1. Antianginal Drugs

2. Angina Pectoris Definition A clinical syndrome due to myocardial ischemia characterized by episodes of precordial discomfort or pressure, typically precipitated by exertion or stress and relieved by rest or drugs. Types Exertional angina, (or angina of effort, Stable,) which is typically triggered by physical activity, persists few minutes and subsides with rest Unstable when there is an increased frequency, intensity or duration of attacks, or changes in precipitating factors. Vasospastic angina (or Prinzmetal’s angina, or variant angina) which tends to occur regularly at certain times of the day and is characterized by pain at rest.

3. Pathophysiology of Angina Angina pectoris occurs when the O2 needs of the heart are not met. The myocardial O2 demand increases when there is an increase in: – heart rate – myocardial contractility – peripheral resistance – ventricular volume – Ejection time

5. 1. Nitrates and nitrites Amyl nitrite, Nitroglycerine, Isosorbide mononitrate Mechanism of action: Nitrates are denitrated (by glutathione S-transferase), thereby releasing free nitrite ions (this reaction requires -SH groups). Nitrite ion is converted to nitric oxide (NO), which activates a cytosolic form of guanylyl-cyclase (this reaction requires -SH groups). cGMP synthesis is increased in smooth muscle. Nitrate Nitrite NO cGMP

6. Effect: 1.Cause smooth muscle relaxation 2.NO stimulates guanylyl-cyclase in platelets and inhibit platelet aggregation 3.A decreased availability of tissue -SH groups reduces the action of nitrates (at least partially).

7. Pharmacodynamics A. Cardiovascular actions 1) After therapeutic doses: Marked relaxation of large veins (the main effect) which leads to: a.Decreased preload and cardiac output (in the absence of cardiac failure). b.Decreased blood pressure (slightly). c.Improved perfusion of subendocardial regions (due to the lowering of left ventricular end-diastolic pressure, which reduces subendocardial compression

8. 1) After therapeutic doses: (continued) Relaxation of large arteries (less pronounced than vein relaxation) which leads to increased blood flow in: a.The skin (face and thorax) and the brain. b.Large epicardial vessels c.Large collateral vessels (perfusion of ischemic regions is increased) 2) After higher doses: Relaxation of all segment of the vascular system which leads to: a.Reflex tachycardia and reflex increase in cardiac contractility b.Postural hypotension

10. Other actions Relaxation of smooth muscle of the bronchi, the biliary system, the GIT and genitourinary tract. Decreased platelet aggregation (likely due to the increase in cGMP) Increased methemoglobin formation (with nitrites, not with therapeutic doses of nitrates) due to the formation of nitrite ion that can oxidize the ferrous ion of hemoglobin to the ferric state.

11. Pharmacokinetics Bioavailability: Oral: generally low (but isosorbide mononitrate > 95%) Sublingual: 10-60 % Transdermal: 50-90 % Distribution In all body tissues including brain. Biotransformation > 99%, mainly in liver (by a high capacity nitrate- reductase).

12. Nitrates Tolerance and Dependence Frequently repeated exposures to nitrates leads to a decrease in most of their pharmacological effects. Tolerance to a nitrate results in tolerance (at least partial) to all other compounds of the class. The amount of tolerance is a function of the dosage and the frequency of administration, and it exhibits a very high individual variability. Since tolerance appears rapidly (24 hours) and disappears rapidly (6-10 hours), brief periods of no therapy (hours of overnight) can be sufficient to permit recovery. Nitrate can cause dependence. In fact sudden death or myocardial infarction have occurred after a few days' break in long-term exposure to an organic nitrate.

13. Duration of antianginal effect of nitrates

14. Adverse effects 1.Central nervous system – Throbbing headache, Dizziness, vertigo, Syncope 2.Cardiovascular system – Flushing of the face, Palpitations, – Postural hypotension 3.Others – Methemoglobinemia (with nitrite, or with toxic doses of nitrates) – Withdrawal reactions (digital vasospasm, coronary spasms, MI) – Drug abuse (with amyl nitrite)

15. Contraindications and Precautions Angina due to hypertrophic Cardiomyopathy Constrictive pericarditis Increased intracranial pressure Severe hypotension (systolic < 90 mm Hg) Hypovolemic states Hyperthyroidism Severe hepatic disease Profound hypotension can occur if taken concomitantly with sildenafil, a specific cGMP phosphodiesterase-5 inhibitor. The interaction can be life-threatening).

