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 was introduced in 1970. As a doctoral candidate at Oxford University, Dr. Bramah N. Singh determined that amiodarone and sotalol had antiarrhythmic properties and belonged to a new class of antiarrhythmic agents (what would become the class III antiarrhythmic agents). Singh developed part of the classification system while working in the lab of Miles Vaughan Williams and part of the system after leaving Oxford. Singh subsequently pioneered the use of these agents at bedside over the next several decades of practice in the United States.
With regards to management of atrial fibrillation, classes I and III are used in rhythm control as medical cardioversion agents, while classes II and IV are used as rate-control agents.
The five main classes in the Singh-Vaughan Williams classification of antiarrhythmic agents are:
- 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.
|Class||Known as||Examples||Mechanism||Medical uses |
|Ia||fast-channel blockers-affect QRS complex||(Na+) channel block (intermediate association/dissociation) and K+ channel blocking effect|
|Ib||Can prolong QRS in overdose||Na+ channel block (fast association/dissociation)|
|Ic||Na+ channel block (slow association/dissociation)|
Propranolol also shows some class I action
|III||K+ channel blocker|
|IV||Slow-channel blockers||Ca2+ channel blocker|
|V||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 torsades de pointes.|
Class I agents
Class I agents are called membrane-stabilizing agents. The 'stabilizing' word is 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.)
- 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 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 III agents
Class III agents predominantly block the potassium channels, thereby prolonging repolarization. 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). The class III agents exhibit reverse-use dependence (their potency increases with slower heart rates, and therefore improves maintenance of sinus rhythm). Inhibiting potassium channels, slowing repolarization, results in slowed atrial-ventricular myocyte repolarization. Class III agents have the potential to prolong the QT interval of the EKG, and may be proarrhythmic (more associated with development of polymorphic VT).
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 V / other agents
Since the development of the original Singh-Vaughan Williams classification system, additional agents have been used that do not fit cleanly into categories I through IV.
- Digoxin, which decreases conduction of electrical impulses through the AV node and increases vagal activity via its central action on the central nervous system, via indirect action, leads to an increase in acetylcholine production, stimulating M2 receptors on AV node leading to an overall decrease in speed of conduction.
- Adenosine is used intravenously for terminating supraventricular tachycardias.
- Magnesium sulfate, an antiarrhythmic drug, but only against very specific arrhythmias  which has been used for torsades de pointes.
- Trimagnesium dicitrate (anhydrous) as powder or powder caps in pure condition, better bioavailability than ordinary MgO
Sicilian gambit classification
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 roughly the Singh-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.
- Action potential
- Cardiac Arrhythmia Suppression Trial (CAST)
- Proarrhythmic agent
- Kloner RA (2009). "A Salute to Our Founding Editor-in-Chief Bramah N. Singh, MD, DPhil, DSc, FRCP". Journal of cardiovascular pharmacology and therapeutics. 14 (3): 154–156. doi:10.1177/1074248409343182.
- Unless else specified in boxes, then ref is: Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4.[page needed]
- 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 . PMID 11350865.
- "protocol for management of haemodynamically stable ventricular tachycardia - General Practice Notebook". www.gpnotebook.co.uk. Retrieved 2016-02-09.
- 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.
- Trevor, Anthony J.; Katzung, Bertram G. (2003). Pharmacology. New York: Lange Medical Books/McGraw-Hill, Medical Publishing Division. p. 43. ISBN 0-07-139930-5.
- Lenz, TL; Hilleman, DE (2000). "Dofetilide, a New Class III Antiarrhythmic Agent". Pharmacotherapy. 20 (7): 776–786. doi:10.1592/phco.20.9.776.35208. PMID 10907968.
- Conti JB, Belardinelli L, Utterback DB, Curtis AB (March 1995). "Endogenous adenosine is an antiarrhythmic agent". Circulation. 91 (6): 1761–7. doi:10.1161/01.cir.91.6.1761. PMID 7882485.
- 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.
- 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. doi:10.1080/07315724.2004.10719388. PMID 15466950.
- 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.
- Lindberg JS, Zobitz MM, Poindexter JR, Pak CY (1990). "Magnesium bioavailability from magnesium citrate and magnesium oxide". Journal of the American College of Nutrition. 9 (1): 48–55. doi:10.1080/07315724.1990.10720349. PMID 2407766.
- "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.
- Vaughan Williams EM (November 1992). "Classifying antiarrhythmic actions: by facts or speculation". J Clin Pharmacol. 32 (11): 964–77. doi:10.1002/j.1552-4604.1992.tb03797.x. PMID 1474169.
- "Milestones in the Evolution of the Study of Arrhythmias". Retrieved 2008-07-31.[dead link]
- Fogoros, Richard N. (1997). Antiarrhythmic drugs: a practical guide. Oxford: Blackwell Science. p. 49. ISBN 0-86542-532-9.