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a drug used to treat an abnormal heart rhythm (同)antiarrhythmic_drug, antiarrhythmic medication

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/05/23 20:07:03」(JST)

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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 Singh Vaughan Williams classification was introduced in 1970. As a doctoral candidate at Oxford University working in the lab of Vaughan Williams, Dr. Bramah 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). See Singh BN, Vaughan Williams EM (1970). "The effect of amiodarone, a new anti-anginal drug, on cardiac muscle". Br. J. Pharmacol. 39 (4): 657–67. doi:10.1111/j.1476-5381.1970.tb09891.x. PMC 1702721. PMID 5485142.

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 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	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	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
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 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.^[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: 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.

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 ^[6]
Magnesium sulfate, an antiarrhythmic drug, but only against very specific arrhythmias ^[7] which has been used for torsades de pointes.^[8]^[9]

Sicilian Gambit classification

Another approach, known as the "Sicilian Gambit", placed a greater approach on the underlying mechanism.^[10]^[11]^[12]

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.^[13]

References

^ Unless else specified in boxes, then ref is: Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. ISBN 0-443-07145-4.
^ 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.
^ 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, Department of Cardiology, Creighton University, Omaha, Nebraska. Dofetilide, a New Class III Antiarrhythmic Agent. Pharmacotherapy 20(7):776–786, 2000. (Medline abstract)
^ 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.
^ "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.

UpToDate Contents

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1. 心筋活動電位および抗不整脈剤の作用 myocardial action potential and action of antiarrhythmic drugs
2. I群抗不整脈薬の主な副作用 major side effects of class i antiarrhythmic drugs
3. 心房細動患者における洞調律維持のための抗不整脈剤：推奨 antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation recommendations
4. 心房細動患者における洞調律維持のための抗不整脈薬：臨床試験 antiarrhythmic drugs to maintain sinus rhythm in patients with atrial fibrillation clinical trials
5. 心筋梗塞後の患者における心室性不整脈に対する抗不整脈剤の役割 role of antiarrhythmic drugs for ventricular arrhythmias in patients with a prior myocardial infarction

English Journal

Therapeutic Drugs that Slow the Heart Rate of Early Rat Embryos. Is there a Risk for the Human?

Webster WS, Nilsson M, Ritchie H.Author information Discipline of Anatomy and Histology, Sydney Medical School, University of Sydney, Sydney, NSW 2006, Australia. bill.webster@sydney.edu.au.AbstractDuring the organogenic period of development the cardiovascular system of the embryo fulfills several functions including delivery of oxygen and nutrients and a hemodynamic role necessary for cardiac morphogenesis, angiogenesis and hematopoiesis. It is expected that at each stage of embryonic development there is an ideal embryonic heart rate and contractility that maintains the optimal blood flow and pressure to fulfill these various functions. In vitro rat embryo culture studies have revealed that many therapeutic drugs (antiarrhythmics, antidepressants, antipsychotics and anticonvulsants), that may be taken during human pregnancy, cause a concentration-dependent slowing of the embryonic heart and irregular heart rate at higher concentrations. The concentrations causing bradycardia in vitro are often close to human therapeutic plasma concentrations and raise concern that these drugs can potentially cause embryonic death or malformations, and that current reproductive toxicity testing does not adequately examine possible effects of drugs on the embryo's cardiac function.
Current pharmaceutical design.Curr Pharm Des.2014 Feb 5. [Epub ahead of print]
During the organogenic period of development the cardiovascular system of the embryo fulfills several functions including delivery of oxygen and nutrients and a hemodynamic role necessary for cardiac morphogenesis, angiogenesis and hematopoiesis. It is expected that at each stage of embryonic develo
PMID 24502593

Sidedness of carbamazepine accessibility to voltage-gated sodium channels.

