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Antiarrhythmicdrug therapy Dr Vinay Verma

This document discusses antiarrhythmic drug therapy. It describes the normal cardiac conduction pathway and how arrhythmias disrupt normal rhythm. There are several classes of antiarrhythmic drugs that work by different mechanisms, such as blocking sodium, potassium, calcium channels or beta receptors. The drugs have various uses for treating supraventricular and ventricular arrhythmias. Adverse effects and drug interactions are also reviewed for specific antiarrhythmic medications.

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ANTI ARRHYTHMIC DRUG THERAPY Dr.Vinay verma group:512
Normal conduction pathway SA node Generates action potential AV node Delivers the impulse to purkinje fibers Purkinje fibers Conduct the impulse to the ventricles
SAN AVN Impulse conductionNormal conduction pathway  Impulses originate regularly at a frequency of 60-100 beat/ min
Normal heartbeat & Arrhythmia Normal rhythm Arrhythmia AV septum
Management of Arrhythmia
Management of Arrhythmia  Pharmacological therapy (Antiarrhythmic Drugs)  Cardioversion  Pacemaker therapy  Surgical therapy e.g. aneurysmal excision  Interventional therapy “ablation”
Antiarrhythmic Drugs
Pharmacologic rationale & Goal  The ultimate goal of antiarrhythmic drug therapy:  Restore normal sinus rhythm and conduction  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 automaticityShrivatsa U, Wadhani M, Singh AB; Mechanisms of antiarrhythmic drug action & their clinical relevance for controlling disorders of cardiac rhythm; Curr Cardiol Rep 2002;4;401
Classification of Antiarrhythmic Drugs Classified a/c to Vaughan William into four classesClass Mechanism Action Notes I Na+ channel blocker Change the slope of phase 0 Can abolish tachyarrhythmia caused by reentry circuit II β blocker ↓heart rate and conduction velocity Can indirectly alter K and Ca conductance III K+ channel blocker 1. ↑action potential duration (APD) or effective refractory period (ERP). 2. Delay repolarization. Inhibit reentry tachycardia Ca++ channel Slowing the rate of rise in phase ↓conduction
Classification of Antiarrhythmic Drugs
Treatment of tachyarrhythmias:  Class I drugs (Membrane stabilizing drugs) : Mechanism:  Class I drugs block fast Na+ channels, thereby Reducing the rate of phase 0 depolarization Prolonging the effective refractory period Increasing the threshold of excitability Reducing phase 4 depolarization  These drugs also have local anestheticWoosely RL. Antiarrhythmic drugs. Hurst’s The Heart (Ed. Fuster V, Alexander RW, O’Rourke RA, et al.) 10th edition.2001;1:899–924
Class IA 1. Quinidine  Alkaloid – cinchona , dextro isomer of quinine.  Blocks sodium channel & potassium channel also  Anti-muscarinic and Alpha blocking action  Administered orally & is rapidly absorbed from gastrointestinal tract  Hydroxylated in the liver  t1/2 of approximately 5—12 hours, longer in hepatic or renal disease & in heart failure  Bitter and irritant  Inhibitor of CYP P450 system.
