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Uploaded byDr.Sayeedur Rumi
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Antiarrhythmic Drugs

This document discusses antiarrhythmic drugs, their mechanisms of action, classifications, and effects on cardiac electrophysiology. It covers 4 main classes of antiarrhythmic drugs - Class I agents which affect sodium channels, Class II agents which are beta blockers, Class III agents which affect potassium channels, and Class IV agents which affect calcium channels. Specific drugs from each class are described in detail including their indications, mechanisms, dosages, side effects, and drug interactions. The document provides an overview of the pharmacological treatment of cardiac arrhythmias.

Education◦
ANTIARRHYTHMIC DRUGS Dr. Sayeedur Rahman Khan Rumi Dr.rumibd@gmail.com MD Final Part Student NHFH&RI
Mechanism of arrhythmias • Three major mechanisms contribute to development of cardiac arrhythmias: – Automaticity – Reentry and – Triggered activity.
Classification of Antiarrhythmic Drugs • There are four established classes of antiarrhythmic action. • The original Vaughan Williams classification with four classes now incorporates ionic mechanisms and receptors as the basis of the more complex Sicilian Gambit system for antiarrhythmic drug classification.
Classification of Antiarrhythmic Drugs • Class I agents decrease phase zero of the rapid depolarization of the action potential (rapid sodium channel). • Class II agents, b-blocking drugs, have complex actions including inhibition of spontaneous depolarization (phase 4) and indirect closure of calcium channels. • Class III agents block the outward potassium channels to prolong the action potential duration and hence refractoriness. • Class IV agents, verapamil and diltiazem, and the indirect calcium antagonist, adenosine, all inhibit the inward calcium channel, which is most prominent in nodal tissue, particularly the atrioventricular node.
Mechanism of AADs in various phase of action potential
Class IA: Quinidine and Similar Compounds
• Historically, quinidine was the first antiarrhythmic drug used. • can cause proarrhythmic complications by prolonging the QT interval in certain genetically predisposed individuals or by depressing conduction and promoting reentry.
Class IB
Lidocaine • Class IB agents act selectively on diseased or ischemic tissue, where they are thought to promote conduction block, thereby interrupting reentry circuits. • Lidocaine acts preferentially on the ischemic myocardium and is more effective in the presence of a high external potassium concentration. • Therefore hypokalemia must be corrected for maximum efficacy. • This intravenous drug has no role in the control of chronic recurrent ventricular arrhythmias. • No value in treating supraventricular tachyarrhythmias.
• Dose: – IV 75-200 mg; then 2-4 mg/min for 24-30 h. (No oral use) – Reduce dose by half if liver blood flow low (shock, b-blockade, cirrhosis, cimetidine, severe heart failure). • Pharmacokinetics and Metabolism: – Effect of single bolus lasts only few min, – T ½ approximately 2 h. – Rapid hepatic metabolism. – Level 1.4-5 mcg/mL; toxic >9 mcg/mL.
• Side Effects: – Generally free of hemodynamic side effects, even in patients with congestive heart failure (CHF), and it seldom impairs nodal function or conduction – High-dose CNS effects - drowsiness, numbness, speech disturbances, and dizziness, especially in patients older than 60 years of age. • Drug Interactions – b-blockers decrease hepatic blood flow and increase blood levels. – Cimetidine (decreased hepatic metabolism of lidocaine).
Class IC
• Class IC agents have acquired a particularly bad reputation as a result of the proarrhythmic effects seen in the Cardiac Arrhythmia Suppression Trial (CAST) (flecainide) and the Cardiac Arrest Study Hamburg (CASH) study (propafenone). • These drugs must be avoided in patients with structural heart disease.
Flecainide • Dose: – Oral 100-400 mg 2 times daily. • Pharmacokinetics and Metabolism: T ½ 13-19 h. Hepatic 2⁄3; 1⁄3 renal excretion uncharged • Indications: – Paroxysmal supraventricular tachycardia (AF, Atrial flutter, WPW) – Life-threatening sustained VT – Catecholaminergic polymorphic VT – For maintenance of sinus rhythm after cardioversion of AF
• Contraindications: – Patients with structural heart disease – Patients with right bundle branch block and left anterior hemiblock – In the sick sinus syndrome, when the left ventricle is depressed, and in the postinfarct state • Side effects: – QRS prolongation. – Proarrhythmia.
