Antiarrhythmic Drugs PDF

LECTURE’S OUTLINE: Electrophysiology of the heart Arrhythmia: definition, mechanisms, types Drugs :class I, II, III, IV Guide to treat some types of arrhythmia Questions Normal conduction path...

LECTURE’S OUTLINE: Electrophysiology of the heart Arrhythmia: definition, mechanisms, types Drugs :class I, II, III, IV Guide to treat some types of arrhythmia Questions Normal conduction pathway: 1- SA node generates Other types of action potential and conduction that delivers it to the atria occurs between and the AV node myocardial cells: When a cell is depolarized  2- The AV node adjacent cell delivers the impulse to depolarizes along purkinje fibers 3- purkinje fibers conduct the impulse to the ventricles Action potential of the heart: In the atria, In the SA node purkinje, and and AV node, AP ventricles the AP curve consists of 3 curve consists of 5 phases phases Non-pacemaker action potential Phase 1: partial repolarization Due to rapid efflux of K+ Phase 2: plateu Phase 0: fast Due to Ca++ upstroke influx Due to Na+ influx Phase 3: repolarization Due to K+ efflux Phase 4: resting membrane potential N.B. The slope of phase 0 = conduction velocity Also the peak of phase 0 = Vmax Pacemaker AP Phase 0: upstroke: Phase 3: Due to Ca++ influx repolarization: Due to K+ efflux Phase 4: pacemaker potential Na influx and K efflux and Ca influx until the cell reaches threshold and then turns into phase 0 Pacemaker cells (automatic cells) have unstable membrane potential so they can generate AP spontaneously Effective refractory period (ERP) It is also called absolute refractory period (ARP) : In this period the cell can’t be excited Takes place between phase 0 and 3  Arrhythmia Causes of If the arrhythmia arrhythmia arises from atria, SA node, or AV node it is called arteriosclerosis supraventricular arrhythmia Coronary artery spasm If the arrhythmia Heart block arises from the ventricles it is called ventricular Myocardial arrhythmia ischemia  Mechnisms of Arrhythmogenesis 1- Abnormal impulse generation Automatic Triggered rhythms rhythms Enhanced normal Ectopic focus Delayed Early after automaticity afterdepolarization depolarization AP arises from sites other than SA node ↑AP from SA node  2-Abnormal conduction Conduction Reentry block Circus 1st degree 2nd degree 3rd degree Reflection movement This is when the 1-This impulse is not pathway is conducted from the blocked atria to the ventricles 3-So the cells here will be reexcited (first by the original pathway and the 2-The impulse other from the from this pathway retrograde) travels in a retrograde fashion (backward) Abnormal anatomic conduction Here is an accessory pathway in the heart called Bundle of Kent Present only in small populations Lead to reexcitation  Wolf-Parkinson-White Syndrome (WPW)  Action of drugs In case of abnormal generation: In case of abnormal conduction: Decrease of phase 4 ↑ERP ↓conduction slope (in pacemaker (so the cell velocity (remember cells) won’t be phase 0) reexcited again) Before drug Raises the threshold after phase4  Types of Arrhythmia Supraventricular Arrhythmias  Sinus Tachycardia: high sinus rate of 100-180 beats/min, occurs during exercise or other conditions that lead to increased SA nodal firing rate  Atrial Tachycardia: a series of 3 or more consecutive atrial premature beats occurring at a frequency >100/min  Paroxysmal Atrial Tachycardia (PAT): tachycardia which begins and ends in acute manner  Atrial Flutter: sinus rate of 250-350 beats/min.  Atrial Fibrillation: uncoordinated atrial depolarizations. AV blocks A conduction block within the AV node , occasionally in the bundle of His, that impairs impulse conduction from the atria to the ventricles.  ventricular Arrhythmias  Ventricular Premature Beats (VPBs): caused by ectopic ventricular foci; characterized by widened QRS.  Ventricular Tachycardia (VT): high ventricular rate caused by abnormal ventricular automaticity or by intraventricular reentry; can be sustained or non-sustained (paroxysmal); characterized by widened QRS; rates of 100 to 200 beats/min; life-threatening.  Ventricular Flutter - ventricular depolarizations >200/min.  