Professor Mohamed Khedr Professor of clinical pharmacology Faculty of medicine Bairut Arab University
A ngina P ectoris. One of the Ischaemic Heart Diseases (I.H.D.) M.I S udden D eath. is a clinical syndrome of Chest Pain Sudden, severe pressing, substernal, radiating to Lt. shoulder& flexor surface of Lt. arm& lasts for few minutes. inadequate coronary blood flow O2-supply. Due to Angina Pectoris
Angina Pectoris Pathophysiology: O 2 demands Exceed the supply Myocardial metabolism Shifts to Anaerobic metabolism From Fat to CHO Accumulation of substance P ↑ glycolysis. ↑ lactate & Pyruvate formation ㊉ sympathetic nerve endings Pain Glucose 2 ATP Pyruvate -> Lactate O 2 Acetyl CO A Citric a cycle->32ATP
Types of Angina Pectoris Stable Angina Variant Angina Unstable Angina Effort , Typical . Atherosclerosis . Exercise, Emotion, Heavy meal. ↓ Pain Prinzmetal . ↓ α - receptor mediated V.C. With or without atherosclerosis. ↓ Pain even at rest Accelrated . ↓ Severe type. ↓ .change in pattern. . ↑ frequency& or duration of pain.
I- General measures : . Change of life style : .Avoid intolerable -> Effort, Stress, Smoking, Heavy meal. .Daily exercise -> walk. . Correct obesity . . ↓ Food intake . Treatment of predisposing factors: . Hyperlipidaemia. .Hypertension. .Heart failure. .Arrhythmias. .Diabetes mellitus. Treatment of Angina Pectoris
Organic Compounds Inorganic Compounds Organic nitrites Organic nitrates Esters of nitrous a. Esters of nitric a. Amyl nitrite: Extremely volatile. Crushed& Inhaled. Rapid effect: Onset-> 15 sec. Peak-> 1 min. Lasts -> 5 min. Nitroglycerine: (Glyceryl trinitrate) .S.L (0.5mg) 30sec. ,2 min. ,20min. .Patch-> skin. .I.V. Isosorbid dinitrate: (Isosrdil)-> Lasts for 3 H. Orally & S.L. Isosorbid mononitrate: Sodium Nitrite: ↓ used For cyanide poisoning. H b + Na nitrite. ↓ Met H b ↓ +cyanide Cyan-met H b + Na thio sulphate Na thiocyanate. (Less toxic,cleared from the body). Ineffective drugs for angina. Nitrites & Nitrates
Time to peak effect and duration of action for some common organic nitrate preparations
Mainly through release of: NO ↓ Binding to specific receptors (Including SH- group ) ↓ ㊉ Guanylate cyclase ↓ ↑ cGMP -> Θ Ca ++ entery ㊉ Ca ++ exit ㊉ Protein kinase Dephosphorylation of Myosin light chain ↓ V.D. Others .Production of PGE. .Production of PGI 2 . .Membrane hyperpol- arization. Mechanism of action
Effects of nitrates and nitrites on smooth muscle. cGMP = cyclic guanosine 3', 5'-monophosphate.
Pharmacokinetics Well absorbed : .Buccal (S.L) -> Rapid onset (2-5 min.). Short duration ( ↓ 30 min). .GIT (oral) -> more prolonged & prophylactic. .Lung (Inhalation) -> Rapid 15 sec, 1 min ,5 min. .Transdermal (Skin). Metabolism: .Liver (90 %) - extensive- -> For dinitrate & tetranitrate (bioavailability -> 10 % ). Mononitrate does not undergo metabolism -> bioavailability is very high. Excretion -> Renal. Nitrites & Nitrates
Pharmacological Effects: Blood Vessels Heart B.P . Venodilation . (Less arterial) -> ↓ R.V . & L.V . enddiastolic pressure. -> ↓ Preload. .Corona. V.D . ( not diseased coronaries ) . Arterial V.D . (Flushing face& Neck). . V.D of mening. Arteries -> (Headache). .Tachycardia. .↓ V. return -> ↓ C.O & ↓ cardiac work Rapid Administr. -> ↓ B.P ↓ C.O Ven. D. -> ↑ Syst. V. capacity. ↓ V. return. ↓ P. pressure. I- CVS:
II- Smooth muscle: Relaxing biliary, bronchial , uterine smooth muscle. III- Respiration: Reflex increase of respiratory rate. (Carotid body & or due to hypotension ). IV- Blood: Met-H B
I-Angina Pectoris All types ->potent V.D (not on diseased atherosclerosed coronaries) ↓ myocardial O2-demand ( venodil. -> ↓ preload & arteriodil.-> ↓ Afterload) Myocardial perfusion -> to ischaemic areas by .selective dilation of epicardial vessels. .direct V.D. of coronary collaterals. Through Terapeutic Uses
II- CHF Through Preload. III- M.I. Nitroglycerine area of myocardial damage IV- Other uses Biliary colic , constriction ring of uterus & treatment of cyanide poisoning.
