Antiarrhythmic agent
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Antiarrhythmic agents are a group of pharmaceuticals that are used to suppress fast rhythms of the heart (cardiac arrhythmias), such as atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation.
While the use of antiarrhythmic agents to suppress atrial arrhythmias (atrial fibrillation and atrial flutter) is still in practice, it is unclear whether suppression of atrial arrhythmias will prolong life.[1][2]
In the past, it was believed that following myocardial infarction (heart attack), suppression of ventricular arrhythmias would prolong life. However large clinical trials found that suppression of these arrhythmias would paradoxically increase mortality,[3][4] which may happen due to the proarrhythmic effect these drugs may have (CAST trial).
In individuals with atrial fibrillation, antiarrhythmics are still used to suppress arrhythmias. This is often done to relieve the symptoms that may be associated with the loss of the atrial component to ventricular filling (atrial kick) that is due to atrial fibrillation or flutter.
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The cardiac action potential
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Class Ia agent decreasing Vmax, thereby increasing action potential duration.
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Effect of class Ib antiarrhythmic agents on the cardiac action potential.
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Effect of class Ic antiarrhythmic agent on cardiac action potential.
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Effect of class III antiarrhythmic agent on cardiac action potential.
In individuals with ventricular arrhythmias, antiarrhythmic agents are often still in use to suppress arrhythmias. In this case, the patient may have frequent arrhythmic events or be at high risk for ventricular arrhythmias. Antiarrhythmic agents may be considered the first-line therapy in the prevention of sudden death in certain forms of structural heart disease, and failure of these agents to suppress arrhythmias may lead to implantation of an implantable cardioverter-defibrillator (ICD).
The use of antiarrhythmic agents in this population may be in conjunction with an ICD. In this case, the ICD is used to prevent sudden death due to ventricular fibrillation, while the antiarrhythmic agent(s) are used to suppress ventricular tachyarrhythmias so that the ICD doesn't shock the patient frequently.
Many attempts have been made to classify antiarrhythmic agents. The problem arises from the fact that many of the antiarrhythmic agents have multiple modes of action, making any classification imprecise.
Vaughan Williams antiarrhythmic classification
The Vaughan Williams classification, introduced in 1970,[5] is one of the most widely used classification schemes for antiarrhythmic agents. This scheme classifies a drug based on the primary mechanism of its antiarrhythmic effect. However, its dependence on primary mechanism is one of the limitations of the VW classification, since many antiarrhythmic agents have multiple action mechanisms. Amiodarone, for example, has effects consistent with all of the first four classes. Another limitation is the lack of consideration within the VW classification system for the effects of drug metabolites. Procainamide—a class Ia agent whose metabolite N-acetyl procainamide (NAPA) has a class III action—is one such example. A historical limitation was that drugs such as digoxin and adenosine – important antiarrhythmic agents – had no place at all in the VW classification system. This has since been rectified by the inclusion of class V.
There are five main classes in the Vaughan Williams classification of antiarrhythmic agents:
- Class I agents interfere with the sodium (Na+) channel.
- Class II agents are anti-sympathetic nervous system agents. All agents in this class are beta blockers.
- Class III agents affect potassium (K+) efflux.
- Class IV agents affect the AV node. They are calcium channel blockers.
- Class V agents work by other or unknown mechanisms.
Class I agents
The class I antiarrhythmic agents interfere with the sodium (Na+) channel. Class I agents are grouped by what effect they have on the Na+ channel, and what effect they have on cardiac action potentials.
- Intensity of Na+ blockade
- 1C>1A>1B (manifests as increased PR and QRS)
Class Ia agents
Class Ia agents block the fast sodium channel. (manifests as increased PR and QRS)
Blocking this channel depresses the phase 0 depolarization (reduces Vmax), which prolongs the action potential duration by slowing conduction.
Prolongation of repolarization due to K+ channel effect. (manifests as prolonged QT interval)
Agents in this class also cause decreased conductivity and increased refractoriness.
