Class Ic antiarrhythmics

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... 

Class IC antiarrhythmic drugs such as flecainide or propafenone block the Na+ channel (open state propafenone open and inactivated state) with a very long dissociation time constant so that they alter normal action potential propagation. Flecainide increased mortality of patients recovering from myocardial infarction due to its proarrhythmic effects (CAST study). Action potential is shortened in Purkinje fibres but is prolonged in the ventricles. 

D6 Tricyclic antidepressants (TCAs), benztropine, perphenazine, clozapine, haloperidol, codeine/oxycodone, risperidone, class Ic antiarrhythmics, 3 blockers, trazodone, paroxetine, maprotiline, amoxapine, duloxetine, mirtazapine (partly), venlafaxine, bupropion Fluoxetine, paroxetine, duloxetine, hydroxybupropion, methadone, cimetidine, haloperidol, quinidine, ritonavir Phenobarbital, rifampin... 

Class Ic antiarrhythmic drug similar to flecainide, blocking sodium channels in both activated and inactivated states, additional weak betablocking effect. 

Proarrhythmic effects of antiarrhythmic drugs In the Cardiac Arrhythmia Suppression Trial (CAST) treatment with encainide and flecainide, two class IC antiarrhythmic agents, successfully prevented ventricular ectopic beats in patients who had myocardial infarction. However, continued therapy with either drug was associated with a two- to three-fold increase in death due to cardiac arrhythmias. Similar results were reported for moricizine. Increased death was probably due to drug-induced fatal arrhythmias triggered by recurrent myocardial ischemia. 

Mechanism of action. Na -channel blocking antiarrhythmics resemble most local anesthetics in being cationic amphiphilic molecules (p.206 exception phenytoin, p.191). Possible molecular mechanisms of their inhibitory effects are outlined on p.202 in more detail. Their low structural specificity is reflected by a low selectivity toward different cation channels. Besides the Na channel. Carotid 1C channels are also likely to be blocked. Accordingly, cationic amphiphilic antiarrhythmics affect both the depolarization and repolarization phases. Depending on the substance, AP duration can be increased (Class IA), decreased (Class IB), or remain the same (Class IC). Antiarrhythmics representative of these categories include Class IA—quinidine, procainamide, ajmaline, disopyramide Class IB—lidocaine, mexile-tine, tocainide Class IC—flecainide, propafenone. 

Figure 2.20 The general structure 72, with different residues X, describes the prototype of a (3-adrenergic antagonist. Cyclization of the side chain produced the antidepressant viloxazine 73, whereas the N-n-propyl analog propafenone 74 turned out to be a class Ic antiarrhythmic with only weak P-antagonistic activity. An attempt to cyclize P-blockers to structures of the prototype 75 finally produced levocromakalim 76 as expected, it had antihypertensive activity but its mode of action is different instead of being a P-blocker, it is a potassium channel opener.

Fujiki A, Usui M, Nagasawa H, Mizumaki K, Hayashi H, Inoue H. ST segment elevation in the right precordial leads induced with class IC antiarrhythmic drugs insight into the mechanism of Brugada syndrome. J Cardiovasc Electrophysiol 1999 10(2) 214-18. 

Schumacher B, Jung W, Lewalter T, Vahlhaus C, Wolpert C, Luderitz B. Radiofrequency ablation of atrial flutter due to administration of class IC antiarrhythmic drugs for atrial fibrillation. Am J Cardiol 1999 83(5) 710-13. 

Kawabata M, Hirao K, Horikawa T, Suzuki K, Motokawa K, Suzuki F, Azegami K, Hiejima K. Syncope in patients with atrial flutter during treatment with class Ic antiarrhythmic drugs. J Electrocardiol 2001 34(l) 65-72. 

N akamura W, Segawa K, Ito H, T anaka S, Y oshimoto N. Class IC antiarrhythmic drugs, flecainide and pilsicainide, produce ST segment elevation simulating inferior myocardial ischemia. J Cardiovasc Electrophysiol 1998 9(8) 855-8. 

Class Ic antiarrhythmic agents are powerful inhibitors of the fast sodium channel. They cause... 

Experimental support for the multiple wavelet hypothesis developed out of work done by Allessie et al. in 1985. They were able to map the spread of excitation in the atria of a dog heart during rapid pacing-induced AF in the presence of acetylcholine, and provided the first demonstration in vivo of multiple propagating wavelets giving rise to turbulent atrial activity (44). They estimated that maintenance of AF would require a critical number of four to six wavelets. In a canine sterile pericarditis model of paroxysmal AF, unstable reentrant circuits of very short cycle length have been shown to be critical for maintenance of AF (45). In addition, pharmacological experiments have further shown that termination of AF by class IC antiarrhythmic drugs is preceded by a decrease in the mean number of wavelets (46,47). 

Fig. 15.21) is an orally active class Ic antiarrhythmic agent that underwent clinical trials and for which a number of soft analogs... 

List the prototypical drugs classified as class Ic antiarrhythmics. 

Flecainide Class IC antiarrhythmic prototype used in ventricular tachycardia and rapid... 

Flecainide acetate is a class Ic antiarrhythmic agent which was developed in the Riker Laboratories as part of a broad-based project investigating the effect of fluorine substitution on local anaesthetic or antiarrhythmic activity. The details concerning the development of this drug have been reported. ... 

An established interaction, but the incidence of serious adverse effects is probably not great. The additive cardiac depressant effects are probably of little importance in many patients, but may represent the last straw in a few who have seriously compromised cardiac function. The authors of one of the reports cited advise careful monitoring if both drugs are used and emphasise the potential hazards of combining class Ic antiarrhythmics and verapamil. 

Ibutilide, a class in antiarrhythmic, is known to increase the QT interval, so increasing the risk of torsade de pointes arrhythmia. Class Ic antiarrhythmics such as propafenone and flecainide generally shorten the QT interval. It is possible that class Ic antiarrhythmics may usefully attenuate the risk of torsade de pointes with ibutilide, and ibutilide may be... 

Melgari D, Zhang Y, El Harchi A, Dempsey CE, Hancox JC (2015) Molecular basis of hERG potassium channel blockade by the class Ic antiarrhythmic flecainide. J Mol Cell Cardiol 86 42-53... 

RED FLAG Class IC antiarrhythmics are usually reserved for refractory arrhythmias because they may cause or worsen arrhythmias. 

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