Ischemic Heart Disease PDF

Faculty of Pharmacy Department of Pharmacy Practice  Course Name: Clinical Pharmacy and Pharmacotherapeutics II Code: PP905 Dr. Aliaa Osman PhD Holder of Clinical Pharmacy Head of Clinical Pharmacy Department, Ain Shams University Specialized Hospital Lecturer of Clinical Pharmacy Sinai Un...

Faculty of Pharmacy Department of Pharmacy Practice  Course Name: Clinical Pharmacy and Pharmacotherapeutics II Code: PP905 Dr. Aliaa Osman PhD Holder of Clinical Pharmacy Head of Clinical Pharmacy Department, Ain Shams University Specialized Hospital Lecturer of Clinical Pharmacy Sinai University  Clinical Pharmacy and Pharmacotherapeutics II III- ISCHEMIC HEART DISEASE Angina Acute Myocardial Infarction 1. Angina Angina pectoris is a clinical syndrome characterized by attack of pain and substernal chest discomfort, which has a characteristic description, precipitation, radiation and relief. Etiology: 1. Imbalance between blood supply and oxygen demands to the cardiac muscle leads to ischemia which results of angina pectoris. 2. Diminished the quantity of blood supply due to: Narrowing of coronary arteries by atherosclerosis which is the commonest cause. Low cardiac output conditions as in aortic stenosis, and mitral stenosis. Coronary osteal stenosis as in syphilis. 3. Diminished quality of blood supply: Anemia usually causes angina pectoris in patients whose coronary arteries are narrowed by atherosclerosis. Cyanotic conditions as in lung diseases. 4. Increased cardiac muscle demands: Ventricular hypertrophy. Thyrotoxicosis causes angina pectoris in patients in whom the coronary arteries are narrowed by atherosclerosis. Pathogenesis:  Myocardial hypoxia leads to accumulation of metabolites (such as lactic and pyruvic acids as well as histamine) which stimulate the nerve endings causing pain. Pain impulses are then transmitted along the sympathetic fibers to the upper 4 thoracic spinal segments, from these segments, radiation occurs in the corresponding neighboring areas. Clinical manifestations: Angina pectoris has the following characteristics: The pain commonly starts retrosternal behind the upper and middle thirds of the sternum and radiate to the left shoulder, inner side of the left arm, elbow and little finger. The pain may radiate to both shoulders or to the right shoulder only (contralateral spread) neck, Jew or to an inflamed tooth or gall bladder. Pain has a definite relation to a provocative cause which increases the heart work e.g., exercise, emotion, exposure to cold, tachycardia or hypoglycemia, and is relieved rapidly by rest or nitroglycerine. Other symptoms associated with the pain, there may be sweating, dizziness, fear of death, dyspnea may occur due to left ventricular fibrillation. Eructation usually takes place at the end of the attack. Types of angina: Risk factors: There are several factors that may implicate in angina pectoris including: Hyperlipidemia. Hypertension. Smoking. Diabetes mellitus. Family history. Adults over 65 years. Sex (incidence in male is much higher than in female). Obesity. Diagnosis: 1.Resting ECG: This is usually normal between attacks. Evidence of old myocardial infarction e.g., pathological waves, left ventricular hypertrophy or left bundle branch block may be present. During an attack, transient ST depression, T-wave inversion or up right T-wave may appear. 2. Exercise ECG: Exercise testing can be extremely useful both in confirming the diagnosis of angina and in giving some indication as to the severity of the coronary artery disease. ST segment depression of greater than or equal to 1 mm suggests myocardial ischemia particularly if typical chest pain occurs at the same time. 3. Echocardiogram: This can be used to assess ventricular wall involvement and ventricular function. Regional wall motion abnormalities at rest, reflects previous ventricular damage. 