy,!PO!and!IV,!renal!excretion,!SE:!pseudo!flu!
syndrome,!fever,!myalgia,!anorexia!
Indinavir:!inhibit!of!replication!by!inhibition!of!protease,!AIDS!therapy,!
decreased!bioavailability!with!protein!rich!foods,!SE:!nausea,!vomiting,!
GIT!disturbances,!headache,!rash,!loss!of!appetite!
Acyclovir:!protease!inhibitor,!treatment:!herpes!(zoster,!simples,!
varicella),!inhibition!of!viral!DNA!polymerase,!PO,!IV,!topical,!SE:!phlebitis,!
eye!irritable!
Vidarabine:!inhibition!of!viral!DNA!polymerase,!used!for!severe!herpetic!
infections!(encephalitis),!IV,!topical,!metabolised:!plasma!by!erythrocyte,!
SE:!tremor,!myalgia!
Amantadine:!inhibition!of!uncoating!and!cell!penetration,!anti7parkinson!
and!antiviral,!mainly!for!influenza!virus!type!A!
Interferones:!immunomodulators,!used!for!hepatitis!B!and!C,!only!SC,!SE:!
pseudoflu!syndrome!!
!
AntiOfungal''
Polyenes!=!amphotericin,!nystatin!
Inhibition!of!synthesis!of!sterolds:!forms!pores!in!cell!membrane!causing!
death!
Amphotericin:!PO,!IV,!treatment!of!candidiasis,!SE:!fever,!headache,!
anaemia,!hypertension!
Nystatin!=!topical,!treatment!of!candida,!NOSE!
Azoles!=!a:!ketokonazol,!mikonazol,!B,!fluconazole,!itraconazole!
o !A)!inhibition!of!ergosterol!synthesis!by!binding!CYP!P450!enzyme!
therefore!inhibiting!cell!growth!!
o Absorbs!well!in!GIT!except!when!drugs!e.g.!antacids,!PPIs!interfere!
with!gastric!juice!
o Elimination!!=!biliary,!SE:!rare=GIT!probs,!drug!interaction:!P450!
inducer,!warfarin!!

o !B)!inhibition!of!ergosterol!synthesis!(see!above),!treats:!large!
scale!systemic!necrosis,!drug!of!choice:!Cryptococcus,!poorly!
metabolized,!treatment!=!hyperactivity!of!adrenal!gland!
(decreased!steroid!production),!well!tolerated!!
Others:!flucytosine!!
o Inhibition!of!DNA!synthesis!and!cell!division!!
o Good!absorption!and!CNS!penetration!!
o Treatment!for!systemic!candidosis!and!septicaemia!
o SE:!GIT,!bone!marrow!depression,!hepatotoxicity!!

'
Examples'of'antiviral'agents'
For!respiratory'infections:!for!influenza,!respiratory!syncytial!virus!(RSV)!and!
orthomyxovirus!we!can!use:!
!!neuraminidase!inhibitors!!Zanamivir,!lead!to!virion!
accumulation!!
!
!
!!inhibitors!of!viral!uncoating!!amantidine,!ranitidine.!!
!
!
!!Ribavirin!!synthetic!guanisine!analogue.!!
!For!hepatic'infections:!
!!interferons!!immune!modulators!&!antiviral,!given!only!by!S.C!
route!for!HCV!and!HBV.!!
!
!
!!Adefovir!!nucleotide!analogue.!!
!
!
!!Entecavir!!guanosine!analogue!!
!For!herpes'virus:!
!!Acyclovir!!can!be!oral!or!topical,!specific!for!herpes!virus.!It!is!
a!protease!inhibitor!which!!inhibit!viral!DNA!polymerase.!!
!
!
!!Ganciclovir!!acyclovir!analogue,!but!better!against!CMV.!!
!
!
!!Penciclovir!!nucleoside!derivative,!inhibit!DNA!polymerase.!!
!For!HIV'infections:!we!use!HAART!(highly!active!antiretroviral!therapy).!
!!NRTI!!nucleotide!reverse!transcriptase!inhibitors!(zidovudine,!
stavudine).!!
!!NNRTI!!non7nucleotide!reverse!transcriptase!inhibitors!
(Nevirapine).!!
!!Protease!inhibitors!!result!in!production!of!non!infectious!
virions!(Indinavir,'ritonavir).!!
!Integrase!inhibitors!!prevent!entry!of!HIV!into!the!cell!
(Raltegravir)!
'
2. Historical'development'of'pharmacology.'Drug''names;'
Pharmacology!as!an!independent!branch!stated!developing!somewhere!in!
the!19.century!but!there!are!evidence!of!pharmacological!therapy!all!the!
way!to!6!B.C!and!written!evidence!from!the!4.or!5.century!in!india.!In!
ancient!Egypt,!various!papyrus!recorded!pharmacological!knowledge!as!
far!as!the!16.century!B.C.!
In!ancient!Greece,!history!of!pharmacotherapy!dates!to!the!4.century!B.C!
when!there!was!a!group!of!experts!in!medicinal!plants.!In!Baghdad!during!
the!8.century,!there!was!a!network!of!state7regulated!pharmacies!during!
the!Islamic!golden!era!and!in!Europe!it!was!recorder!somewhere!in!the!
12.!century.!

Milestones'in'pharmacology:'
o 1805:!isolation!of!Morphine!by!Sertirner.!!
o 1860:!synthesis!of!Salicylic!acid!by!Kolbe!and!Lautemann.!!
o 1874:!synthesis!of!Acetysalicylic!acid.!!
o 1904:!barbiturates.!!
o 1928:!Penicillin!was!discovered!by!Fleming.!!
o WW2:!the!first!use!of!sulfonamides!as!antimicrobial!although!
discovered!way!earlier.!!
o 1960:!Propranolol:!developed!by!Black.!!

'
Drug'names:!!
A!drug!is!given!2!names,!the!first!one!is!a!generic'name,!which!is!the!name!that!
appear!in!the!pharmacopeia!and!can!vary!among!nations!(paracetamol7
acetaminophen).!The!second!name!will!be!the!commercial'name!of!the!drug!
that!was!given!to!it!by!the!manufacturer,!most!of!the!times!its!easier!to!
remember!and!pronounce.!
'
Drug'names:!single!drug!has!variety!of!names:!
I.!
Chemical'name!e.g.!N7Ethanamide,!!
II.!
Generic'name!e.g.!Paracetamol!in!EU!acetaminophen!in!USA,!!
II.!
Commercial/trade!names!e.g.!Panadol,!Acomol!
!
Adrenergic'antagonists'(sympatholytics);'
Adrenergic!antagonists!=!Beta'blockers'
Actions!(A)!! Decreases!HR!and!contractility!(propranolol),!hypoglycaemia,!
hypotension,!decreases!HDL,!bronchoconstriction,!decreases!renin!!
Drugs!(D)! Metoprolol!(B1),!propranolol!(B1!and!B2)!(contraindicated!in!
asthma!patients)!
Therapeutic'uses!(TU)Angina!Pectoris!(propranolol),!hypertension!(all),!
glaucoma!(timolol),!migraine!(propranolol!is!prophylaxis),!
phaeochromocytoma,!hyperthyroidism,!mycocardial!
infarction!!
Side!effects!(SE)!
Bronchoconstriction!!CI!in!asthma!and!COPD!patients,!
arrhythmias,!hypoglycaemia,!bradycardia,!hypotension,!
sleep!disturbances!
!
Alpha'antagonists:''
Selective!A1:!prazosine!for!hypertension!
Non!selectiveA1!and!A2:!phenoxybenzamine!!irreversible!block!leads!to!reflex!
tachycardia,!treatment!for!pheochromocytoma!
(TU)!
Pheochromocytoma,!hypertension,!prostatic!hypertrophy!
(SE)!
orthostatic!hypotension!(phenoxybenzamine),!tachycardia,!
vertigo,!sexual!disturbances!!
!
Sympatholytics,!or!blockers,!bind!to!adrenoreceptors!(!or!)!but!do!not!
trigger!a!response!and!act!by!binding!either!reversibly!or!irreversibly.!They!can!
be!alpha!blockers,!beta!blockers!or!affect!the!uptake!or!release.!
!

Alpha'blockers:'affect!blood!pressure!by!blocking!alpha!1!receptors,!leading!to!
vasodilation!and!decreased!peripheral!resistance,!which!in!turn!will!lead!to!
reflex!tachycardia.!
!
o Prazosin,*Terazosin,*Doxazosin,*Tamsulosin:*selective'competitive'
alpha'1'blockers,!the!first!3!are!used!to!treat!hypertension!while!the!last!
is!used!for!benign!prostatic!hyperplasia.!May!lead!to!orthostatic!
hypotension,!tachycardia,!vertigo!and!sexual!dysfunction!
o Phenoxybenzamine:*a!non'selective'alpha'blocker,!bind!covalently!to!
alpha!receptors!(irreversible),!thus!decrease!peripheral!resistance!
leading!to!reflex!tachycardia.!Not!really!used!today,!but!is!used!only!in!the!
treatment!of!pheochromocytoma!(adrenaline!producing!tumor!in!the!
adrenal!medulla).!!
o Phentolamine:*same!as!phenoxybenzamine,!but!competitive!rather!than!
irreversible.!!
!
Beta'blockers'(all'end'with''olol):'can!be!non!selective!or!beta!1!selective!
(cardioselective)!only.!Can!be!with!or!without!ISA.!
Cardioselective:*through!beta!1!receptors.!
o Atenolol,*Metoprolol,*Acebutolol:-cardioselective!beta!blockers,!
lower!BP,!have!low!!effect!or!even!none!on!pulmonary!functions,!
peripheral!resistance!and!carbohydrate!!metabolism.!!
Non''selective:'!
o Propanolol:-prototype!beta!blocker,!used!to!treat!hypertension,!
glaucoma,!migraine,!!hyperthyroidism,!angina!pectoris!and!M.I.!It!
may!lead!to!bronchoconstriction!(beta!2),!arrhythmias,!sexual!
impairment!(unclear!why)!!
o Timolol*and*Nadolol:-more!potent!than!propranolol,!the!rest!is!the!
same.!!
Antagonists'with'ISA:'!
Acebutolol-!written!above,!a!selective!beta!blocker,!but!has!ability!to!
stimulate!beta!receptors!(partial!agonists),!effective!in!hypertension.!
Pindolol-!non!selective!beta!blocker!with!ISA.!!
!
Mixed'antagonists'(alpha'and'beta):'!
Carvedilol-and-Labetalol:-used!for!hypertension!and!congestive!heart!
failure,!can!lead!to!orthostatic!hypotention.!
!
Drugs'affecting'uptake'and'release:!
Reserpine:-plant!alkaloid,!blocks!the!moving!of!NA,!dopamine!and!
serotoin!to!the!!storage!vesicles!in!the!adrenergic!nerves,!leading!to!
depletion.!!
Guanethidine:-block!the!release!of!stored!NA!and!displaces!NA!from!
storage!vesicles,!!leading!to!depletion.!!
!
!
!
!
!

Sulphonamides'and'quinolones.'
!
Fluroquinolones:!has!4!generation!of!drugs!with!increased!activity!against!G+!
microbes.!These!drugs!diffuse!into!the!cell!via!porins,!inhibit!DNA!replication!by!
inhibiting!DNA!gyrase!(Topoisomerase)!!inhibit!uncoiling.!It!is!considered!to!be!
bacterocidal!and!generally!speaking!is!very!effective!against!gram!negative!
microorganisms.!
!
!1.generation:!Nalidixic'acid!!not!used,!lab!only.!!
2.generation:!Ciprofloxacin!!G+!cocci,!G7!rods,!intracellular!bacteria.!!
nd!
3.generation:!Levofloxacin!!better!than!2 generation,!but!generally!the!
same.!!
4.generation:!Moxifloxacin!!G+!cocci!and!bacilli,!G7!rods!and!anaerobes.!!
!
Resistance!is!via!mutations!of!the!DNA!gyrase!and!porins.!Absorbed!well!orally,!
accumulate!in!Macrophages!and!PMN's,!thus!good!for!intracellular!bacteria.!Side!
effects:!nausea,!vomiting,!allergy,!diarrhea,!headache,!phototoxicity!(accumulate!
in!the!skin).!!
!
Quinolones'*floxacin*'
1st!gen:!nalidixic'acid:!nonfluorinated7!UTIs!!
2nd!gen:!ciprofloxacin!!pneumonia,!drug!of!choice!in!travellers!diarrhoea!
3rd!gen:!gatifloxacin7!mycobacterium!avium!
4th!gen:!tovafloxacin7!broader!spectrum,!anaerobes!
Mechanism'of'action:!inhibition!of!DNA!synthesis7!gyrase!(topois)7!inhibition!of!
coiling!therefore!uncoiled!shape!therefore!bacteriocidal!!
Bactericidal:!G7,!G+!(staph!aureus),!UTI,!GIT,!and!resp!inf!
AE:!GIT!upset,!hepatotoxicity,!photoxicity,!arrhythmias!
Interactions:!decreased!abs:!dairy!+!antacids,!inhibitor:!theophylline!!
!
Sulfonamides:!these!are!inhibitors!of!folate'synthesis.!Folate!is!essential!for!the!
synthesis!of!purines!and!pyrimidines!(G,C,A,T,U)!and!this!is!why!in!its!absence!
the!cell!will!not!be!able!to!grow!or!divide.!These!drugs!inhibit!the!De7novo!
synthesis!of!folate!by!competing!with!the!bacterial!enzyme.!For!the!former!
mentioned!reasons,!these!drugs!are!bacteriostatic.!
!
Active!against!enterobacteria!in!the!U.T!and!drugs!of!choice!for!
toxoplasmosis!and!malaria.!!
Administered!orally,!bind!to!serum!albumin,!penetrate!into!CSF,!
acetylated!in!the!liver,!and!!may!lead!to!crystaluria!(due!to!its!toxic!
metabolite).!!
Side'effects:!crystaluria!(nephrotoxicity),!allergy,!hemolytic!anemia!
(G6PD!deficincy),!kernicterus!(in!newborns).!!
Contraindicated!in!neonates,!pregnant!women!and!G6PD!patients.!!
Drugs:!Sulfamethoxazole,!Sulfadiazine,!Sulfacetamide.!!
'
'
'

Drugs:!sulphonamides:!!
1.!short!acting!sulpadizine,!!
2.!long!acting!sulphametopin!
3.!sulphasalazine!(poor!GIT!absorption)!!
4.!silver!sulphadiazine!(topically)!
'
Pharm'properties:!resistance;!bound!to!plasma!proteins,!!
Spectrum:!enterobacteria,!chlamydia!
Treatment:!IBD,!UTI,!G+,!G7!
AE:!allergic!reaction,!haemolysis,!in!G6PD!def,!crystalluria!(nephrotoxicity!
treatment!!CI!with!vitamin!C!(acidic),!alkalization!of!urine),!CI!in!pregnancy!
TERATOGENIC!
Combination'with'trimethoprim:!block!FA!synthesis!but!at!different!location)!!
'
3. Routes'of'drug'administration'
Determined'by:''
I.!
Drug!properties!(liposolubility!ionization)!
II.!
Therapeutic!objective!!site!of!action,!speed!of!onset,!toxicity!
III.!! Routes:!enteral!(PO,!SL,!PR),!parenteral!(IV,!IM,!SC),!other!(inhalation,!
topical,!transdermal)!
IV.!
Speed:!IV>inhalation>IM>PR>SC>PO!(faster>slower)!
!
Enteral:!GIT!to!portal!circulation!to!liver!to!systemic!!
1.!!
PO7!easy,!first!pass!effect,!long!onset!of!action,!GIT!probably!affects!
absorption!
2.!
SC7!diffusion!into!capillaries!then!into!systemic,!drugs!increase!first!pass!
effect!e.g.!nitroglycerine!
3.!
PR7!50%!bypass!portal!circulation,!vomiting!does!not!interfere!
(antiemetic),!large!surface!for!absorption,!good!for!babies,!uncomfortable!!
4.!
Nasogastric!!
'
Parenteral:'for!drugs!poorly!absorbed!by!GIT!(heparin),!unstable!in!GIT,!
patients!in!coma,!rapid!onset!of!action,!highest!bioavailability!but!risk!of!
infection!
1.!
IV7!100%!bioavailability,!H20!soluble,!rate!of!infusion!=!controlled!to!
prevent!adverse!reaction!
2.!
IM7!rapid!absorption!of!H20!soluble,!painful,!prone!to!infection,!aspiration!
3.!
SC7!slower!than!IC,!lower!risk!of!infection!e.g.!morphine!pumps,!
contraceptive!subcutaneous!capsules!!
4.!
Other:!
A.!
Inhalation7!fast!e.g.!bronchodilators7!terbutaline,!corticosteroids!in!
bronchial!asthma!
B.!
Topical7!local!application7!creams!on!skin,!eye!drops,!anaesthetic!
sprays!
C.!
Transdermal7!systemic!effect,!drug!absorbed!to!systemic!
circulation!via!skin!e.g.!transdermal!patches!of!
nitroglycerine/contraceptives!!
!

The!route!of!administration!of!a!drug!may!be!crucial!for!its!activity!or!alter!the!
absorption!and!the!bioavailability!of!given!drug.!Typical!routes!of!administration!
include!parenteral,!enteral!and!other:!!Enteral!(through!the!GIT):!
!P.O.*7!It!is!the!most!common!method!of!administration,!given!as!a!pill,!a!capsule!
or!lozenge!which!is!easy!for!the!patient!and!does!not!require!any!instruments!or!
medical!staff,!but!undergo!biotransforamtion!in!the!stomach!and!in!the!liver!
(first!pass!effect)!thus!the!bioavailability!is!decreased.!!
S.L.*7!sub7lingual!administration!is!administration!of!a!drug!under!the!tongue!
that!go!straight!to!the!capillary!network!and!thus!bypass!the!liver!and!the!
stomach.!!
Parenteral!(not!from!the!GIT):!used!for!drugs!that!are!poorly!absorbed!from!the!
GIT!(heparin),!unstable!in!the!GIT!(insulin)!and!in!patients!that!require!rapid!
onset.!This!methods!have!the!highest!bioavailability,!because!they!do!not!pass!
through!the!GIT!or!the!hepatic!circulation.!
I.M.*! Intra7muscular!injection!is!a!method!with!a!rapid!absorption!of!water!
soluble!substances,!can!be!given!as!emulsions!(lipids+water)!or!
suspension!(water+powder)!as!well,!it!is!necessary!to!aspirate!to!make!
sure!the!drug!is!in!the!muscle!and!not!vein!or!artery,!relatively!painful!or!
scary!for!the!patient!and!may!be!prone!for!infections.!!
!I.V.*7!intra7venous!injection!is!the!only!method!with!100%!bioavailability!of!
water!soluble!substances.!!
S.C.!7!absorption!of!lipid!soluble!materials!through!the!sub7cutaneous!tissue.!!
'
Other:!
Inhalation*!fast!method!with!intense!effect,!but!can!be!irritating!to!the!
respiratory!system.!!
Transdermal*!slow!sustained!release!of!substances!from!the!skin!to!the!
systemic!circulation!which!may!lead!to!local!irritation.!!
Topical*!creams!or!lotions!or!powder!preparations!that!can!be!given!topically!
on!the!skin.!!
*
P.R.*7!per!rectum!is!administration!through!mucous!membrane!(anus)!and!can!
decrease!the!first!pass!effect!by!50%,!because!50%!of!the!absorbed!drug!bypass!
the!hepatic!circulation,!can!be!given!in!cases!such!as!vomiting!or!to!infants,!but!
can!be!uncomfortable.!!
*
Intrathecal*/*Intraventricular7!administration!of!a!drug!directly!to!the!CSF.!!
Intranasal*-usually!nasal!decongestants!and!is!the!administration!of!drug!
directly!to!the!!nose.!!
!
!
!
!
!

Alpha'Antagonists;'
Alpha'blockers:'affect!blood!pressure!by!blocking!alpha!1!receptors,!leading!to!
vasodilation!and!decreased!peripheral!resistance,!which!in!turn!will!lead!to!
reflex!tachycardia.!
!
o Prazosin,*Terazosin,*Doxazosin,*Tamsulosin:*selective!competitive!
alpha!1!blockers,!the!first!3!are!used!to!treat!hypertension!while!the!last!
is!used!for!benign'prostatic'hyperplasia.!May!lead!to!orthostatic!
hypotension,!tachycardia,!vertigo!and!sexual!dysfunction!
o Phenoxybenzamine:*a!non!selective!alpha!blocker,!bind!covalently!to!
alpha!receptors!(irreversible),!thus!decrease!peripheral!resistance!
leading!to!reflex!tachycardia.!Not!really!used!today,!but!is!used!only!in!the!
treatment!of!pheochromocytoma!(adrenaline!producing!tumor!in!the!
adrenal!medulla).!!
o Phentolamine:*same!as!phenoxybenzamine,!but!competitive!rather!than!
irreversible.!!
!
Antidysrhytmic'drugs.'
Arrhythmia!is!a!dysfunction!which!causes!abnormalities!in!impulse!formation!
and/or!conduction.!It!can!be!either!tachy!or!brady!arrhythmia!and!with!or!
without!a!sinus!rhythm.!Impulses!originating!from!sites!other!than!the!SA!node,!
or!traveling!along!accessory!pathways!(Reentry,!Wolff!7Parkinson!!White!
syndrome).!!
!
Arrhythmias!are!classified!as:!!
Atrial'
o Atrial!flutter:!propranolol,!verapamil,!digoxin.!!
o Atrial!fibrillation:!propranolol,!amioderon,!anticoagulants.!!
''''SupraOventricular:'
o AV!nodal!reentry:!propranolol,!verapamil,!digoxin.!!
o Acute!supra7ventricular!tachycardia:!verapamil,!adenosine.!!
'' Ventricular'tachycardia:'
o Acute!ventricular!tachycardia:!lidocaine,!amioderone.!!
o Ventricular!fibrillations:!lidocaine,!amioderone,!epinephrine.!
!
The!etiology!can!be!abnormal!automaticity,!drug!effect,!conduction!
abnormalities!and!for!treatment!we!have!4!classes!of!drugs:!!!
!
!Class'1'anti'arrhythmic'(sodium'channel'blockers):''
o Block!sodium!channels,!via!the!same!mechanism!as!local!anesthetics,!by!
binding!to!open!or!inactivated!sodium!channels!rather!than!fully!re7
polarized,!thus!they!are!good!in!tachycardia.!This!property!is!called!state7
dependance!and!it!enables!the!blockade!of!abnormally!high!frequency!
discharging!cells,!without!interfering!with!normal!cells.!!
o Has!3!sub7classes:!!
! 1a!!slow!phase!0!depolarization!(quinidine,'procaineamide),!
bind!to!sodium!channels!and!!prevent!sodium!influx!(also!inhibits!
potassium!channels),!used!to!maintain!sinus!rhythm!in!
!tachycardia.!May!lead!to!arrhythmia!by!itself!!!!!!!!

!
!

1b!!shortens!phase!3!(lidocaine),!thus!the!cell!is!unable!to!fire!
another!action!potential!!leading!to!decreased!heart!rate.!!
!1c!!markedly!slows!phase!0!depolarization!(propafenone,'
flecainide),!show!major!effect!!even!on!normal!heart,!slowly!
dissociates!from!resting!sodium!channels.!!!

!Class'2'antiarrhythmics'(beta'blockers):''
Diminish!phase!4!repolarization,!thus!depressing!automaticity,!prolong!
AV!conduction!and!decrease!the!heart!rate!and!contractility.!It!is!very!
useful!in!tachyarrhythmias!caused!by!increased!sympathetic!tone!!
propranolol,'metoprolol,'esmolol.'''
!Class'3'antiarrhythmics'(potassium'channel'blockers):''
Diminish!the!outward!potassium!current!during!repolarization!(phase!3)!
and!prolong!the!duration!of!the!AP,!all!drugs!in!this!class!are!dangerous!
and!may!lead!to!arrhythmia.!!
o Amiodarone!!effective!in!treating!sever!refractory!
tachyarrhythmias,!has!a!very!long!half!life!(weeks)!and!the!effect!
achieved!only!after!6!months,!causes!severe!side!effects!
(pulmonary!fibrosis,!tremor,!hepatotoxicity)!in!around!50%!of!the!
patients.!!
o Sotalol!!may!lead!to!torsades!de!pointes),!it!is!a!dangerous!
ventricular!fibrillation!showing!abnormal!ECG!with!different!
heights!of!R!wave,!if!you!will!draw!a!line!it!will!look!like!a!snake.!!
o Dofetilide!!recommended!for!treatment!of!atrial!fibrillation!(the!
only!one).!!
!Class'4'antiarrhythmics'(calcium'channel'blockers):'!!
Decrease!the!inward!calcium!current,!resulting!in!decreased!rate!of!phase!
4!spontaneous!repolarization.!Bind!only!to!open!depolarized!channels,!
thus!prevent!repolarization!and!does!not!effect!the!normal!heart!tissue,!
but!has!negative!inotropic!effect!and!vasodilatory!properties!so!it!may!
lead!to!decreased!stroke!volume,!reduced!BP,!edema!and!congestion!
formation.!!
Drugs!used:!verapamil!and!Diltiazem.!!!
!
!Other'antiarrhythmics:'!
Digoxin:!may!lead!to!ectopic!ventricular!beat.!!
Adenosine:!decreases!conduction!velocity,!prolong!the!refractory!period!
and!decrease!!automaticity!in!the!AV!nod,!but!has!to!be!in!high!doses.!!
!
4. Mechanisms'of'drug'passage'across'the'membranes;'
Absorption:!transfer!of!drug!from!admin!site!to!blood!!
Rate!and!efficiency!depends!on!route!of!administration!(IV!=!100%!
bioavailability)!
!!
!
!
!

A.'
1.!
2.!
3.!!

Passive'diffusion:''
Along!concentration!gradient!!
No!specific!carriers!
Liposoluble/nonionized!(charged!molecules!cannot!cross!membranes!
passively!!therefore!weak!acid!in!acidic!environment,!weak!base!in!basic!
environment)!
4.! Larger!molecules:!need!facilitated!diffusion!!
5.! Passage!of!specific!molecules!via!specific!proteins!(e.g.!ion!channels)!!
!
B.' Active'transport'
1.! against!concentration!gradient!!
2.! Requires!energy!
3.! Specific!carrier!proteins!(move!molecules!against!concentration!gradient)!
4.! Transport!!uni/sym/anti7port!
5.! Endocytosis!(e.g.!B12)!
6.! Exocytosis!(e.g.!neurotransmitters)!!
!
Also!called!absorption,!a!drug!can!pass!across!a!biological!membrane!in!2!main!
ways:
passive!diffusion.!
active!diffusion.!

