1. Therapeutics for Coronary Vascular Disease Nitrates

2. Nitroglycerin Glyceryl trinitrate(GTN)

3. Nitrates Isosorbide dinitrate (ISDN)

4. Nitrates Isosorbide-5-mononitrate (5-ISMN)

5. Nitrates Amyl Nitrite

6. Nitrates Sodium Nitroprusside

7. ACTION of NITRATES Dilate coronary arteries Dilate Arterioles Dilate venous capacitance vessels Decrease arterial resistance Decrease pre-load

8. Angina pectoris Angina pectoris is the principle symptom of ischemic heart disease. The condition is characterized by sudden, severe substernal pain. The primary cause of angina is an imbalance between myocardial oxygen demand and oxygen supplied by coronary vessels.

9. Angina pectoris This imbalance may be due to a decrease in myocardial oxygen delivery, an increase in myocardial oxygen demand, or both Since the heart normally extracts about 75% of blood oxygen at rest, increasing oxygen supply primarily occurs through increasing coronary blood flow

10. Angina pectoris Stable angina (exertional angina, typical or classic angina, angina of effort, atheroscelorotic angina) The underlying pathology is usually atherosclerosis Anginal episodes can be precipitated by exercise, cold, stress, emotion, or eating

11. Stable Angina Pectoris The Therapeutic Rationale: 1. Decrease cardiac load (preload and afterload) and 2. Increase myocardial blood flow

12. Vasospastic angina Variant angina, Prinzmetal's angina Caused by transient vasospasm of the coronary vessels Usually associated with underlying atheromas Chest pain may develop at rest

13. Vasospastic angina Variant angina, Prinzmetal's angina The Therapeutic Rationale: Decrease vasospasm of coronary vessels

14. Unstable angina Preinfarction angina, crescendo angina, angina at rest Caused by recurrent episodes of small platelet clots at the site of a ruptured atherosclerotic plaque which can also precipitate local vasospasm Associated with a change in the character, frequency, and duration of angina in patients with stable angina and when there are prolonged episodes of angina at rest

15. Unstable angina Preinfarction angina, crescendo angina, angina at rest Unstable angina requires vigorous therapy as it signals the imminent occurrence of a myocardial infarction The Therapeutic Rationale: Inhibit platelet aggregation and thrombus formation, decrease cardiac load, and vasodilate coronary arteries

16. Factors that Affect Myocardial Oxygen Demand The major determinants of myocardial oxygen consumption include: Ventricular wall stress, heart rate, and inotropic state (contractility) Both preload and afterload affect the stress on the ventricular wall

17. Factors that Affect Myocardial Oxygen Demand TRIPLE PRODUCT aortic pressure heart rate ejection time KNOW

18. Factors that Affect Myocardial Oxygen Supply Coronary artery blood flow is the primary determinant of myocardial oxygen supply since myocardial oxygen extraction from the blood is nearly complete, even at rest

19. Factors that Affect Myocardial Oxygen Supply Coronary blood flow is essentially negligible during systole and is therefore determined by perfusion pressure (aortic diastolic pressure), duration of diastole, and coronary resistance

20. Factors that Affect Myocardial Oxygen Supply Coronary Perfusion Pressure (CPP) CPP = Aortic diastolic pressure - LVEDP Normal > 50 mmHg

21. Factors that Affect Myocardial Oxygen Supply Coronary vascular resistance is determined by numerous factors including: Metabolic products that vasodilate coronary arterioles Autonomic activity Extravascular mechanical compression Atherosclerosis Intracoronary thrombi

22. Categories of pharmacological agents are used in the treatment of angina Organic nitrates Calcium channel blockers Beta-adrenergic antagonists

23. Categories of pharmacological agents are used in the treatment of angina Organic nitrates reduce preload, reduce afterload, vasodilate coronary arteries, inhibit platelet aggregation

24. Categories of pharmacological agents are used in the treatment of angina Calcium channel blockers reduce afterload, vasodilate coronary arteries, may inhibit platelet aggregation; some also decrease heart rate, decrease contractility)

25. Categories of pharmacological agents are used in the treatment of angina Beta-adrenergic antagonists decrease heart rate, decrease contractility, decrease afterload due to decrease in cardiac output, may inhibit platelet aggregation

26. Organic Nitrates (Nitrovasodilators) All organic nitrates lead to the formation of the reactive free radical, nitric oxide (NO) Most of these agents are simple nitric and nitrous acid esters of polyalcohols

27. Organic Nitrates (Nitrovasodilators) Glyceryl trinitrate (GTN, nitroglycerin, Nitro-Bid) Isosorbide dinitrate (ISDN, Isordil) Isosorbide-5-mononitrate (5-ISMN, Ismo) Amyl nitrate (highly volatile liquid which is administered by inhalation)

28. Mechanism of Action Veins and large arteries appear to have greater enzymatic capacity than resistance vessels, resulting in greater effects of organic nitrates on these vessels Why?