Indications for Class Ia agents are supraventricular tachycardia, ventricular tachycardia, symptomatic ventricular premature beats, and prevention of ventricular fibrillation.
Procainamide can be used in the treatment of atrial fibrillation in the setting of Wolff-Parkinson-White syndrome, and in the treatment of wide complex hemodynamically stable tachycardias.
While procainamide and quinidine may be used in the conversion of atrial fibrillation to normal sinus rhythm, they should only be used in conjunction with an AV node blocking agent (ie: digoxin, verapamil, or a beta blocker), because procainamide and quinidine can increase the conduction through the AV node and may cause 1:1 conduction of atrial fibrillation, causing an increase in the ventricular rate.
Class Ia agents include quinidine, procainamide and disopyramide.
Class Ib agents
Class Ib antiarrhythmic agents are sodium channel blockers. Class Ib agents have fast onset and offset kinetics, meaning that they have little or no effect at slower heart rates, and more effects at faster heart rates. Class Ib agents shorten the action potential duration and reduce refractoriness. These agents will decrease Vmax in partially depolarized cells with fast response action potentials. They either do not change the action potential duration, or they may decrease the action potential duration. Class Ib drugs tend to be much more specific for voltage gated Na channels than Ia. Lidocane in particular is highly frequency dependent, in that it has more activity with increasing heart rates. This is because lidocane selectively blocks Na channels in their open and inactive states and has little binding capability in the resting state.
Class Ib agents are indicated for the treatment of ventricular tachycardia and symptomatic premature ventricular beats, and prevention of ventricular fibrillation.
Class Ib agents include lidocaine, mexiletine, tocainide, and phenytoin.
Class Ic agents
Class Ic antiarrhythmic agents markedly depress the phase 0 depolarization (decreasing Vmax). They decrease conductivity, but have a minimal effect on the action potential duration. Of the sodium channel blocking antiarrhythmic agents (the class I antiarrhythmic agents), the class Ic agents have the most potent sodium channel blocking effects.
Class Ic agents are indicated for life-threatening ventricular tachycardia or ventricular fibrillation, and for the treatment of refractory supraventricular tachycardia (ie: atrial fibrillation). These agents are potentially pro-arrhythmic, especially in settings of structural heart disease (e.g. post-myocardial infarction), and are contraindicated in such settings.
Class Ic agents include encainide, flecainide, moricizine, and propafenone.
Class II agents
Class II agents are conventional beta blockers. They act by selectively blocking the effects of catecholamines at the β1-adrenergic receptors, thereby decreasing sympathetic activity on the heart. These agents are particularly useful in the treatment of supraventricular tachycardias. They decrease conduction through the AV node.
Class II agents include esmolol, propranolol, and metoprolol.
Class III agents
Class III agents predominantly block the potassium channels, thereby prolonging repolarization.[6] Since these agents do not affect the sodium channel, conduction velocity is not decreased. The prolongation of the action potential duration and refractory period, combined with the maintenance of normal conduction velocity, prevent re-entrant arrhythmias. (The re-entrant rhythm is less likely to interact with tissue that has become refractory).
All clinically available class III drugs block IKr, not IKs
Class III antiarrhythmic agents exhibit reverse use dependent prolongation of the action potential duration (Reverse use-dependence). This means that the refractoriness of the ventricular myocyte increases at lower heart rates. This increases the susceptibility of the myocardium to early after-depolarizations (EADs) at low heart rates. Antiarrhythmic agents that exhibit reverse use-dependence are more efficacious at preventing a tachyarrhythmia than converting someone into normal sinus rhythm. Because of the reverse use-dependence of class III agents, at low heart rates class III antiarrhythmic agents may paradoxically be more arrhythmogenic.
Amiodarone is indicated for the treatment of refractory VT or VF, particularly in the setting of acute ischemia. Amiodarone is also safe to use in individuals with cardiomyopathy and atrial fibrillation, to maintain normal sinus rhythm. Amiodarone prolongation of the action potential is uniform over a wide range of heart rates so this drug does not have reverse use-dependent action.7 In contrast, dofetilide blocks only the rapid K channels; this means that at higher heart rates, when there is increased involvement of the slow K channels, dofetilide has less of an action potential-prolonging effect. 7
Sotalol is indicated for the treatment of atrial or ventricular tachyarrhythmias, and AV re-entrant arrhythmias. Ibutilide is the only antiarrhythmic agent currently approved by the Food and Drug Administration for acute conversion of atrial fibrillation to sinus rhythm.