1. Quinidine  ↑↑ plasma conc of digoxin by displacing it from tissue binding sites & decreasing its renal & biliary clearance.  Uses:  Atrial fibrillation  Ventricular tachycardia  Adverse effects :  GIT : Diarrhea, nausea, vomiting and cinchonism  Thrombocytopenia  Precipitate torsade de pointes by prolonging
1. Quinidine  Drug interactions  Increases digoxin plasma levels &risk of digitalis toxicity  t1/2 reduced by agents that induce drug- metabolizing enzymes (phenobarbital, phenytoin)  May enhance the activity of coumarin anticoagulants & other drugs metabolized by hepatic microsomal enzymes  Cardiotoxic effects exacerbated by
2. Procainamide  Like quinidine, but  Safer to use intravenously  Produces fewer adverse GI effects  Acetylated in liver to N-acetylprocainamide (NAPA)  Eliminated by the kidney (t ½ -3 – 5 hrs)  More likely than quinidine to produce severe or irreversible heart failure  Adverse effects  SLE like syndrome consisting of arthralgia and arthritis specially in slow acetylators
Class IB 1. Lidocaine:  Least cardiotoxic : (t ½ - 1.5 - 2 hrs)  Block inactivated Na channels : preferred for partially depolarized cells in ischemic area  High first pass metabolism – not given orally  Used in:  Ventricular arrhythmia  Digoxin induced arrhythmia  Main toxicity: Neurological – drowsiness, nystagmus &
2. Mexiletine and Tocainide  Similar in action to lidocaine  Can be administered orally  T ½ - Mexiletine – 10-12 hrs - Tocanide – 11-23 hrs  Used for long-term treatment of ventricular arrhythmias associated with previous Myocardial Infarction  Adverse events:  Mexiletine : Ataxia, dizziness, tremors  Tocainide : Blood dyscrasias, pulmonary fibrosis, GI and neurological symptoms
Class IC  Class of potent Na channel blocker  Drugs of this class have negative inotropic effect  High pro-arrhythmogenic potential – sudden death
Class IC 1.Flecainide  Orally active antiarrhythmic  Metabolized by microsomal enzymes (t ½ - 20 hrs)  Used for ventricular tachyarrhythmias & maintenance of sinus rhythm in patients with paroxysmal atrial fibrillation and/or atrial flutter & WPW  C/I in pts with structural heart disease  Adverse events :  Heart failure, dizziness, headache , Blurred
2. Propafenone  Spectrum of action similar to that of quinidine  Possesses β-adrenoceptor antagonist activity  Metabolized by hepatic microsomal enzymes  T ½ - 2 – 10 hrs  Approved for treatment of supraventricular arrhythmias and suppression of life-threatening ventricular arrhythmias  C/I in structural heart disease  Adverse events:  Nausea, Vomitting, altered taste
Class II  They Are β-adrenoceptor antagonists, including propranolol  Act by reducing sympathetic stimulation  Inhibit phase 4 depolarization  Depress automaticity  Prolong AV conduction  Decrease  Heart rate  Contractility
Class II  Major drugs Propranolol, a nonselective β-adrenoceptor antagonist Acebutolol & esmolol, more selective β1- adrenoceptor antagonists Used to treat ventricular arrhythmias Propranolol, metoprolol, nadolol, and timolol frequently used to prevent recurrent MI
Class II  Absorption and elimination:  Propranolol: oral, iv  Esmolol: iv only (very short acting T½, 9 min)  Cardiac effects   APD and refractory period in AV node to slow AV conduction velocity   decrease phase 4 depolarization (catecholamine dependent)
Class II  Uses:  Treating sinus and catecholamine dependent tachyarrhythmias  Converting reentrant arrhythmias in AV  Protecting the ventricles from high atrial rates  Side effects:  Bronchospasm  Hypotension  Don’t use in partial AV block or ventricular failure
Class III  Class III drugs: Prolong action potential duration Prolong effective refractory period  Act by: interfering with outward K+ currents or slow inward Na+ currents
1. Amiodarone  Structurally related to thyroxine.  Net effect:  Increases refractoriness  Depresses sinus node automaticity  Slows conduction.  Long half-life (14—100 days) ↑ risk of toxicity  Plasma conc not well correlated with its effects  After parenteral administration:  Electrophysiologic effects →within hours  Effects on abnormal rhythms may not be seen for several days
1. Amiodarone  Antiarrhythmic effects may last for weeks or months after the drug is discontinued  Uses: Refractory life-threatening ventricular arrhythmias in preference to lidocaine T/t of atrial and/or ventricular arrhythmias  Adverse effects  Pulmonary fibrosis  Skin pigmentation  Corneal deposits  Interferes with the thyroid function
Class IV  Mechanism  Class IV drugs selectively block L-type calcium channels.  These drugs prolong nodal conduction and effective refractory period and have predominate actions in nodal tissues
Class IV
Verapamil  Phenylalkylamine that blocks both activated and inactivated slow calcium channels.  Tissues that depend on L-type calcium channels are most affected  Has equipotent activity on the AV and SA nodes and in cardiac and vascular muscle tissues  Useful in:  Supraventricular tachycardia  Atrial flutter and fibrillation
Verapamil  Adverse effects: Negative inotropic action that limits its use in damaged hearts; Can lead to AV block when given in large doses or in patients with partial blockage. Can precipitate sinus arrest in diseased patients Causes peripheral vasodilation.
