Antiarrhythmic agent

Phases of a cardiac action potential. The sharp rise in voltage ("0") corresponds to the influx of sodium ions, whereas the two decays ("1" and "3", respectively) correspond to the sodium-channel inactivation and the repolarizing eflux of potassium ions. The characteristic plateau ("2") results from the opening of voltage-sensitive calcium channels.

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 Vaughan Williams classification was introduced in 1970. As a doctoral candidate at Oxford University working in the lab of Vaughan Williams, 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).

With regards to management of atrial fibrillation, Class I and III are used in rhythm control as medical cardioversion agents while Class II and IV are used as rate control agents.

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 in cardiology [1]
Ia	fast-channel blockers-affect QRS complex	Quinidine Ajmaline Procainamide Disopyramide	(Na^+) channel block (intermediate association/dissociation) and K+ channel blocking effect.	Ventricular arrhythmias prevention of paroxysmal recurrent atrial fibrillation (triggered by vagal overactivity) procainamide in Wolff-Parkinson-White syndrome Increases QT interval
Ib	Can prolong QRS in overdose	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
Ic		Encainide 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	Carvedilol Propranolol Esmolol Timolol Metoprolol Atenolol Bisoprolol Template:Nebivolol	beta blocking Propranolol also shows some class I action	decrease myocardial infarction mortality prevent recurrence of tachyarrhythmias propranolol has sodium channel blocking effects
III		Amiodarone Sotalol Ibutilide Dofetilide Dronedarone E-4031	K^+ channel blocker Sotalol is also a beta blocker[2] Amiodarone has Class I, II, III & IV activity	In Wolff-Parkinson-White syndrome (sotalol:) ventricular tachycardias and atrial fibrillation (Ibutilide:) atrial flutter and atrial fibrillation (amiodarone): haemodynamically stable ventricular tachycardia[3]
IV	slow-channel blockers	Verapamil Diltiazem	Ca^2+ 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 torsades de pointes.

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' 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.)

Class I agents are divided into three groups (Ia, Ib and Ic) based upon their effect on the length of the action potential.^[4][5]

• 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.^[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). Drugs include: bretylium, amiodarone, ibutilide, sotalol, dofetilide, and dronedarone. 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.

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 / Other agents

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.

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, via indirect action, leads to an increase in acetylcholine production, stimulating M3 receptors on AV node leading to an overall decrease in speed of conduction.
• Adenosine, used intravenously for terminating supraventricular tachycardias.^[7] IV adenosine can also be used to differentiate between atrial fibrillation and PSVT
• Magnesium sulfate, an antiarrhythmic drug, but only against very specific arrhythmias ^[8] which has been used for torsades de pointes.^[9][10]
• Trimagnesium Dicitrate (anhydrous) as powder or powder caps in pure condition, better bioavailability then ordinary MgO.^[11]

Sicilian Gambit classification

Another approach, known as the "Sicilian Gambit", placed a greater approach on the underlying mechanism.^[12][13][14]

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.^[15]

See also

• Action potential
  • Cardiac action potential
• Cardiac Arrhythmia Suppression Trial (CAST)
• Electrocardiogram
• Proarrhythmic agent

References

1. Unless else specified in boxes, then ref is: Rang, H. P. (2003). 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.
3. "protocol for management of haemodynamically stable ventricular tachycardia - General Practice Notebook". www.gpnotebook.co.uk. Retrieved 2016-02-09.
4. 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.
5. 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.
6. 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.
7. 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.
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.
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. doi:10.1080/07315724.2004.10719388. 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.
11. 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. PMID 2407766.
12. "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.
13. 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.
14. "Milestones in the Evolution of the Study of Arrhythmias". Retrieved 2008-07-31.
15. Fogoros, Richard N. (1997). Antiarrhythmic drugs: a practical guide. Oxford: Blackwell Science. p. 49. ISBN 0-86542-532-9.