Ventricular Fibrillation - uncoordinated ventricular depolarizations Pharmacologic Rationale & Goals  The ultimate goal of antiarrhythmic drug therapy: o Restore normal sinus rhythm and conduction o Prevent more serious and possibly lethal arrhythmias from occurring.  Antiarrhythmic drugs are used to:  decrease conduction velocity  change the duration of the effective refractory period (ERP)  suppress abnormal automaticity  Antyarrhythmic drugs Most antiarrhythmic drugs are pro-arrhythmic (promote arrhythmia) They are classified according to Vaughan William into four classes according to their effects on the cardiac action potential class mechanism action notes Can abolish Change the slope of tachyarrhythmia I Na+ channel blocker phase 0 caused by reentry circuit ↓heart rate and Can indirectly alter K II β blocker conduction velocity and Ca conductance 1. ↑action potential duration (APD) or Inhibit reentry III K+ channel blocker effective refractory tachycardia period (ERP). 2. Delay repolarization. Slowing the rate of rise ↓conduction velocity IV Ca++ channel blocker in phase 4 of SA node in SA and AV node  Class I drugs Have moderate K+ channel Class I blockade IA IB IC They ↓ conduction velocity in non-nodal They act on open Na+ tissues (atria, ventricles, and purkinje fibers) channels or inactivated only So they are used when many Na+ channels are opened or inactivated (in tachycardia only) because in normal rhythm the channels will be at rest state so the drugs won’t work  Class IA Quinidine Procainamide  Slowing of the rate of rise in phase 0  ↓conduction velocity  ↓of Vmax of the cardiac action potential  They prolong muscle action potential & ventricular (ERP)  They ↓ the slope of Phase 4 spontaneous depolarization (SA node)  decrease enhanced normal automaticity They make the slope more horizontal Class IA Drugs  They possess intermediate rate of association and dissociation (moderate effect) with sodium channels. Pharmacokinetics: procainamide quinidine Good oral Good oral bioavailability bioavailability Used as IV to Metabolized avoid in the liver hypotension Procainamide metabolized into N-acetylprocainamide (NAPA) (active class III) which is cleared by the kidney (avoid in renal failure) uinidine Methoxy-alpha-(5-vinyl -2-quinuclidinyl)- 4-quinolinemethanol n optical isomer of quinine, extracted from the bark of the Cinchona tree and milar plant species. Quinidine is a pharmaceutical agent that acts as a class I tiarrhythmic agent (Ia) in the heart.This alkaloid dampens the excitability of rdiac and skeletal muscles by blocking sodium and potassium currents across llular membranes. It prolongs cellular action potential, and decreases tomaticity. Quinidine also blocks muscarinic and alpha-adrenergic neurotransmission PB is 80-88%, t1/12- 6-8 hrs, Metabolism:- Hepatic, When the urine pH is less an 7, about 20% of administered quinidine appears unchanged in the urine, but s fraction drops to as little as 5% when the urine is more alkaline. 4-Amino-N-(2- diethylaminoethyl)benzamide It belongs to Class Ia. Procainamide is sodium channel blocker. It stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses thereby effecting local anesthetic action. PPB:- 75 to 95%. Metabolism:- Hepatic. Trace amounts may be excreted in the urine as free and conjugated p-aminobenzoic acid, 30 to 60 percent as unchanged PA, and 6 to 52 percent as the NAPA derivative. N-Acetyl-3-hydroxyprocainamide. Disopyramide 4-[bis(propan-2-yl)amino]-2-phenyl-2-(pyridin-2-yl)butanamide It is a class Ia anti-arythmic agent. Absorption-Nearly complete. Protein binding50%- about 50% of a given dose of disopyramide is excreted in the urine as the unchanged drug, about 20% as the mono-N-dealkylated metabolite and 10% as the other metabolites.65%. Half life-6.7 hours (range 4-10 hours) Lidocaine 2-(Diethylamino)-N-(2,6-dimethylphenyl)acetamide It is a Class Ib agent. it is used intravenously for the treatment of ventricular arrhythmias(for acute myocardial infarction, digoxin poisoning, cardioversion, or cardiac catheterization) if amiodarone is not available or contraindicated. its rate of absorption depending, for example, upon various factors such as the site of administration and thepresence or absence of a vasoconstrictor agent.PPB:- 