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Revision for Final Exam, June 2014

Dr. Ahmed Abdelrahman




1 -First and zero order kinetics.

3- Factors affecting oral absorption.
4--Effect of pH on oral absorption and renal excretion.
5--Factors affecting dose and action of drugs.
6-Types of Tolerance (described within the factors affecting dose and action).
7-Adverse drug reactions.
8-Types of Antagonism (described within Drug Interactions).
1-Parasympathomimetics: -Anticholinesterases (Reversible and Irreversible)
2-Sympathomimetics: -Adrenaline (Uses)-Dopamine- Amphetamine (Uses).
3-Sympathetic Depressants:
-Selective alpha1 blockers (Prazosin).
-Central alpha2 agonists: Alpha methyldopa-Clonidine.
-Beta Blockers.
All except Anti-arrhythmic drugs.
Thiazides-Loop diuretics-Potassium sparing diuretics.
1-Bronchial asthma.
2-Acetylcysteine (Mucolytic).
2-Serotonin agonists and antagonists.
3-Antihyperlipidemics (Statins-Fibrates).
1-Peptic ulcer.
2-Antiemetics and Prokinetics.
3-Physical purgatives: Bulk and Lubricant.
1-Opioid Analgesics: Morphine-Codeine-Meperidine-Fentanyl.
2-NSAIDs: Salicylates-Paracetamol.
4- Benzodiazepines
5-Antiparkinsonians: L-dopa-Bromocryptine.
6-Antiepileptics: Phenytoin-Carbamazepine-Valproate.
3-Oral Contraceptives.
4-Antithyroid drugs.
1-B-Lactam Antibiotics:-Penicillins-Cefalosporins-Monobactams-Carbapenems.
2-Protein synthesis inhibitors: Aminoglycosides -Macrolides-ClindamycinTetracyclines-Chloramphenicol- Fusidic acid.
3- Quinolones.

1-General Pharmacology






-Transmembrane movement of drugs.
-Factors affecting absorption.
-Metabolism (Biotransformation).


Choline esters-Pilocarpine.
2-Parasympatholytics: Atropine-Atropine substitutes-Hyoscine.
3-Sympatomimetics: Noradrenaline-Isoprenaline-Ephedrine-Vasopressors-Nasal
decongestants-B2 agonists
4-Sympatholytics: Non-selective alpha blockers-Yohimbine.
Cough therapy.
Histamine-Leukotrienes-Ergot alkaloids and Migraine.
--------------------------------------------------------------------------------------------------Anti-arrhythmic drugs.
2-Drugs used to treat bleeding (hemostatics and coagulants).
1-Bz receptor agonists-Buspirone-Chloral hydrate.
2-Opioid analgesics: Semisynthetic-Methadone-Propoxyphene-Mixed agonist antagonists.
3-NSAIDs other than Salicylates and Paracetamol.
4-Antiepileptic drugs: Ethosuximide.
5-Antiparkinsonian drugs: MAO-B inhibitors-COMT inhibitors-Amantadine-AnticholinergicsDrugs contraindicated in Parkinsonism.
6-Antidepressants and Lithium
8-CNS stimulants: Methylxanthines.
1-Other purgatives.
3-Treatment of: Ulcerative colitis-Diarrhea-Colics.
2-Calcium homeostasis.
4-Sex hormones (Estrogen-Progestogens)-Antiestrogens (SERMs).
5-Thyroid hormones.
1-Vancomycin. 2-Teicoplanin.
4-Anti-T.B. drugs. 5-Antiviral drugs. 5-Antifungal drugs. 6-Praziquantel.





Day 1 (4 June): General Pharmacology Clinical Pharmacology.
Day 2 (5 June): CNS.
Day 3 (6 June): Hormones.
Day 4 (7 June): Antibiotics.

Day 5 (8 June): Blood- GIT.

Day 6 (9 June): CVS-Diuretics
Day 7 (10 June): ANS-Respiration-Autacoids.
Day 8 (11 June): Revision of CNS, GIT, and General.
Day 9 (12 June): Revision of Hormones, Blood, ANS, and Respiration.
Day 10 (13 June): Revision of Antibiotics, CVS, Diuretics, and Autacoids.
14 and 15 June: Clinical pharmacology + MCQ revision.

Important notes:
1-This is not an obligatory schedule, you can make your own schedule.
2-In any schedule you should leave the last 2-3 days for revision.
3-The most important chapters in the final ESSAY AND MCQ exams-according to the marks are
4-Do not forget that there will be a 10 mark question about GENERAL PHARMACOLOGY in
paper 1 (essay exam).
5-Try to READ the MCQs in the departments book after studying each chapter, especially in
second term chapters (about 70-80% of MCQs will be about second term chapters; mainly on
CNS, Chemotherapy, and Endocrine).
7-In paper (1) take good care of the time, each of the 8 questions should not take more than 15
8-The form of your exam is very similar to the exams of the last 3 years, so please take a look
at these exams in the department book of MCQ (Question Bank).

General Pharmacology
1-Effect of pH on oral absorption and renal excretion
The presence of acidic drugs as salicylates and barbiturates- in acidic medium as the stomach
and urine increases the unionized form of the drug which is lipid soluble (lipohilic), but the
presence of acidic drugs in alkaline medium as the small intestine increases the ionized form
which is lipid insoluble (hydrophilic) leading to "ion trapping".

On the other hand; the presence of basic drugs as ephedrine and amphetamine- in acidic
medium increases the ionized form (ion trapping) and their presence in alkaline medium
increases the unionized form.
1-Gastric acidity increases oral absorption of acidic drugs as salicylates (aspirin) and barbiturates
2-Intestinal alkalinity increases oral absorption of basic drugs as ephedrine and amphetamine.
3-Acidifation of urine (e.g. by ammonium chloride or vitamin C) increases excretion of basic
drugs (ion trapping) but reduces excretion of acidic drugs.
4-Alkalinization of urine (e.g. by sodium bicarbonate) increases excretion of acidic drugs (ion
trapping) but reduces excretion of basic drugs.

2-First order and Zero order Kinetics

Zero order kinetics

First order kinetics

1-A constant amount (number of moles) is

eliminated / unit time.

1-A constant percent (proportion-fraction) of the drug

is eliminated / unit time.

2-The rate of elimination is not proportional to the

concentration of the drug.

2-The rate of elimination is proportional to the drug


3-Drug disappearance curve is non-linear.

3-Drug disappearance curve is linear.

4- t1/2 is variable, it increases with the dose

(plasma concentration of the drug).

4- t1/2 is constant whatever the dose (plasma

concentration of the drug).

5-AUC is not proportional to the drug


5-Area under the plasma concentration/ time curve

(AUC) is proportional to the drug concentration.

6-The drug does not necessarily reach Css after 4-5

t1/2, the drug may cumulate leading to toxicity.

6-Steady state concentration (Css) is reached after 4-5

t1/2 of repeated drug intake at regular intervals.

7-Saturation of enzymes or carriers responsible for 7-No saturation of enzymes or carriers responsible for
drug elimination.
drug elimination.
8-Examples: large doses of aspirin, phenytoin, and

8-Examples: all drugs, including small doses of

aspirin, phenytoin, and alcohol.

3-Factors affecting oral absorption:

A-Factors related to the drug:
1-Lipid solubility (lipid/ water partition coefficient): the higher the lipid solubility (the higher
the lipid/ water partition coefficient) the more the absorption of the drug.
2-Degree of ionization: the more the unionized form of the drug (lipophilic form) the more the

3-Valency: Ferrous salts are better absorbed than the Ferric salts.
4-Nature of the drug: inorganic drugs are better absorbed than organic.
5-Drug formulation: Paracetamol has a rapid rate of dissolution and is rapidly absorbed.

B-Factors related to the patient:

1-Surface area of absorbing surface: drugs are mainly absorbed from the small intestine due to
very large surface area (1000 times that of stomach due to the presence of microvilli).
2-Vascularity of absorbing surface: drugs are mainly absorbed from the small intestine due to
very high vascularity.
3-State of general circulation: drug absorption is impaired in shock.
4-State of health of absorbing surface: oral drug absorption is reduced in gastritis and
malabsorption syndrome.
5-Gut motility and rate of drug dissolution: prokinetic drugs as metoclopramide increase gut
motility and accelerate gastric emptying and accordingly increase absorption of rapidly
disintegrated drugs as paracetamol but decrease absorption of slowly disintegrated drugs as
digoxin. Atropine slows gut motility and delays gastric emptying and has opposite actions
compared to metoclopramide.
6-Gut pH: acidic drugs: weak acidic drugs as aspirin and barbiturates are better absorbed in the
acidic medium of the stomach, whereas weak basic drugs as ephedrine and amphetamine are
better absorbed in the alkaline medium of the small intestine.
7-Gut contents: Food decreases absorption of some drugs as ampicillin-Ca2+ in milk and dairy
products and in some antacids decreases absorption of tetracyclines-Al3+ and Mg2+ salts in
antacids decrease absorption of tetracyclines and fluoroquinolones-Tetracyclinesdecrease
absorption of Ca2+ and iron-Grape fruit inhibits P-glycoprotein leading to increase in oral
absorption-Tea contains tannic acid which decreases oral iron absorption and may lead to irondeficiency anemia.
8-First pass effect:
a-Gut first pass effect: gastric acidity destroys some penicillins as benzyl penicillin G (acidsensitive penicillins)-Proteolytic enzymes destroy polypeptide hormones as insulin-Gut mucosa
metabolizes some drugs as chlorpromazine and alpha-methyl dopa.
b-Hepatic first pass effect: Propranolol and nitroglycerin are extensively metabolized by the
liver, this can be avoided by increasing the oral dose (oral dose is much higher than dose given
IV or SL).
Lidocaine (antiarrhythmic) is almost completely metabolized by the liver, so it is given only IV
in treatment of ventricular arrhythmias.
9-Specific factors: intrinsic factor is essential for oral absorption of B12.

Definition: the fraction (percent or proportion) reaching the systemic circulation
chemically unchanged following administration by any route.
Factors affecting oral bioavailability: = Factors affecting oral absorption.
Calculation of oral bioavailability:

Oral Bioavailability=

X 100

N.B.: IV bioavailability = 100%, but oral bioavailability is variable.

(Bioequivalence and Therapeutic equivalence: see Applied Medical Pharmacology book).

5-Adverse and toxic effects of drugs including types of

See "Applied Medical Pharmacology" book, volume I.

6-Factors affecting the dose and action of drugs

See "Applied Medical Pharmacology" book, volume I.

7-Types of Antagonism
See Drug Interactions ((DI) in Applied Medical Pharmacology book, volume I.

Autonomic Nervous System

1-Organo-Phosphorous Compounds (OPC) Poisoning

1-Occupational: inhalation or skin contamination during spraying insecticides as parathion and
malathion by farmers.
2-Accidental ingestion of insecticides or contaminated fruits and vegetables.
3-Suicidal ingestion of insecticides.
4-Exposure to war gases as sarin, tabun, and soman.
Mechanism of OPC:
OPC bind to the esteratic site of acetylcholinesterase, first by a loose bond, but soon the bond
becomes covalent causing irreversible inhibition of the enzyme (aging of the enzyme), leading to
accumulation of endogenous acetylcholine. Acetylcholine over-activates cholinergic receptors
(Muscarinic and Nicotinic) both peripherally and centrally.
Clinical Manifestations:
1-Muscarinic effects: bradycardia-hypotension-increased bronchial secretion-bronchospasmsalivation-lacrimation-excessive sweating-miosis-abdominal cramps, colics, diarrhea-involuntary
passage of stools and urine.
2-Nicotinic effects: twitches and fasciculations of skeletal muscles followed by flaccid paralysis
of skeletal muscles which may cause death due peripheral respiratory failure.
(N.B.: stimulation of sympathetic ganglia may lead to tachycardia and hypertension in some
3-CNS effects: headache, dizziness, tremors, anxiety, confusions, convulsions, coma, and death
due to depression of R.C. (central respiratory failure).
A-General supportive treatment:
1-Endotracheal intubation and oxygen.
2-Position: comatose patient is kept in lateral position, head down, and neck extension.
In case of skin contamination: remove contaminated clothes and wash the skin with soap and
In case of oral ingestion: gastric lavage within 1-2 hours of ingestion, and activated charcoal to
adsorb the poson and reduce systemic absorption.
N.B.: decontamination is performed after the patient is fully stabilized and not immediately after
B-Specific antidotal treatment:
1-AtropineIV (bolus followed by infusion):
Atropine is a competitive antagonist with acetylcholine at M-receptors (not N-receptors) both
peripherally and centrally. Atropine is given until the following
target end-points are achieved:
Tachycardia: heart rate over 80 beats / minute.
Mydriasis (dilted pupils).
Sweating (dry axillae).
A.B.P. (diastolic BP over 80 mmHg.).
Bronchial secretions (clear chest with absence of wheezes).
2-Oximes (cholinesterase reactivators):
Pralidoxime is the most commonly used oxime.
Oximes bind to the anionic site of cholinesterase and attract OPC leading to free enzyme.
Oximes should be given early before aging of the enzyme.

The main advantage over atropine is restoration of skeletal muscle strength and improvement
of diaphragmatic weakness.
Diazepam IV and other benzodiazepines are given to control CNS stimulation as convulsions
(seizures) due to OPC or sometimes due to atropine therapy.

2-Reversible Anticholinesterases (Carbamates)

2- Neostigmine

1- Physostigmine

Carbamate-quaternary ammonium.

Natural: plant origin.

Carbamate-Tertiary amine.


-Poorly absorbed orally.

-Poorly passes B.B.B.
-As physostigmine.

-Well absorbed orally.

-Penetrates B.B.B.
-Hydrolyzed by (substrate of)


Binds reversibly to both anionic and

esteratic sites of cholinesterases
preventing hydrolysis of endogenous

4-Mechanism of action:

-Muscarinic actions (by accumulated

endogenous acetylcholine).
-Nicotinic actions (by accumulated
endogenous acetylcholine).
-CNS action: stimulation, which may
lead to convulsions.


1-Diagnosis and treatment of

1-Local uses in the eye:
Myasthenia gravis (atropine should
- Glaucoma.
be given before neostigmine).
- To counteract mydriatics
2-Treatment of poisoning by curare
-Alternatively with mydriatics to cut
and other competitive neurorecent adhesions in iritis.
muscular blockers (atropine should 2-Treatment of acute atropine poisoning
be given before neostigmine).
especially if CNS manifestations are
3-Treatment of peripheral present (however physostigmine may be
symptoms of acute atropine dangerous as it causes CNS stimulation
4-Non-obstructive post-operative
3-Treatment of Alzheimer's disease
urine retention.
5-Non-obstructive post-operative
paralytic ileus.
7- Glaucoma.

6-Therapeutic uses:

As physostigmine.

-Muscarinic actions (by

accumulated acetylcholine).
-Nicotinic actions (by accumulated
-Direct skeletal muscle stimulation.
-No CNS actions.

As physostigmine but no CNS


-bronchospasm and bronchial
secretion- HCl secretion.-CNS
stimulation (convulsions).

7-Adverse effects:

As physostigmine (except

asthma-peptic ulcer-hyperthyroidismparkinsonism.


Manifestations: as physostigmine
except CNS Treatment: stomach
wash and atropine.

-Muscarinic: bradycardia-hypotension,
bronchospasm, miosis.
-Nicotinic: twitches of skeletal muscles.
-CNS: convulsions, coma, death to
depression of R.C
1-Stomach wash.
2-Artificial respiration.
3-Specific antidote= atropine.

9-Acute toxicity:

1-Adrenaline (Epinephrine)
*Mechanism of action:
Direct agonist that stimulates (activates) all types of adrenergic receptors: all receptors (1, 2,
3), and all receptors (1, 2).
*Pharmacological actions:
A-Local actions:

1-Eye: decongestion and reduction of IOP (1), but no mydriasis except in cases of
supersensitivity as glaucoma, pancreatitis.
2-Bronchi: bronchodilatation (2) and decongestion (1).
3-Skin and mucous membranes: decongestion, hemostatsis, and prolongation of the duration of
local anesthesia and decrease of systemic effects. All these actions are due to V.C. (1).
B-Systemic actions:
1-Heart: adrenaline increases all cardiac properties (1) including: heart rate (positive
chronotropic)-conductivity (positive dromotropic)-contractility (positive inotropic)excitability-rhythmicity. Adrenaline also increases cardiac output and myocardial oxygen
2-Blood vessels: V.C. of blood vessels of skin and mucous membranes (1) but vasodilatation of
coronary blood vessels and skeletal muscle blood vessels (2)
3-Arterial blood pressure (ABP): adrenaline elevates ABP (pressor effect)
elevates systolic BP due to increase in cardiac output mainly-the effect on diastolic BP is
variable: in small doses there is reduction in DBP due to vasodilatation of skeletal muscle
blood vessels, but with higher doses there is vasoconstriction especially in skin and
mucous membrane blood vessels and DBP may rise-finally adrenaline markedly increase
pulse pressure.
Adrenaline reversal: adrenaline elevates ABP but when given after alpha blockers as
phentolamine, adrenaline decreases ABP. This is due to the unopposed action of
adrenaline on 2 receptors leading to vasodilatation and hypotension.
II-Smooth muscle fibers:
1-Bloov vessels: see before.
2-Eye: active mydriasis due to stimulation of 1 receptors in dilator pupillae muscle.
3-Bronchi: bronchodilatation (2).
4-GIT: relaxation of the wall ( and ) and contraction of sphincter (1).
5-Urinary bladder: relaxation of the wall=detrusor muscle (2) and contraction of the sphincter
and trigone (1) leading to urine retention.
6-Male sex organs: ejaculation of semen (1).
7-Uterus: variable action but adrenaline relaxes the uterus in human females in late pregnancy
and during labor (2).
8-Pili-erector muscle: contraction (1).
9-Nictitating membrane in cats: contraction (1).
III-Exocrine glands:
1-Salivary glands: thick viscid saliva.
2-Sweat glands: adrenaline increases sweating from apocrine (non-thermoregulatory) sweat
glands in palm and sole (1), but has no effect on eccrine (thermoregulatory) sweat glands
which contain M3 receptors and not 1.
IV-CNS: adrenaline poorly penetrates BBB so it causes mild CNS stimulation causing tremors,
irritability, and anxiety (1).
V-Metabolic actions:
1-Calorigenic action: adrenaline increases BMR, oxygen consumption, and heat production.

2-Hepatic glycogenolysis leading to hyperglycemia (2).

3-Skeletal muscle glycogenolysis leading to increase in blood lactate (2).
4-Hypokalemia due to increase in K+ uptake by skeletal muscles (2).
5-Lipolysis and elevation of free fatty acids in blood (1 and 3).
VI-Skeletal muscles:
Vasodilatation, glycogenolysis, increased K uptake, and tremors (all action are mediated by 2
VII-Anti-allergic action:
Adrenaline is the physiological antagonist of histamine; that is why adrenaline is life saving in
anaphylactic shock.
Adverse Effects
1-Tachyarrhythmia. 1-Tachycardia, palpitations, and arrhythmia (treated by blockers as
2-Pulmonary embolism.
propranolol). These adverse effects are particularly more dangerous
3-Thyrotoxicosis. in thyrotoxicosis, pulmonary embolism, and when adrenaline is given
with digitalis or with halothane (an inhalation general anaesthetic
4-With halothane.
which sensitizes the heart to catecholamines) as serious ventricular
arrhythmias may occur as ventricular fibrillation (V.F.).
5-With digitalis.
6-Angina pectoris (ischemic heart
2-Increased cardiac work and precipitation of anginal attacks.
disease=coronary heart disease).
3-Elevation of A.B.P. and may cause cerebral hemorrhage in
8-Severe hypertension if adrenaline is
hypertensive patients.
given with non-selective blockers as
9-Gangrene if added to L.A. in fingers and
toes, and during circumscision.

4-Gangrene if added to L.A. in fingers and toes, and during

circumscision (treated by 1 blockers).
5-Weak CNS stimulation: anxiety, headache, and tremors.
6-Lacrimation, irritation, and pigmentation of the eye when applied
locally for long time.

10-With MAO inhibitors, ganglion

blockers, cocaine, guanethidine, and
11-Hemorrhagic shock.

7-Supersensitivity occurs with MAO inhibitors, ganglion blockers,

cocaine, guanethidine, and reserpine.

*Drug interactions:
1-With general anesthesia as halothane sensitization of the heart to catecholamines
arrhythmias (treated by -blockers).
2-With LA as procaine prolongation of action of L.A., reduction of systemic toxicity of LA as
convulsions, and hemostasis.
3-With cocaine severe V.C. which may lead to gangrene.
4-With LA in fingers, toes, and circumscision gangrene.

5-With non-selective -blockers as propranolol severe hypertension due to unopposed 1

stimulation by adrenaline.
6-With digitalis ventricular arrhythmia which may be fatal.
7-With MAOIs, reserpine, guanethidine supersensitivity.
*Therapeutic Uses (Indications):
A-Local uses:
1-With LA: to prolong the action and reduce systemic toxicity of LA (except in fingers, toes, and
2-Open angle glaucoma: adrenaline is given as eye drops to reduce I.O.P., but Dipivefrin
(prodrug converted into adrenaline) is preferred as it more lipophilic, more diffusible, and
less toxic.
3-Hemostatic as in cases of epistaxis, given as nasal pack (except in hypertension).
4-Decongestion of mucous membranes of eyes and nose.
B-Systemic uses:
1-Anaphylactic shock: SC adrenaline is life-saving and the drug of choice due to its anti-allergic
action (adrenaline is the physiological antagonist of histamine).
2-Cardiac arrest: adrenaline is given intra-cardiac for cardiac resuscitation.
3-Contraction ring of the uterus (B2 agonists as Ritodrine and Isoxsuprine are preferred).
4-Acute bronchial asthma: adrenaline is given S.C. (SABA as Salbutamol and Terbutaline are
5-Hypoglycemic coma: adrenaline is given S.C. (I.V. glucose 50 mL 50% is preferred).

