Dr. Wael H. Mansy, MD Assistant Professor College of Pharmacy King Saud University 2009

4. Pathophysiology of myocardial ischemia: Under conditions of rest, myocardial oxygen supply and delivery of nutrients through the coronary arteries should match the metabolic requirements of the heart. When the metabolic needs of the heart increase, the coronary blood flow must increase accordingly. The myocardial oxygen balance is affected by several factors that : will increase the oxygen and nutrient demand of the myocardium as: exercise, stress and cold. will increase coronary blood flow as cardiac metabolites and nitric oxide. Myocardial Ischemia

8. Silent ischemia is a particularly dangerous form of myocardial ischemia as there is a lack of clinical symptoms, i.e., ischemia without angina. Usually diagnosed by exercise stress testing or Holter monitoring Myocardial Ischemia

12. Mechanism of action: • Dilate coronary arteries and increase myocardial blood flow. • Dilate peripheral arteries and reduce afterload. • Dilate peripheral veins and reduce preload. Examples Amyl nitrate, nitroglycerine, isosorbide dinitrite Route of administration : Inhalation, sublingual, oral, transdermal, intravenous Long-acting forms such as isosorbide dinitrite used for prophylaxis of angina Short-acting forms such as sublingual nitroglycerin may be used during angina attacks Major adverse effects :include headache, hypotension. Tolerance may develop rapidly.

13. Mechanism of action: Block myocardial ß-adrenergic receptors. Reduce heart rate and cardiac output (reduced myocardial workload and oxygen demand). Examples of ß-Adrenergic Receptor Antagonists : May be selective ß1 (atenolol), or nonselective ß1 and ß2 blockers (propranolol) Major adverse effects : include bradycardia, reduced cardiac output, pacemaker depression and bronchoconstriction with nonspecific drugs

19. Myocardial infarction or “heart attack” is an irreversible injury to and eventual death of myocardial tissue that results from ischemia and hypoxia. Myocardial infarction is the leading killer of both men and women in the United States. Most heart attacks are the direct result of occlusion of a coronary blood vessel by a lipid deposit. These lipid deposits may accumulate to the point where they completely block a coronary vessel or, more commonly, accumulated lipid plaques may break off from the vascular endothelium and act as a thrombus that blocks a coronary artery at a narrower point downstream. Prolonged vasospasm might also precipitate a myocardial infarction in certain individuals.

20. Coronary blood flow and myocardial infarction The location of a myocardial infarction will be largely determined by which coronary blood vessel is occluded. The two main coronary arteries supplying the myocardium are: the left coronary artery (which subdivides into the left anterior descending and circumflex branches) and the right coronary artery

22. The left anterior descending artery supplies blood to the bulk of the anterior left ventricular wall, while the left circumflex artery provides blood to the left atrium and the posterior and lateral walls of the left ventricle. The right coronary artery provides blood mainly to the right atria and right ventricles. Nearly 50% of all myocardial infarctions involve the left anterior descending artery that supplies blood to the main pumping mass of the left ventricle. The next most common site for myocardial infarction is the right coronary artery, followed by the left circumflex.

23. A myocardial infarction may be: transmural, meaning it involves the full thickness of the ventricular wall, or subendocardial, in which the inner one third to one half of the ventricular wall is involved. Transmural infarcts tend to have a greater effect on cardiac function and pumping ability since a greater mass of ventricular muscle is involved.

24. 1. Severe chest pain and discomfort : Pressing or crushing sensation often accompanied by nausea, vomiting, sweating and weakness due to hypotension. A significant percentage of myocardial infarctions are “silent” and have no symptoms. 2. Irreversible cellular injury: Generally occurs 20 to 30 minutes after the onset of complete ischemia. 3. Release of myocardial enzymes such as creatine phosphokinase (CPK) and lactate dehydrogenase (LDH) into circulation from myocardial damaged cells.

26. Depending on the extent of the area involved in a myocardial infarction, a number of complications might arise, including: 1. Rupture of weakened myocardial wall. Bleeding into pericardium may cause cardiac tamponade and further impair cardiac pumping function. This is most likely to occur with a transmural infarction. Rupture of the septum between the ventricles might also occur if the septal wall is involved in the infarction. 2. Formation of a thromboembolism from pooling of blood in the ventricles. 3. Pericarditis : Inflammation due to pericardial friction rub. Often occurs 1 to 2 days after the infarction. 4. Arrhythmia : Common as a result of hypoxia, acidosis and altered electrical conduction through damaged and necrotic areas of the myocardium. May be life-threatening and lead to fibrillation.