60-80%. Metabolism-Primarily t1/2-109 minutes hepatic. Tocainide 2-amino-N-(2,6- Dimethylphenyl)propanamide Tocainide (Tonocard) is a class Ib antiarrhythmic agent. For the treatment of documented ventricular arrhythmias, such as sustained ventricular tachycardia, AbsorptionFollowing oral administration, the bioavailability approaches 100 percent, and is unaffected by food.that, in the judgment of the physician, are life threatening Protein bindingApproximately 10 percent bound to plasma protein. Encainide 4-Methoxy-2'-[2-(1-methyl-2-piperidyl)ethyl]benzanilide Encainide is a class Ic antiarrhythmic agent which was used for management of irregular heartbeats, such as atrial fibrillation, atrial flutter, ventricular tachycardia, and Encainide is a sodium channel blocker, binding to voltage gated sodium channels. It stabilizes the neuronal membrane by inhibiting the ionic fluxes required for the initiation and conduction of impulses. Ventricular excitability is depressed and the stimulation threshold of the ventricle is increased during diastole,ventricular fibrilation Half life1-2 hrs Mexilitine 1-(2',6'-Dimethylphenoxy)-2-aminopropane Class IB anti-arrhythmic group of medicines. For the treatment of ventriculartachycardia and symptomatic premature ventricular beats, and prevention of ventricular fibrilation.Absorption Well absorbed (bioavailability 90%) lHalf life1-2 hr. Metabolism -Primarily hepatic (85%) via CYP2D6 and CYP1A2 (primarily CYP2D6) Route of eliminationApproximately 10% is excreted unchanged by the kidney. The urinary excretion of N-methylmexiletine in man is less than 0.5%. Amiodarone Amiodarone is a class III antiarrhythmic agent used for various types of cardiac dysrhythmias, both ventricular and atrial. 2-N-Butyl-3',5'-diiodo-4'-N-diethylaminoethoxy-3-benzoylbenzofuran The antiarrhythmic effect of amiodarone may be due to at least two major actions. It prolongs the myocardial cell-action potential (phase 3) duration and refractory Intravenously, for initiation of treatment and prophylaxis of frequently recurring ventricular fibrillation and hemodynamically unstable ventricular tachycardia in patients refractory to other therapy. Orally, for the treatment of life-threatening recurrent ventricular arrhythmias such as recurrent ventricular fibrillation and recurrent hemodynamically unstable ventricular tachycardia. period and acts as a noncompetitive a- and b-adrenergic inhibitor.AbsorptionSlow and variable (about 20 to 55% of an oral dose is absorbed). Protein binding>96% Amiodarone is extensively metabolized in the liver via CYP2C8 (under 1% unchanged in urine), and can effect the metabolism of numerous other drugs. The major metabolite of amiodarone is desethylamiodarone (DEA), which also has antiarrhythmic properties. Propafenone 1-{2-[2-hydroxy-3-(propylamino)propoxy]phenyl}-3-phenylpropan-1-one The electrophysiological effect of propafenone manifests itself in a reduction of upstroke velocity (Phase 0) of the monophasic action potential. In Purkinje fibers, and to a lesser extent myocardial fibers, propafenone reduces the fast inward current carried by sodium ions, which is responsible for the drugs antiarrhythmic actions. Diastolic excitability threshold is increased and effective refractory period prolonged. Nearly completely absorbed following oral administration (90%). Systemic bioavailability ranges from 5 to 50%, due to significant first-pass metabolism. This wide range in systemic bioavailability is related to two factors: presence of food (food increases bioavailability) and dosage (bioavailability is 3.4% for a 150-mg tablet compared to 10.6% for a 300-mg tablet). Protein binding 97% Metabolized primarily in the liver where it is rapidly and extensively metabolized to two active metabolites, 5-hydroxypropafenone and N- Metabolism depropylpropafenone. These metabolites have antiarrhythmic activity comparable to propafenone but are present in concentrations less than 25% of propafenone concentrations. Approximately 50% of propafenone metabolites are excreted in the urine following administration of immediate release tablets. 