4. Coronary angiography (x-ray): This is occasionally useful in patients with chest pain, where the diagnosis is unclear. More often the test is performed to delineate the exact coronary anatomy in patients being considered for revascularization (e.g., coronary artery bypass grafting or coronary angioplasty). Drug therapy: A. Nitrates B. β-adrenergic blocking agents C. Calcium-channel blockers D. Potassium channel activators E. Platelet inhibiting agents F. New Agents A. Nitrates Mechanism:  ++ cyclic guanosine monophosphate (cGMP)  ++ nitrate receptors in smooth muscle fiber  ++ prostaglandins (PGE2 & PGI2) 1. Nitrates: Action: I. CVS a. B.V: Vasodilator to arteries, arterioles, capillaries, vein and venules Skin B.V------------- flush of face and neck Meningeal B.V------------ headache Retinal B.V ------------------ ++ IOP Pulmonary B.V ------------- pulmonary pressure b. B.P: -- B.P c. Heart: Reflex tachycardia -- preload and afterload II. Relaxation of smooth muscles: bronchi, GIT, gall bladder and uterus Therapeutic uses: 1. Angina pectoris: all form of angina 2. Stable angina ---------- decrease preload and afterload. 3. Variant angina --------- relief spasm (vasodilator) 4. Mixed and unstable ---------- by both mechanisms Side effects: 1) Headache --------- (Monday syndrome) 2) ++ IOP ------- glaucoma 3) Decrease B.P --------- syncopal attack. 4) Allergy 5) Tolerance 6) Reflex tachycardia 7) Coronary dependence ---------sudden stop -----angina 8) Methemoglobinemia; B. Calcium-channel blockers: The calcium-channel blockers are accepted for the treatment of stable angina, unstable angina, and Prinzmetal’s angina. Nifedipine, nicardipine, diltiazem, and verapamil are the agents currently available. The calcium-channel blockers have four major physiologic effects: 1. They cause systemic arterial dilation leading to a decrease in systemic vascular resistance, which reduces myocardial oxygen demand. 2. They dilate epicardial coronary arteries and reduce coronary vascular resistance. 3. This improves coronary blood flow and myocardial oxygen supply. 4. They reduce myocardial contractility. This reduces myocardial oxygen consumption. The adverse effects of the calcium-entry blockers are: Vasodilation, negative inotropic effects (verapamil and diltiazem), conduction disturbances, nausea and dizziness. N.B. Vasodilatory side effects include headaches, flushing, hypotension, and peripheral edema. C- Beta-blockers: Beta-blockers reduce oxygen demand, both at rest and during exertion, by decreasing heart rate and myocardial contractility, which also decreases arterial blood pressure. Beta-blockers are contraindicated in Prinzmetal’s angina because they increase coronary resistance (by blocking vasodilatory β2-adrenoceptors). D- Potassium channel activators: Nicorandil, a compound that has several mechanisms of action including activation of potassium channels and nitrate like activity, is available for the management of angina. E-Platelet inhibiting agents: Aspirin in low doses (75-100 mg/day orally) reduces the incidence of acute myocardial infarction in patients with coronary artery disease. It reduces thromboxane A2 synthesis in platelets by irreversible acetylation and inhibition of cyclooxygenase enzyme. Dipyridamole increases intracellular levels of cAMP by inhibiting phosphodiesterase. This inhibits thromboxane A2 synthesis and may potentiate the effect of prostacyclin and therefore decreases platelet adhesion to thrombogenic surface. NEWER ANTIANGINAL DRUGS 1. Ranolazine: It appears to act by reducing a late sodium current (INa) that facilitates calcium entry via the sodium-calcium exchanger. The resulting reduction in intracellular calcium concentration reduces diastolic tension, cardiac contractility, and work. Several studies demonstrate ranolazine effectiveness in a stable angina, but it does not reduce the incidence of death in acute coronary syndromes. Ranolazine is approved for use in angina in the USA. 2. Trimetazidine Certain metabolic modulators are known as pFOX inhibitors because they partially inhibit the fatty acid oxidation pathway in myocardium. Because metabolism shifts to oxidation of fatty acids in ischemic myocardium, the oxygen requirement per unit of ATP produced increases. Partial inhibition of the enzyme required for fatty acid oxidation appears to improve the metabolic status of ischemic tissue. Trimetazidine has demonstrated efficacy in a stable angina but is not approved for use in the USA. 3. Ivabradine Also called bradycardic drug. It is selective sodium channel blocker that reduce cardiac rate by inhibiting the hyperpolarization-activated sodium channel in the sinoatrial node. Ivabradine appears to reduce anginal attacks with an efficacy similar to that of calcium channel blockers and β-blockers. It is approved for use in angina and heart failure outside the USA. 4. Fasudil The Rho kinases (ROCK) comprise a family of enzymes that inhibit vascular relaxation. Excessive activity of these enzymes has been implicated