Antiarrhythmic agent

The cardiac action potential

Antiarrhythmic agents are a group of pharmaceuticals that are used to suppress abnormal rhythms of the heart (cardiac arrhythmias), such as atrial fibrillation, atrial flutter, ventricular tachycardia, and ventricular fibrillation.

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.

Singh Vaughan Williams classification

The Singh Vaughan Williams classification, introduced in 1970 based on the seminal work of Bramah N. Singh in his doctoral thesis at Oxford where Vaughan Williams was his advisor and on subsequent work by Singh and his colleagues in the United States, 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 Singh-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 Singh-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.^{[citation needed]}

There are five main classes in the Singh Vaughan Williams classification of antiarrhythmic agents:

• Class I agents interfere with the sodium (Na⁺) channel.
• Class II agents are anti-sympathetic nervous system agents. Most agents in this class are beta blockers.
• Class III agents affect potassium (K⁺) efflux.
• Class IV agents affect calcium channels and the AV node.
• Class V agents work by other or unknown mechanisms.

Overview table

Class	Known as	Examples	Mechanism	Clinical uses [1]
Ia	fast-channel blockers-Affect QRS complex	Quinidine Procainamide Disopyramide	(Na+) channel block (intermediate association/dissociation)	Ventricular arrhythmias prevention of paroxysmal recurrent atrial fibrillation (triggered by vagal overactivity) procainamide in Wolff-Parkinson-White syndrome
Ib- Do not affect QRS complex		Lidocaine Phenytoin Mexiletine Tocainide	(Na+) 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 Moricizine	(Na+) channel block (slow association/dissociation)	prevents paroxysmal atrial fibrillation treats recurrent tachyarrhythmias of abnormal conduction system. contraindicated immediately post-myocardial infarction.
II	Beta-blockers	Propranolol Esmolol Timolol Metoprolol Atenolol Bisoprolol	beta blocking Propranolol also shows some class I action	decrease myocardial infarction mortality prevent recurrence of tachyarrhythmias
III		Amiodarone Sotalol Ibutilide Dofetilide Dronedarone E-4031	K+ channel blocker Sotalol is also a beta blocker[2] Amiodarone has Class I, II, and III activity	In Wolff-Parkinson-White syndrome (sotalol:) ventricular tachycardias and atrial fibrillation (Ibutilide:) atrial flutter and atrial fibrillation
IV	slow-channel blockers	Verapamil Diltiazem	Ca2+ channel blocker	prevent recurrence of paroxysmal supraventricular tachycardia reduce ventricular rate in patients with atrial fibrillation
V		Adenosine Digoxin Magnesium Sulfate	Work by other or unknown mechanisms (Direct nodal inhibition).	Used in supraventricular arrhythmias, especially in Heart Failure with Atrial Fibrillation, contraindicated in ventricular arrhythmias. Or in the case of Magnesium Sulfate, used in Torsade de Pointe.

Class I agents

The class I antiarrhythmic agents interfere with the sodium channel. Class I agents are grouped by what effect they have on the Na⁺ channel, and what effect they have on cardiac action potentials.

Class I 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 II agents like propranolol also have a membrane stabilizing effect.)

Class I agents are divided into three groups (Ia, Ib and Ic) based upon their effect on the length of the action potential.^[3][4]

• Ia lengthens the action potential (right shift)
• Ib shortens the action potential (left shift)
• Ic does not significantly affect the action potential (no shift)

• 

  Class Ia

• 

  Class Ib

• 

  Class Ic

Class II agents

Class II agents are conventional beta blockers. They act by 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 atenolol, esmolol, propranolol, and metoprolol.

Class III agents

Class III

Class III agents predominantly block the potassium channels, thereby prolonging repolarization.^[5] 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). Drugs include: amiodarone, ibutilide, sotalol, dofetilide, and dronedarone.

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.

Other agents ("Class V")

Since the development of the original Vaughan-Williams classification system, additional agents have been used that don't fit cleanly into categories I through IV.

Some sources use the term "Class V".^[6] However, they are more frequently identified by their precise mechanism.

