Editing Antiarrhythmic agent (section)

==Vaughan Williams classification==
The '''Vaughan Williams classification'''<ref>{{cite book |last1=Rang |first1=Humphrey P. |last2=Ritter |first2=James M. |last3=Flower |first3=Rod J. |last4=Henderson |first4=Graeme |title=Rang and Dale's pharmacology |date=2012 |publisher=Elsevier |isbn=9780702034718 |page=255 |edition=7th}}</ref> was introduced in 1970 by [[Miles Vaughan Williams]].<ref name=VW70>Vaughan Williams, EM (1970) "Classification of antiarrhythmic drugs". In ''Symposium on Cardiac Arrhythmias'' (Eds. Sandoe E; Flensted-Jensen E; Olsen KH). Astra, Elsinore. Denmark (1970){{ISBN?}}</ref>

Vaughan Williams was a pharmacology tutor at [[Hertford College]], Oxford. One of his students, [[Bramah N. Singh]],<ref>{{cite journal | vauthors = Kloner RA | year = 2009 | title = A Salute to Our Founding Editor-in-Chief Bramah N. Singh, MD, DPhil, DSc, FRCP | journal = Journal of Cardiovascular Pharmacology and Therapeutics | volume = 14 | issue = 3| pages = 154–156 | doi=10.1177/1074248409343182| pmid = 19721129 | s2cid = 44733401 | doi-access = free }}</ref> contributed to the development of the classification system. The system is therefore sometimes known as the '''Singh-Vaughan Williams classification'''.

The five main classes in the Vaughan Williams classification of antiarrhythmic agents are:
* '''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.

With regard 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.

{| class="wikitable"
|-
!Class
!Known as
!Examples
!Mechanism
!Medical 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 |isbn=978-0-443-07145-4 }}{{page needed|date=January 2016}}</ref>
|-
!Ia
|Fast sodium channel blockers
|
* [[Ajmaline]]
* [[Disopyramide]]
* [[Procainamide]]
* [[Quinidine]]
* [[Sparteine]]
| [[sodium channel|Na<sup>+</sup> channel]] block (intermediate association/dissociation) and K+ channel blocking effect.
Class Ia drugs prolong the action potential and has an intermediate effect on the 0 phase of depolarization.
|
* Increase QT interval
* Prevent paroxysmal recurrent [[atrial fibrillation]] triggered by [[vagus nerve|vagal]] overactivity
* Treat ventricular [[arrhythmia]]
* Treat [[Wolff-Parkinson-White syndrome]] (procainamide with caution)
|-
!Ib
|
|
* [[Lidocaine]]
* [[Mexiletine]]
* [[Phenytoin]]
* [[Tocainide]]
| Na<sup>+</sup> channel block (fast association/dissociation).
Class Ib drugs shorten the action potential of myocardial cell and has a weak effect on the initiation of phase 0 of depolarization
|
* Treat and prevent ventricular [[arrhythmia]] during and immediately after [[myocardial infarction]], though this is now discouraged given the increased risk of [[asystole]]
|-
!Ic
|
|
* [[Encainide]]
* [[Flecainide]]
* [[Moricizine]]
* [[Propafenone]]
|Na<sup>+</sup> channel block (slow association/dissociation).
Class Ic drugs do not affect action potential duration and have the strongest effect on the initiation phase 0 of depolarization
|
* Contraindicated immediately after myocardial infarction
* Prevent paroxysmal [[atrial fibrillation]]
* Treat recurrent [[tachycardia]] associated with abnormal [[electrical conduction system of the heart|conduction pathways]], such as [[Wolff–Parkinson–White syndrome]]
|-
!II
|Beta-blockers
|
* [[Atenolol]]
* [[Bisoprolol]]
* [[Carvedilol]]
* [[Esmolol]]
* [[Metoprolol]]
* [[Nebivolol]]
* [[Propranolol]]
* [[Timolol]]
| [[Beta blocker]]<br />Propranolol also has some sodium channel-blocking effect.
|
* Decrease mortality in patients with [[myocardial infarction]]
* Prevent recurrence of [[tachycardia]]
|-
!III
|Potassium channel blockers
|
* [[Amiodarone]]
* [[Dofetilide]]
* [[Dronedarone]]
* [[E-4031]]
* [[Ibutilide]]
* [[Sotalol]]
* [[Vernakalant]]
| [[Potassium channel blocker|K<sup>+</sup> channel blocker]]
[[Sotalol]] is also a [[beta blocker]]<ref name="pmid11350865">{{cite journal |vauthors=Kulmatycki KM, Abouchehade K, Sattari S, Jamali F |title=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 |journal=Br. J. Pharmacol. |volume=133 |issue=2 |pages=286–294 |date=May 2001 |pmid=11350865 |pmc=1572777 |doi=10.1038/sj.bjp.0704067 }}</ref><br>
[[Amiodarone]] has mostly Class III activity, but also I, II, & IV activity<ref>{{cite book|last1=Waller|first1=Derek G.|last2=Sampson|first2=Tony|title=Medical Pharmacology and Therapeutics E-Book|date=2013|publisher=Elsevier Health Sciences|isbn=9780702055034|page=144|url=https://books.google.com/books?id=UYZRAAAAQBAJ&pg=PA144|language=en}}</ref>
|
* Prevent paroxysmal atrial fibrillation<ref>{{cite web |title=treatment of paroxysmal atrial fibrillation – General Practice Notebook |url=http://www.gpnotebook.co.uk/simplepage.cfm?ID=-469368831 |website=www.gpnotebook.co.uk}}</ref> and haemodynamically stable ventricular tachycardia<ref>{{Cite web|title = protocol for management of haemodynamically stable ventricular tachycardia – General Practice Notebook|url = http://www.gpnotebook.co.uk/simplepage.cfm?ID=-1590362085|website = www.gpnotebook.co.uk|access-date = 2016-02-09}}</ref> (amiodarone)
* Treat [[atrial flutter]] and atrial fibrillation (ibutilide)
* Treat [[ventricular tachycardia]] and [[atrial fibrillation]] (sotalol)
* Treat [[Wolff-Parkinson-White syndrome]]
|-
!IV
|Calcium channel blockers
|
* [[Diltiazem]]
* [[Verapamil]]
|[[Calcium channel blocker|Ca<sup>2+</sup> channel blocker]]
|
* Prevent recurrence of [[paroxysmal supraventricular tachycardia]]
* Reduce [[ventricular rate]] in patients with [[atrial fibrillation]]
|-
!V
|
|
* [[Adenosine]]
* [[Digoxin]]
* [[Magnesium sulfate (medical use)|Magnesium sulfate]]
|Work by other or unknown mechanisms
|
* Contraindicated in ventricular arrhythmias 
* Adenosine is used to treat [[supraventricular tachycardia]]s, especially in heart failure and atrial fibrillation<ref>{{Citation |last=Singh |first=Shashank |title=Adenosine |date=2023 |url=http://www.ncbi.nlm.nih.gov/books/NBK519049/ |work=StatPearls |access-date=2023-12-12 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=30085591 |last2=McKintosh |first2=Rebecca}}</ref>
* Magnesium sulfate is used to treat ''[[torsades de pointes]]'', a type of arrhythmia
|- <!-- THIS IS TRUE
 -->
|}