Miscellaneous Antiarrhythmic Drugs  Adenosine  Acts through specific purinergic (P1) receptors.  Causes an increase in potassium efflux and decreases calcium influx.  This hyperpolarizes cardiac cells and decreases the calcium-dependent portion of the action potential.  Drug of choice for the treatment of paroxysmal supraventricular tachycardia, including those associated with Wolff-
Digoxin  Mode of action: Na-K ATPase inhibition Positive inotrope Vagotonic  T ½ - Premature (61hrs), Neonate (35hrs), Infant (18hrs), Child (37hrs), Adult (35-48hrs )  Uses: Supraventricular Tachycardia
Digoxin  Interactions:  Coumadin- ↑ PT  ↑ Digoxin level  Quinidine, amiodarone, verapamil  ↓ renal function/renal tubular excretion (Spironolactone)  Worse with ↓ K+, ↓ Ca++
Investigational Drugs  Analogs of Amiodarone are being developed such as:  ATI-2001  Dronedarone  SR-33589  Dronedarone:  Resonable safety profile  Well characterized pharmacokinetic & pharmacodynamic profile  Effective in doses lower than 2000 mg/dayWolbrette D et al ; Dronedarone for the treatment of atrial fibrillation and atrial flutter: Approval and efficacy ; Vasc Health Risk Manage 2010;6;517
Investigational Drugs  Azimilide :  Potassium-channel blocking properties  Prolongs cardiac AP & refractory periods  Found to be effective in patients with symptomatic tachyarrhythmias and ICDs therapies in recent studies  Other drugs, such as Ambasilide, are also in clinical development  Chromanol 293B is in preclinical testing Reynolds RM, Josephson ME. Sustained ventricular tachycardiain ischemic cardiomyopathy : current management. ACC Current Journal Review 2005;14:63-71
Treatment of bradyarrhythmias  Atropine  Blocks the effects of acetylcholine.  Elevates sinus rate and AV nodal and sinoatrial (SA) conduction velocity, & decreases refractory period  Used to treat bradyarrhythmias that accompany MI  Adverse effects:  Dry mouth, mydriasis, and cycloplegia;  May induce arrhythmias.
T/t of Atrial Flutter/Fibrillation 1. Reduce thrombus formation by using anticoagulant warfarin 2. 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 drugs  Third choice: digoxin  Only in heart failure of left ventricular
T/t of Atrial Flutter/Fibrillation 3. 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)  Class IC:  Oral propaphenone or IV/oral flecainide  Use direct current in case of unstable hemodynamic patient Fuster V et al; ACC/AHA/ESC Guidelines for the management of patients with atrial fibrillation. Circulation
T/t of Ventricular Arrhythmia  Premature ventricular beat (PVB)  First choice: class II  IV followed by oral  Early after MI  Second choice: amiodarone  Avoid using class IC after MI  ↑ mortality
T/t of Ventricular Tachycardia  First choice: Lidocaine IV  Repeat injection if needed  Second choice: procainamide IV  Adjust the dose in case of renal failure  Third choice: class III drugs  Especially amiodarone and sotalol Grant AO, Recent advances in the treatment of arrhythmia. Circ J 2003;67;651
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