Acute Coronary Syndrome PDF

Acute Coronary Syndrome Advanced Pharmacology Dru Riddle Student Performance Objectives 1. Describe the pathophysiology of angina pectoris in terms of myocardial oxygen supply and demand. 2. List the therapeutic objectives of antianginal therapy. 3. Describe the therapeutic approaches to antiangin...

Acute Coronary Syndrome Advanced Pharmacology Dru Riddle Student Performance Objectives 1. Describe the pathophysiology of angina pectoris in terms of myocardial oxygen supply and demand. 2. List the therapeutic objectives of antianginal therapy. 3. Describe the therapeutic approaches to antianginal therapy. 4. List the effects, mechanism, indications, toxicity and contraindications of nitroglycerin. 5. List the effects mechanism indications, toxicity and contraindication of b blockers and calcium channel blockers. 6. Describe the risk and benefits of using combination therapy. Drugs Used in Angina • Organic nitrates • Nitroglycerin • Isosorbide mononitrate or isosorbide dinitrate § b blockers § Atenolol, metoprolol, propranolol • Ca channel blockers • Dihydropyridine--amlodipine, felodipine, nifedipine • Non-dihydrophyridine--diltiazem, verapamil • Ranolazine (Ranexa)—sodium channel antagonist • Anticoagulation lecture • Antiplatelets Nitrates • Nitroglycerin • Isosorbide mononitrate • Isosorbide dinitrate Beta-Blockers labeled for use in angina • Non-Selective • Propranolol • Beta1 Selective • Metoprolol • Atenolol Calcium Channel Blockers for Angina • Cardio Selective • Diltiazem • Verapamil • Vascular (“pines” -- pronounced “peens”) • Nifedipine • Amlodipine • Felodipine Drugs Used in Angina • Aspirin • Clopidogrel (Plavix) • GP IIb/IIIa Inhibitors Angina pectoris Classifications • Painful clinical syndrome • temporary and reversible imbalance between myocardial O2 supply and demand • coronary artery disease (CAD) usually the underlying cause • Typical Angina • Stable • Effort-induced • Classic • Prinzmetal, variant, vasospastic or rest angina • Unstable angina Classifying angina • Typical or Classic angina • • • • • Angina of Effort = atherosclerotic angina Most common form Hx = angina induced by exercise, relieved by rest and/or NTG lasts no longer than 15 min, 5 - 15 episodes/wk ST segment depression Classifying Angina • Atypical angina • Vasospastic (Prinzmetal’s) • frequent angina at rest • transient ST segment elevation during angina • Unstable angina • progression from stable • rest angina severe or frequent enough to warrant admission to a CCU, at least 2 attacks per 24 hr period • MI imminent ® vigorous therapy required Pathophysiology of Angina • O2 supply available to the heart is significantly lowered • O2 demands of exertional situations can no longer be met • Autoregulatory mechanisms usually fail to mitigate this imbalance Pathophysiology of Angina Associated with Effort • In the next slide, note that the plaque is in the LARGE (R1 = artery) vessel, not in the small vessel (R2 = arteriole). • At rest, the small vessel can dilate sufficiently to maintain blood flow. However, when great O2 demand occurs, blood flow is inadequate. Coronary circulation Limited coronary vasodilator reserve Angina can also be induced by largevessel vasospasm Large-Vessel Vasospasm Myocardial Ischemia Myocardial Infarction Angina Pectoris LV Dysfuncton Rhythm Disturbances (and Sudden Death) Prinzmetal’s Angina • Coronary artery spasm • Etiology is not clear • Although plaques are common, spasm does not seem to result from decreased flow • Spasm is not a consequence of increased sympathetic activity Pathology of Unstable Angina • Additional artery block • Clot • Plaque rupture Therapeutic objectives • Acute prophylaxis • anticipate angina-inducing situations • Treat attack in progress • rapidly-acting drug • Chronic prophylaxis Therapeutic approaches • Increase oxygen supply (difficult with atherosclerotic plaque) • Decrease oxygen demand • Exertion angina • Unstable angina • Relax the vasculature • Prinzmetal’s angina Determinants of myocardial oxygen supply and demand • Oxygen demand • • • • Heart rate Myocardial contractility Systolic blood pressure LV volume (preload) • Oxygen supply • Coronary blood flow Mechanism of Beneficial Effects of Interventions that Decrease MVO2 CONTROL INTERVENTION MVO 2 ANGINA THRESHOLD EXERCISE INTENSITY Organic Nitrates (nitroglycerin, others) • Pharmacodynamic effects • Relax vascular smooth muscle • Mainly relaxation of large veins ® ¯ venous return ® ¯ preload ® ¯ O2 demand (major effect) • smaller ¯ in afterload § in oxygen supply (transient), effective in prevention of coronary vasospasm Mechanism of Nitrates • In healthy subjects, NO dilates coronary arteries • Hypothesis was that NO improved perfusion to hypoxic areas of heart • This hypothesis has been expanded • In angina of effort, direct infusion of NTG into heart does not relieve angina, but sublingual NTG does. Why? Mechanism of NTG Katzung, 15th ed, Fig 12-2 NTG: Therapeutic indications • Angina • Congestive Heart Failure • Cardiac output • After MI • ¯ work of heart • ¯ platelet aggregation • Raynaud’s disease Adverse Effects/Limitations • Headaches, dizziness • Orthostatic hypotension • Tolerance • Dose/frequency