Antiarrhythmics 2024 PDF

Antiarrhythmic Drugs Dr. Tom Murray Professor and Provost Emeritus Department of Pharmacology and Neuroscience School of Medicine Twitter: @tfmurray44 Electrical and chemical gradients for K+ and for Na+ in a resting cardiac cell The...

Antiarrhythmic Drugs Dr. Tom Murray Professor and Provost Emeritus Department of Pharmacology and Neuroscience School of Medicine Twitter: @tfmurray44 Electrical and chemical gradients for K+ and for Na+ in a resting cardiac cell The Timing of Life’s Fundamental Events: Fast Events Involve Electrical Signals 1 day DNA replication and cell division 1 hour Gene transcription; protein synthesis 1 minute Hormone regulation 0.1-1 second Typical enzyme activity 1 millisecond Electrical signaling Vision Hearing Nerve conduction Muscle contraction  Voltage-gated ion channel superfamily More than 140 members. Conductance varies by 100 fold. Variable gating. KL  Cav  Nav Bacterial ancestor likely similar to KcsA channel.  Nernst equation Equilibrium potential is the membrane potential that will exactly balance the diffusion gradient The equilibrium potential depends on the ratio of the ion concentration on two sides of membrane This equation allows this theoretical potential to be calculated for a given ion EX = 61/Z log[Xo]/[Xi] where: EX = equilibrium potential for ion in millivolts (mV) [Xo] = concentration outside of cell [Xi] = concentration inside of cell Z = valence of ion  Control of membrane potential * If the membrane potential (Em) equals Nernst potential for an ion (Eion), there will be no net flux of that ion across the membrane * Illustration: * vary membrane potential of cell (Em) while measuring flux of K+ * when Em = EK, no net flux * when Em is more negative (-80 mV) than EK (-70 mV) as in hyperkalemia, influx of K+ (K+ flows into of cell) * influx of K+ makes the membrane potential less negative = depolarization * when Em (-80 mV) is more positive than EK (-94 mV), efflux of K+ (K+ flows out of cell) * efflux of K+ makes the membrane potential more negative = hyperpolarization * thus, when the the equilibrium potential for a permeant ion differs from the membrane potential, that ion will tend to flow across membrane so as to draw the membrane potential closer to its equilibrium potential  Functional properties of voltage-gated sodium channels George, A. L. J. Clin. Invest. 2005;115:1990-1999 Inactivated state renders cardiomyocytes resistant to immediately firing a second AP, until the channels recover from inactivation. The activation and inactivation processes ensure the appropriate temporal and directional spread of electrical activity throughout the myocardium for coordinated contraction necessary to propel blood throughout the body.  Electrical Signal of Single Sodium Channel 15 picoamp (pAmp) 10 million Na+ ions per second One trillionth of the typical 15 Amp household wall socket  Voltage-gated sodium channel Extracellular Intracellular Structural and pharmacological characterization of voltage-gated sodium channels Annu Rev Pharmacol Toxicol 60, 133-54, 2020. Action potential waveforms and underlying ionic currents in adult human cardiac myocytes Pacemaking mechanisms Halina Dobrzynski et al. Circulation. 2007;115:1921-1932 Copyright © American Heart Association, Inc. All rights reserved. Temporal relationship between AP, cytoplasmic Ca2+ and contraction Congenital long-QT syndrome: channelopathies  hERG current s and LQTS M2 muscarinic and A1 adenosine receptors couple to and activate Kir currents Inward rectifiers are a class of K+ channels that can conduct much larger inward currents at membrane voltages negative to the K+ equilibrium potential than outward currents at voltages positive to it Early and late components of sodium current (INa)  Indirect effects on QT interval Modulation of channel trafficking or expression Furosemide-induced hypokalemia (inverse relationship between the plasma potassium levels and QT interval) Changes in plasma glucose levels (hypoglycemia- induced hERG inhibition - due to decrease in intracellular ATP) Change in autonomic tone (adrenergic regulation of IKs channel - β-adrenergic stimulation increases IKs) Electrical remodeling in HF  Mechanisms of Cardiac Arrhythmias Ectopic automaticity Afterdepolarizations and triggered activity (ectopic activity) Reentry (circus movements) Mechanisms of ectopic firing INa, 2011 American Heart Association, Inc Afterdepolarizations and triggered activity DAD (Ca2+ EAD overload) hypokalemia myocardial ischemia congenital long QT adrenergic stress syndrome (loss of digitalis toxicity repolarization reserve heart failure renders myocardium susceptible to EADs) drug-induced  action potential duration Reentry circuit in small branches of Purkinje system Circus movement (or re-entry excitation) occurs when a wave of excitation traverses heart muscle in a circuitous pathway and returns to the point of origin where it encounters excitable cells, excites them; and the process (circuit) begins again. Shortened refractory period and reduced conduction velocity promote reentry phenomena. Yu-ki Iwasaki. Circulation. Atrial Fibrillation Pathophysiology, Volume: 124, Issue: 20, Pages: 2264-2274, DOI: (10.1161/CIRCULATIONAHA.111.019893) © 2011 American Heart Association, Inc. Abnormal impulse formation or impulse propagation are pathological mechanisms underlying atrial fibrillation Nat Rev Cardiol. 2024 21(10):682-700.  Vaughn-Williams Classification Based on cellular properties of normal His- Purkinje cells Classified on drug’s ability to block specific ionic currents (i.e. Na+, K+, Ca++) and beta- adrenergic receptors Advantages: – Physiologically based – Highlights beneficial/deleterious effects of specific drugs  Antiarrhythmic Agents Vaughn-Williams Classification Class I - Na+ - channel blockers Class II - Sympatholytic agents Class III - Prolong repolarization Class IV- Ca++ - channel blockers Purinergic agonists Digitalis glycosides Antiarrhythmic drug mechanisms Na+ channel blockade β-adrenergic receptor blockade Prolong repolarization (K+ channel blockade) Ca2+ channel blockade Adenosine Digitalis glycosides  Classification of antiarrhythmics Class I – blocker’s of voltage-gated Na+ channels Subclass IA Cause moderate reduction in Phase 0 slope Increase effective refractory period (ERP) Increased action potential duration (APD) Medium duration of blockade (off-rates) Includes Quinidine – 1st antiarrhythmic used, used for both atrial and ventricular arrhythmias, increases refractory period Procainamide - increases refractory period but side effects Disopyramide – extended duration of action, used only for treating ventricular arrhythmias  Classification of antiarrhythmics Subclass IB Small decrease in Phase 0 slope May decrease ERP May decrease APD Brief duration of blockade (off-rates) Negligible interaction with voltage-gated K+ channels Preferentially interact with inactivated sodium channels Selectivity is conferred by strong rate-dependent actions that produce little conduction slowing at sinus rhythm rates but important INa blockade at rapidly discharging rates Includes Lidocaine – blocks Na+ channels mostly in ventricular myocytes Mexiletine - oral lidocaine derivative, similar activity  Classification of antiarrhythmics Subclass IC Pronounced decrease in Phase 0 slope Markedly slow conduction Little effect on APD and ERP Long duration of blockade (off-rates) Includes Flecainide (initially developed as a local anesthetic) Slows conduction in all parts of heart Also inhibits abnormal automaticity Propafenone Also slows conduction Weak β – blocker Also some Ca2+ channel blockade  Dronedarone  Class I antiarrhythmic drugs  Classification of antiarrhythmics Class II – β–adrenergic blockers Based on two major actions 1) blockade of myocardial β–adrenergic receptors 2) Na+ channel blockade (propranolol) Includes Propranolol causes both myocardial β–adrenergic blockade and Na+ channel blockade Slows SA node and ectopic pacemaking Can block arrhythmias induced by exercise or apprehension Other β–adrenergic blockers Metoprolol Atenolol Sotalol Esmolol  Classification of antiarrhythmics Class III – K+ channel blockers Cause delay in repolarization and prolonged refractory period Includes Amiodarone – prolongs action potential by delaying K+ efflux but many other effects characteristic of other classes Ibutilide – slows inward movement of Na+ in addition to delaying K + efflux. Bretylium – first developed to treat hypertension but found to also suppress ventricular fibrillation associated with myocardial infarction Dofetilide - prolongs action potential by delaying K+ efflux  Classification of antiarrhythmics