1-Absorption: not absorbed orally, given by I.V. drip.
2-Distribution: poor passage across B.B.B.
3-Fate: metabolized by COMT and MAO (mainly) into homovanilic acid (HVA) which is
excreted in urine.
-Mechanism of action: direct stimulation of specific dopaminergic (D1) receptors, 1-receptors,
and 1-receptors according to the rate of infusion.
- Pharmacological actions: depend on the rate of infusion as follows:
1-Slow rate of infusion (2.5-5 g/kg/minute): dopamine stimulates D1-receptors in blood vessels
leading to V.D. especially renal, mesenteric, and coronary blood vessels, which increases blood
flow to the vital organs as the kidney.
2-Moderate rate of infusion (5-10 g/kg/minute): dopamine stimulates cardiac 1-receptors
leading to increase in COP.
3-Rapid rate of infusion (> 10 g/kg/minute): dopamine stimulates 1-receptors leading to V.C.,
increase in TPR and ABP.
(Renal V.C. leads to acute renal failure and death).
*Therapeutic uses:
1-Shock (hypovolemic, cardiogenic, and endotoxic): dopamine is given at a slow-moderate rate
to increase tissue perfusion and blood flow to vital organs as the kidney, and to increase COP and
accordingly urine output and ABP especially systolic - increase.

Blood volume should be corrected, e.g. by blood transfusion, before administration of dopamine
"fill up then open up".
2-Heart failure: especially acute and resistant heart failure, dopamine is given in a moderate
infusion rate.
*Adverse effects:
1-Tachycardia, palpitation, arrhythmias (ventricular), and anginal pains due to direct and reflex
1-stimulation (treated by 1- blockers).
2-Hypertension if given with MAO inhibitors or in rapid infusion rate due to 1-stimulation
(treated by 1- blockers).
3-Nausea and vomiting (due to stimulation of D2-receptors in C.T.Z.)
4-weak CNS actions as headache and anxiety.
*Important notes:
1-Dopamine is not effective in treatment of Parkinsonism as it cannot pass B.B.B., but its
precursor L-dopa can pass easily and is converted into dopamine by dopa decarboxylase in CNS.
2-Dopamine receptor subtypes are D1, D2, D3, D4, and D5 (see CNS).
3-To antagonize the pharmacological actions of dopamine we have to block the following
-D1- receptors: by dopaminergic antagonists as "haloperidol".
-1- receptors by: 1-blockers as" propranolol".
-1- blockers by: 1-blockers as "phentolamine".
4-The dose of dopamine should be reduced in patients treated with MAO inhibitors to avoid
elevation of ABP (explain).
5-Precautions during infusion: monitor heart rate by ECG -monitor ABP and urine volume
-replace fluids before dopamine -avoid extravasation-stop infusion gradually.

Source: synthetic.
Chemistry: catecholamine.
Pharmacokinetics: Given by I.V.infusion-Does not cross BBB-metabolized by MAO.
1-Direct selective B1 agonist.
2-Positive inotropic with much less increase in heart rate (more inotropic than chronotropic).
3-Almost no effect on T.P.R., i.e. no vasoconstriction (no action on alpha1) or vasodilatation (no
effect on D1).
Therapeutic uses:
1-Cardiogenic shock as due to acute myocardial infarction.
2-Acute heart failure (especially with hypotension).
Adverse effects:
1-Tachycardia, palpitation, arrhythmia, angina pains if given in large doses (less than dopamine).
2-Nausea and vomiting.







Summary of Catecholamines:



as adrenaline.

as adrenaline.

as adrenaline.

as adrenaline.

as adrenaline.

as adrenaline.

as adrenaline.

as adrenaline.

3- I.V. infusion

I.V. infusion

I.V. infusion

I.V. infusion

1,2,3 no

selective 1
no D or .
Minimal effect
(more ino- than
chrono- and no
effect on blood

directly and
(diastolicvariable effect
on systolicpulse
1-AV block.

shock (due to
2-Heart failure.

, 1.D1,

Mainly 1 weak
1 no 2.
H.R. (slowH.R. (reflex)moderate rate)A.B.P. (both
A.B.P (rapid
systolic and
effect on pulse
pressureabolished after blockers).
1-Shock. To elevate A.B.P.
2-Heart failure.
in severe

*L-isomer is
more active.
*Not absorbed.
*Poor passage
across BBB.
*Metabolism by
MAO and
3-Eye drops.
4-Nasal pack.
All and .




Agonist on:

H.R. -A.B.P.
(systolicvariable effect on
after -blockers).

Action on
H.R. and

3-With L.A.
ring of uterus.


Comparison between adrenaline and Amphetamine:

Chemistry: Non-catecholamine.
Mechanism of action:
Indirect acting sympathomimetic by releasing
noradrenaline from adrenergic neurons.
*Therapeutic Uses (Indications):

Chemistry: Catecholamine.
Mechanism of action:
Direct acting sympathomimetic by stimulation of all adrenergic receptors
(Beta1,2,3 and Alpha1,2).
*Therapeutic Uses (Indications):


Uses are due to its CNS actions:

1-Delays mental and physical fatigue.
2-Elevates mood in psychic depression, Parkinsonism,
alcohol withdrawal in chronic alcoholism.
3-Lightens sleep in narcolepsy and nocturnal enuresis.
4-Attention Deficit Hyperkinetic Disorder in children
(ADHD) to calm the patient and increase attention span.
II-Anorexigenic: in treatment of obesity (not preferred due
to liability to addiction.
III-Analeptic: to stimulate vital medullary centers (R.C.
and V.M.C) in cases of acute toxicity by morphine or

Adverse effects and Toxicity:

As adrenaline+ psychic and physical dependence
(addiction) + Marked CNS manifestations as insomnia,
anxiety, psychosis (schizophrenia), and anorexia + Acute
Manifestations: hypertension (treated by alpha blockers as
phentolamine)-psychosis (treated by
antipsychotics as chlorpromazine) and
convulsions (treated by anticonvulsants as

As adrenaline + CNS symptoms as insomnia, anxiety,
psychosis, and anorexia.

A-Local uses:
1-With LA: to prolong the action and reduce systemic toxicity of LA (except
in fingers, toes, and circumscision).
2-Open angle glaucoma: adrenaline is given as eye drops to reduce I.O.P.,
but Dipivefrin (prodrug converted into adrenaline) is preferred as it
more lipophilic, more diffusible, and less toxic.
3-Hemostatic as in cases of epistaxis, given as nasal pack (except in
4-Decongestion of mucous membranes of eyes and nose.
B-Systemic uses:
1-Anaphylactic shock: SC adrenaline is life-saving and the drug of choice
due to its anti-allergic action (adrenaline is the physiological
antagonist of histamine).
2-Cardiac arrest: adrenaline is given intra-cardiac for cardiac resuscitation.
3-Contraction ring of the uterus (B2 agonists as Ritodrine and Isoxsuprine
are preferred).
4-Acute bronchial asthma: adrenaline is given S.C. (SABA as Salbutamol
and Terbutaline are preferred).
5-Hypoglycemic coma: adrenaline is given S.C. (I.V. glucose 50 mL 50% is
Adverse effects:
1-Elevation of arterial blood pressure which may lead to cerebral
hemorrhage in hypertensive patients.
2-Gangrene if given with L.A. in fingers and toes, and during circumscision.
3-Cardiac manifestations: tachycardia, arrhythmia, palpitations, and angina
pains in patients with ischemic heart disease.
4-Cardiac arrhythmias (ventricular arrhythmia up to V.F.) if given with
general anesthesia (G.A.) as halothane (treated by beta blockers).
5-Weak CNS manifestations as irritability, tremors and insomnia.
6-Exaggerated action if given in thyrotoxic patients, with MAO inhibitors or
Contraindications:1-Hypertension.2-Angina pectoris
3Arrhythmia.4-Thyrotoxicosis.5-With: L.A. in fingers, toes,
circumscision- halothane-sympatholytics-MAOIs.

Sympathetic Depressants (Sympatholytics)

I-Central Alpha2 Agonists
- Well absorbed orally. Clonidine can be given as a transdermal patch.
- Passes B.B.B.
- Partly metabolized and partly excreted unchanged in urine.
-Mechanism of action: direct agonist on 2-receptors centrally and peripherally (presynaptic).
-Pharmacological actions:
1- Stimulation of central 2-receptors inhibition of V.M.C and C.A.C.

sympathetic outflow from CNS V.D. (and decrease in TPR) and bradycardia (and decreased
C.O.P.) and accordingly decrease ABP.
2- Stimulation of presynaptic 2-receptors release of noradrenaline from adrenergic
neurons V.D. and decrease in TPR, Heart rate and COP (bradycardia is due to reduced
sympathetic tone and predominance of vagal tone).
3-Stimulation of 2 receptors in kidneyRenin release.
Both central and peripheral actions decrease A.B.P.
4-blocks postsynaptic 1 receptors on blood vessels V.D.
5-Anti-serotonin action.
*Therapeutic uses:
1- Treatment of hypertension, including hypertension with renal impairment (clonidine increases
renal blood flow) and high renin hypertesion.
2- Prophylaxis of migraine headache.
3- Control of withdrawal symptoms in morphine and nicotine addicts.
4- Analgesic (given intrathecal).
*Adverse effects:
1- Rebound hypertension if clonidine is stopped suddenly. This is due to upregulation of 1receptors with chronic use of clonidine, it may be accompanied by tachycardia (due to
upregulation of 1-receptors). Rebound hypertension can be treated by re-administration of
clonidine (to reduce noradrenaline release) or by 1-blockers -blockers but never use nonselective -blockers without 1-blockers to avoid more hypertension by unopposed 1stimulation.
2- Sedation and drowsiness due to decreased sympathetic activity.
3- Dry mouth (may be due decreased acetylcholine release from cholinergic neurons to salivary
4-Bradycardia (see before).
*Drug interaction:
Tricyclic antidepressants (TCAs) inhibit neuronal reuptake of noradrenaline (cocaine-like action)
and antagonize the effect of clonidine.
N.B. Apraclonidine and brimonidine are 2 agonists used in treatment of glaucoma (as eye
drops), whereas tizanidine is a central 2 agonist used as central skeletal muscle relaxant.

2-Alpha-Methyl Dopa
Mechanism of action:
1-Alpha-methyl dopa competitively inhibits dopa decarboxylase enzyme leading to inhibition of
synthesis of noradrenaline (from dopamine) in adrenergic neurons.
2-Alpha- methyl dopa itself is converted-by dopa decarboxylase-into alpha-methyl dopamine
then into alpha-methyl noradrenaline. Alpha-methyl noradrenaline acts as 2-agonist,
stimulating 2-receptors both centrally and peripherally.
Pharmacological actions:
1-Stimulation of central 2-receptors decreases sympathetic discharge from CNS leading to
vasodilatation and TPR (due to inhibition of VMC), bradycardia and COP, both
actions ABP.

2-Stimulation of peripheral pre-synaptic 2-receptors leading to decrease in release of

noradrenaline release from adrenergic neurons, and this also leads to vasodilatation and
TPR, bradycardia and COP, both actions
3-Stimulation of 2-receptors in JGA in the kidney decreases renin release and further ABP.
4-Vadodilatation of renal blood vessels and increase in RBF.
1-Inhibition of VMC.
2-Sedation and drowsiness.
3-Night mares and psychic depression (due to synthesis of serotonin, noradrenaline and
4-Iatrogenic Parkinsonism may occur with large doses (due to synthesis of dopamine in basal
5-Hyperprolactinemia (due to synthesis of dopamine in hypothalamus).
III-Parasympathetic predominance:
1-Bradycardia COP.
2-Increase in GIT secretion and motility leading to diarrhea.
3-Miosis and IOP.
*Adverse effects:
1-Sedation, drowsiness, night mares, depression (due to deficiency of monoamines). 2Hyperprolactinemia (gynecomastia in males, galactorrhea-amenorrhea in females).
II-Sympatholytic actions and parasympathetic predominance:
1-Postural (orthostatic) hypotension (due to venodilatation).
2-Nasal congestion (stuffiness).
4-Diarrhea and colics.
III-Hypersensitivity (Type II) reactions:
1-Hepatitis and hepatotoxicity.
2-Hemolytic anemia (diagnosed by positive Coomb's test).
3-Bone marrow depression.
IV-Others: Fever (Type I hypersensitivity reaction)-Salt and water retention.
1-Hypersensitivity (allergy).
2-Liver diseases.
4-Psychic depression.
*Indications: Treatment of mild and moderate hypertension especially in pregnancy (drug of
choice) and in hypertension with renal impairment (as it RBF).
It can be also given IV in emergency hypertension.

II-Selective 1-blockers (Prazosin)

Mechanism of action:
1-Competitive selective 1-blocker.

2-Inhibits phosphodiesterase enzyme (PDE) both c-AMP (which causes V.D. and
tachycardia) and c-GMP (which causes V.D. and bradycardia).
Pharmacological actions:
1- V.D. of both arteries (TPR= afterload) and veins (venous return= preload) by blocking postsynaptic 1 receptors, and increase c-AMP and c-GMP. V.D. leads to A.B.P.
2- No (or minimal) reflex tachycardia because:
-No 2-blocking action and no increase in noradrenaline release from adrenergic neurons
innervating the heart.
-Inhibition of PDE leading to increase in both c-AMP ( heart rate) and c-GMP (heart rate).
3- Relaxation of urinary bladder sphincter.
Therapeutic uses:
1-Treatment of essential (primary) hypertension (a diuretic may be added on prolonged use).
2-Treatment of congestive heart failure (CHF) as it reduces both preload due to venodilatation
and afterload due to arteriodilatation. This increases COP in these patients.
3- P.V.D. as Raynaud's disease.
4- Secondary hypertension due to pheochromocytoma (beta blockers may be added)..
5- BPH (Tamsulosin is better because it is a selective 1A blocker ).
6-Other use: Rebound hypertension after sudden clonidine cessationHypertensive crisis in depressed patients treated by MAO inhibitors (cheese reaction)-Severe
V.C. if extravasation of noradrenaline occurs during IV infusion.
Adverse effects:
1-"First dose phenomenon": severe postural hypotension after the first dose due to potent
venodilatation. It can be prevented by starting treatment with a small dose given at bed time, and
then the dose is gradually increased.
2- Nasal congestion.
3- Failure of ejaculation.
4- Na+ and water retention due to decreased RBF, corrected by adding a diuretic.
5-Headache and dizziness (due to cerebral V.D.).
Question: How to correct hypotension induced by -blockers as phentolamine?
Answer: Angiotensin II given by IV infusion (physiological antagonism). Alpha agonists as
phenylephrine and noradrenaline will not effective because alpha receptors are blocked, whereas
adrenaline is dangerous because it will stimulate 2-receptors leading to V.D. and more

III-eta Adrenoceptor Antagonists(-Blockers)

A-Classification according to selectivity:
1- Non-selective -blockers= First generation -blockers:
- They block both 1- and 2-receptors.
- Examples: Propranolol, Pindolol, Oxprenolol, Nadolol, Sotalol, and Timolol.
2- Cardioselective -blockers= Selective 1-blockers= Second generation -blockers:
- They block 1-receptors (but if given in large doses or for long periods, they can block 2receptors because "selectivity is not absolute").
- Examples: Atenolol, Metoprolol, Acebutolol, Bisoprolol, and Esmolol.
3--Blockers with additional action= Vasodilator -blockers= Third generation -blockers:
- Labetalol and Carvedilol: they block 1, 2, and 1-receptors. Carvedilol has also an antioxidant

- Celiprolol: blocks 1-receptor and is an agonist (or partial agonist) on 2-receptors.

- Nebivolol: blocks 1-receptor selectively and acts as a 2-agonist, and releases nitric oxide (NO)
causing vasodilatation. It is known as "nitrogenic -blocker".
- Medroxalol.
- Bucindolol.
4- Selective 2-blocker: Butoxamine which has no clinical uses and used only experimentally.
B-Classification according to degree of lipid solubility:
Most -blockers are lipophilic drugs, and a few -blockers are hydrophilic drugs as Nadolol,
Atenolol, Sotalol.
The differences between lipophilic and hydrophilic -blockers are shown in this table:
Hydrophilic -Blockers
Lipophilic -Blockers
Incomplete (poor-delayed) oral
Well absorbed orally.
Poorly penetrates B.B.B.weak CNS

Passes easily B.B.B.marked CNS



Less bound to plasma proteins and less

liable to drug interactions.

Highly bound to plasma proteins drug


3-Plasma protein

Mainly excreted slowly unchanged in

urine less liable to drug interactions,
but we should adjust the dose according
to renal function.

Mainly rapidly metabolized by hepatic

microsomal enzymes (HME) drug
interactions with HME inducers and
inhibitors. Metabolism is slow in cases
of decreased hepatic blood flow, liver
diseases, and if given with HME


Long, given as single daily dose good


Short, requires frequent daily doses

poor compliance.

5-Duration and t1/2:


C-Classification according to "Membrane Stabilizing Activity"(MSA):

1-Some -blockers have the ability to block Na+ channels leading to an additional antiarrhythmic
action known as "quinidine-like action", and local anaesthetic action. Examples: PropranololMetoprolol.
2- Other -blockers do not block Na channels and have no MSA. Examples: Nadolol-Atenolol.
D-Classification according to "Intrinsic Sympathomimetic Activity"(ISA):
1-Most -blockers are "pure antagonists", i.e. they block -receptors without initial stimulation.
Examples: Propranolol- Atenolol- Metoprolol- Nadolol.
2-Few -blockers have partial agonistic activity (P.A.A.), i.e. they stimulate -receptors before
blocking them, and are said to have intrinsic sympathomimetic activity (I.S.A.). Examples:
Pindolol- Oxprenolol- Acebutolol.

A-Mechanism of action:
Competitive non-selective -antagonist. Propranolol is a pure antagonist (no ISA).
Propranolol also blocks Na+ channels = MSA = L.A. action and antiarrhythmic action
(quinidine-like action).
B-Pharmacological actions:
Heart: blocking of 1-receptors leads to:
- automaticity= negative chronotropic action (heart rate and may cause bradycardia). The
effect of -blockers on heart rate is more marked during exercise than during rest.
-conductivity=negative dromotropic action (conductivity all over the heart including AV
- myocardial contractility= negative inotropic action.
-myocardial O2 requirements.
-The anti-arrhythmic action of propranolol is due to: 1-blocking action (decreases excitability,
automaticity, and conductivity) + membrane stabilizing activity (MSA) due to Na+-channel block
Blood vessels: blocking of 2-receptors in blood vessels leads to initial V.C. especially in
skeletal muscles, coronary, and hepatic blood vessels.
-At the start of treatment of hypertensive patients with propranolol; ABP is not reduced although
propranolol COP, because it causes initial V.C. especially in skeletal muscle blood vessels by
blocking 2-receptors.
-After continous treatment with propranolol (at least for 4 weeks); ABP is reduced due to the
following mechanisms:
1- COP.
2- renin release by blocking 1-receptors in juxta-glomerular apparatus in kidney.
3- noradrenaline release from adrenergic neurons by blocking pre-synaptic -receptors.
4- sympathetic outflow from CNS by blocking central 1-receptors (propranolol is "lipophilic").
5- Re-setting of baroreceptors.
6- Stimulation of synthesis of vasodilator prostaglandins, as prostacyclin (PGI2) and PGE2.
N.B.: Propranolol and all non-selective -blockers "abolish" the hypotensive action of
isoprenaline and "augment" the hypertensive (pressor) action of adrenaline (they have no effect
on the hypertensive action of noradrenaline).
Propranolol and all non-selective -blockers induce bronchospasm by blocking 2-receptors in
bronchial smooth muscles. This is very dangerous in asthmatic patients as it may precipitate
attacks of asthma.
Cardio-selective -blockers are less dangerous but remember that "selectivity is not absolute".
3-Metabolic actions:
- lipolysis by blocking 1and 3-receptors and reduces free fatty acids.

- glycogenolysis by blocking 2-receptors in liver and skeletal muscles. This may be dangerous
in case of insulin-induced hypoglycemia.
-Long-term (chronic) use of propranolol may induce atherosclerotic changes as it increases
VLDL and LDL and decreases HDL (this is less marked with -blockers having ISA, and with
cardio-selective -blockers).
- uptake of K by skeletal muscles, and may lead to "hyperkalemia", by blocking 2-receptors in
skeletal muscles.
Important Notes:
1- Hypoglycemia=stress sympathetic activity tachycardia and palpitation (1-stimulation),
Glycogenolysis and increased blood glucose (2-stimulation), and increased sweating (M3stimulation in thermoregulatory sweat glands).
2-Propranolol will mask the symptoms of hypoglycemia except sweating (why?). This may lead
to "silent hypoglycemia" and coma in diabetic patients receiving overdoses of insulin or oral
hypoglycemic drugs.
- Formation of aqueous humor by blocking -receptors (2 mainly) in ciliary body, and
accordingly decrease IOP.
- No change in the size of the pupil and no action on the ciliary muscle.
- Local application of timolol may lead to systemic actions as bradycardia and bronchospasm
5-CNS actions:
- Reduces anxiety by blocking 1-receptors in CNS.
- Reduces tremors mainly by blocking 2-receptors in skeletal muscles and mainly by CNS
action (propranolol is lipophilic).
6- Liver:
-V.C. of hepatic blood vessels and decreases portal pressure in cases of portal hypertension due
to liver cirrhosis.
-Reduction of hepatic blood flow reduces HME activity leading to "non-specific" or "indirect"
HME inhibition which may decrease hepatic metabolism of drugs.
*Thearpeutic Uses of -Blockers:
1- Prophylaxis of angina pectoris (ischemic heart disease), useful in stable angina and in unstable
angina as it decreases cardiac work and myocardial oxygen requirements, but it is
contraindicated in variant=Prinzmetal angina=vasospastic angina which is due to sudden
coronary V.C. (due to supersensitive 1-receptors in coronary blood vessels) as it leads to more
V.C. due to "unopposed 1 effect.
2-Treatment of essential hypertension (propranolol decreases ABP after prolonged use).
3-Treatment of supra-ventricular tachycardia (as PAT) and ventricular arrhythmias (due to
general anaesthesia, digitalis, 1agonists as adrenaline and isoprenaline, acute myocardial
infarction, thyrotoxicosis, and cardiac surgery).
(-blockers are "Class II" antiarrhythmic drugs).
4-After acute myocardial infarction (AMI) to decrease size of infarction, treat arrhythmias,
decrease cardiac work and myocardial oxygen requirements, and increase survival (decrease
mortality rate).
5-Acute dissecting aortic aneurism (with sodium nitroprusside).