===Class I agents===
The class I antiarrhythmic agents [[Sodium channel blocker|interfere with the sodium 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 I agents are called membrane-stabilizing agents, "stabilizing" referring to 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.<ref name="pmid6723689">{{cite journal |vauthors=Milne JR, Hellestrand KJ, Bexton RS, Burnett PJ, Debbas NM, Camm AJ |title=Class 1 antiarrhythmic drugs – characteristic electrocardiographic differences when assessed by atrial and ventricular pacing |journal=Eur. Heart J. |volume=5 |issue=2 |pages=99–107 |date=February 1984 |pmid=6723689 |doi= 10.1093/oxfordjournals.eurheartj.a061633}}</ref><ref name="isbn0-07-139930-5">{{cite book |author1=Trevor, Anthony J. |author2=Katzung, Bertram G. |title=Pharmacology |publisher=Lange Medical Books/McGraw-Hill, Medical Publishing Division |location=New York |year=2003 |page=43 |isbn=978-0-07-139930-2 }}</ref>
* Class Ia drugs lengthen the action potential (right shift)
* Class Ib drugs shorten the action potential (left shift)
* Class Ic drugs do not significantly affect the action potential (no shift)

<div class="skin-invert-image">
<gallery mode="packed" widths="360px" heights="160">
File:Action potential class Ia.svg|Class Ia
File:Action potential Class Ib.svg|Class Ib
File:Action potential class Ic.svg|Class Ic
</gallery>
</div>
{{clear}}

===Class II agents===
Class II agents are conventional [[beta blockers]]. They act by blocking the effects of [[catecholamine]]s at the [[Adrenergic receptor#β1 receptor|β<sub>1</sub>-adrenergic receptors]], thereby decreasing sympathetic activity on the heart, which reduces intracellular cAMP levels and hence reduces Ca<sup>2+</sup> influx. 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.svg|thumb|class=skin-invert-image|Effect of class III drugs on length of action potential]]
Class III agents predominantly [[Potassium channel blocker|block the potassium channels]], thereby prolonging repolarization.<ref>{{cite journal | last1 = Lenz | first1 = TL | last2 = Hilleman | first2 = DE | year = 2000 | title = Dofetilide, a New Class III Antiarrhythmic Agent | pmid = 10907968 | journal = Pharmacotherapy | volume = 20 | issue = 7| pages = 776–786 | doi=10.1592/phco.20.9.776.35208| s2cid = 19897963 }}</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). 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 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 III agents include: [[bretylium]], [[amiodarone]], [[ibutilide]], [[sotalol]], [[dofetilide]], [[vernakalant]], and [[dronedarone]].