Adverse Reactions 1-Throbbing headache. 2-Flushing in the face. 3-Tachycardia & palpitation. 4-Postural hypotension , dizziness & syncope. 5-Rarely ( Chronic high doses) -> Met H.b . Sildenafil (Viagra) potentiates this action of the nitrates. To preclude the dangerous hypotension that may occur, this combination is contraindicated .
6-Nitrate Tolerance: -> due to -> i- Oxidation of SH-group (essential for formation of NO) or ii-Depletion of SH-donors. iii-Reflex sympathetic ㊉ n -> V.C. Can be prevented by Daily nitrate free interval (10-12h.) at night.
.Start with the smallest dose ( side effects ). .Not abruptly stopped. ( withdrawal symptoms). .If the dose increased more than 3 tab. S.L. -> fear of M.I. .Expiry date must be checked. .Severe anaemia. . I.C.P. .Idiosyncrasy. .w sildenafil. Precautions Contraindications
β -Bs -> Suppress the activation of the heart ( β 1 ). Reduce the work of the heart by ↓ heart rate& cardiac contractility -> ↓ C.O.& slight ↓ B.P. ↓ β -Adrenoceptor Blockers
.It is not a vasodilator , so it may worsen variant angina.. .It is used prophylactically to severity& frequency of typical anginal attacks. .It cardiac O2 demand through: .-ve chronotropic & inotropic actions. .Slight of B.P. Propranolol can be combined with Nitrates for typical angina. ( to side effects of both drugs). Propranolol
Nifedipine, Verapamil, Diltiazem Mechanism of action on vascular tissue : Blocking of Ca++ transmembrane channels in vascular sm.m.fibers. -> interference with inward of movement of Ca++ -> affects depolarization & contraction processes -> with relaxant effects mainly on arteriol. smooth muscle. Ca++ channel blockers
Nifedipine : Prominent vasodilator actions, used in all types of angina with reflex tachycardia & leg œdema. Verapamil : .Slows conduction & ↓ Heart rate. . Greater –ve inotropic effect with little V.D. effects. Diltiazem : .CVS effects similar to verapamil. .It is used in angina by ↓ coronary spasm (variant angina).
Provide -> Enough Energy -> to maintain an efficient myocardial contraction . Trimetazidine It causes: .Metabolic switch during ischaemia -> Θ FFA oxidation. ㊉ Glucose oxidation. . Θ intracellular acidosis & accumulation of Na+ & Ca++. .Preserve contractile force function & limits cytolysis. .Antioxidant effect-> limits membrane damage induced by by O 2 -free radicals. Cytoprotective agents
It has: .coronary V.D activity (on small resistant vesells). .Antiplatelet activity. Main disadvantage is: Coronary steal (diverting blood from ischaemic area) Aggrevate angina. Dypyridamol
Selection of antianginal drugs For patients with concomitant diseases: Concomitant disease Most preferred drugs Less preferred drugs Bronchial asthma. Heart failure Hypertension. Diabetes Mellitus. C.C.Bs, Nitrites& Nitrates. Nitites & Nitrates. β -Bs , C.C.Bs. C.C,Bs ,Nitrites & Nitrates. β -Bs. β -Bs ,verapamil, Diltiazem. Nitrites & Nitrates. β -Bs.