6-Obstructive hypertrophic cardiomyopathy= chronic hypertrophic subaortic stenosis (it may

increase COP in this case by reducing cardiac muscle spasm).
7-Some -blockers as metoprolol, carvedilol, and bisoprolol are given in small doses (then the
dose is very gradually increased) in congestive heart failure. However; -blockers are
contraindicated in "compensated" heart failure when COP is dependent on sympathetic drive on
the heart (see CVS pharmacology) and should never be given suddenly or in large doses.
An additional benefit is by renin release and ABP.
8-To reduce portal pressure in portal hypertension due to bilharzial or alcoholic cirrhosis.
9-Teatment of glaucoma: Timolol, Betaxolol, Levobunolol, and Carteolol are used. (Timolol may
induce bradycardia and bronchospasm in asthmatic patients although it is given as eye drops,
10- To control CVS symptoms (tachycardia, angina, and arrhythmia) and CNS symptoms
(anxiety, tremors and insomnia) of thyrotoxicosis.
Propranolol is the drug of choice because:
-Has no ISA.-Passes B.B.B.-Decreases conversion of T4 (active) into T3 (more active), i.e. it
inhibits peripheral deiodination.-Can be given orally (in chronic cases) and I.V. (in thyrotoxic
11-Treatment of pheochromoctoma but should be combined with 1-blockers, non-selective blockers should never be used alone (why?).
12- Prophylaxis of migraine headache.
13- Treatment of "situational anxiety".
Skeletal Muscles:
14- To control tremors (as essential tremors in old age and Parkinsonism).


Adverse Effects
1-Bradycardia (treated by atropine).


2-AV block. 2-Decreases AV conduction and may cause AV block (treated

by atropine).

3-Hypotension (no postural hypotension, WHY?).

4-Bronchial asthma.

4-Bronchospasm especially in asthmatics (treated by

antimuscarinic drugs as Ipratropium).

5-Peripheral vascular diseases (PVD) as Raynaud's

6-Prinzmetal (variant or vasospastic) angina.

5-Cold extremities, claudication, and fatigue (due to V.C.).

7-Never use non-selective -blockers ALONE in these

conditions (combine with -blockers, or use drugs
blocking both -and -receptors as labetalol).

7-Unopposed -effect if propranolol is used alone in

pheochromocytoma, rebound hypertension due to sudden
clonidine withdrawal, and cheese reaction more

8-Severe heart failure or if the case is compensated by

sympathetic stimulation.
9-Use non-selective -blockers "cautiously"in diabetics
treated by insulin or oral hypoglycemics.

6-V.C. of coronary blood vessels especially in variant


8-Decrease myocardial contractility and may precipitate

heart failure.
9-Aggravate insulin-induced hypoglycemia and mask the
symptoms=silent hypoglycemia (except sweating).
10-Sexual dysfunction in males (decrease sexual desire due
to central effect).
11-Increse in LDL and decrease in HDL causing
atherosclerosis (non-selective blockers mainly).

10-Severe depression.

12-Hyperkalemia especially in renal impairment.

11-Never Stop -Blockers Suddenly (Abruptly).

13-CNS manifestations: sedation, sleep disturbances,

depression (lipophilic blockers).
14-"Rebound" angina, arrhythmia, and even infarction if
suddenly stopped after chronic use, due to up-regulation
(and supersensitivity) of 1-receptors.

*Drug Interactions of Propranolol (-Blockers):

A-Pharmacokinetic Interactions:
1-Propranolol (and other lipophilic -blockers) are highly bound to plasma proteins and can
displace other drugs as digitalis leading to "digitalis toxicity".
2-Propranolol decreases hepatic blood flow and indirectly decreases activity of HME, thus
reducing its own hepatic metabolism and of other drugs as lidocaine.
3-HME inducers as nicotine and phenytoin increase hepatic metabolism of propranolol thus
reducing its activity (the dose of propranolol should be increased).
4-HME inhibitors as cimetidine decrease hepatic metabolism of propranolol and may lead to
marked adverse effects (the dose of propranolol should be reduced).
B-Pharmacodynamic Interactions:

1-Propranolol + digitalis severe bradycardia and AV block.

2-Propranolol + verapamil or diltiazem (Ca2+-Channel blockers) severe bradycardia and AV
3-Propranolol augments the hypertensive action of adrenaline.
4-NSAIDs as aspirin antagonize the anti-hypertensive action of propranolol because they reduce
synthesis of vasodilator prostaglandins and also cause Na+ and water retention.
5-Propranolol augments the insulin-induced hypoglycemia and masks the symptoms.
6-Propranolol augments rebound hypertension due to sudden clonidine withdrawal if used alone
(without -blocker).
Cardio-Selective -Blockers:
Advantages over non-selective blockers:
1-Allowed in variant angina.
2-Allowed in P.V.D.
3-Allowed in bronchial asthma.
4-Allowed in D.M. treated by insulin or oral hypoglycemics.
5-Less liable to cause hyperlipidemia.
6-Less liable to cause hyperkalemia.
REMEMBER: selectivity is not absolute and it is lost with large doses or long-term therapy.
Similar to nadolol and sotalol:
Hydrophilic.No ISA.No MSA.
Similar to propranolol:
Lipophilic.No ISA.Has MSA.
Similar to oxprenolol:
Lipophilic.Has ISA.Has MSA.
Metabolized very rapidly by RBC esterase, so it has very short duration (ultra-short), given by
IV infusion in emergency arrhythmias.
Has no ISA, and no MSA.

-and -Blockers:
Blocks - and 1-receptors in a ratio of 3:1.
Less potent than propranolol as -blocker, and less potent than phentolamine as 1-blocker.
Decreases ABP by decreasing both COP and TPR.
It causes V.D. and hypotension without reflex tachycardia (why?).
Used in: 1-Essential hypertension, including emergency hypertension.
2-Pheochromocytoma (it is used alone).
As labetalol: and 1 blocker + Antioxidant.


Autacoids: Antihistaminics
(2nd generation)
Poor passage across BBB.
As sedating antihistaminics.

Sedating Antihistaminics
(1st generation)
Pass BBB.
Competitive antagonists with histamine at
H1 receptors.

1-Passage across BBB:

2-Mechanism of action:

Long duration: 12-24 hours.

Short duration: 4-6 hours.


1-Antihistaminic and Antiallergic

action (as 1st generation).

1-Antihistaminic and Antiallergic action: antagonize

the actions of histamine mediated through H1 receptors
on the skin, blood vessels, and smooth muscles.
2-Sedating action.
3-Antimuscarinic action (atropine-like action).
4-Antiemetic action by blocking H1 and M-receptors in
medullary vomiting center.
5-Antiparkinsonian action by blocking M-receptors in
basal ganglia.
5-Antiserotonin action by Cyproheptadine.
6-Antiarrhythmic action (Na+ channel block by
7-Alpha blocking action.


1-Treatment of allergic reactions as urticaria, rhinitis,

conjunctivitis, common cold (chlorpheniramine),
atopic dermatitis, angioedema, and anaphylaxis.
2-Antiemetics in all causes of vomiting including
motion sickness (promethazine-diphenhydraminedimenhydrinate-cyclizine-meclizine).
3-OTC Sleep aids in situational insomnia.
4-Parkinsonism (e.g. diphenhydramine).

4-Therapeutic uses:

1-Sedation and dizziness, excitation may occur and is

more common in children.
2-Atropine-like manifestations: dry mouth,
constipation, urine retention, IOP.
3-Teratogenicity (Cyclizine and Meclizine are
teratogenic in experimental animals as rodents, but not
proved in humans).

5-Adverse effects:



No (or less) sedation.

No antimuscarinic action.
No antiemetic action.
No antiparkinsonian action.
No antiserotonin action.
No antiarrhythmic action.
No alpha blocking action.
Treatment of allergic reactions (as 1st

1-CNS: Analgesic-Antipyretics
3-Iatrogenic Peptic ulcer.
4- RBF Na+ and water retention,
and may lead to nephropathy.
5-Antiplatelet action by Aspirin
(pediatric dose) by inhibition of
TXA2 synthase.

Prostaglandins (PGs)
1-CNS: Algesia-Pyrexia.
3-GIT: protect the stomach and duodenum by HCl,
mucus, HCO3 (PGE2).
4-Renal V.D. and RBF.
5-V.D. by PGI2 and PGE2 or V.C. by PGF2 and
6- Platelet aggregation by PGI2 or platelet
aggregation by TXA2.
7-Oxytocic action (PGF2 and PGE2).


6-Tocolytic action.
7-Bronchoconstriction due to shift of
arachidonic acid into LT pathway.
8-Premature closure of DA if given
in late pregnancy.
1-Analgesic in superficial pains
2-Antipyretic (non-specific).
3-Antiinflammatory in acute gouty
arthritis, rheumatic fever, rheumatoid
4-Prophylaxis of thrombo-embolism
by aspirin.
5-Tocolytics in premature labor and
6-Obliteration of patent ductus
arteriosus (by Indomethacin).
2-Peptic ulcer (iatrogenic).
3-Asthmatic attacks in bronchial
6-Premature closure of ductus
7-Delayed labor and increase postpartum hemorrhage.
2-Peptic ulcer.
3-Bronchial asthma.
4-Bleeding disorders.
5-Pregnancy (early and late).

8-Bronchodilatation by PGD2 and PGE2, or

bronchoconstriction by PGF2
9-Maintain the patency of Ductus Arteriosus (DA) in
fetus by PGE2.
10-Induction of ovulation and enhance erection.
11- IOP (PGF2).
1-Prophylaxis and treatment of iatrogenic ulcer
2-Antiplatelet (Epoprostenol).
3-Induction of labor and abortion, and to control postpartum hemorrhage (Carboprost-Dinaprostone).
4-Treatment of erectile dysfunction (Alprostadil).
5-Maintain the patency of DA before surgical
treatment of congenital heart diseases (Alprostadil).
6-Glaucoma (Latanoprost).

Therapeutic uses:

1-Diarrhea and colics, bone pains (Misoprostol).

2-Anaphylactic shock and CVS collapse (Carboprost
intra-amniotic for induction of abortion).
3-Abortion (Misoprostol in peptic ulcer).
4-Short duration.

Adverse effects:

Misoprostol in treatment of peptic ulcer is

contraindicated in pregnancy.


Serotonin agonists and antagonists

Serotonin Antagonists
1) 5-HT2 Antagonists:
Used in:
1-Prophylaxis of migraine headache.
2-Carcinoid tumor.
3-Appetite stimulants (except methysergide).
4-Cyproheptadine has also antihistaminic action and is used in
treatment of allergic conditions.
Adverse effects:

Serotonin agonists
5-HT1A agonist.
Non-Benzodiazepine anxiolytic (anxio-selective).
Used in generalized anxiety disorder, but has slow onset of action.
2-Triptans: Sumatriptan-Zolmitriptan:
5-HT1D agonists,
Cause vasoconstriction of cranial, coronary, and systemic blood

Methysergide causes fibrosis of serous membranous leading to

retro-peritoneal fibrosis.
2) 5-HT3 Antagonists: Ondansetron-Granisetron:
Block 5-HT3 receptors in medullary C.T.Z.
Used as antiemetics in nausea and vomiting due to cancer
chemotherapy and post-operatively.

Used in acute attacks of migraine headache, given orally 2 doses /

Adverse effects:
1-Tingling, numbness, cold hands.
2-Elevation of blood pressure.
3-Anginal pains.
4- Abortion due to their oxytocic action..
5-Dizziness and neck pain.
2-Angina pectoris.
3-Peripheral vascular disease.
3-Metoclopramide and Itopride:
5-HT4 agonists in enteric ganglia.
Prokinetics: stimulate release of acetylcholine from cholinergic
nerves in GIT leading to increase in tone of lower esophageal
sphincter and accelerate gastric emptying.
Used in GERD and gastroparesis.
Appetite suppressant (anorexigenic) in obesity,
5-SSRIs: Fluoxetine-Fluvoxamine:
Antidepressants used in treatment of psychic depression.

Drug Therapy of Migraine:

Drugs used in Prophylaxis
1-Propranolol: the most commonly used.
2-Serotonin antagonists:
3-TCAs as Amitriptyline.
4-Valproic acid.
5-CCBs as Flunarizine: blocks selectively Ca2+ channels in
cranial blood vessels without affecting Ca2+ influx in the heart
or smooth muscles.

Drugs used in Acute Attacks

Mild attack:
1-Analgesics as Paracetamol or NSAIDs as Aspirin.
2-Antiemetics as Metoclopramide or Domperidone may be added
in case of migraine-induced vomiting.
Severe attacks:
1-Ergot alkaloids:
-Given orally but poorly absorbed, also given S.L., I.M, I.V.,
inhalation, suppository-Passes BBB-Metabolized by liver and
excreted in urine.
-Pharmacodynamics:Partial agonist on alpha1 and
5-HT2 receptors leading to vasoconstriction-Spasmogenic on
smooth muscles including uterus (oxytocic)-CNS actions:
stimulation of CIC leading to bradycardia and CTZ causing
nausea and vomiting.
-Adverse effects: elevation of ABP-anginal pain-cold hands,


tingling, numbness, and may be gangrene-nausea and vomitingbradycardia-abortion.

-Contraindications: Hypertension-angina-PVD-pregnancy-liver
and kidney diseases-old age.
B-Dihydroergotamine: less toxic than ergotamine.
C-Cafergot (Caffeine + Ergotamine): caffeine improves oral
absorption of ergotamine and causes cranial vasoconstriction.
2-Triptans as Sumatriptan and Zolmitriptan:
-Given orally.
-5HT1D agonists leading to vasoconstriction.
-Adverse effects: elevation of ABP-anginal pain-cold hands,
tingling, numbness-abortion
Contraindications: Hypertension-Angina-PVD-Pregnancy-With
ergotamine within 24 hours.

*Drug Therapy in Bronchial Asthma:
A-Bronchodilators (Short-term asthma relievers):
1-Sympathomimetic 2-Agonists.
3-Antimuscarinic drugs (Anticholinergic drugs-Muscarinic antagonists).

B-Anti-inflammatory drugs (Long-term asthma controllers):

1-Glucocorticoids (Corticosteroids).
2-Leukotriene antagonists=Leukotriene inhibitors=Leukotriene modifiers=Antileukotrienes: LT
receptor antagonists (Montelukast and Zafirlukast) and LT synthesis inhibitors (Zileuton) which
5-lipooxygenase enzyme.
3-Degranulation inhibitors = Mast cell stabilizers.
Anti-inflammatory drugs are not bronchodilators and are not used in acute attacks of bronchial
asthma, but used for prophylaxis.
NSAIDs except Paracetamol-are contraindicated in bronchial asthma (why?).


Stimulation of 2-receptors activation of adenylate cyclase synthesis of c-AMP
bronchodilatation + mast cell stabilization and inhibition of release of bronchoconstrictor
mediatorsfrom mast cells + reduction of mucus secretion + increase muco-ciliary clearance +
decrease microvascular leakage (capillary permeability).
A-Selective 2-Agonists: They are the most important drugs in treatment of bronchial asthma,
they include:
1-Short-acting 2-agonists=Asthma relievers:
Salbutamol and Terbutaline given by inhalation in acute attacks duration 3-4 hours.
2-Long-acting 2-agonists=Asthma controllers:
Salmeterol, Formoterol by inhalation, and Bambuterol given orally-duration 12 hours.
Role in bronchial asthma:
1-The drugs of choice in acute attacks: SABA are given by inhalation.
2-LABA are given for long-term prophylaxis with inhaled steroids.
3-Salbutamol is given by inhalation (nebulizer) or IV in severe acute asthma (status asthmaticus).
Adverse effects:
1-Tremors of the skeletal muscles.
2-Tachycardia (mostly reflex due to V.D. and hypotension, but may be due to direct stimulation
of cardiac 1 receptors especially with repeated doses because selectivity is not absolute).
3-Tolerance (due to down-regulation of 2-receptors, corrected by corticosteroids).
4-Nervousness Tension.
7-LABA increase the risk of asthma-related death if used alone in patients with ischemic heart
disease or arrhythmia, that is why they should be combined with inhaled corticosteroids (ICS).
B-Non-Selective -Agonists:
They are not commonly used because of cardiac adverse effects as tachycardia,
palpitation,arrhhythmia and anginal pains due to 1-stimulation. Examples:
1-Adrenaline (inhalation and S.C.).
2-Isoprenaline (inhalation and S.L.).

II- Methylxanthines:
Theophylline and Aminophylline (theophylline ethylene diamine).
Mechanism of action:
1-Inhibit phosphdiesterase type 4 intracellular c-AMP bronchodilatation + mast cell
stabilization and inhibition of release of bronchoconstrictor mediatorsfrom mast cells + reduction
of mucus secretion + increase muco-ciliary clearance + decrease microvascular leakage
(capillary permeability) .
2-Block of adenosine receptors bronchodilatation + decrease histamine release..
3-Improve diaphragmatic contractions.
4-Inhibition of PDE-4 in inflammatory cells reduces the release of cytokines and reduces cell
The Role of Methylxanthines in Bronchial asthma:

1-Aminophylline may be given very slowly IV (250-500 mg.) in acute attacks (asthma reliever)
if there is no response to inhaled selective 2- agonists. This may be dangerous especially if
aminophylline is rapidly injection as it may lead to arrhythmia and severe hypotension (velocity
2-Theophylline is given as sustained release tablets or capsules in prophylaxis of bronchial
asthma (asthma controller).
Aminophylline may be also given as rectal suppositories (500 mg.).
3-Aminophylline is given by IV infusion in life-threatening asthma (status asthmaticus =severe
acute asthma).
Adverse effects:
-Theophylline and Aminophylline have low therapeutic index and the plasma level should be
measured to avoid toxicity.
-Therapeutic plasma concentration of theophylline: 5-20 mg / L (5-20 g / mL) and the toxic
level > 20 mg / L.
-Adverse effects include:
1-CNS manifestations: nervousnss, insomnia, headache, and seizures (convulsions).
2-CVS manifestations: tachycardia, palpitations, arrhythmias, anginal pains, and hypotension.
3-GIT manifestations: anorexia, nausea, vomiting, ulceration, and proctitis (rectal suppository).
4-Thrombophlebitis (IV injection).
Symptoms of toxicity may start at plasma level of 15 mg/L.
Seizures and arrhythmia occur at plasma levels above 40 mg/L.

Drug interactions:
A-The clearance of theophylline is reduced by:
1-HME inhibitors as: Erythromycin (Macrolide antibiotics)-Fluroquinolones-ChloramphenicolCimetidine-Contraceptive pills.
2-Hepatic cirrhosis.
3-Heart failure (decreases COP and so decreases hepatic blood flow).
In these conditions the dose of theophylline should be reduced to avoid toxicity.
2-The clearance theophylline is increased by:
-HME inducers as: Phenobarbitone- Phenytoin-Rifampicin Cigarette smoking (nicotine).
The dose of theophylline should be increased in these conditions to achieve therapeutic levels.

III- Anti-Muscarinic Drugs:

Atropine was previously used in prophylaxis of bronchial asthma but is now replaced by
synthetic substitutes.
Examples: Ipratropium -Oxtropium Tiotropium.
Mechanism of action:
They are competitive antagonists that block muscarinic receptors in bronchi by competition with
acetylcholine released as a result of vagal stimulation.
Role of Antimuscarinic Drugs in Bronchial asthma:
1-They are given by inhalation in prophylaxis of bronchial asthma (the response varies according
to degree of vagal stimulation on bronchi).

2-They are used as alternatives to LABA patients who are intolerant to LABA as in cases of
arrhythmia or ischemic heart diseases.
3-They may be added to LABA to achieve synergism.
4-They are the drugs of choice in asthmatic attacks precipitated by non-selective beta antagonists
as propranolol.
5-Chronic obstructive pulmonary disease (COPD).
Advantages of Synthetic substitutes:
Advantages of Ipratropium
Disadvantages of Atropine
1-Quaternary ammonium-given by inhalation.
1-Tertiary amine-given orally-Passes BBB.
2-Minimal systemic anticholinergic actions. 2-Systemic anticholinergic actions: dry mouth
constipation-urine retention-tachycardia-blurred
vision and elevation of IOP.
3-No CNS (cannot penetrate BBB).
3-CNS actions.
4-Little effect on bronchial secretion. 4-Causes dryness of bronchial secretion leading
to thick viscid sputum.
5-No effect on muco-ciliary clearance.
5-Decreases muco-ciliary clearance.