Class IV – Ca2+ channel blockers slow rate of AV-conduction in patients with atrial fibrillation Includes Verapamil – blocks Na+ channels in addition to Ca2+; also slows SA node in tachycardia Diltiazem  Antiarrhythmic drugs - Class II and IV may be used to achieve rate dependent control of arrhythmias (negative chronotropic effect). - Class I and III may be used to achieve rhythm dependent control of arrhythmias  Lidocaine Blocks both open and inactivated cardiac Na+ channels Decreases automaticity especially in ectopic pacemakers Not useful in atrial arrhythmias possibly because atrial action potentials are so short that the Na+ channel is in the inactivated state only briefly  Adverse Reactions Large intravenous doses of lidocaine administered rapidly may produce seizures Tremor, dysarthria, and altered levels of consciousness more common Uses Acute intravenous therapy of ventricular arrhythmias  Mexilitine Congener of, and similar to, lidocaine Orally effective Used in treatment of ventricular arrhythmias Flecainide Flecainide exerts its main pharmacological effect as a potent inhibitor of cardiac sodium channels, Nav1.5 Very long recovery from Na+ channel block Also blocks ryanodine receptor calcium release channels Has become a cornerstone of rhythm control strategy in atrial fibrillation (AF) management of patients without structural heart disease  Adverse Effects Dose-related blurred vision is the most common noncardiac adverse effect Has negative ionotropic effects Does not cause EADs or torsades de pointes Use Maintenance of sinus rhythm in patients with supraventricular arrhythmias In the CAST study, flecainide increased mortality (2.5-fold) in patients convalescing from myocardial infarction  -adrenergic receptor blockers: Propanolol Effects  -blockade Quinidine-like effect Reduces automaticity of SA node Reduces automaticity and conduction velocity in AV node, His Purkinje and ventricles May reverse effects of epinephrine on mean arterial pressure Effects of vasoconstrictor on local anesthetic action local adrenaline duration of anesthetic anesthesia (min) lidocaine (2%) - 5-10 lidocaine (2%) 1:100,000 60 lidocaine (2%) 1:50,000 60  Cardiovascular effects of epinephrine Patients medicated with nonselective beta-blockers (eg. propranolol) have a significant risk for acute hypertensive episodes if they receive vasopressors (epinephrine) contained in local anesthetics. Dent Clin North Am. 2010 Oct;54(4):687-96. Beta-adrenergic blocking agents and dental vasoconstrictors.  Administration of epinephrine (E) 10 µg/kg, norepinephrine (NE) 10 µg/kg or isoproterenol (Iso) 10 µg/kg after propranolol (1 mg/kg)  Adverse effects Reduced myocardial contractility Bradycardia Angina upon sudden withdrawal Bronchospasm Uses Supraventricular tachycardia Many studies indicate that, unlike flecainide, -blockers provide prominent beneficial effect after myocardial infarction Amiodarone HCl - Pharmacologic Effects Widely-used antiarrhythmic Indications - unstable VT, VF and SVT - AF Class III effects -  duration of action potential and effective refractory period Systemic toxicity - Pulmonary toxicity - Bradyarrhythmias with loading dose  Amiodarone actions Blocks Na+ (class I effect) and Ca2+ channels (class IV effect) and β-adrenoceptors (class II effect) Delays repolarization and increases the refractory period via K+ channel blockade (class III effect) Decreases automaticity Slows conduction A vasodilator  Effects of a selective hERG blocker Effects of non-selective hERG blocker  Amiodarone (uses) Recurrent ventricular tachycardia or fibrillation resistant to other drugs Maintaining sinus rhythm in patients with atrial fibrillation Intravenous amiodarone more effective than liddocaine for out-of-hospital VF resistant to shocks and epinephrine Adjunct with implantable cardioverter- defibrillators NB: does not exacerbate CHF and is rarely proarrhythmic; however, adverse effects and drug- drug interactions warrant caution NEJM 356, 935-941,2007. Efficacy of amiodarone in treatment of atrial fibrillation  Dronedarone: -structurally modified amiodarone derivative to reduce toxicities. -FDA approved July 2009 for atrial fibrillation suppression. -multichannel blocking and sympatholytic properties similar to amiodarone NEJM 360, 1811-1813, 2009.  