© 2000 by European Society of Cardiology
Copyright © 2000, European Society of Cardiology
Kinetics of onset of rate-dependent effects of Class I antiarrhythmic drugs are important in determining their effects on refractoriness in guinea-pig ventricle, and provide a theoretical basis for their subclassification
Professor of Medicine, Head of the Department of Medicine, St Vincent's Hospital, Victoria St, Darlinghurst 2010, NSW, Australia
* Tel.: +61-2-9361-2352; fax: +61-2-9361-2794 tcampbell{at}stvincents.com.au
KEYWORDS Antiarrhythmic agents; Conduction (block); Membrane potential; Ventricular arrhythmias
This paper consolidated the work I had been carrying out for the preceding 3 years as a graduate student in the laboratory of Dr. E.M. Vaughan Williams in the Department of Pharmacology at Oxford and it formed the basis of my D.Phil thesis.
I had gone to Oxford from Sydney, Australia on a Nuffield Scholarship, (the same scholarship that had brought Dr. Bramah Singh to the same laboratory from New Zealand approximately a decade earlier). We had both gone to study with Dr. Vaughan Williams, recognised then and now as one as the pioneering figures in the study of antiarrhythmic drug mechanisms.
I had arrived at the beginning of 1980, fresh from Clinical Fellowships in Internal Medicine and Cardiology, but with very little training in basic research. I was keen to learn more about cardiac electrophysiology and particularly about the mechanisms of action of antiarrhythmic agents, and I spent most of the first year and a half learning the technique of long-term intracellular action potential recording from guinea pig and rabbit myocardium and reading the literature of the day.
At the time, there was little awareness of the problems of proarrhythmia, and new Class I drugs were appearing on the market at a rapid rate. It was apparent to anyone with an interest in the field that while all of these agents blocked the fast inward sodium channel, they did not all behave in exactly the same way when administered to patients, even allowing for pharmacokinetic differences between them.
In the early 1970s, Singh, Vaughan Williams and Hauswirth had already suggested subdividing the then available agents into ‘Class la’ (comprising quinidine, procainamide and the new agent disopyramide) and ‘Class lb’ (lignocaine, diphenylhydantoin and mexiletine [1]. This initial subclassification was based on the fact that the sodium channel blocking effect of the la agents was apparent in normal myocardium at therapeutic concentrations whereas it was seen with lb agents only at high levels of external potassium (i.e. depolarised myocardium) or in the presence of high concentrations of drug.
Later in the 1970s there appeared a group of agents that markedly reduced the sodium current in both normal and depolarised myocardium. These agents, which included flecainide, encainide and lorcainide were labelled ‘Class lc’ by Harrison in a lecture which I heard him give during my first visit to an American Heart Association meeting in 1980. Harrison's subclassification was based on the differential effects of the three subclasses on conduction velocity and QRS duration (both measures of sodium channel blockade) at therapeutic concentrations [2]. He observed that Class lb agents had minimal effects on these parameters at therapeutic concentrations, whereas Class la agents slowed conduction and prolonged the QRS interval in high therapeutic concentrations and Class lc agents slowed conduction and broadened the QRS even in low therapeutic concentrations in normal hearts. This empirically based, clinical classification was open to criticism on the grounds that it subdivided the drugs purely on dose–effect relationships rather than on any fundamental differences between them in terms of their interactions with the sodium channel.
At about the same time, I became aware of the work of Hondeghem and Katzung and others, demonstrating that Class I drugs do not act primarily by simply ‘blocking’ the sodium channel but by preventing (or prolonging) recovery from inactivation of this channel, possibly by binding directly to the inactivation gating mechanism [3,4]. Thus, repetitive stimulation, by producing repetitive inactivation, enhances the binding of Class I drugs to the sodium channel, giving rise to a so-called ‘use-dependent’ or ‘rate-dependent’ effect. The seeds of this idea had been sown as far back as 1962 by Szekeres and Vaughan Williams [5].