B-Anti-inflammatory Drugs:
I- Corticosteroids (Glucocorticoids):
Mechanism of action:
1-Anti-inflammatory action by inhibition of phospholipase A2 leading to inhibition of synthesis
of arachidonic acid, leukotrienes and prostaglandins.
2-Anti-inflammatory action by inhibition of synthesis of cytokines as interleukins (IL1,2,3,4) and
tumor necrosis factor (TNF).
3-Potentiate the effects of 2-agonists (by upregulation of receptors) thus prevent tolerance.
4-Inhibit IgE antibody synthesis and antigen-antibody reaction.
Corticosteroids are not bronchodilators and are not used in acute attacks.
The Role of Corticosteroids in Bronchial asthma:
1-Inhaled corticosteroids (ICS) as Beclomethasone, Fluticasone, Triamcinolon, Budesonide,
are used in prophylaxis of bronchial asthma. This is the preferred route to avoid the serious
adverse effects of systemic steroids (immunosuppression-osteoporosis-edema-hypertensionulcer).
2-Systemic steroids as Hydrocortisone sodium succinate or methylprednisolone IV is the drug
of choice in status asthmaticus (200 mg. / 4-6 hours for 24 hours).
This is followed by oral prednisolone for 7-10 days then gradually withdrawn to avoid acute
adrenocortical insufficiency.

3-Systemic steroids as predisolone orally are used only in severe persistent asthma not
responding to other anti-asthmatic drugs (see later).
Adverse effects of Inhaled steroids:
1-Oro-pharyngeal candidiasis (moniliasis): prevented by mouth wash after corticosteroid
inhalation, and treated by oral Nystatin.
2-Dysphonia (voice abnormality, e.g. weakness and hoarseness).
3-Systemic adverse effects may occur on prolonged use, e.g. growth retardation in children and
osteoporosis in females

II- Mast Cell stabilizers = Degranulation Inhibitors:

Cromolyn (Disodium cromoglycate) and Nedocromil.
Mechanism of action:
Inhibition of the release of allergic mediators from mast cells and other inflammatory
mediators by stabilizing the cell membrane by altering the permeability of chloride channels.
They are not bronchodilators and are not used in acute attacks.
Role of Mast Cell stabilizers in Bronchial asthma:
1-Used only for prophylaxis and given by inhalation, either in the form of solution (inhaler) or in
the form of powder (by spinhaler).
2-They are used before exposure to allergen (environmental asthma), before exposure to
industrial fumes (occupational asthma), and before exercise (exercise-induced asthma).
3-They decrease: bronchial hyper-responsiveness, the need bronchodilators, and the severity of
4-They may be used with ICS.
Other uses:
1-Allergic rhinitis (given as nasal drops or nasal spray).
2-Allergic conjunctivitis (given as eye drops).
Adverse effects:
Bronchospasm, cough, chest tightness, throat irritation, dry mouth, and anaphylaxis (rare).

III- Leukotriene Modifiers:

Mechanism of action:
1-Inhibition of 5-Lipooxygenase and inhibition of leukotrienes synthesis by Zileuton (not
commonly used as it may cause hepatotoxicity).
2-Competitive antagonists of cysteinyl leukotriene receptors (LTD4 mainly): by Montelukast
and Zafirlukast.
Role in Bronchial asthma:
They are given for prophylaxis against bronchial asthma.
They have the following advantages: 1-Montelukast is safely used in children (as young as 6
months) 2-easy administration as they are given orally.
New Drugs in Treatment of Bronchial Asthma:
1-Omalizumab: anti-IgE monoclonal antibody
Synthesized by recombinant DNA technology.
Mechanism of action: binds to IgE thus prevents binding of IgE to its receptors on mast cells,
and inhibits degranulation and release of allergic mediators.
It is given SC in severe persistent asthma not controlled by other drugs as ICS and LABA (see
2-Calcium channel blockers.

3-Potassium channel openers as cromokalim.

4-Prostaglandin E2.
5-Nitric oxide donors.

Drugs Contraindicated in Bronchial Asthma:

1-NSAIDs (except paracetamol=acetaminophen).
2-Non-selective -Blockers (Propranolol-Nadolol-Timolol-Sotalol-Oxprenolol-Pindolol).
3-ACE inhibitors as Captopril.
4-Morphine (depresses R.C., cough centre, and releases histamine).
5-Muscarinic agonists = Parasympathomimetics (Carbachol-Bethanechol-PilocarpinePhysostigmine-Neostigmine).
6-Other drugs: Histamine liberators as morphine-curare-trimetaphan-Histamine like drugs as
phentolamine and tolazoline-Barbiturates (due to depression of R.C.).

Cough Therapy
1-Mucolytic: by splitting the disulfide bonds of mucoproteins of respiratory secretion. This leads
to reduced viscosity and tenacity of mucus.
2-Acetaminophen (Paracetamol) antidote: by normalizing hepatic glutathione (SH donor) which
binds to the hepatotoxic metabolite of acetaminophen (NABQ) and protects liver cells.
Therapeutic uses:
1-Mucolytic: used as adjuvant in treatment of acute and chronic respiratory diseases as bronchial
asthma, T.B., pneumonia, cystic fibrosis-also used to clear the airways as in bronchoscopy.
2-Treatment of acute acetaminophen toxicity, considered as its antidote


K Sparing diuretics

Loop diuretics

Thiazides and Thiazide-like


Oral only.
Very slow.
Distal part of DCT.

Oral and IV.

Loop of Henle.

Oral only.
Proximal segment of DCT.

4-Site of action:

2-Spironolactone and Eplerenone
reduce mortality in Heart failure.

2- RBF.

1-Diuretic (mainly by V.D.).

2-Antidiuretic in nephrogenic
diabetes insipidus by RBF.


1-Edema due to hyperaldosteronism.

2-Edema: with thiazides or loop.
3-Hypertension: with thiazides or loop.
4-Heart failure (class IV).

1-Edema: acute and resistant.

2-Hypertension; emergencysevere-and with renal impair.
3-Acute renal failure.

1-Edema due to: Heart failureRenal-Hepatic.

3-Nephrogenic diabetes insipidus.
4-Idiopathic hypercalciuria.
5-Pre-menstrual tension.



3-Gynecomastia and sexual
disturbances (by Spironolactone due to
steroid structure).
4-Gut upset.
5-CNS disturbances.

4-Hypochloremic alkalosis.
5-Hypovolemia and

1-Renal impairment (to avoid

2-With ACEIs or ARBs (to avoid

2-Digitalis toxicity.
3-With Lithium lithium
4-With Aminoglycosides.
5-Diabetes mellitus.
7-With Steroids.
Frusemide-BumetanideTorsemide-Ethacrynic acid.

Aldosterone antagonists:
Spironolactone, Eplerenone. Nonaldosterone antagonists: AmilorideTriamterene.

4-Hypochloremic alkalosis.
5-Hypovolemia and dehydration.

8-Adverse effects:

2-Digitalis toxicity.
3-Renal insufficiency.
4-Hepatic insufficiency.
5-Diabetes mellitus.
7-With Steroids.


Thiazides: ChlorothiazideHydrochlorothiazide.
Thiazide-like: IndapamideChlorthalidone-Metolazone.


How to avoid hypokalemia caused by Thiazides or Loop diuretics:

1-Adding a K+-sparing diuretic as spironolactone, amiloride, or triamterene.
2-Adding ACEI as captopril or ARB as losartan.
3-K+ syrup or SR potassium tablets (irritant and should be avoided in peptic ulcer).
4-Dietary potassium supplementation.
5-Intermittent use of K+ losing diuretics.
Drug Interactions:
Loop diuretics (Frusemide)
Thiazides (Hydrochlorothiazide)

K-sparing diuretics
1-Hyperkalemia antagonizes
1-Hypokalemia induced by thiazide may
the action of digoxin.
precipitate digoxin toxicity.
2-Spirnolactone + Thiazide
2-Thiazides + loop diuretics severe
synergism and correction
of serum K .
3-Frusemide + K sparing diuretics as
3-Spironolactone + loop spironolactone, amiloride, or triamterene
diuretics synergism and
synergism and correction of serum K+.
correction of serum K .
4-Frusemide + ACEIs as captopril
4-Spironolactone + ACEIs
synergism in treatment of HF and
severe hyperkalemia.
hypertension and correction of serum K+.
5- Spironolactone + ARBs
5- Frusemide + ARBs as losartan

1-Hypokalemia induced by thiazide may

precipitate digoxin toxicity.
2-Thiazides + loop diuretics severe
3-Thiazides + K sparing diuretics as
spironolactone, amiloride, or triamterene
synergism and correction of serum K+.
4-Thiazides + ACEIs as captopril
synergism in treatment of HF and
hypertension and correction of serum K+.
5- Thiazides + ARBs as losartan

severe hyperkalemia.

synergism in treatment of HF and

hypertension and correction of serum K+.
6-Frusemide + corticosteroids severe
7-Frusemide antagonizes the hypoglycemic
action of insulin secretagogues as
sulfonylureas (less than thiazides).
8-Frusemide antagonizes the uricosuric
action of uricosuric drugs as probenicid.
9-NSAIDs antagonize partially effect of
frusemide on RBF.
10-Probenicid decreases tubular secretion
of frusemide and antagonizes their diuretic
11-Cross allergy between most most loop
diuretics except ethacrynic acid-and
12-Frusemide displaces warfarin from
plasma proteins and may lead to bleeding.
13-Frusemide decreases renal clearance of
lithium and may lead to lithium toxicity.
14-Frusemide should never be given with
Aminoglycosides as streptomycin because
both are ototoxic.

synergism in treatment of HF and

hypertension and correction of serum K+.
6-Thiazides + corticosteroids severe
7-Thiazides antagonize the hypoglycemic
action of insulin secretagogues as
8-Thiazides antagonize the uricosuric
action of uricosuric drugs as probenicid.
9-NSAIDs antagonize partially the
diuretic and antihypertensive actions of
10-Probenicid decreases tubular secretion
of thiazides and antagonizes their diuretic
11-Cross allergy between thiazides and

Anti-Anginal Drugs
Summary of anti-anginal drugs:
CCBs: Verapami and
(non DHP)

CCBs: Nifedipine


Atreriodilatation and
afterload (much less than

arteriodilatation and

Arteiodilatation and

No vasodilatation.

1-Effect on arteries and

afterload (TPR):

Almost no

Almost no

Potent venodilatation
and preload.

No venodilatation.

2-Effect on veins and

preload (EDV):

V.D. (much less than


V.D. of normal subendocardial vessels

"coronary steal"

V.D of big epicardial

vessels redistribution
of blood into ischemic

Non-selective BB may
cause V.C. due to
unopposed effect.

3-Effect on coronary blood



Reflex tachycardia.

Reflex tachycardia.


Beta Blockers



Decrease (systolic >

Decrease by preload
(mainly) and afterload.

Decrease by cardiac
properties (mainly) +

Decrease by

Beneficial in long-term

1-Beneficial in longterm prophylaxis.

2-May be used S.L
after crushing the

1-Beneficial in acute
attacks (S.L.).
2-Beneficial in
immediate prophylaxis
3-Beneficial in longterm prophylaxis (SR
oral preparations).




Not used because they

should not be combined
with BB to avoid severe
bradycardia and AV




4-Effect on hear rate:


5-Effect on ABP:

Decrease by cardiac
properties and ABP.

6-Effect on cardiac work

and myocardial oxygen

Beneficial in long-term

7-Role in stable angina:


8-Role in variant angina:


9-Role in unstable angina:

All -blockers both selective and non-selective- are useful in prophylaxis of stable angina
because they decrease heart rate, contractility, and ABP leading to decreased cardiac work and
myocardial oxygen demands.
Non-selective -blockers are contraindicated in variant angina because they lead to
"unopposed 1-action" causing more vasospasm.
Cardio-selective -blockers are used with great caution and are better avoided in variant angina
because selectivity is not absolute.
In unstable angina: -blockers without ISA are used (in addition to
I.V. nitroglycerin, nifedipine(CCB), heparin and antiplatelet drugs as aspirin).
Adverse effects and contraindications: see ANS,
But remember that they should never be stopped suddenly.
1-The dose of -blockers is adjusted according to the heart rate, which should not exceed 50-60
beats/minute at rest, and 100-120 beats/minute during exercise.
2--blockers decrease heart rate prolongation of diastole increased end-diastolic volume
(EDV) and ejection time increased cardiac work and oxygen consumption which partially
antagonizes their beneficial effect in angina. This can be corrected by co-administration of
nitrates (nitrates increase heart rate reflexly and shorten diastole).

2-Nitrates and Nitrites:

Organic Nitrates:
1-Nitroglycerin (Glyceryl Tri-Nitrate =GTN).
2-Isosorbide Dinitrate.
3-Isosorbide Mononitrate.
Mechanism of action:
1-The molecule is "de-nitrated" in the tissues, i.e. a nitrite ion is released by glutathione -Stransferase which requires sulfhydryl group.
2-Nitrite molecule is converted into "Nitric Oxide" (N.O.) which stimulates guanylyl cyclase and
increases synthesis of c-GMP which in turn leads to smooth muscle relaxation particularly blood
vessel and mainly veins(by dephosphorylation of myosin light chain kinase).
Pharmacological actions:
1-Nitrates and nitrites are mainly venodilators more than arteriodilators.
*2-Venodilatation decreases venous return (pre-load) which decreases end-diastolic volume
(EDV). This leads to reduction of COP and consequently cardiac work and myocardial oxygen
demands are decreased. Reduction of COP decreases systolic BP.
-Venodilatation causes postural hypotension.3
*4-Arteriodilatation decreases TPR (after-load) which leads to
reduction of cardiac work
and myocardial oxygen demands. Reduction of TPR decreases both systolic and diastolic BP.
(they decrease systolic BP more than diastolic, why?).
5-Reduction of ABP causes reflex sympathetic stimulation causing increased heart rate (reflex
tachycardia) and myocardial contractility, which increases cardiac work and myocardial oxygen
demands. Tachycardia also shortens diastole and decreases coronary perfusion (filling of the
coronaries occurs during diastole).
To correct these unwanted effects of nitrates they are combined with -blockers (or verapamil).
*6-V.D. of normal epicardial coronary vessels leads to opening of collaterals and re-distribution
of blood into the ischemic areas.
(Remember that atherosclerotic vessels can not be dilated).
7-V.D. of cutaneous blood vessels causes flushing.
8-V.D. of meningeal blood vessels causes "throbbing" (pulsating) headache.
*Indicates the beneficial actions of nitrates in angina.
II-Platelets: Nitrates inhibit platelet aggregation by stimulating synthesis of c-GMP in platelet.
III- Other smooth muscle fibres: nitrates cause smooth muscle relaxation of bronchi, GIT,
uterus, and ureters.
IV-Methemoglobinemia: nitrites -and to a much less extent nitrates- oxidize ferrous iron of
hemoglobin into ferric iron. This is especially dangerous in IHD as it causes more hypoxia.
However; methemoglobinemia is useful in treatment of cyanide poisoning (see Pharmacology of
*Therapeutic uses:
1-Angina pectoris: nitrates are useful in all types of angina (stable, variant, and unstable) and all
conditions of angina (acute attacks, immediate prophylaxis, and long-term prophylaxis).
The aim of therapy with nitrates in stable and unstable angina is to reduce cardiac work and
myocardial oxygen demands and not to dilate the coronaries, whereas the aim of the aim of
therapy in variant angina is to dilate the coronaries. They are given S.L. or by buccal spray in

acute attacks and immediate prophylaxis, and are given orally, as skin ointment, and as
transdermal patch for long-term prophylaxis. Nitroglycerin is given by IV infusion in unstable
2-Heart failure: they reduce pre-load mainly and after-load to a lesser extent. Nitroglycerin is
given by IV infusion in acute heart failure. Reduction of pre-load in patients with heart failure
improves myocardial contractility and increases COP (but in patients without heart failure COP
is reduced due to reduction of venous return and EDV).
3-Emergency hypertension: nitroglycerin IV infusion is used.
4-Acute myocardial infarction: nitroglycerin IV infusion decreases cardiac work, dilates the
coronaries, and decreases pulmonary congestion. It may also reduce the size of infarction.
5-Nitrites as amyl nitrite (inhalation) and sodium nitrite (IV) are used in cyanide poisoning
because they cause methemoglobinemia.
6-Treatment of acute bronchial asthma, colics (intestinal, biliary, or renal colics), and contraction
ring of uterus.
*Precautions (Instructions to the patient):
1-Instruct the patient to sit after S.L. administration to avoid postural hypotension.
2-Instruct the patient to get rid of the pellet-by swallowing or spitting- as soon as pain is relieved
to avoid adverse effects.
3-Never stop nitrates suddenly after long use which may lead to rebound ischemia and infarction
(nitrate dependence).
4-Never double the dose: if a dose is missed wait for the next dose.
5-Nitrate-free interval is essential to avoid nitrate tolerance.
6-Do not use after expiry date (drug is ineffective).
7-Never combine with sildenafil.
*Adverse effects:
1-Reflex tachycardia (due to hypotension. It is avoided by adding -blockers or verapamil to
2-Postural hypotension and dizziness, and may cause syncopal attacks (nitrate syncope). This
can be prevented by asking the patient to take S.L. pills when sitting - not in the standing
position- and to get rid of the pill after relief of pain, either by swallowing or spitting.
3-Throbbing (pulsating) headache.
5-Methemoglobinemia and cyanosis especially with nitrites.
6-Allergic reactions as skin rash.
7-GIT disturbances.
8-Nitrate Tolerance: it is due to depletion of tissue SH group required for de-nitration of nitrates.
It is prevented by allowance of "nitrate-free" intervals of 8-10 hours or by alternative use with
other anti-anginal drugs as CCBs and -blockers.
9-Nitrate dependence.
10-Carcinogenicity due to formation of nitrosamines.
1-In factory workers exposed to nitrates it has been noticed that headache and dizziness occur
rapidly after 1-2 days of exposure but rapidly disappear due to the development of nitrate

tolerance. However the symptoms recur at the beginning of the week (after the week-end) and
then disappear again and so on.
2-Nitrate dependence has been observed after prolonged exposure to nitrates if the workers
spend 1-2 days away from nitrates and is manifested as "variant angina".
*Drug Interactions:
1-Nitrates + -blockers (propranolol) = beneficial combination.
2-Nitrates + Verapamil = beneficial combination.
3-Nitrates + Nifedipine = unfavorable combination.
4-Nitrates + Sildenafil (Viagra)) = very dangerous combination because sildenafil causes V.D.,
hypotension, and reflex tachycardia through inhibition of phosphodiesterase 5 leading to
increased intracellular
c-GMP. They are given at least 6-hours apart.
(All are pharmacodynamic interactions)

3-Calcium Channel Blockers (CCBs):

1-Phenylalkylamines as Verapamil.
2-Benzothiazepines as Diltiazem.
3-Dihydropyridines as Nifedipine, Amlodipine, Nimodipine, Nicardipine, Nitrendipine, and
Mechanism of action:
CCBs block voltage-gated Ca2+ channels and inhibit Ca2+ influx into cardiac and smooth muscles
especially arterioles. They act from the inner side of the cell membrane.
It should be noted that CCBs have no effect on skeletal muscles because they do not depend on
Ca2+ influx to induce muscle contraction but depend on release of the stored Ca2+ from the
sarcoplasmic reticulum.
Pharmacological actions:
1-Heart: verapamil and diltiazem have marked effect on the heart more than on arterioles
leading to: bradycardia (-ve chronotropic) decreased AV conduction (-ve dromotropic)
decreased contractility (-ve inotropic) decreased excitability reduction in COP reduction in
myocardial oxygen needs.
(The actions of verapamil on the heart are similar to -blockers).
2-Blood Vessels:
Dihydropyridines as nifedipine relax smooth muscles of arterioles mainly, leading to V.D. of
normal coronaries and other arterioles. Nifedipine causes reduction of TPR and ABP, with
consequent reflex sympathetic stimulation of the heart leading to reflex tachycardia and
increased myocardial contractility. Headache, dizziness, and flushing also occur following V.D.
3-ABP: all CCBs cause hypotension (not related to posture, why?). The hypotensive action of
verapamil is mainly due to reduction in COP, but nifedipine causes hypotension mainly due to
V.D. and reduction of TPR.
B- Smooth muscle fibres: CCBs relax smooth muscles of the uterus, bronchi, GIT, and ureters.
*Therapeutic uses:


1-Angina pectoris: Prophylaxis of all types of angina. Verapamil is usually used in stable angina
as it reduces cardiac work and myocardial oxygen requirements. Nifedipine is usually used in
variant and unstable angina, due to its potent vasodilator effect.
2-Hypertension: all CCBs are useful in treatment of hypertension. Nicardipine I.V. is useful in
emergency hypertrension.
3-Arrhythmias: verapamil and diltiazem are used in supraventricular arrhythmia and are
classified as class IV antiarrhythmic drugs.
(Dihydropyridines as nifedipine are contraindicated in tachyarrhythmias as they lead to reflex
cardiac stimulation).
4-Hypertrophic obstructive cardiomyopathy (verapamil).
5-Cardioprotective in acute myocardial infarction.
6-PVDs as Raynaud's disease (nifedipine).
7-Prophylaxis of migraine headache (flunarizine and verapamil).
8-Premature labor (tocolytic action) and toxemia of pregnency.
9-Nimodipine is used to prevent cerebral vasospasm after subarachnoid hemorrhage.
10-Acute bronchial asthma.
11-Acute and chronic renal failure (to increase RBF).
(N.B. Nifedipine is given S.L. in acute anginal attacks and in emergency hypertension).
*Adverse effects:
A-Common Adverse effects:
2-Constipation (more with verapamil).
3-Headache, flushing, and ankle edema (due to V.D., so they are more marked with
dihydropyridines as nifedipine).
B-Specific adverse effects of verapamil:
2-Reduction of AV conduction.
3-Decreases myocardial contractility.
C-Specific adverse effects of nifedipine:
1-Reflex tachycardia.
2-"Coronary Steal Phenomenon": nifedipine dilates normal coronaries and not atherosclerotic
vessels so the normal myocardium "steals" the blood from the ischemic myocardium.
2-Verapamil is contraindicated in: Bradycardia- AV block Congestive heart failure.
3-Nifedipine is contraindicated in tachyarrhythmias.
*Drug interactions:
A-Pharmacokinetic interactions:
1-CCBs especially verapamil displace digitalis from plasma proteins.
2-CCBs especially verapamil decrease renal excretion of digitalis (digoxin).
B-Pharmacodynamic interaction:
1-Verapamil + -blockers = severe bradycardia, AV block, and diminished contractility and may
cause cardiac arrest.