2-10 hoursHalf life propranolol, Propranolol 1-(naphthalen-1-yloxy)-3-[(propan-2-yl)amino]propan-2-ol 4 hours Propranolol competes with sympathomimetic neurotransmitters such as catecholamines for binding at beta(1)-adrenergic receptors in the heart, inhibiting sympathetic stimulation. This results in a reduction in resting heart rate, cardiac output, systolic and diastolic blood pressure, and reflex orthostatic hypotension. Propranolol is almost completely absorbed from the GI tract; however, plasma concentrations attained are quite variable among individuals. Propranolol is extensively metabolized with most metabolites appearing in the urine. Half life sotalol* N-(4-{1-hydroxy-2-[(propan-2-yl)amino]ethyl}phenyl)methanesulfonamide An adrenergic beta-antagonist that is used in the treatment of life-threatening Sotalol has both beta-adrenoreceptor blocking (Vaughan Williams Class I) and cardiac action potential duration prolongation (Vaughan Williams Class I) antiarrhythmic properties. Sotalol is a racemic mixture of d- and l-sotalol. Both isomers have similar Class I antiarrhythmic effects, while the l-isomer is responsible for virtually all of the beta- blocking activity. Sotalol inhibits response to adrenergic stimuli by competitively blocking β1-adrenergic receptors within the myocardium and β2-adrenergic receptors within bronchial and vascular smooth muscle. The electrophysiologic effects of sotalol may be due to its selective inhibition of the rapidly activating component of the potassium channel involved in the repolarization of cardiac cells. The class II electrophysiologic effects are caused by an increase in sinus cycle length (slowed heart rate), decreased AV nodal conduction, and increased AV nodal refractoriness, while the class III electrophysiological effects include prolongation of the atrial and ventricular monophasic action potentials, and effective refractory period prolongation of atrial muscle, ventricular muscle, and atrio-ventricular accessory pathways (where present) in both the anterograde and retrograde directioarrhythmias. Sotalol he oral bioavailability of sotalol is 90-100%. Protein binding does not bind to plasma proteins. Sotalol is not metabolized. Metabolism Excretion is predominantly via the kidney in the unchanged form. Sotalol is excreted in the milk of laboratory animals and has been reported to be present in human milk. Class IA Drugs Uses  Supraventricular and ventricular arrhythmias  Quinidine is rarely used for supraventricular arrhythmias  Oral quinidine/procainamide are used with class III drugs in refractory ventricular tachycardia patients with implantable defibrillator  IV procainamide used for hemodynamically stable ventricular tachycardia  IV procainamide is used for acute conversion of atrial fibrillation including Wolff-Parkinson-White Syndrome (WPWS) defibrillator Class IA Drugs Toxicity quinidine procainamide AV block Asystole or Torsades de ventricular pointes arrhythmia arrhythmia because it ↑ ERP (QT interval) Hypersensitivity Shortens A-V nodal : fever, refractoriness (↑AV agranulocytosis conduction) by antimuscarinic like effect Systemic lupus erythromatosus (SLE)-like ↑digoxin symptoms: arthralgia, fever, pleural- concentration by : pericardial inflammation. 1- displace from tissue binding sites Symptoms are dose and time dependent 2- ↓renal clearance Common in patients with slow hepatic Ventricular acetylation tachycardia  Notes: Torsades de pointes: twisting of the point. Type of tachycardia that gives special characteristics on ECG At large dosesof quinidine  cinchonism occurs:blurred vision, tinnitus, headache, psychosis and gastrointestinal upset Digoxin is administered before quinidine to prevent the conversion of atrial fibrillation or flutter into paradoxical ventricular tachycardia Class IB Drugs Class IB lidocaine mexiletine tocainide  They shorten Phase 3 repolarization  ↓ the duration of the cardiac action potential  They suppress arrhythmias caused by abnormal automaticity  They show rapid association & dissociation (weak effect) with Na+ channels with appreciable degree of use-dependence  No effect on conduction velocity Agents of Class IB Lidocaine Mexiletine  Used IV because of extensive 1st  These are the oral analogs of lidocaine pass metabolism  Mexiletine is used for chronic  Lidocaine is the drug of choice