Passive'diffusion!will!be!a!process!in!which!the!drug,!or!the!substance!
crosses!the!membrane!along!the!concentration!gradient.!In!order!to!
achieve!that!the!drug!must!be!liposoluble!and!non!ionized!(charged!
molecules!cannot!cross!membranes!passively)!which!is!achieved!due!to!
the!drug's!pKA.!!
No!specific!carrier!is!required!and!the!substance!can!pass!through!
channels!(for!ionized!forms).!Weak!acid!will!cross!membrane!easily!in!an!
acidic!environment!and!weak!bases!in!alkali!environment.
Molecules! larger! than! a! certain! size! (1007200! Dalton)! will! not! pass!
through!pores.

'

Fascilitated'diffusion!
Passage!of!a!molecule!through!special!proteins!(i.e!ion!channels)!that!do!
not!require!energy.!

'
Active'transport!is!a!process!that!require!energy!and!involves!a!specific!carrier!
molecule!or!a pump!(Na/Kpump)!in!order!to!move!substances!against!their!
concentration!gradient.!The!transport!can!be!uniport!(one!substance,!one!way)!
symport!(2!substances!together,!one!way!!i.e!glucose!and!sodium!in!the!
intestines)!and!antiport!(one!substance!one!way!the!other!substance!to!the!
other!way,!i.e!sodium/calcium!pump).!
!
!
!
!
!
!

Cholinergic'agonists'(parasympathomimetics);'
Drugs!that!act!on!the!cholinergic!nervous!system!and!can!be!direct!and!
indirect!acting.!!
Direct'acting'agonists:!Do!not!need!nerve!ending!and!act!directly!on!the!
level!of!the!receptor.!They!can!be!Ach,!synthetic!choline!esters!
(carbachol,!bethanechol)!and!natural!alkaloids!(pilocarpin).!
!
Ach!!therapeutically!not!important,!can!activate!everything!basically,!
and!is!rapidly!inactivated!by!AchE.!!
Bethanechol!!not!hydrolized!by!AchE,!lacks!nicotinic!action,!but!has!
strong!muscarinic!action.!Its!main!action!is!on!smooth!musculature!
(bladder!and!GIT).!It!is!used!for!treatment!of!urinary'retention.!
Carbachol!!not!hydrolized!by!AchE,!has!strong!effect!over!the!CVS!and!
GIT!thus!rarely!used!therapeutically!except!the!eyes!as!a!miotic!agent,!
leading!to!miosis!due!to!contraction!of!the!circular!muscle!and!lead!to!
spasms!of!accomodation!(only!cholinergic!drugs!causes!contraction!of!the!
ciliary!muscles!leading!to!iris!accommodation!and!blurred!vision).!!
Pilocarpin!!alkaloid,!uncharged!(penetrate!CNS),!used!primarily!in!
ophthalmology!to!reduce!intraocular'pressure!in!closed!and!open!angle!
glaucoma,!lead!to!miosis!and!contaction!of!ciliary!muscle!(opposite!to!
atropine).!Sjorgren's!syndrome!!dry!mouth!and!lack!of!tears!is!treated!
with!this!agent.!
!
Indirect'acting'agonists:'
Work!by!binding!to!AchE,!either!reversibly!or!irreversibly!(echothiopate),!
thus!terminate!its!action!and!prolong!the!life!of!Ach!in!the!synaptic!cleft.!
Physostigmine!!found!naturally!in!plants!which!bind!reversibly!to!AchE!
(competitive!inhibition).!Used!therapeutically!to!increase!intestinal!and!
bladder!motility,!reduce!pressure!in!glaucoma.!!
Neostigmine!!reversibly!inhibits!AchE,!but!more!polar!than!
physostigmine!and!cannot!penetrate!the!BBB,!used!to!stimulate!the!
bladder!and!the!GIT.!!
Rivastigmine!!used!in!Alzheimer's'disease,!can!only!delay!the!disease.!!
Demecarium!and!Edrophonium!!AchE!inhibitors.!Edrophonium!is!a!
very!short!acting!!drug!that!is!used!in!the!diagnosis!of!Myasthenia'Gravis!
only.!!
Echothiophate!!it!is!an!organophosphate!that!binds!covalently!to!
AchE.!It!is!impossible!to!reactivate!the!enzyme!after!its!aging!(loss!of!ethyl!
group).!!
In!case!of!intoxication!with!insecticides!we!can!use!ASAP!atropine!or!
pralidoxime!(any!oxime!will!do)!
Side'effects!of!cholinergic!agonists!are!nausea,!vomiting,!diarrhea,!
salivation,!sweating,!hypotension,!miosis,!bronchoconstriction!and!flush.!
!
'
'
'
'

Direct:'
!
!

AchOnonselective'(M+N)'
Betanechol!(urinary!retention!+!GIT);!Carbachol!(glaucoma)!!
Pilocarpine!(glaucoma);!Muscarine!(Mushroom!poison,!antidote!=!
atropine)!
Inhibit'cholinesterases''
Reversible!(anticholinesterases):!neostigmine,!physostigmine!!
Irreversible!(organophosphates):!war!gases,!insecticides!!

Indirect:''
!
!
!
!
!
Action:!Cardiovascular!(M2):bradycardia;!Decreased!contractility;!Decreased!AV!
conduction;!smooth!muscle!(not!vascular)!contraction;!Increased!GIT!activity;!
bladder!contraction;!SM!(vascular)!vasodilation!(via!NO);!exocrine!
glands=gastric!acid!secretion!(M1)+sweating=salivation=bronchial!secretion!
(M3);!eyes!=!Decreased!intraocular!pressure!
'
Therapeutic'uses:!Myasthenia!gravis!(neo+phys),!glaucoma!(phys),!curare!
muscle!paralysis!(neo!+!phys),!UTI!stimultant!(neo),!GIT!stimulant!(neo)!
'
Side'effects:!Bronchoconstriction,!hypotension,!flushing,!salivation,!NVD,!
intoxication!
!
*Intoxication*:!by!organophosphates:!hypotension,!mm!contractions!and!
convulsions,!leads!to!respiratory!failure.!Treatment:!Pralidoxime/!trimadoxime!
+atropine)!causes!reactivation!of!Ach!esterases!
!
Antidiabetic'drugs.'
Antidiabetic!drugs!!
Regulation!of!blood!glucose!=!glucagon!=!increase!blood!glucose!!
Insulin!=!decrease!blood!glucose!!
Insulin!secretion!=!increased!glucose!in!blood!!uptake!by!GUT!2!into!cell!!ATP!
to!rise!in!cell!!inactivate!K!channels!!depolarization!!opening!of!Ca!channels!!
influx!of!Ca!!secretion!of!insulin!!
'
Insulin'actions!=!regulation!of!glucose,!stimulation!of!lipogens,!decrease!
lipolysis,!increase!AA!transport!into!cells,!stimulation!of!growth,!DNA!synthesis,!
cell!replication,!increase!AA!into!cells,!decrease!lipolysis,!stimulate!lipogenesis!!
!
1.!human'insulin:!insulin!lispro!(274!hours),!insulin!glargine!(24726!hours)!!
SE:!hypoglycaemia!(NB:!interaction!with!oral!hypoglycaemics,!sulphonamides,!
anti7depressants),!lipodystrophy,!allergy,!down!regulation!of!receptors!!
2.!oral'hypoglycaemic'agents7!after!non7pharmacological!dont!work!!
Sulfonylureas:!tolazamide,!glibenclamide7!block!K+!channel,!therefore!Ca2+!
influx,!therefore!increase!insulin!release,!increase!peripheral!sensitivity,!can!
cause!severe!hypoglycaemia!
Biguanides!=!metformin7!increase!uptake!of!glucose!in!target!cells,!decrease!
LDL!and!increase!HDL,!does!not!cause!!hypoglycaemia,!monotherapy/combined!!
Alpha'glucosidase'inh'='acrabose!!slows!breakdown!of!cmplex!caarbs!into!
monos,!delays!absorption!of!glucose,!decrease!hyperglycaemia!after!meals!!

Metglitinides'='repaglinide!!short!half!life!than!su!!taken!before!meals:!NOs!
increase!levels!of!insulin!and!less!SU!(due!to!half!life)!combination!is!very!
effective!!
Thiazolidenedienes'='rosiglitazone,'pioglitazome,!increases!insulin!
sensitivity!in!periphery,!no!production!of!extra!insulin,!pio!=!increase!HDL,!ROS!=!
decrease!LDL,!once!daily!!
'
There!are!generally!2!types!of!DM,!with!several!other!sub7types,!there!is!the!
Type'1'DM'(insulin'dependent7!juvenile!type)!and!Type'2'DM!(insulin!
resistance).'
!
The!sub!types!would!be!gestational!(also!called!type!3!DM)!and!LADA!(Late!
Autoimmune!Diabetes!of!Adults).!
A!good!way!to!differentiate!between!type!1!and!2!is!C7peptide,!which!will!be!
present!in!type!2!but!will!be!absent!in!type!1.!the!blood!sugar!level!is!mediated!
via!to!hormones!which!are!secreted!from!the!pancreas,!these!are!the!Glucagon!
(alpha!cells)!and!Insulin!(beta!cells).!
!
!
!!Glucagon!increase!blood!sugar!level!via!glycogenolysis.!!
!!Insulin!promote!intake!of!glucose!into!the!cells,!thus!deceasing!
blood!sugar!level.!!
!Mechanism'of'insulin'secretion:!
!blood!glucose!levels!!the!uptake!of!glucose!(by!GLUT2!transporter)!!
glycolytic!phosphorylation!(rise!in!ADP!:!ATP!ratio)!!inactivation!of!K+!
channels!(ATP!!dependent)!!depolarization!of!the!membrane!!Ca+2!channel!
opening,!exocytotic!release!of!insulin.!
!
Insulin!!mediated!glucose!uptake:!insulin!binds!to!insulin!receptor!on!the!cell!
surface!!glucose!transported!through!GLUT4!into!the!cell!!!of!hepatic!glucose!
release.!
!
!Actions'of'insulin:'Regulates!glucose!metabolism,!stimulates!lipogenesis,!
diminishes!lipolysis,!!AA!transport!into!the!cells,!modulates!transcription,!
stimulates!growth,!DNA!synthesis!and!cell!replication!(together!with!IGF!and!
relaxin).!
There!are!several!types!of!recombinant!human!insulin.!
short!acting!insulin:!insulin'lispro!(274!hours).!!
Long!acting:!insulin'glargine!(16724!hours).!!
!
!Taking!insulin!may!lead!to!hypoglycemia!and!lipodystrophy!or!even!down!
regulation!of!the!receptors!due!to!insulin!overdose,!can!occur!in!type!1!diabetics!
and!athletes!(anabolic!drug).!!
!
!Hypoglycemic'oral'medications'for'use'in'DM2:!
Sulfonylureas:!+!channel!blockers,!the!drug!has!an!effect!on!the!pancreatic!
Beta!!islet!cells!to!allow!an!influx!of!Ca+2!into!the!cell!!!in!the!release!of!
insulin.!!
Drugs!used!are!only!the!2.generation7!Glibenclamide,'Glyburide,'Glipizide,'
Glicazide,'Glimepiride'.!

Biguanids!(metformin):!Anti!!hyperglycemic,!they!do!not!stimulate!
endogenous!insulin!secretion!(hypoglycemia!will!not!occur!when!they!are!used!
alone).!Works!by!!excessive!hepatic!glucose!production!and!!glucose!utilization!
in!peripheral!tissues.!LDL/HDL!Weight!loss/no!gain!!
'
Alpha'Glucosidase'Inhibitors!(AGI):!Acarbose'is!the!prototype,!slow!down!the!
breakdown!of!disaccharides,!polysaccharides,!other!carbohydrates!into!
monosaccharides.!!
Meglitinides:!Repaglinide'is!the!prototype,!useful!as!a!Sulpanylurea!
replacement.!!
Thiazolidinediones:!primary!effect!is!peripheral!(!insulin!sensitivity!and!!
glucose!uptake),!!hepatic!glucose!uptake!and!!hepatic!sensitivity!to!glucose!!!
blood!glucose!levels,!they!DO!NOT!stimulate!the!pancreas!to!produce!more!
insulin.!!Drugs:!Rosiglitazone,'Pioglitazone'!
'
5. Distribution'of'drugs.'Binding'of'drugs'to'proteins;'
Distribution!=!Process!whereby!drug!reaches!different!organs!and!tissues!
'
Factors'affecting'distribution'of'drugs''
1.!
!Ability!of!drug!to!bind!to!plasma!!
2.!
!Liposolubility!!
3.!
!Blood!flow!in!area!of!distribution!!
4.!
!Capillary!permeability!!
5.!!
Effect!of!pH!in!area!of!distribution!!
6.!!
Drug!structure!!
!
Binding'to'proteins:''
A.!
Systemic!=!free!drug/!bound!drug!
B.!
Only!free!drug!can!interact!with!target!molecule!and!pass!membrane!!
C.!
Bound!drug!is!stuck!and!only!when!bound!drug!is!spent!becomes!free!
drug!
D.!
Drugs!are!bound!to!plasma!proteins:!albumin!=!acidic!and!lipophilic,!
globulins!+!glycoproteins!=!basic!
E.!
Binding!depends!on:!drug!concentration,!protein!concentration,!drug!
affinity!!
F.!
Drug!affinity!=!(%bound!=!bound!drug/(bound+free))*100!
G.!
Factors!affecting!binding:!Renal!disease,!liver!disease,!inflammation,!
malnutrition,!drug!interactions!e.g.!sulphonamides!may!displace!warfarin!
!
Volume'of'distribution'
A.!
Definition:!amount!of!H20!in!which!drug!is!distributed!in!litres!
B.!
Formula:!!Volume!of!Dist!=!total!amount!of!drug!in!body/drug!blood!
concentration!
C.!
Factors:!oedema,!loss!of!H20,!physiological!changes!in!body!H20!!
'
'
'
'
'

'
Cholinergic'antagonists'(parasympatholytics);'
There!are!generally!speaking!2!types!of!cholinergic!antagonists,!the!first!being!
antimuscarinic'agents!and!the!second!antinicotinic'agents!(ganglionic!
blockers7!the!next!question,!neuromuscular!blockers).!!
Muscarinic'blockers:!block!muscarinic!receptors!,!causing!inhibition!of!
muscarinic!!functions,!have!no!action!on!neuromuscular!transmission!or!
autonomic!ganglia.!!
Atropine:!an!alkaloid!from!the!plant!atropa!belldona!with!high!affinity!to!
muscarinic!!receptors,!binds!competitively!and!acts!centrally!and!
peripherally.!Used!in!ophthalmology!to!cause!mydriasis!(for!eye!tests).!
Used!as!antispasmodic'agent!,!antisecretory!(prior!to!respiratory!
surgery)!and!to!tread!organophosphate'poisoning.!May!lead!to!
tachycardia,!constipation,!blurred!vision,!xerostomia!and!dry!eyes!as!well!
as!confusion!and!hallucinations.!!
Scopolamine:!belladona!alkaloid,!has!peripheral!effects!similar!to!
atropine!but!higher!effects!over!the!CNS,!thus!is!one!of!the!most!effective!
motion'sickness!drugs!and!has!amnestic!properties!(brief!loss!of!short!
term!memory!7!great!for!surgery).!!
Ipratropium:!used!in!inhalation,!useful!in!treating!asthma!and!COPD.!!
!
Ganglionic'blockers:!Nicotine*and*Mecamylamine!!next!topic!!!!!!!!
Neuromuscular'blocking'drugs:!Succinilcholine,*curarine,!etc..discussed!on!
the!next!!topic!!!!!!
!
Ganglionic'blockers:!specifically!act!on!nicotinic!receptors!at!the!ganglia!of!SNS!
and!PSNS,!these!drugs!block!the!entire!output!of!the!ANS!and!only!serve!as!a!tool!
inexperimental!pharmacology.!!
'
Nicotine!!a!poison,!with!no!therapeutic!benefit!and!many!unwanted!effects.!The!
only!use!of!nicotine!is!to!eliminate!the!nicotine!craving!of!smokers.!Causes!
tachycardia,!high!BP,!increased!peristalsis!increased!secretions!(both!SNS!and!
PSNS).!Its!worse!side'effect!is!that!it!may!lead!to!pheochromocytoma!in!the!
future!due!to!repetitive!stimulation!of!the!adrenal!medulla.!
!
Myorelaxants:!also!known!as!neuromuscular'blocking'agents,!they!block!the!
transmission!between!motor!nerve!endings!and!the!nicotinic!receptors!on!the!
neuromuscular!end!of!skeletal!muscle.!These!are!structural!analogues!of!Ach!and!
act!either!as!an!agonist!or!antagonist.!
They!are!clinically!useful!in!surgery!and!in!facilitated'intubation.!!
'
Antagonist'blockers'(competitive''nondepolarizing):!
Significantly!increased!the!safety!of!!anesthesia!(less!anesthetics!are!required).!
The!first!drug!historically!is!Tubocurarine,!synthesized!from!the!curarine!the!
native!amazonians!use!to!hunt!with.!Mechanism:-competitive!binding!over!the!
nicotinic!receptor,!thus!inhibiting!muscle!contraction!(can!be!displaced!with!
neostigmine!or!other!AchE!inhibitors).!!Injected!IV,!do!not!cross!BBB,!not!
metabolized!(excreted!unchanged)!or!undergo!spontaneous!metabolism.!Side!
effects!are:!may!induce!histamine!release!and!reduced!BP.!!

Examples:-Mivacurium,'Cistacurium,'Tubocurarine,'Metocurine,'
Rocuronium,'Pipercuronium.!!
!
!
Agonist'agents'(depolarizing'agents):!the!only!relevant!drug!is!
Succinylcholine!which!acts!as!Ach,!but!is!not!destroyed!by!AchE,!thus!leading!to!
desensitization!of!the!receptor!(incapable!transmitting!further!impulses)!and!
flaccid!paralysis.!Its!is!very!fast!in!onset!and!very!short!in!duration,!thus!very!
good!for!endotracheal'intubation.!!Side!effects:!malignant'hyperthermia!
(treated!by!cooling!and!dantrolene),!apnea,!hypekalemia.!!
!
Antimycobacterial'agents.'
Treatment'of'TB:''
1st!line!therapy:!isoniazid!+!rifampin!+!pyrazinamide!(=2!months)!
2nd!line!therapy:!isoniazid!+!rifampin!(4!months)!
If!resistance!arises!add:!amino/fluoroquin!
!
Drugs:'isoniazid'
Inhibitor!of!mycolic!acid!synthesis;!bacteriocidal;!BBB;!PO!but!w/o!food;!
resistance!
SE:!parasthesis!(treatment!with!B6)!hepatitis!!
Drug'interaction:!phenytoin!(anti7epileptics)!(inhibits!metabolism)!
Allergy!risk!
!
RifamycinsO'rifampin'
Interacts!with!RNA!polymerase!therefore!inhibits!mRNA!synthesis!!
Spectrum!=!TB,!leprosy,!H.!infl!
PO,!cross!BBB,!drug!interaction,!inducer!P450,!decrease!half!life!of!drug!!
SE:!nausea,!vomiting,!rash,!flu!like!syndrome,!decrease!urine,!faces!orange7red!
!
Pyrazinamide'
Bacteriocidal,!unkown!mechanism,!prodrug!
2.line!drugs7!higher!toxicity!=!streptomycin,'cycloserine,'fluoroquinolones,!!
!
Macrolides'
Strep:!most!toxic,!interact!with!30s!+!causes!translational!errors,!resistance,!
bacteriocidal,!IC,!no!BBB,!spectrum!G7!
SE:!narrow!therapeutic!index,!ototoxic,!nephrons!+!neurotoxic!!
!
6. Drug'metabolism;'
Process!of!transforming!lipophilic!drug!to!hydrophilic!drug!
Liver!(main);!kidneys!and!intestines!also!(enzymes=non7specific!for!most!drugs,!
found!in!microsomes!in!SER!in!liver)!
Metabolism!=!2!phases!
Phase'1:'oxidation,'reduction,'hydrolysis'
Group!of!enzymes:!CYTP450:!!
6!isoforms:!e.g.!CYP3A4/5!!40%!drugs!,!CYP2D6!!20%!!
*oxidations!=!free!radical!formation!

Metabolic'inducers!increase!metabolism!and!decrease!action!of!drug!e.g.!
ethanol,!barbiturates,!rifampicine!
!
Inhibitors!decrease!metabolism!therefore!increase!action!of!drug!e.g.!grapefruit,!
cimetidine,!erythromycin!
'
Phase'2:'conjugation''
With!endogenous!compounds,!glucoronate,!AcCoA,!methyl,!glucothiolase,!
sulphur!NB:!glucoronidation!!
Neonates!cannot!conjugate!glucoronate:!chloramphenicol!!grey!baby!syndrome!
Non!cyt7P!drug!oxidation!:!monoamine;!diamineoxidase!(MAO;DAO)!!dominate!
endogenous!substances:!DOP,!SER,!NE,!EPI!(MAO),!histamine!and!polyamines!
(DAO)!alcohol!and!aldehyde!dehydrogenase:!ethanol!!acetaldehyde!!acetic!acid!!
Xanthine!oxidase:!hypoxanthine!!xanthine!!uric!acid!!
Esterases!(in!blood)!!degrade!esters!(e.g.!ester!LA)!
'
Rate'of'metabolism:''
1st'order'kinetics:!connected!with!half!life,!dependent!on!drug!concentration!in!
body!(increase!concentration!=!increase!elimination!rate)!
!
Zero'order'kinetics:!saturated!kinetics:!constant!amount!of!drug!eliminated!per!
unit!time!e.g.!ethanol!aspirin!
!
Factors'affecting'drug'metabolism:!age,!gender,!disease,!genetic!
polymorphism,!interaction!!
'
Ganglionic'blocking'agents'and'myorelaxants;'
Ganglionic'blockers:!specifically!act!on!nicotinic!receptors!at!the!ganglia!of!SNS!
and!PSNS,!these!drugs!block!the!entire!output!of!the!ANS!and!only!serve!as!a!tool!
inexperimental!pharmacology.!!
Nicotine!!a!poison,!with!no!therapeutic!benefit!and!many!unwanted!effects.!The!
only!use!ofnicotine!is!to!eliminate!the!nicotine!craving!of!smokers.!Causes!
tachycardia,!high!BP,!increased!peristalsis!increased!secretions!(both!SNS!and!
PSNS).!Its!worse!side!effect!is!that!it!may!lead!to!pheochromocytoma!in!the!
future!due!to!repetitive!stimulation!of!the!adrenal!medulla.!
!
Myorelaxants:!also!known!as!neuromuscular'blocking'agents,!they!block!the!
transmission!between!motor!nerve!endings!and!the!nicotinic!receptors!on!the!
neuromuscular!end!of!skeletal!muscle.!These!are!structural!analogues!of!Ach!and!
act!either!as!an!agonist!or!antagonist.!
!
They!are!clinically!useful!in!surgery!and!in!facilitated'intubation.!!
'
Antagonist'blockers'(competitive''nondepolarizing):!
Significantly!increased!the!safety!of!!anesthesia!(less!anesthetics!are!required).!
The!first!drug!historically!is!Tubocurarine,!synthesized!from!the!curarine!the!
native!amazonians!use!to!hunt!with.!Mechanism:-competitive!binding!over!the!
nicotinic!receptor,!thus!inhibiting!muscle!contraction!(can!be!displaced!with!
neostigmine!or!other!AchE!inhibitors).!!Injected!IV,!do!not!cross!BBB,!not!

metabolized!(excreted!unchanged)!or!undergo!spontaneous!metabolism.!Side!
effects!are:!may!induce!histamine!release!and!reduced!BP.!Examples:Mivacurium,'Cistacurium,'Tubocurarine,'Metocurine,'Rocuronium,'
Pipercuronium.!!
!
!
Agonist'agents'(depolarizing'agents):!the!only!relevant!drug!is!
Succinylcholine!which!acts!as!Ach,!but!is!not!destroyed!by!AchE,!thus!leading!to!
desensitization!of!the!receptor!(incapable!transmitting!further!impulses)!and!
flaccid!paralysis.!Its!is!very!fast!in!onset!and!very!short!in!duration,!thus!very!
good!for!endotracheal'intubation.!!Side!effects:!malignant'hyperthermia!
(treated!by!cooling!and!dantrolene),!apnea,!hypekalemia.!!
'
Antihypertensive'drugs'
Hypertension!is!a!very!common!disorder,!named!also!the!silent!killer!and!
defined!as!more!than!140/90!mmHg.!In!the!treatment!of!hypertension,!lack!of!
patient!compliance!is!the!biggest!problem.!Drugs!that!are!used!as!
antihypertensives!are:!
'
Diuretics:'first!line!drugs!in!hypertension!therapy!(thiazide,!loop!and!
spironolactone).!!
Beta'blockers:'!
Decreased!activation!of!B1!receptors!!decreased!cardiac!output.!!
Decreased!renin!!decreased!angiotensin!2!!decreased!peripheral!
resistance.!!
Decreased!angiotensin!2!!decreased!aldosterone!!decreased!water!and!
sodium!retention!!!decreased!blood!volume.!!
To!summarize!they!decrease!cardiac!output,!decrease!renin!production!
and!decrease!aldosterone!production.!They!are!used!more!in!young!white!
people,!may!lead!to!bradycardia,!hypotension,!fatigue,!insomnia!and!
sexual!dysfunctions.!!
!
RAS'inhibitors:'renin7angiotensin!system!inhibitors,!divided!to!ACE!And!ARB.!!
!
ACE'inhibitors:!angiotensin!converting!enzyme!inhibitors!are!indicated!as!the!3.
line!of!therapy,!they!reduce!peripheral!vascular!resistance!by!inhibiting!ACE!
(which!is!also!responsible!for!the!breakdown!of!bradykinin,!thus!when!inhibited!
there!is!dry!persistent!cough),!may!also!be!effective!in!the!management!of!
diabetic!nephropathy.!
All!these!drugs!end!with!!pril....!prototype!is!captopril,'ramipril,!etc..!!
!
ARB's:!angiotensin'receptor'blockers!block!only!AT1!receptor!(angiotensin!1),!
thus!they!work!the!same!as!ACE,!but!do!not!cause!the!irritating!cough!(no!
bradykinin!breakdown!inhibition).!All!these!drugs!end!with!!sartan....!prototype!
is!Losartan,!valsartan,!etc...!
!
Renin'inhibitors:'
Directly!inhibits!renin,!there!is!only!1!drug!!Aliskiren.'Which!is!contraindicated!
in!pregnancy.!!

