Antiarrhythmic Drugs

Arrhythmias These are drugs used to prevent or treat irregularities of cardiac rhythm. Arrhythmias are the most important cause of sudden cardiac death. Types : extra beats (extrasystoles): premature atrial contractions premature ventricular contractions supraventricular tachyarrhythmias: atrial fibrillation (irregular heart rates of 350 to 700  bpm) atrial flutter( ’flutter waves’ at a regular rate of 240 to 440 bpm) paroxysmal supraventricular tachycardia (150-200 bpm) ventricular arrhythmias: ventricular fibrillation (fatal unless reverted within 2–5 min; the most common cause of sudden cardiac death) ventricular tachycardia Torsades de pointes (twisting of points) is a life-threatening form of ventricular tachycardia with rapid asynchronous complexes and an undulating baseline on ECG. It is generally associated with long Q-T interval. bradyarrhythmias

Phases of a cardiac action potential. The sharp rise in voltage ("0") corresponds to the influx of Na ions The decay ("1”) corresponds to the Na-channel inactivation, efflux of K+ ions The plateau ("2") results from the opening of Ca2+channels. The decay ("3") corresponds to the repolarizing efflux of K+ ions.

Phases of a cardiac action potential Phase-0 - rapid depolarization Phase-1 – repolarization phase-2 - plateau phase Phase-3 - rapid repolarization Phase-4 – stable phase or resting membrane potential

Refractory period Effective refractory period (ERP) is the minimum interval between two propagating APs or from the beginning of phase 0 until phase 3, during which it is impossible to evoke another action potential.

Mechanisms of cardiac arrhythmias Enhanced/ectopic pacemaker activity Ectopic impulse may be increased pathologically in the automatic fibres or such activity may appear in ordinary fibres. Triggered activity These are secondary depolarizations accompanying a normal or premature action potential (AP). Early after-depolarization Repolarization during phase-3 is interrupted and membrane potential oscillates. If the amplitude of oscillations is sufficiently large, neighbouring tissue is activated and a series of impulses are propagated. Delayed after-depolarization After attaining resting membrane potential (RMP) a secondary deflection occurs which may reach threshold potential and initiate a single premature AP.

Mechanisms of cardiac arrhythmias C. Re-entry Due primarily to abnormality of conduction, an impulse may recirculate in the heart and cause repetitive activation without the need for any new impulse to be generated. These are called reentrant arrhythmias.

Class I: Fast Na-channel blockers Class II: Beta blockers(decreases slope of phase 4) Class III: K-channel blockers(prolongs phase 3) Class IV: Slow Ca-channel blockers(prolongs phase 2) Variable mechanism: Adenosine Digoxin Magnesium sulf.

CLASS I Class I: Fast Na-channel blockers Ia -Quinidine, procainamide, disopyramide (depress phase 0, prolonging repolarization) Ib -Lidocaine, phenytoin, mexiletine (depress phase 0 selectively in abnormal/ischemic tissue, shorten repolarization) Ic -Flecainide, propafenone, moricizine (markedly depress phase 0, minimal effect on repolarization)

See the phase 3 of the curve to apply the mnemonic: IB antiarrhytmics show the line Before the (normal) face. IA antiarrhytmics show the line After the (normal) face. IC antiarrhytmics show the line Cara (spanish world of face), because is the same as normal in phase 3.

Clinical uses in cardiology Ia Ventricular arrhythmias prevention of paroxysmal recurrent atrial fibrillation (triggered by vagal overactivity) procainamide in Wolff-Parkinson-White syndrome Increases QT interval ADR Risk of torsades de pointes !!! neurological effects (ringing in ears, vertigo) Marked fall in BP Synergistic cardiac depression with β-blockers, verapamil, K+ salts.

Clinical uses Ib only for ventricular tachycardia (VT) (inefficacy in atrial arrhythmias) treatment and prevention VT during and immediately after myocardial infarction ADR Proarrhythmic potential !!! neurological effects(paresthesias, blurred vision)

Clinical uses Ic prevents paroxysmal atrial fibrillation treats recurrent tachyarrhythmias of abnormal conduction system. contraindicated immediately post-myocardial infarction. ADR High proarrhythmic potential Sudden deaths

CLASS II Class II agents include: They act by: Atenolol Esmolol Propranolol Metoprolol Uses prevent and treatment of supraventricular tachyarrhythmias decrease myocardial infarction mortality They act by: blocking the β1-adrenergic receptors, decreasing sympathetic activity on the heart. decrease conduction through the AV node.

CLASS III Class III: Potassium (K) channel blockers Amiodarone (prolongs phase 3; also acts on phases 1, 2, and 4) Sotalol (prolongs phase 3, decreases slope of phase 4) Ibutilide (prolongs phase 3) Dofetilide (prolongs phase 3) The characteristic action of this class is: prolongation of repolarization (phase-3); AP is widened ERP is increased.

Amiodarone Iodine containing highly lipophilic long-acting antiarrhythmic drug exerts multiple actions: Amiodarone has Class I, II, III & IV activity It accumulates in muscle and fat. The duration of action is exceptionally long: t½ 3–8 weeks It is useful both in supraventricular arrhythmias and ventricular arrhythmias (e.g. ventricular fibrillation, ventricular tachycardia, atrial fibrillation) Side effects: Pulmonary fibrosis Hypothyroidism Hyperthyroidism Corneal micro-deposits Blue-grey discoloration of the skin Photosensitization Peripheral neuropathies Possible association between amiodarone and an increased risk of cancer Fall in BP Bradycardia Myocardial depression

CLASS IV Calcium (Ca) channel blockers Verapamil (prolongs phase 2) Diltiazem (prolongs phase 2) They decrease conduction through the AV node They thus reduce the contractility of the heart, so may be inappropriate in heart failure. Poor /no efficacy in ventricular arrhythmias Uses: paroxysmal supraventricular tachycardia reduce ventricular rate in patients with atrial fibrillation. ADR bradycardia, A-V block, cardiac arrest and hypotension

Class V / Other agents Digoxin decreases conduction of electrical impulses through the AV node and increases vagal activity. Adenosine Is used intravenously for terminating supraventricular tachycardias (PSVT). Magnesium sulfate an antiarrhythmic drug, but only against very specific arrhythmias which has been used for torsades de pointes.

Adenosine Very short t½ ~ 10 sec Uses : Termination of attack of PSVT Advantages of adenosine: Efficacy equivalent to or better than verapamil. Action lasts < 1 min adverse effects are transient. Can be given to patients with hypotension, CHF or those receiving β blockers. Verapamil is contraindicated in these situations. Effective in patients not responding to verapamil. ADR Transient dyspnoea, chest pain, fall in BP, cardiac arrest

Digoxin Indications: atrial fibrillation atrial flutter By slowing down the conduction in the AV node and increasing its refractory period, digoxin can reduce the ventricular rate. The arrhythmia itself is not affected, but the pumping function of the heart improves, owing to improved filling.

Clinical classification of antiarrhythmic drugs

Bradyarrhythmias and A-V Block Treatment of chronic heart block - implanted cardiac pacemaker. For acute/transient A-V block : Atropine Atropine abbreviates A-V node ERP and increases conduction velocity in bundle of His. Adrenomimetics (Adr, isoprenaline) These drugs may overcome partial heart block by facilitating A-V conduction and shortening ERP of conducting tissues. They may also be used in complete heart block to maintain a sufficient idioventricular rate (by increasing automaticity of ventricular pacemakers) till external pacemaker can be implanted.