in emergency treatment of treatment of ventricular arrhythmias ventricular arrhythmias associated with previous myocardial  Has CNS effects: drowsiness, infarction numbness, convulstion, and nystagmus Adverse effects: 1- neurological effects 2- negative inotropic activity Uses They are used in the treatment of ventricular arrhythmias arising during myocardial ischemia or due to digoxin toxicity They have little effect on atrial or AV junction arrhythmias (because they don’t act on conduction velocity)  Class IC Class IC Drugs flecainide propafenone  They markedly slow Phase 0 fast depolarization  They markedly slow conduction in the myocardial tissue  They possess slow rate of association and dissociation (strong effect) with sodium channels  They only have minor effects on the duration of action potential and refractoriness  They reduce automaticity by increasing the threshold potential rather than decreasing the slope of Phase 4 spontaneous depolarization.  Uses:  Refractory ventricular arrhythmias.  Flecainide is a particularly potent suppressant of premature ventricular contractions (beats) Toxicity and Cautions for Class IC Drugs:  They are severe proarrhythmogenic drugs causing: 1. severe worsening of a preexisting arrhythmia 2. de novo occurrence of life-threatening ventricular tachycardia  In patients with frequent premature ventricular contraction (PVC) following MI, flecainide increased mortality compared to placebo. Notice: Class 1C drugs are particularly of low safety and have shown even increase mortality when used chronically after MI  Compare between class IA, IB, and IC drugs as regards effect on Na+ channel & ERP  Sodium channel blockade: IC > IA > IB  Increasing the ERP: IA>IC>IB (lowered) Because of K+ blockade  Class II ANTIARRHYTHMIC DRUGS (β-adrenergic blockers) Uses Mechanism of action  Treatment of increased  Negative inotropic sympathetic activity-induced and chronotropic arrhythmias such as stress- action. and exercise-induced  Prolong AV arrhythmias conduction (delay)  Atrial flutter and fibrillation.  Diminish phase 4  AV nodal tachycardia. depolarization   Reduce mortality in post- suppressing myocardial infarction patients automaticity(of  Protection against sudden ectopic focus) cardiac death Class II ANTIARRHYTHMIC DRUGS  Propranolol (nonselective): was proved to reduce the incidence of sudden arrhythmatic death after myocardial infarction  Metoprolol reduce the risk of bronchospasm selective  Esmolol: Esmolol is a very short-acting β1-adrenergic blocker that is used by intravenous route in acute arrhythmias occurring during surgery or emergencies  Class III ANTIARRHYTHMIC DRUGS K+ blockers  Prolongation of phase 3 repolarization without altering phase 0 upstroke or the resting membrane potential  They prolong both the duration of the action potential and ERP  Their mechanism of action is still not clear but it is thought that they block potassium channels  Class III sotalol amiodarone ibutilide Uses:  Ventricular arrhythmias, especially ventricular fibrillation or tachycardia  Supra-ventricular tachycardia  Amiodarone usage is limited due to its wide range of side effects  Sotalol (Sotacor)  Sotalol also prolongs the duration of action potential and refractoriness in all cardiac tissues (by action of K+ blockade)  Sotalol suppresses Phase 4 spontaneous depolarization and possibly producing severe sinus bradycardia (by β blockade action)  The β-adrenergic blockade combined with prolonged action potential duration may be of special efficacy in prevention of sustained ventricular tachycardia  It may induce the polymorphic torsades de pointes ventricular tachycardia (because it increases ERP) Ibutilide Used in atrial fibrillation or flutter IV administration May lead to torsade de pointes Only drug in class three that possess pure K+ blockade  Amiodarone (Cordarone)  Amiodarone is a drug of multiple actions and is still not well understood  It is extensively taken up by tissues, especially fatty tissues (extensive distribution)  t1/2 = 60 days  Potent P450 inhibitor  Amiodarone antiarrhythmic effect is complex comprising class I, II, III, and IV actions Dominant effect: Prolongation of action potential duration and refractoriness It