Calcium'channel'blockers:'verapamil,'dilitazem'and'amlopidine!are!useful!
and!are!good!for!treating!patients!with!co7!morbidities!(angina,!arrhythmia).!!
!
Alpha'blockers:'produce!competitive!block!of!alpha!1!adrenoreceptors,!thus!
decrease!peripheral!resistance.!All!drugs!end!with!!osin!!lead!to!reflex!
tachycardia.!!Drugs:!doxazosin,'prazosin.!
!
Other'drugs:'clonidine!(alpha!2!blocker),!alpha7methyl!dopa!(alpha!2!agonist),!
minoxidil!(dilation!of!persistent!vessels).!
'
7. Drug''excretion'
Occur!via!number!of!routes,!such!as!the!hepatic!(bile),!intestines,!lungs!
(breath),!lactation,!but!by!far!the!most!important!is!the!renal'clearance.!
!
Renal'excretion:!removal!of!water!soluble!molecules!(lipophilic!are!
reabsorbed)!which!result!from!3!processes:!
!!Glomerular*filtration*'free!drug!flows!the!the!capillary!slits!
into!the!Bowman's!capsule,!normal!rate!is!125!ml/min.!!
!!Proximal*tubular*secretion*!occur!primarily!by!2!energy!
requiring!processes,!anion!system!and!cation!system,!which!can!
transport!many!compounds,!thus!competition!for!these!systems!
can!occur!between!drugs.!!
!!Distal*tubular*reabsorption*!if!the!drug!is!uncharged!it!
diffuses!through!the!membrane,!thus!weak!acids!may!be!
eliminated!by!alkalization!of!the!urine!and!vice!versa!(known!as!
ion!trapping).!
Factors'influencing'renal'excretion''
1.!age:!(newborns!have!decrease!tubular!secretion!and!elderly!have!decrease!
renal!blood!flow!and!function)!
2.!disease:!(renal,!CVS,!liver)!
3.!drug!interaction!(e.g.!probenecide!+!PNC)!
!
Clearance!of!a!drug!is!via!the!sum!of!the!routes!of!elimination,!meaning!!
Cl!total!=!CL!renal!+!CL!hepatic!+!CL!pulmonary+!CL!other!=!KeVd!!!
CL'total'='KeVd'!(Ke!=!elimination!constant!and!Vd!equal!the!volume!of!
distribution!and!both!are!usually!known).!!
!
GIT'excretion!7!in!liver!there!is!a!similar!transport!system!as!in!renal!tubules,!
and!then!the!substance!is!transported!into!bile.!Also!exist!transport!systems!
from!steroids!and!similar!substances.!Bile!is!excreted!to!intestine,!it!could!be!
reabsorbed!(enterohepatic!circulation)!thus!prolonging!the!effect!of!the!drug!
(e.g.!digoxin,!morphine)!!
'
Antipsychotic'drugs''(neuroleptics);'
Used!to!treat!SCHIZOPHRENIA!and!other!disorders!(MANIA,!
DEPRESSION)!or!GRANDIOSITY,!PARANOIA.!HALLUCINATIONS!and!
DELIRIUM.!!

SCHIZOPHRENIA(type!of!psychosis)!has!excitatory!effects!like:!
hallucinations,!delusion,!thinking!and!speech!disorders!and!negative!
symptoms!such!as!no!emotions!and!social!contact!problems.!!
The!cause!of!schizophrenia!is!combined!with!genetic!and!environmental!
factors!that!affects!several!brain!areas!causing:!a!dysfunction!of!the!
MESOLIMBIC!or!MESOCORTICAL!DOPAMINERGIC!neurons.!!

!
The'Dopamine'Theory'!!
A) The!use!of!amphetamine!or!D!agonists!can!cause!schizophrenia!and!
elevate!the!symptoms!and!the!use!of!DP!antagonists!decrease!the!
symptoms!of!schizophrenia.!!
B) Hyperactivity!of!DP!neurons!=!Schizophrenia!
!
Classification'of'Drugs'!!
1.(Classical)'TYPICAL'NEUROLEPTIC''competitive!inhibitors!of!DOPAMINE!
receptors!!!
LOW-POTENCY:-CHLORPROMAZINE;'PROCHLORPERAZINE;'THIORIDAZINE;!
HIGH-POTENCY:-HALOPERIDOL;!FLUPHENAZINE;!(PIMOZIDE;!THIOTHIXENE)!7!
!effect!tegmentum!main!extrapyramidal!effect.!!
!
2.'(new)'Atypical'NEUROLEPTIC''blockade!both!serotonin!and!dopamine!
receptors,!lower!tendency!to!motor!side!effects!+!effective!against!negative!
symptoms.!They!also!D2,!,!M!receptors.!High!affinity!with!D4!receptor!and!low!
affinity!with!D2.!
CLOZAPINE!7!high!affinity!to!D4!Receptor!+!nonselective!D1,D2!affinity.!!
RISPERIDONE!7!blocks!serotonin!greater!than!D2.!
OLANZAPINE!7!blocks!serotonin!greater!than!D2.!
QUETIAPINE!7!blocks!D2!receptors!more!potently!than!57HT!2a!receptors!
'
Mechanism:!
Blockage!of!DP'receptors'in!the!brain,!occupying!the!receptor!!!
intracellular!response.!
The!newer!agents!are!more!selective!to!D2!then!D1.!!
Initially!they!cause!increase!of!DP!and!increase!activity!of!midbrain.!!
Later!there!is!a!decline!in!activity!and!reaching!a!steady!level!after!3!
weeks.!
D1!and!D5!receptors!activate!adenylyl!cyclase!D2,D3!and!D4!receptors!
inhibit!adenylyl!cyclase!!
'
Effects'of'ANTILEPTICS!
Apathy!
Slow!response!to!stimuli.!!
Inhibits!aggressively.!!
Anti!!emetic!!
No!loss!of!intellectual!functions,!no!cognitive!impairment!and!motor!
incoordination!is!minimal(in!this!point!they!differ!mostly!from!CNS!
depressant!like!BARBITURATES).!
'

Unwanted'effects!
Extra7pyramidal!effects!7!Tremors,!chorea!excessive!Ach,dystonia,!tardive!
dyskinesia,!Parkinson7like!symptoms!due!to!chronic!treatment;!But!
Atypical!neuroleptics!exhibit!a!lower!incidence!of!these!symptoms.!!
Anti7muscarinic!effects!7!Blurred!vision,!dry!mouth,!constipation,!but!the!
effect!may!counteract!the!motor!disturbances!(CLOZAPINE)!!Sedation!
(H1)!!Orthostatic!hypotension!(alpha)!!Weight!gain!(SEROTONIN).!!
Antiemetic!effects!7!with!the!exception!of!ARIPIPRAZOLE!and!
THIORIDAZINE!most!of!the!neuroleptic!drugs!have!antiemetic!effects!that!
are!mediated!by!blocking!D27dopaminiergic!receptors!of!the!
chemoreceptor!trigger!zone!of!the!medulla.!Basically!combats!NAUSEA!!
Adverse'effects:!tremors,!postural!hypotension,!constipation,!urinary!
retention,!confusion,!sexual!dysfunction.!!
'
Drugs' ' affecting' hemostasis' ' (' anticoagulants,' antiaggregatory' drugs),'
antianemic'drugs'
'
Haemostasis!!is!a!stopping!of!blood!loss,!essential!for!survival!!
Thrombosis!!pathologic!formation!of!haemostatic!plug!inside!of!blood!vessels,!
without!!bleeding.!!
Arterial'thrombosis!(white)!!atherosclerosis,!platelets!and!leukocytes!!
Venous'thrombosis!(red)!!stasis,!white!"head"!+!red!"tail"!!
Thrombophilia!!hereditary!increased!coagulation!!
!

!
!Drugs!for!venous!and!arterial!thrombosis:!!
A.'Oral'anticoagulants:'
!Warfarin,!Ximelagatran!!
Warfarin:!
Mechanism:!Competitive!inhibitor!of!vit.K!(from!oxidized!to!reduced!form)!!
reduced!form!participates!in!the!carboxylation!of!several!blood!coagulation!
proteins,!mainly!prothrombin!and!factor!VII!!carboxylation!!binding!to!
phospholipid!surface!!activation.!

'
Pharmacokinetics:!fast!and!complete!GI!absorption,!strong!albumin!binding!!
small!VD!,!Cmax!!up!to!1!h.,!effect!!after!48!h!(results!from!T1/2!of!inhibited!
factors,!effect!lasts!475!days,!liver!metabolism!P450.!!
'
Effect'modifying'factors!(increase):!1)!Drugs:!!7!inhibitors!of!liver!metabolism!
(cimetidine,!imipramine,!cotrimoxazol,!ciprofloxacin,!amiodaron)!7platelet!
inhibitors!(NSAIDs,!moxalactame,!carbenicilline,!ASA)!7!inhibition!of!vit.!K!
reduction!(cephalosporines)!!7!!in!vit.!K!supply!!2)!Hepatopathies!!
'
Effect'modifying'factors'(inhibition):!!1)!Drugs:!7!liver!metabolism!inducers!
(rifamicin,!carbamazepin,!barbiturates,!grizeofulvine)!7!agents!decreasing!
absorption!(cholesteramin)!2)!!synthesis,!!degradation!of!coagulation!factors!
(pregnancy,!hypothyroidism).!!
'
Side'effects:!bleeding!(vit.K,!fresh!plasma,!coagulating!factors);!teratogenity!(67
14!week);!!in!protein!C!synthesis!!procoagulatory!state!!thrombosis!of!
venules!!necrosis!of!soft!tissues!(heparin!before!warfarin).!!
'
Contraindications:!bleeding,!coagulations,!GI!bleeding,!anaemia,!surgery!or!CNS!
trauma,!malignant!hypertension,!pregnancy.!!
'
Clinical'uses:!lung!embolism;!deep!vein!thrombosis!(DVT);!thromboembolism!
prevention.!!
'
Ximelagatran'
Direct!thrombin!inhibition,!bio7conversion!to!active!Melagatran,!no!food!or!drug!
interactions,!monitoring!!not!needed.!!
Clinical'uses:!thromboembolism!(prevention!and!therapy),!prevention!of!stroke!
in!patients!with!atrial!fibrillation.!!!
!
B.'Injection'anticoagulants'("red"thrombi):''
Heparin'(H),'Low'molecular'weight'(LMW),'Heparin'(LMWH)''
'
Heparin'(H)'and'LMWH''
H:!m.w.:!up!to!40,000;!LMWH:!4,000!!15,000!!
Mechanism:!ATIII!activation!!!thrombin!(IIa)!and!other!serine!proteases!!
binds!to!!IIa!and!ATIII!(H!in!size!>!18!polysaccharide!residues;!LMWH!in!size!<!18!
polysaccharide!residues,!binds!only!ATIII)!!!effect!of!ATIII!to!factor!Xa!but!
NOT!IIa.!Clinical'result:!similar!effect!in!venous!thrombosis!prevention!and!
therapy!with!lower!risk!of!bleeding!complications.!!
'
Pharmacokinetics:!H!!I.V,!S.C;!onset:!I.V.!!immediately,!S.C!!up!to!60!
min!LMWH!!S.C.,!twice!longer!T1/2!(4h.),!bioavailability!S.C.!90%!vs.!20%!in!H!
(lower!binding!to!endotel!and!macrophages);!lower!binding!to!plasma!albumins!
(more!predictable!effect).!!
'
Side'effects:!7!bleeding!!7!thrombocytopenia!and!thrombosis!(paradoxically,!
caused!by!IgM!or!IgG!against!complex!heparin/platelet!F4,!which!binds!Fc!

receptors!of!platelets!!activates!F4!release!!thrombocytopenia)!7!osteoporosis!
(long!term!therapy!!activation!of!osteoclasts)!!7!hypoaldosteronism!(extremely!
rare)!!
'
Clinical'uses:!prophylaxis!of!venous!thrombosis,!therapy!of!thromembolic!
disorders,!!haemodialysis!!
'
'C.'Oral'antiplatelet'drugs/Antiaggregants'("white"'thrombi):''
'Acetylsalicylic'acid'(ASA),'Ticlopidin,'Dipyridamol,'Clopidogrel'''
'
Mechanism:'
7 ASA:!!COX!(irreversible),!!thromboxan!synthesis!(TXA2),!
!thrombocyte!activation!
7 !Ticlopidin,'Clopidogrel:!!of!ADP7dependent!activation!of!
GP!IIb/IIIa!receptor!(after!platelet!aggregation),!!all!
pathways!of!platelet!activation.!!!
7 Dipyridamol:!!PDE!
'
Side'effects:!7!ASA:!!risk!of!bleeding!7!Ticlopidin:!neutropenia!(long!term!
treatment),!rash,!diarrhea.!7!Clopidogrel:!nausea,!vomiting.!7!Dipyridamol:!
headache,!DOES!NOT!!the!risk!of!bleeding.!!
'
Clinical'uses:!prevention!of!MI,!prevention!of!cerebral!ischemia,!therapy!of!
"unstable!angina!pectoris",!maintenance!of!coronary!artery!passage!after!
angioplasty!(ticlopidin),!combination!(ticlopidin!+!ASA,!dipyridamol!+!ASA)!has!
an!addictive!effect!!!!
!
D.'Fibrinolytics'("white"'thrombi)''
Streptokinase!(streptococcal!enzyme,!Ag)!Urokinase!(human!kidney,!non7
antigenic)!tPA!(isolated!from!tissues,!recombinant!tissue!plasminogen!activator!
r7tPA!(alteptase)).!!
All!I.V.!infusions!!
'
Mechanism:!streptokinase!!plasminogen!!plasmin!!fibrin!!fibrin!
breakdown!!
'
Side'effects:!!7!Streptokinase:!Hypersensitivity,!decrease!of!fibrinolytic!effect;!
bleeding!7!Urokinase:!bleeding!7!tPA:!bleeding,!incidence!of!reoclusion!!
'
Clinical'uses:!arterial!thrombosis,!DVT,!acute!lung!embolism,!acute!MI.!!
strepto7!and!urokinase!act!only!in!new7formed!thrombi.!!
reoclusion!after!tPA!can!be!prevented!by!ASA.!!!
!
2.'Antianemic'drugs:''
!
Major!causes!of!anemia:!!Low!count!of!RBC,!abnormality!of!RBC,!abnormality!of!
the!haemoglibin.!!
Reason!for!low!count!of!RBC:!blood!loss,!inadequate!production!of!blood,!
excessive!!breakdown!of!RBC,!or!all!3!factors.!!

!
Inadequate!production!of!blood:!7!microcytic!!iron'deficiency'anaemia:!most!
common,!inadequate!Hb!production,!less!ability!to!absorb/store!iron.!7!
megaloblastic'anaemia!(pernicious!anaemia/B12!defficiency!anaemia;!folic!
acid!deficiency!anaemia).!7!aplastic'anaemia!!idiopathic,!toxic,!radiation,!viral..!
!
A.'Therapy'for'Iron'deficiency'anemia'O'Iron'supplements:'
Ferrous!sulfate!!37%!iron!(ferrous!gluconate!only!13%)!!
1!tablet/day,!dosage!depends!on!the!iron!needs.!!
Side'effects:!stomach!and!intestinal!problems!(cramps,!constipation,!diarrhea,!
!nausea,!vomiting,!heartburn,!urine!discoloration);!frequency!and!severity!!with!
the!!dosage.!!
!
Interactions:!!7!ATBs!(Tetracycline,!quinolone)!!iron!!their!effectiveness.!7!
Levodopa!7!iron!!its!effectiveness.!7!With!Mg,!Trisilicate,!an!antacid,!
penicillamine!!good!interaction!7!Vit.!C!7!!the!absorption!of!iron!(with!no!!in!
side!effects).!!
!
B.'Therapy'for'Pernicious'anemia'(low'RBC'count'and'Lack'of'Hb):'
Vitamin!B12!(Cyanocobalamine)!!
Responsible!for!many!functions!in!the!body!(incl.!NS)!!
Anemia!should!always!be!treated!with!S.C.!or!I.M.!!
10!mg/day!for!677!days,!if!improvement!is!seen!!reduce!the!dose,!after!that!
!monthly!injection.!!
'
Side'effects:!diarrhea!and!itching,!severe!allergy!(very!rare!)!!
Interactions:!!7!Aminosalicylic!acid!and!cochicine!!may!!the!effectiveness!of!
B12!!7!Alcohol!may!affect!the!efficacy!of!vit.!B12.!!!
!
C.'Therapy'for'Folic'acid'deficiency'anemia:''
Folic!acid!!
Found!in!many!common!foods!(liver,!dried!peas,!lentils,!oranges,!whole!!wheat!!
products,!asparagus,!beets)!
1!mg/day!!dose!!
Folic!acid!in!patients!with!B12!deficiency!!improves!RBC!count,!but!the!nerve!
damage!continues!to!progress.!!
!
Side!effects:!safe!!On!rare!cases!!allergy!!
Interactions:!Phenytoins!(!of!phenytoin!effectiveness);!!Trimethoprom!and!
Methotrexate!(!the!metabolism!of!folic!acid).!!!
!
D.'Bone'marrow'stimulation'for'erythrocyte'production''
Epoetin!alfa!!synthetic!form!of!erythropoietin!(produced!by!kidney,!stimulates!
RBC!!production!and!release).!!
Useful'because:!anemia!ass.!with!kidney!failure,!Zidovudine!therapy!in!HIV!
!patients,!cancer!patients!on!chemotherapy,!!in!RBC!in!surgical!patients,!
!prematurity,!sickle7cell!anemia,!rheumathoid!arthritis.!!
Dosage!!individualized,!507100!units/kg!3x!a!weeks,!NOT!in!patients!with!
!uncontrolled!Hypertension!!!!!

'
Adverse'effects:!joint!pain,!chest!pain,!diarrhea,!swelling,!fatigue,!fever,!
weakness,!!headache,!!BP,!nausea!!
Aplastic!anemia!therapy!!Anabolic!steroids:!Nandrolone,!Oxymetholone!!
Nandrolone!!for!treatment!with!kidney!failure!anemia.!!
Oxymetholone!!treats!aplastic!anemia,!172!mg/day,!slow!response,!long!side!
effects!!(acne,!!urinary!frequency,!breast!growth!in!males,!breast!pain,!
masculinization!in!women).!!
'
Hemolytic'anemia'therapy!:!excessive!break7down!of!RBC!!
Causes:!intrinsic(hereditary)/Extrinsic!factors!!
Types:!Hemolysis,!Inherited!hemolytic!anemia,!hemolytic!transfusion!reaction.!!
Folic!acid,!Iron!replacement,!corticosteroids!7!depends!on!the!type!of!cause.!!
Blood!transfusion/splenemectomy!!in!emergencies.!!
!
8. Bioavailability.'Factors'influencing'bioavailability'
It!is!the!fraction!of!administered!drug!that!reaches!the!systemic!
circulation!in!a!chemically!unchanged!form.!!
It!is!determined!by!comparing!the!plasma!levels!of!a!drug!after!a!
particular!route!of!administration!(oral,!P.R,!etc)!with!plasma!drug!levels!
achieved!by!an!IV!injection.!
Mathematically!it!is!defined!as!the!area!under!the!curve,!plotted!over!time!
of!a!given!dose!(oral,!PR,!etc)!divided!by!area!under!the!curve!of!an!
injected!dose,!multiple!100!for!percentage.!
'
Bioavailability'='AUC'route'/'AUC'injected'x'100'='?!
Bioequivalence:!2!related!drugs!that!show!comparable!bioavailability!
and!similar!times!to!achieve!peak!levels.!!
Theraputic'equivalent:!2!similar!drugs!with!comparable!efficacy!and!
safety.!!
'
Factors'influencing'bioavailability:!
First'pass'effect:!drug!absorbed!from!the!GIT!enters!the!portal!
circulation!before!entering!the!systemic!circulation!where!it!is!
metabolized!in!the!liver!(p450)!reducing!the!amount!in!the!systemic!
circulation.!!
Solubility!of!a!drug.!!
Chemical'instability:!degradation!in!the!GIT.!!
Other:!coating,!size,!crystal!formation,!etc.!!
1.!Route!of!administration!!
2.!Physicochemical!factors!!
3.!Drug!solubility!!
4.!Drug!concentration!!
5.!Blood!flow!at!site!of!absorption!!
6.!Surface!area!for!absorption!!
7.!Contact!time!with!absorbing!surface!!
8.!Environment!(e.g.!stomach!acidity)!!
'
'

Antidepressants;'
DEPRESSION'=!Intense!feeling!of!sadness!+!hopelessness!+!no!pleasure!in!usual!
activities!+!sleep!disorders!+!no!concentration!+!suicide!thoughts.!
While!MANIA!is!characterized!by!the!opposite!behavior!(enthusiasm!rapid!
thought!and!speech!patterns,!extreme!self7!confidence!and!impaired!judgment)!!
'
Theory'of'Monoamine'NT:'NOA'+'5OHT''
Main!NT!in!charge!of!mood!
Alterations!causes!mood!change!
Can!be!caused!by!loss!of!sensitivity!of!inhibition!of!receptors.!
Serotonin!is!the!main!mediator.!
'
Problem'of'the'theory:!Lag!Period!of!2!weeks!between!start!of!the!treatment!
and!effect,!but!the!amount!of!N!rise!immediately.!
'
New'theory:'The!antidepressant!drugs!inhibit!the!reuptke!of!57HT!!serotonin!
in!the!synaptic!cleft!!Down!regulation!of!the!presynaptic!rec.!over!273!wks!!!
postsynaptic!response!because!of!more!secretion!and!less!negative!feedback.!
!
Note:*The*onset*of*therapeutic*effects*of*the*major*antidepressant*
drugs*requires*several*weeks**1)'at!the!administration!time!(still!
persist!DEPRESSION);'2)'after!2!to!12!weeks!the!effects!manifest!!
!MAO'inhibitors:''
PHENELZINE'is!the!first!clinically!active!agent.!It!inhibits!the!MAO!
(irreversibly)!preventing!the!inactivation!of!monoamines!within!the!
neuron!!cause!more!molecules!to!be!secreted!into!the!cleft!and!an!
excess!of!neurotransmission.!
It!is!not!selective!and!affects!MAO!all!over!the!body!and!also!!levels!of!
Nor!Adrenaline!=!!sympathetic!activity!=!hypertension.!
Contraindications:!
High!interaction!with!food!that!contain!tyramine!(hard!cheese,!red!wine)!
!can!cause!hypertension,!headache,!MI,!intracranial!bleeding.!
Should!not!be!given!together!with!SSRI!!serotonin'syndrome''life!
threatening.!!
Serotonin'syndrome'
o Caused!by!inhibitors!of!reuptake!of!serotonin!and!inhibitor!of!
MAO!!7!increased'serotonin!
o Tremor!
o Collapse!
o Abdominal!pain!
o Hyperreflexia!
o Hypotension!
o diare!
o Tachycardia!
!RIMA'(reversible'inhibitors'of'MAO):'Moclobenide!
Less!effect!on!tyramine.!!
Side!effects!of!NOA:!nausea,!headache,!nervousness.!

