Class I antiarrhythmic agents

Class I Antiarrhythmic Agents The Sodium Channel Blockers... 

The Class I antiarrhythmic agents inactivate the fast sodium channel, thereby slowing the movement of Na" across the cell membrane (1,2). This is reflected as a decrease in the rate of development of phase 0 (upstroke) depolarization of the action potential (1,2). The Class I agents have potent local anesthetic effects. These compounds have been further subdivided into Classes lA, IB, and IC based on recovery time from blockade of sodium channels (11). Class IB agents have the shortest recovery times (t1 ) Class lA compounds have moderate recovery times (t 2 usually <9 s) and Class IC have the longest recovery times (t 2 usually >9 s). 

The imidazoline denvative cibeiuoline (64) is a class I antiarrhythmic agent which has undergone clinical trials in the United States with apparently satisfactory results It is synthesized by diphenylcyclopropananon of acrylonitrile by thermal carbene generation from diphenyldiazo methane (62) to give 1 cyano 2,2 diphenylc>clopropane (63) Reaction of this with ethylenedia mine tosylate completes the synthesis of ciben/oline (64) [221... 

Ohmura K, Kobayashi Y, Miyauchi Y, et al. Electrocardiographic and electrophysiological characteristics of atrial fibrillation organized into atrial flutter by oral administration of class I antiarrhythmic agents. Pacing Clin Electrophysiol. 2003 26 692-702. 

Table 4 IC50 (pM) and Hill coefficient ( h) values for some Class I antiarrhythmic agents against hERG potassium channels expressed in the human embryonic kidney (HEK 293) cell line...

TYB-3823 (74), an antiarrhythmic agent synthesized at the University of Hawaii, exhibits an electrophysiological profile similar to the Class I/III agents discussed above, but there is a broader separation of the two effects. 

In addition to the amiodarone-related compounds, (81) and (82), described above, BASF has been exploring some novel heterocyclic compounds as Class III antiarrhythmic agents. A series of imidazo[l,2-c]pyrro-lo[l,2-a]quinazoline derivatives have been patented which are several times more potent than (-I- )-sotalol in lengthening QT interval of the electrocardiogram in the anaesthetized guinea-pig model [230], One of the most potent compounds is (85), which was 17-times more potent than the standard. These compounds represent one of the unique Class III structural types described to date. 

Bepridil has Class I antiarrhythmic properties and, like other such drugs, can induce new arrhythmias, including ventricular tachycardia/ventricular fibrillation (VTA/F). In addition, because of its ability to prolong the QT interval, bepridil can cause torsades de pointes type VT. Because of these properties, reserve bepridil for patients in whom other antianginal agents do not offer a satisfactory effect (see Warnings). P.285... 

Class I antiarrhythmic drugs are essentially sodium channel blockers.5,27,29 These drugs bind to membrane sodium channels in various excitable tissues, including myocardial cells. In cardiac tissues, class I drugs normalize the rate of sodium entry into cardiac tissues and thereby help control cardiac excitation and conduction.8,27 Certain class I agents (e.g., lidocaine) are also used as local anesthetics the way that these drugs bind to sodium channels is discussed in more detail in Chapter 12. 

Class III antiarrhythmic agent with additional classes I, II, III, and IV actions. Prolongs action potential duration and effective refractory period in all cardiac tissues,... 

Sanguinetti MC, Jurkiewicz NK. Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents. J Gen Physiol I990 96(I) I95-2I5. 

Gwilt M, Arrowsmith JE, Blackburn KJ, Burges RA, Cross PE, Dalrymple HW, Higgins AJ. UK-68,798 a novel, potent and highly selective class III antiarrhythmic agent which blocks potassium channels in cardiac cells. J Pharmacol Exp Ther I99I 256(I) 3I8-24. 

Drug related Use of antiarrhythmic agents (class I or class III)... 

Bunaftine (21) is a naphthalenecarboxamide derivative, that has been developed as an antiarrhythmic agent. The compound exhibits both Class I and Class III electrophysiological effects. Fenici and co-workers studied bunaftine in patients with paroxysmal atrial tachyarrhythmia and recorded right atrial monophasic action potentials [72]. A mean increase of 18% in atrial repolarization time and an increase in monophasic APD during pac-... 

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