Transcript Ca 2+
Calcium Antagonists Tatyana Voyno-Yasenetskaya [email protected] 312-996-9823 Regulation of Ca2+ extrusion Ca2+-ATPase Na+ -driven Ca2+ antiport Ca2+ Ca2+ 2 mM Na+ ATP ADP 100 nM ADP Ca2+-ATPase ATP Ca2+ Ca2+-sequestering compartments Ca2+ Ca2+-binding proteins Ca2+ Mitochondria Regulation of Ca2+ entry Receptor-dependent Ca2+ entry R Gq PLCb IP3 DAG Voltage-dependent Ca2+ channel Closed Open-inactive Polarized Depolarized Open-active Subunit composition of L-type Ca2+ channel SS a2 g a1 d b • L-type (long-lasting)-excitation/contraction coupling of cardiac myocytes (nifedipine, verapamil, diltiazem) • T-type (transient) - participate in pace making, highly expressed in sinusal cells (mibefradil) • N-, P-type - expressed in neurons, are not affected by Ca2+ antagonists STRUCTURE OF THE L-TYPE CHANNEL4 ALPHA SUBUNIT ACTIVATION SELECTIVITY NIFEDIPINE DILTIAZEM VERAPAMIL P P P P P P INACTIVATION E/C COUPLING VOLTAGE SENSOR Control of smooth muscle contraction and the site of action of calcium channel-blocking drugs Ca2+ channels Ca2+ channels blockers Ca2+ (intracellular) Calmodulin Ca2+ - calmodulin complex MLCK Myosin light chain Myosin-actin interaction Contraction P Calcium Antagonists • Bind to specific sites on the alpha1 subunit of the L-type Ca2+ channel • Reduce the probability of channel opening rather then calcium current flow through an open channel • Tissue selectivity is one of the most beneficial properties of Ca2+ antagonists • In general, skeletal muscle, bronchial, tracheal, and intestinal smooth muscle and neuronal tissue are relatively insensitive to Ca2+ antagonists SMOOTH MUSCLE Relaxation due to Ca2+ decrease •Decrease in blood pressure •Decrease in vascular resistance CARDIAC MUSCLE * Excitation/contraction * Impulse generation in sinoatrial node * Conduction in atrioventricalar node Require Ca2+ influx DECREASE IN OXYGEN REQUIREMENT VASCULAR SELECTIVITY INCREASED CORONARY PERFUSION FLOW IMPROVED OXYGEN SUPPLY DECREASED PERIPHERAL RESISTANCE AFTERLOAD BP CONTRACTION ENERGY SAVING IMPROVED HEART PERFORMANCE Degree of tissue selectivity of calcium antagonist in clinical use myocardium verapamil diltiazem nifedipine nimodipine felodipine nisoldipine amlodipine + + + + + + + vessels + + ++ +++ ++++ ++++ ++++ sino-atrial node + + - Amlodipine is currently the most commonly prescribed calcium blocker for hypertension Angina and Calcium Antagonists • Angina is a chest pain that occurs when coronary blood flow is inadequate to supply the oxygen required by heart • Classic angina is caused by atherosclerosis • Angiospastic or variant angina is caused by vasospasm Angina and Calcium Antagonists • VASODILATION Can be used in Prinzmetal’ angina Effective at coronary vasospasm Not recommended in unstable angina or MI • INCREASED OXYGEN SUPPLY Myocardial oxygen extraction is almost maximal ~75% of the available oxygen under no stress condition, thus there is no reserve to meet increased demand. The increased demand is me by increasing coronary blood flow • DECREASE OXYGEN DEMAND Three major determinants of the myocardial oxygen uptake are heart rate, blood pressure, and the contractile status of the myocardium Angina and Calcium Antagonists Calcium Antagonists • Reduce blood pressure because of peripheral vasodilation • Reduce heart rate, especially diltiazem and verapamil • Decrease contractility thereby reducing the oxygen demand Hypertension and Calcium Antagonists • Mechanism of action is VASODILATION • Nifedipine is used commonly because is 10 times more selective to vascular smooth muscle cells than to myocardial cells • Often used in patients with contraindications to betaantagonists Arrhythmia and Calcium Antagonists Arrhythmia results from • Abnormal pacemaker activity • Abnormal impulse propagation Aim of therapy • To reduce ectopic pacemaker activity • To modify impulse propagation Arrhythmia and Calcium Antagonists Supraventricular dysrhythmia(diltiazem, verapamil) • Mechanism of action is selectivity for pacemaker and nodal cells. Blocks Ca2+-dependent conduction in AV node, thereby reducing atrioventricular conduction • Restores synapse rhythm in 75% cases Other Uses • Migraine • Prevent development of atheromatous lesions • Pulmonary artery hypertension Side Effects Diltiazem • Edema • Headache • Depresses sinoatrial nodal function because of high degree atrioventricular nodal block Nifedipine • Dizziness is the result of acute vasodilation and rapid blood pressure fall • Headaches is the result of vasodilation • Ankle edema is caused by precapillary vasodilation Verapamil • May increase digoxin level when used in combination • Absolutely contraindicated in digoxin toxicity because will cause high grade AV block • High rate of constipation up to 30%, presumably due to a specific interaction of verapamil with calcium channels in smooth muscle cells of the gut • Depresses sinoatrial nodal function, may cause high degree atrioventricular nodal block Contraindications • Patients with low baseline blood pressure -may develop hypotension • Patients with decreased left ventricular systolic function - may worsen the heart failure •Arrythmias with antegrade conduction down a bypass tract, such as syndrome Wolff-Parkinson-White DRUG INTERACTION DRUG AFFECTED MECHANISM PHAR MACOKINETIC POTENTIAL EFFECTCT CLINICAL EFFECT Digoxin Decreased clearance Decreased clearance Incr eased serum digoxin con centration Incr eased serum carbmazepin e conc entration Incr eased expo sure to active drug Incr eased expo sure to active drug Incr eased expo sure to active drug Incr eased expo sure to active drug Carbmazepine Antihistami nes HMG-CoA reduc tase inhibit ors Immuno suppressive drugs Beta-blockers Decreased clearance Decreased clearance Decreased clearance Decreased clearance Digoxin toxicit y Neurotoxicit y (dizzines s, head ache, a taxia) Ven tricular arrhy thmi a Myop athy Nephrotoxicit y Bradyc ardia, asystole