Pharmacology of Angina Pectoris Lecture PDF

Pharmacology of Angina Pectoris Maria A. Pino, Ph.D Department of Clinical Specialties [email protected] Office of Academic Affairs  Session Objectives Review the pathophysiology of angina pectoris Distinguish between the types of anginas and the appropriate therapeutics. Describe the me...

Pharmacology of Angina Pectoris Maria A. Pino, Ph.D Department of Clinical Specialties [email protected] Office of Academic Affairs  Session Objectives Review the pathophysiology of angina pectoris Distinguish between the types of anginas and the appropriate therapeutics. Describe the mechanism of nitrates in angina. Include adverse effects and specific drug interactions, mainly drugs for erectile dysfunction Review the mechanism of beta-adrenergic receptor antagonists. Identify patients which this class of drug is contraindicated. Describe the differences between the classes of calcium channel blockers. Identify other drugs used to manage angina, including ranolazine. Review the mechanisms of antiplatelet drugs. Source: Course Syllabus O2 Supply and Demand Imbalance Reduced by Beta blockers? Reduced by Calcium channel blockers? Reduced by Nitrates? https://www.cvphysiology.com/CAD/CAD007 https://slidetodoc.com/angina-angina-pectoris-learning- outcomes-on-completion-of/  Angina and Drug Management Stable: Nitrates, BB, CCB Vasospastic: Nitrates, CCB Unstable: Nitrates, CCB, BB plus antiplatelets, ACE-, Statin. PCI. https://www.drawittoknowit.com/course/pathology/glossary/pathophysiolo gic-disorder/ischemic-heart-disease-symptoms-angina-others Nitrates: Increase cGMP  Nitric oxide (NO) donors Nitroglycerin is denitrated by glutathione S-transferase. Free nitrite is converted to NO. Another metabolic release of NO is by mitochondrial aldehyde reductase. Tolerance: with continuous use. May be due to depletion of the sulfur group or inhibition of aldehyde reductase. An 8-hour drug holiday is required to restore action. NO donor results: Increased venous capacitance, decreased preload, reduced venous return, less cardiac output  Nitrates: Clinical Uses Immediate relief of angina: sublingual nitroglycerin Suppression of severe, recurrent angina at rest, Prinzmetal’s, and atypical: IV nitroglycerin Recurrent typical and atypical angina: oral, buccal, transdermal Other: Heart Failure (decreases preload) Unresponsive hypertension (sodium nitroprusside = added arteriolar vasodilator action).  Nitrates: Formulations and duration Nitroglycerin (sl): 10-30 min Isosorbide dinitrate (sl) 10-60 min Amyl nitrite inhaled 3-5 min Nitroglycerin (oral): 6-8 hr Nitroglycerin (transdermal): 8-10 hr Isosorbide dinitrate (oral, chewable): 2-6 hr Isosorbide mononitrate (oral; 100% bioavailable): 6-10 hr  Nitrates: Adverse Effects Throbbing, vascular headache Vasodilation, hypotension (orthostatic) and compensatory tachycardia, with increased ventricular contractility Compensatory retention of salt and water due to renin- angiotensin II-aldosterone NO activates guanylyl cyclase. Increased cGMP decreases platelet activation. Use as antiplatelet not established. Drug interactions: PDE5 inhibitors: sildenafil, vardenafil, tadalafil. Nitrates and Erectile dysfunction drugs Sodium nitroprusside Nitroglycerin Hydralazine sildenafil https://cvpharmacology.com/vasodilator/nitro Sodium Nitroprusside Short-acting NO donor, IV use for hypertensive emergencies. Dilates arterioles and venules. Decreases afterload and preload. Adverse effect: Rare accumulation of cyanide. Drug is a complex of iron, cyanide, and nitroso moiety. Antidote: sodium thiosulfate or hydroxycobalamin (vitamin B12).  Cyanide Toxicity http://brownemblog.com/blog-1/2021/8/28/fire-related-injuries-in-children  Coronary Steal and Vasodilators https://www.amboss.com/us/knowledge/coronary-artery-disease  Calcium Channel Blockers (CCB) Calcium is essential for the function of all nerves, smooth, cardiac and skeletal muscle, and exocrine glands. For CV, primary targets are arterioles and heart. Blockade of L-type channels Calcium Channel Blockers (CCB)  Calcium Channel Blockers (CCB) Arterioles relax, TPR and afterload decrease. Blood pressure falls, heart works less for systole. Common to all CCBs for antianginal and antihypertensive use. Verapamil and diltiazem: Heart automaticity and ventricular contractility are decreased. Phase IV antiarrhythmic, antihypertensive, and antianginal use.  