2-Verapamil + Nitrates = beneficial combination (verapamil prevents reflex tachycardia caused

by nitrates).
3-Nifedipine + -blockers = beneficial combination (-blockers prevent reflex tachycardia
inducedc by nifedipine).
4-Nifedipine + Nitrates = severe hypotension and reflex tachycardia.
5-Verapamil + Nifedipine ???
*Other CCBs:
Bepridil: as verapamil.
Amiodarone: K+-channel blocker + CCB + -blocker + -blocker.
Used as antiarrhythmic (class III) and antianginal but is highly toxic.

4-Antiplatelet Drugs:
They inhibit platelet aggregation and are used in stable and unstable angina. They include:
1-Aspirin (pediatric dose=75-150 mg. /day) and Dazoxiben. They inhibit TXA2 synthesis.
2-Dipyridamole: inhibits phosphodiesterase c-AMP in platelets, blood vessels, and heart
inhibition of platelet aggregation, V.D., and myocardial stimulation (also reflexly due to
hypotension). It is used in stable angina and in thrombo-embolic diseases.
3-Ticlopidine and Clopidogrel: inhibit ADP-dependent platelet aggregation.
4-Sulphinpyrazone: inhibits COX.
5-PGI2 analogues as Epoprostenol.

Anti-Hypertensive Drugs
1-ACE inhibitors (as Captopril) and Angiotensin receptor antagonists (as Losartan).
2-Sympathetic Depressants:
a-Central 2-agonists (as Clonidine and alpha- methyldopa).
b- Competitive ganglion blockers (they are obsolete except Trimetaphan).
c- Adrenergic neuron depressants: Guanethidine-Reserpine (rarely used).
d- Adrenoceptor antagonists: -blockers (as Propranolol) selective 1-blockers (as Prazosin) drugs that block and -receptors(as Labetalol).
3- Calcium channel blockers (as Verapamil and Nifedipine).
4- Diuretics: Thiazide diuretics (as Hydrochlorothiazide)- Loop diuretics (as Frusemide) K+sparing diuretics (Spironolactone- Amiloride- Triamterene).
a- Arteriodilators:

Common action: they cause V.D. of arterioles TPRABP.

Common Adverse effects: hypotension causes reflex sympathetic stimulation leading to:
1- Increased myocardial contractility and heart rate (reflex tachycardia).
2- Increased renin-angiotensin system which stimulates aldosterone synthesis and release causing
Na+ and water retention.
That is why they should be combined with -blockers and loop diuretics.
3- Headache and flushing.
Examples include: Hydralazine Minoxidil- Diazoxide.
b- Venodilators as Nitrates (see Angina Pectoris).
c- Mixed (Balanced or Combined) Dilators: they dilate both arteries and veins, as sodium
(N.B.:ACE inhibitors and selective 1-blockers are also mixed dilators).
1- Arteriodilators cause throbbing headache, flushing, reflex tachycardia, and salt and water
2- Arteriodilators are useful in treatment of hypertension and heart failure as they decrease TPR
= After-load.
3- Venodilators cause postural hypotension and may be syncope which is particularly dangerous
in old patients.
4- Venodilators are less effective in treatment of hypertension than arteriodilators, and are also
used in treatment of angina and heart failure.
5- Drugs that are given orally are used in chronic patients (Thiazides, -blockers, CCBs, ACE
inhibitors, Minoxidil), drugs that are given parenterally only (IV, IV infusion, IM) are used in
emergency hypertension only (Na+ nitroprusside, Diazoxide, Trimetaphan, Fenoldopam). Drugs
that can be given both orally and parenterally are useful in both chronic and emergency
conditions (loop diuretics as Frusemide, Enalaprilat, Hydralazine).

Summary of vasodilators:



IV (injection of large bolus dose rapidly

followed by IV infusion).


Oral and Parenteral.


Excretion in urine by active secretion.

Prodrug, converted into active

minoxidil sulfate.



Opens K+-channel efflux of K+ and

hyperpolarization V.D.

Direct V.D., may be by by release of


Mechanism of

TPR ABP (diastolic > systolic).
2- Arteriodilatation
AfterloadCOP in heart failure.

TPR ABP (diastolic > systolic).
2- Arteriodilatation
AfterloadCOP in heart failure.


Opens K+-channel efflux of K+ and

hyperpolarization V.D.
TPR ABP (diastolic > systolic).
2- Arteriodilatation
AfterloadCOP in heart failure.

3-Reflex sympathetic stimulation due to

hypotension leading to: reflex tachycardia
(avoided by BB) and
RAAS aldosterone salt and
water retention and edema (avoided by
loop diuretics).
2-Inhibits insulin release.

3-Reflex sympathetic stimulation due

to hypotension leading to: reflex
tachycardia (avoided by BB) and
RAAS aldosterone salt and
water retention and edema (avoided by
loop diuretics).

3-Reflex sympathetic stimulation due

to hypotension leading to: reflex
tachycardia (avoided by BB) and
RAAS aldosterone salt and
water retention and edema (avoided
by loop diuretics).

1-Emergency hypertension.
(IV as before).
2-Treatment of insulinoma (given orally).

1-Severe and resistant hypertension

(add BB and frusemide)
2-Heart failure.
3-Treatment of alopecia (topical hair

1-Severe hypertension (add BB and

2-Emergency hypertension.
3-Heart failure.


1-Reflex sympathetic stimulation due to

hypotension leading to: reflex tachycardia
(avoided by BB) and
RAAS aldosterone salt and
water retention and edema (avoided by
loop diuretics).
2-Headache, flushing, and nasal
congestion (due to V.D.).
4-Hyperuricemia (due to reduction of
tubular secretion of uric acid).

1-Reflex sympathetic stimulation due

to hypotension leading to: reflex
tachycardia (avoided by BB) and
RAAS aldosterone salt and
water retention and edema (avoided by
loop diuretics).
2-Headache, flushing, and nasal
congestion (due to V.D.).
3-Hypertrichosis (excessive growth of
body hair).

1-Reflex sympathetic stimulation due

to hypotension leading to: reflex
tachycardia (avoided by BB) and
RAAS aldosterone salt and
water retention and edema (avoided
by loop diuretics).
2-Headache, flushing, and nasal
congestion (due to V.D.).
3-Peripheral neuritis especially in
slow acetylators (prevented and
treated by pyridoxine).
4-Hypersensitivity: fever, rash,
Rheumatoid arthritis-like syndrome,
Systemic lupus erythematosus

Adverse effects:

3-D.M. 4-Gout. 5-Allergy.




4- Fenoldopam:
Selective D1-agonist V.D. of arterioles.
Given by IV infusion.
Used in emergency hypertension.
Adverse effects: Reflex tachycardia- Headache Flushing Elevation of IOP.

Arteriovenodilators (Mixed-Balanced Dilators):

Sodium Nitroprusside:
-Mechanism of action:
Releases nitric oxide (NO) activation of guanylyl cyclase
c-GMP V.D. of both arterioles and veins and inhibition of platelet aggregation.
-Pharmacological actions:
1-Arteriodilatation TPR (after-load) and ABP.
2-Venodilatation Pre-load.
3- Reflex sympathetic stimulation Tachycardia.

4- Inhibits platelet aggregation.

(N.B.: Nitroprusside in normal individuals causes slight reduction of COP due to decrease in
venous return, but in patients with heart failure it increases COP due to reduction in after-load
and ABP).
*Therapeutic uses:
1- Emergency hypertension.
2- Acute heart failure (acute pulmonary edema due to acute left ventricular failure).
3- Controlled hypotension during plastic and neurosurgery (Trimetaphan and Halothane may be
also used).
4-Acute dissecting aortic aneurysm (combined with -blockers).
*Adverse effects:
1- Severe hypotension, reflex tachycardia and arrhythmia, and angina pains are observed with
2- Accumulation of cyanide occurs in hepatic insufficiency and may cause death (It is prevented
and treated by thiosulphate or hydroxocobalamin).
3- Accumulation of thiocyanate occurs in renal impairment and leads to disorientation, weakness,
psychosis, delirium, and convulsions.
It is treated by hemodialysis.
4- Teratogenicity.
5- Rebound hypertension if stopped suddenly.
Precautions during IV infusion of Nitroprusside:
1- Should be freshly prepared.
2- Should be covered with foil-paper to avoid metabolism by sun-light into cyanide.
3- Dose should be adjusted in liver and/or renal impairment and in old age to avoid accumulation
of cyanide and/or thiocyanate.
4- Monitor ABP and heart rate.
5- Never stop infusion suddenly to avoid rebound hypertension.
Very important note: for details of antihypertensive drugs see Applied Medical
Pharmacology Book.

Anti-Heart Failure Drugs

Compensatory Mechanisms in Heart Failure:
They try to increase COP but will eventually fail and heart failure becomes "manifest" or
"decompensated".The compensatory mechanisms include:
1-Increase in cardiac size by hypertrophy and dilatation.
2-Reflex sympathetic stimulation: low COP low ABP (except in hypertensive heart failure)
1- Tachycardia. 2-V.C. of both arteries and veins (after-load and pre-load). 3-Increased reninangiotensin activity increased aldosterone synthesis and release sodium and water
retention edema and increased blood volume.
Drugs Used

Aim of Treatment in Heart Failure

1- Positive inotropic drugs (myocardial stimulants).

2- Vasodilators: Venodilators-Arteriodilators-Mixed
3- Diuretics.
4-BB (Metoprolol-Carvedilol-Bisoprolol), ACEIs,
ARBs, and Spironolactone.

1- Increase myocardial contractility to increase COP.

2-V.D. of both veins and arteries to reduce pre-load
and after-load.
3- Decrease blood volume and edema.
4-To prevent myocardial damage due to high level of
circulating catecholamines.

Positive Inotropic Drugs (Myocardial Stimulants):

To increase myocardial contractility it is essential to increase free Ca2+ inside cardiac cells.
Mechanisms to increase free Ca2+ include:
A- Increasing intracellular c-AMP by:
1- Stimulation of 1-receptors by Dopamine, Dobutamine, and Prenalterol activation of
adenylyl cyclase synthesis of c-AMP.
2- Inhibition of phosphodiesterases (PDE) by Methylxanthines (as Aminophylline) and
Bipyridines (as Amrinone and Milrinone).
B- Increasing intracellular Na+ by inhibition of Na+/K+ ATPase by Cardiac Glycosides (Digitalis

Cardiac Glycosides (Digitalis Preparations):

-Mechanism of action:
Cardiac glycosides partially inhibit membrane-bound Na+/K+ ATPase (Na+ pump) in cardiac cells
increase in intraceullar Na+ increase in intracellular Ca2+ by:
1- Ca2+/Na+ exchange.
2-Release of Ca from sarcoplasmic reticulum.
3- Opening of voltage-gated Ca2+ channels.
Elevation of free Ca2+ increases myocardial contractility.
Very important note:
Cardiac glycosides and potassium (and to a less extent magnesium) compete for Na+/K+ ATPase;
that is why hypokalemia is the most important predisposing factor for digitalis toxicity.
(K+ and Mg2+ activate but digitalis and Ca2+ inhibit the enzyme).
-Pharmacological actions:
1-Positive Inotropic action especially in left ventricular systolic dysfunction.
2-Increased COP in patients with congestive heart failure, but it has no effect or may even
decrease COP in normal individuals due to bradycardia and decreased cardiac size.
3-Increased mechanical efficiency of the heart as digitalis increases contractility (work done)
without marked increase in oxygen consumption (energy consumed).
4-Reduction of cardiac size to normal, and reduction of EDV, ESV, and venous pressure.
5-Heart rate:
Digitalis decreases SAN automaticity; it has negative chronotropic action leading to decrease in
heart rate. Remember that before digitalis there is compensatory tachycardia.
Reduction in heart rate is due to:

1-Vagal action: digitalis stimulates vagal C.I.C. both directly and reflexly through stimulation of
baroreceptors, and sensitizes SAN to acetylcholine. This vagal action is the mechanism of
bradycardia in the beginning of treatment by digitalis (early digitalization).
2-Direct action (extra-vagal action): digitalis decreases SAN automaticity directly and decreases
sensitivity of SAN to catecholamines (anti-adrenergic action). This action occurs after full
Very important note: the earliest objective manifestation of digitalis toxicity is
"BRADYCARDIA 60 beats / minute.
Give reason: Atropine can cause tachycardia if given in early digitalization but cannot produce
tachycardia in fully digitalized patients?
6- Refractory Period (R.P.):
Net effect

Direct Action

Vagal Action
No effect.

1-Atrial R.P.
2-AV R.P.
3-Ventricular R.P.
7- Conductivity:

Net Effect

Direct Action

Vagal Action






No effect.

1-Atrial Conductivity.
2-AV Conductivity.

- SAN: digitalis decreases SAN automaticity leading to heart rate (negative chronotropic).
-AV system: digitalis decreases AV conduction (negative dromotropic). This may lead to AV
block, but it is beneficial in supra-ventricular arrhythmias as it protects the ventricles.
-Purkinje fibres: in therapeutic levels, digitalis has no effect but in digitalis toxicity there is
increased automaticity leading to ectopic pace-makers and ventricular arrhythmias.
Very important note:
Digitalis is useful in treatment of supra-ventricular arrhythmias but is contraindicated in
ventricular arrhythmias.
-In therapeutic levels digitalis increases excitability due to increased intra-cellular Na+ which
causes partial depolarization.
-In cases of digitalis toxicity; excitability may be reduced due to inactivation of fast Na+channels.
-Digitalis "normalizes" ABP if it was low as it increases COP. However; it may increase ABP in
case of toxicity by V.C. (direct action and by stimulation of VMC).
-Digitalis can be used in patients suffering from hypertensive heart failure.
11-Diuretic Action:

Digitalis has a diuretic action only in cases of congestive heart failure as it increases COP
renal blood flow (RBF) GFR. In addition; improvement of COP reduces sympathetic
activity renin-angiotensin-aldosterone system.
12-Blood Volume:
Diuretic action of digitalis in heart failure decreases blood volume.
13-Coronary vessels:
-Therapeutic levels of digitalis have no effect on coronary circulation and it can be used in
patients with angina and heart failure.
-In digitalis toxicity coronary vasospasm may occur.
14- E.C.G.
Prolongation of P-R interval: due to delay in AV conduction.
Short QRS and Q-T segment due to strong short systole and rapid repolarization.
Depressed S-T segment (especially in case of toxicity).
Flat or inverted T-wave. Bradycardia.
Ventricular arrhythmias (extrasystole-Pulsus Bigeminus or Trigeminus-Ventricular tachycardiaVentricular Fibrillation=V.F.).
Therapeutic uses:
1-Congestive heart failure, especially left ventricular systolic dysfunction. Digitoxin and digoxin
can be used in chronic cases whereas digoxin and ouabain can be used in acute heart failure
(acute L.V.F.).
2-Atrial Fibrillation (A.F.): digitalis is useful in A.F. with or without heart failure. It has the
following advantages:
After Digitalis
Before Digitalis
1-Worsens atrial arrhythmia (due to
1-Atrial rate: 400 or more-irregular.
atrial conductivity).
2-Slows ventricular rate to normal by
2-Ventricular rate: about 150-irregular.
AV conduction (protects the ventricle).
3-Eliminates pulse deficit.
3-Pulse deficit present.
4-Restores mechanical efficiency.

4-Diminished ventricular efficiency.

3-Atrial Flutter: digitalis protects the ventricles by reducing AV conduction but it may convert
atrial flutter into A.F.
After stopping digitalis one of the following may occur:
-Normal sinus rhythm is restored and the patient is cured.
-A.F. persists.
-The condition reverses into atrial flutter.
If A.F. persists or atrial flutter recurs; Quinidine is given to restore normal sinus rhythm. It
should be noted that quinidine should never be given before digitalis because quinidine may
increase AV conduction due to atropine-like action leading to ventricular arrhythmia which may
be fatal. In addition; quinidine should never be given with digitalis to avoid serious drug
interactions (see later).
4-Paroxysmal Atrial Tachycardia (PAT) and Nodal Tachycardia: digitalis decreases SAN
automaticity and AV conductivity.
N.B. PAT is also treated by -blockers, verapamil, and M2-agonists as edrophonium and

*Adverse effects (Toxicity):

1-CVS: Bradycardia Partial AV block Ventricular arrhythmias (extrasystole- pulsus
bigeminus or trigeminus - ventricular tachycardia V.F.).
2-GIT: anorexia, nausea, vomiting, colics, and diarrhea. Nausea is mainly due to central
stimulation of CTZ and less probably due to local GIT irritation.
3-CNS: headache, drowsiness, confusion, hallucinations, and convulsions (rare but indicates
serious toxicity).
4-Eye: blurring of visison, disturbance of green and yellow vision (chromatopsia), amblyopia, or
5-Gynecomastia: may be due to steroid structure (remember spironolactone).
1- Bradycardia (including carotid sinus hyperactivity).
2- Partial AV block.
3- Ventricular arrhythmias.
4- Hypertrophic obstructive cardiomyopathy (treated by -blockers or CCBs).
5- Constrictive pericarditis.
6- Severe valve stenosis.
7- Wolf-Parkinson-White syndrome (abnormal conducting fibres).
8-With sympathomimetics as adrenaline (fatal ventricular arrhythmia may occur).
9-Renal impairment (with digoxin) and hepatic impairment (with digitoxin).
*Drug interactions:
A-Pharmacokinetic interactions:
-Drugs that decrease digitalis absorption:
Antacids (Mg. and Al. salts), Antiemetics (metoclopramide), Antidiarrheal drugs (kaolin and
pectin), Antibiotics (neomycin), and Antihyperlipidemic drugs (cholestyramine).
-Drugs that increase digitalis absorption:
Antimuscarinic drugs as atropine and propantheline. They may lead to digitalis toxicity.
Many drugs displace digitalis from plasma proteins and may lead to digitalis toxicity; as
propranolol, NSAIDs as aspirin, CCBs as verapamil and nifedipine, amiodarone, sulphonamides,
and quinidine.
-HME inducers as rifampicin, nicotine, phenytoin, and phenobarbitone decrease bioavailability
of digitalis.
-HME inhibitors as contraceptives and erythromycin increase bioavailability and may induce
digitalis toxicity.
Quinidine and CCBs especially verapamil decrease renal clearance of digoxin and may cause
N.B. Quinidine induces digitalis toxicity by displacing digitalis from plasma proteins and
decreasing its renal excretion.

B-Pharmacodynamic interactions:
1-K+-losing diuretics as thiazides and loop diuretics cause hypokalemia and hypomagnesemia
which predispose to digitalis toxicity.
2-K+-sparing diuretics cause hyperkalemia which antagonizes digitalis.
3--blockers and verapamil antagonize inotropic action of digitalis but augment bradycardia and
AV block.
4-Sympathomimetics acting as 1-agonists as adrenaline may lead to ventricular arrhythmia.
5-Ca2+ salts increase the action of digitalis and may lead to toxicity.

*Digitalis Toxicity:
Cardiac glycosides have low therapeutic index (narrow safety margin).
The earliest manifestations of toxicity: nausea and vomiting, and bradycardia below 60
beats /minute. Other manifestations of toxicity: see before.
Digitalis toxicity is usually chronic (digitalis is a cumulative drug) and rarely acute due to high
loading dose especially in old age.
Factors predisposing to digitalis toxicity:
1-Hypokalemia and hypomagnesemia due to concurrent use of thiazides or loop diuretics with
digitalis in treatment of heart failure. Corticosteroids and carbenoxolone (aldosterone-like) also
cause hypokalemia.
4-HME inhibitors (see before).
5-Drugs that displace digitalis from plasma proteins (see before).
6-Drugs that reduce renal clearance of digoxin (see before).
7-Acidosis, hypoxia, and ischemia: decrease activity of Na+/K+ ATPase and increase the effect of
8-Hypothyroidism decreases elimination of digitalis.
9-Old age: dimished liver and kidney functions reduce elimination of digitalis.
10-Hepatic insufficiency reduces metabolism of digitoxin and renal impairment reduce renal
excretion of digoxin.
*Prevention of digitalis toxicity:
1-Avoid and correct predisposing factors.
2-Monitoring plasma level of digoxin (therapeutic level: 0.5-2ng./mL.) and digitoxin (therapeutic
level: 10-25 ng./mL).
*Treatment of digitalis toxicity:
1-Stop digitalis.
2-In case of hypokalemia: stop K+-losing diuretics and give KCl (syrup, sustained release tablets,
or slowliy IV infusion) except in case of renal impairment and AV block.
3-In case of hypercalcemia: give Ca2+ chelating agent as disodium edetate IV.
4- To treat AV block use atropine.
5- To treat ventricular arrhythmias With AV block: Phenytoin.
To treat ventricular arrhythmias Without AV block: Lidocaine or -blockers.


6- In case of acute toxicity: Digoxin antibodies (Fab fragments) are given, and cholestyramine to
decrease oral absorption of digitoxin.
Very important notes:
1-DC shock (electric cardioversion) is contraindicated in digitalis toxicity as it may lead to V.F.
2-Quinidine is contraindicated in treatment of arrhythmias due to digitalis toxicity (why?).