27. 5. Reduced cardiac function : Typically presents with reduced myocardial contractility, reduced wall compliance, decreased stroke volume and increased left ventricular end diastolic volume. 6. Congestive heart failure may result if a large enough area of the myocardium has been damaged such that the heart no longer pumps effectively. 7. Cardiogenic shock : Marked hypotension that can result from extensive damage to the left ventricle. The resulting hypotension will trigger cardiovascular compensatory mechanisms that will further tax the damaged myocardium and exacerbate impaired function. Cardiogenic shock is associated with a mortality rate of 80% or greater.

28. As a result of the hypotension and hemodynamic changes that accompany a myocardial infarction, the cardiovascular system initiates a number of reflex compensatory mechanisms designed to maintain cardiac output and adequate tissue perfusion: 1.Catecholamine release : Increases heart rate, force of contraction and peripheral resistance. 2. Sodium and water retention. 3. Activation of renin–angiotensin system leading to peripheral vasoconstriction. 4. Ventricular hypertrophy. Unfortunately, these compensatory changes may increase oxygen demand and workload on the infarcted heart and worsen overall cardiac function.

29. A main goal of intervention for myocardial infarction is to limit the size of the infarcted area and thus preserve cardiac function. Early recognition and intervention in a myocardial infarction have been shown to significantly improve the outcome and reduce mortality in patients. If employed in the early stages of myocardial infarction, antiplatelet-aggregating drugs such as aspirin and clot-dissolving agents such as streptokinase and tissue plasminogen activator may be very effective at improving myocardial blood flow and limiting damage to the heart muscle.

30. Other drugs such as vasodilators, ß -adrenergic blockers and ACE inhibitors can also improve blood flow and reduce workload on the injured myocardium and thus reduce the extent of myocardial damage. The development of potentially life-threatening arrhythmias is also common during myocardial infarction as a consequence of hypoxia, acidosis and enhanced autonomic activity and must be treated with appropriate antiarrhythmic drugs. Supportive therapies such as oxygen, sedatives and analgesics are also utilized.

31. Oxygen : Used to maintain blood oxygenation as well as tissue and cardiac O2 levels. Aspirin : If administered when myocardial infarction is detected, the antiplatelet properties of aspirin may reduce the overall size of the infarction. 3. Thrombolytic therapy :If employed in the first 1 to 4 hours following the onset of a myocardial infarction, these drugs may dissolve clots in coronary blood vessels and re-establish blood flow. 4. Vasodilator drugs : Intravenous nitroglycerin can increase blood flow to the myocardium and reduce myocardial work.

32. 5.ß -Blockers : Blunt the effect of catecholamine release on the myocardium, reduce heart rate and myocardial work. 6. Pain management : Sublingual nitroglycerin, morphine if necessary 7. Antiarrhythmic drugs : To treat and prevent a number of potentially life-threatening arrhythmias that might arise following a myocardial infarction. 8. ACE inhibitors : the negative effects of vasoconstriction and salt and water retention on the myocardium.

33. Streptokinase : Derived from ß -hemolytic streptococcus bacteria; involved in the activation of plasmin Anistreplase (APSAC) : Complex of human lys-plasminogen and streptokinase; Administered as a prodrug Alteplase (TPA): Recombinant tissue plasminogen activator Urokinase : Endogenous human enzyme that converts plasminogen to active plasmin Routes of administration : Intravenous. for all of the above Major unwanted effects : Internal bleeding, gastrointestinal bleeding, stroke, allergic reactions

34. Sublingual nitroglycerin : Potent vasodilator of coronary arteries, also dilates peripheral arteries and veins to reduce preload and afterload on the heart Morphine sulfate : Powerful opioid analgesic that also provides a degree of sedation and vasodilatation; although the opioid analgesics have little effect on the myocardium, they are powerful respiratory depressants

35. • Inhibits the cyclo-oxygenase pathway for the synthesis of prostaglandins, prostacyclins and thromboxanes. • Inhibits aggregation of platelets and is effective in reducing myocardial infarction, stroke and mortality in high-risk patients.

36. Key terms • Cardiac tamponade : Excessive pressure that develops from the accumulation of fluid in the pericardium. • Pericarditis : Inflammation of the pericardium. • Stroke volume : Volume of blood ejected from each ventricle per beat. • End-diastolic volume : Volume of blood remaining in the ventricle at the end of systole (contraction).