Anti-Anginal Drugs •Red : important •Black : in male / female slides •Pink : in female’s slides only •Blue : in male’s slides only •Green : Dr’s notes •Grey: Extra information, explanation OBJECTIVES: ✓ Recognize variables contributing to a balanced myocardial supply versus demand. ✓ Differentiate between drugs used to alleviate acute anginal attacks and those meant for prophylaxis & improvement of survival. ✓ Detail the pharmacology of nitrates and other drugs used as antianginal therapy. Editing File Extra information(recommended) Ventricular Muscle Cells Action Potential 4- Resting membrane potential (polarized) 0- Rapid Depolarization Phase: Passage of cations (Sodium and Calcium) from neighboring cardiac cells causes the resting membrane potential to slightly increase, allowing voltage gated Na channels to open, and the cell is said to be depolarized. 1- Initial Repolarization: Short-term Voltage-gated K channels open and Na channels close at peak positivity of the cell and allow the membrane potential to be slightly decreased to create a potential difference for voltage gated Ca channels to open. 2-Plateau (refractory period): Voltage gated calcium channels are open for about most of the period, but the channels are inactivated around the end of this phase and K efflux starts, if this phase is prolonged inactivated Ca channels can reopen, creating an afterdepolarization (torsades de pointes) “more on this later in the lecture” 3- Repolarization: Extra specialized K channels are opened to bring about repolarization and a return to the resting membrane potential. Pacemaker Action Potential SA Node is made of specialized cardiac cells, (Modified Cardiomyocytes), the cells have high permeability to Na and K, allowing constant, spontaneous action potentials to be generated and a unique way of generating an action potential. Pacemaker potential (slow depolarization): Slow Na influx and a decreased K efflux, makes the cells more positive gradually. Rapid Depolarization: Calcium channels open, allowing the cells to be depolarized and action potential is reached. Repolarization: Inactivation of calcium channels and K channels are open, the cell repolarizes and Na channels begin to open allowing the cycle to restart. Which signs or symptoms suggest diagnosis of angina pectoris? Pain is due to Angina Pectoris: accumulation of • Angina pectoris is a consequence of Myocardial oxygen metabolites (K + , A clinical Pain is caused PGs, Kinins, demand exceeding myocardial oxygen supply. syndrome of chest either by Adenosine….) pain (varying in • Mainly caused by obstruction of blood flow Resulting in obstruction (e.g. secondary to the severity) due to atherosclerotic ischemia. These ischemia of heart ischemia. plaque) or spasm metabolites are muscle body’s response to ischemia as vasodilators. Which signs or symptoms suggest diagnosis of angina pectoris? What is Basic mechanism of angina pectoris? 1 • Angina pectoris is a consequence of Myocardial oxygen A clinical syndrome of chest pain (varying in severity) due to ischemia of heart muscle demand exceeding myocardial oxygen supply. • Mainly caused by obstruction of blood flow Resulting in 2 Pain is caused either by obstruction (e.g. atherosclerotic ischemia. plaque) or spasm (usually causes pain even at rest) Types: 3 Pain is due to accumulation of metabolites (K + , PGs, Kinins, Adenosine….) secondary to the ischemia. These metabolites are body’s response to ischemia as vasodilators. Stable Variant UnstableUnstable angina anginaangina anginaangina known as : known as : known as : Stable angina Unstable angina Variant angina Effort-induced / typical / Effort-induced / typical / Accelerated angina known as : known as : classical / chronic classical / chronic Effort-induced, typical, Accelerated (Progressive) classical, chronic or crescendo Angina cause: cause: cause: reduction of coronary a form of acute coronary perfusion due to a fixed coronary artery spasm syndrome, caused by obstruction of a coronary (Alpha receptor mediated rupture of an artery produced by vasoconstriction) With or atherosclerotic plaque and atherosclerosis. The heart without Atherosclerotic partial or complete becomes vulnerable to plaque thrombosis of a coronary ischemia whenever there is -Reduction of coronary -A form of acute coronary -Coronary artery spasm artery increased demand perfusion due to a fixed syndrome, caused by (Alpha receptor mediated obstruction of a coronary rupture of an vasoconstriction) With or Frequency of pain: Frequency of pain: Frequency of pain: artery produced by atherosclerotic plaque and without Atherosclerotic Change in pattern of chronic atherosclerosis. partial or complete plaque Pain upon exertion Exercise angina: There’s increased The heart becomes thrombosis of a