Essentially what I did was to take all of these threads and to combine them with data I had been collecting for some time on the rate at which the various Class I agents bind to and unbind from the sodium channel during bursts of stimulation at various frequencies. As is outlined in the Cardiovascular Research paper, it turned out that the drugs fell very neatly into three subgroups with ‘fast’ (lignocaine, tocainide and mexiletine), ‘intermediate’ (quinidine, disopyramide and procainamide) and ‘slow’ (flecainide, encainide and lorcainide), kinetics. Because of their ability to respond rapidly to a premature stimulus (equivalent to an increased rate) by blocking more sodium channels (rapid onset kinetics), the ‘fast’ drugs were found to share the ability to markedly prolong the effective refractory period relative to the action potential duration. The ‘slow’ drugs had only minor effects on this parameter, and the intermediate drugs produced modest increases in refractoriness relative to action potential duration.
Thus, when classified entirely according to in vitro behaviour concerning kinetics of interaction with the sodium channel, these nine drugs fell into exactly the same classes which Harrison and others had proposed on other grounds, thus establishing a missing link between the laboratory and the clinic.
In subsequent work I was able to establish some correlations between the physicochemical properties of the various drugs and their kinetics of interaction with the sodium channel [6]. Others, more mathematically inclined than myself, including Hondeghem, Katzung and Grant have carried the work further in terms of mathematical models, and there is still significant controversy as to whether the kinetic differences I and others observed relate more to differing affinities of the drugs for different channel states, or to a primarily voltage-dependent process [7].
These arguments aside, I believe my paper has been so widely cited because it provides a basis for understanding the differences between the various subclasses of sodium blocking drugs. These differences became more and more clinically relevant over the decade following publication, culminating with the publication of the results of the Cardiac Arrhythmia Suppression Trial and similar studies, suggesting that the Class 1c (slow kinetics) agents were particularly prone to proarrhythmia. My work provided an explanation for this, in the sense that these agents would be expected to block the sodium channel in essentially all myocardial tissues at all clinically relevant rates in the presence or absence of ischaemia, whereas the ‘faster’ agents offered some chance of being selective for suppression of abnormal myocardium and, therefore, potentially less proarrhythmic [8].
What has happened of course is that the Class I agents are being used much less often and with greater care and understanding. They have tended to be replaced by the Class III antiarrhythmic drugs which act largely by blocking the repolarising potassium currents and prolonging refractory periods.
Soon after submitting the Cardiovascular Research manuscript, I returned to Sydney where I continue to practise clinical cardiology and carry on basic research. Times and techniques have changed. I now work with cloned human potassium channels expressed in non-cardiac mammalian cell lines and study their modulation by Class Ill antiarrhythmic agents and other drugs.
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- Singh B.N., Hauswirth D. Comparative mechanisms of action of antiarrhythmic drugs. Am Heart J (1974) 87:367–382.[CrossRef][Web of Science][Medline]
- Harrison D.C., Winkle R.A., Sami M., Mason J.W. Cardiac arrhythmias: a decade of progress. Harrison D.C., ed. (1981) Boston: Hail Medical. 315–330.
- Hondeghem L.M., Katzung B.G. A unifying molecular model for the interaction of antiarrhythmic drugs with cardiac sodium channels: application to quinidine and lidocaine. Proc West Pharmacol Soc (1977) 20:253–256.[Web of Science][Medline]
- Hondeghem L.M., Katzung B.G. Test of a model of antiarrhythmic drug action. Circulation (1980) 61:1217–1224.
[Abstract/Free Full Text] - Szekeres L., Vaughan Williams E.M. Antifibrillatory action. J Physiol (Lond) (1962) 160:470–482.
[Free Full Text] - Campbell T.J. Importance of physico-chemical properties in determining the kinetics of the effects of class I antiarrhythmic drugs on maximum rate of depolarization in guinea-pig ventricle. Br J Pharmacol (1983) 80:33–40.[Web of Science][Medline]
- Grant A.O. Mechanisms of action of antiarrhythmic drugs: From ion channel blockage to arrhythmia termination. Pacing Clin Electrophysiol (1997) 20:432–444.[CrossRef][Medline]
- Campbell T.J. Subclassification of class I antiarrhythmic drugs: Enhanced relevance after CAST. Cardiovasc Drugs Ther (1992) 6:519–528.[CrossRef][Web of Science][Medline]
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