16. Therapeutic uses 1.Angina pectoris A.Treatment of the acute attack. Nitroglycerin (sublingual route) or amyl nitrite (inhalant route). [pain is relieved; protection lasts 30-40 min]. B.prophylaxis Nitroglycerin (oral, transdermal), other nitrates (oral) [attacks are reduced or eliminated].

17. Main mechanisms of antianginal effects: A.In exertional angina: decreased myocardial O2 demand B.In variant angina: increased myocardial O2 supply (they are not the treatment of choice) C.In unstable angina: The main mechanism is still uncertain (decreased myocardial O2 demand, increased myocardial O2 supply, and decreased platelet aggregation, all might contribute to the therapeutic efficacy). High doses may cause undesirable effects due to: A.reflex tachycardia B.reflex increase in cardiac contractility

18. 2. Heart failure Unlike in normal subjects, nitrates can increase stroke volume and cardiac output in patients with systolic heart failure (the decreased preload lowers the ventricular filling pressure, so allowing a more efficient ventricular contraction). They are not used routinely in heart failure but can be used when: Symptoms of pulmonary congestion predominate (redistribution of blood volume away from the chest relieves the congestion. This improves exercise tolerance even when cardiac output is not increased) pulmonary edema occurs or is impending.

19. 3. Myocardial infarction It has been shown that IV infusion of nitrates lead only to a minor reduction in short-term mortality. Therefore they are not recommended for routine use, but it is reasonable to use IV nitroglycerin in more complicated patients, such as those with impending heart failure or hypertension. 4. Cyanide poisoning Amyl nitrite and sodium nitrite are sometimes used to produce methemoglobin which can complex cyanide ion to form cyanomethemoglobin. Then IV sodium thiosulphate is used to convert cyanomethemoglobin to thiocyanate and methemoglobin.

20. 2. Beta-blockers 1) Therapeutic doses of beta-blockers are effective in angina because: a) They decrease cardiac O2 demand (the main mechanism) by: Reducing heart rate Reducing cardiac contractility Lowering blood pressure b) They increase myocardial perfusion in certain parts of the heart (mainly subendocardial regions) due to an augmented diastolic perfusion time.

21. Therefore: a) They are effective in chronic prophylaxis of exertional angina and in the acute treatment of unstable angina. b) They are not effective in variant angina (where instead they may be dangerous, by causing coronary vasoconstriction). 2) High doses may cause undesirable effects due to: increased end diastolic volume increased ejection time

22. NB: Beta-blockers with sympathomimetic activity have been clearly demonstrated to reduce mortality in myocardial infarction. They should be given early and continued indefinitely. Warning! withdrawal effects after chronic use of beta blockers in ischemic heart disease are well documented. In risk patients abrupt withdrawal may cause hypertension, angina, myocardial infarction, and sudden death.

23. 3. Calcium channel blockers Calcium channel blockers bind to the L- type voltage- gated Ca ++ channel in blood vessels and heart Pharmacological effects: A. Cardiac actions (Only verapamil and diltiazem can cause these effects) Decreased conduction Increased refractoriness Decreased automaticity (mainly in ischemic zones, by preventing Ca ++ overload). Dose-dependent decrease of cardiac contractility.

24. B. Vascular actions (All Ca++ channel blockers can cause these effects) Vasodilation (mainly in arterioles, where the calcium- dependent tone of the smooth muscle is more pronounced). Some dihydropyridines have a relative vascular selectivity (nicardipine for cerebral and coronary vessels)

25. Other Actions C. Other actions Relaxation of bronchiolar, gastrointestinal and uterine smooth muscle (modest). Inhibition of insulin release (verapamil, nifedipine, after very high doses) Inhibition of platelet aggregation (in vitro) Blockade of P-glycoprotein which is a multidrug transporter associated with the development of drug resistance in cancer cells (verapamil).

