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Department of Clinical Pharmacology Pharmacotherapy of chronic ischemic heart disease Jerzy Jankowski, MD FORMS OF ANGINA PECTORIS (AP) • ATHEROSCLEROTIC (CLASSIC) ANGINA • VARIANT (VASOSPASTIC ANGINA) Anginal conditions other than CAD causing chest discomfort Non-CAD causes of chest discomfort Syndrome X: Chest pain syndrome with objective evidence of ischemia and normal coronary arteries on angiography Prinzmetals angina: Vasospastic angina with normal or nearnormal coronary arteries; can have Prinzmetals angina with significant CAD Aortic stenosis: Myocardial ischemia can be caused by an imbalance between the increased myocardial oxygen demand related to left ventricular hypertrophy and increased wall stress and the available coronary blood supply in the absence of coronary atherosclerosis Esophageal disease: Esophagitis, reflux, motility disorders ANTIANGINAL DRUGS • ORGANIC NITRATES • ΒETA- ADRENORECEPTOR- BLOCKING DRUGS • CALCIUM CHANNEL- BLOCKING DRUGS • METABOLIC AGENTS DRUG ACTION IN ANGINA • DECREASE MYOCARDIAL O2 REQUIREMENT BY: decreasing peripheral vascular resitance decreasing cardiac output both ways • INCREASE MYOCARDIAL O2 DELIVERY nitrates calcium channel antagonists ORGANIC NITRATES PHARMACOKINETICS CHARACTERISTICS • EXTENSIVE FIRST-PASS EFFECT (90%) • LOW BIOAVAILABILITY (10%) • RAPID ONSET OF ACTION (1-3 min) • BRIEF DURATION OF ACTION (up to 30 min) Adverse effects of nitrates EFFECT OCCURRENCE Headache Common Nausea and vomiting Occasional Dizziness or overt syncope Occasional Palpitations and tachycardia Uncommon Tolerance and attenuation Common Avoidance of nitrate tolerance Use smallest effective dose Administer the fewest possible doses per day Avoid continuous or sustained exposure to nitrates Provide a nitrate-free interval of ≥10 h every day BETA-ADRENORECEPTOR BLOCKING DRUGS MAJOR DIFFERENCES AMONG BBs • ISA • Beta-receptor selectivity Cardioselective Nonselective • Local anesthetic action • Pharmacokinetic characteristics Beta-blockers with ISA Acebutolol Cartreolol Celiprolol Oxprenolol Penbutolol pindolol Cardioselective beta-blokckers Acebutolol Atenolol Betaxolol Bisoprolol Celiprolol Metoprolol Non-selective beta-blockers Labetalol Nadolol Penbutolol Pindolol Propranolol Sotalol Timolol Generations of beta-blockers I generation: non-selective BBs II generation: cardioselective BBs III generation: beta-blockers (non-selective or cardioselectve BBs) with vasodilator activity: carvedilol, celiprolol, nebivolol Local anesthetic action Acebutolol Betaxolol (slight) Labetalol Metoprolol Pindolol Propranolol Pharmacokinetic differences Lipid solubility: penbutolol, propranolol labetalol, metoprolol, pindolol, timolol low lipid solubility: acebutolol, atenolol, betaxolol, bisoprolol, esmolol, nadolol, sotalol Mechanism of action in angina and cardiovascular effects of -blocking agents Decreased myocardial oxygen consumption Decreased heart rate Decreased blood pressure Decreased myocardial contractility Increased coronary blood supply Preserved coronary blood flow because of prolonged diastole A. Solubility characteristics of -blocking agents Hydrophilicity Lack of hepatic first-pass effect lowers the chance of drug interactions and food interference Often results in longer half-life Low penetrability into CNS, resulting in fewer side effects Lipophilicity Requires hepatic metabolism Greater chance of significant first-pass effect Often results in shorter half-life Higher penetrability into the CNS Adverse effects of -blocking agents Cardiac Increased ventricular volume resulting in congestive heart failure Excessive heart rate slowing or heart block Withdrawal syndrome Noncardiac Fatigue Mental depression Insomnia Nightmare Raynauds phenomenon Worsened claudication symptoms Bronchoconstriction Metabolic Increased LDL cholesterol and triglycerides; lowered HDL cholesterol Worsening of insulin-induced hypoglycemia; masking of hypoglycemic symptoms Increased blood sugar in insulin-resistant diabetics CALCIUM CHANNELBLOCKING DRUGS PHARMACOLOGIC EFFECTS OF CALCIUM CHANNEL BLOCKERS HR A-V CONDUCTION CONTRACTILITY PERIPHERAL VASODILATION CO CBF MO2 DEMAND VER ↓ ↓↓↓ ↓↓ ↑ v ↑ ↓ DIL DHPS ↓ ↑↔ ↓ ↔ ↓ ↓↔ ↑ v ↑ ↓ ↑↑ v ↑ ↓ ↑INCREASE; ↓ DECREASE; v VARIABLE; A. Adverse cardiovascular effects of calcium channel antagonists SYMPTOM CAUSE Dizziness, light-headedness, syncope, Excessive hypotension palpitation IMPLICATED CALCIUM CHANNEL ANTAGONIST All Bradycardia Verapamil, diltiazem Reflex tachycardia Dihydropyridines Exacerbation or precipitation of congestive heart failure Negative inotropic action Most; amlodipine, felodipine are the safest to use, even in heart failure Severe bradycardia or heart block Negative chronotropic action, especially sick sinus node disease Verapamil, diltiazem Precipitation of angina Hypotension, coronary steal Nifedipine and possibly other dihydropyridines B. Noncardiac Side Effects Associated with Calcium Channel Blockers SYMPTOM VERAPAMIL DILTIAZEM NIFEDIPINE Headache Rare Rare Occasional Postural dizziness Rare Rare Common Flushing Rare Rare Common Peripheral edema Rare Rare Common Common Rare Rare Other gastrointestinal disorders Rare Rare Rare Paresthesias Rare Rare Occasional Constipation METABOLIC DRUGS • METABOLIC INHIBITORS WITH CARDIOCYTOPROTECTIVE EFFECT • RANOLAZINE • TRIMETAZIDINE (PREDUCTAL MR 35mg) • 3-KETOACYLO-CoA THIOLASE INHIBITOR Combinations of antianginal drugs COMBINATION BENEFICIAL Nitrates + b-blocker X Nitrates + diltiazem, verapamil X Nitrates + dihydropyridine b-blockers + dihydropyridine b-blockers + diltiazem, verapamil SHOULD BE AVOIDED OR IS RELATIVELY CONTRAINDICATED X X X Thienopyridines Ticlopidine (2 x 250 mg) Clopidogrel (1 x 75 mg) P2Y12 adenosine diphosphate receptor blocker For 1 year after NSTEMI, PCI + DES EUROPA TRIAL EUropean trial on Reduction Of cardiac evens with Perindopril in stable coronary Artery disease • Randomized, placebo controled, duble blind study • 4 years follow-up • 12218 patients at low risk; perindopril 8 mg vs placebo EUROPA TRIAL - RESULTS • The primary end-point ( cardiovascular death + nonfatal MI + non fatal cardiac arrest ) ↓ 20% • Risk of MI ( fatal + nonfatal ) ↓ 24% • Hospitalisation for HF ↓ 39% PERTINENT TRIAL PERindopril, Thrombosis, INflammation, Endothelial dysfunction and Neurohormonal activaTion • • • • • • • Rate of apoptosis of EC Activity and expression of NOS Proapoptotic protein Bax Antiapoptotic protein Bcl-2 Von Willebrand factor Levels of AT II, bradykinin, TNF Assesment at baseline and after 1 year of treatment PERTINENT TRIAL - RESULTS One year of treatment with perindopril was able significantly reduce the rate of apoptosis and increase the activity and expression of NOS Major purposes of the treatment To improve short and long term prognosis by preventing MI and death and thereby increase the length of life To improve quality of life by reducing symptoms of angina and occurrence of ischemia Recommendations for Pharmacotherapy To Prevent MI and Death and To Reduce Symptoms The following agents should be used in patients with symptomatic chronic stable angina to prevent MI or death and to reduce symptoms: Aspirin (level of evidence: A) or clopidogrel when aspirin is absolutely contraindicated (level of evidence: B) ß-Blockers in patients with previous MI (level of evidence: A) or without previous MI (level of evidence: B) Low-density lipoprotein cholesterol–lowering therapy with a statin (level of evidence: A) ACE inhibitor (level of evidence: A) Recommendations for Pharmacotherapy To Prevent MI and Death and To Reduce Symptoms The following agents should be used in patients with symptomatic chronic stable angina to reduce symptoms only: Sublingual nitroglycerin or nitroglycerin spray for the immediate relief of angina (level of evidence: B) Calcium antagonists (long-acting) or long-acting nitrates when ß-blockers are clearly contraindicated (level of evidence: B) Calcium antagonists (long-acting) or long-acting nitrates in combination with ß-blockers when ß-blockers alone are unsuccessful (level of evidence: B). TREATMENT OF STABLE ANGINA ACCORDINGLY TO CCS CLASSIFICATION CLASS I correction of risk factors, nitroglycerin sl aspirin 75-150mg CLASS II as above+ chronic therapy with LA nitrates or ß1-blockers or LA Calcium antagonists or Trimetazidine or combination of these drugs TREATMENT OF STABLE ANGINA ACCORDINGLY TO CCS CLASSIFICATION CLASS III and IV As above and establish indications for invasive treatment