Pharmacotherapy of Ischemic Heart Disease and MI PDF

Pharmacotherapy of Ischemic Heart Disease and MI Prof. Ahmet AKICI, M.D.  Learning Objectives Describe the role and clinical effects of agents used in the management of patients with ischemic heart disease and MI Learn pharmacological details of Nitrates, Beta-blockers,...

Pharmacotherapy of Ischemic Heart Disease and MI Prof. Ahmet AKICI, M.D.  Learning Objectives Describe the role and clinical effects of agents used in the management of patients with ischemic heart disease and MI Learn pharmacological details of Nitrates, Beta-blockers, and Calcium Channel Blockers, and other drugs that used in MI.  Ischemic Heart Disease The primary symptom of ischemic heart disease is angina pectoris, caused by transient episodes of myocardial ischemia. The causes of the myocardial ischemia that produces angina are defined in terms of the myocardial oxygen supply-demand relationship.  Definition of Angina A clinical syndrome typically characterized by a deep, poorly localized chest or arm discomfort that is reproducibly associated with physical exertion or emotional stress and relieved promptly by rest or sublingual nitroglycerin.  Angina Angina pectoris is the development of chest pain due to myocardial ischemia (not infarction) – coronary blood flow is inadequate to supply the heart with the needed oxygen and nutrients – patients often have underlying coronary artery obstruction – diagnosis of angina and its sub-classification requires evaluation of the nature of the chest pain and circumstances surrounding its development.  Types of Angina Stable Angina Unstable Angina Prinzmetal’s Angina (Variant) Silent Ischemia  Stable Angina The patient has occasional periods of anginal symptoms, which are usually predictable and related to the amount of work the heart is doing. Often a chronic condition characterized by the need for chronic and/or prophylaxis medication to prevent chest pain, which is usually associated with physical activity or stress.  Unstable Angina Most often due to a ruptured coronary plague and platelet aggregation/thrombosis leading to a decrease in blood flow and oxygen supply. Critical condition requiring urgent need for aggressive medical management. UA – part of the clinical spectrum of acute coronary syndrome  Unstable Angina Stable Angina Acute Coronary Syndrome Plague Rupture Unstable Angina Acute Myocardial Infarction  Prinzmetal’s Angina variant angina, vasospastic angina characterized by the unprovoked coronary artery spasm resulting in chest pain. – Patients with this angina may be relatively young and have few or even no cardiac risk factors – the chest pain is often unpredictable and cyclical in nature, sometimes reverting spontaneously into remission.  Silent Ischemia Transient episodes of myocardial ischemia not associated with angina or other symptoms despite ECG changes consistent with ischemic heart disease. Silent ischemia is very common, as demonstrated by continuous Holter Monitor recordings. Controversy – repetitive bouts produce collateralization (protective) vs. production of small areas of patchy necrosis.  Lateral Wall Anterior Wall Inferior Wall Angina Time Line Cardiac Angiography  Risk Assessment Low Risk High Risk Stable angina Unstable angina Absence of CHF CHF symptoms symptoms Resting ECG with Q- Normal resting ECG waves or ST-T wave Normal LVF changes Markedly depressed LVF  Therapeutic Objectives Stable Angina – Improve exercise tolerance – Decrease anginal symptoms – Relieve chest pain – Prevent ischemia Unstable Angina – Stabilize pattern of chest pain – Decrease risk of infarction – Prevent recurrence of ischemic events – Decrease mortality  Therapeutic Decisions Non-Pharmacologic – Coronary intervention (revascularization surgery) – Lifestyle modification – treat aggressively Diet Weight reduction Exercise Smoking cessation  Therapeutic Decisions Pharmacologic – Main anti-ischemic agents B-blockers, Calcium channel blockers (CCBs), Nitrates All 3 drug groups currently approved for use in angina decrease myocardial oxygen requirement by decreasing the determinants of oxygen demand (heart rate, ventricular volume, blood pressure, and contractility). Other anti-ischemic agents: Molsidomine, Ranolazin, İvabradin, Nikorandil, Trimetazidin. …………………………………………………………… – Antiplatelet agents Aspirin (ASA), ADP inhibitors, GP IIb/IIIa inhibitors – Anticoagulants Heparins, warfarin – ACE inhibitors – HMG-CoA reductase inhibitors  Pharmacologic Management Treatment of IHD is directed toward effecting either the DEMAND or SUPPLY of the heart, or both. Reducing Demand – Nitrates, B-blockers, CCBs Increasing Supply – Nitrates, CCBs Therapeutic targets in angina  Strategies for angina Normal Coronary Reduced requirement obstruction ▪ Nitrates Coronary ▪ Beta blockers vasodilation ▪ Calcium channel blockers = Angina Reduced requirement Coronary vasodilation ▪ Revascularization ▪ Nitrates* ▪ Calcium channel blockers* *in reversible vasospasm  Mechanism of antianginal drugs Β-Blockers – Metoprolol, Atenolol,… Calcium Channel Blockers – Diltiazem, Nifedipine,… Organic nitrates – Nitroglycerin,… Nitrate converted to nitric oxide Ca++ Nifedipine cGMP Propranolol Nitrate NO Pi Myosin Light Chain Angina Treatment Mnemonic A – aspirin, anti-anginals (and ACEI) B – B-blockers and blood pressure C – cholesterol and cigarettes D – diet and diabetes E – education and exercise  Beta-blockers They reduce myocardial oxygen demand by blocking the β1 receptors of the heart, leading to a decrease in – heart rate, contractility, cardiac output and blood pressure. The reduced heart rate allows the coronary arteries to fill longer in diastole, thereby increasing myocardial perfusion. They are therefore effective in the prophylaxis of atherosclerotic angina. These drugs reduce myocardial oxygen demand during exertion and at rest and can be used to increase exercise duration and tolerance in patients with exercise-induced angina. They are therefore effective in preventing exercise-induced angina and β blockers are recommended as initial antianginal therapy in all patients unless contraindicated. They are ineffective against vasospastic angina and should not be used in this indication.  