in coronary spasm, pulmonary hypertension, apoptosis, and other conditions. Fasudil is an inhibitor of smooth muscle Rho kinase and reduces coronary vasospasm. Favorable antianginal combinations Unfavorable antianginal combinations  2- MYOCARDIAL INFARCTION (MI) Acute myocardial infarction (AMI) is a result of myocardial necrosis. This usually results from plaque rupture with thrombus formation in a coronary vessel, resulting in an acute reduction of blood supply to a portion of the myocardium. Pathophysiology: Patient with coronary thrombus {consists of platelets rich core (white clot) and fibrin rich core (red clot)}. After 6 hours of onset of MI, the myocardium is swollen and pale and at 24 hours, the necrotic tissue appears deep containing hemorrhage. In the next few weeks, an inflammatory reaction develops, and the infracted tissue turns to grey and gradually forms a thin, fibrous scar. The predominant cause is a rupture of an atherosclerotic plaque with subsequent spasm and clot formation. Ventricular hypertrophy. Hypoxia is due to carbon monoxide poisoning. Emboli to coronary arteries. Coronary artery vasospasm. Coronary anomalies, including aneurysms of the coronary arteries. Cocaine, amphetamines, and ephedrine. Age Being male and younger than 70 years Smoking Hypercholesterolemia and hypertriglyceridemia Diabetes mellitus Poorly controlled hypertension Family history Risk Factors Age Being male and younger than 70 years Smoking Hypercholesterolemia and hypertriglyceridemia Diabetes mellitus Poorly controlled hypertension Family history Clinical picture: Chest pain is described as tightness, pressure, or squeezing. The pain is sever and may radiate to the jaw, neck, arms, back, and epigastrium. The left arm is affected more frequently than the right arm, so that the patient fears sudden death. However, 20% of patient with MI have no pain and are called “Silent MI. MI are more common in diabetics and elderly. MI is accompanied by sweating, breath-lessness, nausea, vomiting and restlessness. Anxiety, lightheadedness and syncope, cough, nausea and vomiting and wheezing. Patients with acute MI appear pale, sweating and grey and Modest fever (up to 38⁰C). Diagnosis and investigation: ECG: Q wave is broad and deep. ST-segment depression or T-wave inversion.  Cardiac enzymes and other laboratory studies: Include Creatine kinase (CPK), Troponin I, LDH, AST and others. o These enzymes must be assayed every 8 h for the first 24 hr. o CPK …… estimate infarct size (It is not practical because it increases in skeletal muscle trauma, exercise or I.M. injection). o CPK-MB or (CK-MB): Standard for detection of myocardial necrosis (specificity of test for AMI is 100%). o This is the criterion levels begin to rise within 4 hours after injury, peak at 18-24 hours, and subside over 3-4 days. o The serum lactate dehydrogenase (LDH) level rises within 24 hours of an AMI, reaches a peak within 3-6 days, and returns to the baseline within 8-12 days. Since there are two LDH isoenzymes in blood LDH-1 and LDH-2 in which LDH-2 is > LDH-1. Serum pattern change is seen in MI, renal necrosis and hemolysis. (LDH-1 increases in MI) o Troponin I, this is a contractile protein that normally is not found in serum. It is released only when myonecrosis occurs. For early detection of myocardial necrosis, sensitivity of this study is superior to that of the CK-MB. o Troponin I is detectable in serum 3-6 hours after an AMI, and its level remains elevated for 14 days. Troponin T has similar release kinetics and specificity for myocardial necrosis, but it is slightly less sensitive than troponin I within the first 6 hours.  Imaging studies: Chest radiography reveals complications of AMI, particularly pulmonary edema, and CHF. Complications: 1. Lethal arrhythmias: (lidocaine). 2. Refractory arrhythmias (procainamide). 3. Serious arrhythmias include ventricular fibrillation, tachycardia and atrial flutter 4. Congestive heart failure: Left ventricular failure causes pulmonary congestion. Diuretics, especially furosemide, help reduce congestion. Digitalis glycosides have a positive inotropic effect, which improves myocardial contractility, helping to compensate for myocardial damage. 