Other Positive Inotropic Drugs:

*Mechanism of action: inhibit PDE type 3 increase in c-AMP.
*Pharmacological actions: Positive inotropic action and V.D. which reduces pre-load and afterload (they are known as "Ino-dilators").
-Amrinone = Inamrinone: given IV for short-term treatment of acute heart failure. It is highly
toxic and may cause thrombocytopenia and hepatotoxicity.
-Milrinone: more potent and less toxic than amrinone.
*Mechanism of action: inhibits PDE type 4 and increases c-AMP.
*Pharmacological actions: positive inotropic + V.D. (also inodilator) + bronchodilator +
Diuretic + CNS stimulant.
*Given slowly IV in acute heart failure (increases COP for 30 minutes).
3-1-Agonists: Dopamine Dobutamine Prenalterol (see ANS).
The Role of -Blockers in Heart Failure:
Traditionally -blockers are contraindicated in heart failure because the have negative inotropic
action and may precipitate heart failure in compensated cases.
Recently some -blockers as Bisoprolol, Metoprolol, and Carvedilol are given in very small
doses and very gradually increased, to protect the heart against the mitogenic effect of high
circulating catecholamines on cardiac cells which induces remodeling and apoptosis.

CNS Pharmacology
Sedative/ Hypnotics and Anxiolytics:
Bz1 Agonists
Well absorbed orally.

well absorbed orally. Pharmacokinetics:

Metabolized in the liver.

Specific Bz1 agonists.

2-Hypnotic action (little REM
and minimal hangover).
Anticonvulsant-AntispasticityTolerance and dependence.

Given IV.
Irregular absorption after IM injection due to
binding to muscle proteins, except Lorazepam.
Highly bound to plasma proteins.
Pass BBB.
Pass placental barrier.
Fate: most Bz are activated in the liver-some Bz
are inactivated by the liver (Lorazepam and
Oxazepam)-Clorazepate is a prodrug activated by
Bz are Agonists that stimulate specific Bz 1,2
(omega) receptors opening of chloride channels
hyperpolarization and post-synaptic neuronal
inhibition , i.e. facilitate GABA transmission.
2-Anxiolytic action.
3-Hypnotic action (little REM and minimal
4-Anesthetic action.
6-Anticonvulsant and Antiepileptic action.
7-Antispasticity action.
8-Taming action in wild animals.
9-Alprazolam has anti-depressant action.
NO: Autonomic-Extrapyramidal-HME inductionCVS or Respiratory actions in therapeutic doses.

Mechanism of

Bz1 Agonists

Day-time anxiety (due to short


1-Anxiety disorders.
2-Insomnia (Flurazepam-Temazepam-Triazolam).
3-Epilepsy (Diazepam-Clonazepam-Lorazepam).
4-Convulsions (DiazepamIV
5-Skeletal muscle spasticity (Clonazepam).
6-Pre-anesthetic medication and IV anesthesia
7-Depression and anxiety (Alprazolam).
8-Alcohol withdrawal.
9-Diagnostic aids in Psychiatry.
1-Amnesia, Ataxia.
2-Day-time Sedation (with long acting Bz),
rebound insomnia and anxiety (with short acting

Therapeutic Uses:

Adverse effects;



4-Increased appetite and weight gain.
5-Sexual dysfunction.
7-Gut upset.
8-Tolerance and dependence (addiction).
10-Mental confusion and hypotension in old age.
11-Acute toxicity: if given with other CNS
depressants as alcohol.
Short acting: Triazolam-Midazolam.
Intermediate acting: Lorazepam-OxazepamAlprazolam-Temazepam-Clonazepam-Estazolam.
Long acting: Diazepam-FlurazepamChlordiazepoxide-Clorazepate-QuazepamPrazepam.
Flumazenil: selective Bz competitive antagonist.



1- Agonist (or partial agonist) on 5-HT1A receptors.
Therapeutic uses:
Generalized Anxiety Disorders (GAD).
Advantages over Benzodiazepines:
1-No: sedation, drowsiness, hypnosis, amnesia, ataxia, no effect on driving skills.
2-Little tolerance, dependence, and additive effect with alcohol.
3-No cross tolerance with barbiturates or benzodiazepines.
1- Delayed onset of action.
2-No anticonvulsant, antiepileptic, skeletal muscle relaxant actions.
3-Adverse effects: nervousness, tachycardia, GIT distress (nausea mainly).

Less potent-relieves mainly low intensity
pain (superficial pain).
Irreversible non-selective inhibition of all

Comparison between Morphine and Aspirin:

Potent-relieves any type of pain
(especially deep visceral pain) except
Agonist on specific opiate receptors

2-Mechanism of action:

types of COX leading to inhibition of

prostaglandin synthesis centrally and
Central on subcortical level (thalamus) and
peripheral (due to anti-inflammatory action).
Antipyretic-Anti-inflammatoryNo narcosis, drowsiness, euphoria, tolerance,
or dependence.
Superficial pain as headache-toothachearthralgia-myalgia-dysmenorrhea.


(mu, kappa, and delta).

Central on cortical and subcortical
levels (supraspinal and spinal).

3-Analgesic action:

Narcosis-Stupor and DrowsinessEuphoria-Tolerance-Dependence

(addiction) on prolonged use.
Deep visceral pain as cancer painsacute myocardial infarction-ColicsPostoperative pain.

4-Other actions:
5-Analgesic in:

Comparison between Morphine and Meperidine:


Not an opium alkaloid.
Into normeperidine (active) and
meperidinic acid (inactive).
Rapid onset and short duration.
Agonist on opiate receptors (mainly

Natural from plant origin (Papaver somniferum).

Phenanthrene opium alkaloid.
Into morphine -6-glucuronide (more active) and
morphine -3-glucuronide (inactive).
Delayed onset and longer duration.
Agonist on opiate receptors ( and ).

Less potent (1/10).

Less or no narcosis.
Less; especially in newborn.
Not antitussive.
In large and toxic doses.
In large and toxic doses or with
MAO inhibitors.
Has atropine-like action.
No miosis; may be mydriasis

In some human females and some animals.
In large and toxic doses due to inhibition of GABA
No atropine-like action.
Miosis (central).

Less or no action (atropine-like).


Less addictive.

Highly addictive.

-Analgesic in deep visceral pain.

-Pre-anaesthetic medication.
Better than morphine in:

-Analgesic in deep visceral pain.

-Acute heart failure.
-Pre-anaesthetic medication.

5-Onset and duration:
6-Mechanism of
R.C .depression:
Atropine-like action:

Potent due stimulation of CTZ.


Emetic action
(nausea, vomiting):
Spasmogenic action
on GIT and

Colics-Obstetric analgesiaPreanaesthetic medication.

-Neurogenic shock.
-Insomnia due to pain.

Comparison between Aspirin and Paracetamol (Acetaminophen):

Aniline derivative.
-Well absorbed orally.
-Passes BBB.
-Passes placental barrier.
-Slightly bound to plasma proteins.
-95% is metabolized by: conjugation with
glucuronic acid and sulphate (major
pathway), and oxidation into NABQI (minor
-5% excreted unchanged.
Inhibition of PG synthesis centrally by
reversible selective COX-3 inhibition.

Salicylic acid derivative.

-Well absorbed orally, partially absorbed from
the stomach.
-Passes BBB.
-Passes placental barrier.
-Highly bound to plasma proteins.
-75% is metabolized mainly by conjugation with
glucuronic acid and glycine, 1% oxidized into
gentisic acid.
-25% is excreted unchanged in urine (excretion
is enhanced by alkalinization of urine).

Inhibition of PG synthesis centrally and -Mechanism of action:

peripherally by irreversible non-selective COX

Analgesic Antipyretic only.

Analgesic Antipyretic Antiinflammatory

Antiplatelet Uricosuric.

1-Analgesic in superficial pains.

2-Antipyretic in fever.

1-Analgesic in superficial pains.

2-Antipyretic in fever.
3-Anti-inflammatory in RF, RA, OA.
4-Antiplatelet for prophylaxis of thromboembolic diseases.

Allergy Acute toxicity.

Allergy Bronchospasm Gut upset and

ulceration Bleeding-Teratogenicity, delayed
labor, and premature closure of DA Salicylism
Hemolytic anemia in G6PD deficiency Reye's
syndrome Acute toxicity.
Allergy-bronchial asthma-peptic ulcerpregnancy-favism-bleeding disorders children
with viral infections (as influenza).

Allergy to acetaminophen.



*Adverse effects:


Anti-epileptic drugs
Valproic acid and Sodium valproate Phenytoin (Diphenylhydantoin)
1-Blocks sodium channels (as phenytoin)
2-Blocks T-type calcium channels (as
3-Inhibits GABA transaminase so increases GABA

Blocks sodium channels leading to

membrane stabilization.

Mechanism of

4-Antagonizes excitatory transmitters as aspartate.
All types of epilepsy (broad-spectrum antiepileptic)
including petit-mal, but:
1-Not the drug of choice in petit-mal epilepsy as it
may cause sedation and hepatotoxicity
(Ethosuximide is the drug of choice).
2-The drug of choice in mixed epilepsy (petit-mal +
grand-mal) and in myoclonic epilepsy.

1-Grand-mal epilepsy.
2-Partial epilepsy (seizures).
3-Status epilepticus (given slow I.V.).
Not in petit-mal epilepsy as it may worsen

Uses in Epilepsy:

1-Manic-depressive disorders (as mood stabilizer).

2-Prophylaxis of migraine headache.

1-Trigeminal neuralgia (neropathic pains).

2-Class I-B antiarrhythmic in ventricular
arrhythmias with AV block as in digitalis
toxicity (drug of choice).

Other uses:

1-GIT irritation.
1-CNS: confusion-hallucinations2-Transient alopecia.
cerebellovestibular dysfunction (ataxia,
3-Teratogenicity (spina bifida).
vertigo, diplopia, nystagmus).
4-Bone marrow depression (thrombocytopenia).
2-Gut upset: anorexia,nausea,vomiting
5-CNS: ataxia and sedation.
(irritant due to high alkalinity, so it is given
6-Cholestatic hepatitis (and may lead to
after meals).
3-Hirsutism due to its androgenic effect.
7-Drug interactions:
-HME inhibition leading to decreased metabolism of
5-Gum hyperplasia which is irreversible
phenytoin. 6-Allergy and lymphadenopathy which may
-Displaces phenytoin from plasma protein binding
be mis-diagnosed as Hodgkins lymphoma.
sites and increases its plasma level. 7-During pregnancy:cleft palate and hare lip
(fetal hydantoin syndrome) if given in first
trimester, and hypoprothrombinemia and
bleeding of newborn if given before labor
due to increased metabolism o vitamin K
(prevented and treated by vitamin K).
8-Blood: hypoprothrombinemia (see
before), and folic acid deficiency leading to
megaloblastic anemia due to increased
metabolism of folic acid (prevented and
treated by folic acid).
9-Osteomalacia of bones due to increased
metabolism of vitamin D (prevented and
treated by vitamin d and calcium).
10-Decreased release of ADH and insulin
(may cause hyperglycemia).
11-Drug interactions:
-Induces its own metabolism tolerance to
the anti-epileptic action.

Adverse effects and

drug interactions:


-Induces metabolism of other drugs as

digitoxin, theophylline, cortisone, and oral
-Displaces thyroxine and TCAs from plasma
proteins but is displaced by aspirin,
sulphonamides, and valproic acid.
-Other HME inducers as barbiturates and
carbamazepine increase its metabolism.
-HME inhibitors as valproic acid and
cimetidine decrease its metabolism and may
lead to phenytoin toxicity.
-Increases metabolism of vitamin K leading
to hypoprothrombinemia and bleeding.
-Increases metabolism of vitamin D leading
to hypocalcemia and osteomalacia.
-Increases metabolism of folic acid leading
to folic acid deficiency anemia
(megaloblastic anemia) and increases
toxicity of methotrexate (anticancer folate

Related to tricyclic antidepressants (cross allergy).
Mechanism of Action: as phenytoin.
Pharmacological actions:
2-Mood stabilizer.
Therapeutic uses:
1-Treatment of epilepsy: grand-mal and partial seizures.
2-Manic-depressive illness.
4-Trigeminal neuralgia.
4-Diabetic neuropathy.
Adverse effects and Drug interactions:
As phenytoin except: gum hyperplasia-hirsutism-increases ADH release causing fluid retention.



Selective inhibition of neuronal reuptake Inhibition of neuronal reuptake (uptake 1)

(uptake 1) of Serotonin only by neurons
of both Noradrenaline and Serotonin (5-

Mechanism of action:

leading to increased Serotonin level HT) by neurons leading to increased level

of both neurotransmitters
intersynaptically (cocaine-like action).
1- Antidepressant action: mood elevation 1-Antidepressant action: mood elevation
occurs after 2-3 weeks and lasts for 2-3
occurs after 2-3 weeks and lasts for 2-3
after stopping.
after stopping.
2-No antimuscarinic action.
2-Antimuscarinic (atropine-like) action.
3-No alpha blocking action.
3-Alpha blocking action.
4-No antiserotonin action.
4-Antiserotonin action.
5-No antihistaminic action. 5-Antihistaminic and H2 blocking actions.
6-No sedation, they cause Insomnia.
7-No lowering of seizure threshold.
7-Lower the seizure threshold.
8-No weight gain, they cause Anorexia and
8-Increase appetite and weight gain.
weight loss.
1-Psychic depression.
1-Psychic depression (SSRIs are the most
2-Anxiety disorders (Neurosis) as Panic
commonly prescribed antidepressants).
and Phobic disorders.
2-Anxiety disorders (Neurosis) as Panic
3-Obsessive Compulsive Disorders
and Phobic disorders.
3-Obsessive Compulsive Disorders (OCD).
4-Nocturnal enuresis in children.
4-Eating disorders as Bulimia nervosa.
5-Chronic Neuropathic pains as
Trigeminal neuralgia.
1-Anorexia and weight loss.
3-Sexual dysfunction.
4-Anxiety, aggression, violence, and
suicidal tendency.

2-Lowering of seizure threshold.
3-Increased appetite and weight gain.
4-Atropine-like manifestations: dry
retention-blurred vision and elevation of
5-Cardiotoxicity: ventricular arrhythmias
which may be fatal.
6-Alpha blocking actions: Postural
hypotension, reflex tachycardia, and
delayed ejaculation.
7-Allergy: agranulocytosis and
cholestatic hepatitis (jaundice).
8-Acute toxicity: TCAs have low
therapeutic index and toxicity occurs with
large doses, manifested by: Coma,
Cardiotoxicity, Convulsions, and
atropine-like signs as red hot dry skin and
passive mydriasis.

Pharmacological actions:

Therapeutic uses:

Adverse effects:

1-With MAOIs Serotonin syndrome:

excitation, convulsions, hyperpyrexia,
coma and may be fatal.
2-Fluoxetine is a HME inhibitor.

7-With MAOIs Atropine-like toxicity.


Imipramine (active) Desipramine

Amitriptyline (active) Nortriptyline



Chlorpromazine (Typical Antipsychotic-Neuroelptic-Major Tranquilizer):


Adverse effects

1-Treatment of
Psychosis as
Schizophrenia. It
improves mainly

A-Receptor Blocker:
1-Potent D2 blocker in: limbic
system-CTZ-basal gangliahypothalamus.

Blocks D
receptorsmainly D2-in
the limbic

3-Hypotension and
cardiac diseases as
angina and
7-Liver diseases.


(Akathisia, dystonia,
tremors) and
(prevented and
treated the dose
and by
antimuscarinics as
impotence and loss
of libido in malesgalactorrhea and
amenorrhea in
obstructive hepatitis
and jaundice.
9-Increased appetite
and weight gain.
10-Corneal and lens

positive signs as
2-Antiemetic, but not
effective in motion
sickness and
contraindicated in
3-Severe persistent
5-Hypothermic agent
during GA.
6-Severe itching

2-Potent 1 blockerpostural
hypotension, reflex tachycardia,
delayed ejaculation.
3-Potent 5-HT blocker.
4-Weak M-blocker (atropinelike).
5-Weak H1-blocker
6-Weak ganglion blocker.
7-Weak NM blocker (curare-like
2-Antiemetic not motion
3-Extrapyramidal manifestations
and Parkinsonism.
5- Appetite.
8-Lowers seizure threshold.
9-Potentiates CNS depressants
as morphine, barbiturates,
C-Autonomic actions:
1-Alpha blocking action.
2-Atropine-like action.
3-Ganglion blocking action.
4-Inhibits neuronal reuptake.
1-Heart: tachycardia (reflex +
G.B. + atropine-like)Myocardial depression
(quinidine-like action).
2-B.V.: V.D. (alpha block mainly
+ GB + direct).
3-ABP: hypotension (postural).
E-Othe actions:
Na+-channel blocker L.A.

GIT Pharmacology


The aim of treatment of peptic ulcer is to restore the balance between the mucosal offensive
agents (HCl, pepsin, and H.pylori) and the mucosal protective agents (PGs mainly) by the
following drugs:
I-Anti-secretory drugs: they reduce HCl secretion, and are used for "healing of the ulcer".
II-Anti-microbial drugs: to eradicate H.pylori.
III-Mucosal protective agents.
IV-Antacids: to relieve pain and hyperacidity, i.e they are used only for "symptomatic treatment"
and not for healing of the ulcer.
N.B.: Corticosteroids and NSAIDs except paracetamol- cause peptic ulcer by inhibition of PG
synthesis; this is known as Iatrogenic ulcer and is best prevented and treated by PG analogues as

I- Anti-secretory Drugs:
These drugs reduce HCl secretion from the parietal cell of the stomach and are classified
according to the mechanism of action into:
1-H2-Antagonists: Cimetidine, Ranitidine, Nizatidine, Famotidine.
2-Proton Pump Inhibitors (PPIs): Omeprazole, Esomeprazole, Lansoprazole, Pantoprazole,
3-Anti-Muscarinic Drugs (Anticholinergic drugs = Muscarinic antagonists): Pirenzepine,
Telenzepine, Dicyclomine (selective M1-blockers), Propantheline, Oxphenonium, Atropine
methyl nitrate, Hyoscine butyl bromide (quaternary ammonium compounds).
They decrease HCl secretion and also reduce pain by decreasing motility of GIT.
4-Prostaglandin Analogues: e.g. Misoprostol.
It is a prostaglandin E1 analogue.
It acts both as anti-secretory drug and mucosal protective agent.
It is the drug of choice in prophylaxis and treatment of iatrogenic ulcers caused by cortisol and
It causes abdominal cramps and diarrhea.
It is contraindicated in pregnancy because it is a powerful oxytocic and may lead to abortion.

Cimetidine Ranitidine Nizatidine Famotidine.
Absorbed orally and can also be given by IV injection.
-Pass BBB and may cause CNS adverse effects especially in old age and in renal impairment.
-Pass placental barrier and may cause teratogenicity.
-Bound to plasma proteins.
Partly metabolized by the liver and excreted in urine (unchanged mainly and as metabolites).
They are also excreted in breast milk.
-Mechanism of action:
Competitive antagonists with histamine released from enterochromaffin-like cells (ECL) at H2receptors in gastric parietal cells.
-Pharmacological actions:

1-Reduction of HCl secretion (basal, nocturnal, stimulated by histamine, food, gastrin, vagus,
insulin, and drugs as methylxanthines and muscarinic agonists).
2-Reduction of both volume and H+ ion concentration of gastric juice.
3-Reduction in pepsin secretion.
4-Mild reduction of intrinsic factor without impairment of vitamin B12 absorption, so no
incidence of pernicious anemia.
5-No effect of gastric emptying or GIT motility (in contrast to antimuscarinic drugs).
*Therapeutic uses:
1-Peptic ulcer; both gastric and duodenal ulcers. They are given in a dose of 2 tablets / day for 68 weeks until healing of the ulcer, then given in a maintenance dose of 1 tablet / day for 6 months
to prevent recurrence of the ulcer.
2-Zollinger Ellison syndrome: gastrin-secreting tumor of the pancreas accompanied with peptic
3-Gastro-Esophageal Reflux Disease (GERD) = Reflux esophagitis.
4-Prevention and treatment of upper GIT bleeding following severe trauma, burns, and acute
renal failure. They are given IV.
5-Treatment of stress ulcers and iatrogenic ulcers.
6-Treatment of hiatus hernia.
7-Other uses: Combined with H1-blockers (antihistaminics) and NSAIDs in treatment of
symptoms of systemic mastocytosis Combined with antihistaminics in treatment of resistant
*Adverse effects:
1-Recurrence of the ulcer in case of sudden stoppage of H2-antagonists.
2-Allergic reactions: skin rash.
3-GIT disturbances: diarrhea.
4-Blood dyscrasias: bone marrow depression as aplastic anemia and granulocytopenia.
5-Cholestatic hepatitis and jaundice.
6-CNS disturbances: drowsiness, confusion, tremors, slurred speech, delirium and hallucinations.
They are more common in old age and in renal impairment (dose should be adjusted according to
renal function).
7-Teratogenicity and affect nursing babies.
8-Rarely CVS manifestations as bradycardia and hypotension.
9-Cimetidine causes sexual dysfunctions in males (gynecomastia, impotence, loss of libido and
decreased sperm count causing infertility), and in females (galactorrhea and breast tenderness).
This is probably due to hyperprolactinemia in both sexes and due to anti-androgenic effect in
*Drug interactions:
1-Cimetidine is a hepatic microsomal enzyme inhibitor (inhibitor of CYP 450) and decreases
clearance of theophylline, warfarin, phenytoin, digitoxin, and propranolol and may cause serious
adverse effects by these drugs.
2-Decreased gastric acidity may decrease the effect of clorazepate (prodrug activated by gastric
acid) and sucralfate (see later), and may decrease absorption of Ca2+, iron, and some drugs as
digoxin, and ketoconazole (antifungal).


