University:
West Coast University
Course:
PHAR 740 | IPC Cardiopulmonary and Renal III
Academic year:

2024
Views:

98

Pages:

25
Author:

Asal A.

Antianginal Pharmacology Use the Handout and the Presentation as a guidance to study the book chapter Required Reading: Basic & Clinical Pharmacology 16th edition, Katzung, Chapter 12 (Access Pharmacy) Parto Khansari Ph.D. 1/23/2024 Learning Outcomes  Describe the mechanism of vascular smooth muscle contraction  Describe the mechanism of vascular smooth muscle relaxation  List the pharmacological classes of medication used in the treatment of angina  Describe the mechanism of action of nitric oxide donors and calcium channel blockers on vascular smooth muscles  Describe the mechanism of action of potassium channel opener and Ranolazine in treatment of angina  list the major pharmacokinetic characteristics and adverse effects of drugs used in the treatment of angina Treatment of Angina Pectoris Angina: mainly caused by an imbalance between oxygen requirements and demand of the heart coronary vessels. i Treatment of Ischemic Heart Disease  Direct Vasodilators (reduce Vascular tone) o Nitrates (activate cGMP)  Sodium Nitroprusside (arterial and venous dilator) picosM  Organic Nitrates: Nitroglycerine, Isosorbide Dinitrate M to o qCalcium channel blockers mono o Potassium Channel Opener (Induce hyperpolarization) Benzo Dil o Hydralazine pheonvena por reducethehestre me  β-adrenoceptors antagonists (Previously covered)  Antiplatelet/Anticoagulant agents (will be covered in the following days)  Lipid lowering agents (will be covered in the following weeks) FYI Treatment of Angina Pectoris Angina: mainly caused by an imbalance between oxygen requirements and demand of the heart coronary vessels. Did no itsthe as Vascular Tone tension wanttorefinethetension t Adjustvassalageto Adjust thedemandandsupply  Vascular Tone: the degree of contraction of vascular smooth muscle  Key regulator to determine tissues receive oxygen and nutrients to meet metabolic demands  Control blood flow and volume by the tone of arterial resistance and vein capacitance If you resistance not BP hotffnued 4 Pmeans bio more Mr Capacitance Venous Tone Venous Return Blood pressure relax vasant i Tore BP me reduceResistance Arterial Tone BE Paacaritone Peripheral Vascular Resistance Blood Pressure Regulation of Vascular Smooth Muscle (VSM)Contraction Contraction: • Calcium enters the cell (through L-type Ca2+ ch.) • Binds to IP3 and Ryanodine Receptor • Result in Rise in Intracellular Ca2+ from SRE • Triggers Actin-myosin cross bridge Clearance from cytoplasm: • Ca2+ ATPase in Sarcoplasmic Reticulum • Ca2+ ATPase pump in plasma membrane • Sodium/Calcium exchanger pump Ca++ dependent Vascular Smooth muscle contraction vasodilation t Gastopcalon calcianchomalbor phosphorylation stop t Vascular Smooth Muscle Relaxation Ca2+/calmodulin (Ca2+/CaM) complex also stimulates endothelial nitric oxide synthase (eNOS), to form Nitric oxide (NO) which then diffuses from the endothelial cell into vascular smooth muscle cells, where it activates guanylyl cyclase (cGMP) promoting smooth muscle cell relaxation. on to cant ens Gob NO can also directly activate Ca2+dependent K+ channels contributes to relaxation by hyperpolarizing the smooth muscle cell. relaxation Production of NO is stimulated by agonists such as acetylcholine or bradykinin. Topenfause Ago POMP fuse relaxation Nitric Oxide Mechanisms of Action of NO I NO activate guanylyl cyclase (GC) to form cGMP Increasing cGMP inhibits calcium entry into the cell 3 cGMP-dependent protein kinase dephosphorylates myosin light chains + d NO also activates K channels, which leads to hyperpolarization Myocytes Contraction Nature 451, 929-936 Drug Target for VSM Relaxation by Calcium Channel Blocker Vs. Nitrates Calcium channel blockers prevents the formation of calcium/calmodulin complex. Nitrates and other sources of nitric oxide (NO) increase cGMP synthesis, and phosphodiesterase (PDE) inhibitors reduce cGMP metabolism. Organic Nitrates t toIntracaborat Mechanisms of