coronary -Pain even at rest. Pain even at rest. Emotion, Heavy meal frequency & duration of vulnerable when there’s artery. Treatment: pain. increased demand. -There’s increased -coronary vasodilators, Common treatment : Common treatment : Common treatment : -Pain occurs upon frequency & duration of such as nitroglycerin and . coronary vasodilators, such as requires hospital admission exertion Exercise pain. calcium channel blockers th rest or nitroglycerin. nitroglycerin and calcium and more aggressive Emotion, Heavy meal. Treatment: 4 type: silent angina → Treatment: -Hospital admission and Ischemia without pain, the most channel blockers. therapy. -Rest or nitroglycerin more aggressive therapy. dangerous What are the determinants of oxygen demand and supply? Oxygen Demand Myocardial Oxygen Myocardial Oxygen demand is determined demand is diminished 1 Oxygen Demand: by: by: 1- Reducing contractility Contractile Wall tension Heart rate 2- Reducing heart rate state affected by: O₂ demand is O₂ demand is 3- Reducing the preload determined by: diminished by: 2- Ventricular 1- LV Pressure volume 4- Reducing the afterload (Afterload). 1-Contractility 1-Reducing contractility (Afterload). 2-Heart rate 2-Reducing Heart rate 3-Wall tension(pressure exerted by the 3-Reducing the Preload fibers itself)(affected by): 4-Reducing the Afterload -LV pressure (Afterload) Peripheral vascular resistance Oxygen Supply -Ventricular volume (Preload) Myocardial Oxygen Myocardial Oxygen supply is determined supply is enhanced by: by: 2 Oxygen Supply: 1- Reducing coronary Regional Arterio-venous vascular resistance. myocardial oxygen distribution difference. 2- Prolong diastolic period. O₂ supply is O₂ supply is 3- Dilating collateral determined by: enhanced by: Coronary blood vessels. flow, affected by: 4- Reducing external 1-Regional myocardial distribution 1-Reducing coronary vascular compression. 2-Arterio-Venous O₂ difference resistance (difference between O content between atria and 2 2-Reducing external 5- Reducing LV end ventricles, it increases during exercise) compression diastolic pressure. 3-Coronary blood flow (affected by): Coronary vascular 3-Reducing LV + diastolic pressure Aortic pressure -Aortic pressure resistance. 4-Prolong diastolic period -Coronary vascular resistance 5-Dilating collateral vessels 6-Optimizing hemoglobin & RBCs It is important to point out that restoration of oxygen supply to ischemic tissue should be restored 3 hours after ischemia at most, after that period the cells will be overly acidic due to lactate accumulation from anaerobic metabolism, and the introduction of oxygen to the damaged mitochondria will result in the formation of free radicals, particularly H2O2, as a final product of ETC, causing further damage to the cells and possible inflammatory reaction. This is known pathophysiologically as Inadequate Tissue Reperfusion. 1- Agents that improve symptoms and ischemia. Treatment of angina pectoris 1- Agents that improve symptoms and 2- Agents that improve prognosis Traditional Approaches New Approaches ischemia: (Halt progression, prevent acute insult, improve survival): Traditional Approaches: ● Nitrates. ● Metabolic acting ● Beta-blockers. agents, e.g. ● Nitrates. The main therapy of angina ● Calcium channel Trimetazidine. ● Beta-blockers. ● Calcium channel blockers (CCP). ● Potassium channels A ● Statins (stops cholesterol blockers (CCB). openers, e.g. synthesis) Nicorandil. ● ACE inhibitors ● Late Na+ current New Approaches: C 2nd line or add up therapy ● Beta-blockers inhibition, e.g. Ranolazine. ● Metabolic acting agents, e.g. B ● Aspirin / other Trimetazidine. ● Sinus node inhibition, antiplatelet agents eg. Ivabradine. ● Potassium channels openers, e.g. Nicorandil. ● Late Na+ current inhibition, e.g. Ranolazine. ● Sinus node inhibition, eg. Ivabradine. (↓ Heart rate, without effectinging force of contraction) 2- Agents that improve prognosis (Halt progression, prevent acute insult, improve survival). General mechanism of antianginal Aspirin / other ACE Statins B-blockers antiplatelet inhibitors drugs: agents. Regional flow distribution Heart rate Oxygen Oxygen Oxygen Cardiac extraction Supply = Demand contractility Coronary Myocardial blood flow wall tension: -Preload Regional flow distribution: -Afterload Flow to ischemic subendocardial tissue improved by nitrates, CCBs, B-blockers Coronary blood flow: Increased by nitrates and CCBs Heart rate + Cardiac contractility: Decreased by B-blockers and some CCBs Preload: Decrease by nitrates Afterload: Decreased by CCBs Antianginal drugs: 1.Organic Nitrates Classification Short acting Long Acting Nitroglycerine (GTN) Isosorbide mononitrate & 1. Organic Nitrates Drugs -Prototype of organic nitrates dinitrate -active ingredient of dynamite