slows cardiac conduction, works as Ca2+ channel blocker, and as a weak β- adrenergic blocker Toxicity  Most common include GI intolerance, tremors, ataxia, dizziness, and hyper-or hypothyrodism  Corneal microdeposits may be accompanied with disturbed night vision  Others: liver toxicity, photosensitivity, gray facial discoloration, neuropathy, muscle weakness, and weight loss  The most dangerous side effect is pulmonary fibrosis which occurs in 2- 5% of the patients  Class IV ANTIARRHYTHMIC DRUGS (Calcium Channel Blockers) Calcium channel blockers decrease inward Ca2+ currents resulting in a decrease of phase 4 spontaneous depolarization (SA node) They slow conductance in Ca2+ current- dependent tissues like AV node. Examples: verapamil & diltiazem Because they act on the heart only and not on blood vessels. Dihydropyridine family are not used because they only act on blood vessels  Mechanism of action  They bind only to depolarized (open) channels  prevention of repolarization So they act only in cases of arrhythmia because many Ca2+ channels are depolarized while in normal rhythm many of them are at rest  They prolong ERP of AV node  ↓conduction of impulses from the atria to the ventricles Uses More effective in treatment of atrial than ventricular arrhythmias. Treatment of supra-ventricular tachycardia preventing the occurrence of ventricular arrhythmias Treatment of atrial flutter and fibrillation  contraindication Contraindicated in patients with pre-existing depressed heart function because of their negative inotropic activity Adverse effects Cause bradycardia, and asystole especially when given in combination with β-adrenergic blockers Miscellaneous Antiarrhythmic Adenosine Drugs o Adenosine activates A1-purinergic receptors decreasing the SA nodal firing and automaticity, reducing conduction velocity, prolonging effective refractory period, and depressing AV nodal conductivity o It is the drug of choice in the treatment of paroxysmal supra-ventricular tachycardia o It is used only by slow intravenous bolus o It only has a low-profile toxicity (lead to bronchospasm) being extremly short acting for 15 seconds only class ECG QT Conduction Refractory velocity period IA ++ ↓ ↑ IB 0 no ↓ IC + ↓ no II 0 ↓In SAN and ↑ in SAN and AVN AVN III ++ No ↑ IV 0 ↓ in SAN and ↑ in SAN and AVN AVN  1st: Reduce thrombus formation by using anticoagulant warfarin 2nd: Prevent the arrhythmia from converting to ventricular arrhythmia: First choice: class II drugs: After MI or surgery Avoid in case of heart failure Second choice: class IV Third choice: digoxin Only in heart failure of left ventricular dysfunction 3rd: Conversion of the arrhythmia into normal sinus rhythm: Class III: IV ibutilide, IV/oral amiodarone, or oral sotalol Class IA: Oral quinidine + digoxin (or any drug from the 2nd step) Use direct current in case Class IC: of unstable hemodynamic Oral propaphenone or IV/oral flecainide patient  Premature ventricular beat (PVB) First choice: class II IV followed by oral Early after MI Avoid using Second choice: amiodarone class IC after MI  ↑ mortality First choice: Lidocaine IV Repeat injection Second choice: procainamide IV Adjust the dose in case of renal failure Third choice: class III drugs Especially amiodarone and sotalol  :‫تجميعات‬ (IA, IC, class III)  torsades de pointes. Classes II and IV  bradycardia (don’t combine the two) In atrial flutter use (1st ↓impulses from atria to ventricular to prevent ventricular tachycardia) 1. Class II 2. Class IV 3. Digoxin. )‫(على الترتيب‬ 2nd convert atrial flutter to normal sinus rhythm use: 1. Ibutilide 2. Sotalol 3. IA or IC. )‫(على الترتيب‬ If you use quinidine combine it with digoxin or β blocker (because of its anti muscarinic effect) Avoid IC in myocardial infarction because it ↑ mortality 1- In ventricular tachycardia and stable hemodynamic which drug to be used? A- propranolol B- procainamide C- quinidine D- verapamil 2- Mr.Green devloped an arrhythmia and was treated. A month later, he has arthralgia, fever, pleural inflammation. What was the treatment of arrhythmia? A- esmolol B- class III C- procainamide D- propafenone 3- Cinchonism occurs with digoxin (F) A- pulmonary fibrosis diltiazem B- bradycardia amiodarone