Antiarrhythmic agent 618938 224216348 2008-07-07T21:06:35Z 132.192.46.237 /* Overview table */ '''Antiarrhythmic agents''' are a group of [[pharmaceutical]]s 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.<ref>{{cite journal | author = Wyse D, Waldo A, DiMarco J, Domanski M, Rosenberg Y, Schron E, Kellen J, Greene H, Mickel M, Dalquist J, Corley S | title = A comparison of rate control and rhythm control in patients with atrial fibrillation | journal = N Engl J Med | volume = 347 | issue = 23 | pages = 1825–33 | year = 2002 | pmid = 12466506}}</ref><ref>{{cite journal | author = Nichol G, McAlister F, Pham B, Laupacis A, Shea B, Green M, Tang A, Wells G | title = Meta-analysis of randomised controlled trials of the effectiveness of antiarrhythmic agents at promoting sinus rhythm in patients with atrial fibrillation | journal = Heart | volume = 87 | issue = 6 | pages = 535–43 | year = 2002 | pmid = 12010934 | doi = 10.1136/heart.87.6.535}}</ref> 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,<ref>{{cite journal | author = | title = 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 | journal = N Engl J Med | volume = 321 | issue = 6 | pages = 406–12 | year = 1989 | pmid = 2473403}}</ref><ref>{{cite journal | author = | title = Effect of the antiarrhythmic agent moricizine on survival after myocardial infarction. The Cardiac Arrhythmia Suppression Trial II Investigators | journal = N Engl J Med | volume = 327 | issue = 4 | pages = 227–33 | year = 1992 | pmid = 1377359}}</ref> 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 [[atrial flutter|flutter]]. 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 [[cardiac arrest|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). [[Image:action potential.png|thumb|275px|The cardiac action potential]] 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,<ref>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.</ref> 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]]&mdash;a class Ia agent whose metabolite [[N-acetyl procainamide]] (NAPA) has a class III action&mdash;is one such example. A historical limitation was that drugs such as [[digoxin]] and [[adenosine]] &ndash; important antiarrhythmic agents &ndash; had no place at all in the VW classification system. This has since been rectified by the inclusion of class V.{{Fact|date=September 2007}} There are five main classes in the Vaughan Williams classification of antiarrhythmic agents: * Class I agents interfere with the [[sodium]] (Na<sup>+</sup>) channel. * Class II agents are anti-[[sympathetic nervous system]] agents. Most agents in this class are [[beta blockers]]. * Class III agents affect [[potassium]] (K<sup>+</sup>) efflux. * Class IV agents affect [[calcium]] channels and the [[AV node]]. * Class V agents work by other or unknown mechanisms. ===Overview table=== {| class="wikitable" |- !Class !Examples !Mechanism !Clinical uses <ref name=Rangunless> Unless else specified in boxes, then ref is: {{cite book |author=Rang, H. P. |title=Pharmacology |publisher=Churchill Livingstone |location=Edinburgh |year=2003 |pages= |isbn=0-443-07145-4 |oclc= |doi=}} </ref> |- !Ia | *[[disopyramide]] *[[procainamide]] *[[quinidine]] | [[sodium channel|(Na<sup>+</sup>) channel]] block (intermediate association/dissociation) | *[[Ventricular arrhythmia]]s *prevention of paroxysmal [[recurrent atrial fibrillation]] (triggered by [[vagus nerve|vagal]] overactivity), *procainamide in [[Wolff-Parkinson-White syndrome]] |- !Ib | *[[lidocaine]] *[[phenytoin]] | [[sodium channel|(Na<sup>+</sup>) channel]] block (fast association/dissociation) | *treatment and prevention during and immediately after [[myocardial infarction]], though this practice is now discouraged given the increased risk of asystole **[[ventricular tachycardia]] **[[atrial fibrillation]] |- !Ic | *[[flecainide]] *[[propafenone]] |[[sodium channel|(Na<sup>+</sup>) channel]] block (slow association/dissociation) | *prevents [[paroxysmal atrial fibrillation]] *treats [[recurrent tachyarrhythmias]] of abnormal [[Electrical conduction system of the heart|conduction system]]. |- !II | *[[propranolol]] *[[timolol]] *[[metoprolol]] *[[sotalol]] *[[atenolol]] | [[beta blocker|beta blocking]] | *decrease [[myocardial infarction]] mortality *prevent recurrence of [[tachyarrhythmia]]s |- !III | *[[amiodarone]] *[[sotalol]] *[[bretylium]] -no longer manufactured *[[nibentan]] * dofetilide | [[potassium channel|K<sup>+</sup> channel]] block | *In [[Wolff-Parkinson-White syndrome]] *(sotalol:) [[ventricular tachycardias]] and [[atrial fibrillation]] *(nibentan:) [[atrial flutter]] and [[atrial fibrillation]] |- !IV | *[[verapamil]] *[[diltiazem]] |[[calcium channel|Ca<sup>2+</sup> channel]] block | *prevent recurrence of [[paroxysmal supraventricular tachycardia]] *reduce [[ventricular rate]] in patients with [[atrial fibrillation]] |} === Class I agents === <!