29. Mechanism of Action NO is an important endogenous diffusible mediator of smooth muscle contraction and neuronal transmission NO is very short-lived (half-life of a few seconds) Endogenous NO produced by vascular endothelium in response to acetylcholine is known as EDRF (endothelium-derived relaxing factor)

30. Mechanism of Action NO activates a cytosolic form of soluable guanylate cyclase (sGC)by binding to iron in the heme prosthetic group of the enzyme Activated guanylate cyclase catalyzes the formation of cyclic GMP (cGMP), which subsequently activates cGMP-dependent protein kinase

31. Mechanism of Action Activation of cGMP-dependent protein kinase in smooth muscle results in relaxation through several possible mechanisms, all of which involve protein phosphorylation: Activation of Ca 2+ -ATPases which increases Ca 2+ efflux Inhibition of Ca 2+ channels which decreases Ca 2+ influx Hyperpolarization of the sarcolemmal membrane by stimulation of Ca 2+ -activated K + channels

32. Routes of Administration Amyl nitrate, a gas at room temperatures, can be administered by inhalation and has a very rapid onset and very short duration of action (3 - 5 min)

33. Routes of Administration The sublingual route of administration is rapid (onset of action 1-3 min) and effective for the treatment of acute attacks of angina pectoris and avoids first-pass effects The short duration of action (20-30 min) is not suitable for maintenance therapy

34. Routes of Administration Intravenous nitroglycerin may be useful in the treatment of severe recurrent unstable angina because the onset of action is also rapid

35. Tolerance and Dependence Continuous or frequent exposure to organic nitrates may lead to the development of complete tolerance (tachyphylaxis) Transdermal administration of GTN may provide therapeutic blood levels for 24 hours or more, but efficacy does not persist for more than 8-10 hours

36. Tolerance and Dependence The mechanism of tolerance remains uncertain but several theories have been suggested: Diminished ability to convert nitrate to NO (no cross-tolerance with acetylcholine) Diminished release of NO because of depletion of endogenous sulfhydryl compounds (sulfhydryl-regenerating agents can partially reverse tolerance) Alterations in guanylate cyclase activation

37. Tolerance and Dependence

38. Adverse Effects The major acute adverse effects of nitrovasodilators are due to excessive vasodilation: – Orthostatic hypotension – Tachycardia – Severe throbbing headache – Dizziness – Flushing – Syncope (fainting)

39. Continuous Rx for Stable Angina Combination therapy may be more effective than monotherapy in many patients A beta-blocker with a dihydropyridine calcium channel blocker (e.g. propanolol and nifedipine)

40. Continuous Rx for VariantAngina Beta-blockers may worsen angina due to increased coronary resistance secondary to the unopposed effects of catecholamines acting at alpha- adrenergic receptors

41. Continuous Rx for Unstable Angina Verapamil has been found to be more effective than propanolol in controlling unstable angina Nifedipine alone is no more effective than nitrates or beta-blockers in reducing the frequency of rest angina

42. Continuous Rx for Unstable Angina Adding nifedipine to beta- blocker and nitrate therapy can decrease the frequency of rest angina, the incidence of myocardial infarction, and the necessity for emergency revascularization

43. Continuous Rx for Unstable Angina Aspirin has been shown to reduce the incidence of cardiac events in these patients IV heparin or thrombolytic agents may also be indicated in some patients

44. Hemodynamic Effects Nitrate Alone Heart Rate Reflex Increase Afterload Decrease Preload Decrease Contractility Reflex Increase Ejection Time Decrease

45. Hemodynamic Effects Channel Blockers Alone Heart Rate Decrease Afterload Decrease Preload Increase Contractility Decrease Ejection Time Increase

46. Hemodynamic Effects Combined Ca ++ or  -blocker with Nitrates Heart Rate Decrease Afterload Decrease Preload None or Decrease Contractility None Ejection Time None

47. Action of Anti-anginals

48. PHCL 554 Remember there will be an examination on Mar 4 th.