Effect of class III antiarrhythmic agent on cardiac action potential.
Potassium channel blockers used in the treatment ofcardiac arrhythmia are classified as class III antiarrhythmic agents. Atrial cardiomyocytes contain a specific subset of potassium ion channels which are absent in the ventricles.[1] Safety and efficacy of anti-arrhythmic potassium channel blockers will be improved by discovery of blockers specific to atria or ventricle.[1]
Class III agents predominantly block the potassium channels, thereby prolonging repolarization.[2] More specifically, their primary effect is onIKr.[3]
Since these agents do not affect thesodium 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).
Amiodarone is indicated for the treatment of refractoryVT orVF, particularly in the setting of acute ischemia. Amiodarone is also safe to use in individuals withcardiomyopathy andatrial fibrillation, to maintain normal sinus rhythm. Amiodarone prolongation of the action potential is uniform over a wide range of heart rates, so this drug doesnot have reverse use-dependent action.Amiodarone was the first agent described in this class.[4] Amiodarone should only be used to treat adults with life-threatening ventricular arrhythmias when other treatments are ineffective or have not been tolerated.[5]
Dofetilide blocks only the rapid K channels; this means that at higher heart rates, when there is increased involvement of the slow K channels, dofetilide has less of an action potential-prolonging effect.
A study appears to indicate that topical spray of a selective Tandem pore Acid-Sensitive K+ (TASK 1/3 K+) (potassium antagonist) increases upper airway dilator muscle activity and reduces pharyngeal collapsibility during anesthesia and obstructive sleep apnoea (OSA).[9][10]
Potassium channel blockers exhibit reverse use-dependent prolongation of the action potential duration. Reverse use dependence is the effect where the efficacy of the drug is reduced after repeated use of the tissue.[11] This contrasts with (ordinary) use dependence, where the efficacy of the drug is increased after repeated use of the tissue.
Reverse use dependence is relevant for potassium channel blockers used as class III antiarrhythmics. Reverse use dependent drugs that slow heart rate (such asquinidine) can be less effective at high heart rates.[11] Therefractoriness of the ventricularmyocyte increases at lowerheart rates.[citation needed] This increases the susceptibility of the myocardium toearly Afterdepolarizations (EADs) at low heart rates.[citation needed] Antiarrhythmic agents that exhibit reverse use-dependence (such asquinidine) are more efficacious at preventing a tachyarrhythmia than converting someone into normal sinus rhythm.[citation needed] Because of the reverse use-dependence of class III agents, at low heart rates class III antiarrhythmic agents may paradoxically be more arrhythmogenic.
Drugs such as quinidine may be both reverse use dependent and use dependent.[11]
^Riera AR, Uchida AH, Ferreira C, et al. (2008). "Relationship among amiodarone, new class III antiarrhythmics, miscellaneous agents and acquired long QT syndrome".Cardiol J.15 (3):209–19.PMID18651412.
^abcHondeghem, L. M. (1995), Breithardt, Günter; Borggrefe, Martin; Camm, A. John; Shenasa, Mohammad (eds.), "Use Dependence and Reverse Use Dependence of Antiarrhythmic Agents: Pro- and Antiarrhythmic Actions",Antiarrhythmic Drugs: Mechanisms of Antiarrhythmic and Proarrhythmic Actions, Springer Berlin Heidelberg, pp. 92–105,doi:10.1007/978-3-642-85624-2_6,ISBN9783642856242
^Jin, W; Lu, Z (1998). "A novel high affinity inhibitor for inward-rectifier K+ channels".Biochemistry.37 (38):13291–13299.doi:10.1021/bi981178p.PMID9748337.
^Kindler CH, Paul M, Zou H, Liu C, Winegar BD, Gray AT, Yost CS (Jul 2003). "Amide local anesthetics potently inhibit the human tandem pore domain background K+ channel TASK-2 (KCNK5)".The Journal of Pharmacology and Experimental Therapeutics.306 (1):84–92.doi:10.1124/jpet.103.049809.PMID12660311.S2CID1621972.
^Meadows HJ, Benham CD, Cairns W, Gloger I, Jennings C, Medhurst AD, Murdock P, Chapman CG (Apr 2000). "Cloning, localisation and functional expression of the human orthologue of the TREK-1 potassium channel".Pflügers Archiv.439 (6):714–22.doi:10.1007/s004240050997.PMID10784345.
^abWang, Shao-Ping; Wang, Jian-An; Luo, Rong-Hua; Cui, Wen-Yu; Wang, Hai (September 2008). "Potassium channel currents in rat mesenchymal stem cells and their possible roles in cell proliferation".Clinical and Experimental Pharmacology & Physiology.35 (9):1077–1084.doi:10.1111/j.1440-1681.2008.04964.x.ISSN1440-1681.PMID18505444.S2CID205457755.
^Guillemare E, Marion A, Nisato D, Gautier P, “Inhibitory effects of dronedarone on muscarinic K+ current in guinea pig atrial cells,” in Journal of Cardiovascular Pharmacology, 2000 7
^Kim I, Boyle KM, Carrol JL (2005) Postnatal development of E-4031-sensitive potassium current in rat carotidchemoreceptor cells.J Appl Physiol98(4):1469-1477,
