This document summarizes drug therapy for angina pectoris. It discusses the types of angina and general measures for treatment. Specific drug treatments discussed include nitrates, beta-blockers, calcium channel blockers, trimetazidine, and dipyridamole. The mechanisms of action, pharmacokinetics, effects, uses, precautions and contraindications are described for each class of drugs. Factors like concomitant diseases are also considered for selecting the most appropriate antianginal medications.

1. Drug Therapy of Angina Pectoris

2. Professor Mohamed Khedr Professor of clinical pharmacology Faculty of medicine Bairut Arab University

3. 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

4. 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

6. 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.

7. 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

8. II-Specific Drugs During Acute Attacks In-between Attacks .Nitrates & nitrites. (Short acting) .Sedatives. .Tranquilizers. .Analgesics. .Long acting Nitrates. . β -Blockers. .C.C.Bs. .Cytoprotectives. .Dipyridamol. .Prenylamine. .Perhexiline. .Aspirin.

10. 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

11. Time to peak effect and duration of action for some common organic nitrate preparations

12. 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

14. Effects of nitrates and nitrites on smooth muscle. cGMP = cyclic guanosine 3', 5'-monophosphate.

15. 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

16. 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:

17. 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

18. 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

21. 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.

22. 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 .

23. 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.

24. .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

25. 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

26. .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

27. 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

29. 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).

31. 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

32. 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

33. 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.

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