Classification of Antiarrhythmic Drugs Keitaro Hashimoto1,* 1Professor Emeritus, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan
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J Pharmacol Sci 103, 333 – 346 (2007) Journal of Pharmacological Sciences ©2007 The Japanese Pharmacological Society Critical Review Arrhythmia Models for Drug Research: Classification of Antiarrhythmic Drugs Keitaro Hashimoto1,* 1Professor Emeritus, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi 409-3898, Japan Received December 31, 2006 Abstract. The aim of this study was to classify antiarrhythmic drugs based on their effective- ness on 6 in vivo arrhythmia models, mainly using dogs. The models were produced by two-stage coronary ligation, digitalis, halothane-adrenaline, programmed electrical stimulation in old myo- cardial infarction dogs, coronary artery occlusion/reperfusion, or chronic atrioventricular block. Na+-channel–blocking drugs suppressed two-stage coronary ligation and digitalis arrhythmias. Ca2+-channel blockers and β-blockers suppressed halothane-adrenaline arrhythmia. Positive inotropic drugs aggravated halothane-adrenaline arrhythmia, but did not aggravate digitalis arrhythmia. K+-channel blockers suppressed programmed electrical stimulation induced arrhythmia, but induced torsades de pointes type arrhythmia in chronic atrioventricular block dogs and aggravated halothane-adrenaline arrhythmia. Na+/H+-exchange blockers suppressed coronary artery occlusion/reperfusion arrhythmias. This classification may be useful for predict- ing the clinical effectiveness in the preclinical stage of drug development. Keywords: arrhythmia model, antiarrhythmic drug, proarrhythmic potential of drugs, ion channel, classification 1. Introduction sary. Also for applying the ablation technique to elimi- nate substrates of arrhythmias, only the proper area, Currently, interest in arrhythmia treatment is turning automatic foci, or a part or the entire re-entry circuit towards new devices and ablation techniques; and it is, need to be known. But what about pharmacological of course, certain that a failed sinus or Tawara’s (AV) treatments? Is there no room for developing new anti- node should be replaced by appropriate electronic pace- arrhythmic drugs? As Christ and Ravens discussed in makers and that cardiac collapse by ventricular fibrilla- her review (1), the relative importance of antiarrhythmic tion (VF) or potentially lethal torsades de pointes (TdP) drugs might have decreased, but they still are relied on should be stopped by electrical external or implantable for prevention of atrial fibrillation and sudden cardiac defibrillators. To implant pacemakers, only evidence of death by cardiologists world wide. More importantly, for malfunction of pacemaking and atrioventricular conduc- developing antiarrhythmic drugs, it has been necessary tion is necessary. To install a defibrillator, the genetic to know the precise mechanisms of the generation of preponderance of the occurrence of these arrhythmias, or action potentials, the different forms of action potentials, evidence of existence of ventricular arrhythmia types and the abnormalities of normal action potentials that are likely to develop into fatal sudden death or other precip- responsible for development into arrhythmias, and so on. itating factors should be known. Knowledge of pace- Thus introduction of newer drugs or understanding of making or precise mechanisms of generation of arrhyth- drug actions developed in parallel with the advances in mias in cellular and molecular levels is no longer neces- the knowledge about cardiac electrophysiology. Electri- cal mechanisms of the heart are generated by complex, multi-factorial phenomena simultaneously occurring *Corresponding author. [email protected] with channel- or receptor-related events. Molecular Published online in J-STAGE: April 4, 2007 doi: 10.1254/jphs.CRJ06013X research aims to elucidate the single function of a single molecule and the action of drugs on ion channels, trans- Invited article porters, or extracellular or intracellular receptors, but 333 334 K Hashimoto how these drugs work on arrhythmias is only known 2. Drug effects on arrhythmia models from experimental or clinical arrhythmias. After the CAST study (2) revealed the possible proarrhythmic 2-1. Canine two-stage coronary ligation arrhythmia effects of Na+-channel–blocking antiarrhythmic drugs, 2-1-1. Characteristics pharmacologists and cardiologists tried to make a new Ischemia, being a serious disorder of the myocardium, classification or guide for choosing proper drugs to treat causes pump and electrical failure; thus it is used often to clinical arrhythmias, namely the Sicilian Gambit, by produce experimental arrhythmias. Ischemia is a time- defining drug actions on cardiac tissues based on newer dependent phenomenon and starts