2- Proton Pump Inhibitors (PPIs):

Omeprazole Esomeprazole Lansoprazole- Pantoprazole Rabeprazole.
*Chemistry: PPIs are basic drugs.
Absorbed orally and are given in the form of "enteric-coated tablets" to prevent degradation by
HCl. Pantoprazole may be given IV.
-Pass BBB and may cause CNS disturbances.
-Highly bound to plasma proteins.
Metabolized in the liver by CYP 450 and metabolites are excreted in urine.
-Mechanism of action:
PPIs are concentrated in the acidic secretory canaliculi of parietal cell because they are basic
drugs, then they are activated (they are "prodrugs") into active metabolites which cause
"irreversible inhibition of H+/K+ ATPase", also known as the proton pump. They have long
duration of action.
-Pharmacological actions:
1-Reduction of HCl secretion (as H2-blockers).
2-Reduction of H+ ion concentration with minimal effect on volume of gastric juice, pepsin
secretion, and intrinsic factor secretion.
3-No effect on gastric emptying and GIT motility.
*Therapeutic uses:
1-Peptic ulcer: given in a dose of 1 tablet / day for 4 weeks in duodenal ulcer, and for 8 weeks in
gastric ulcer.
2-Zollinger Ellison syndrome.
3- GERD.
*Adverse effects:
1-Allergy: skin rash.
2-GIT disturbances: nausea, abdominal pains, diarrhea.
3-CNS disturbances: headache, dizziness, and somnolence.
4-Decreased gastric acidity may lead to:
-GIT infections.
-Increased gastrin secretion (no negative feedback of HCl) which may lead to gastric carcinoma
(carcinoid tumor due to hyperplasia of ECL cells). However; this was found to occur in rodents
and not in humans.
-Colonization of bacteria producing carcinogenic nitrosamines.
-Decreased absorption of Ca2+, iron, and some drugs as digoxin and ketoconazole.
*Drug interactions:
1-HME inhibitors (inhibit CYP 450) and decrease clearance of warfarin, theophylline, and
2-Decreased acidity decreases absorption of Ca2+, iron, digoxin and ketoconazole.

II- Mucosal Protective Agents:

1-Prostaglandin Analogues: e.g. Misoprostol (see before).

2-Sucralfate (Aluminium sucrose sulphate):

*Mechanism of action:
1-Sucralfate is given orally and dissociates in the presence of HCl into Al3+ and sucrose sulphate
(negatively charged) which adheres to the positively charged proteins in the base of the ulcer
forming a protective layer against HCl and pepsin.
2-It adsorbs pepsin.
3-It stimulates synthesis of PGs.
*Role in peptic ulcer:
Stimulates healing and prevents recurrence. It is given orally on an empty stomach (at least 1
hour before meals) in a dose of 1 g. 4 times daily.
*Adverse effects: (most adverse effects are due to aluminium)
2-Decreases absorption (and oral bioavailability) of many drugs given orally at the same time as
quinolones, tetracyclines, digitalis, ketoconazole, and phenytoin.
Important note: Sucralfate should not be given with anti-secretory drugs as H2-antagonists and
PPIs or with antacids because it is "activated" in the acidic medium of the stomach.
3- Carbenoxolone:
-Derivative of glycyrrhizic acid which is obtained from liquorice.
-Aldosterone like structure.
*Pharmacokinetics: absorbed orally highly bound to plasma proteins eliminated in bile.
Stimulates healing of the ulcer and protects mucosa by stimulation of mucus secretion and PG
synthesis (it acts on aldosterone receptors).
*Adverse effects: are due to aldosterone-like action:
1-Na+ and water retention leading to elevation of ABP, edema, and heart failure in cardiac
Hypertension Congestive heart failure-Renal and liver impairment and old age.
*Important note:
To correct Na+ and water retention and hypokalemia caused by carbenoxolone amiloride and
triamterene (non-aldosterone K+ sparing diuretics) are used but spironolactone (aldosterone
antagonist) is avoided because it will antagonize the ulcer healing action of carbenoxolone.
4- Colloidal Bismuth Compounds: e.g. Bismuth subcitrate.
1-Mucosal protective action by: coating the ulcer decreasing pepsin stimulating PG synthesis
leading to increased mucus secretion.
2-Anti-microbial action against H.pylori.
*Adverse effects:
Black discoloration of mouth, tongue, teeth, and stools.

III- Antacids:
Antacids are drugs that neutralize excess HCL.


Antacids are used for symptomatic treatment to relieve ulcer pain and hyperacidity and are not
useful for healing of ulcers.
Antacids are classified into:
A-Physical antacids: they adsorb HCl and pepsin.
B-Chemical antacids: they chemically antagonize HCl and are further subdivided into:
1-Systemic antacids: NaHCO3 which causes "systemic alkalosis".
2-Local (non-systemic) antacids: Aluminium and magnesium salts which do not cause systemic

Comparison between different antacids:

Sodium Bicarbonate


Aluminium Salts


1-Rapid onset.
2-No diarrhea or constipation.
3--Alkalinize the urine in:
treatment of acute toxicity by
acidic drugs as salicylates
with uricosuric drugs in
prophylaxis of gout
prevention of crystalluria
caused by some drugs as

1-No systemic alkalosis.

2-No CO2 release.
3-Long duration.
4-Mg trisilicate acts
both chemically and

1-No systemic alkalosis.

2-No CO2 release.
3-Long duration.
4-Al hydroxide gel acts both
chemically and physically.


1-Systemic alkalosis.
2-Releases CO2 leading to
distension, discomfort,
rebound acidity, and may be
rupture (perforation).
3-Hypernatremia which may
cause edema, elevate ABP,
and heart failure.
4-Short duration.
5-Alkalinization of urine may
precipitate phosphate stones
and decreases renal excretion
of basic drugs as ephedrine
and amphetamine.

1-Delayed onset.
3-Decreases oral
absorption of
tetracyclines, warfarin,
digoxin, ketoconazole,
theophylline, ranitidine.

1-Delayed onset.
3-Decreases oral absorption of
quinolones, tetracyclines,
warfarin, digoxin, ketoconazole,
theophylline, ranitidine.
4-Hypophosphatemia (except Al
phosphate gel).

Important Notes:
1-NaHCO3 is also used:
-To alkalinize the urine in: treatment of acute toxicity by acidic drugs as salicylates with
uricosuric drugs in prophylaxis of gout prevention of crystalluria caused by some drugs as
-To treat systemic acidosis.

-To dissolve thick mucus and facilitate expectoration (alkaline expectorant).

2-Magnesium salts include: Mg oxide- Mg hydroxide Mg trisilicate which is both a chemical
and physical antacid.
3-Aluminium salts include: Al hydroxide gel which acts both physically and chemically- Al
Phosphate gel which acts both physically and chemically and have the advantage that it does not
decrease absorption of dietary phosphate and accordingly does not cause hypophosphatemia.
IV- Anti-Microbials To Eradicate H.pylori:
Combination of 2 or 3 of the following anti-microbials are used for 2 weeks in cases of peptic
ulcers associated with H.pylori infection:
2-Amoxycillin (broad spectrum penicillin).
3-Clarithromycin ( Macrolide).
5-Colloidal Bismuth compounds.

Intestinal Evacuants (Treatment of Constipation)

II-Glycerin suppository III-Cleansing Enema
Softens stools.
Large volume of fluid.
Mild irritation of rectum.
Mild irritant.
Suitable for children &adults.High head pressure.

I-Physical (Luminal)Purgatives
II-Irritant (Chemical)
A-Bulk forming B-Lubricant C-Surfactant
1-Bran (food).
Liquid paraffin. Dioctyl sodium Castor oil. 1-Anthracenes:
4-Plantago seeds.
5-Osmotic purgatives=
3-Bisacodyl. Saline
purgatives as Magnesium sulphate.
I-Physical (Luminal)Purgatives
A-Bulk forming Purgatives:
They increase bulk of gastric and intestinal contents stretch of wall reflex peristalsis.
They act on BOTH small and large intestine.
Onset of action: 1-3 hours taken in the morning.
1-Food: contains bran and methylcellulose (undigested fibers in vegetables) and is suitable and
safe for chronic constipation in elderly.
2-Plantago seeds and agar: imbibe water.
3-Osmotic (Saline) purgatives:
Examples: Magnesium sulphate (Epsom salt) Sodium sulphate- Mg oxide + Mg hydroxide
(Milk of Magnesia).
Given orally in the morning on empty stomach (15 g. isotonic solution).
Non-absorbable osmotic salts retain water in bowel
increase bulk of gastric and intestinal contents stretch of wall reflex peristalsis.
Release cholecystokinin evacuation of bile from gall bladder into small intestine
Synthetic disaccharide made up of Galactose + Fructose.
Non-digested Non-absorbed osmotic laxative retain water in bowelincrease bulk of
gastric and intestinal contents stretch of wall reflex peristalsis.
Split in the colon by colonic bacteria into Lactic acid and other acids which lower pH of
colon inhibition of proteolytic bacteria (ammonia-forming bacteria).
2-Hepatic (ammonia) encephalopathy given with Neomycin to reduce synthesis of ammonia in
B-Lubricant purgatives: Paraffin oil (Liquid paraffin):
Non-absorbable synthetic mineral oil.
Softens and lubricates hard stools and mucosa of large intestine.
Onset of action: 8-10 hours; so given at night.
Useful in chronic habitual constipation.
Adverse effects (disadvantages);

1-Bad consistency (usually added to fruit juice or given as emulsion).

2-Decreases absorption of fats and fat-soluble vitamins as vitamin L leading to
hypoprothrombinemia and augments action of warfarin, and vitamin D leading to decreased bone
and teeth calcification in children.
3-Decreases absorption of other drugs as oral contraceptives.
4-Systemic absorption leads to hepatic foreign body reaction or lipoid pneumonia.
5-Leakage from the anus leads to: anal polypi -pruritus ani -delayed anorectal wound healing
(after piles or anal fissures).
C-Surfactants = Surface active agents (Detergents).
Lower surface tension of hard stools facilitate water penetration wetting and softening of
Given at night.
Example: Dioctyl sodium sulphosuccinate.
II-Irritant (Chemical ) Purgatives:
Common Action: chemically irritate sensory nerve endings in gut mucosa reflex peristalsis
evacuation of the bowel.
1-Colics, diarrhea, and dehydration (avoided by adding small doses of atropine or hyoscine).
2-Decrease absorption of food and other drugs.
3-Induces pelvic congestion leading to dysmenorrheal and increase menstrual bleeding, and
abortion in pregnant females.
4-May be excreted in breast milk and affect suckling babies.
A-Mild Irritant Purgatives= Castor oil:
Plant oil.
Split in small intestine by Lipase enzyme in bile into Glycerin and Ricinoleic acid which
irritates the nerve endings in small intestine inducing reflex peristalsis.
Given in the morning.
B-Moderate Irritant Purgatives:
1-Anthracene derivatives:
Examples: Aloe-Senna-Cascara.
They release Emodin and Crysophanic acid in large intestine which cause irritation.
Given at night.
1-See before (common adverse effects).
2-Red discoloration of alkaline urine.
3-Pigmentation of mucosa of large intestine.
Has entero-hepatic circulation long duration.
Given at night.
1-See before (common adverse effects page 19).
2-Red discoloration of alkaline urine.

3-Liver damage.
Chemically related to phenolphthalein but no entero-hepatic circulation and so short duration.
Given orally and rectally (suppository).
Sodium Picosulphate is related to Bisacodyl.
Severe Irritant Purgatives (as croton oil and colocynth) are obsolete due to severe colics,
diarrhea, dehydration, and GIT perforation.
Therapeutic uses of Intestinal evacuants (Purgatives):
1-Treatment of constipation.
2-Before abdominal surgery, radiology, and endoscopy.
3-Drug and food poisoning: e.g after morphine poisoning.
4-To prevent straining in heart failure, hernia, after eye and neurological operations.
5-Before and after treatment of Helminthes as Tinea solium.
Stool softeners: Glycerin suppository-Liquid paraffin-Dioctyl sodium sulphosuccinate. They are
useful in chronic (habitual) constipation.

Endocrine Pharmacology
Anti-Diabetic drugs
GLP-1 receptor agonists

1-Exenatide (short duration).

2-Liraglutide (long duration).

DPP-IV inhibitors

Amylin analogues

Mechanism and

S.C. injection.
Stimulate Glucagon-Like
Peptide-1 (GLP-1) receptors
leading to:
1-Stimulation of insulin release
from B-cells.
2-Decrease glucagon release
from A-cells.
3-Delay gastric emptying (to
prevent sudden elevation of
blood glucose after meals).
4-Suppress appetite (CNS

Inhibit Di-PeptidylPeptidase-4 (DPP-IV)
enzyme endogenous
GLP-1 stimulation of
GLP-1 receptors leading to:
1-Stimulation of insulin
release from B-cells.
2-Decrease glucagon release
from A-cells.
3-Delay gastric emptying (to
prevent sudden elevation of
blood glucose after meals).
4-Suppress appetite (CNS


Type II D.M.step 4.

Type II D.M. step3 and 4

Adverse effects

1-Hypoglycemia (when
combined with SU).
2-Nausea is very common.
3-Decreased absorption of
some drugs as paracetamol due
to delayed gastric emptying.
4-Given only by injection.

1-Animal insulin: from animal pancreatic extracts and is either:

S.C. injection.
Stimulates amylin
receptors leading to:
1-Decrease glucagon
release from A-cells.
2-Delay gastric emptying
(to prevent sudden
elevation of blood
glucose after meals).
3-Suppress appetite
(CNS action).
N.B. amylin does not
stimulate insulin release
(it may even reduce
insulin release but this is
Type I and Type II D.M.
to prevent post-prandial

-Bovine: differs from human insulin in 3 amino acids and is highly antigenic.
-Porcine: differs from human insulin in 1 amino acid and is less antigenic than bovine insulin.
2-Human insulin: obtained by 2 different techniques:
-Synthesis by recombinant DNA technology (Bio-synthetic insulin).
-Enzymatic modification of animal insulins (Semi-synthetic insulin).
Human insulin is the least antigenic but is much more expensive.
Insulin is composed of 2 polypeptide chains: A chain made up of 21 amino acids, and B chain
made up of 30 amino acids. Both chains are connected by 2 disulphide links which are essential
for the biological activity of insulin.
*Factors Affecting Insulin Release:
Factors Stimulating Insulin Release
Factors Inhibiting Insulin Release
1-Glucose (the most potent stimulus): glucose
1-Fasting and starvation: increase sympathetic
enters B-cells by GLUT 2 and undergoes
activity leading to release of adrenaline and
glycolysis to form ATP, which in turn blocks
noradrenaline which stimulate 2-receptors thus
ATP-sensitive K+ channels depolarization inhibit insulin release.
opening to voltage-dependent Ca2+ channels 2-Somatostatin (inhibits glucagon release more
influx of Ca2+ insulin release.
than its inhibitory action on insulin).
2-Amino acids (leucine and arginine) and fatty
2-PG E1.
acids in diet.
3-Autonomic innervation and receptors:
3-GIT hormones (incretins) as Glucagon-like
2 stimulation, 2 block, and muscarinic block.
peptide 1 (GLP-1) and Gastrin inhibitory
peptide (GIP).
Thiazides, Loop diuretics, and Diazoxide:
4-Systemic Hormones: Glucagon and growth
open ATP-sensitive K+ channels in B-cells
hormone (secondary to increased blood
leading to hyperpolarization.
Phenytoin (Na+ channel blocker).
5-Autonomic innervation and receptors:
CCBs as Verapamil.
Muscarinic stimulation, 2 stimulation, and 2
block increase insulin release.
6-Insulin secretagogues (Oral hypoglycemic
drugs, e.g. sulfonylureas and meglitinides).
-Insulin is never given orally because it is a polypeptide; i.e. it is destroyed by proteolytic
enzymes in GIT.
-All insulin preparations are given by S.C. injection.
-Only regular (soluble) insulin is given IV Only in case of diabetic ketoacidosis (D.K.A.).
-Insulin is distributed to all tissues.
-Fate: insulin is metabolized by glutathione insulin transhydrogenase (insulinase) in liver and
kidney which breaks the disulphide links, then the polypeptide chains are degraded by
-Mechanism of action:
Insulin acts by stimulation of specific insulin receptors.
Insulin receptors are "Tyrosine Kinase linked".

Each receptor is composed of 2 -subunits on the cell membrane, and 2 -subunits that transfix
the cell membrane (partly extracellular and partly intracellular). These subunits are linked by
disulphide links.
Insulin molecule binds to -subunits of insulin receptors which then activate -subunits leading
to activation of tyrosine kinase and phosphorylation of different enzymes which initiate the
biological actions of insulin; e.g. glucose transporters (GLUT) which glucose uptake.
The insulin receptor then undergoes "conformational change" and "internalization", then it is
either degraded or "recycled" to the cell membrane.
-Pharmacological actions:
"Remember that insulin is an anabolic hormone".
1-Action on Carbohydrate Metabolism:
Insulin tends to reduce blood glucose by the following mechanisms:
-Stimulation of glucose uptake by formation of "glucose transporters" as GLUT 4 which is
responsible for glucose uptake into skeletal muscles and adipose tissue.
-Stimulation of glucose utilization by glycolysis (glucose by glucokinase glucose 6 phosphate
-Stimulation of glycogenesis and inhibition of hepatic glycogenolysis.
-Inhibits gluconeogenesis.
2-Action on Protein metabolism:
-Amino acid transport and stimulates synthesis of proteins.
-Inhibits gluconeogenesis ( protein degradation).
3-Action on Fat Metabolism:
-Stimulates lipogenesis by stimulating lipoprotein lipase andadipocyte fat storage.
-Inhibits lipolysis by inhibition of triglyceride lipase.
-Free fatty acids in blood.
-Fatty acid oxidation and inhibits ketone bodies synthesis (inhibits ketogenesis).
4-Stimulates transport of K+, Mg2+, and phosphate and decreases their plasma level.
Insulin deficiency in D.M. is characterized by:
1-Hyperglycemia and glucosuria due to:
-Glucose uptake and utilization.
2-Free fatty acids in blood due to:
3-Oxidation of free fatty acids and formation of ketone bodies (ketogenesis).
4-Amino acid uptake and protein synthesis and protein catabolism.
5-Weakness, immunocompromization and recurrent infections.
*Indications of insulin:
A-Diabetic indications:
1-Treatment of Type I (IDDM): replacement therapy from the time of diagnosis and throughout
2-Treatment of Diabetic Keto-Acidosis (DKA) by soluble insulin IV.


3-Temporarily in Type II (NIDDM) in cases of "stress" due to: infections surgery pregnancy
4-Permanently in Type II (NIDDM) in cases of:
-Failure to control hyperglycemia by diet + exercise + oral anti-diabetics.
-Development of renal or hepatic impairment.
-After recovery from DKA.
B-Indications of insulin in "non-diabetic cases":
-Treatment of hyperkalemia due to renal impairment (glucose should be given with insulin to
avoid hypoglycemia).
*Adverse effects:
A-Local Adverse Effects:
1-Lipodystrophy: either hypertrophy (more common due to insulin-induced lipogenesis) or
atrophy of subcutaneous fats. It is prevented by changing (rotating) the site of injection.
2-Local allergic reactions; they are rare nowadays due to the use of human insulin instead of
animal insulin.
3-Localized infections.
B-Systemic Adverse Effects:
Hypoglycemia is the most dangerous adverse effect of insulin therapy.
1-Insulin overdose (too much insulin).
2-Ommission of meals (too little food).
3-Exhaustive physical exercise (too much exercise).
-Sympathetic stimulation: tachycardia and palpitations (the most important warning symptoms)
tremors sweating pallor.
-Neuroglycopenia: headache blurred vision and diplopia confusion coma and may end in
-If the patient is conscious: treatment by oral glucose or sweeting agents (juice, chocolate, etc.).
-If the patient is comatosed: treatment by IV glucose (50 mL. of 50% glucose) or by glucagon
(1mg.) given IM or SC followed by oral glucose.
2-Systemic allergic reactions (uncommon because human insulin has largely replaced animal
3-Insulin resistance (daily insulin requirements exceed 200 Units, common in obese nonexercising patients, and may improve by adding insulin sensitizers as glitazones).
4-Hypokalemia may occur especially with insulin therapy in DKA.

Biguanides (Metformin)
-Mechanism of action: unclear but may act

Comparison between Sulfonylureas and Biguanides:

Mechanism of action:


1-Increases insulin sensitivity by stimulation
of binding to its receptors.
2-Decreases oral absorption of glucose from
3-Decreases glucagon release from pancreas.
4-Increases action of insulin in peripheral
tissues and thus stimulates glucose uptake and
utilization by skeletal muscles and adipose
5-Stimulates anaerobic glycolysis.
6-Inhibits hepatic gluconeogenesis ( hepatic
glucose output).
7-Decreases appetite leading to weight
(Remember that metformin does not stimulate
insulin release, this is why it is euglycemic not

Sulphonylureas block ATP-sensitive K+channels in pancreatic cells depolarization

and influx of Ca2+ release of insulin from
pancreatic B cells of islets of Langerhans.
Pharmacological actions:
1-Stimulation of insulin release from
pancreas. This is the main action of
sulphonylureas, and depends on the presence
of some insulin in the pancreas.
2-Inhibition of glucagon release from
3-Increase sensitivity of -cells to glucose.
(Actions 1, 2, and 3 are known as "Pancreatic
4-Increase tissue sensitivity to insulin.
5-Suppress hepatic gluconeogenesis.
(Actions 4 and 5 are known as "Extrapancreatic action".