Class III agents include amiodarone, azimilide, bretylium, clofilium, dofetilide, tedisamil, ibutilide, sematilide, and sotalol.
Class IV agents
Class IV agents are slow calcium channel blockers. They decrease conduction through the AV node, and shorten phase two (the plateau) of the cardiac action potential. They thus reduce the contractility of the heart, so may be inappropriate in heart failure. However, in contrast to beta blockers, they allow the body to retain adrenergic control of heart rate and contractility.
Class IV agents include verapamil and diltiazem.
Class V agents
Class V agents include digoxin and adenosine. Digoxin increases vagal activity via its central action on the central nervous system, thus decreasing the conduction of electrical impulses through the AV node
Major Routes of Elimination of Antiarrhythmic drugs
Hepatic: Amiodarone, Propafenone, Lidocaine, Mexilitine, Verapamil, Diltiazem.
Renal: Sotalol, Digoxin, Dofetilide, Bretylium
Mixed: Procainamide, Flecainide (70% hepatic), Quinidine (50-70% hepatic), Ibutilide, Azimilide (not FDA approved)
General Principles of Antiarrhythmic drugs
- All anti-arrhythmic drugs should be considered pro-arrhythmic.
- Pro-arrhythmia increased in presence of structural heart disease, (especially myocardial ischemia and left ventricular systolic dysfunction.
- Beta-adrenoreceptor blockers are the only drug class shown definitively to improve mortality.
- Amiodarone and Dofetilide have neutral impact on mortality following MI and in the presence of structural heart disease.
- Consider altered drug clearance in both renal and hepatic impairment and drug interactions.
Specific Drugs
Digoxin Class 1A
- Infrequently used.
- Used in atrial and ventricular arrhythmias.
- Dosing guided by efficacy, adverse effects, ECG intervals and serum levels (rule of thumb: do not exceed dose that prolongs QRS more than 25% or QT >550ms)\
- Adverse effects
- Nausea (common)
- Vomiting (common)
- Anorexia (common)
- Diarrhea (common)
- Thrombocytopenia (occasionally)
- Marrow suppression (occasionally)
- Lupus (rare)
- Fever
- Pro-arrhythmia (0.5-8%) - dose independent - may occur soon after initiation (i.e. when plasma levels low)
- Drug interactions
- Digoxin - increased Digoxin
- Phenytoin, Rifampicin, Phenobarbital - decreased Quinidine
- Ketoconazole, Azole antifungals - increased Quinidine
Procainamide Class 1A
- Useful for atrial fibrillation, atrial flutter, ventricular tachycardia, ventricular fibrillation.
- 50-60% renal excreted.
- N-acetyl-procainamide (metabolite) renal excretion (therefore adjust dose in renal impairment).
- IV dose 15-20 mg/kg.
- For each 1mg/kg dose given, blood level increases 0.5 mcg/ml.
- Acute IV use largely supplanted by amiodarone.
- Adverse effects
- 25% develop gastrointestinal side effects.
- 80% +ANA.
- 30% develop a lupus like syndrome.
- Do not check ANA unless clinically indicated.
- Pro-arrhythmia (Torsade de Pointes)
- Dose independent (similar to Quinidine).
- Infra-Hisian block.
- Care with Bundle Branch Block and Intra-ventricular conduction delay.
- Accelerated ventricular response to Atrial flutter (use in conjunction with AV nodal blocking agent).
Lidocaine Class 1B
- Voltage dependent sodium channel block (enhanced action in depolarized i.e. ischemic tissue).
- Therefore, useful against arrhythmias in myocardial ischemia.
- Hepatic metabolism proportional to hepatic blood flow.