Propafenone • Dose: – Oral 150-300 mg 3 times daily. • Pharmacokinetics and Metabolism: – T ½ variable 2-10 h, up to 32 h in nonmetabolizers. – Level 0.2-3 mcg/mL. • Indications: – Life-threatening ventricular arrhythmias – Suppression of supraventricular arrhythmias, including those of WPW syndrome and recurrent atrial flutter or fibrillation.
• Contraindications: – preexisting sinus, AV or bundle branch abnormalities – depressed left ventricular (LV) function. – Patients with asthma and bronchospastic disease including chronic bronchitis • Side effects: – QRS prolongation. – Modest negative inotropic effect. – GI side effects. – Proarrhythmia.
Class II Agents: b-Adrenoceptor Antagonists
• At present, b-blockers are the closest to an ideal class of antiarrhythmic agents for general use because of their broad spectrum of activity and established safety record. • Furthermore, the use of b-blockers in combination with other antiarrhythmic agents may have a synergistic role and can reduce the proarrhythmic effects
Mixed Class III Agents: Amiodarone and Sotalol
Amiodarone • Lengthens the effective refractory period by prolonging the APD in all cardiac tissues, including bypass tracts • Amiodarone makes the action potential pattern more uniform throughout the myocardium, thereby opposing EP heterogeneity that underlies some serious ventricular arrhythmias. • The incidence of torsades with amiodarone is much lower than expected from its class III effects. • The weak calcium antagonist (class IV) effect might explain bradycardia and AV nodal inhibition and the relatively low incidence of torsades de pointes.
Dose • Oral loading dose 1200-1600 mg daily; maintenance 200-400 mg daily • IV 150 mg over 10 min, then 360 mg over 6 h, then 540 mg over remaining 24 h, then 0.5 mg/min. • For AF in AMI or after cardiac surgery, 5 mg/kg over 20 minutes, 500 to 1000 mg over 24 hours, then orally, and then 0.5 mg/minute • Caution: Be aware of the risk of hypotension with intravenous amiodarone. • Generally, intravenous amiodarone is used for 48 to 96 hours while oral amiodarone is instituted.
Pharmacokinetics • T ½ 25-110 days (up to 6 months) • The therapeutic range 1-2.5 mcg/mL. • Hepatic metabolism. • Lipid soluble with extensive distribution in body. Because of this, amiodarone must fill an enormous peripheral-tissue depot to achieve adequate blood and cardiac concentrations. • Excretion by skin, biliary tract, lachrymal glands.
Indications • VT • VF • AF, Atrial flutter: Amiodarone is probably the most effective of the available drugs to prevent recurrences of paroxysmal AF or flutter and reasonable choice for patients with structural cardiac disease or CHF • AF in WPW syndrome • Other SVTs
Benefits of Amiodarone in AF may be explained at least in part by prolongation of the refractory periods of both the left and right superior pulmonary veins, and inhibition of the AV node
Contraindications • Severe sinus node dysfunction with marked sinus bradycardia or syncope • Second- or third-degree heart block • Known hypersensitivity • Cardiogenic shock • Severe chronic lung disease.
Side effects • Sinus bradycardia (in older adults) • QT prolongation • Hypothyroidism • Hyperthyroidism • Pulmonary toxicity (very rarely occurs with the low doses of about 200 mg daily) • Hepatotoxicity (elevated enzyme levels, epatitis and cirrhosis) • Optic neuropathy/neuritis • Blue-gray skin discoloration • Photosensitivity • Peripheral neuropathy • Testicular dysfunction
Recommended preventative actions • baseline and 6-monthly thyroid function tests and liver enzymes • baseline and yearly ECG and chest radiography • physical examination of skin, eyes, and peripheral nerves if symptoms develop
Drugs interactions • A serious and common interaction is with warfarin. Amiodarone prolongs the prothrombin time and may cause bleeding in patients on warfarin • Amiodarone increases the plasma digoxin concentration, predisposing to digitalis toxic effects (not arrhythmias because amiodarone protects) • an additive proarrhythmic effect with other drugs prolonging the QT interval, such as class IA antiarrhythmic agents, phenothiazines, tricyclic antidepressants, thiazide diuretics, and sotalol.
