Cardiovascular Pharmacology Part II - PHA4107 - Feb 2024 - PDF

PHA4107 Cardiovascular Pharmacology-Part II Smooth Muscle and Antianginals (Drugs for Ischemic Heart Disease) Dr. Wenbin Liang Associate Professor Department of Cellular and Molecular Medicine University of Ottawa Director, Cardiac Electrophysiology Laboratory University of Ottawa Heart Institute wl...

PHA4107 Cardiovascular Pharmacology-Part II Smooth Muscle and Antianginals (Drugs for Ischemic Heart Disease) Dr. Wenbin Liang Associate Professor Department of Cellular and Molecular Medicine University of Ottawa Director, Cardiac Electrophysiology Laboratory University of Ottawa Heart Institute [email protected] Feb 26, 2024 Outline I. Vascular smooth muscle II. Coronary artery & Angina pectoris III. Antianginals (anti-ischemic agents) Vasodilators ‒ Organic nitrites & nitrates ‒ Calcium channel blockers β blockers New class of drugs Vascular Smooth Muscle (1) Blood Vessel Three layers: Inner layer: endothelial cells Middle layer: smooth muscle cells Outer layer: collagen + fibroblasts Vascular smooth muscle cell Contraction of smooth muscle Vessel diameter Blood flow rate Vascular Smooth Muscle (2) Mechanisms of Smooth Muscle Contraction Smooth muscle contraction: 1. Initiated by Ca2+ increases (from 0.1 µM to 10 µM) 2. Ca2+ binds to Calmodulin 3. The Ca2+/Calmodulin complex activates Myosin Light Chain Kinase (MLCK) 4. The MLCK then phosphorylates Myosin 5. The phosphorylated myosin binds to actin forming cross-bridge, triggering contraction Relaxation: Ca2+ decreases or activation of MLC phosphatase Coronary Arteries (1) Coronary arteries: The first to branch off the aorta Left & right coronary arteries Supply blood to heart muscle ~5% of total cardiac output ~11% of total body O2 consumption (Heart weight/body weight ratio = ~0.45%) O2 supply rate to heart = Coronary blood flow rate x O2 content Coronary Arteries (2) Balance between O2 supply and demand in normal heart Exercise At rest Coronary blood flow O2 supply Cardiac contraction Coronary blood flow Cardiac contraction O2 demand O2 supply O2 demand Vessel dilation Resting coronary artery Coronary Arteries (3) Coronary Artery Disease Cardiac contraction Artery blocked Coronary blood flow www.mountelizabeth.com.sg Ischemic Heart Disease:  Angina Pectoris (partial block) Crushing chest pain (accumulation of metabolites)  Myocardial Infarction (MI) (complete block) Coronary Arteries (4): Angina Pectoris 1. Typical Angina: Stable angina: Atherosclerotic plaque + vasoconstriction Similar characteristics (pattern and duration of pain, triggered by same events) www.123rf.com Unstable angina: Rupture of plaque + platelet aggregation + thrombus Sudden increases in frequency, duration, and severity of angina (a precursor of myocardial infarction) 2. Variant Angina (Prinzmetal’s Angina): Intense vasospasm Can occur at any time, even at rest/sleep Antianginal Drugs (1): Goal of therapies: to restore the balance Vasodilators Organic nitrites & nitrates β blockers Calcium channel blockers Preload Afterload O2 supply O2 demand Coronary flow rate Heart rate, contractility Preload and afterload (determinants of wall tension) Pulmonary circulation Antianginal Drugs (2): Vasodilators: Organic nitrites and nitrates Mechanisms of action Organic Nitrites & Nitrates: - release nitric oxide (NO) (which is normally generated by endothelial cells) Myosin light chain Phosphatase Drug interactions: Cannot be used together with Sildenafil (PDE5 inhibitor) Antianginal Drugs (3): Vasodilators: Organic nitrites and nitrates Amyl Nitrite Amyl Nitrite: volatile liquid; inhalation. onset: almost immediately (~30 s) short duration of action (3-5 min) treatment of acute anginal attacks Antianginal Drugs (4): Vasodilators: Organic nitrites and nitrates Nitroglycerin: - used since 1879 - fast-acting and inexpensive - lipid soluble Formulations: Oral formulation (well absorbed from gut, but metabolized by liver): extended-release preparation for long-term prophylaxis (prevention) of anginal attacks Sublingual tablets and translingual spray (rapid absorption, bypasses liver inactivation): - terminating an ongoing attack (relieving pain) - short-term prophylaxis (e.g., before excise) Transdermal patch or ointment (delayed onset, slow release, sustained effects): - prevention of anginal attacks Intravenous (IV): treatment of myocardial infarction (MI) and acute heart failure (works by reducing preload and afterload). Antianginal Drugs (5): Vasodilators: Organic nitrites and nitrates Mechanisms of antianginal actions Nitric Oxide (NO) released from nitrites & nitrates Dilation of coronary arteries of the heart Dilation of veins Coronary blood flow Venous return preload O2 supply For treatment of variant angina Wall tension O2 demand For treatment of stable and unstable angina https://edhub.ama-assn.org/jn-learning