Action of Vasodilators a Decreasing intracellular calcium 2 Increasing Hyperpolarization of the vascular smooth muscle cell membrane Increasing cGMP Increasing cAMP Nitrates • Low Bioavailability: sublingual route avoids the first-pass effect, rapid effect Enzymatic Activity: Nitroglycerin activation requires enzymatic action, nitroprusside and NO donors do not. Activation jot OLENBI • Nitroglycerin relaxes VSM, no direct effect on cardiac or skeletal muscle • Nitric oxide stimulates guanylyl cyclase in platelets as in smooth muscle • Major acute toxicities: results from excessive therapeutic vasodilation: orthostatic hypotension, tachycardia, and throbbing headache • Tolerance: continuous exposure to nitrate • Nitroprusside retains activity for a long time • Nitroglycerine develops tolerance faster than other nitrites of Beneficial and deleterious effects of nitrates in the treatment of angina TABLE 12–2 Effect Mechanism and Result Potential beneficial effects Decreased ventricular volume Decreased arterial pressure Decreased ejection time Vasodilation of epicardial coronary arteries Increased collateral flow Decreased left ventricular diastolic pressure Decreased work and myocardial oxygen requirement Relief of coronary artery spasm Improved perfusion of ischemic myocardium Improved subendocardial perfusion Potential deleterious effects Reflex tachycardia Increased myocardial oxygen requirement; decreased diastolic perfusion time and coronary perfusion Reflex increase in contractility Increased myocardial oxygen requirement pre Calcium Channel Blocker me Iggy more effectieon t artery reducecontraction causingthe relaxation effed more C ofbloodarteriesreive comeback Calcium Channel Blockers Dihydropyridines to selective • Prototype: Amlodipine (Norvasc) • Potent peripheral vasodilators (Vascular selectivity) • Long acting (extended release) have fewer side effect Major Side Effects • Reflex tachycardia, • Dizziness, headache, flushing, and peripheral edema z Non-Dihydropyridines • Prototype: Diltiazem (Cardizem) • Potent cardioselective • Extended-release products are preferred for hypertension • have additional benefits in patients with atrial tachyarrhythmia Major Side Effects: • Excessive bradycardia • Impaired electrical conduction • Depressed contractility i Calcium Channel Blockers Major Characteristics: Orally active, high first-pass effect, high plasma protein binding, low bioavailability, rapid onset of action, between 20 deactiveby enzyme inlier minutes and 2 hours Major Toxicity: at high therapeutic level causes headache, dizziness, flushing, bradycardia, atrioventricular block, cardiac arrest, and heart failure K+ Channel Opener • Minoxidil • MOA: Induce Vasodilation by opening the K+ATP channels in the plasma membrane of vascular smooth muscle • Enhance potassium efflux, results in membrane hyperpolarization and preventing Ca2+ channel opening which leads to decrease in calcium influx (smooth muscle relaxation) • Mainly act on arterial smooth muscle membrane • Adverse effects: headache and flushing, caused by excessive dilation of cerebral arteries, • respectively. Late Na+ Channel Inhibitor • Ranolazine TIntracavor open Directly • MOA: Inhibit late phase of sodium current, reduction in intracellular Na+ results in reduction in intracellular Ca+ overload through Na+/Ca2+ exchanger. Increase in intracellular calcium is required for VSM contraction. • Adverse effects: Dizziness, headache, constipation and nausea. Dizziness may be doserelated. SUMMARY Drugs Used in Angina Pectoris SUMMARY Drugs Used in Angina Pectoris Amonifinicer Action Ehf Endou vessel minoxidil stableangina stablepain longterm msexercise Podemand lingually s fasterrespondAlgidfirstpass Nitroglycerin Sgb metabolism n't gothroughliver nirductasel dos Nitroglycerinis a vasodilator vasodilators that has Any whyptsfeelinglightheaded NI cause suddendripin theBy thats before of kin tissuesulfhydrygroups hersandcystinegroup tolerance happened G B ease of

Antianginal Pharmacology

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