Dronedarone: clinical studies Reduces rate of recurrent AF compared to placebo Reduces ventricular rate Decreases cardiovascular morbidity and mortality in AF patients Lower incidence of adverse effects, though less effective than amiodarone May increase mortality in HF patients T1/2 = 24-30 h May produce an increase in serum creatinine without a reduction in renal function due to inhibition of renal cation transport Metabolized by CYP3A4: concurrent use of ketoconazole, cyclosporine, ritonavir, clarithromycin and nefazodone contraindicated  Sotalol A Class III drug Prolongs cardiac action potentials by inhibiting delayed rectifier and possibly other K+ currents l-enantiomer is a much more potent -adrenergic receptor antagonist than the d-enantiomer, but the two are equipotent as K+ channel blockers Used in patients with both ventricular tachyarrhythmias and atrial fibrillation or flutter Therapy must be initiated in hospital setting to monitor QT interval Torsades de pointes is the major toxicity with sotalol ( ~ 5%)  Ibutilide An IKr blocker that in some systems also activates an inward Na+ current Administered as a rapid infusion (1 mg over 10 minutes) for the immediate conversion of atrial fibrillation or flutter to sinus rhythm Major toxicity with ibutilide is torsades de pointes, which occurs in up to 6% of patients  Dofetilide – A “pure” class III antiarrhythmic – Potent and selective IKr blocker – Can prolong the QT interval (1-3% incidence of torsades) – Therapy must be initiated in a hospital and monitored for 72 h due to the risk of torsades. – Maintenance of sinus rhythm in patients with atrial fibrillation  Proarrhythmia: Torsades de Pointes Class IA – Quinidine 2-9% – Procainamide 2-3% – Disopyramide 2-3% Class III – d,l-Sotalol 1-5% – d-Sotalol 1-2% – Ibutilide 6% – Dofetilide 1-3% – Amiodarone < 1% Early Rhythm-Control Therapy in Patients with Atrial Fibrillation (EAST-AFNET 4) Class IC Antiarrhythmics Used Flecainide Amiodarone Dronedarone Propafenone NEJM 383, 1305-16, 2020.  Guideline recommendations for antiarrhythmic drug use in patients with AF J.G. Tardos et al J Am Heart Assoc Mar 16;10 (6) 2021.  Catheter Ablation or Antiarrhythmic Drugs for Ventricular Tachycardia End-Point = death, VT storm or sustained VT (sotalol or amiodarone) Sotalol dose 120 mg 2X/day Amiodarone dose 400 mg 2X/day/2wks; 400 mg/day/4 wks; 200mg/day. NEJM Nov 18, 2024  Calcium channel blockers: Verapamil, Diltiazem Block slow inward Ca2+ current Reduce automaticity Increase refractory period and decrease conduction velocity of AV Node Inhibit contractility Vasodilation  Calcium channel blockers (adverse effects) Flushing etc. Reduced contractility of the heart AV node conduction defects Constipation Use Supraventricular arrhythmias Self-administered intranasal etripamil (L-type calcium channel blocker) using a symptom-prompted, repeat- dose regimen for atrioventricular-nodal-dependent supraventricular tachycardia The Lancet, June 15, 2023  Ranolazine Initially approved (2006) for treatment for chronic angina pectoris Exerts beneficial antianginal effects and has unique antiarrhythmic efficacy in AF and ventricular tachyarrhythmias – Works primarily by preferentially blocking Na+ channel late phase of influx (INaL); potency ratio for INaL/INaF = 13 – Less [Na+]i allows Na+/Ca2+ exchanger to operate in normal forward mode – Also blocks IKr at therapeutic concentrations Ivabradine reduces heart rate through inhibition of the If current and exerts an antianginal effect Approved by FDA in 2015 for treatment of chronic stable angina in patients with normal sinus rhythm who cannot take beta blockers  Adenosine (Adenocard®) Adenosine released by most cells Normal plasma levels ~300 nM Can reach micromolar levels in ischemic tissue  Adenosine Receptors Four receptor subtypes have been classified: – A1, A2A, A2B, A3 (Fredholm, 1993) All four subtypes are G-protein coupled receptors Methylxanthines such as caffeine and theophylline are competitive antagonists  Adenosine (effects) Stimulates adenosine receptors (A1 receptors in the heart) Increases K+ conductance Inhibits opening of Ca2+ channels Reduces norepinephrine release Reduces automaticity and AV nodal conduction  Adenosine (adverse effects) Flushing Asthma – dyspnea – chest pain SA nodal arrest, AV nodal block GM Marcus et al. N Engl J Med 2023;388:1092-1100.