Sotalol • Dose: – 160-640 mg daily, occasionally higher in two divided doses. • Pharmacokinetics: – T ½ 12 h – Not metabolized – Hydrophilic – Renal loss • Side effects: – Myocardial depression – Sinus bradycardia – AV block – Torsades if hypokalemic
• Indications: – severe ventricular arrhythmias – AF for maintenance of sinus rhythm in patients with recurrent symptomatic AF or atrial flutter. – can be given to patients with structural heart disease • Contraindications: – Asthma – reduced creatinine clearance, below 40 mL/minute
Dronedarone • Should only be prescribed for maintaining sinus rhythm in patients with paroxysmal AF or persistent AF after successful cardioversion. • Without a history of heart failure and with good ventricular function
Class IV and Class IV- Like Agents
Verapamil and diltiazem • They slow the ventricular response rate in atrial arrhythmias, particularly AF. • They can also terminate or prevent reentrant arrhythmias in which the circuit involves the AV node. • For the termination of AV nodal dependent supraventricular tachycardias, verapamil and diltiazem are alternatives to adenosine.
Adenosine • It is a first-line agent for terminating narrow complex PSVTs • Dose: – For paroxysmal SVT, initial dose 6 mg by rapid IV. If the dose is ineffective within 1 to 2 minutes, 12 mg may be given and if necessary, 12 mg after a further 1 to 2 minutes. – The initial dose needs to be reduced to 3 mg or less in patients taking verapamil, diltiazem, or b-blockers or dipyridamole or in older adults at risk of sick sinus syndrome • T ½: 10-30 seconds.
• Indications: – Paroxysmal narrow complex SVT (usually AV nodal reentry or AV reentry such as in the WPW syndrome or in patients with a concealed accessory pathway). – In wide-complex tachycardia of uncertain origin, adenosine can help the management by differentiating between VT or SVT (with aberrant conduction) • Contraindication – In asthmatic, – Second- or third-degree AV block, – Sick sinus syndrome.
• Side effects: Usually transient and include – nausea – light-headedness – headache – flushing – bronchospasm – provocation of chest pain – sinus or AV nodal inhibition – bradycardia – and with large dose infusion rare side effects hypotension, tachycardia
Antiarrhythmic drugs In pregnancy and Lactation • In pregnancy, only Sotalol is category B. • It is not teratogenic, but does cross the placenta and may depress fetal vital functions. • Sotalol is also excreted in mother’s milk.
Newer Antiarrhythmic Agents
Vernakalant  Vernakalant is the first in the new generation of AADs that demonstrate electrophysiological effects preferentially in the atrium and not in the ventricle.  Atrial-selective agents are currently being developed to restore and maintain sinus rhythm in AF while avoiding adverse ventricular events, such as QTc prolongation and torsades de pointes. • The recommended dose is a single intravenous infusion of 3 mg/kg administered over 10 minutes. • No dose adjustment is necessarily based on patient characteristics and concomitant drugs.
• The ACT I(Atrial Arrhythmia Conversion) and ACT III trials investigated vernakalant in the treatment of patients with sustained AF  No episodes of drug-induced torsades de pointes were reported in the ACT trials.  The AVRO trial demonstrated that vernakalant achieved a superior conversion rate (51.7% of patients to sinus rhythm at 90 minutes) compared to amiodarone (5.2%).
Tedisamil • Tedisamil blocks multiple potassium channels. • These ion channels effect prolong atrial and ventricular action potential duration and refractoriness.