--Class I antiarrhythmic agent redirects here--> The class I antiarrhythmic agents interfere with the [[sodium channel|(Na<sup>+</sup>) channel]]. Class I agents are grouped by what effect they have on the Na<sup>+</sup> channel, and what effect they have on cardiac [[action potential]]s. Class 1 agents are called Membrane Stabilizing agents. The 'stabilizing' is the word used to describe the decrease of excitogenicity of the plasma membrane which is brought about by these agents. Also noteworthy is that a few class 2 agents like propranolol also have a [[membrane stabilizing effect]]. ==== Class Ia agents ==== [[Image:Action potential Class Ia.png|thumb|275px|Class Ia agent decreasing V<sub>max</sub>, thereby increasing action potential duration.]] Class Ia agents block the fast sodium channel. Blocking this channel depresses the phase 0 depolarization (reduces V<sub>max</sub>), which prolongs the action potential duration by slowing conduction. Agents in this class also cause decreased conductivity and increased [[Refractory period (cardiac)|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 [[tachycardia]]s. Oral procainamide is no longer being manufactured in the US. Intravenous formulations are still available. 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 agent redirects here--> [[Image:Action potential Class Ib.png|thumb|275px|Effect of class Ib antiarrhythmic agents on the cardiac action potential.]] 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 V<sub>max</sub> 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. [[Lidocaine]] in particular is highly frequency dependent, in that it has more activity with increasing heart rates. This is because lidocaine 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 ==== [[Image:Action potential Class Ic.png|thumb|275px|Effect of class Ic antiarrhythmic agent on cardiac action potential.]] Class Ic antiarrhythmic agents markedly depress the phase 0 depolarization (decreasing V<sub>max</sub>). 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]]. Encainide is not available in the US. === Class II agents === Class II agents are conventional [[beta blockers]]. They act by blocking the effects of [[catecholamine]]s at the [[Adrenergic receptor#Type .CE.B21|β<sub>1</sub>-adrenergic receptor]]s, thereby decreasing sympathetic activity on the heart. These agents are particularly useful in the treatment of [[supraventricular tachycardia]]s. They decrease conduction through the [[AV node]]. Class II agents include [[atenolol]], [[esmolol]], [[propranolol]], and [[metoprolol]]. === Class III agents === [[Image:Action potential Class III.png|thumb|275px|Effect of class III antiarrhythmic agent on cardiac action potential.]] Class III agents predominantly block the potassium channels, thereby prolonging repolarization.<ref>Lenz TL, Hilleman DE, Department of Cardiology, Creighton University, Omaha, Nebraska. Dofetilide, a New Class III Antiarrhythmic Agent. Pharmacotherapy 20(7):776-786, 2000. ([http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=10907968 Medline abstract])</ref> 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). 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 rate]]s. 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 [[Ventricular tachycardia|VT]] or [[Ventricular fibrillation|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.<sup>7</sup> 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. <sup>7</sup> 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 blocker]]s. 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. It should be noted that Class V agents are not part of the original Vaughan-Williams classification system. ==Trials== The ''Cardiac Arrhythmia Suppression Trial''<ref>[http://www.clinicaltrials.gov/ct/show/NCT00000526 Entry on Clinical Trials.gov]</ref> was a medical study that demonstrated that some class 1 anti-arrhythemic 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) Also - remembering that of all anti-arrhythmics "some block potassium channels" can help you: Class I "Some" = S = Sodium Class II "Block" = B =Beta blockers Class III "Potassium" = Potassium channel blockers Class IV "Channels" = C =Calcium channel blockers Sodium channel blockers, Beta blockers, Potassium channel blockers, Calcium channel blockers To remember the Class I agents: Class IA “Double Quarter Pounder” (Disopyramide, Quinidine, Procainamide), Class IB “Lettuce, Tomato, Mayo” (Lidocaine, Tocainide, Mexilitine), Class IC “More Fries Please” (Moricizine, Flecainide, Propafenone). To remember the Class III agents: "A Big Dog Is Scary" (Amiodarone, Bretylium, Dofetilide, Ibutilide, Sotalol). Dr. Hrometz 2008, Ohio Northern University == See also == *[[Action potential]] **[[Cardiac action potential]] *[[Electrocardiogram]] *[[Plasma membrane Stabilization]] == References == {{reflist|2}} {{Antiarrhythmic agents}} {{Major Drug Groups}} [[Category:Antiarrhythmic agents|*]] [[Category:Cardiac electrophysiology]] [[ca:Antiarítmic]] [[de:Antiarrhythmikum]] [[es:Agente antiarrítmico]] [[fr:Antiarythmique]] [[hr:Antiaritmici]] [[hu:Antiarritmiás szerek]] [[ja:抗不整脈薬]] [[pl:Leki antyarytmiczne]] [[pt:Antiarrítmico]]