!Tricyclic'Antidepressants'(TCA):'!
Lead!to!inhibition!of!re7uptake!of!noradrenaline!(NOA)!and!serotonin!(57
HT)!and!to!Blockage'of'M,'H,'1'receptors'(side!effects).!
!M=Dry!mouth,!constipation.!
M+1=Tachycardia,!hypertension.!!
H=Sedative!effect,!weight!gain.!
Adverse'effects:'DRY!MOUTH,!CONSTIPATION,!URINARY!RETENTION,!
BLURRED!VISION,!TACHYCARDIA,!ARRHYTMIAS,!NAUSEA,!DROWSINESS.!
Drugs:!IMIPRAMINE'(Good!GIT!absorption)!MITRIPTYLINE,'
CLOMIPRAMINE,'DOXEPIN,'TRIMIPRA'MINE.!
!Selective'Serotonin'ReOuptake'Inhibitors''SSRI:'!
These!drugs!BLOCK!THE!RE7UPTAKE!OF!SEROTONIN,!thus!leading!to!!
concentration!of!neurotransmitters!in!the!synaptic!cleft!and!to!greater!
postsynaptic!neuronal!activity.!
!No!inhibition!of!Noradrenalin!reuptake.!
Mild'blockage'of'M,'H,'1'receptors.!(side!effects=!same!as!TCA).!
'
Pharmacokinetics:''
well!absorbed!ORALLY;!peak!levels!are!seen!in!278h;!food!has!little!effect!
on!absorption(except!for!SERTRALINE);!plasma!half!life!of!16736!h;!
methabolism!by!P7450!dependent!enzymes!and!glucuronide.!
'
Contraindications:'!
Not!given!together!with!MAO!!serotonin'syndrome,'life!threatening!
(tremor,!abdominal!pain,!HT,!tachycardia!and!collapse)!
!
List'of'main'drugs:!
FLUOXETINE'(PROZAK)'for!BULIMIA!NERVOSA!(this!is!the!indication!
approved!for)!7!most!frequently!used.!Fluoxentine!and!paroxentine!are!
potent!inhibitors!of!a!hepatic!cytochrome!P7450!responsible!for!
elimination!of:!tryciclic!antidepressant!drugs,!neuroleptics!and!
antiarrhytmic.!
CITALOPRAM'7!No!affinity!to!M,!H,!!R.!7!less!side!effects!(nausea,!
insomnia)!!
ESCITALOPRAM,FLUVOXAMINE7!for!OBSESSIVE7COMPULSIVE!
DISORDERS!!!
o Adverse'effects:'NAUSEA,!ANXIETY,!DROWSINESS,!INSOMNIA,!
SEXUAL!DYSFUNCTION,!DRUG!INTERACTIONS,!
DISCONTINUATION!SYNDROME.!!NEW'ANTIDEPRESANTS'!
'
NOA'Reuptake'Inhibitors'(NRI):'REBOXETINE''
(depression,!narcolepsy!and!panic).!!
NOA'and'Dopamine'Reuptake'Inhibitors'(NDRI):'BUPROPION'!
Weak!inhibitor!(as!a!pro7drug),!when!metabolized!is!a!strong!inhibitor.!
Given!when!SSRI!is!not!tolerated.!!Treatment!of!nicotine!withdrawal.!!CI!
in!epilepsy!!
'

Serotonin'and'NOA'Reuptke'Inhibitors'(SNRI):'VENLAFAXINE,'Like!TCA,!
without!M,!H,!!effect.!!
!
DULOXETINE'(not!administer!with!hepatic!and!renal!insufficiency!)!
'
NOA'and'specific'serotoninergic'antidepressant'(NASSA):'MIRTAZAPINE!7!
block!presynaptic!alpha!2!receptor.!It!is!an!H1!receptor!antagonist!as!well!7!cause!
sedation!and!weight!gain.!!
'
Serotonin'2A'antagonist'reuptake'inhibitor'(SARI):'NEFAZODONE!7!CI!in!
patient!with!liver!disease.!!
'
ANTIOMANIA'(BIPOLAR'DISORDER):'
LITHIUM'SALTS!7!Unknown!mechanism.!Lead!to!prevention!in!acute!manic!
episode.!95%!of!it!excreted!in!urine.!Its!side!effects!are:!First!days!7!tremor,!
polyuria,!nausea,!thirst.!
Intoxication!7!vomiting,!diarrhea,!mm!weakness!Tinnitus,!ataxia!in!high!doses.!!
!VALPROIC!ACID!CARBAMAZEPINE!
'
Drugs'used'in'respiratory'tract'diseases'(antiasthmatics,'antitussics)'
Aim'of'therapy:''
1.!bronchoconstriction!!therefore!bronchodilators!
2.!inflammation!!therefore!corticosteroids!!
!
AntiOinflammatory'drugs''
Corticosteroids!!inhibits/modulates!inflammatory!respose!in!airways,!
inhalation!or!if!does!not!improve!then!systemic!oral!dose!of!prednisone,!!
SE:!hyperglycaemia/hypertension,!immunosuppression,m!adrenal!suppression,!
cushings!syndrome!(oropharyngeal!candidiasis!!therefore!mouth!washes!to!
treatment!
!
Inhaled!=!beclomethasone!*brown!inhaler*!=!reduction!of!bronchial!
hyperactivity,!improves!pulmonary!function,!reduce!symptoms,!9712!month!
therapy!needed!for!max!reduction!!
!
Inhibition!of!mast!cell!degradation7!sodium'bromoglycate!!goal!in!children!!
prevention/prophylaxis!treatment,!SE:!cough,!HA?,!bad!taste!
!
Leukotriene!receptor!antagonist7!montelucast!!(prophylaxis)!
Lipoxygenase!inhibition!!zileuton!
!
2.'bronchodilators''
a.!sympathomimetic'agents!(B7agonist)!!
!
i.!Non7selective:!adrenaline!(ER7bronchodilation)!
!
ii.!B27!selective!agonist:!salbutatmol,'terbutalin!
!
iii.!non7selective:!salmeterol,!SE:!arrhythmias,!headache,!flushing!
b.!Methylxanthines7!theophylline7!vasodilation!bronchodilation!!increased!
HCl!secretion,!increased!alertness,!tremor,!nervousness,!high!toxicity!
c.!Muscarinic!antagonist7!ipratropium'bromide!!

d.!Treatment!of!status'asthmaticus:!O2,'salbutamol/terbutaline,'
prednisolone!!
!
3.!Antitussives7!codeine,!dextromethorphan:!dry!cough!only,!opiods!=!suppress!
cough!center!in!medulla,!non7opioids7!suppress!cough!reflex!(peripheral!
cough??)!
4.!Expectorants!!iodinated'glycerol!!
5.!Mucolytics!!bromhexine7!breaks!down!fibers!in!sputum,!acetylcysteine!!
opens!disulphide!bonds!in!mucoproteins!!
!
Asthma:'!
An!inflammatory!condition!affecting!the!bronchi!leading!to!increased!
mucous!secretion!and!muscle!spasms,!which!in!turn!lead!to!narrowing!of!
the!lumen!and!to!airflow!obstruction.!
!The!main!symptoms!are!dyspnea,!wheezing,!cough!and!tachypnea.!!
The!goal!of!the!therapy!is!to!maintain!normal!activity!levels!and!to!
minimize!the!need!for!an!emergency!unit.!
It!is!an!obstructive!lung!disease,!probably!related!to!exposure!to!an!
antigen!or!inhaled!irritants,!leading!to!bronchial!hyperreactivity!and!
inflammation!of!the!airway!mucosa.!Drug!used!to!treat!asthma!are:!
!
Adrenergic'agonists:!!
Inhaled!Beta'2'agonists!are!the!drugs!of!choice!for!mild!asthma.!!
Short'acting:!not!be!used!alone,!unless!it!is!exercise!induced!asthma,!they!
have!rapid!onsed!!of!action!and!provide!relief!for!476!hours.!!
Drugs!are:!Salbutamol'(albuterol).'!
Long'acting:!same!as!salbutamol,!but!provide!relief!for!12!hours!with!a!
slow!onset!of!!action,!thus!cannot!be!used!for!quick!relief.!!
Drug!is!Salmeterol.!!
!
Corticosteroids:!
Drugs!of!choice!in!any!degree!of!persistent!asthma,!glucocorticoids!must!
be!!taken!continuously!for!effective!control!of!the!inflammation.!It!
reverses!mucosal!edema,!decrease!capillary!permeability!and!inhibit!
leukotrien!release.!!
Administered!by!inhalation!or!spacers!and!even!oral!(only!in!status!
asthmaticus)!and!may!lead!to!oral!candidosis!and!hoarseness!!usually!
they!do!not!produce!systemic!effect!and!maintain!their!action!bound!to!
the!respiratory!tract.!!
!
Alternative'treatment:!!
Leukotriens!antagonist!(Zileuton)!
Leukotriene!receptor!blockers!(Cromolyn,'montelucast)!
Cholinergic!antagonist!(Ipratropium)'and!monoclonal!antibody!
(Omalizumab).!
!
'
'

'
Allergic'Rhinitis:'!
An!inflammation!of!the!mucous!membranes!of!the!nose!which!is!
characterized!by!sneezing,!itchy!nose/eyes,!rhinorrhea!and!nasal!
congention.!!
Allergen!production!!IgE!mediated!response!!release!of!Histamine,!
leukotriens!and!chemotactiv!factors.!
For!the!treatment!we!use!combination!therapy!of!antihistamines!and!
nasal!decongestants.!
AntiOhistamines:'
H1!receptor!blocker!as!Diphenylhydramine,'Chlorpheniramine!and!
!Loratidine!are!useful.!!
Decongestants:!!
Can!be!nasal!spray!containing!corticosteroids!or!nasal!spray!containing!
alpha!!adrenergic!antagonist!(phenylepherine,'oxymetazoline),!which!
should!not!be!used!more!than!4!days.!!
!
AntiOtussives:'!
These!are!drugs!against!cough,!technically!speaking!we!can!use!2!types!of!
drugs!
The!first!will!lead!to!central'inhibition!of!the!cough!(in!case!of!dry!
cough)!while!the!second!will!lead!to!decreased!mucous!viscosity!(in!
productive!cough).!
!
Mucokinetic'agents:!!
Divided!into!expectorants!(Guaifenesin),!which!are!a!universal!
component!of!cough!sirup,!leading!to!increased!hydration!of!secretion!
lowering!its!viscosity!and!to!mucolytics!(Acetyl7cysteine,!Bromhexin)!
which!dissolve!the!thick!mucous.!!
These!agents!are!used!in!productive!cough!(cough!with!mucous).!!
!
Central'inhibitors:!opiates!are!used!to!decrease!the!cough!center!sensitivity!in!
the!CNS!and!to!decrease!mucous!secretion!(Codeine,'hydrocodon)'and!is!used!
in!dry!cough!(irritative!cough)!!
!
9. Molecular'aspects,'drugOreceptor'interaction,'second'messengers;'
In!general!we!can!say!that!no!drug!is!100%!specific!toward!a!single!
molecule!or!receptor,!thus!increasing!the!concentration!of!the!drug!will!
influence!other!targets!too.!!
The!binding!of!the!drug!to!its!receptor!is!usually!reversible,!but!in!some!
instances!can!be!covalent!and!irreversible.!Drugs!exert!their!action!by!
several!different!mechanisms:!!
Indirect:'!
On!the!basis!of!their!physiochemical!properties!with!no!specific!binding!
site,!i.e!osmotic'diuretics.!!
'
Direct:'interact!with!a!specific!target!molecule,!which!can!be:!!
Enzymes!!mainly!inhibitors,!such!as!MAO!or!COX!or!ACE!inhibitors.!!

Ion!channel!!blockers!or!modulators,!such!as!calcium!channel!blockers,!
PPI's.!!
Carrier'molecules!!such!as!reuptake!of!neurotransmitters!(SSRI7!
selective!serotonin!reuptake!inhibitor),!glucose!transporters.!!
Receptors!7!Most!of!the!drugs!exert!their!effect!by!interacting!with!
receptors!which!are!present!on!the!cell!surface!or!intracellularly.!!

!
DrugOreceptor'interactions:'!
Interaction!of!receptors!and!ligands!invloves!the!formation!of!chemical!
bonds,such!as!hydrogen,!Van!Der!Waals!and!electrostatic!bonds.!These!
are!weak!bonds,!thus!require!short!distance!between!the!atoms!for!
proper!bonding,!hence!the!specificity,!the!old!theory!states!that!there!is!a!
lock!and!key!fit!between!the!ligand!and!receptor!(good!for!
understanding)!but!the!newer!theory!is!the!induced!fit!model!which!
state!that!the!receptor!undergo!conformational!changes!in!the!presence!of!
the!ligand.!
!
There!are!4'major'types'of'receptors:!
Ligand*gated*ion*channels:*responsible!for!the!regulation!of!the!flow!of!
ions!across!cell!membranes,!it!is!regulated!by!the!binding!of!the!ligand!to!
the!channel,!important!representatives!of!this!group!are!nicotinic!
receptors!and!GABA!receptors.!!
G*proteinRcoupled*receptors:*comprised!of!a!single!peptide!with!7!
different!membrane7!spanning!regions!which!is!linked!to!a!G!protein,!
which!has!3!subunits!(alpha,!beta,!gamma).!!G!protein!can!be!stimulatory!
(Gs)!or!inhibitory!(Gi),!by!binding!to!a!ligand!there!is!a!conformational!
change!of!the!receptor!which!then!interact!with!the!alpha!subunit!of!the!G!
protein,!which!in!turn!binds!GTP!and!activate!adenylyl!cyclase!which!
change!the!concentration!of!the!second!messenger!in!the!cell.!!
Enzyme*linked*receptors:*having!cytosolic!enzyme!activity!as!an!integral!
part!of!their!structure!or!function!(insulin!receptor),!binding!of!a!ligand!to!
the!receptor!will!activate!or!inhibit!the!enzyme.!!The!most!common!
receptors!are!those!having!Tyrosine!kinase,!which!when!activated!
phosphorylates!tyrosine!residues!of!proteins.!!
Intracellular*receptors:*the!ligand!must!diffuse!into!the!cell!to!interact!
with!the!receptor,!thus!the!ligand!must!be!lipid!soluble!and!for!this!reason!
it!is!transported!through!the!plasma!bound!to!serum!proteins!(such!as!
albumin),!example!for!such!are!steroid'hormones!(cortisol)!and!thyroid!
hormones.!The!activated!ligand7receptor!complex!migrate!to!the!nucleus!
and!bind!to!specific!DNA!sequence,!resulting!in!regulation!of!gene!
expression.!!
!
Drug!can!be!agonists!(bind!to!receptor!and!produce!response),!partial'agonist!
and!antagonist!(occupy!receptor!without!producing!a!response)!!!
Antagonist!can!be!competitive!(displace!agonist7!i.e!propranolol!for!beta!
receptors)!or!bind!irreversibly!to!the!receptor.!!
'
'
'

'
'
Second'messenger:'!
Compounds!which!conduct!signals!from!G7protein!coupled!receptors.!!
Adenyl'cyclase!7!activated!by!alpha!GTP!subunit,!result!in!production!of!
cAMP!!regulates!protein!phosphorylation.!!
Phospholipase'C!!responsible!for!the!generation!of!diacylglycerol!and!
IP3!(inositol!triphosphate),!which!responsible!for!the!regulation!of!
intracellular!free!calcium!concentration!(increase).!!
Guanylyl'cyclase!!convert!GTP!to!cGMP!that!stimulate!cGMP!protein!
kinase!(in!intestinal!mucosa!and!vascular!smooth!muscle).!!
!
Antianxiety'and'hypnotic'drugs'
Anxiety!is!sympathetic!activation!with!symptoms!such!as!fear!/!
tachycardia!/!dyspnoea!/!sweating,!etc.!
Both!in!the!same!category:!
o Sedation!=!Suppression!of!response!to!stimuli!
o Hypnotic!=!Prolonged!depression!of!CNS,!dose!from!sedative!
causes!hypnotic!effect.!
!
1st!Generation!7!Barbiturates'7!not!used!anymore.!!
2nd!Generation!!Benzodiazepines'!
3rd!Generation!7!Zolpidem,'Zaleplon,'Zopiclone'
'NB!!!Only!symptomatic!drugs,!doesn't!treat!the!anxiety.!
'
BENZODIAZEPINES!
Targets!the!GABA7A!receptors.!!
!both!affinity!to!GABA!and!influx!of!Cl7!into!the!cell!hyperpolarization.!
This!causes!inhibition!of!the!sympathetic!neurons.!!
Well!absorbed!p.o.!passes!the!BBB,!fast!onset!!
Strongly!bind!to!plasma!proteins.!
MAIN'EFFECTS:!
ANTIOANXIETY:'TRIAZOLAM'can!produce!aggression!in!some!
individuals.!
ANTIOCONVULSANT:'CLONAZEPAM'used!to!treat!epilepsy.!
!
DIAZEPAM:'STATUS'EPILEPTICUS!control!of!life!threatening!seizures.!
EFFECTS:!Sedation!and!induction!of!sleep.!Reduction!of!muscle!tone!and!
coordination.!7!used!!to!treat!spasms.!!
SIDE'EFFECTS:!!!Affects!Manuel!skill!7!driving!!!Can!enhance!depressant!
action!of!other!drugs!!!Overdose!7!Severe!CNS!and!respiratory!
depression!if!combined!with:!Alcohol,!Barbiturates!and/or!Narcotics!
(Antidote'=!FLUMAZENIL)'!
!
TOLERANCE:'via!down!regulation!of!receptors!!tolerance!in!all!BZD.!!
DEPENDANCE:'When!stopping!the!drug!it!causes!!in!anxiety!with!tremor!and!
dizziness.!!!

!
!
!
B)SEROTONIN'DRUGS'!!
1)BUSPIRONE:'Strong!anxiolytic!effect!without'sedative!or!muscle!relaxant!
effect.!It!is!and!Agonist!of!57HT!receptor.!!
PHARMACOKINETICS:!Metabolized!quickly!in!liver!7!grapefruit!juice!effect.!!
Disadvantage!=!slow!onset!of!action.!!!
!
2)HYDROXYZINE:'It!is!an!antihistamine!with!antiemetic!activity!(used!for!dental!
and!surgical!procedures,!in!patients!with!anxiety.!!
!Side'effects:'DROWSINESS!!
!
!
3)ANTIDEPRESSANT:'for!managing!chronic!anxiety!disorders!(SSRIs,!TCAs,!
VENLAFAXINE,!DULOXETINE,!MAO7Is)!
'
C)NEW'DRUGS!
1)'ZOLPIDEM:'Same!effect!as!BZD!with!minimal!muscle!relaxant!and!anti7
convulsant!activity,!possess!a!small!risk!of!tolerance!and!dependance.!
2)'ZALEPLON:'Rapid!onset!and!short!duration.!It!is!good!for!people!that!have!
trouble!sleeping.!
!
Drugs'affecting'gastrointestinal'tract'(treatment'of'gastric'ulcer,'diarrhoe,'
constipation)'
Peptic!ulcer,!GERD,!diarrhea!and!constipation!are!common!problems!of!the!GIT.!
!
Peptic'ulcer'disease:''
Cause:'
NSAID's!
H.pylori!
Increased!HCL!secretion!
Inadequate!mucosal!
Defense!against!gastric!acid!are!associated!with!PUD.!!
!
Antimicrobial'therapy:!!
Eradication!of!H.pylori,!after!histologic!approval!or!positive!urea!
breath!test!we!use!Amoxicillin'+'Clarythromycin'+'PPI'or!PPI'+'
Metronidazole'+'Tetracyclines.!
!
H2'receptor'agonists:!!
Inhibit!histamine!binding!to!H2!receptor,!thus!decrease!HCL!production!
by!decreasing!the!level!of!intracellular!cAMP!!Ranitidine,'Cimetidine,'
Famotidine,.!!PPI!are!better!than!H2!blockers!!
!
PPI's:!!
Suppress!secretion!of!HCL!by!inhibiting!the!Hydrogen!proton!pump,!may!
lead!to!B12!absorption!problems!and!to!pseudomembranous!colitis!!
Omeprazole,'Pantoprazole,'Esomeprazole.'!

!
!
!
Prostaglandins:!!
PGE2!inhibits!secretion!of!HCL!and!stimulate!secretion!of!mucous!and!
bicarbonate.!!
Misoprostol'is!a!PG!analogue!approved!for!NSAID's!induced!PUD.!!
!
Antacids:!!
Weak!bases!that!react!with!gastric!acid!to!form!water!and!salt!(sodium'
bicarbonate,'magnesium'hydroxide,'aluminum'hydroxide)!!usually!
combination!therapy!of!aluminum!hydroxide!and!magnesium!hydroxide!
(constipation+diarrhea!=!normal).!!
!
Mucosal!protecting!agents:!bismuth'subsalicylate!and!sucralfate.!!
!
Antidiarrheal:!
Antimotility'agents:!!
Loperamide'HCL'is!the!prototype!drug,!has!opioid!like!actions!on!the!!gut!
(constipation),!activating!presynaptic!opioid!receptors!in!the!enteric!
nervous!system!to!!inhibit!Ach!release.!!
!
Absorbents:!!
Methylcellulose,'aluminum'hydroxide'and'bismuth'subsalicylate'are!
used!to!!control!diarrhea,!they!absorb!intestinal!toxins!and!microbes.!!
!
Electrolyte'transport'modifiers:''
Bismuth'subsalicylate'decrease!fluid!secretion!in!the!!bowel.!!
!
Laxatives:'potentiate!the!risk!for!abuse.!
Irritants!and!stimulants:!Senna!is!a!very!common!laxative!as!well!as!Bisacodyl'
!They!act!directly!on!nerve!fibers!in!the!mucosa!of!the!colon!
!Castor'oil'is!an!irritant!which!increase!peristalsis.!!
!
Bulk'laxatives:!!
Hydrophylic'colloids,'Methylcellulose'and!Bran'from!food.!!
!
Osmotic'laxatives:!PEG'(poly7ethyl7glycerol),!sodium'phosphate,'magnesium'
citrate.'!
!
Stool'softeners:!surface!active!agents!!Docusate'
Sodium/Calcium/Potassium.'!
!
Lubricant'laxatives:!Paraffin'oil,'Glycerin.'!
!
10. 'Harmful'effects'of'drugs;'
Directly!related!to!pharmacodynamics!
Predictable!!
Dose!dependent!!

!
!
!
Indirectly!!toxic!effects!!
1.!augmented!!
Intoxication,!Most!common,!dose!dependent!mechanism,!preasias!!after!
long!term!antipsychotics!(predictable,!e.g.!bleeding!after!warfarin!(avoid!
by!predict!predisposing!factors!use!lower!doses)!
2.!bizarre!!
Not!predictable,!not!dose!dependent,!rare,!increase!mortality!rate,!elg.!
Haemolysis!in!G6PD!deficiency,!take!drug!history,!take!family!history,!
avoid!certain!drugs!in!disease!
3.!Continuous!
Due!to!long!term!use!e.g.!tardive!dyskinesias!(after!long!term!
antipsychotics/neuroleptics!use)!
4.'Delayed!!
After!use!e.g.!carcinogenesis!!uterine!in!breast!cancer!after!oestrogen!
use,!teratogenesis!!thalidomide!!antiemetic!!
5.'End'of'use!!withdrawal!symptoms!!
!
Classification'of'side'effects':''
Mild:!no!need!for!interruption!e.g.!sedation!with!antihistamines!!
Middle:!changes!of!regimen!needed!e..!nausea!after!iron!
Severe!interruption!is!mandatory!e.g.!myelosuppression!after!anti7cancer!
drugs!!
!
Drug'allergy:!differs!from!toxicity!in:!!
1.!reaction!appears!only!in!part!of!population!!
2.!not!dose!dependent!!
3.!symptoms!differ!from!pharmacological!effect!
4.!reaction!=!result!from!previous!sensitization!!
5.!allergen!!protein/hapton!!circulation!atb!present!!
6.!severe!reactions!!anaphylaxis!(LA,!ATB),!haemolysis!!
7.!other:!fever,!(ATB),!rash,!liver!necrosis!!
'
Antiepileptics;'
EPILEPSY:''
SYMPTOMATIC!EPILEPSY,'IDIOPATIC!EPILEPSY!(young!adults!75%);!
*
Trigger*mechanism*of*epilepsy:''
Hyperpyrexia!(infections),!CNS!infections,!Metabolic!disorders,!Toxic!
agents,!Brain!hypoxia,!Expanding!process!(tumor,!haemorrhage),!CNS!
developmental!disorder,!Brain!trauma,!Anaphylactic!reaction.!
*
Main*goal*of*drug:'the!ideal!anti7epileptic!drug!is!non7sedative.!
'
Drugs'in'different'forms'of'epilepsy:!
Grand'mal(tonicOclonic):!CARBAMAZEPINE,!PHENYTOIN,!VALPROATE.'!
Petit'mal'(ABSENCE):'ETHOSUXIMIDE,!VALPROATE.'!

Partial'complex:!CARBAMAZEPINE,!PHENYTOIN,!PRIMIDON!and!VALPROATE.'!
Atonic'and'myoclonic:'VALPROATE,!CLONAZEPAM.!!
Acute'epileptic'attack:'DIAZEPAM,!LORAZEPAM.!!!
!
!Phenobarbital''Acts!on!GABA!7!A!receptors!!Prolong!Cl!opening.!!
High!doses!block!Ca!channels!!Rarely!used!(sedative!effect!+!danger!of!
overdose!and!toxicity.)!!for!Grand!mal!or!partial!seizures.!
!Phenytoin'"'Na!channel!blocker.!
Used!for!partial!attacks!or!generalized!tonic7clonic!seizures.!Side'Effects:!
Nystagum!(depression!of!cerebellum),!Hyperplasia!of!gingiva,!
Teratogenic!effect,!Allergies,!Osteoporosis.!
!
!Carbamazepine''Effect!similar!to!phenytoin.!!
Na+!channel!blockers!!!,!Inhibits!synaptic!transmission.!It!is!the!drug!of!
choice!in!partial!attacks!and!used!against!painful!seizures!in!DM!or!
trigeminal!neuralgia.!
Side'Effects:!Diplopia,!ataxia,!restlesness,!GIT!intolerance,!elderly!aplastic!
anemia!Inducers!of!enzymes.!
!Ethosuximide''Inhibits!T7type!calcium!channels.!!
Used!for!petit!mal!seizures!Side!Effects:!GIT,!Fatigue,!headache.!
!Benzodiazepines''Targets!the!(gamma7!aminobutyric!acid)!GABA7A!
receptors.!(GABA!is!the!major!inhibitory!neurotransmitter!in!the!CNS).!
3!main!steps!of!action!on!Benzodiazepine7GABA7chloride!ion!channel!complex:!
1)!RECEPTOR'EMPTY'(no!agonist)!!receptor!is!inactive!and!the!coupled!
chloride!channel!is!closed.!
2)!RECEPTOR'binding'GABA'!causes!the!opening!of!chloride!ion!channel!!
hyperpolarization!of!cell.!
3)!RECEPTOR'binding'GABA'and'Benzodiazepine'!binding!of!GABA!is!!by!
benzodiazepine!!greater!entry!of!chloride!ion!>!hyperpolarization!of!the!cell!
and!making!it!more!difficult!to!depolarize!!!neural!excitability.!
(!both!affinity!to!GABA!and!influx!of!Cl7!into!the!cell!!hyperpolarization!'
inhibition!of!the!sympathetic!neurons)!
!
ROUTE:'Well!absorbed!p.o.!7!passes!the!BBB,!fast!onset.!Strongly!bind!to!plasma!
proteins.!
!
Main'Effects:'
A)'TRIAZOLAM:'Anti7anxiety!7!(aggression!in!some!individuals).!
B)!CLONAZEPAM:'long!acting,!absences,!myoclonic!seizures,!highly!effective!
anti7epileptic!drug.!
C)'DIAZEPAM:'Status!epilepticus.!!
D)'LORAZEPAM'O'more!effective!then!diazepam!!Sedation!and!induction!of!
sleep!+'treat!spasms.!!
Side'Effects:!!
1)Affects!manual!skill!!
2)!enhance!depressant!action!of!other!drugs!!