===Class IV agents===
Class IV agents are slow [[Calcium channel blocker#Non-dihydropyridine|non-dihydropyridine]] [[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.{{cn|date=March 2023}}

Class IV agents include [[verapamil]] and [[diltiazem]].

===Class V and others===
Since the development of the original Vaughan Williams classification system, additional agents have been used that do not fit cleanly into categories I through IV. Such agents include:
* [[Adenosine]] is used intravenously for terminating [[supraventricular tachycardia]]s.<ref name="pmid7882485">{{cite journal |vauthors=Conti JB, Belardinelli L, Utterback DB, Curtis AB |title=Endogenous adenosine is an antiarrhythmic agent |journal=Circulation |volume=91 |issue=6 |pages=1761–1767 |date=March 1995 |pmid=7882485 |doi=10.1161/01.cir.91.6.1761 }}</ref>
* [[Digoxin]] decreases conduction of electrical impulses through the AV node and increases vagal activity via its action on the central nervous system. Via indirect action, it leads to an increase in [[acetylcholine]] production, stimulating M2 receptors on AV node leading to an overall decrease in speed of conduction.
* [[Magnesium sulfate]] is an antiarrhythmic drug, but only used against very specific arrhythmias<ref name="pmid10924290">{{cite journal |author=Brugada P |title=Magnesium: an antiarrhythmic drug, but only against very specific arrhythmias |journal=Eur. Heart J. |volume=21 |issue=14 |page=1116 |date=July 2000 |pmid=10924290 |doi=10.1053/euhj.2000.2142 |doi-access=free }}</ref> such as [[torsades de pointes]].<ref name="pmid15466950">{{cite journal |vauthors=Hoshino K, Ogawa K, Hishitani T, Isobe T, Eto Y |title=Optimal administration dosage of magnesium sulfate for torsades de pointes in children with long QT syndrome |journal=J Am Coll Nutr |volume=23 |issue=5 |pages=497S–500S |date=October 2004 |pmid=15466950 |doi=10.1080/07315724.2004.10719388 |s2cid=30146333 }}</ref><ref name="pmid16635167">{{cite journal |vauthors=Hoshino K, Ogawa K, Hishitani T, Isobe T, Etoh Y |title=Successful uses of magnesium sulfate for torsades de pointes in children with long QT syndrome |journal=Pediatr Int |volume=48 |issue=2 |pages=112–117 |date=April 2006 |pmid=16635167 |doi=10.1111/j.1442-200X.2006.02177.x |s2cid=24904388 }}</ref>

===History===
The initial classification system had 4 classes, although their definitions different from the modern classification. Those proposed in 1970 were:<ref name=VW70/>
# Drugs with a direct membrane action: the prototype was [[quinidine]], and [[lidocaine|lignocaine]] was a key example. Differing from other authors, Vaughan-Williams describe the main action as a slowing of the rising phase of the action potential.
# Sympatholytic drugs (drugs blocking the effects of the [[sympathetic nervous system]]): examples included [[bretylium]] and [[Beta blocker|adrenergic beta-receptors blocking drugs]]. This is similar to the modern classification, which focuses on the latter category.
# Compounds that prolong the action potential: matching the modern classification, with the key drug example being [[amiodarone]], and a surgical example being [[thyroidectomy]]. This was not a defining characteristic in an earlier review by Charlier et al. (1968),<ref>{{cite journal|last1=Charlier|first1=R|last2=Deltour|first2=G|last3=Baudine|first3=A|last4=Chaillet|first4=F|title=Pharmacology of amiodarone, and anti-anginal drug with a new biological profile.|journal=Arzneimittel-Forschung|date=November 1968|volume=18|issue=11|pages=1408–1417|pmid=5755904}}</ref> but was supported by experimental data presented by Vaughan Williams (1970).{{r|VW70|p=461}} The figure illustrating these findings was also published in the same year by Singh and Vaughan Williams.<ref>{{cite journal|last1=Singh|first1=BN|last2=Vaughan Williams|first2=EM|title=The effect of amiodarone, a new anti-anginal drug, on cardiac muscle.|journal=British Journal of Pharmacology|date=August 1970|volume=39|issue=4|pages=657–667|pmid=5485142|doi=10.1111/j.1476-5381.1970.tb09891.x|pmc=1702721}}</ref>
# Drugs acting like [[diphenylhydantoin]] (DPH): mechanism of action unknown, but others had attributed its cardiac action to an indirect action on the brain;<ref>{{cite journal|last1=Damato|first1=Anthony N.|title=Diphenylhydantoin: Pharmacological and clinical use|journal=Progress in Cardiovascular Diseases|date=1 July 1969|volume=12|issue=1|pages=1–15|doi=10.1016/0033-0620(69)90032-2|pmid=5807584}}</ref> this drug is better known as antiepileptic drug [[phenytoin]].