Antianginal Drugs (6): Vasodilators: Organic nitrites and nitrates Adverse effects & Tolerance Adverse Effects: Excessive vasodilation Blood Pressure Hypotension, headache Reflex tachycardia (can be prevented with β-blockers) Tolerance of nitrates: Continuous use Vasodilation effect Nitrites Nitrates Prevention of tolerance ( dose and frequency): (at least 8 drug-free hours/day) Skin patch: removed for > 10-12 h/day Long-acting oral drugs: only 1 or 2 times/day Mechanism of tolerance: NO releasing enzyme (aldehyde dehydrogenase) is inactivated by oxygen free radicals Aldehyde dehydrogenase NO Oxygen free radicals Antianginal Drugs (7): Vasodilators: Calcium channel blockers (CCBs) Two classes: 1. Dihydropyridine (DHP) class (-dipine): Amlodipine (half-life 40 h) Felodipine (14 h) Nicardipine (3 h) Nifedipine (3 h) Nimodipine (1.5 h) 2. Non-dihydropyridine class: Diltiazem (5 h) Verapamil (5 h) Antianginal Drugs (8): Vasodilators: Calcium channel blockers (CCBs) Mechanisms of action L-type Ca2+ channels: Expressed in the cell membrane of: CCBs Vascular smooth muscle cells X Cardiomyocytes Sinoatrial node & AV node cells When open, allow Ca2+ influx into cells Myosin light chain Phosphatase In vascular smooth muscle cells: Blockade of these channels by CCBs: reduced Ca2+ influx vasodilation Sinoatrial node (SAN) Atrioventricular (AV) node Another type of Ca2+ channel (T-type) is also expressed in the heart, but is not blocked by CCBs discussed here. Antianginal Drugs (9): Vasodilators: Calcium channel blockers (CCBs) Antianginal actions Calcium channel blockers Dihydropyridine (DHP) Drugs (e.g., nifedipine) Dilation of coronary artery Diltiazem Heart rate Verapamil Contractility O2 supply O2 demand Antianginal action Cardiomyocyte Sinoatrial node (SAN) Antianginal Drugs (10): Vasodilators: Calcium channel blockers (CCBs) Clinical uses & Adverse effects Clinical uses: All CCB drugs: Stable and unstable angina Variant angina Diltiazem and verapamil: also used for atrial fibrillation (by AV node inhibition) Atrioventricular (AV) node www.hopkinsmedicine.org Adverse effects: Headache, dizziness Peripheral edema Constipation Vasodilation, hypotension Relaxation of gut smooth muscle Antianginal Drugs (11): β Blockers (-olol) β blockers used for angina e.g., Atenolol Metoprolol Nadolol Propranolol Norepinephrine β blockers AC cAMP PKA Sinoatrial node (SAN) Antianginal Drugs (12): β Blockers (-olol) Selective β1 blockers Atenolol Metoprolol Blocking β1 receptors in heart: Reduce heart rate & contractility reduced O2 demand 1. Treatment of stable and unstable angina 2. Prevention of tachycardia induced by vasodilators Non-selective (block β1 and β2) Nadolol Propranolol Blocking β2 receptor (adverse effects) In smooth muscle: blocking β2 contraction Lung airway tract (bronchoconstriction) Arteries in skeletal muscle (reduced blood flow during exercise) Liver cells: blocking β2 release when needed reduced glucose prolonged hypoglycemia Antianginal Drugs (13): Summary of classical antianginals β blockers have no direct effects on coronary arteries and are not used for variant angina. New Class of Antianginal Drugs (1): Ivabradine Ivabradine: inhibits funny current (If) (which determines heart rate) in sinoatrial node (SAN) pacemaker cells. selectively reduces heart rate reduces O2 demand used for stable angina and heart failure A SAN pacemaker cell 50 µm Liang Lab, unpublished www.shift-study.com New Class of Antianginal Drugs (2): Ranolazine Ischemia of heart muscle: increased late Na+ current increased Ca2+ entry via Na+/Ca2+ exchanger (NCX) increased diastolic wall tension & increased O2 demand Normal Ischemia Ranolazine: Inhibits late Na+ current in cardiomyocytes Reduces diastolic wall tension 1. Reduces O2 demand 2. Improves blood supply of heart muscle (less compression of blood vessels) Treatment of stable angina https://smw.ch New Class of Antianginal Drugs (3): Trimetazidine Trimetazidine inhibits β Oxidation and reduces fatty acid metabolism (which uses more O2 per unit ATP generation) Uses less O2 Uses more O2 ( Trimetazidine https://smw.ch increased glucose metabolism (which uses less O2) Reduced O2 consumption of the heart (by ~20%) Figures in this presentation are from textbooks and internet, including: 1. Pharmacology, 5th Edition. by G. M. Brenner and C. Stevens 2. Cardiovascular Physiology Concepts, 2nd ed. By R.E. Klabunde 3. Heart Physiology: From Cell to Circulation, 4th ed. By L. H. Opie 4. http://tmedweb.tulane.edu 5. https://thedrugclassroom.co0 6. https://healtheappointments.com 7. https://ecgwaves.com 8. https://www.istockphoto.com Disclosures Conflict of Interest Disclosure: none Social Media Disclosure: You may only access and use this PowerPoint presentation for educational purposes You may not post this presentation online or distribute it without the permission of the author