Differential Effects on Action Potential Duration of Class Ia, B and C Antiarrhythmic Drugs: Modulation by Stimulation Rate and Extracellular K+ Concentration

Abstract

1. Standard microelectrode techniques were used to study the effects on the action potential duration (APD) of canine Purkinje fibres of a therapeutic concentration of nine Class I antiarrhythmic drugs. At an extracellular K+ concentration of 5.6 mmol/L all nine agents reduced APD at all drive rates studied (range of interstimulus intervals = 200-1000 ms). At lower levels of K+, quinidine (5 mumol/L) and disopyramide (10 mumol/L) (Class Ia agents) revealed dual effects on APD. At the lowest levels of K+ (2 mmol/L) and the longest interstimulus interval used (2000 ms), both agents significantly prolonged APD. Under all other conditions, APD was either unchanged or reduced. Lignocaine, 15 mumol/L (Class Ib agent) reduced APD at all rates and all K+ concentrations and this effect was greatest at the slowest rates. 2. Flecainide (1 mumol/L) (Class Ic) shortened APD at K+ = 5.6 and 4 mmol/L but had no effect at K+ = 2 mmol/L. 3. We conclude that these data result from opposing drug actions on inward sodium and outward potassium currents flowing during the plateau of the action potential. 4. Class Ia drugs exhibit significant depression of both currents, with the resultant effect on APD being modulated by external K+ concentration and drive rate. 5. Class Ib agents predominantly depress the sodium current and hence shorten APD, and Ic compounds have intermediate actions. 6. These differential effects on APD must be considered when planning antiarrhythmic therapy, and are directly relevant to the proarrhythmic propensities of these agents.

Inhibition of the current of heterologously expressed HERG potassium channels by flecainide and comparison with quinidine, propafenone and lignocaine

“…Class Ib antiarrhythmic agents are typically associated with action potential shortening rather than lengthening (Campbell et al, 1991). Having compared the e ects of the Class Ic FLEC with a Class Ia drug (QUIN) and a second Class Ic drug (PROPAF), we therefore considered it to be useful to determine whether or not a Class Ib agent (LIG) could block I HERG under the same set of experimental conditions used to test the other agents.…”

Probing kinetic drug binding mechanism in voltage-gated sodium ion channel: open state versus inactive state blockers

“…From clinical stand point, drugs that have strong open channel blocking potency are called class 1a antiarrhythmics, such as quinidine, mexilitine and disopyramide whereas class 1b antiarrhythmics like lidocaine preferentially block peak over late current. 43 Unlike most positively charged local anesthetics the neutral tricyclic anticonvulsant drugs, namely phenytoin, carbamazepine, and lamotrigine etc have similar blocking affinities for both open or inactivated-state. 44 Till 25 In this model the ion conducting state or open state is represented by P 5 , whereas the states P 1 to P 4 are closed states and P 6 to P 8 are the inactivated states.…”

Spatiotemporal dynamics of reentrant ventricular tachycardias in canine myocardial infarction: pharmacological modulation

“…cle (Dangman and Miura 1989;Campbell et al 1991). It is possible that in ischemically damaged muscle, changes in action-potential duration might have contributed to prolongation of refractory periods and to the progressive increase Fig.…”

“…Therefore, they act more selectively on partially depolarized tissue (Campbell et al 1991) and display marked rate-dependent depressant effects on action potential upstroke in ischemia (Schmitt et al 1988;Kay et al 1989). However, procainamide's kinetics of interaction with the sodium channel are slow, to the point that cumulative effects are induced at relatively slow depolarization rates.…”