Ivabradine  High resting sinus heart rates have been independently associated with mortality and major adverse cardiovascular outcomes.  Ivabradine is a selective If current blocker in the sinus node, resulting in sinus slowing, independent of autonomic tone.  Ivabradine, in combination with a b-blocker, can be effective to prevent angina.  Usual dose for ivabradine is 5–7.5 mg twice a day.
• Systolic Heart Failure Treatment with If Inhibitor Ivabradine Trial (SHIFT)159 of patients with congestive heart failure (LV EF ≤35% and HR ≥70 despite standard medical therapy) indicated that ivabradine can consistently lower the heart rate over long-term when compared to matching placebo and can significantly improve the primary endpoint of cardiovascular death or hospitalization for worsening heart failure. • Ivabradine has emerged as a promising treatment for inappropriate sinus tachycardia (IST), which, at times, can be debilitating and refractory to medical therapy.
Ranolazine  Ranolazine is an antianginal drug approved for the treatment of chronic angina in patients who have not responded to standard antianginal medications. • The antianginal mechanism of ranolazine was believed to result from the drug’s ability to block the late sodium current, thereby, suppressing calcium and sodium overload in response to ischemia.  Selective affinity for the late sodium current has resulted in ranolazine being investigated as a novel AAD.
 (MERLIN-TIMI 36) trial, ranolazine significantly lowered nonsustained VT and supraventricular tachyarrhythmias in patients with non-ST elevation myocardial infarction when compared to placebo.  Early clinical studies have shown that a single dose of 2 g of ranolazine was highly effective as a “pill-in- thepocket” approach to AF, converting 77% of patients, without any significant side effects. • These included patients with structural heart disease, a contraindication for current class IC agents, and could potentially expand the use of ranolazine.
On the horizon • Cellular Calcium Handling • Gene therapies—potential (“near practical”) applications: There are a variety of exciting possibilities with regard to the use of gene therapies as antiarrhythmic therapy. Consideration has been given to use gene therapy  to enhance automaticity in patients with bradycardia (a biological pacemaker)  gene therapy to affect AV conduction and slow conduction in AF  to affect the presence of VT by affecting repolarization and accelerating conduction.
Outpatient Vs. In-hospital Initiation for antiarrhythmic drug therapy • The severity of the arrhythmia and the proarrhythmic risk of the AAD determine whether the drug should be initiated in the hospital. • All class IA AADs should be started in the hospital given the potential risk of idiosyncratic, non dose dependent torsades de pointes. • Mexiletine, the only orally available class IB AAD, can be started and titrated as an outpatient treatment, as the risk of proarrhythmia is low. • Class IC AADs have a very low risk of proarrhythmia and can be started as an outpatient treatment, provided structural heart disease and severe left ventricular hypertrophy are ruled out. • If initiated for AF, it is recommended to add an AV blocking drug along with the class IC agent to reduce the risk of atrial flutter with rapid ventricular rates.
• Sotalol and dofetilide should be initiated in the hospital due to the risk of developing dose-dependent QT prolongation and torsades de pointes. Dofetilide must be started in the hospital and strict regulations govern its initiation and titration. • Amiodarone can be started as an outpatient for patients who have AF and atrial flutter, as the proarrhythmic risk is low. • On the other hand, if used for secondary prevention of VT, it is preferable to initiate amiodarone in the hospital. • Although amiodarone prolongs QT interval, incidence of torsades de pointes with amiodarone is extremely low. • Dronedarone is generally not proarrhythmic and can be started outside the hospital.
Pill-in-the-pocket • Intermittent oral administration of single doses of flecainide (200 to 300 mg) or propafenone (450 to 600 mg) when an episode begins—may be effective in selected patients with AF and no structural heart disease. • The major potential complication of this approach is the possibility for organization and slowing of the arrhythmia to atrial flutter, which may then conduct with a 1:1 AV ratio at a very high ventricular rate. • Intermittent drug self-administration should be used cautiously and only in patients likely to tolerate this potential proarrhythmic effect. • The efficacy of this approach is often tested in a monitored setting before being used on an outpatient basis.
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