Antiarrhythmic agents class

Glass lA Antiarrhythmic Agents. Class lA antiarrhythmic agents decrease automaticity, ie, depress pacemaker rates, especially ectopic foci rates produce moderate depression of phase 0 depolarization and thus slow conduction in atria, A-V node, His-Purkinje system, and ventricles prolong repolarization, ie, lengthen action potential duration increase refractoriness and depress excitabiHty. These electrophysiological effects are manifested in the ECG by increases in the PR, QRS, and QT intervals. 

Glass IB Antiarrhythmic Agents. Class IB antiarrhythmic agents produce less inhibition of the inward sodium current than Class lA agents. In normal myocardial tissue, phase 0 may be unaffected or minimally depressed. However, in ischemic or infarcted tissue, phase 0 is depressed. Myocardial tissue exposed to Class IB agents exhibits decreased automaticity, shortened action potential duration, ie, shortened repolarization, and shortened refractory period. Excitability of the myocardium is not affected and conduction velocity is increased or not modified. The refractory period is shortened less than its action potential duration, thus the ratio of refractory period to action potential duration is increased by these agents. The net effect is increased refractoriness. The PR and QT intervals of the ECG are shortened and the QRS interval is unchanged (1,2). 

Glass IG Antiarrhythmic Agents. Class IC antiarrhythmic agents have marked local anesthetic effects. They slow the rapid inward sodium current producing marked phase 0 depression and slow conduction. Action potential duration of ventricular muscle is increased, ie, prolonged repolarization, but decreased in the His-Purkinie system by these agents. The effects on the ECG are increased PR interval, marked prolongation of the... 

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

ANTIARRHYTHMIC agents (Class I agents, e.g. disopyramide, flecainide. lignocaine. procainamide, quinidine) are sodium-channel blockers and are mainly used to treat atrial and ventricular tachycardias (see antiarrhythmic agents). ANTIEPILEPTICS have a number of mechanisms of action, but some appear to have a component involving modulation of sodium-channel function, e.g. carbamaxepine and phenytoin (see anticonvulsants). 

Class lA antiarrhythmic agents Class III antiarrhythmic agents Calcium antagonists Antihypertensives Antidepressant agents... 

Quinidine is used as an antiarrhythmic agent (class I A), and it is also used rarely as an anti-malarial drug. 

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). 

Class II Antiarrhythmic Agents The p-Adrenoceptor Blocking Agents... 

The Class III antiarrhythmic agents markedly prolong action potential duration and effective refractory period of cardiac tissue. The QT interval of the ECG is markedly prolonged. 

Class V Antiarrhythmic Agents Selective Bradycardic Agents... 

Other Glass III Antiarrhythmic Agents. Clofihum phosphate is a benzene-butanaminium derivative that has highly specific Class III antiarrhythmic activity. It is orahy active, has a rapid onset of action, and a reasonably long duration of antiarrhythmic activity. In preliminary clinical studies, clofihum has shown efficacy against spontaneous ventricular tachycardias (69). 

Verapamil. Verapamil hydrochloride (see Table 1) is a synthetic papaverine [58-74-2] C2qH2 N04, derivative that was originally studied as a smooth muscle relaxant. It was later found to have properties of a new class of dmgs that inhibited transmembrane calcium movements. It is a (+),(—) racemic mixture. The (+)-isomer has local anesthetic properties and may exert effects on the fast sodium channel and slow phase 0 depolarization of the action potential. The (—)-isomer affects the slow calcium channel. Verapamil is an effective antiarrhythmic agent for supraventricular AV nodal reentrant arrhythmias (V1-2) and for controlling the ventricular response to atrial fibrillation (1,2,71—73). 

Propranolol. Propranolol (Table 1), a Class II antiarrhythmic agent, is usefiil in the management of hypertrophic subaortic stenosis, especially for the treatment of exertional or other stress-induced angina by improving blood flow. The dmg can increase exercise tolerance in patients suffering from angina. Propranolol has been shown to have cardioprotective action in post-MI patients (37—39,98,99,108). 

Metoprolol. Metoprolol tartrate (Table 1), also a Class II antiarrhythmic agent, is a HpophiHc, cardioselective P -adrenoceptor blocking agent... 

Other P"Adrenoceptor Blocking Agents. Carteolol hydrochloride (Table 1) is also a Class II antiarrhythmic agent. In three separate studies in patients having angina pectoris, carteolol was considered effective as evidenced by a reduction in the frequency and severity of anginal episodes, reduction in the amount of nitroglycerin consumed, improvement of ECG parameters, or an increase in the duration of trea dmill exercise (42). 

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... 

Paul, A.A., Witchel, H.J. and Hancox, J. C. (2001) Inhibition of HERG potassium channel current by the class la antiarrhythmic agent disopyramide. Biochemical and Biophysical Research Communications, 280, 1243—1250. 

Jurkiewicz, N.K. and Sanguinetti, M.C., Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class III antiarrhythmic agent. Specific block of rapidly activating delayed rectifier K+ current by dofetilide, Circ. Res., 72, 75-83, 1993. 

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-... 

The Pfizer group in the United Kingdom has been actively involved in the search for new Class III antiarrhythmic agents. It has patented a variety of structural types that make extensive use of the methylsulphonylamino moiety. These include indanes [173,174], pyridines [175,176], piperazines [177-179], benzazepines [180], bisarylalkylamines [181] and diazabicyclic compounds [182], From this extensive work, two compounds, UK-66914 (65) and UK-68798 (66), have entered clinical trials. Compound (65) increases the effective refractory period (ERP) of ferret papillary muscle by 25% at a concentration of 0.5 //M [183]. Whole-cell patch-clamp studies... 

The Class III antiarrhythmic agent under development by Eisai is a meth-ylsulphonylamino-substituted benzoyl piperidine, E-4031 (67). In guinea-pig papillary muscle E-4031 increased APD90 by 25% at a eoncentration of 10 [190] and increased ERP in ferret papillary muscle by 25% at 58 nM... 

Like RS-87337, Win 54177-4 (72) is reported to be a combined Class I/III antiarrhythmic agent. At a dose of 3 mg/kg, the compound increased effective refractory period by 2f% in anaesthetized guinea-pigs [204]. The com-... 

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. 

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