5. Cardiogenic shock: This is characterized by a decreased cardiac output and elevated pulmonary artery pressure. Vasopressors e.g., noradrenaline, adrenaline and high dose dopamine improve blood pressure through alpha receptor stimulation. Inotropic drugs such as dobutamine, isoprenaline and digitalis are used to increase contractility and improve cardiac output. Treatment of myocardial infarction: The aim is. To relieve the pain and anxiety To identify and control life threatening arrhythmias, To limit infarct size and to prevent complication as well as reduction the mortality rate. Analgesia: Attenuates autonomic hyperactivity. (severe pain increases vagal tone = hypotension and bradycardia) Sublingual nitroglycerine. If hypotension and bradycardia develops, I.V. Atropine (0.5-1.0 mg) should be administered. 2. Many analgesic drugs (morphine, meperidine, pentazocine and nalbuphine) have been used in AMI. Morphine is used except in the case of hypersensitivity and pulmonary edema. It is a potent vasodilator, increases venous capacitance and decrease systemic vascular resistance. Meperidine is a suitable alternative in morphine-intolerant patients. Anticoagulation: Anticoagulant may prevent embolic complications: infarcted extension, deep venous thrombosis, pulmonary emboli and arterial emboli from cardiac mural thrombi. Anticoagulant is indicated more in patients suffering from elevated risk of embolization e.g., ventricular aneurysm, marked obesity, cardiogenic shock, present or past thrombophlebitis, arterial or pulmonary embolism. Two types are used: heparin and the vitamin K antagonists (warfarin and dicoumarol). Treatment and prophylaxis of arrhythmias: Ventricular fibrillation is the most common cause of death few hours post myocardial infarction and it may occur without prior evidence. Lidocaine is the preferred agent for rapid control of Ventricular fibrillation. Excessive doses of lidocaine can cause CNS toxicity. Procainamide are alternatives in AMI. 1. Vasodilators: It maintains coronary perfusion in cardiogenic shock. Vasodilator drugs can reduce ventricular wall stress and improvement C.O. through their effects on arterial and venous beds. Sodium nitroprusside is the most vasodilator used in cardiogenic shock; its rapid onset and short duration make it more useful. Nitroglycerine: It improve myocardial blood flow and lowers systemic vascular resistance. 2. Mechanical circulatory support: Intra-aortic balloon pump: improve aortic and coronary blood flow and reduce left ventricular workload in cardiogenic shock. It is a balloon-tipped arterial catheter that is placed just below the aortic arch via the femoral artery. Limitation of infarct size: -adrenergic blockers are used such as propranolol, and metoprolol. Calcium channel blockers which suppress myocardial ischemia and subsequent necrosis. Verapamil reduced infarct size. Also, nifedipine, Deltiazem are used. Nitroglycerine and nitroprusside reduce pre and after load. ACEIs and ARBs: An ACE inhibitor (captopril) should be given orally within the first 24 hours MI to patients with anterior infarction, pulmonary congestion or left ventricular fibrillation. An ARB (valsartan or candesartan) should be used in patient’s intolerance to ACEIs. Thrombolytic agents: They activate plasminogen to plasmin which digest fibrin clot. The goals of thrombolytic therapy are. To lyses coronary thrombi during the early phase of AMI. To limit infarct size To reduce morbidity and mortality. They can administer by infusion by I.V. or intra-coronary route. ❑ Streptokinase is an extracellular protein derived from purified culture broth of group C beta-hemolytic streptococci. It is a foreign protein and is antigenic. ❑ Urokinase is extracted from cultured human kidney cells. It is more expensive than streptokinase and is usually employed in patients who are sensitive to streptokinase. It is not a foreign protein and is therefore nonantigenic. ❑ Anistreplase is a complex of purified human plasminogen and acetylated bacterial streptokinase. The major advantage of Anistreplase over the other agents is its ease of administration as a rapid intravenous bolus dose of 30 units injected over 5 minutes prior to hospital admission. ❑ Alteplase is a recombinant tissue plasminogen activator (rt-PA). ❑ Reteplase is a modified human t-PA constructed by genetic engineering in an attempt to improve the therapeutic properties of t-PA without increasing its bleeding potential. ❑ Aspirin administered 160-325 mg during acute thrombolytic therapy has been shown to affect thrombolysis positively by preventing platelet aggregation. ❑ clopidogrel should be used when aspirin use is contraindicated. Thank You