26. Pharmacokinetics Biotransformation > 99% in liver and other organs. Some metabolites are active. Excretion < 1 % excreted by the kidney. Half-life: very variable (Diltiazem:. 3 hours; amlodipine. 40 hours)

27. Adverse Effects Central Nervous System Headache, Dizziness, lightheadedness, weakness Cardiovascular System Flushing, Peripheral edema, Tachycardia, palpitations Profound hypotension, Aggravation of myocardial ischemia (nifedipine) A-V block, bradycardia, arrhythmias (verapamil, diltiazem). Ventricular fibrillation (verapamil, diltiazem, in patients with accessory AV pathways) Other systems Constipation, gingival hyperplasia (verapamil ) Nausea, heart burn, abdominal pain.

28. Contraindications and Precautions CVS: A. Verapamil, diltiazem Hypotension Cardiogenic shock, systolic heart failure SA and AV block, Ventricular tachycardia Arrhythmias associated with Wolff-Parkinson-White syndrome Digoxin overdose B. Dihydropyridines Hypotension, Myocardial ischemia Others: GERD, constipation, fecal impaction

29. Therapeutic Uses 1.Angina pectoris A. Exertional angina: Mainly because they decrease myocardial O2 demand (due to decreased afterload, heart rate and contractility) Verapamil and diltiazem are the preferred drugs. High doses may cause undesirable effects due to: Increased end diastolic volume The increased ejection time

30. B. Variant angina Mainly because they increase myocardial O2 supply (due to coronary vasodilation) All calcium channel blockers are considered drugs of choice High doses of dihydropyridines may cause undesirable effects due to: Reflex tachycardia Reflex increase in cardiac contractility

31. 2. Unstable angina and myocardial infarction During myocardial ischemia, an increase in Ca ++ influx (due to membrane depolarization) can trigger a secondary cellular damage. These drugs can reduce the rate of reinfarction and death in patients without heart failure. 3. Hypertrophic cardiomyopathy and diastolic heart failure Diltiazem (alone or in combination with beta-blockers) improves diastolic compliance by reducing myocardial contractility.

32. 4. Cardiac arrhythmias 5. Hypertension 6. Subarachnoid hemorrhage nicardipine dilate cerebral vessels at doses that have little effects in the periphery. Therefore they inhibit delayed reactive vasospasm arising from hemorrhage. 7. Raynaud's phenomenon 8. Migraine They are sometimes used for migraine prophylaxis (mechanism not established).

33. Antianginal Drug interactions CI = Clinical importance

34. Combination Therapy 1. Nitrates and B-blockers Each blocks the adverse effect of the other B-blockers – blocks the reflex tachycardia associated with nitrates Nitrates – attenuate the increase in the left ventricular end diastolic volume associated with B- lockers by increasing venous capacitance

35. 2. CCBs (dihydropyridines) and B-blockers These two drugs produce decrease blood pressure Useful in the treatment of exertional angina that is not controlled adequately with nitrates and B-blockers B-blockers – attenuate reflex tachycardia produce by nifedipine 3. Nitrates and CCB (dihydropyridines) Useful in severe vasospastic 4. CCB, BB, nitrates Useful in patients with exertional angina not controlled by the administration of two types of anti-anginal agent.

36. Drug therapy of acute myocardial infarction Oxygen if hypoxic Relief of pain: Morphine sulfate Beta-blockers, Nitroglycerin, ACEIs or Angiotensin II receptor blocker, antiplatelets (clopedogril, aspirin), statin Fibrinolytic therapy if STEMI: e.g. Streptokinase, Alteplase Anticoagulants: low molecular weight heparin Treatment of complications: (arrhythmias, heart failure and cardiogenic shock) Control of risk factors: Stop smoking; control hypertension, diabetes mellitus and correction of plasma lipids, correct electrolyte disturbace.

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