Agents include:

• Digoxin, which decreases conduction of electrical impulses through the AV node and increases vagal activity via its central action on the central nervous system.
• Adenosine^[7]
• Magnesium sulfate,^[8] which has been used for torsades de pointes.^[9][10]

Sicilian Gambit classification

Another approach, known as the "Sicilian Gambit", placed a greater approach on the underlying mechanism.^[11][12][13]

It presents the drugs on two axes, instead of one, and is presented in tabular form. On the Y axis, each drug is listed, in approximately the Vaughan Williams order. On the X axis, the channels, receptors, pumps, and clinical effects are listed for each drug, with the results listed in a grid. It is therefore not a true classification in that it does not aggregate drugs into categories.^[14]

See also

• Action potential
  • Cardiac action potential
• Electrocardiogram
• Proarrhythmic agent

References

1. ^ Unless else specified in boxes, then ref is: Rang, H. P.. Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4. 
2. ^ Kulmatycki KM, Abouchehade K, Sattari S, Jamali F (May 2001). "Drug-disease interactions: reduced beta-adrenergic and potassium channel antagonist activities of sotalol in the presence of acute and chronic inflammatory conditions in the rat". Br. J. Pharmacol. 133 (2): 286–94. doi:10.1038/sj.bjp.0704067. PMC 1572777. PMID 11350865. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1572777. 
3. ^ Milne JR, Hellestrand KJ, Bexton RS, Burnett PJ, Debbas NM, Camm AJ (February 1984). "Class 1 antiarrhythmic drugs--characteristic electrocardiographic differences when assessed by atrial and ventricular pacing". Eur. Heart J. 5 (2): 99–107. PMID 6723689. http://eurheartj.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=6723689. 
4. ^ Trevor, Anthony J.; Katzung, Bertram G. (2003). Pharmacology. New York: Lange Medical Books/McGraw-Hill, Medical Publishing Division. pp. 43. ISBN 0-07-139930-5. 
5. ^ 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)
6. ^ Fogoros, Richard N. (1999). Electrophysiologic testing. Oxford: Blackwell Science. pp. 27. ISBN 0-632-04325-3. 
7. ^ Conti JB, Belardinelli L, Utterback DB, Curtis AB (March 1995). "Endogenous adenosine is an antiarrhythmic agent". Circulation 91 (6): 1761–7. PMID 7882485. http://circ.ahajournals.org/cgi/pmidlookup?view=long&pmid=7882485. 
8. ^ Brugada P (July 2000). "Magnesium: an antiarrhythmic drug, but only against very specific arrhythmias". Eur. Heart J. 21 (14): 1116. doi:10.1053/euhj.2000.2142. PMID 10924290. http://eurheartj.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=10924290. 
9. ^ Hoshino K, Ogawa K, Hishitani T, Isobe T, Eto Y (October 2004). "Optimal administration dosage of magnesium sulfate for torsades de pointes in children with long QT syndrome". J Am Coll Nutr 23 (5): 497S–500S. PMID 15466950. http://www.jacn.org/cgi/pmidlookup?view=long&pmid=15466950. 
10. ^ Hoshino K, Ogawa K, Hishitani T, Isobe T, Etoh Y (April 2006). "Successful uses of magnesium sulfate for torsades de pointes in children with long QT syndrome". Pediatr Int 48 (2): 112–7. doi:10.1111/j.1442-200X.2006.02177.x. PMID 16635167. http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=1328-8067&date=2006&volume=48&issue=2&spage=112. 
11. ^ "The 'Sicilian Gambit'. A new approach to the classification of antiarrhythmic drugs based on their actions on arrhythmogenic mechanisms. The Task Force of the Working Group on Arrhythmias of the European Society of Cardiology". Eur. Heart J. 12 (10): 1112–31. October 1991. PMID 1723682. http://eurheartj.oxfordjournals.org/cgi/pmidlookup?view=long&pmid=1723682. 
12. ^ Vaughan Williams EM (November 1992). "Classifying antiarrhythmic actions: by facts or speculation". J Clin Pharmacol 32 (11): 964–77. PMID 1474169. http://jcp.sagepub.com/cgi/pmidlookup?view=long&pmid=1474169. 
13. ^ "Milestones in the Evolution of the Study of Arrhythmias". http://www.medscape.com/viewarticle/412798_3. Retrieved 2008-07-31. ^{[dead link]}
14. ^ Fogoros, Richard N. (1997). Antiarrhythmic drugs: a practical guide. Oxford: Blackwell Science. pp. 49. ISBN 0-86542-532-9.