Beta-blockers Mechanism of action – Blockade of beta1 and beta2 receptors on myocardial and smooth muscle cells Myocardial effect - HR,  force of contraction, diastolic period – Reduce cardiac workload Myocardial effects Smooth muscle effects (central and renin blocking) BP – Decrease myocardial oxygen consumption – Improve myocardial perfusion due to lower heart rate  Beta-blockers Administration – PO or IV – Initial titration to achieve resting HR: 50-60 Modify dose to eliminate anginal symptoms as well as untoward effects Indications – Chronic management – BBs decrease mortality of patients with recent MI – Selection of agent depends upon clinical factors Reactive airway disease or PVD (beta1 selective) Pharmacologic issues – Modest t1/2, cardioselectivity, ISA, alpha-blockade Role of ISA agents – sinus bradycardia  Beta Blocking Agents Selective With Non-Selective Alpha-Blocking Activity - ISA + ISA - ISA + ISA Carvedilol Labetalol Propranolol Pindolol Metoprolol Acebutolol Nadolol Carteolol Atenolol Celiprolol Timolol Penbutolol Bisoprolol Oxprenolol Betaxolol Nebivolol Esmolol  Beta-blockers Toxicity – Conduction abnormalities, fatigue, depression, hypotension, bradycardia, impaired exercise tolerance, insomnia, unpleasant dreams, erectile dysfunction. Contraindications – Bradycardia, conduction abnormalities, COPD, diabetes, severe unstable left ventricular failure. Patient information – Side effects Important to counsel male patients! – Abrupt withdrawal Discontinuation should be over 5-10 days to avoid rebound angina or hypertension Associated with sudden cardiac death and AMI  Calcium Channel Blockers (CCBs) CCBs can be used as monotherapy or frequently in combination with beta blockers in the treatment of angina. Diltiazem and verapamil are preferred when beta blockers are contraindicated or not tolerated, while dihydropyridine groups such as amlodipine, felodipine or nifedipine are preferred in combination with beta blockers.  Calcium Channel Blockers Mechanism of action – Block calcium entry into myocardial and smooth muscle cells Muscular relaxation and vascular relaxation (dihydropyridines) Exert inhibitory effect on sinus and atrioventricular nodes reducing HR (non-dihydropyridines) – Reduce myocardial oxygen consumption via Afterload reduction via peripheral vascular dilation  HR and contractility – Vasodilation of coronary arteries – Platelet inhibition  CCBs – mechanism of action ▪ Dilate peripheral arterioles □ Decreased afterload □ Decreased myocardial O2 demand* ▪ Dilate coronary arteries □ Increased myocardial O2 supply ▪ Decreases contractility, automaticity at SA node, conduction at AV node □ Decreased myocardial O2 demand ▪ Minimal or no venodilation * Dihydropyridines cause reflex tachycardia and may paradoxically increase myocardial O2 demand!  CCBs’ effect on vascular smooth muscle ▪ Contraction □ results from phosphorylation of myosin light chains (MLC) by myosin light-chain kinase (MLCK) ▪ MLCK is activated by Ca2+ □ calcium channel blockers reduce this step by blocking voltage-gated L-type calcium channels CCBs – Dihydropyridines – amlodipine, lacidipine, nifedipine, felodipine, isradipine, nicardipine, nisoldipine, lercanidipine, benidipine and nitrendipine. Potent vasodilators of peripheral and coronary arteries – Non-dihydropyridines – verapamil, diltiazem Less potent vasodilators, negative chronotropic and inotropic actions  Calcium Channel Blockers Agent AV Node SA Node Myocardial Heart Cardiac Peripheral conduction automaticity contractility rate output resistance (hours) Diltiazem       3.5 to 6 Verapamil       3 to 7 Nifedipine       2 to 5 Nicardipine       2 to 4 Felodipine       10 to 36 Isradipine       Amlodipine       Nimodipine N/A N/A N/A N/A N/A N/A 1 to 2 Bepridil        Calcium Channel Blockers Administration – PO or IV Indications – Mainly chronic therapy when B-blockers or nitrates not efficacious and/or tolerable – frequently in combination with beta blockers in the treatment of angina. Pharmacologic issues – Short-acting dihydropyridines, conduction abnormalities, negative inotropic properties, drug interactions  Calcium Channel Blockers Toxicity - The most important toxic effects are direct extentions of their therapeutic action; Depression of contractility, HF, AV nodal blockade, bradycardia, hypotension. - constipation, flushing, edema, dizziness, and nausea. Contraindications – Conduction abnormalities Patient information – Side effects, drug interactions  Nitrates These agents are simple nitric and nitrous acid esters of polyalcohols. Nitroglycerin (glyceryl trinitrate) may be considered the prototype of the group. All therapeutically active agents in the nitrate group have identical mechanisms of action and similar toxicities.  Nitrates Oral bioavailability of the traditional organic nitrates (eg, nitroglycerin and isosorbide dinitrate) is very low (