3)!Overdose!
4)!Severe!CNS!and!resp.!depression!if!combined!with:!Barbiturates,!Narcotics!
!Antidote=Flumazenil!
!
Tolerance:!There!is!a!down!regulation!of!receptors!in!all!BZD.!
Dependance:!When!stopping!after!a!long!time!use!!!in!anxiety!with!tremor!
and!dizziness.!
'
Addiction'is'not'a'major'problem!''
'
!Valproic'acid''
The!mechanism!of!action!is!not!fully!understood,!but!generally!it!inhibits!
GABA!transaminase!(enzyme!that!degrades!GABA)!and!also!!aspartate!
level!in!brain.!
Effects:!!propagation!of!abnormal!impulses!in!brain.!!
Adverse'effects:!nausea,!vomiting,!ataxia,!sedation,!hepatotoxicity,teratogen.!!
Clinical'use:!myoclonic!seizures,!!incidence!and!severity!of!tonic7clonic!seizure.!!
!
NEWER'DRUGS:''
Vigabatrin,'Lamotrigine,'Gabapentine(GABA'analogue),'Felbamate,'
Topiramate'!
'
Corticosteroids'
Steroids:!glucocorticoids!(cortex!=!fasciculate)!;!mineralocorticoids!(cortex!=!
glomerulosa)!!
1.!Glucocorticoids!=!cortisol,'prednisone'(prodrug),'beclomethasone!!
'
Function:''
1.!Anti7inflammatory:!lipocortin:!inhibits!migration!of!WBCs!and!blocks!
phospholipase!C!and!decrease!AA!
2.!Metabolic:!increase!gluconeogenesis,!increases!lipolysis,!increases!protein!
catabolism,!increases!lipolysis,!decreases!osteoblast!action,!increases!osteoclast!
action!
3.!Anti7allergic:!decreases!mucosa!edema,!decreases!inflammatory!response,!
decreases!fibroblast!function,!decreases!collagen!production!
4.!Effects!on!mediators:!decreases!compliment!concentration,!decreases!NO!
production,!decreases!histamine!production!!
!glycogenolysis!and!gluconeogenesis!!!glycemia.!!
!protein!catabolism!and!!protein!synthesis!as!well!as!!lipolysis.!!
!WBC,!!immunity,!!inflammation!(by!inhibiting!phospholipase!A2,!thus!
blocking!the!production!of!PGE2!and!Leukotriens).!!
!Calcium!absorption,!!osteoblast!activity!and!!osteoclast!activity.!!
'
Mechanism:'!It!is!highly!lipid!soluble,!bound!in!the!plasma!to!cortisol!binding!
protein!or!albumin,!diffuses!easily!through!the!membrane!and!bind!to!the!
glucocorticoid!receptor!located!on!the!nuclear!envelope,!this!will!initiate!
translocation!of!the!receptor!and!the!hormone!to!initiate!lipocortin!and!gene!

expression.!!Glucocorticoid!levels!are!according!to!the!circadian!rhythm!with!the!
highest!peak!around!4!am!and!another!peak!around!4!pm.!!
'
'
Indication:!!
a.!Adrenal'insufficiency:!acute/chronic!
b.!AntiOinflammatory'+'immunosuppression:!RA,!allergic!reactions,!
autoimmune,!bronchial!asthma,!ulcerative!colitis!
c.!Myeloproliferative'diseases:!lymphomas,!leukemia!!
'
SE:!suppress!normal!secretion!of!hormones!in!body,!stop!gradualy!!do!not!stop!
abruptly,!steroid!diabetes,!peptic!ulcers,!cushing!syndrome,!osteoporosis,!poor!
immunity7!prolong!wound!healing!!
!
Therapeutic'principles:!dont!use!in!acute!infection7!apply!with!lower!dose,!
treatment!for!shortest!period!possible,!increases!CA!uptake,!decrease!NaCl!
'
2.'Mineralocorticoids:'aldosterone,'spironolactone''
Function:!!
Kidney!tubules!and!collecting!ducts:!resorption!of!Na!+!H20!
Increase!BP!(elevated!levels!=!HTN,!hypernatremia,!hypokalemia,!
alkalosis)!!
Hyperproduction!=!primary!hyperaldosteronism,!hypertension,!
secondary!!HTN,!pregnancy,!liver!cirrhosis,!CKD!
!
Spironolactone!=!aldosterone!antagonist!=!diuretic!!potassium!sparing!diuretic!
used!to!treat!increased!levels!of!aldosterone!!
Hypofunction!=!metyrapone,!hyperfunction!=!fludrocortisone!!
!
11. 'Drug'allergy;'
It!differs!than!toxicity!in!that!the!reaction!appear!in!only!part!of!the!
population,!it!is!not!dose7!dependent,!the!symptoms!differ!from!
pharmacological!effect!and!the!presence!of!circulating!antibodies.!It!can!
be:
o Acute!anaphylaxis,!circulating!antibodies,!fever,!haemolysis,!
fever,!etc.!
o It!is!a!delayed!type!hypersensitivity,!or!type!1!hypersensitivity!
(IgE!mediated),!meaning!that!!there!has!to!be!prior!sensitization!
by!an!allergen!in!order!to!cause!an!allergic!reaction.!
Type'I!7!Antibody!(Ig!E)!mediated!(anaphylaxis!7!PNC)!
o Sensitisation!phase!
! Immunogenic!complex!(drug7carrier)!induces!
production!of!!specific'IgE'antibodies!
! IgE!ab!is!bound!on!the!cell!surface!of!mast!cells!and!
basophiles!via!!high!affinity!receptors!
o Allergic!reaction!triggering!!
! After!re7exposition,!the!drug+carrier!is!directly!bound!
on!the!IgE!!
! Cross7linking!of!the!IgE!

! Degranulation!of!the!mast!cells!=!release!of!H,!LT,!Pg!
o Clinical'manifestation:!urticaria,!itching,!nose/eye!hyperemia!
and!secretion,!soft7tissue!swelling,!bronchospasm,!anaphylactic!
reaction!
o Examples:!PNC,!CS,!LA,!quinolones,!macrolides,!streptokinase,!
thiazides,!salicylates,!skeletal!muscle!relaxants!!
o Anaphylactic'shock!
! Shock!or!shock7like!status!as!a!result!of!fully!blown!
multiorgan!anaphylaxis!with!possible!progression!into!
the!total!collapse!
! May!be!lethal!
! Pharmacological!treatment:!adrenalin!+!glucocorticoids!!
i.v.,!antihistamines!
!

Type'II!!Cytotoxic!(IgG)!mediated!(methyldopa!!haemolytic!anemia,!
heparin!7!trombocytopenia)!
o Drug!(hapten)!is!bound!on'the'surface'of'target'cells'(these'
are'carriers)!
o Antibody!production:!IgG'(IgG1!and!IgG3),!rarely!IgM!
o After!re7exposition!!the!drug!is!bound!again!on!the!cell!surface!
and!IgG!is!attached!!
o The!activation!of!the!complement!system!and!NK!cells!execute!
the!cytotoxic!reactions!!
o The!cell!is!destructed!and/or!taken!up!by!the!RES!
o The!main!target!cells:!erythrocytes,!leukocytes,!trombocytes,!!
o Clinical'outcome:!anemia!or!7!penia!
o Drugs:!quinidine,!heparin,!sulfonamides,!cephalosporins,!
penicillins,!anticonvulsants.!
!
Type'III!7!Drug7antibody!complexes!are!deposited!in!the!tissues!
(vasculitis!!minocycline,!drug7induced!lupus!erythematosus!7!quinidine)!
o Drug7carrier!or!drug!as!a!chimeric!protein!induces!production!
of!IgG!antibodies!
o Formation!of!IgG7drug(carrier)!complexes!
o Normally!these!complexes!are!cleared!by!the!RES!with!only!
some!decrease!in!the!clinical!response!
o In!some!circumstances!(huge!amount!of!complexes,!deficient!
decomposition!system)!it!results!to!development!of!
symptomatic!reaction!
o Time!window:!173!weeks!after!exposition!
o Clinical'manifestation:!vasculitis!and/or!serum!sickness,!
! Urticaria,!dermatol.!affections,!pruritus,!
fever,arthritis/arthralgia,!glomerulonephritis,!
lyfmadenopathy!
o Serum'sickness!first!described!after!passive!immunization!
with!animal!serum!!
! Within!4710!day!the!abs!were!produced!and!formed!
complexes!with!antigenic!proteins.!

These!complexes!were!deposited!in!postcapillary!
venules!and!attracted!neutrophils!
! Development!of!inflammation!with!release!of!
proteolytic!enzymes!destructing!vessel!and!surrounding!
tissue!!
o Drugs:!chimeric!abs!(e.g.,!infliximab)!or!cephalosporins!
(cefaclor,!cefalexin),!amoxicillin,!
sulfamethoxazole/trimethoprim,!NSAIDs,!amiodaron!
!
!
!
Type' IV! 7! A! delayed! reaction! occurring! when! drug! molecules! are!
presented! to! special! cells! called! T! cells,! which! are! responsible! for!
mediating! an! inflammatory! response! (variety! of! clinical! manifestations!
from!skin!alone!to!fulminant!systemic!disease!7!sulfonamides,!ATB)!
o Cellular!reaction!mediated!by!T7cells!
o General' principle:! drug7carrier! complex! is! presented! by! APC!
to!T7cells!with!their!following!clonal!proliferation!
o After!re7exposition!the!drug!gets!into!contact!with!T7cells!with!
release! of! specific! cytokines! and! inflammatory! mediators!
which!activate!the!target!cells!
o Clinical'manifestation:!mostly!drug7related!contact!dermatitis!
(rash)! in! many! forms! +! pruritus,! tuberculin! reaction,!
maculopapular!exanthema!or!e.g.!allergic!hepatitis!!
o Drugs:!aminoglycosides,!penicillins!
o Time!window:!278!days!
!

!
Treatment'of'Parkinsonism;'
DEFINITION:!!
Parkinsonism!is!a!progressive!neurological!disorder!of!muscle!
involvement,!characterized!by:!TREMORS,!MUSCULAR!RIGIDITY,!
BRADYKINESIA!and!HYPERTONIA,!+!POSTURAL!and!GAIT!
ABNORMALITIES.!!
ETIOLOGY:!
is!related!with!destruction!of!DOPAMINERGIC!NEURONS!IN!THE!
SUBSTANTIA!NIGRA!with!a!consequent!REDUCTION!OF!DOPAMINE!
ACTIONS!IN!THE!CORPUS!STRIATUM(basal!ganglia)!
Clinical'manifest.'
Occurs!when!the!dopamine!depletion!of!60780%!!!
SECONDARY!PARKINSONISM!!is!caused!by!drugs:!HALLOPERIDOL!and!
PENOTHIAZINES,!which!work!pharmacologically!by!BLOCKING!OF!
DOPAMINERGIC!RECEPTORS!in!the!brain.!(they!shouldnt!be!used!in!
Parkinsonian!patients).!!
!
ROLE'OF'SUBSTANTIA'NIGRA'in'PARKINSONS'disease:''
SN!is!a!part!of!extra7pyramidal!system!is!the!source!of!DOPAMINERGIC!neurons!
(works!as!a!TONIC!support!and!influence!on!the!motor!activity)!that!end!in!the!
NEUROSTRIATUM!which!has!cell!neurons!that!end!in!SN!and!that!secrete!
INIBITORY!TRANSMITTER!GABA!!!

!
PATHOPHYSIOLOGY:!
1)!Cell!death!results!in!less!dopamine!release!in!the!neurostriatum,!
2)loss!of!the!inhibitory!effect!of!dopamine!results!in!Ach!!triggers!a!chain!of!
ABNORMAL!SIGNALING!leading!to!IMPAIRED!MOTILITY!!
!DRUGS!USED!IN!PARKINSON:!!
Main'goal:!temporary!relief!from!the!symptoms!of!the!disorder!but!they!
dont!arrest!or!reverse!the!neuronal!degeneration!of!the!disease.!
!
!
!
A)LEVODOPA''
(precursor!of!dopamine,!can!cross!BBB),!used!to!restore!dopaminergic!
neurotransmission!in!the!striatum!by!!DOPAMINE!SYNTHESIS!IN!THE!
SURVIVING!and!HEALTHY!NEURONS!of!the!SN.!
'
Problem:'!DOSES!of!LEVODOPA!because!much!of!the!drug!is!
DECARBOXYLATED!to!DOPAMINE!already!in!the!periphery,!causing:!
1)!side'effects:!vomiting,!nausea,!cardiac!arrhytmia.,!tachycardia,!psychiatric!
problems!(levodopa!exacerbate!the!symptoms!of!psychiatric!patients),!
hypotension!and!dyskinesias.!
2)!Waste!of!drug!effect!when!combines!with!VIT.!B6!(pyridoxine)!!
'
Solution:'use!a!combination!of!LEVODOPA!+!CARBIDOPA!(a!dopa!decarboxylase!
inhibitor,!decrease!the!metabolism!of!levodopa!in!the!periphery)!!
'
B)'SELEGINE'and'RASAGILINE(agents'dopamine'effect)!
!SELEGINE!!DOPAMINE!levels!in!the!brain.!LEVODOPA!actions!when!those!
drugs!are!combined.!!required!dose!of!LEVODOPA.!
1)!at!low/moderate!doses,!inhibits!selectively!MAO!type!B!(metabolizes!
DOPAMINE).!!
2)!doesnt!inhibit!MAO!type!A(metabolizes!NOREPINEPHRINE!and!SEROTONIN).!!
!
SIDE'EFFECTS:!!
1)!At!recommended!doses!can!cause!SEVERE!HYPERTENSION.!
2)!selegine!is!metabolized!to!amphetamine!and!methamphetamin!!producing:!
INSOMNIA.!
!
!RASAGILINE!!is!an!irreversible!and!selective!inhibitor!of!brain!(MAO!type!B);!
x5!times!the!selegine!potency;!it!is!NOT!methabolized!to!any!amphetamine7like!
substance!!
!
C)!CATHECOLOOOMETHYLTRANSFERASE(COMT)'INHIBITORS:!
The!combination!LEVODOPA+CARBIDOPA!works!for!the!purpose!already!
explained!before,!but!when!carbidopa!inhibits!the!peripheral!
decarboxylation!of!the!levodopa!it!formes!a!new!metabolite!in!significant!
concentration!that!is!the!37O7methyldopa!which!competes!with!levodopa!
for!the!active!transport!in!the!CNS.!

The!inhibition!of!COMT!by!ENTACAPONE'or!TOLCAPONE''plasma![c]!
of!37O7!methyldopa!!restoring!the!central!uptake!of!LEVODOPA!!
TOLCAPONE'differs!from!ENTACAPONE'in!its!long!duration!and!the!fact!
that!it!crosses!BBB!for!inhibition!in!CNS!of!the!COMT,!but!both!excreted!
by!feces!and!urine.!
ENTACAPONE'is'not'toxic'to'the'liver'in'respect'to'TOLCAPONE!!
SIDE'EFFECTS:!diarrhea,!postural!hypotension,!nausea,!anorexia,!
dyskinesias,!hallucinations!and!sleep!disorders.!

'
'
'
'
D)'DOPAMINEORECEPTOR'AGONISTS!
The!group!includes:!!
o BROMOCRIPTINE'(ERGOTAMINE!derivative,!which!is!a!
vasoconstrictive!alkaloid)!!
o ROPINIROLE,!PRAMIPEXOLE!and!ROTIGOTINE.!
!
BROMOCRIPTINE:''
Is!the!2nd!drug!of!choice!and!is!an!agonist!of!D2!presynaptic!receptors.!
It!has!longer!duration!of!action!then!Levodopa.!And!can!be!combined!with!
L7dopa!to!prolong!the!tolerance!effect.!
S.E.:!Nausea,!Vomiting!Hypotension!Diskinesia!Confusion!and!
hallucinations.!!
ROPINIROL,'CARBEGOLINE,'PRAMIPEXOL:''
2nd!generation!of!agonists.!
Monotherapy,!in!severe!cases!combined!with!L7dopa,!MAO!Inhibitors.!
(influenza!anti7viral!drug)!that!may!increase!release!of!dopamine!and!block!
cholinergic!receptors.!
!
E)'Amantadine'
Antiviral!agents!(flu)!(short!acting,!effects!rigidity!and!tremor.!Side!
effects:!depression,!sleep!disorders)'
F)'BIPERIDOL,'PROCYCLINE,'TRIHEXYFENIDIL'O'acethylcholine!blocking!
agents!
'
Estrogen,'Oral'contraceptives.'
Estrogens!!estradiol!
Progesterone!!
Testosterone!!
Antiestrogen!=!tamoxifen,!cloiphene!
Antiprogesterone!=!mifepristone!!
Antiandrogens!=!flutamide!!
!
1.'estrogens''estradiol''
Therapeutic'uses!=!replacement!in!deficiency,!menstrual!disorders,!
contraceptives,!breast!and!prostate!cancer!!

HRT!=!hot!flashes,!decreases!risk!of!osteoporosis,!not!used!to!treat!
osteoporosis!due!to!increased!risk!of!breast!cancer,!decreases!risk!fo!
colon!cancer!
Primary!hypogonadism!=!estrogen!+!progestin!!
Metastatic!breast!cancer!=!if!estrogen!receptors!in!cancer,!therefore!increases!
doses!=!tumor!regression!
SE:!nausea,!vomiting,!breast!tenderness,!hyperpigmentation,!HTN,!
miraine,!edema!
CI:!estrogen!dependent!neoplasia,!artery!disease,!thromboembolism!
disease,!liver!disease!!
Antiestrogens:'tamoxifen=!treatment!of!breast!cancer,!clomiphene!=!
stimulation!of!ovulation!!
!
!
2.!Progesterone!!
Naturally!secreted!from!corpus!luteum,Testes!and!adrenal!cortex!!
Treatment:!contraceptive!(lower!chance!of!vascular!complication)!!
SE:!weight!gain:!edema,!depression!
!
Antiprogesterone'(mifepristone)!!used!in!early!pregnancy!for!abortion!
!
3.!Testosterone!!protein!and!muscle!synthesis!of!male!sex!characteristics,!!
Physio'effects:!enlarged!sex!organs,!hair!growth,!red!cell!??,!increased!
musle!development,!larynx!enlargement!!
Treatment:!replacement!theraepy,!delayed!puberty,!cryptochorism,!
breast!cancer!in!women!
SE:!female:!masculinisation,!hirsutism!male:!gynecomastia,!decreased!
sperm,!CI!in!pregnancy,!other:!edema,!increased!risk!of!hepatic!cancer!
!
Antiandrogens:'flutamibe7!treatment!of!hirsutism!in!females!+!prostate!cancer!
in!males!!
Drugs!=!decrease!fertility!by!preventing!ovulation,!impaired!gametogenesis,!
interfering!gestation!!
'
ORAL'CONTRACEPTIVES'!
1.!Combination'estrogen'and'progestin,!21!days!+!7!day!period,!mimics!
natural!cycle!=!E7ethinyl,!mestranol!
2.!transdermal'patches!=!ethinyl!estradiol!!applied!once!every!4!weeks!+!patch!
free!week!!increased!thromboembolism!=!ethinyl!estradiol,!norelgeestromin!!
3.!vaginal'ring:!ethinyl!estradiol,!etonogestrel,!3!weeks!+!1!free.!AE:!may!slip!out!
accidently''
4.!progestin'only'pill!=!norethinedrone/norgestril,!daily,!may!cause!irregular!
menstrual!cycles,!breast!feeding!mothers!can!take!it!!
5.!progestin'implants!=!subdural!implant!with!etonogestrel7!long!term!
contraception!4!cm!capsule!in!upper!arm7!3!year!period,!reliable!less!
sterilization!and!totally!reversible,!SE:!irregular!menstruation!+!headaches!!
6.!progestin'intrauterine'device!=!levonorhestrel!!released!in!uterine,!highly!
effective!!long!term!up!to!5!years!good!for!women!after!1!pregnancy!with!
ectopic!pregnancy!!

7.!postcoital'contraception7!emergency!contraception!!high!doses!of!
levonorhestrel/ethinyl!estradiol!+!progesterone!administer!within!72!hours,!2nd!
dose!should!be!taken!after!12!hours!of!first!dose!for!maximum!effectivity,!
progressin!only!are!better!tolerated!!
!
AE:!CVS,!breast!fullness,!depression,!fluid!retention,!headache,!nausea,!vomiting,!
carcinogenic,!metabolism!(weight!gain),!incease!HDL,!decrease!LDL,!CI:!CVS!
problems,!thromboembolic,!estrogen!dependent!neoplasms!!!
'
'
'
'
'
'
12. Drug'abuse'(Dependence/Tolerance);'
'
It!is!a!serious!social,!medical!and!financial!problem!that!occur!in!any!state!
and!all!the!levels!of!society!and!is!an!habitual!use!of!substance!in!order!to!
alter!one's!mood,!emotion!or!state!of!conscious.!Can!also!be!defined!as!the!
use!of!drug!not!for!a!non7therapeutic!effect.!!
!
Cannabis:!!
A!psychoactive!drug!in!which!the!active!substance!is!THC!
(tetrahydrocanabiol)!which!is!usually!smoked,!but!can!be!also!ingested!
(hush!cakes),!leading!to!euphoria,!relaxation!and!amplification!of!senses!
!Short'term'effects:!increased!appetite,!tachycardia,!redness!of!the!eye,!
impaired!intellectual,!may!lead!to!panic,!anxiety,!hallucinations!or!
psychosis.!!
Long'term'effects:!tolerance,!psychological!dependance,!lung!cancer,!etc.!
Medical!use:!anti7emetic!(cancer),!appetizer!(AIDS),!lower!intraocular!
pressure,!decrease!muscle!spasms.!
'
Coca:!!
From!the!plant!erythroxylon,!the!psychoactive!substance!is!cocaine,!can!
be!chewed,!smoked,!ingested,!injected!or!sniffed!(the!most!common).!Can!
lead!to!euphoria,!alertness!and!postponed!hunger!and!fatigue,!but!
tolerance!develops!rapidly!and!it!may!lead!to!!
o Serious'side'effects:!tachycardia,!tachypnea,!hypertension,!
midriasis,!violent!behavior,!hallucinations,!restlessness,!psychosis,!
convulsions!and!nasal!septal!defect!(typical!nose!bleeding!from!a!
weak!membranous!circular!part!on!the!septum).!
o It!is!used!in!medicine!as!a!local!anesthetic!in!surgery.!!
Opium:'!
From!the!poppy!flower!(Papaver),!the!main!substances!are!morphine,!
codeine,!papaverine!(used!medically)!and!Heroin!(semi!synthetic!abuse!
drug).!!
o Leading!to!euphoria!and!analgesia.!!
o Hallmark!of!intoxication!is!pin!point!pupils!(severe!miosis).!!

o Causes!also!constipation,!malnutrition!and!rapid!tolerance!and!has!
severe!withdrawal!symptoms!(nalaxone!is!antagonist).!!
o Medically!used!as!anti7tussive!(codein),!for!abdominal!pain!
(papaverine),!anti7diarrheal!in!some!countries!and!as!analgestic!
(morphine).!!
'
CNS'depressants:'!
Benzodiazepines!and!barbiturates.!They!relief!tension,!anxiety!and!
stress!but!can!lead!to!depression,!ataxia,!confusion,!!amnesia,!insomnia,!
tolerance!and!dependance.!!!
Used!in!medicine!as!anxiolytics,!sedatives,!myorelaxants!and!antiepileptic.!!
'
'
'
'
CNS'stimulants:'!
Amphetamines:!similar!action!to!cocaine,!stimulant,!may!cause!the!same!
problems!as!!cocaine,!but!is!used!medically!in:!ADD,!narcolepsy,!nasal!
congestion.!!
Ecstasy:!fascilitate!empathy,!closeness!to!others,!sociability,!increase!
physical!and!emotional!energy,!but!may!lead!to!depression,!anxiety,!visual!
and!auditory!hallucinations,!stroke.!!
Hallucinogens:!best!known!is!LSD,!its!effects!are!extremely!variable!and!
largely!depend!on!the!abuser!state!of!mind.!!
o It!leads!to!alterations!in!though,!mood!and!sensory!perception!+!
similar!to!ecstasy.!
o Side'effects!are:!paranoia,!distorted!perception,!prolonged!
anxiety,!hallucinations,!flashbacks!and!depression.!
!
AnalgeticOantipyretic'drugs;'
PAIN('for'analgesic'action):!!
The!sensation!of!painful!stimuli!depends!on!nerve!ending!transmission.!
Prostaglandins!(PGE2)!sensitize!nerve!endings!to!effect!of!pain!mediators!
(mainly!bradykinin,!histamine).!!
We!may!treat!pain!either!by:!
1) Lowering!PGs!level(!PGE2!synthesis)!by!ASPIRIN!and!other!NSAIDs;!
2) !By!inhibition!of!pain!transmission!and!perception!in!the!CNS!(OPIOID!
ANALGETICS).!
'
FEVER:!PGE2!has!a!direct!pyrogenic!effect!on!neurons!in!the!hypothalamus.!!its!
level!has!!a!beneficial!anti7pyretic!effect.!!
'
PROSTAGLANDINS:!are!synthesized!by!the!enzyme!COX1!(physiologic!
prostaglandins)!and!COX2!(prostaglandins!in!inflammation)!from!arachidonic!
acid!found!in!cell!membranes.!!
!
The!COX!pathway!is!responsible!for!production!of!thromboxans!and!
prostacyclines,!while!the!LOX!pathway!produces!leukotrines.!!

Main!strategy!of!reducing!pain,!fever,!inflammation!is!the!inhibition!of!COX!
pathway!in!order!to!!amount!of!PGs.!Some!drugs!posses!analgetic7antipyretic!
properties!while!other!posses!more!anti7inflammatory!properties.!!!
!
Drugs'used'to'treat'pain'and'fever'(mainly'NSAID's'and'Paracetamol):'!
1.'NSAIDs:'all!NSAID's!are!able!to!inhibit!COX,!lowering!PGs!level.!
'
Classification:!
Salicyclates'aspirin'(ASA):'irreversibly!inhibits!COX!non7selective.!!
Effects!(dose):!!
o 1)!Anti7agreggatory!(!platelet!aggregation).!
o 2)!Anti7pyretic;!
o !3)Analgesic!!
o 4).!Anti7inflammatory!
o !5).!Possibly!anti7cancer!!!
Adverse'effects:!Gastric'ulcer'(!protective!function!of!PGs!in!stomach),!
Allergy,'tachypnea'in!higher!doses!(respiratory!alkalosis),!Reyes'
syndrome:'in!children!after!viral!!infection!and!children!under!12!is!CI,!
paracetamol!should!be!used,!tinnitus'and!fever.'!
!
!Propionic'acid'derivatives'(IBUPROFEN):'Reversible!COX!inhibitors.!!
Effects:!Analgetic,!Anti7pyretic,!Anti7inflamatory!(Less!side!effects!than!
aspirin!7!dyspepsia,!bleeding!are!the!most!common).!!
!
!Acetic'acid'derivatives'(indometacine,'diclofenac):'Rev.!COX!inh,!not!anti7
pyretics.!!
Effects:!analgetic,!anti7inflammatory.!!
Adverse!effects:!mostly!GI.!Arthritis!and!gout!(urea!accumulation).!
COX2'selective'NSAIDs'(COXibs)'O'CELECOXIB:'Reversibly!inhibit!COX2.!!
Lower!risk!of!GI!bleeding.!Doesnt!inhibit!platelet!aggregation.!
CI:!IHD!or!stroke!(!level!of!prostacyclines!!!platelet!aggregation)!
'
2.'NonOnarcotic'analgetics'(PARACETAMOL'/'ACETAMINOPHEN)''
MECHANISM'OF'ACTION:!block!COX!in!CNS!only!and!have!no!effect!on!
peripheral!COX.!
Only!analgetic!and!antipyretic!properties.!No!GI!side!effects.!
ADVERSE'EFFECTS:!allergy.!In!high!doses:!glutathione!in!liver!is!depleted!
!paracetamol!exert!toxic!effects!on!hepatocytes!!liver!necrosis!
TREATMENT:!NOACETYLCYSTEIN.!ACETAMINOPHEN'has'STRONG!
ANALGESIC!and!ANTIPYRETIC!effect,!but!WEAK!ANTI7INFLAMMATORY!
effect.!
!
Macrolides,'lincosamides'
Macrolides:'!
Bind!irreversibly!to!the!50S!ribosomal!sub7unit!and!is!considered!to!be!
bacteriostatic!protein!synthesis!inhibitor.!
There!are!4!drugs!that!belong!to!this!group:!

o Erythromycin:!same!spectrum!as!PNC!G,!thus!given!to!patients!
with!PNC!allergy.!!
o Clarithromycin:!has!activity!against!intracellular!pathogens!
(chlamydia,!legionella,!!moraxella).!!
o Azithromycin:!for!respiratory!tract!infection!(Streptococcus!
pneumonia,!Klebssiella).!!
o Telithromycin:!used!when!the!other!macrolides!are!ineffective.!!
These!drugs!are!given!orally,!absorbed!well,!distributed!well!(except!CSF),!
diffuses!also!to!the!prostate!and!uniquely!accumulate!in!Macrophages.!It!
is!metabolized!in!the!liver,!the!metabolite!is!excreted!in!the!bile!(active)!
and!urine!(inactive).!!
Treatment:!respi!infection!(note:!common!sub!for!patients!with!allergy!
to!PNC)!
SE:!inhibition!of!P450!system,!QT!prolongation!on!ECG,!acc!in!liver:!
nausea,!hepatotoxicity,!epigastric!pain,!cholestatic!jaundice,!ototoxicity.!!
Contraindicated:!toxic!if!taken!with!warfarin,!carbamazepine!
(antiepileptic),!theophylline!