with reversible molecular aspects of cardiac excitation and classifying damage finally reaching the stage of irreversible damage clinical arrhythmias to correlate or match the drugs and or scar formation; thus it is no wonder that ischemia the arrhythmias (3). However since the molecular related arrhythmias also show a variety of electrical mechanisms of arrhythmias are still not well known, and abnormalities. The two-stage coronary ligation tech- also comparative effectiveness of drugs on clinical nique was originally reported by Harris (9) and is arrhythmias are not fully known, we have been examin- characterized by consistent and stable sub-acute to ing drugs on various experimental animal arrhythmias chronic ischemic arrhythmias, showing severe ventri- models. It is obvious that the present antiarrhythmic cular tachycardia (VT), but never deteriorating to VF. drugs are not ideal ones, and also for many different This arrhythmia is thought to be an automaticity arrhythmias, many different types of drugs are neces- arrhythmia because overdriving the atria or ventricle, by sary. Drugs are still used to maintain sinus rhythm after electrical stimulation at rates higher than the rate of VT, conversion from atrial defibrillation, to stop the transi- suppressed the VT to conducted sinus rhythm (5). tion to VF clinically, and to target pathophysiological alterations to prevent the occurrence of lethal arrhyth- 2-1-2. Methods mias. It may be worthwhile to review our studies and try “Two-stage” means that the first stage is the start of to classify drugs by their effectiveness on arrhythmias of 30 min of ischemia, followed by the second stage of a dogs, rats, guinea pigs, and so on. Our previous results permanent occlusion of the left anterior descending on classical and investigational antiarrhythmic drugs and coronary artery (LAD) of the dog. In the first stage, our recent results on cardioprotective drugs have been isolated LAD soon after bifurcation with the left circum- summarized here. flex coronary artery (LCX) was surgically isolated from Antiarrhythmic drugs have been classified by the neighboring coronary veins or connective tissues and Vaughan Williams mainly based on their effects on then tied completely with one of double threads together cardiac action potentials into classes I to IV and later with a needle of about 1 mm outer diameter, which was correlated to their effects on Na+ channel, β-receptors, immediately withdrawn to make the needle size patency and K+ and Ca2+ channels (4). Here our animal experi- to produce a state of ischemia, but not result in complete mental arrhythmia models, both the automaticity in- occlusion. This usually produces ischemic changes in duced and re-entry induced arrhythmias are presented, the electrocardiogram (ECG) and produces only prema- which we used to quantitatively compare drug effects on ture ventricular contractions (PVC) lasting for a few min the arrhythmias. There have been many studies of anti- followed by a quiescent 30 min, and then another suture arrhythmic drug efficacies using animal arrhythmias, but is used to completely occlude the LAD. After the final most of them showed the effectiveness of a single drug ligature, the thoracotomized chest is closed, and the or made comparisons of that drug with one or two animal is left to recover from the anesthesia for use 24 or standard drugs. To make a preclinical prediction of the 48 h after coronary ligation. Though cardiac surgery usefulness of the drug, comparisons among many drugs under anesthesia in a sterile environment is needed, and were almost impossible. We used standard and repro- the technique of LAD isolation is not always easy, very ducible models that can occur clinically and tried to stable arrhythmias, PVC and VT (defined by more than study the antiarrhythmic drugs’ effects by comparing 3 continuous PVC), can be obtained which usually them quantitatively and qualitatively to find common appear several hours later, and the VT becomes fulmi- pharmacological properties and predict antiarrhythmic nant 24 h later in a conscious state, lasting up to 48 h; mechanisms of action of drugs. We have already written thus this arrhythmia can be used to evaluate and compare several summary review papers (5 – 8), but in this drug effects. The arrhythmias are continuous, and at the review, we have added new data obtained in recent peak of about 24 h after ligation, the PVC consists of years to compare a wide range of drugs. almost all the beats. To judge whether the beats are sinus beat or PVC, atrial electrodes were sutured on the epicardial surface of the right atrial appendage during Arrhythmia Models and Drugs 335 the operation, and ECG and atrial electrogram were channel–blocking drugs suppress this two-stage coro- simultaneously obtained. Preferably a His electrogram nary ligation arrhythmias