- Conditions that decrease hepatic blood flow decrease clearance and increase blood levels (toxicity common with Congestive Heart Failure).
Propafenone Class 1C
- Structurally similar to propranolol (also has weak β-blocking action).
- Useful for atrial fibrillation, atrial flutter, SVT.
- Cautious use in VT.
- Hepatic transformation to 5-OH propafenone by P450 2D6 enzyme.
- 7% of United States population deficient in this enzyme.
- Increased propafenone level, increased beta blocker effect, longer half-life.
- Proarrhythmia: increased in the presence of reduced ejection fraction/ischemia.
- May manifest as increased VT.
- Tachycardia provoked proarrhythmia (use dependence)
- Exercise ECG useful screening test.
- Watch for impairment of AV conduction and QRS widening.
- Increases digoxin, warfarin, and metoprolol levels.
Amiodarone
- Not as good as ICD for preventing sudden cardiac death.
- Thyroid toxicity
- Inhibition of T4 de-iodination to T3 leading to accumulation of rT3.
- Hypothyroid (10%); Hyperthyroid (2-12%)
- Hypothyroidism: Treat with exogenous T4 or stop amiodarone.
- Hyperthyroidism: More difficult to treat. Usually need to stop drug and consider specific anti-thyroid agents. Surgical removal of gland if unable to control ir if need to continue drug. I¹³¹ not useful.
- Pulmonary toxicity
- Always consider pulmonary toxicity with worsening CHF despite therapy.
- Diagnosis
- PFT's - low DLCO and low ρO2
- High resolution CT
- Biopsy
- Bronchoalveolar lavage
- Drug interactions
- Warfarin - increased INR.
- Digoxin - increased Digoxin
- Cyclosporine - increased Cyclosporine
Dofetilide
- Pure IKr blocker
- Approved for atrial fibrillation and atrial flutter
- Inpatient loading mandatory due to risk of Torsades de Pointes VT.
- Dosing adjusted by QT interval change (at rest).
- Careful dosing in renal insufficiency (80% renally excreted).
- 20% liver (cytochrome P450)
- Initiation and Dosing
- Plan on atleast 3 days hospitalization or 12 hours after conversion to normal sinus rhythm. (whichever is greater)
- Withdraw/avoid: verapamil, cimetidine, trimethoprim, ketoconazole, prochlorperazine.
- Get potassium >4.0
- Measure QTc: if >440 msec (500 msec w/Intraventricular conduction delay) find another drug.
Ibutilide
- Blocks IKr and slow inactivation of sodium channels (increases atrial refractoriness).
- Mostly used for acute termination of atrial fibrillation and to facilitate cardioversion in resistant cases.
- Good for WPW.
- Risk of Torsades de Pointes VT is 2-3%; higher with advanced LV dysfunction (EF<20%).
- Adjunctive use of magnesium after ibutilide may prevent proarrhythmia.
Dronedarone
- Chemically similar to Amiodarone but has no Iodine (lower risk of pulmonary, liver and thyroid complications).
- Shorter elimination half-life (24 hours versus weeks).
- Indicated for atrial Flutter and atrial fibrillation (not ventricular arrhythmias or sudden death prevention).
- More effective than placebo in maintaining sinus rhythm.
- Reduces hospitalization due to cardiovascular events or death.
- Reduces rate of strokes.
- Contraindicated in
- NYHA class IV heart failure
- NYHA II-III heart failure with recent decompensation requiring hospitalization.
Digoxin
- Still commonly used.
- Effects mediated via central and peripheral augmentation of vagal tone.
- Direct action on atria and AV node only at toxic concentrations.
- Increases sympathetic tone and Calcium loading leading to increased automaticity and delayed afterdeploarisations.
- Electrophysiology
- Inotropic action via inhibition of Na-K ATPase and Na-Ca exchange.
- Minimal effects on surface ECG at therapeutic doses.
- May improve conduction in some accessory pathways (avoid in WPW syndrome).
- No effect on rate of conversion to sinus rhythm in patients with acute episode of atrial fibrillation.