!
!Lincosamides:'!
To!this!group!belong!Clindamycin.!!
Its!mechanism!of!action!is!exactly!the!same!as!erythromycin!(meaning!
bind!to!50S!sub7unit).!The!only!difference!is!that!is!used!for!the!treatment!
of!anaerobic!infections,!such!as!bacteroides!fragilis.!!
Well!absorbed!orally,!distribute!well!(except!CSF),!metabolized!and!
excreted!into!the!bile!and!urine.!
Its!major!side!effect!is!that!it!may!lead!to!fatal!pseudomembranous'
colitis,!thus!usually!given!with!metronidazole!or!vancomycin!(always!
start!with!metronidazole)!
!
13. Absorption'of'drugs;'
Absorption!is!the!transfer!of!a!drug!from!its!site!of!administration!to!the!
blood!stream!which!!may!be!influenced!by!many!factors.!!
o The!route!of!administration!!only!I.V!has!100%!bioavailability,!
because!it!is!directly!to!the!blood.!!
o The!pH!and!the!pKa!!most!drugs!are!either!weak!base!or!weak!
+!
acid,!acidic!(HA)!is!non!ionized!in!acidic!environment!(HA!!H +!
7
+!
+
A )!and!basic!is!non!ionized!in!alkali!environment!(BH !B!+H )!
o A!drug!passes!the!membrane!when!it!is!uncharged.!!
o Blood!flow!in!the!absorption!site,!surface!area!and!contact!at!the!
absorption!time.!!
o Food!and!drink!can!influence!the!absorption!rate!and!
biotransformation!of!a!drug!!!
o The!absorption!can!be!either!via!passive!diffusion!(through!
membrane!or!pores),!active!(through!pumps!and!transport!
molecules)!or!via!endo/exocytosis!(for!very!large!molecules).!!
A.'
Passive'diffusion:''
1.!
Along!concentration!gradient!!
2.!
No!specific!carriers!

3.!!

Liposoluble/nonionized!(charged!molecules!cannot!cross!membranes!
passively!!therefore!weak!acid!in!acidic!environment,!weak!base!in!basic!
environment)!
Larger!molecules:!need!facilitated!diffusion!!
Passage!of!specific!molecules!via!specific!proteins!(e.g.!ion!channels)!!

4.!
5.!
'
B.'
1.!
2.!
3.!
4.!
5.!

6.!

Active'transport'
against!concentration!gradient!!
Requires!energy!
Specific!carrier!proteins!(move!molecules!against!concentration!gradient)!
Transport!!uni/sym/anti7port!
Endocytosis!(e.g.!B12)!
Endocytosis!is!an!energy7using!process!by!which!cells!absorb!molecules!
(such!as!proteins)!by!engulfing!them.!It!is!used!by!all!cells!of!the!body!
because!most!substances!important!to!them!are!large!polar!molecules!
that!cannot!pass!through!the!hydrophobic!plasma!or!cell!membrane.!
Exocytosis!(e.g.!neurotransmitters)!!
is!the!durable,!energy7consuming!process!by!which!a!cell!directs!the!
contents!of!secretory!vesicles!out!of!the!cell!membrane!and!into!the!
extracellular!space.!

'
Opioid'analgesics;'
The!primary!use!of!opioid!analgesics!is!to!relieve!intense!and!chronic!pain!and!
anxiety!that!accompanies!it!(surgery,!injury,!cancer).!It!acts!by!binding!to!specific!
opioid!receptors!in!the!CNS!and!mimic!the!effect!of!endorphins,!enkephalins!and!
dynorphins.!!
'
Pharmacodynamics:''
The!major!effect!is!mediated!by!3!main!receptors!7!,!,!.!(mu,!kappa,!delta)!from!
the!G7!!protein7coupled!receptor!family.!
!
Binding!to!an!opioid!receptor!will!cause:!!
1.!Inhibition!7!cAMP!content!is!reduced!
2.'Opening!of!K!channels.!(postsynaptic!K+!efflux!!hyperpolarization).!
3.'Inhibits!the!opening!of!Ca!channels.!(presynaptic!Ca++!influx).!!
4.'Receptors!on!spinal!cord!affect!the!release!of!substance!P!(decrease).!This!
causes!hyperpolarization!and!!in!NeuroTransmitter!release.!!
!
Classes'of'opioids:'!
Full'agonists:!Morphine,!hydromorphine,!Methadone,!fentanyl,!
oxycodon,!Heroin!7!binds!to!!receptor.!!
Moderate'Agonist:!Codeine,!Propoxyphene.!!
Mixed'agonist/antagonist:'Buprenorphine!!binds!to!!receptor!in!
dorsal!horn.!Pentazocine!7!!suppresses!,!activates!.!!
Full'antagonists:'Naloxone!7!treat!overdose!of!opioids.!!
Other'analgesics:'Tramadol!7!7opioid!receptor!!
'
Therapeutic'Uses'of'Opioids:!

Pain!relief,!terminal!illnesses,!pre/post!operative,!lead!to!constipation,!
relives!dyspnea!(!pulmonary!edema)!and!cough.!!
Side'effects:'!
Sedation,!constipation,!nausea,!urinary!retention,!addiction,!respiratory!
depression.!

!Full'agonists:!
MORPHINE:!acts!on!!receptors!in!the!dorsal!horn!!!Substance!P!
release!(substance!P!!modulates!pain!perception!in!the!spinal!cord)!and!
inhibits!NT!release!from!nociceptive!nerve!ending!carrying!terminals.!
Actions:!Analgesia'(raises!pain!threshold),!Euphoria,!Respiration'
depression,!AntiOtussive,!Miosis'(pinpoint!pupils),!Constipation,!
Urinary'retention,!Sedation,!Histamine'release,!Hormonal'changes'
(ACTH,!GTH,!CTH,!LH,!FSH,!7ENDORPHIN!and!GH,PROLACTIN,!ADH).!
Therapeutic!uses:!Analgesia,!Treat.!of!diarrhea,!Relief!of!cough,!Treat.!
Acute!pulmonary!edema.!!
Pharmacokinetics:!well!absorbed!by!IM,!IV,!SC!injections.!!
Toxicity:!!
o Acute''coma,!cyanosis,!shock!!death.!Treatment:!naloxone.!!
o Chronic:!dependence,!tolerance,!withdrawal!symptoms!(flu!like!
symptoms!with!insomnia),!irritability!involuntary!movements,!HT.!
Treatment:!methadone.'!
Morphine!has!very!high!first!pass!effect!!should!be!administered!
parenteraly!and!not!P.O.!!
!
METHADONE(Oreceptor)'!is!synthetic!!orally!effective!opioid!equal!to!the!
potency!of!morphine!but!induce!less!euphoria!and!longer!duration!of!action,!
used!for!weaning!the!addicted!to!heroin!or!morphine,!as!substitute!for!injected!
opioid.!!
!
FENTANYL'7!chemically!related!to!meperidine,!x100!the!analgesic!potency!of!
morphine,!!lipophilic,!short!duration!of!time,!injected!(IV)!epidurally!or!
intrathecally.!Used!during!and!postoperatively,!also!used!in!cardiac!surgery.!!
!
OXYCODONE'7!semi7synthetic!derivative!of!morphine.!orally!active,!combined!
often!with!aspirin!or!acetaminophen.!!
!
!Heroin'O'not!a!natural!product!!obtained!by!diacetylation!of!morphine!!x3!its!
potency,!lipid!soluble=!across!BBB!more!than!morphine;!Converted!to!
morphine!in!the!body!(no!medical!use).!!!MODERATEAGONISTS:!!
CODEINE'7!used!for!its!DRY7COUGH/ANTI7TUSSIVE!activity.!
!
!MIXEDAGONIST/ANTAGONIST:!
!
PENTAZOCINE7!acts!as!an!agonist!on!!receptors!and!is!a!weak!agonist!of!!and!
.!Causes!!less!euphoria!than!morphine,!but!in!higher!doses!can!lead!to!
respiratory!and!GIT!activity!depression,!!b.p.,!hallucinations,!nightmares,!

dysphoria,!tachycardia!and!dizziness,!work!load!of!the!heart.!can!induce!
tolerance!and!dependence.!!
!
BUPRENORPHINE7!partial!agonist,!on!!receptor.!Use!in!opiate!detoxification!
coz!it!has!less!severe!and!shorter!duration!of!withdrawal!symptoms!compared!to!
methadone.!Indicated!for!the!treatment!of!opioid!dependence.!!!!
'
OTHERANALGESICS:''
'
TRAMADOL7!analgesic!centrally!acting!by!binds!to!7opioid!receptor.!For!
management!of'moderate!to!severe!pain.!Extensive!metabolism.!Not!to!be!used!
in!patients!taking!MAO!inhibitors.'
!
!
!
!
!
!
Antiprotozoal'and'anthelmintic'drugs'
!
Antiprotozoal:'!
Drugs!that!are!being!used!to!treat!parasitic!infections!such!as:!Malaria,!
amebiasis,!leishmaniasis,!giardiasis,!trichomoniasia.!It!is!harder!to!treat!
protozoal!infections!than!bacterial!infections!and!usually!takes!more!time!
while!causing!serious!toxic!effects!on!the!host.!
!
AntiOMalarial'drugs:!!
Malaria!is!an!acute!inflammation!caused!by!the!genus!Plasmodium,!it!is!
transmitted!by!a!mosquito!(Anopheles)!vector!which!lives!in!humid!
swampy!areas.!!
Admission'of'the'protozoa''liver'maturation''invade'RBC''
multiply'and'rupture'RBC,'then'pass'to'infect'other'RBC'(some'
become'gametocytes)''female'mosquito'picks'up'gametocytes'to'
pass'to'another'host.!
There!are!several!drugs!used!for!malaria:!!
o Primaquine'!prevent!the!transmission!of!the!disease!and!kill!the!
parasite,!effective!against!parasites!outside!the!RBC.!
o Chloroquine'!kills!the!intracellular!(RBC)!parasites!by!
preventing!the!enzymatic!change!of!Heme!(toxic!to!the!parasite)!to!
a!non!toxic!substance.!!
o Pyrimethamine'!effective!against!the!gametocyte!form!and!free!
blood!plasmodium.!!
o Mefloquine,'Quinine,'Artemisinin'!same!as!Chloroquine,!but!
are!used!in!therapy!resistant!!(which!spreads!very!fast)!
plasmodium.!!
o Chloramphenicol!is!also!an!option!for!treating!Malaria.!!
All!are!given!orally,!hepatic!metabolism.!
Side'effects!are:!Hemolytic!anemia,!GI!disturbances!(rare),!rash!and!
headache!!safe!agents.!

'
AntiOAmebiasis'drugs:!!
It's!an!infection!of!intestinal!tract!caused!by!Entamoeba!histolytica.!The!
diagnosis!is!done!by!isolating!E.!hestolytica!from!feces,!can!form!cysts!
(mainly!in!the!liver).!
The!best!agents!used!for!treatment!of!amebiasis!are:!
o Paramomycin'!work!only!in!the!intestines.!!
o Metronidazole'!mixed!action,!systemic!and!luminal!and!is!the!
best!known!drug.!!
o Chloroquine'7!used!to!treat!the!liver!abscesses!formed!by!the!
cysts!(also!anti7Malarial).!!
o Emetine'!same!as!chloroquine.!Side!effects!may!include!GI!
disturbances,!rash!and!headache.!!
!
AntiOTrichomoniasis'''
For!the!treatment!of!the!STD!caused!by!T.Vaginalis!we!use!metronidazole.!
Anti7trionosomiasis!!fatal!disease!(known!as!sleeping!disease)!caused!by!
the!agent!T.brucei!or!T.!gamebiasis,!which!invade!the!CNS!and!cause!
inflammation!of!the!brain!and!spinal!cord!thus!producing!lethargy!and!
continuous!sleep.!The!vector!for!it!is!the!Tse7Tse!fly.!!
Drugs!used!are:!!
o Nifurtimox'!for!the!T.!crusi!infection!(Chaga's!disease),!produces!
free!radicals!and!may!lead!to!hypersensitivity.!!
o Suramine,'Pentamidine'and'Melarsoprol'!they!inhibit!the!
agents!enzymes,!decrease!DNA!synthesis!and!lead!to!energy!
metabolism!disorders.!!Side!effects:!nausea,!vomiting,!hypotension,!
ferility,!purpura.!!
AntiOLeishmaniasis''
Caused!by!leishmania!transmitted!by!the!sand!fly!vector!and!can!be!
!cutaneous!and!visceral.!The!agent!invades!Macrophages!!multiply!and!
destroy!them!!invade!new!Ma.!!
Drug:!Sodium'stibogluconate'!inhibit!the!parasites!glycolysis.!
!
AntiOHelmitic:'!
These!drugs!use!as!narcotizing!&!paralytic!agents!for!the!worm,!leading!to!
inability!of!the!worm!to!adhere!to!the!intestinal!wall!thus!removed!in!the!
feces.!Other!mechanisms!are!inhibition!of!protein!secretion!&!glucose!
transport!or!interference!with!microtubular!arrangement.!
The!worm!can!be!either!in!the!intestines!or!in!the!tissue!in!the!cystic!form!
(mainly!liver!and!muscles),!thus!require!usually!also!careful!surgery.!!
Effective!drugs!are:!
o Benzimidazole'7used!for!helmitoses!in!general.!!
o Ivermectin'7!used!for!onchocerciasis!(liver!blindness)!!
o Praziquantel'!used!for!schistosomiasis!All!anti7helmitic!drugs!
are!contraindicated!in!pregnancy!!!!
!
14. Effects'of'age'and'disease'on'drug'disposition'

There!are!may!factors!that!may!influence!the!metabolism!of!a!drug!in!the!
body,!age!and!disease!state!are!2!of!those!factors.!
o Age:'it!is!relevant!for!2!age!groups!mainly,!to!the!pediatric!(mainly!
newborns)!and!geriatric!patients.!
! Pediatric!patients!!there!are!insufficient!liver!functions,!
glucoronization!is!insufficient,!there!is!high!amount!of!
extra7cellular!fluid!and!decreased!renal!functions!and!
glomerular!filtration,!all!these!lead!to!decreased!
metabolism!of!a!drug,!and!to!decrease!excretion!of!a!drug!
(elimination).!!Some!examples!include!chloramphenicol!!
leading!to!gray!baby!syndrome!and!aspirin!!leading!to!
Reye's!syndrome.!!
! Elderly!patients!!there!is!an!age!dependent!decrease!in!
liver!functions,!associated!with!normal!aging,!disease!state,!
substance!abuse,!co7morbidities.!!In!patients!>!70!years!of!a!
age!the!drugs!accumulate!in!the!kidney!due!to!decrease!in!
GFR!and!tubular!secretion,!together!with!the!decrease!in!
liver!function,!requiring!dose!adjustment!of!the!drug!in!
order!to!reach!the!therapeutic!effect!and!not!the!toxic!effect.!
!There!is!also!decrease!in!other!factors,!such!as!platelet!
count!or!RBC,!requiring!decrease!in!agent!such!as!Warfarin.!!
o Disease'state:'in!systemic!diseases!that!damage!the!kidneys,!liver!
or!heart!there!is!a!possibility!for!accumulation!of!harmful!
substances!in!the!body!with!decrease!elimination,!thus!all!patient!
with!a!severe!disease!state!require!dose!adjustment.!
! Renal'failure!!uremia!!increased!BBB!penetration!
drugs!accumulate!in!the!kidney!!intoxication.!!
! Cardiac'failure!!decreased!tissue!perfusion!!decreased!
elimination!!activation!of!RAS!!elevated!plasma!levels!of!
a!drug!!toxicity.!
! Liver'disease!!impaired!metabolism!and!glucoronization!
!intoxication.!
! Liver!disease!may!also!lead!to!decreased!albumin!
production,!increasing!the!free!drug!in!the!plasma,!leading!
to!side!effects.!As!well!there!is!a!reduction!in!clotting!
factors,!leading!to!bleeding!tendencies!(think!about!it!
before!giving!Warfarin).!
o Genetic'factors:'pharmacogenetics!is!a!branch!in!pharmacology!
that!study!the!effect!of!genetic!polymorphism,!or!genetic!variations!
over!the!drug!activity,!or!the!activity!of!the!drug!over!the!body.!
! Genetic'polymorphism!!variations!of!genes!coding!for!
various!proteins!in!a!population,!in!pharmacology!it!can!
affect!pharmacokinetics!(transport,!protein!binding,!
metabolism)!and!pharmacodynamics!(ion!channels,!
receptor!variations,!enzymatic!problems,!etc).!!The!best!
studied!is!the!metabolism!at!the!P450!enzymatic!location,!
on!the!smooth!ER!of!the!liver!cells!which!can!affect!large!
spectrum!of!metabolizing!enzymes.!!

From!the!point!of!view!of!metabolism,!the!CYP450!has!60!
genes!with!only!8!relevant!in!pharmacology.!The!enzyme!
with!the!biggest!polymorphism!in!the!society!is!CYP2D6,!
the!second!biggest!enzyme!system!responsible!for!the!
metabolism!of!20%!of!the!drugs,!its!function!is!to!catalyze!
hydroxylation!of!demethylation!(beta!blockers,!
antiarrhythmics,!analgestics).!!There!are!3!types!of!
metabolizers!in!the!society:!extensive'metabolizers!(EM!!
most!of!the!society),!poor'metabolizers!(accumulation!of!
drugs),!ultra'extensive'metabolizers!(lower!effect!of!drug!
!mostly!Saudi!Arabians).!!
From!pharmacodynamic!point!of!view,!there!can!be!
receptor!polymorphism!(can!decrease!or!increase!reaction!
to!drug),!enzymatic!problems!(G6PD7!haemolytic!anemia),!
etc.!!

'
'
'
'
'
'
Nonsteroidal'antiOinflammatory'drugs;'
Inflammation!is!a!protective!response!to!tissue!injury!and!repair.!
Inflammation!may!be!triggered!by!non7harmful!agents!(pollen),!or!as!an!
autoimmune!reaction!(rheumatoid!arthritis).!
Anti!inflammatory/immunosuppressive!drugs!are!used!to!suppress!the!
reactions.!!
Main!chemical!mediators:!PGs!and!LTs.!Inflammatory!disease!will!
improve!when!treated!with!anti!inflammatory!drugs.!Immune7
suppressants!(corticosteroids!and!methotrexate)!may!be!used!to!
counteract!inflammation.!
All!NSAID's!are!able!to!inhibit!COX,!lowering!PGs!level.!!
Classification:!
AcetylOSalycilic'acid'(ASA):'rapidly!and!irreversibly!inhibits!COX!non7
selective.!Aspirin!resets!thermostat!of!the!body!!the!heat!dissipation.!
Effects'(dose):'!
o ANTI7AGREGGATORY!(!platelet!aggregation),!!TIAs!and!strokes,!
!death!due!to!ischemic!attack!or!myocardial!infarction!and!
neonatal!m.i.!or!unstable!angina!pectoris,!!cardiovascular!risk!
with!revascularization!procedures;!!
o ANTI7PYRETIC;!ANALGESIC!!!PGE2!synthesis!(headache,!
arthralgia,!myalgia);!
o !ANTI7INFLAMMATORY(gout,!RF,!RA,!osteoarthritis);!!
o POSSIBLY!ANTI7CANCER;!external!applications:!topically!for!corns,!
calluses!and!warts.!
Effect'on'platelets:'(TXA2!!platelet!aggregation!while!PGI2!!it).!!Low!
doses!of!aspirin!inhibit!thromboxane!production!in!platelets!via!
acetylation!of!the!cyclooxygenase!>!platelet!aggregationanticoagulant!
effect!with!prolonged!bleeding.!!

Actions'on'the'kidney:'COX7!inhibitors!prevent!synthesis!of!PGE72!and!
PGI72;!these!prostaglandins!are!responsible!for!maintaining!renal!blood!
flow!in!the!presence!of!circulating!vasoconstrictors!!!Pgs!!!retention!
of!sodium!and!water!!cause!EDEMA!and!HYPERKALEMIA.!
Adverse'effects:!
1)!Gastric!ulcer!(!protective!function!of!PGs!in!stomach);!!
2)!respiratory!depression!+!(respiratory!and!metabolic!acidosis);!!
3)!In!very!high!doses!!tinnitus,!fever,!hyperthermia.!!
4)!Hypersensitivity:!15%!of!patients!taking!aspirin!get!hypersensitivity!
reactions!(allergy,!urticaria,!bronchoconstriction,!angioedema)!!
5)!Reyes*syndrome:!fulminating!hepatitis!with!cerebral!edema!when!child!
gets!salycilates.!!
Contraindications:'to!avoid!in!PREGNANCY!and!BREAST7FEEDING!time,!
exclude!any!drug!interaction!with!WARFARIN,!PHENYTOIN!or!VALPROIC!
ACID,!avoid!chronic!aspirin!in!patient!which!already!receive!PROBENECID!
or!SULFINPYRAZONE;!to!avoid!for!at!least!6!weeks!in!children!that!
received!live!varicella!virus!vaccine!!prevent!REYES!syndrome.!!
!
!
!
!
Pharmacokinetics:'!
o A)!oral!administration!(unionized!salicyclates)!7!passively!
absorbed!from!the!stomach!and!the!small!intestine/!liver/!kidney,!
half!life!3.5h.!!!
o B)!rectal!absorption!!slow!and!unreliable,!but!useful!for!vomiting!
children.!!
Dosage:'2!tablets!x!325!mg!x!4times!daily!=!ANALGESIA;!12720!tablets!x!
day!=!analgesic!and!anti7inflammatory!activity.!!Reversible!COX!inhibitors!
7!inhibits!the!!synthesis!of!prostaglandins!but!not!of!leukotrienes.!(others:!
naproxen,!fenoprofen,!ketoprofen,!flurbiprofen!and!oxaprozin).!!

!
b)!PROPIONIC'ACID'derivatives!
(IBUPROFEN):!
Effects:'ANALGESIC,!ANTI7PYRETIC,!ANTI7INFLAMMATORY,!+!they!can!alter!
platelet!function!and!prolong!bleeding!time.!!
Pharmacokinetics:'oral!administration,!bound!to!serum!albumin,!liver/kidney!
excretion.!!
Adverse'effects:'Less!side!effects!than!aspirin,!GI!(dyspepsia,!bleeding)!is!most!
common.!!
Side'effects:'CNS!involvement!like!headache,!tinnitus,!dizziness.!
!
c)!ACETIC'ACID'derivatives!
(INDOMETACINE,!
SULINDAC,'ETODOLAC):!
Inhibiting!the!COX.!(not'used'for'low'fever!)!Effects:'ANALGESIC,!ANTI7
INFLAMMATORY!and!ANTI7PYRETICS.!Used'for:'treatment!reserved!for!ACUTE!
GOUTY!ARTHRITIS,!AKYLOSING!SPONDYLITIS!and!OSTEOARTHRITIS!OF!THE!
HIP!due!to!its!toxicity.!Adverse'effects:'similar!to!NSAIDs,!less!common!GI!
problems!and!toxicity.!
Reversibly!
!

d)!COX2'selective'NSAIDs!
(COXibs)'CELECOXIB:!
DEPENDENT!inhibition!of!COX2.!Effects:'treatment!of!RA,!OSTEOARTHRITIS!and!
PAIN;!Lower!risk!of!GI!bleeding!and!Dyspepsia,(lost!when!added!
ASPIRIN)!Doesnt'inhibit'platelet'aggregation'and'doesnt''bleeding'time!!
'
Pharmacokinetics:!colecoxib!is!readily!absorbed,!half7life:11h,!peak!in!3h,!
metabolized!in!the!LIVER!by!cyt.!P7450,!excreted!by!feces!and!urine.!CI:!IHD'or!
STROKE'(!level!of!prostacyclines!!!platelet!aggregation);,!moderate!hepatic!
impairment(reduced!to!50%),!avoid!in!severe!hepatic!and!renal!disease.!
Contraindicated!in!patients!with!allergies!to!sulfonamides.!
Adverse'effects:'headache,!dyspepsia,!diarrhea!and!abdominal!pain.!
!
Cardiac'glycosides'
This!is!an!important!class!of!naturally!occurring!whose!actions!are!both!
beneficial!and!toxic!to!the!heart.!To!these!agents,!the!clinically!relevant!are!
Digoxin!and!strophantin,!but!digoxin!is!almost!solely!used.!
!
The!Digoxin!enhance!the!cardiac!muscle'contractillity!(positive!inotropic)!and!
thus!increase!the!cardiac'output,!it!does!so!by!increasing!the!intracellular!
calcium!concentration.!Digoxin!is!a!naturally!occuring!substance!from!the!plant!
Digitalis'purpurae!(fox7glove!!.which!influence!the!sodium!and!calcium!ion!
flow!into!the!cardiac!muscle)!
It!is!a!very!toxic!substance!with!very!low!therapeutic!index!.!!
Digoxin!acts!by!inhibiting!the!ability!of!the!myocyte!to!actively!pump!
sodium!from!the!cell!!ant!the!ability!to!move!calcium!out!of!the!cell!by!
!
working!on!the!Na/K and!Na/Ca!exchangers.!!
It!is!administered!only!to!patients!with!severe!left'ventricular'systolic'
dysfunction,!thus!is!!used!only!in!left!heart!failure,!it!can!also!useful!in!
treating!arrhythmias!but!can!lead!to!!dangerous!arrhythmias.!!
Side!effects:!cardiac!toxicity,!arrhythmia!(bradyarrhythmia,!SA/AV!
block),!nausea,!!vomiting,!blurred!vision.!!
Contraindicated!in!case!of!arrhythmia!or!IV!calcium!application.!!
Risk'factors:!electrolyte!disturbances,!diuretics,!warfarin!(competition!
for!albumin),!renal!!failure,!myocarditis.!!
Treatment:!antiarrhythmic!(lidocaine!mainly),!drug!cessation,!digoxin!
antibodies!(digoxine!!immune!Fab).!!
!
15. Genetic'factors'influencing''drug'action;'
Genetic'factors:'!
Pharmacogenetics!is!a!branch!in!pharmacology!that!study!the!effect!of!
genetic!polymorphism,!or!genetic!variations!over!the!drug!activity,!or!the!
activity!of!the!drug!over!the!body.!
Genetic'polymorphism!!variations!of!genes!coding!for!various!proteins!
in!a!population,!in!pharmacology!it!can!affect!pharmacokinetics!
(transport,!protein!binding,!metabolism)!and!pharmacodynamics!(ion!
channels,!receptor!variations,!enzymatic!problems,!etc).!!The!best!studied!
is!the!metabolism!at!the!P450!enzymatic!location,!on!the!smooth!ER!of!the!
liver!cells!which!can!affect!large!spectrum!of!metabolizing!enzymes.!!