1-NIDDM especially in obese patients, and

may be combined with sulphonylureas.
2-Treatment of diabetes insipidus.
3-Polycystic ovary with anovulatory cycles
(often in obese diabetic females).
1-Lactic acidosis: it is the most serious
adverse effect and may lead to coma and death
in 50% of cases. It is common in cases of:
renal impairment-hepatic insufficiency and
alcoholism-congestive heart failure (CHF)chronic obstructive pulmonary disease
(COPD)-old age.
2-GIT upsets (most common): anorexia,
nausea, vomiting, bloating, colics and
3-Prolonged use decreases GIT absorption of
vitamin B12 and may lead to macrocytic
hyperchromic anemia.

1-NIDDM: alone in non-obese patients, or in

combination with metformin if one drug can
not control hyperglycemia.
2-Chlorpropamide is used in pituitary diabetes
insipidus because it stimulates ADH release.
1-Hypoglycemia: is the most serious adverse
effect. The causes, manifestations, and
treatment are identical to insulin-induced
2-Hypersensitivity reactions: skin rash and
photosensitivity, and cross allergy with
3-Gut upsets: nausea, vomiting, diarrhea.
4- Stimulation of appetite and increased
5-Cholestaic jaundice especially with
6-Disulfiram-like action (alcohol-intolerance)
especially with chlorpropamide.
7-Dilutional hyponatremia due to excessive
release of ADH especially with
8-Teratogenicity and fetal hypoglycemia.
9-High incidence of acute myocardial
infarction and sudden death especially with
first generation sulphonylureas.


Adverse effects:

Metformin is contraindicated in conditions

that increase lactic acidosis:
1-Renal impairment (elimination of
metformin and lactic acid).
2-Hepatic insufficiency and alcoholism
(elimination of lactic acid).
3-CHF (causes hypoxia).
4-COPD (causes hypoxia).
5-Old age (associated with renal and hepatic

10-CNS disturbances: drowsiness, confusion,

and ataxia.
11-Bone marrow depression (blood
12-Failure of therapy: either "primary" failure
(no response to sulphonylureas from the start
of therapy), or "secondary" failure (failure to
control hyperglycemia after 1-2 years of
initial improvement, which may be due to
refractoriness of -cells or loss of dietary
1-Type I D.M.
3-Pregnancy and lactation.
4-Renal and hepatic impairment.
5-After recovery from DKA.
6-NIDDM in conditions of stress: pregnancyinfections-surgery.

Pharmacokinetic interactions:
1-Sulphonylureas displace oral anticoagulants
as warfarin from plasma proteins leading to
2-Sulphonylureas are displaced by NSAIDs as
aspirin and phenylbutazone, and
sulphonamides from plasma proteins and may
augment the hypoglycemic effect of
3-Probenecid decreases renal excretion of
sulphonylureas and may augment their
hypoglycemic effect.
4-Alcohol hypoglycemia.
Pharmacodynamic interactions:
1-Thiazide diuretics, loop diuretics,
diazoxide, and phenytoin antagonize the
hypoglycemic effect of sulphonylureas
because they inhibit insulin
release (thiazides, loop diuretics, and
diazoxide open ATP-sensitive K+-channels
and phenytoin blocks Na+-channels).
2-Corticosteroids and oral contraceptives
cause hyperglycemia and antagonize the
hypoglycemic effect of sulphonylureas.


Drug interactions:

3-Non-selective -blockers as propranolol

inhibit 2-mediated hepatic glycogenolysis
thus may augment the hypoglycemic effect of
sulphonylureas, and all -blockers mask the
warning symptoms of hypoglycemia
especially tachycardia and palpitations- and
may lead to "silent hypoglycemia". They do
not inhibit sweating, which is a cholinergic
action not mediated by -receptors.
4-Sympathomimeics cause hyperglycemia by
stimulation of hepatic glycogenolysis (2).
Metformin only. First Generation: they are less potent than
the second generation and not used clinically
anymore in D.M.:
Tolbutamide: metabolized mainly by the liver
and is "short acting".
Acetohexamide: metabolized into active
metabolite and excreted mainly in urine and is
"intermediate acting".
Chlorpropamide: about 80% excreted in urine
and 20% metabolized by the liver, and is
"long acting" (action lasts up to 60 hours).
It stimulates secretion and action of ADH and
is used in pituitary (central) diabetes
Second Generation: they are more potent
and well tolerated (less adverse effects) than
the first generation and all are "intermediate
acting", i.e. act for about 12 to 24 hours. They
Glibenclamide (also known as Glyburide and
is contraindicated in patients with creatinine
clearance less than 50 ml. / min.) -Glipizide
Gliclazide- Glimeperide (most potent).


Mechanism of action: see Applied Medical Pharmacology book, page 286.

1-Sudden withdrawal of
glucocorticoids after
prolonged use.

2-Peptic ulcer.
3-Diabetes mellitus.


6-In digitalis toxicity and

with K+ losing diuretics.

Adverse effects
Toxic effects from
sudden withdrawal:
1-Suppression of HPA
axis and adrenal atrophy
which leads to acute
insufficiency if
exogenous steroids are
suddenly stopped after
prolonged therapy.
withdrawal syndrome:
fever, myalgia, arthralgia,
and malaise.
Toxic effects due to
continued use of large
1-Iatrogenic Cushing'
syndrome: moon facebuffalo hump-trunkal
obesity- wasting of
2-Iatrogenic peptic ulcer
and acute pancreatitis.
3-Hyperglycemia and
4-Skeletal muscle
wasting and myopathyosteoporosis-sublaxation
of joints-delayed wound
healinggrowth retardation in
5-Na+ and water retention
leading to edema and
weight gain, elevation of
ABP, and may cause HF.

1-Acute adrenocortical
1-Negative feed-back inhibition of
insufficiency (acute
Addisonian crisis) due to
cortex with suppression of
sudden withdrawal of endogenous glucocorticoid synthesis.
exogenous steroid
Atrophy of the adrenal cortex may
therapy, or due to stress
occur due to inhibition of ACTH.
(trauma or infection).
2-Metabolic Actions:
Treatment by
On Carbohydrate metabolism:
Hydrocortisone sodium
-Anti-insulin actions: stimulate
succinate IV +
gluconeogenesis and inhibit glucose
0.9% NaCl IV infusion +
uptake and utilization.
glucose 5% IV infusion.
-Stimulate glycogenesis in liver.
2-Chronic adrenocortical -The net result is Hyperglycemia and
insufficiency (chronic
Addison's disease):
On Protein metabolism:
treated by oral steroids
Glucocorticoids cause protein
having both gluco- and
catabolism in most tissues except
mineralocorticoid actions
liver- as skeletal muscles, bone,
as cortisol or
lymphoid tissue, and connective
fludrocortisone (see tissue leading to muscle wasting and
myopathy, osteoporosis, growth
B-Suppressive Therapy:
retardation in children, and delayed
Suppression of ACTH in
wound healing.
treatment of
On Fat metabolism:
-Lipolysis of fats in limbs, thighs,
and buttocks.
Therapy: -Lipogenesis in face, back, and trunk
1-Anti-allergic in
leading to "moon face", "buffalo
angioneurotic edema,
hump", and trunkal obesity. This is
dermatitis, allergic
known as Fat Redistribution.
rhinitis, allergic
3-Mineralocorticoid action:
conjunctivitis, glucocorticoids have aldosterone-like
anaphylactic shock.
action causing Na+ and water
2-Anti-inflammatory and
reabsorption and hypokalemia. This
anti-allergic in bronchial may lead to edema, elevation of ABP,
asthma (inhaled steroids
and may dangerous in patients with
as beclomethasone in
CHF. Severe hypokalemia occurs if
prophylaxis, and
given with thiazides and loop
hydrocortisone sodium
succinate IV in status
In addition; they are essential for
diuresis of excess water (may be
3-Anti-inflammatory and
through inhibition of ADH).
immunosuppressive in
4-On vitamin D and Ca2+:

7-Uncontrolled infections.


and masking of
inflammation leading to
infection by T.B., viral
and fugal infections (as
candidiasis). Inhaled
steroids cause
candidiasis and
9-Increased blood
coagulability and
10-Catarct and glaucoma.


11-Hirsutism and
menstrual disturbances.
12-CNS manifestations:
psychosis or mania.

10-Psychotic patients. 13-Teratogenicity.


auto-immune diseases
glucocorticoids have anti-vitamin D
(collagen diseases) as
action and decrease Ca2+ absorption
rheumatic carditis, R.A., from GIT and increase Ca2+ excretion
S.L.E., nephrotic
by the kidney, leading to
syndrome, chronic
Hypocalcemia (negative calcium
hepatitis, and ulcerative
colitis (may be given as
5-Anti-inflammatory action:
retention enema).
-By inhibition of phospholipase A2
4-Anti-inflammatory in:
(through synthesis of lipomodulin
acute gouty arthritis
and macrocortin by neutrophils and
resistant to NSAIDs,
macrophages, respectively) leading
osteoarthritis (may be
to inhibition of synthesis of
given intra-articular), and
inflammatory mediators: PGs,
cerebral edema (avoid
leukotrienes, and platelet activating
glucocorticoids with saltfactor (PAF).
retaining effect).
-Inhibit migration of macrophages.
-Decrease circulating lymphocytes,
after organ
eosinophils, monocytes, basophils.
transplantation to prevent -Decrease synthesis of inflammatory
cytokines and interleukins.
5-Blood diseases as:
-Stabilize lysosomal membrane and
leukemia (acute inhibit release of lysosomal enzymes.
lymphocytic leukemia),
-Decrease capillary permeability.
6-Immunosuppression and Antipurpura, agranulocytosis,
allergic actions:
and hemolytic anemia.
Through inhibition of antibody
6-Hypercalcemia and formation, antigen-antibody reaction,
hypervitaminosis D
and tissue response to
(vitamin D intoxication).
7-Action on blood:
-Increased number of RBCs due to
increased release from bone marrow
-Increased number of neutrophils due
to inhibition of migration
-Increased number of platelets
-Increased blood coagulability.
-Decreased number of lymphocytes
due to catabolic effect on lymphoid
tissue (lymphopenia).
-Decreased number of eosinophils
8-Action on Serum Uric Acid:
Uricosuric action and decrease serum

uric acid.
9-Action on CNS: cause euphoria
and may lead to psychosis.
10-Action on Respiratory system:
-Anti-inflammatory in bronchial
-Increase number of 2-receptors and
prevents down regulation by 2agonists.
-Stimulate production of surfactant in
11-Action on GIT: inhibit synthesis
of cytoprotective PGE2 and
PGI2and accordingly increase HCl
and decrease mucus leading to peptic
ulcer. This iatrogenic ulcer is best
prevented and treated by
12-Anti-stress and Anti-shock: (by
increasing blood volume and BP by
hypernatremia, by increasing blood
sugar, and by CNS action).

Anti-Thyroid drugs

Given orally and concentrated in thyroid

1-Antagonizes the action of TSH and

decreases iodide trapping and reduces
the size and vascularity of the gland if
given for 10-15 days (see
2-Iodide also inhibits protease enzyme
and inhibits release of stored hormones
and so it has a rapid onset of action.
3-Inhibition of iodide organification.

1-Pre-operative preparation before

subtotal thyroidectomy.
2-Treatment of thyrotoxic crisis (with
PTU and Propranolol).
3-Prophylaxis of goiter (added to salt,
bread, and water).
4- Iodine is also used as "saline
expectorant" in productive cough.

Thioamides (Thioureas)
Absorbed orally. PTU is incompletely absorbed
and can also be given IV in thyrotoxic crisis.
-Highly bound to plasma proteins.
-Concentrated in thyroid gland.
-Pass BBB.
-Pass placental barrier and may cause fetal
goiter or cretinism. PTU is the safest thioamide
in pregnancy (PTU does not cross placental
-Carbimazole is a prodrug and is metabolized
into active methimazole.
-Thioamides are metabolized by the liver by
conjugation and metabolites are excreted in
urine. They are excreted in breast milk and
affect suckling infants.
Mechanism of action:
1-Inhibit peroxidase enzyme and accordingly
inhibit oxidation of iodide into iodine.
2-Inhibit organification of iodine and formation
of MIT and DIT.
3-Inhibit coupling of MIT with DIT and DIT
with DIT thus inhibiting synthesis of T3 and T4.
4-PTU also inhibits peripheral de-iodination.
5-Inhibition of iodine absorption from GIT.
Pharmacological actions:
Inhibition of synthesis of "new" thyroid
hormones but no effect on iodide uptake and no
effect on release of already formed and stored
hormones. That is why they have delayed onset
of action (about 2 weeks) until the stored
hormones are depleted and due to long t1/2
of thyroid hormones.
1-Treat mild cases of hyperthyroidism. They
are given until the patient is "euthyroid" then a
smaller maintenance dose is given to prevent
2-Temporary control of hyperthyroidism in
patients treated by radioactive iodine which has
very delayed onset of action (about 2-3
3-Pre-operative preparation before subtotal
thyroidectomy to decrease the stored hormones




Rapid onset within 24 hours by

inhibition of proteolysis and release of
the stored hormones.

1-Allergy: skin rash, angioedema,

anaphylaxis,ulceration of mucous
2-Iodism: iodide is concentrated in
exocrine glands as the salivary glands,
nasal glands, lacrimal glands, and
bronchial glands leading to irritation and
increased secretion which causes:
metallic taste-sialadenitis and salivationrhinorrhea (runny nose)- lacrimationproductive cough.
It also causes nausea, vomiting, and

Allergy to iodide.

before operation, but they have the

disadvantage of increasing the size and
vascularity of the gland (corrected by iodides
before thyroidectomy).
4-PTU is also used in thyrotoxic crisis.
Delayed onset for 1-2 weeks at least, because
thioamides prevent synthesis of new thyroid
hormones but have no effect on the already
formed stored hormones as they do not inhibit
the release of hormones, and the long t1/2 of
thyroid hormones (t1/2 of T4=7 days).
1-Allergy: is common and may manifest as skin
rash, pruritis, fever, cholestatic hepatitis and
jaundice, or nephritis.
2-Bone marrow depression (blood dyscrasias):
is the most dangerous and is usually in the form
of toxic (dose-dependent) agranulocytosis.
Frequent blood count should be performed to
detect agranulocytosis. Low-grade fever and
sore throat are the earliest manifestations of
agranulocytosis which is treated by: Stopping
the drug- fresh blood transfusion-broad
spectrum penicillins-anabolic steroids.
3-Arthralgia and joint stiffness.
4-Gut upsets: anorexia, nausea, vomiting, and
5-Increase size and vascularity of the gland:
thioamides T3 and T4 TSH (reduced
negative feed-back inhibition) increased size
and vascularity of the gland.
6-Goitre and hypothyroidism in fetus and
suckling infants if given during pregnancy
(except PTU) and lactation.
7-Other adverse effects: headachedepigmentation and loss of hair aggravate
exophthalmos-iatrogenic hypothyroidismrecurrence if stopped suddenly.
2-Pregnancy (except PTU) and lactation.

Onset of action in

Adverse effects:


Comparison between Thioamides and Radioactive Iodine I131:

Given orally-concentrated in thyroid colloid.

See before.


Emits destructive beta and gamma particles that destroy thyroid follicular
Very slow onset after 1-2 months. Maximum response appears after other
2 months.
2-Thyroid carcinoma.
1-Iatrogenic hypothyroidism (main disadvantage).
2-Thyroid storm (due to excessive release of stored hormones).
3-Cretinism if given during pregnancy or lactation.
4-Very slow onset.
5-Repeated doses may be needed.
6-Leukemia and carcinomas of the neckmay appear after 15-20years?
1-Pregnancy and lactation.
2-Young age.

See before.


See before.

Onset of action:

See before.


See before.

Adverse effects:

See before.



Oral Contraceptive Pills

Mechanism of action:
1-Inhibition of the development of ovarian follicles by inhibiting the release of FSH (Estrogen).
2-Inhibition of ovulation by inhibiting LH (Progestogen).
3-Formation of thick mucus (mucus plug) at the cervix to prevent passage of sperms
4-Alter the endometrium making it unsuitable for implantation of the fertilized ovum (both
estrogen and progestogen).
5-Interference with the coordinated contractions of the smooth muscles of the Fallopian tubes,
cervix and uterus to prevent fertilization and implantation (both estrogen and progestogen).


Adverse effects

1-Hypertension, ischemic heart disease, and heart


3-Diabetes mellitus.
4-Fibroids and endometrial carcinoma (estrogendependent).
5-Pre-menopausal breast carcinoma (estrogendependent).
6--Undiagnosed vaginal bleeding (which may be due to
endometrial or vaginal carcinoma).
7-Thromboembolic diseases.
8-Females over 35 years to avoid thromboembolism,
hypertension, DM, especially in obese and smokers.

9-Liver and gall bladder diseases.


1-Nausea mainly and less commonly vomiting.

2-Breast tenderness (mastalgia).
3-Salt and water retention leading to edema, weight
gain, hypertension, and heart failure.
4-Decreased libido (corrected by adding progestins).
5-Headache and increased frequency of migraine.
6-Increase TBG and CBG, and elevate sedimentation
7-Failure of withdrawal bleeding (misinterpreted as
8-Hyperglycemia and impaired glucose tolerance.
9-Fibroids and Endometrial carcinoma (corrected by
adding progestins).
10-Premenopausal breast carcinoma (estrogendependent tumors).
11-Vaginal carcinoma in females whose mothers
received estrogen (diethylstilbestrol) as post-coital pills
(see later).
12-Thromboembolism and antagonizes the action of
oral anticoagulants as warfarin due to increase in
hepatic synthesis of coagulation factors II
(prothrombin), VII, IX, and X. This may cause deep
venous thrombosis (DVT) leading to pulmonary
embolism. Acute myocardial infarctions and
cerebrovascular strokes may also occur.
The risk of thromboembolism is higher in females over
35 years and in smoker females.
13-Cholestatic hepatitis and jaundice, gall stones,
cholangitis, and cholecystitis.
15-Feminization in males with cancer prostate treated
by estrogen.

Summary of Antibiotics
I- Cell Wall Inhibitors:
Adverse effects (toxicity)

Mechanism of action

Action on


1-Hypersensitivity (allergy).
2-Diarrhea-superinfectioninhibition of floravitamin
K and B synthesis.
3-CNS toxicity (seizures in
large doses).
4-Platelet dysfunction.
interstitial nephritis.
7-Jarisch-Herxheimer reaction
in syphilis.
1-Hypersensitivity (allergy
and cross allergy with
3-Diarrhea-superinfectioninhibition of floravitamin
K and B synthesis.
4-Bleeding (platelet
dysfunction + anti-vitamin K).
5-Pain at site of IM injection.
1-Allergy and cross allergy
with penicillin.
2-Gut upset.
3-Seizures (in large doses).
4-Neutropenia and

1-Bind to PBPinhibit
transpeptidase inhibit
formation of cross linking
between peptidoglycan
layersinhibition of cell
wall synthesis.
2-Activation of
autolysinscell wall lysis.



As Penicillins.



As Penicillins.



As Penicillins.



1-Ototoxicity. Not as Penicillins (inhibit as

2-Nephrotoxicity. earlier step: polymerization
of peptidoglycan.).
3-"Red man syndrome".


Vancomycin and


II- Inhibitors of Protein Synthesis:

Adverse effects (toxicity)

Mechanism of

Action on


Erythromycin mainly:
1-Epigastric pain, diarrhea, and colics.
2-Cholestatic jaundice and hepatitis
(caused by esteolate ester).
3-Allergy (skin rash).
4-Ototoxicity (azithromycin).
5-Erthromycin and clarithromycin are
HME inhibitorstoxicity by warfarin
and phenytoin
1-Pseudomembranous colitis (treated
by oral vancomycin + metronidazole).
2-Liver impairment.
3-Gut upset.
4-Allergy (skin rash).
1-Ototoxicity (deafness-vertigo).
3-Skeletal muscle weakness
4-Allergy (contact dermatitis).

Bind irreversibly to
50 S ribosomal
of protein synthesis.

Bacteriostatic in low
concen. and
bactericidal in high


As Macrolides.

As Macrolides.


Bind to 30 S
of protein synthesis
(formation of
defective proteins).
Bind to 30 S
ribosomal subunit
inhibition of
protein synthesis.





Bacteriostatic and
may be bactericidal.


1-Epigastric pain, hyperacidity,

ulcerations, bleeding.
3-Chelation with Ca2+ in bone (bone
deformity) and teeth (enamel
5-Fanconi syndrome (nephrotoxicity
by expired tetracyclines).
6-Allergy and phototoxicity.
7-Diarrhea, superinfection by candida,
vitamin B and K deficiency.
1-Bone marrow depression=Aplastic
anemia (reversible or irreversible).
2-Hemolytic anemia in favism
(deficiency of G-6PD).
3-Grey baby syndrome.
4-Diarrhea, superinfection, deficiency
of vitamin K and B.

Bind to 50 S
ribosomal subunit
inhibition of
protein synthesis.

5-HME inhibition toxicity by


III- Inhibitors of Nucleic Acid Synthesis:

Adverse effects

Mechanism of

Action on


2-Hemolysis in favism.
3-Bone marrow depression.
jaundice, and kernicterus
(in neonates).
Megaloblastic anemia (folic
acid deficiency anemia).

Inhibit folic acid

synthesis by competition
with PABA.



Inhibits folic acid

synthesis by inhibition
of dihydrofolate
As sulpha +



As sulpha + trimethoprim.
2-CNS disturbances.
3-Gut upset.
4-Allergy (skin rash) and
6-HME inhibition.
1-Orange-red discoloration.
2-Flu-like syndrome.
4-CNS disturbances
5-Gut upset.
6-HME inducer.
1-Gut upset (metallic taste).
2-CNS disturbances
3-Teratogenicity and
4-Disulfiram-like action in



Inhibits DNA gyrase

inhibit DNA

Inhibits DNA-dependent
RNA synthesis.



Converted inside
organism (bacteria or
protozoa) into active
metabolite Inhibits
DNA synthesis.

Bactericidal and