Dihydropyridines (DHPs) Nifedipine types “dipines” Arteriole action only Decreases TPR, BP. May elicit the SANS reflex and tachycardia. Amlodipine and felodipine (once-a-day dosing) Nifedipine can be used in pregnant hypertension (first-line is methyldopa) Verapamil and Diltiazem (non-DHP) Arteriole and Heart action; Verapamil > Diltiazem Resist the SANS reflex, replaces beta blockers in COPD, asthma, diabetes patients Uses: hypertension, angina, Phase IV antiarrhythmic (manages SVT, atrial fibrillation) Adverse Effects: Hypotension without high HR. SA and AV node depression. Negative inotropic effect = contraindicated in CHF.  CCB Adverse Effects Dizziness, headache, edema Tachycardia (DHP) Bradycardia (non-DHP) Constipation (most with verapamil) Gingival overgrowth (review past drugs??) Grapefruit drug interactions (CYP 3A4) Verapamil increases digoxin plasma levels. Antidote: Supportive care; IV calcium, insulin Beta-adrenergic receptor antagonists https://www.cvpharmacology.com/cardioinhibitory/beta-blockers Beta-adrenergic receptor antagonists Beta 1: decrease HR, CO, and renin from JXA Use: hypertension, MI, CHF, antianginal (except vasospastic), Phase II antiarrhythmic Beta 1: (atenolol, metoprolol)—AV block adverse effect Beta 1, 2: (nadolol, propranolol, timolol). Bronchoconstriction, hypoglycemia, complicates PVD (Beta 2) Labetalol and Carvedilol (alpha and beta blocker) Pindolol and Acebutolol (ISA)-can worsen angina Esmolol (ultrashort acting) Nebivolol (nitric oxide effect) Antidote: supportive therapy, glucagon Ranolazine  Ranolazine Reduces late sodium current. Prevents calcium entry via the Na+/Ca2+ exchanger. Angina prophylaxis (chronic) Adverse effects: nausea, constipation, dizziness. CYP inhibitors increase ranolazine action. Prolongs QT interval  Other Therapies Percutaneous Coronary Intervention (PCI) Coronary artery bypass grafting (CABG) Antihypertensives (ACEIs) Smoking Cessation/Lifestyle modifications Antiplatelet drugs (Review) Lipid-lowering agents (future lecture) Ivabradine (future lecture) Antidiabetics (future lecture) Antiplatelet Drugs Cilostazol dipyridamole  Antiplatelet drugs Aspirin irreversibly blocks COX 1,2 (NASIDs reversible). Analgesic, anti-inflammatory, antipyretic ADP receptor blockers (clopidogrel) Glycoprotein IIb/IIIa inhibitors (abciximab) Phosphodiesterase inhibitors (cilostazol, dipyridamole)—for peripheral artery disease Thromboxane Synthesis Platelet Membrane-bound fatty acids Free fatty acid Aspirin irreversible COX-1 acetylation Thromboxane A2 Platelet Aggregation, release response, arterial constriction Low Dose Aspirin Blocks TXA2 not Prostacyclin Cells have a nucleus Platelets have no nucleus & can recover and cannot make more COX. COX No TXA2 for life of platelet PGH2 Less aggregation Less TXA2 healthy cell may repel Prostacyclin platelets platelets Will make more stops prostacyclin aggregation and adhesion  Aspirin Prevents (primary) cardiovascular disease and recurrence (secondary) Consider individual patient (benefit vs risk) Adverse effects: GI bleed, hypersensitivity, metabolic acidosis (overdose). Uncoupling of oxidative phosphorylation. Salicylates not for pediatric patients.  ADP receptor blockers Ticlopidine, clopidogrel, prasugrel, ticagrelor All are prodrugs, but ticagrelor. Clopidogrel is activated by 2C19 (mutations or drug inhibiting 2C19 will reduce antiplatelet effect). Clopidogrel used for unstable angina or non-ST-elevation acute myocardial infarction (NSTEMI) in combination with aspirin (also STEMI, recent MI, and PAD) All prevent thrombosis: Considered standard practice in patients undergoing stenting. And for acute coronary syndromes. Adverse effect: bleeding. (Ticagrelor most) Ticlopidine (Neutropenia)  GP IIb/IIIa Inhibitors Abciximab (monoclonal antibody) Reversible inhibitors: Eptifibatide, tirofiban. Short half lives= administer by continuous infusion. Use: Acute coronary syndrome or PCI Adverse effect: bleeding Pathology Correlate: Glanzmann disease results from absent or defective GP IIb/IIIa.  Summary Slide Distinguish between the types of anginas and the appropriate therapeutics. Identify other drugs used to manage angina, including ranolazine. Review the mechanisms of antiplatelets. Core References: 1. Katzung & Trevor Basic and Clinical Pharmacology, 16e, 2024; Chapter 12: Vasodilators and Treatment of Angina Pectoris; Chapter 11: Antihypertensive Agents; Chapter 34: Drugs Used in Disorders of Coagulation. 2. Pharmacology of Angina Pectoris Summary Guide (Maria A. Pino, Ph.D) 3. Scholar Bricks: https://exchange.scholarrx.com/brick/treatment-of-acute-coronary-syndrome https://exchange.scholarrx.com/brick/treatment-of-acute-coronary- syndrome?edition=edition-1  Lecture Feedback Form: https://comresearchdata.nyit.edu/redcap/surveys/?s=HRCY448FWYXREL4R