From!the!point!of!view!of!metabolism,!the!CYP450!has!60!genes!with!only!
8!relevant!in!pharmacology.!The!enzyme!with!the!biggest!polymorphism!
in!the!society!is!CYP2D6,!the!second!biggest!enzyme!system!responsible!
for!the!metabolism!of!20%!of!the!drugs,!its!function!is!to!catalyze!
hydroxylation!of!demethylation!(beta!blockers,!antiarrhythmics,!
analgestics).!!!
There!are!3!types!of!metabolizers!in!the!society:!extensive'metabolizers!
(EM!!most!of!the!society),!poor'metabolizers!(accumulation!of!drugs),!
ultra'extensive'metabolizers!(lower!effect!of!drug!!mostly!Saudi!
Arabians).!!
From!pharmacodynamic!point!of!view,!there!can!be!receptor!
polymorphism!(can!decrease!or!increase!reaction!to!drug),!enzymatic!
problems!(G6PD7!haemolytic!anemia),!etc.!!

!
Stimulants'of'CNS;'
There!are!2!groups!of!drugs!that!act!primarily!to!stimulate!the!CNS:!
A)PSYCHOMOTOR'STIMULANTS'O'Excitement,!Euphoria,!Fatigue,!
Motor!Activity.!
B)PSYCHOTOMIMETIC'drugs'or'HALLUCINOGENS'O'Change!Of!
Thinking,!Mood!And!Perceptual!state!(dream!like).!
'
A')PSYCHOMOTOR'STIMULANTS!
!METHYLXANTINES'7!Caffeine,!Theophylline'(tea),'Theobromine'(cocoa)'!
Mechanism'of'action:!
1)'Influx!of!Ca.!
2)'!in!cAMP!and!cGMP!(by!inhibition!of!phospodiesterase!+!blockade!of!!!
adenosine!receptors).!
CNS'O'(cortex!stimulation):!Allertness,''in'fatigue.In!high!doses!may!
lead!to!anxiety'and!tremors.!Tolerance!develops!fast!with!withdrawal!
syndromes!(caffeine)!7!fatigue!and!sedation.!
CVS'O'!HR'and!contractility(positive!inotropic!and!chronotropic!effects!
on!the!heart).!In!higher!dose!can!cause!arrythmia'and!tachycardia.!
Mild'diuretic'action'Ourinary!output!of!Cl7,!NA+,!K+.!
GIT'7!Stimulates!secretion!of!HCl!from!gastric!mucosa!!!acidity!
!Relaxation'of'SM'of'bronchioles'7!treatment!of!asthma!in!the!past;now!
B2!agonists!or!corticosteroids!!
'
PHARMACOKINETICS:!well!absorbed!orally!(can!across!placenta!and!
accumulate!in!the!mothers!milk)!metabolized!in!the!liver!and!excreted!in!the!
urine.!
SIDE!EFFECTS:!!INSOMNIA!!DEPENDANCE!!LETHAL!DOSE!AT!10g!(100!CUPS!
OF!COFFEE)!!!!!

!NICOTINE'O'(induce'the'highest'dependence)O'At!low!doses!cause!ganglionic!
stimulation!by!depolarization!leading!toAROUSAL!and!RELAXATION.!
At!high!doses!it!causes!ganglionic!blockade!leading!to!RESPIRATORY!PARALYSIS!
and!HYPOTENSION!due!to!MEDULLARY!PARALYSIS!!

CNS'7!some!degree!of!Euphoria,!Arousal!and!relaxation;!severe!
hypotension!and!respiratory!paralysis!in!high!doses!for!medullary!
paralysis.!
Peripheral'7!stimulation!of!sympathetic!ganglia!and!adrenal!medulla!
leading!to:!!
o BP.!
o 'HR'+'Vasoconstriction'of'blood'vessels'like'coronary'aa.'!
o 'bowel'activity.'!
o At'high'dosesO'BP'falls'and'all'Motility'stops,'dependance,'
addiction,'tolerance.'The'lethal'dose'is'60'mg!
PHARMACOKINETICS:!lipid!soluble=!absorption!can!occur!via!oral!
mucosa,!lungs,!GIT!mucosa!and!skin;!(mothers!milk!accumulation)!>!
methabolism!of!lung!and!liver!!excreted!by!urine.!!!
SIDE'EFFECTS:!TREMOR,!INTESTINAL!CRAMPS,!HYPERTENSION.!!

!COCAINE:!!
Block!of!reuptake!of!monoamine:!norepinephrine,!epinephrine,!serotonin!
and!dopamine(Do),connecting!to!the!monoaminergic!reuptake!
transporters!!potentiates!and!prolongs!the!CNS!and!peripheral!actions:!
!Prolongs!dopaminergic!effects!on!limbic!system!!intense!euphoria;!!
Chronic!intake!of!dopamine:!!dopamine!!!
CNS'7!Well!being,!euphoria,!feeling!of!greatness.!!
Sympathetic'nervous'system'7!Fight!or!flight!response(!typical!
adrenergic!stimulation).!
Hyperthermia!!!!(impairs!sweating!and!cutaneous!vasodilatation).!
THERAPEUTIC'USES:!7!Local!anesthetic!on:!eye,!ear,!nose,!throat!
surgery.!Major!effects!of!cocaine!use:!euphoria!+!tachycardia!+!tachypnea!
>!agitation!+!hypertension!+!!dyspnea!!seizure!+!arrhythmias!+!
respiratory!failure!!DEATH!!!!!!!
PHARMACOKINETICS:!often!self!administered!by!chewing,!intranasal!
snorting!(powder),!smoking!(crack)!or!I.V.;!intranasal!intake!manifests!
effects!after!15720!min!and!lasts!for!171.5!h!while!IV!has!a!faster!onset!of!
the!effects!but!shorter!duration.!Then!it!is!de7esterified!and!demethylated!
!excreted!in!the!urine.!!
SIDE!EFFECTS:!ANXIETY!!DEPRESSION!!SEIZURES!TOXIC!EFFECTS!
and!CARDIAC!ARRHYTHMIAS.!Anatomically!the!damage!is!due!to!the!
VASOCONSTRICTION!!NECROSIS!AND!PERFORATION!of!the!NASAL!
SEPTUM!seen!by!chronic!inhalation!of!cocaine!powder!!
!AMPHETAMINE'!it!is!a!non7catecholaminergic!sympathetic!amine!with!
effects!clinical!and!neurological!like!cocaine,!2!main!drugs!are!used:!
METHAMPHETAMINE!and!DEXTROAMPHETAMINE.!
Inhibitor!of!MAO!(monoamine!oxydase)!!!amount!of!cathecholamine!
neurotransmitters!in!the!synaptic'space,!like!norepinephrine,!serotonin!
and!dopamine!!!response!of!action!on!CNS!and!in!periphery!
amphetamine!acts!on!the!adrenergic!system,!indirectly!stimulating!the!
receptors!through!norepinephrine!release!!

CNS'7!ALLERTNESS,!!FATIGUE!and!APETITE!CONTROL.!THERAPEUTIC!
USE:!ADHD'(is!also!used!methylphenidate!7!known!also!as!RITALIN);'
NARCOLEPSY.!
SIDE'EFFECTS:!DEPENDENCY/TOLERANCE!SCHIZOPHRENIA!
HYPERTENSION!ANOREXIA!NAUSEA,!VOMITING;!CONFUSION,!
INSOMNIA,!DIARRHEA,VERTIGO.!
PHARMACOKINETICS:!completely!absorbed!from!the!GIT!!metabolized!
in!the!LIVER!!excreted!in!the!URINE!

'
B)'PSYCHOTOMIMETIC'drugs'or'HALLUCINOGENS:!

!LSD'(LYSERGIC'ACID'DIETHYLAMINE):'stimulates!serotonin!(57HT!1!and!2)!
Receptors!!activation!of!sympathetic!nervous!system!!PUPULARY!
DILATATION,!!BP,!BODY!TEMP,!PILOERECTION.!May!lead!to:!
!
HALLUCINATIONS'with!brilliant!colors!+!MOOD!ALTERATION!(at!LOW!
doses!of!LSD)!!HALOPERIDOL!and!other!neuroleptics!(antidote!for!
hallucinations!induced!by!LSD).!Tolerance!and!physical!dependence!(true!
one!is!rare!
SIDE!EFFECTS:'HYPERREFLEXIA,!NAUSEA!and!MUSCULAR!WEAKNESS.!
!
!!THC'(marihuana):'THC=TETRAIDROCANNABINOL!available!as!
DRONABINOL.!
Lead!to!EUPHORIA(first)!!DROWSINESS!and!RELAXATION(second).!
Other'effects'are:'appetite!stimulation,!xerostomia,!visual!hallucinations,!
delusions!and!!in!sensory!activity.!
PHARMACOKINETICS:'the!THC!effects!appear!immediately!after!the!
drug!is!smoked,!maximum!effect!takes!about!20!min!and!lasts!for!3h!!
DRONABINOL!(oral!admin.!Has!peak!effect!in!2!to!4!h!and!lasts!even!for!6!
h,!but!appetite!persists!fro!24!h)!
SIDE'EFFECTS:'Tachycardia,!Hypertension,!Hallucinations,!Anxiety,!Panic!
in!long!term!use.!!
USAGE:'Treat!emesis!in!chemotherapy,!appetite!in!HIV!patients!and!in!
Glaucoma.!
!
Cephalosporins!
Semisynthetic!antibiotic!with!the!same!mode!of!action!as!penicillin,!but!they!are!
little!bit!more!resistant!to!beta!lactamase.!BACTERIOCIDAL!
!There!are!4!generations!of!cephalosporins.!!
1. generation:'act!as!PNC!G!substitute,!resistant!to!staphylococcal!
penicillinase!and!hasactivity!against!E.Coli!and!Klebsiella!pneumonia.!!
Drugs:!Cefazoline,'cephalexin.!
2. generation:'greater!activity!against!G7,!but!activity!agains!G+!is!weaker.!!
Drugs:!cefuroxime,'cefoxitin.!!
3. generation:'inhanced!activity!against!G7!bacilli,!and!even!P.!
aeroguinosa.!!Drugs:!ceftriaxone,!ceftazidime,!cefixime,!cefotaxime.!
4. generation:'must!be!administered!parenterally!only!!!!!!!and!has!wide!
antimicrobial!spectrum.!!Drugs:!Cefepime.!

These!drugs!administered!mostly!IM!or!IV,!but!some!can!be!given!orally,!
!
all!but!the!3. generation!do!not!cross!BBB!and!do!not!reach!therapeutic!
value!in!the!CSF,!excreted!by!the!kidney!(beside!ceftriaxone7!eliminated!in!
the!bile).!!
Side!effects:Its!main!side!effect!is!allergy,!but!it!may!also!lead!to!
pseudomembranous!colitis!(C.difficile)!due!to!dysmicrobia.!
Patients!allergic!to!penicillin!are!also!allergic!to!cephalosporin!!

16. Drug'interactions'(Pharmacokinetics);'
Drug!interactions!can!occur!on!the!pharmacokinetic!or!pharmacodynamic!
level,!they!can!be!a!!significant!cause!of!drug!related!problems!and!
contribute!to!both!morbidity!and!mortality.!!
High!risk!patients!for!drug!interactions!are!the!elderly,!because!they!
usually!have!co7!morbidity,!reduced!metabolism!and!accumulation!of!
substances!together!with!the!fact!that!they!are!usually!on!more!than!one!
drug.!!Children!are!also!in!increased!risk.!!
High!risk!drugs!for!drug!interactions!will!be!those!with!low!therapeutic!
index,!due!to!the!fact!that!any!increase!in!their!plasma!concentration!is!
dangerous!(i.e!Digoxin,'Warfarin).!
Pharmacodynamic'interactions:'these!are!competition!at!the!site!of!
activity!(receptor!level).!It!can!be!antagonist,!synergist!(additive)!or!
indirect!(diuretics!increase!plasma!levels!of!digoxin).!!
Pharmacokinetic'interactions:'it!is!when!one!drug!affects!the!
absorption,!distribution,!metabolism!or!excretion!of!another!drug,!thus!
leading!to!change!in!its!blood!concentration!and!effect.!!
o Absorption:*most!of!the!time!it!is!decrease!in!absorption,!due!to!
chelating!agents,!changes!in!gastric!pH,!dysmicrobia!and!by!side!
effects,!such!as!vomiting,!of!a!given!drug.!!
o !Distribution:*usually!due!to!competition!for!binding!to!plasma!
proteins!(Warfarin!+!NSAID's)!!usually!insignificant!due!to!the!
fact!that!the!increase!is!usually!transient!only!and!there!is!
increased!metabolism!in!order!to!compensate!the!increased!
plasma!levels.!!
o Metabolism:*some!drugs!are!either!inducers!or!inhibitors!of!
enzymes,!mainly!in!the!P450!system,!leading!to!altered!
metabolism!and!possible!harmful!effects.!!
! Substrate:!a!drug!which!is!metabolized!by!the!enzyme!
system.!!
! Inducer:!a!drug,!or!substance,!that!causes!an!increased!
activity!of!the!CYP!system!by!causing!increased!synthesis,!
thus!increasing!the!velocity!of!drug!metabolism!!Rifampin!
is!a!potent!inducer.!!
! Inhibitor:!drug!binds!to!the!CYP!isoenzyme!and!prevents!
binding!(and!therefore!metabolism)!of!the!substrate!drug.!
For!most!drug!interactions!the!inhibition!is!due!to!
reversible,!competitive!binding.!!For!example:!Grapefruit'
juice'inhibits!CYP3A4,!Cimentidine'inhibits!the!
metabolism!of!propranolol,!Amiodarone'inhibits!the!
metabolism!of!digoxin.!!

o Excretion:!may!be!influenced!by!change!in!the!active!excretion!by!
competing!for!the!same!transport!mechanism,!may!lead!to!change!
in!the!urine!pH!(used!for!treatment!of!salicylate!or!barbiturate!
poisoning)!and!thus!the!ionization!of!a!drug!and/or!may!change!
the!renal!blood!flow.!!
!
AntiOHistamine'&'AntiOEmetic;'
Histamine!is!a!chemical!messenger!that!mediate!cellular!responses!as!
allergy,!HCL!secretion!and!neurotransmitter!in!some!parts!of!the!brain.!It!
is!found!in!high!concentration!in!mast!cells!and!basophils,!synthesized!
from!histidine!and!stored!in!intracellular!granules,!it!is!released!by!
destruction!of!cells!(trauma,!cold)!and!as!a!response!to!an!allergen!(type!1!
hypersensitivity).!!
Histamine!binds!to!the!one!of!the!receptor!H17H4,!while!H1!and!H2!are!
most!widely!expressed,!the!histamine!receptors!are!G!protein!type.!H1!
mediated!smooth!muscle!contraction!and!increase!capillary!permeability!
while!H2!are!important!for!gastric!acid!secretion.!!
'
H1'antihistamines:'!
This!is!what!people!mean!when!the!say!antihistamines,!they!are!H1!
receptor!blockers!and!divided!into!first!and!second!generations.!
1.!Generation:!still!widely!used,!but!they!penetrate!CNS!and!cause!
sedation!!(chlorphenyramine,'diphenhydramine,'promethazine).!!
2.!Generation:!specific!H1!that!to!not!penetrate!the!CNS!(loratadine,!
fexofenadine).!!These!drugs!are!used!against!allergy,!motion!sickness!
and!nausea!(1.generation)!and!insomnia!(1.generation7!sedatives).!
1.generation!can!bind!cholinergic,!alpha!adrenergic!and!
serotoninergic!receptors!leading!to!side!effects.!Side'effects:!
cholinergic!(xerostomia,!urinary!retention,!tachycardia),!adrenergic!
(hypotension,!reflex!tachycardia),!serotonin!(increased!appetite),!
histamine!(sedation).!!
H2'antihistamines:'
Antagonists!to!H2!receptors!in!the!stomach!and!inhibit!the!binding!of!
histamine!to!H2!receptors,!thus!inhibiting!the!production!of!HCL!for!the!
treatment!of!ulcers!and!reflux.!By!binding!the!receptor!they!competitively!
decrease!the!levels!of!cAMP!and!secretion!of!gastric!acid.!
These!drugs!are!less!potent!then!PPI's!and!are!less!commonly!used!today,!
because!they!do!not!inhibit!gastrin!receptors!or!Ach!receptor!so!there!is!
still!some!degree!of!acid!production.!!Drugs:!cimetidine,'ranitidine,'
famotidine.'
'
Antiemetics!
In!chemotherapy!emesis!must!be!controlled,!uncontrolled!emesis!can!
produce!dehydration,!rejection!of!curative!drug,!metabolic!imbalance!and!
nutrient!depletion.!
There!are!2!brainstem!sites!that!have!key!role!in!vomiting!as!well!as!the!
peripheral!receptors:!!
o The!chemoreceptor!trigger!zone!in!the!4.!ventricle.!!

o The!vomiting'center,!located!in!the!reticular!formation!and!
coordinates!motor!mechanisms!!of!vomiting.!!
o The!receptors!will!be:!57HT3,!M1!D2!and!H1!Drugs!effective!
against!emesis!are:!!
Phenothiazines:!act!by!blocking!dopamine!receptors,!effective!against!
low!to!moderate!emesis!!drug!is!prochlorperazine.!!
5OHT3'receptor'blockers:!they!have!long!duration!of!action!and!are!very!
effective!against!vomiting,!they!are!metabolized!in!the!liver!and!excreted!
in!the!urine!!all!drugs!end!with!7setron!(granisetron,'dalasetron,'
ondansetron).!!
Butyrophenones:!act!by!blocking!dopmine!receptor!!prototype!drug!is!
Halloperidol.!!
Benzodiazepines:!have!low!anti7emetic!properties,!mostly!sedatives,!
anxiolytics!and!amnestics!!!prototype!drug!is!Lorazepam.!!
Corticosteroids:!used!in!drug!combination,!effective!against!emesis!but!
their!mechanism!of!action!is!unknown!!drugs:!methylprednisone,!
dexamethasone.!
Cannabinoids:!effective,!but!can!cause!hallucination,!sedation,!
dependance,!etc.!can!be!used!as!medicinal!marijuana!or!as!marijuana!
derivatives!!dronabinol.!!
Substance'P/neurokininO1'receptor'blocker:!blocks!the!neurokinin!
receptor!in!the!CNS!and!block!its!action!!drug!is!Aprepitant.!
Of!course!almost!any!disease!can!cause!vomiting,!so!we!need!to!treat!the!
underlying!cause,!either!GIT,!ICH,!infection,!or!motion!sickness!with!the!
appropriate!drugs,!such!as!diuretics,!chelating!agents!or!anti!motion!sickness!
(scopolamine).!
Drugs' used' in' the' treatment' of' neoplastic' diseases' (principles' of' action,'
classification,'therapeutic'uses)'
Tumor!cells!are!characterized!by!an!uncontrolled!proliferation,!
differentiation!and!loss!of!function,!they!can!be!invasive!and!to!
metastasize!and!lead!to!angiogenesis.!
The!tumor!cells!arise!from!over!activity!of!oncogenes!or!under!activity!of!
tumor!suppressor!genes!(p53,!p16)!and!it!may!arise!due!to!radiation,!
viruses,!bacterial!infection,!chemicals,!free!radicals!and!drugs.!
Tumors!may!be!divided!into:!
Chemo7sensitive.!!
Intermediate!chemo7sensitive.!!
Chemo7resistant.!!
!
Response!to!chemotherapy!depends!on:!!
Fraction!of!proliferating!cells,!tumor!mass,!cell!cycle!rate,!synchronization!
of!cell!cycle!within!the!tumor,!resistance!of!tumor!cells!(deactivation,!DNA!
repair,!efflux).!!
!
Anti!cancer!drugs!are!divided!according!their!mechanism!of!action!to:!!!
!Alkylating'agents:'!!Cyclophosphamide!!after!activation!in!the!liver!
(prodrug)!it!cross!link!with!the!DNA!to!damage!it,!given!orally!and!may!lead!to!
alopecia,!nausea,!vomiting,!bone!marrow!depression,!etc.!!!
!

!AntiOmetabolite:'structural!analogs!of!purines!and!pyrimidines!causing!
synthesis!of!defective!nucleic!acids!and!folic!acid.!!
!
# Methotrexate!!antagonist!of!folic!acid,!work!by!inhibiting!DiHydroFolate!
Reductase!(DHFR),!thus!inhibiting!folic!acid!from!becoming!tertahydrofolic!
acid!(FH4).!May!lead!to!stomatitis,!myelosuppression,!erythema,!rash,!
urticaria!and!alopecia!(preventable!with!Leucovorin),!nephrotoxicity,!
hepatotoxicity,!pulmonary!toxicity!and!neurotoxicity.!
!
!!Cytotoxic'ATB's:'cytotoxic!action,!primarily!by!interactions!with!the!DNA,!
leading!to!disruption!of!DNA!function!and!inhibiting!topoisomerase!1!and!2!
(uncoiling)!!free!radicals.!!!Bleomycin.!!!Dactomycin.!!
!
!!Mitosis'inhibitors'(microtubules):'derivatives!from!a!plant!called!Vinca'
Rosea,!thus!they!are!!vinca!alkaloids,!interfere!with!microtubular!apparatus.!May!
lead!to!cellulitis!and!phlebitis.!!Drugs!are:!Vincristine'and'Vinblastine.'!
!
!!Topoisomerase'inhibitors:'Topotecan.!!
!!Hormones:'tumor!can!be!hormone!responsive,!hormone!dependent!or!both.!!
!Glucocorticoids!!prednisone.!
!Tamoxifen!7!estrogen!antagonis,!in!estrogen!dependent!breast!cancer.!
!
!!Protein'kinase'inhibitors''Imatinib,!against!growth!factor.!!
!!Monoclonal'antibodies:'effects!the!angiogenesis!or!direct!against!tumor!cells.!
!Drugs:!Bevacizumab,'Rituximab,'Cetuximab.'May!lead!to!myelosuppression,!
bleeding,!susceptibility!for!infections,!alopecia,!nausea,!!vomiting!and!many!
more.!!
!
17. Discovery'of'drugs.'Evaluation'of'drugs;'
Drug'discovery:'it!is!the!process!by!which!drugs!are!discovered!and!
designed.!
In!the!past,!most!drugs!were!discovered!by!identifying!the!active!substance!
from!traditional!remedies!or!by!screening!of!thousands!of!naturally!occurring!
substances!for!biological!effect.!
Today,!as!scientists!and!doctors!are!well!aware!of!the!molecular!basis!of!
disease!and!its!pathophysiology!there!is!the!possibility!to!synthesize!specific!
compounds!to!interact!in!the!molecular!level.!The!process!of!drug!discovery!
involves!the!identification!of!candidates,!synthesis,!characterization,!
screening,!and!assays!for!therapeutic!efficacy.!Once!a!compound!has!shown!
its!value!in!these!tests,!it!will!begin!the!process!of!drug!development!prior!to!
clinical!trials.!
Evaluation'of'drugs:'or!drug!development!is!the!process!that!come!after!the!
process!of!drug!discovery!and!include!pre7clinical!research!
(microorganisms/animals)!and!clinical!trials!as!well!as!the!approval!for!drug!
safety!and!marketing.!
'
PreOclinical'research:'

Little!is!known!after!drug!discovery!about!the!pharmacokinetics,!safety,!
toxicity!of!the!newly!discovered!drug,!so!this!is!why!these!trials!are!
conducted!as!well!as!to!determine!the!dose!and!dosing!intervals.!
It!is!conducted!on!animal!subjects!(rats,!mice,!monkeys,!dogs)!and!is!used!
mainly!to!determine!the!dose,!route!of!administration,!type!of!drug!(tab.,!
lozz.,!capsule,!etc),!toxicity,!major!organ!toxicity,!lethality,!etc.!
It!evaluates:!
o Acute!toxicity:!by!calculating!LD50!(lethal!dose!for!50%!of!the!
subjects).!!
o Sub7actue!toxicity:!toxic!manifestations!in!lower!doses.!!
o Chronic!manifestation:!to!determine!carcinogenesis!or!
teratogenicity!properties.!!!Therapeutic!index:!TD50!/!ED50.!!

Pharmacokinetic'and'metabolic'processes.'
!Clinical*trials:!
Involve!3!steps!of!evaluation!+!the!4.!step!of!marketing!approval.!
o Phase'1:!explorative!evaluation:!usually!done!on!healthy!
individuals!and!is!made!in!order!to!define!the!safety!and!dosing,!
best!route!of!administration!and!pharmacokinetics.!!
o Phase'2:!controlled!clinical!evaluation,!used!to!study!the!toxicity!
and!efficacy!of!a!drug!compared!to!placebo!drug!and/or!other!
drugs.!!
o Phase'3:!extended!clinical!evaluation,!involve!large!group!of!
people,!last!many!years!and!study!the!chronic!use!and!the!
risk:benefit!ratio.!!
o After!all!these!stages!of!evaluation!are!finished,!it!is!possible!to!
send!a!request!for!approval!of!the!drug!for!marketing.!
o Phase!4:!post!marketing!surveillance,!collection!of!data!regarding!
efficacy!and!adverse!reactions!(usually!for!the!rare!adverse!
reaction!that!did!not!came!up!during!the!clinical!trials).!
'
General'anesthetics;'
Absence!of!pain!sensation!with!loss!of!consciousness!!
Preanaesthesia:!myorelaxants,!benzodiazepines!(prevents!anxiety),!
parasympatholytics!(atropine),!analgesics,!H27blockers!(prevents!ulcers)!
o 3!stages:!induction!(thiopental),!maintenance,!recovery!!
Depth'of'anaesthesia:''
1. Analgesia:!loss!of!pain!
2. Excitement:!increase!BP,!increase!respiratory!rate,!unconsciousness!!
3. Surgical:!state!of!relaxation!!
4. Medullary!paralysis:!depression!of!respiratory!centre/vasomotor!centre;!
death!within!minutes!!
'
Drug'classes:''
1. Inhalation'anaesthetics:!mechanism!=!volume!expansion!theory!
a. Halothane7!weak!anaelgesic7!hepatotoxic,!malignant!
yyperthermia!(occurs!when!combined!with!succinylcholine7!
antidote!=!dantrolene)!

b. Isoflurane7!drug!of!1st!choice!(does!not!induce!arrhythmia),!
hypotension!
c. Enflurane7!may!cause!convulsions,!CI!in!epileptic,!psychiatric!and!
renal!failure!patients!due!to!excretion!via!kidney!(fluoride!ions)!
d. NO7!strong!analgesic!+!weak!anaesthetic,!combination!with!other!
drug!!
e. Side'effects:!malignant!hyperthermia!!
2. Intravenous'anaesthetics:!mechanism!=!effect!on!receptors:!!
a. Barbiturates/BZD7!GABA!
b. Ketamine7!blocks!glutamate!
c. Thiopental7!quick!inducer,!CI!with!alcohol,!coughing!(no!analgesic!
effect),!laryngospasm,!cardiac!depression7!decreased!CO,!decrease!
BP!
d. Ketamine7!mainly!children!for!short!procedures;!adverse!effects:!
recovery!includes!hallucinations,!disorientation,!amnesia!!