- Rarely effective as sole agent for rate control. Must confirm heart rate control by exercising (aim for heart rate less than 110 with moderate walking).
- Clinical Pharmacology
- 60-80% oral bioavailability (decreased with cholestyramine, antacids, colestipol).
- P-glycoprotein: excretes absorbed digoxin back in to gut lumen (also controls renal elimination).
- Drug interactions
- Quinidine: Increase digoxin levels by displacing from binding sites and inhibiting P-glycoprotein system.
- Amiodarone, Propafenone, Verapamil: decrease renal and non-renal clearance.
- Cyclosporine, anti-fungals, benzodiazepines: inhibit P-glycoprotein.
- Toxicity
- Non-cardiac - anorexia, nausea, vomiting, changes in color vision including scotoma, halo vision and altered color perception.
- Cardiac - due to exaggerated effects on sinus and AV node and intracellular Ca loading causing delayed afterdeploarizations.
- Arrhythmias: almost any, but high grade AV block with accelerated junctional rhythm or bi-directional VT strongly suggestive.
Adenosine
- Activates IK Ado shortens action potential duration (direct effect).
- Decreases cAMP, decreased delayed afterdeploarizations, early afterdepolarizations (indirect effect).
- All actions mediated via A1 receptor and G proteins (not present in ventricle).
- Extensive first pass metabolism.
- Re-uptake blocked by dipyridamole.
- Methylxanthines block A1 receptor.
- Drug interactions
- Dipyridamole: increases effect.
- Methylxanthines: No effect.
- Transplanted heart: increases effect.
Choice of agent in PSVT
- Hypotension, Uncertain diagnosis (especially if WCT), Heart failure - Adenosine
- Dipyridamole, Theophyllines, Bronchoconstriction, Transplanted heart, PSVT recurs post adenosine - Verapamil/Diltiazem
Trials
The Cardiac Arrhythmia Suppression Trial[7] was a medical study that demonstrated that some class 1 anti-arrhythmic drugs were not helpful to people suffering from ventricular premature depolarization. Specifically, for populations of recent heart attack survivors, the study observed lower mortality in a control population than in populations treated with encainide, flecainide or moricizine (all class 1c drugs).
Mnemonics
Mnemonic for Class I-IV agents: SoBe PoCa (SOBE as in South Beach or the drink, POCA as in Polka)
Sodium channel blockers, Beta blockers, Potassium channel blockers, Calcium channel blockers
See also
References
- ↑ Wyse D, Waldo A, DiMarco J, Domanski M, Rosenberg Y, Schron E, Kellen J, Greene H, Mickel M, Dalquist J, Corley S (2002). "A comparison of rate control and rhythm control in patients with atrial fibrillation". N Engl J Med. 347 (23): 1825–33. PMID 12466506.
- ↑ Nichol G, McAlister F, Pham B, Laupacis A, Shea B, Green M, Tang A, Wells G (2002). "Meta-analysis of randomised controlled trials of the effectiveness of antiarrhythmic agents at promoting sinus rhythm in patients with atrial fibrillation". Heart. 87 (6): 535–43. PMID 12010934.
- ↑ "Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. The Cardiac Arrhythmia Suppression Trial (CAST) Investigators". N Engl J Med. 321 (6): 406–12. 1989. PMID 2473403.
- ↑ "Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction. The Cardiac Arrhythmia Suppression Trial II Investigators". N Engl J Med. 327 (4): 227–33. 1992. PMID 1377359.
- ↑ Vaughan Williams EM. "Classification of anti-arrhythmic drugs." In: Symposium on Cardiac Arrhythmias, Sandfte E, Flensted-Jensen E, Olesen KH eds. Sweden, AB ASTRA, Södertälje, 1970;449-472.
- ↑ Lenz TL, Hilleman DE, Department of Cardiology, Creighton University, Omaha, Nebraska. Dofetilide, a New Class III Antiarrhythmic Agent. Pharmacotherapy 20(7):776-786, 2000. (Medline abstract)
- ↑ Entry on Clinical Trials.gov
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