dependent • 8-hr drug-free/day • mechanism? • Drug holidays can alleviate Drug Interactions • Sildenafil • Inhibits phosphodiesterase-5 enzymes • Leads to reduced breakdown of cyclic GMP • Nitrates enhance production of cyclic GMP • = dramatically enhanced vascular effects, including severe hypotension • Therefore, sildenafil is contraindicated with nitrates Mechanism of NTG/Sildenafil Interaction Katzung, 15th ed, Fig 12-2 Specific agents • NTG • large first-pass effect if taken p.o. • sublingual = short onset, short-acting • Isosorbide mononitrate or dinitrate • slower, less potent than NTG • short and long-acting preparations Nitrate therapy in chronic stable angina • Short-acting • Relief during acute episodes • Prophylaxis of acute episodes • Long-acting • monotherapy for mild angina • adjunctive for more severe angina • Limitations • side-effects • tolerance b blockers in anginal therapy • ¯ heart rate (major effect); and also ¯ contractility (lesser effect) ® ¯ cardiac work ® ¯ O2 demand • ¯ peripheral resistance (block renin release) – longer term effect – which ® ¯ O2 demand • no effect on O2 supply -3 Pressure-Rate Product (x 10 ) b BLOCKER THERAPY IN CHRONIC STABLE ANGINA 25 * * * 20 15 10 5 0 * 0 5 Placebo Propranolol - 240 mg/day Propranolol - 480 mg/day Angina 10 15 Treadmill Grade (%) 20 bBlockers in Chronic Stable Angina • Indications • monotherapy for mild to moderate angina of effort (not for Prinzmetal’s) • combination therapy (angina of effort) • after MI • Limitations • bradyarrhythmias • congestive heart failure • extracardiac effects Beta-Blockers in Angina • Non-Selective • Propranolol • Beta1 Selective • Metoprolol • Atenolol Prinzmetal’s Angina • Therapy is to relax vasculature • Nitrates • Ca Channel Blockers Ca Channel Blockers in Angina • Pharmacodynamics: block Ca entry through L-type channels • ® relaxation of arteriolar smooth muscle • ® ¯ afterload ® ¯ O2 demand § Also, supply due to dilation of coronaries Ca++ Role in Vascular Smooth Muscle Contraction • Intracellular Ca++ Increases by 3 Mechanisms • Voltage Gated Channels • L, N and T • Receptor Mediated Activation of Internal Stores (e.g., alpha1) • Receptor Mediated Influx of Ca++ • All mechanisms lead to cell contraction Increased Intracellular Ca++ in Smooth Muscle Contraction Katzung, 15th ed, Fig 12-1 Ca Channel Blockers Two Classes 1. Predominately Vascular 1. dihydropyridines (e.g., nifedepine, “pines”) 2. Predominately Cardiac 1. verapamil and diltiazem Ca++ Channel Blockers • Block L-type Ca++ Channels • “Pines” bind to a slightly different region than verapamil/diltiazem • Presumably accounts for different spectrum of vascular vs. cardiac effects Mechanism of Beneficial Effects of Ca Channel Blockers in Angina • ¯ Excitability of vascular smooth muscle • ¯ propensity of arteries to spasm (helpful in Prinzmetal’s) • ¯ Tone of vascular smooth muscle • ¯ afterload (helpful in angina of effort) Mechanism of Beneficial Effects of Ca Channel Blockers in Angina • In addition to their vascular effects, verapamil and diltiazem • ¯ SA and AV node function • ¯ Cardiac contractility • Both effects lead to less cardiac work (useful in angina of effort) Ca Channel Blockers as Monotherapy 1. Angina with historical features suggesting dynamic coronary vasoconstriction (Prinzmetal’s) 2. Patients with sinus bradycardia, AV dysfunction – use a “pine” 3. Patients with atrial fib/flutter – use verapamil 4. Patients resistant/tolerant to nitrates or b blockers Combination therapy of Ca channel blocker and b blocker • More effective than either individually for angina of effort Factors Influencing Myocardial Oxygen Supply-Demand Relationships During Treatment with Calcium Channel Blockers, b-blockers, and the Combination Calcium Channel Blockers b-blockers Myocardial oxygen supply Coronary blood flow Diastolic filling* Myocardial oxygen demand Heart rate* LV systolic wall tension Contractility* Calcium Channel Blockers + b-blockers ­­ 0 or ­ or ­­ ¯ 0 ­ ­­ 0 or ¯ or ­ ¯ 0 or ¯ ¯ ¯ ¯ ¯ or ¯¯ ¯¯ ¯¯ Factors influencing combination of Ca channel blocker and b blocker • Choice of calcium channel blocker • Presence of antecedent LV dysfunction or conduction system abnormalities • Other drug interactions (e.g., digoxin, alpha adrenergic blockers, nitrates) THERAPEUTIC GUIDELINES • Acute prophylaxis and treatment of single attacks • NTG is mainstay Onset: 1-3 min, duration:20-30 min • Maintenance therapy of chronic stable angina • b blockers, Ca channel blockers, or long duration nitrates or combination • Vasospastic angina • Ca channel blockers or nitrates • New Approved Therapies for ACS • Ivabradine (Corlanor)-funny current antagonist, reduces heart rate • Ranolazine (Ranexa)—sodium current antagonist—does not impact heart rate and blood pressure, but improving metabolism of the ischemic myocardial cells. ANTIPLATELET AGENTS IN TREATMENT OF ANGINA • Aspirin • clearly demonstrated to ¯ mortality in patients with unstable angina, reducing incidence of MI and death • ¯ incidence of MI in chronic stable angina • effect due to inhibition of platelet aggregation • similar effect seen with heparin • Will be covered in Antiplatelet and Anticoagulation Lecture