'
Mechanism'of'action'of'antibiotics,'resistance,'classification.'
Antibiotic!therapy!utilizes!the!differences!that!exist!between!humans!and!
microorganisms!or!simply!put!they!have!the!ability!to!injure!or!kill!
invading!microbes!without!hurting!the!patient!(selevtive!toxicity!!not!
absolute).!!
The!differences!are!cell!wall,!different!ribosomes,!different!enzymes!(e.g.!
topoisomrases),!etc.!
For!the!appropriate!selection!of!antibiotics!we!need!knowledge!of!the!
organism,!its!susceptibility,!the!main!site!of!infection,!the!patient!factors,!
the!safety!of!an!agent!and!its!cost.!
!
!
o Identification!!gram!stain,!PCR,!culture,!FISH,!serology,!etc!
o Empiric!therapy!!an!educated!guess,!used!in!critically!ill!patients,!
take!sample!and!immediately!initiate!therapy!
o Antimicrobial!susceptibility!!obtained!after!culture,!can!be!
bacteriostatic'(arrest'growth)'or'bacteriocidal'(kill'bacteria).!
! MIC!!the!minimal!inhibitory!concentration!that!inhibits!
bacterial!growth.!!
! MBC!!the!minimal!bacteriocidal!concentration.!
o Physical'factors!!lipid!solubility,!size,!ionization,!protein!binding!
of!a!drug.!
o Patient'factors!!immune!state,!co7morbidities,!pregnancy,!age,!
renal!or!hepatic!dysfunction.!!
Drug!can!be!administered!IV,!IM,!SC,!PR,!PO,!SL,!PV!(per!vagina)!and!the!
dose!is!based!on!the!pharmacological!properties!of!the!drug!and!the!
patient!factors.!
'
Mechanism'of'action'
1. Inhibition!of!cell!wall!synthesis:!PNC,!chephalo,!vancomycin!
2. Inhibition!of!cell!membrane:!polymixines!
3. Interference!with!protein!synthesis:!macrolides,!aminoglycosides,!
chloramphenicol,!Linezolid!

4. Inhibition!of!DNA!synthesis:!quinolones,!rifampicin,!sulphonamides!
Mechanism'of'resistance'
1. Enzymes:!B7lactamase/penicillinase!!
2. Change!of!cell!wall!permeability!!
3. Increased!synthesis!of!antagonist:!folic!acid!by!altering!pathway!
4. Change!of!PNC!binding!protein!(PBP)!
Classification'
1. According!to!mechanism:!!
a. Inhibition!of!protein!synthesis:!tet,!amn,!macr,!linc!
b. Inhibition!of!folic!acid!synthesis:!sulf!
c. Anti7DNA!synthesis:!quinolones!!
d. Anti7staph:!PNC,!vancomycin!
2. According!to!spectrum!!
a. Broad!(G+!and!G7):!tet,!macro,!sulf,!cephalo!
b. Narrow!(G7!or!G+):!amino,!quino,!anti7staph!
3. Bacteriocidal:!amino/quino/penicillins!;!Bacteriostatic:!tet/macro/dapto!
(anti7staph)!
'
Toxic'effects:''
1. Allergy:!PNC,!cephalo,!sulphonamides!
2. Superinfection:!broad!spectrum!ATB,!tet,!cephalosporin!
(pseudomembranous!colitis)!
3. Hematotoxicity:!hemolysis,!chloramphenicol!(aplastic!anaemia,!grey!baby!
syndrome)!
4. Nephrotoxicity:!AMP,!ceph,!amino!
5. Ototoxicity:!strep,!aminog!
6. Neurotoxicity:!strep,!rifampicin!
7. GIT:!colitis!(ceph,!ery)!
8. Jerish7herxheimer:!PNC!in!treatment!of!syphilis!
9. Hoigne!syndrome:!embolization!to!lungs!PNC!
10. Nikelow!syndrome:!embolization!to!leg!veins!
11. Phototoxicity:!TTC,!sulfonamines,!quinolones!!
!
!
!
!
!
!
!
18. Harmful'effects'of'drugs'(toxic'effect'of'drugs);'
Directly!related!to!pharmacodynamics!
!
7predictable!!
!
7dose!dependent!!
Indirectly!!toxic!effects!!
1.'augmented''
Intoxication,!Most!common,!dose!dependent!mechanism,!preasias!!after!
long!term!antipsychotics!(predictable,!e.g.!bleeding!after!warfarin!(avoid!
by!predict!predisposing!factors!use!lower!doses)!
2.'bizarre''

Not!predictable,!not!dose!dependent,!rare,!increase!mortality!rate,!elg.!
Haemolysis!in!G6PD!deficiency,!take!drug!history,!take!family!history,!
avoid!certain!drugs!in!disease!
3.!Continuous!!
Due!to!long!term!use!e.g.!tardive!dyskinesias!(after!long!term!
antipsychotics/neuroleptics!use)!
4.!delayed!!!
After!use!e.g.!carcinogenesis!!uterine!in!breast!cancer!after!oestrogen!
use,!teratogenesis!!thalidomide!!antiemetic!!
5.!End'of'use!!withdrawal!symptoms!!
'
Classification'of'side'effects':''
Mild:!no!need!for!interruption!e.g.!sedation!with!antihistamines!!
Middle:!changes!of!regimen!needed!e..!nausea!after!iron!
Severe!interruption!is!mandatory!e.g.!myelosuppression!after!anti7cancer!drugs!!
!
Toxic'effects:''
1. Allergy:!PNC,!cephalo,!sulphonamides!
2. Superinfection:!broad!spectrum!ATB,!tet,!cephalosporin!
(pseudomembranous!colitis)!
3. Hematotoxicity:!hemolysis,!chloramphenicol!(aplastic!anaemia,!grey!baby!
syndrome)!
4. Nephrotoxicity:!AMP,!ceph,!amino!
5. Ototoxicity:!strep,!aminog!
6. Neurotoxicity:!strep,!rifampicin!
7. GIT:!colitis!(ceph,!ery)!
8. Jerish7herxheimer:!PNC!in!treatment!of!syphilis!
9. Hoigne!syndrome:!embolization!to!lungs!PNC!
10. Nikelow!syndrome:!embolization!to!leg!veins!
11. Phototoxicity:!TTC,!sulfonamines,!quinolones!!
!
Local'Anhesthetics;'
Generally!applied!locally!and!block!nerve!conduction!of!sensory!impulses!
from!the!periphery!to!the!CNS.!Reversible!loss!of!sensation.!Works!on!the!
pathway!to!dorsal!horn.!GA!on!the!pathway!to!cortex.!It!selectively!binds!
to!the!intracellular!surface!of!Na!channels!and!blocks!the!entry!of!Na!
causing!block!of!depolarization.!
Weak'base:!
o Non!ionized!=!able!to!cross!membranes,!in!acidosis!LA!becomes!
ionized!and!are!unable!to!!cross!the!membrane.!!
o After!penetration!to!the!cell,!the!LA!becomes!ionized!and!trapped!
in!the!cytosol.!!
Action'of'various'nerves:'works!faster!in!small!diameter!nerves,!rather!
than!large!diameter.!
o Fiber!A!7!pain,!thermal!and!tactile!sensation:!largest!and!last!to!be!
influenced.!!
o Fiber!B!7!Autonomic!paralysis!(causes!vasodilatation):!
preganglionic.!!

o Fiber!C!!Touch,!Itchy!pain.!(smallest!diameter,!influenced!first):!
postganglionic.!!!
Note:!local!anesthetics!are!always!combined!with!adrenaline!to!promote!
vasoconstriction!and!to!prevent!the!absorption!of!the!drug!to!the!
systemic!circulation,!unless!given!intrathecally.!!

!
Classification:!
Esters:!!
o Procaine,!Tetracaine!(cocaine!derivatives)!!Metabolized!in!
plasma!by!!pseudocholine!esterase,!they!have!high!allergic!profile!
and!short!half7life.!!
Amides:!!
o Lidocaine,'Ropivacaine,'Mevicaine.'These!can!be!hepatotoxic.!!
!
Methods'of'application:!
Topical!7Skin!or!mucosa.!Nasal,!eye,!rectum.!May!use!higher!
concentration!because!no!systemic!absorption!(Tetracaine,!Lidocaine).!!
Infilative!(under!the!skin!injection)!7Near!nerve!endings.!Lower!
concentration.!(Lidocaine.!Bupivacaine).!!
Plexus'block!7!Near!nerve!trunks!7!Procaine,!Lidocaine.!!
Intrathecal!!can!be!subarachnoid!or!subdural.!!
I.V.!7!paradoxical,!used!only!when!it!is!impossible!to!get!to!systemic!
circulation.!!
!
Side'effects:'Allergy,!systemic!absorption!(arrhythmia,!tachy/bradycardia),!
tremor,!convulsions,!respiratory!depression.!
!
Penicillins.'Penicillins'with'broader'spectrum'
Cell!wall!in!composed!of!peptidoglycan!chain!consist!of!NAM!(N7acetyl!
muramic!acid)!and!NAG!(N7acetyl!glucoseamine).!The!most!widely!
effective!and!least!toxic!among!the!cell!wall!inhibitors,!but!has!high!
resistance!profile!which!keeps!increasing!all!the!time.!!
Penicillins!interfere!with!the!last!step!of!cell!wall!synthesis!(cross7
linkage),!thus!resulting!in!cell!lysis.!They!are!only!effective!against!rapidly!
growing!organisms!and!act!by!binding!to!penicillin7binding!proteins!
(transpeptidase),!which!are!the!bacterial!enzymes!involved!in!the!
synthesis!of!cell!wall,!and!disable!them.!
!
!1.'Generation:'also!called!natural!penicillins,!obtained!from!penicillium!
chysogenum!(mold)!and!has!only!2!subtypes:!
PNG:!penicillin!G!(benzylpenicilline),!effective!against!G!+!and!G!!cocci,!G!
+!bacilli!and!!spirochetes,!but!susceptible!to!inactivation!by!penicillinase.!
PNV!!penicillin!V!!same!as!G,!but!with!higher!MBC.!!
'
'
'
'
'
'

2.'Generation:'!
Called!also!penicillinase!resistant!penicillins,!used!in!penicillinase!
producing!staphylococci!infection!only!(methicillin!is!used!only!in!
laboratories!due!to!high!toxicity).!!
Drugs:!Oxacillin,!Nafcillin,!Dicloxacillin,!Methicillin!(theory!only)!
3.'Generation:'
Same!spectrum!as!PNC!G,!with!extra!effectiveness!against!G7!bacilli,!
usually!given!with!beta!lactamase!inhibitors.!
Drugs:!Amoxicillin,'Ampicillin!(Augmentin!!amoxicillin!+!Clavulonic!
acid).!
!
4.Generation:'!
Also!called!anti7pseudomonal,!effective!against!many!G7!rods!and!
pseudomona!aeroguinosa,!broad!spectrum.!The!only!one!given!IV.!
Drugs:!Pipercarcillin,!Ticarcilline,!Carbenicillin.!
!Administered!orally!or!IV,!incomplete!absorption,!secreted!in!the!urine.!!
Side'effects:!allergy,!diarrhea,!nephritis.!
!
19. Changes'of'drug'action'after'repeated'aplications;'
'
Antianginal'drugs'
Angina!pectoris!is!a!sudden,!severe!chest!pain!radiating!to!the!neck,!jaw,!
back!and!arm!(left).!It!is!caused!by!insufficient!coronary!blood!flow!and!
ischemia.!!
There!are!several!types!of!angina!pectoris:!
o Stable:!called!also!typical!angina,!characterized!by!a!burning,!
heavy!feeling!in!the!chest!due!to!reduction!of!coronary!perfusion!
with!fixed!obstruction!from!coronary!atherosclerosis.!Occur!in!
workout!or!any!increased!demand,!relieved!by!nitoglycerin!(NG).!
o Unstable!angina:!chest!pain!from!progressively!less!or!even!
absent!effort,!not!relieved!by!nitroglycerine!(NG)!and!require!
hospital!admission!to!prevent!M.I.!!
o Vasospastic'angina:!occur!at!rest!and!sue!to!vasospasm,!respond!
well!to!NG.!
Drugs'used'to'treat'angina'are:'
Organic*nitrates:*cause!relaxation!of!coronary!arteries!and!relax!veins,!
thus!reducing!preload!!and!oxygen!demand.!Thought!to!act!by!
intracellular!conversion!to!nitric!oxide!(NO)!which!activate!guanylate!
cyclase,!increases!intracellular!cAMP!and!leading!to!smooth!muscle!
relaxation!and!vasodilation.!
!Drug!of!choice!is!Nitroglycerine!which!is!given!sub7lingual!or!
transdermal!patch!(due!to!major!first!pass!effect),!may!lead!to!headache,!
postural!hypotension!and!tachycardia.!Has!to!be!given!in!intervals!
because!of!the!rapid!development!of!toelrance.!!
!
!
!

Beta*blockers:*have!negative!inotropic!effect,!block!beta!1!
receptors.!Atenolol!(thus!preferred)!is!cardioselective!while!
propranolol!is!not!cardioselective.!Contraindications!for!non!selective!
are!asthma,!COPD,!DM!and!severe!bradycardia.!!

Calcium*channel*blockers:*decrease!muscle!tone!and!vascular!resistance,!
drugs!used!are!mainly:!!
o Verapamil:*diphenyalkylamine**slows*conduction.**
o Nifedipine:*dihydropyridine**arterial*vasodilator.**
o Dilitazem:*Benzothiazepine.**

'
Aminoglycosides'&'Tetracyclines'
!
Aminoglycosides:!
It!is!the!old!mainstay!treatment!for!series!of!G7!bacilli!which!was!replaced!
by!3.!generation!cephalosporins!due!to!its!serious!toxicity.!There!are!
several!drugs!in!this!family:!!
o Streptomycin'(used!also!in!mycobacterial!infection)!,!
o Gentamicin!
o Tobramycin!
o Neomycin!
These!drugs!diffuse!into!the!microbe!via!porin!channels!or!via!oxygen!!
dependent!system.!!It!binds!the!30S!ribosome!leading!to!misread!or!
wrong!ribosome!formation.!!
They!are!very!effective!against!G7!bacilli,!including!P.!aeroguinosa,!they!
are!often!combined!!with!Beta!lactam!antibiotic.!Although!this!drug!
inhibits!cell!growth!and!should!not!really!!destroy!the!bacteria,!it!is!
bacteriocidal!(unknown!why)!and!it!only!affects!aerobic!bacteria.!!
The!highly!polar,!polycationic!structure!of!the!aminoglycoside!is!poorly!
absorbed!orally,!!thus!given!parenterally.!!
Resistance!is!via!decreased!uptake,!plasmin!associated!production!of!
enzymes.!!
Side'effects:!have!very!high!nephro!and!ototoxicity!(accumulate!in!the!
renal!cortex!and!perilymph!of!the!inner!ear),!neuromuscular!paralysis!
(neostigmine!will!alter!this)!and!allergy.!!
Note:'neomycin!is!very!toxic,!thus!given!only!topically!!
!
Tetracyclines:!
As!its!name!indicate,!it!is!composed!of!4!fused!rings!with!a!system!of!
conjugated!double!bonds.!The!drugs!in!this!group!are:!!
o Tetracycline,'Doxycycline,'and'Minocycline.'!
The!drug!diffuses!into!the!cell!or!enter!via!energy!dependent!transport!
protein!mechanism,!!then!it!binds!to!the!30S!ribosome,!thus!blocking!
tRNA!from!binding!to!mRNA!(same!idea!as!!aminoglycosides).!It!is!a!
protein!synthesis!inhibitor.!!
It!is!a!broad!spectrum!antibiotic,!works!as!a!bacteriostatic!drug!and!is!
effective!against!G+!!and!G7!bacteria.!!
Resistance!is!via!active!Mg2+!active!efflux!or!enzymatic!breakdown.!!

'

Absorbed!well!after!oral!administration,!concentrate!in!the!liver,!kidney,!
spleen!and!skin.!!
Metabolized!and!conjugated!in!the!liver,!excreted!by!the!bile!and!kidney.!!
Side!effects:!gastric!discomforts,!hepatotoxicity,!phototoxicity!
(accumulate!in!the!skin),!!superinfection,!vestibular!toxicity.!!
Contraindicated!in!liver!or!kidney!failure.!!

'
20. Treatment'of'drug'poisoning'
Definition:'!
The!study!of!adverse!effects!of!chemicals!on!living!organisms.!All!
chemicals!have!some!degree!of!toxicity.!The!right!dose!differentiates!a!
poison!from!a!remedy!common!target!tissues!!lungs,!liver!and!tissues!
with!high!blood!flow!(brain!or!kidneys).!
o Non'selective'actions!!some!chemicals!(such!as!corrosive!
compounds)!lead!to!local!irritation!and\or!causing!effects!that!are!
non7selective.!Example!!exposure!to!strongly!alkaline!or!acidic!
substances,!causing!injury!by!denaturation.!!
o Selective!!by!interfering!with!functions!of!specific!biochemical!
pathway!or!macromolecules!within!tissues.!Example!!warfarin!
inhibits!the!vitamin!K7dependent!posttranslational!modification!of!
certain!clotting!factors!by!the!liver.!!
o Immediate'and'delayed'actions!!AchE!inhibitors!and!asbestos.!
o Occupational'and'Specific'Environmental!Toxins:!halogenated!
hydrocarbons!(carbon!tetrachloride,!chloroform),!aromatic!
hydrocarbons!(benzene,!toluene),!alcohols!(methanol,!!
isopropanol),!pesticides!(organophosphates,!pyrethroids),!
rodenticides!(warfarin),!heavy!metals!(lead,!mercury),!gases!and!
inhaled!particles!(carbon!monoxide,!cyanide,!silica,!asbestos).!
Antidotes:'!
Exist!for!only!a!small!class!of!chemicals.!The!following!strategies!are!the!
basis!of!treatment:!
Pharmcologically'antagonize'toxic'action'!atropine'vs.'anticholinesterases!!
'
Accelerate'detoxification'of'toxic'agent'!
Acetaminophen!at!very!high!dosease!will!produce!!liver!necrosis!as!a!
result!of!its!metabolic!activation!by!P450.!Administration!of!NO'
acetylcysteine!will!serve!as!a!substitute!for!glutathione!by!binding!to!and!
inactivating!the!reactive!metabolites!produced.!Must!be!given!within!8710!
hours.!!
Provide'alternative'target'!
Cyanide!is!treated!in!2!steps!!sodium'nitrite!is!administered!to!induce!
the!oxidation!of!hemoglobin!to!methemoglobin.!The!second!step!is!to!
accelerate!its!detoxification.!!
'
Reduce'metabolic'activation'!
After!metabolism!of!methanol!by!alcohol!dehydrogenase,!there!is!
formation!of!formic!acid.!Fomepizole!inhibits!alcohol!dehydrogenase,!

reducing!the!metabolism!(and!the!rate!of!formic!acid!production)!
protecting!the!patient!from!the!toxic!affects.!!

'
Chelators'!
Drugs!that!will!form!covalent!bonds!with!cationic!metals,!then,!the!
complex!is!excreted!in!urine.!Unfortunately,!this!is!not!specific!to!heavy!
metals,!and!may!react!with!essential!metals!as!well!(such!as!zinc).!!
'
'Diuretics'
These!drugs!are!useful!in!relieving!pulmonary!congestion!and!peripheral!
edema,!also!useful!in!reducing!volume!overload!symptoms!(decrease!
preload!and!afterload).!!
!
Thiazide'diuretics:''
The!most!widely!used,!derivatives!of!sulfonamides!and!are!relatively!
weak!diuretics.!They!affect!the!distal!tubule!to!decrease!the!reabsorption!
of!sodium,!they!work!on!Na/Cl!cotransporter!on!the!luminal!membrane,!
produces!hyperosmolar!urine,!but!does!not!change!the!acid7base!balance!
of!the!body.!!
Used!in!HF,!hypertension,!diabetes!insipidus.!!
Drugs:!Chlorthiazide,'Chlorthalidone!and!Metolazone.!
!
!Loop'diuretics:''
Work!on!the!ascending!loop!of!Henle!and!are!the!most!potent!diuretics,!
they!work!by!decreasing!the!reabsorption!of!Na/K/2Cl!in!the!luminal!
membrane!and!are!used!as!the!drug!of!choice!for!reducing!pulmonary!
edema!in!HF,!but!they!are!effective!for!only!274!hours.!!
Drugs:!Bumetanide,!Furosemide,!Torsemide.!
'
Potassium'spearing'diuretics:''
Act!on!the!collecting!tubule,!they!inhibit!sodium!reabsorption!and!
potassium!excretion.!!
Drugs:!Spironolactone!(aldosterone!antagonist),!Amiloride.!!
'
Carbonic'anhydrase'inhibitors:'
'Not!really!used!as!a!diuretic.!Inhibit!carbonic!anhydrase!located!
intracellularly!at!the!proximal!tubule!!carbonic!anhydrase!catalyzes!CO2!
and!H2O,!leading!to!H2CO3.!!
Mainly!used!in!glaucoma!patients!and!prophylaxis!of!mountain!sickness.!!
Drugs:!Acetazolamide.!
'
Osmotic'diuretics:''
Result!in!some!degree!of!diuresis!because!they!are!osmotically!active.!!
Drugs:!Mannitol!and!Urea.!
'
'
'
'
'

Antiviral'and'antifungal'drugs'
Antiviral'drugs:''
Viruses!lack!cell!wall!and!cell!membrane!and!they!do!not!carry!out!
metabolic!processes,!thus!they!use!the!host's!cell!machienary!for!their!
own!needs!(replication,!metabolism)!and!therefor!the!clinical!symptoms!
appear!relatively!late,!only!after!the!virus!replicated!and!budded!!
Antiviral!drugs!work!by!one!of!the!following!mechanisms:!
!
!
!!Block!virus!attachment!to!the!cell.!!
!
!
!!Block!uncoating!of!the!virus!!Amantidine,!Rimatidine.!!
!
!
!!Inhibit!viral!protein!synthesis!!interferons.!!
!
!
!!Inhibit!specific!virus!enzymes.!!
!
!
!!Inhibit!virus!assembly.!!
!
!
!!Inhibit!virus!release.!!
!
!
!!Stimulate!host!immune!response.!!
!
For!respiratory'infections:!for!influenza,!respiratory!syncytial!virus!(RSV)!and!
orthomyxovirus!we!can!use:!
Neuraminidase!inhibitors!!Zanamivir,!lead!to!virion!accumulation!!
Inhibitors!of!viral!uncoating!!amantidine,!ranitidine.!!
Ribavirin!!synthetic!guanisine!analogue.!!
!
For!hepatic'infections:!
Interferons!!immune!modulators!&!antiviral,!given!only!by!S.C!route!for!
HCV!and!HBV.!!
Adefovir!!nucleotide!analogue.!!
Entecavir!!guanosine!analogue!!
!
For!herpes'virus:!
Acyclovir!!can!be!oral!or!topical,!specific!for!herpes!virus.!It!is!a!protease!
inhibitor!which!!inhibit!viral!DNA!polymerase.!!
Ganciclovir!!acyclovir!analogue,!but!better!against!CMV.!!
Penciclovir!!nucleoside!derivative,!inhibit!DNA!polymerase.!!
For!HIV!infections:!we!use!HAART!(highly!active!antiretroviral!therapy).!
NRTI!!nucleotide!reverse!transcriptase!inhibitors!(zidovudine,!
stavudine).!!
NNRTI!!non7nucleotide!reverse!transcriptase!inhibitors!(Nevirapine).!!
Protease!inhibitors!!result!in!production!of!non!infectious!virions!
(Indinavir,!ritonavir).!
Integrase!inhibitors!!prevent!entry!of!HIV!into!the!cell!(Raltegravir)!
'
Antifungal'drugs:!
Infectious!diseases!which!are!caused!by!fungi!are!termed!mycoses,!it!is!
caused!by!eukaryote!with!a!rigid!cell!wall!made!of!chitin!(NAG!polymer)!
with!cell!membrane!that!contain!ergosterols!(rather!than!cholesterol)!
they!are!most!often!chronic!infections!that!resistant!to!many!forms!of!
ATB's.!The!differences!between!fungi!and!human!cells!are!utilized!
clinically.!
!

There!are!3!classes!of!antifungal!drugs:!
!Polyenes:!!
Amphotericine!&!Nystatin!!cell!membrane!ergosterol!binding!drug!
leading!to!pore!formation,!these!are!fungicidal!drugs.!Amphotericine!is!
used!for!almost!all!infections,!while!nystatin!is!used!topically!in!oral!
candidiasis,!vaginal!mycosis!and!topical!mycosis.!!
Griseofulvin!!nucleic!acid!synthesis!inhibitor,!a!fungistatic!drug!used!for!
onychomycosis.!!
!!Azoles:!!
They!work!by!decreasing!ergosterol!synthesis!by!fungal!CYP450!binding,!
can!be!!administered!topically!or!orally,!even!IV!if!needed.!!7!
representatives:!Chlotrimazole,'Ketonazole,'Fluconazole,'
Itraconazole.''
!
!!Other:!!
Work!the!same!as!azoles,!it!is!a!synthetic!pyrimidine!antimetabolite,!thus!
disrupt!DNA!!synthesis.!Has!good!CNS!penetration,!used!mainly!for!
systemic!candidosis!or!cryptococcosis.!!
To!this!belong!only!Flucytosine.!May!lead!to!GIT,!hematologic!and!
hepatal!disturbances.!
!
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