Jo S, Bean BP.Author information Department of Neurobiology, Harvard Medical School, Boston, Massachusetts.AbstractVoltage-gated sodium channels are inhibited by many local anesthetics, antiarrhythmics, and antiepileptic drugs. The local anesthetic lidocaine appears to be able to access its binding site in the sodium channel only from the membrane phase or from the internal face of the channel. In contrast, the antiepileptic drug carbamazepine was found to inhibit voltage-gated sodium channels only with external, but not internal, application, implying a major difference. We investigated this point using both whole-cell and inside-out patch recordings from human Na(v)1.7 channels in a stable cell line. In the whole-cell configuration, carbamazepine inhibited sodium current within seconds when applied externally, but had little or no effect when applied internally for up to 15 minutes, confirming previous results. However, carbamazepine inhibited sodium channels effectively and rapidly when applied to the internal face of the membrane using inside-out patch recording. We found that lidocaine also has little or no effect when applied intracellularly in whole-cell recording, but blocks effectively and rapidly when applied to the internal surface using inside-out patches. In contrast, the cationic lidocaine derivative QX-314 (N-ethyl-lidocaine) blocks effectively when applied internally with whole-cell dialysis, as well as when applied to inside-out patches. We conclude that carbamazepine and lidocaine access the sodium channel in similar ways and hypothesize that their lack of effect with internal dialysis in whole-cell recording reflects rapid exit through membrane near the pipette recording site. This effect likely limits the ability of any compound with significant membrane permeability to be applied intracellularly by whole-cell dialysis.
Molecular pharmacology.Mol Pharmacol.2014 Feb;85(2):381-7. doi: 10.1124/mol.113.090472. Epub 2013 Dec 6.
Voltage-gated sodium channels are inhibited by many local anesthetics, antiarrhythmics, and antiepileptic drugs. The local anesthetic lidocaine appears to be able to access its binding site in the sodium channel only from the membrane phase or from the internal face of the channel. In contrast, the
PMID 24319110

Role of small-conductance calcium-activated potassium channels in atrial electrophysiology and fibrillation in the dog.

Qi XY, Diness JG, Brundel BJ, Zhou XB, Naud P, Wu CT, Huang H, Harada M, Aflaki M, Dobrev D, Grunnet M, Nattel S.Author information Research Center (X.-Y.Q., P.N., C.-T.W., H.H., M.H., M.A., S.N.), Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada; Cardiac and Circulatory Research Section (J.G.D., M.G.), Faculty of Health Sciences, University of Copenhagen and Acesion Pharma, Copenhagen, Denmark; Department of Clinical Pharmacology (B.J.J.M.B.), University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Division of Experimental Cardiology (X.-B.Z., D.D.), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany; Chang-Gung Memorial Hospital and University Taoyuan (C.-T.W.), Taoyuan, Taiwan, China; Institute of Pharmacology (D.D.), Faculty of Medicine, University Duisburg-Essen, Essen, Germany.AbstractBACKGROUND: Recent evidence points to functional Ca(2+)-dependent K(+) (SK) channels in the heart that may govern atrial fibrillation (AF) risk, but the underlying mechanisms are unclear. This study addressed the role of SK channels in atrial repolarization and AF persistence in a canine AF model.
Circulation.Circulation.2014 Jan 28;129(4):430-40. doi: 10.1161/CIRCULATIONAHA.113.003019. Epub 2013 Nov 4.
BACKGROUND: Recent evidence points to functional Ca(2+)-dependent K(+) (SK) channels in the heart that may govern atrial fibrillation (AF) risk, but the underlying mechanisms are unclear. This study addressed the role of SK channels in atrial repolarization and AF persistence in a canine AF model.ME
PMID 24190961

Japanese Journal

外傷性ショックが疑われたフレカイニド中毒の1例

田原慎太郎,小野雄一郎,当麻美樹
日本集中治療医学会雑誌 21(5), 506-510, 2014
外傷性ショックとして搬送されたフレカイニド中毒の1症例を経験したので報告する。症例は89歳の男性，原付自転車乗車中に自損転倒し，救急搬送された。来院時意識清明であったが，収縮期血圧60 mmHg台，心拍数75 /minの非常に幅広いQRS波形の心室調律を認めた。血圧の低下は心室調律によるものと判断し，電気的除細動を試みたが奏効せず，アミオダロンの静脈内投与で洞調律へ復帰した。原因精査に冠動脈造影も …
NAID 130004691322

Impact of Medical Treatment on Long-Term Results after Surgical Ablation of Atrial Fibrillation in Cardiac Surgical Patients

, , , ,
Annals of Thoracic and Cardiovascular Surgery 20(3), 207-212, 2014
… Long-term results, up to 4 years, and postablation antiarrhythmics were evaluated. … At discharge, 53% of patients on antiarrhythmics and 55%, not on AADs were free of AF. …
NAID 130003377877