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Recent data with encainide and flecainide (CAST study) question the benefit of reducing premature ventricular contractions in survivors of myocardial infarction. Proarrhythmic mechanisms might include excessive slowing of conduction. In patients with supraventricular tachycardias, proarrhythmic effects of Class 1c agents are very uncommon.
Surgical patients often are receiving antiarrhythmic therapy. Thus, because anaesthetic agents can affect cardiac function and may interact with concurrent antiarrhythmic medications, the anaesthetist should be aware of the electrophysiology associated with dysrhythmias and their management. Tocainide, flecainide, mexiletine, encainide and amiodarone have been introduced recently and each has an unique pattern of bioavailability, metabolism and toxicity. Patients treated with these drugs need special concern as they have abnormal cardiovascular systems and may be at increased risk for perioperative morbidity. In addition, unexpected untoward reactions and toxicity can result from interactions of anaesthetic agents and these drugs. This review discusses normal cardiac electrophysiology, common dysrhythmias and the electrophysiological effects of the newer oral antiarrhythmic drugs.
Propafenone, encainide and flecainide have been categorized as class Ic antiarrhythmic drugs, since they produce similar clinical electrophysiological effects. However, propafenone has also modes of action that differ substantially from pure class Ic activity. The most distinctive electrophysiological difference from other class Ic antiarrhythmic drugs stems from its structural similarity with other beta-adrenoceptor antagonists. The potency of the beta-adrenoceptor blocking property of propafenone has been estimated to range from 1/20 to 1/50 that of propranolol on a molar basis. Because the plasma concentrations of propafenone during long-term treatment may be up to 50 or more times that of propranolol, the beta-adrenoceptor blocking effect may be clinically relevant. However, although the beta-adrenoceptor blocking effects are readily demonstrable in vitro, clinical data are more inconsistent, because the beta-adrenoceptor blocking action has been reported as being undetectable to significant. During atrial fibrillation, with or without accessory pathways, propafenone exerts effective and prompt control of the ventricular rate in patients who fail to convert to sinus rhythm. However, compared with other class Ic antiarrhythmic drugs, propafenone has not been proved generally better in controlling the ventricular rate.
INTRODUCTION: Retroconduction (ventriculo-atrial conduction) remains a problem for patients with implanted cardiac rhythm devices. Pacemaker algorithms can detect and terminate endless loop tachycardia (ELT), but actual prevention of ELT may require anti-arrhythmic drugs (AADs). Similarly, AADs can affect ICD rhythm discrimination algorithms that depend on atrio-ventricular ratios. There is concern whether these drugs remain effective during stress situations. METHODS: Electrophysiologic studies that included retroconduction testing using slow ramp pacing were done in 1332 patients. The presence or absence of retroconduction at baseline and with drug was recorded, as was the rate at block. As a stress surrogate, isoproterenol was used to test retroconduction and reversal of drug-induced block. RESULTS: Procainamide, mexiletine, phenytoin, disopyramide, quinidine, beta-blockers, encainide, and amiodarone caused complete retrograde block or decreased the rate at which block occurred (mean 76% of patients, p < 0.008), whereas digoxin, lidocaine, diltiazem, and verapamil did not. Isoproterenol (in the absence of AADs) increased the rate at block in 82% of 404 patients with retroconduction at baseline (p < 0.005). Of 319 patients without retroconduction at baseline, 134 (42%) developed retroconduction after isoproterenol. Isoproterenol reversed retrograde block in 39% of patients with block on an AAD. Amiodarone, digoxin, and the combination of digoxin plus a beta-blocker were most effective at resisting this reversal of ventriculo-atrial block (80%, 68%, and 75% respectively). CONCLUSION: Most of the AADs reviewed increase the cycle length at block or abolish retroconduction, while isoproterenol has the opposite effect. Anti-arrhythmic medications, particularly amiodarone, digoxin, and the combination of digoxin plus a beta-blocker may be considered for a patient with multiple ELT episodes or certain ICD detection problems.
The aim of antiarrhythmic drug therapy is to terminate or suppress specific arrhythmias and improve cardiovascular function. Short-term studies of the new Class I drugs encainide, mexilitine, and tocainide have demonstrated only minor falls in cardiac index with modest rises in mean aortic pressure. In contrast, disopyramide has been shown to depress myocardial function in both animals and patient studies. Heart failure may be precipitated by therapy with disopyramide and electromechanical dissociation has been reported. Class II agents with beta-adrenergic blocking actions all produce a degree of myocardial depression. Atenolol resembles propranolol in patients with coronary artery disease in its hemodyanmic effects, whereas acebutolol is less of a depressant, resembling practolol. The Class III agent amiodarone has only a mild depressant effect associated with a reduction in afterload and an increase in coronary blood flow. The Class IV agent verapamil, which is a calcium channel blocker, has potent myocardial depressant actions and causes peripheral vasodilatation. Hypotension, heart failure, and shock have been precipitated particularly in patients receiving beta-blocking drugs concurrently. While all the new antiarrhythmic drugs currently studied will cause some degree of hemodyanmic depression in an appropriately high concentration, present investigations suggest that particular caution needs to be taken when disopyramide, aprindine, atenolol, and verampamil are administered either acutely by the intravenous route or chronically by the oral route.
Changes in the pharmacokinetics of antiarrhythmic agents may be anticipated in patients with congestive heart failure (CHF), although the magnitude or direction of change is not always predictable. Factors complicating antiarrhythmic therapy in patients with CHF include both physiologic changes resulting from the disease state and unwanted effects of drug therapy for CHF. The volume of distribution is often significantly decreased (by as much as 50%) and loading doses should be reduced proportionately. Decreased blood flow to the liver and kidneys and decreased hepatic drug-metabolizing activity serve to diminish drug clearance. In some cases, simultaneous decreases in volume of distribution and clearance may result in little, if any, change in elimination half-life, despite higher plasma concentrations. Conversely, the elimination half-life of antiarrhythmic agents may be doubled in patients with CHF, necessitating a reduction in dosage. In the latter case, the time needed to reach steady state is lengthened, so that premature escalation of dosage may lead to excessive drug accumulation. In terms of their pharmacodynamics, most antiarrhythmic agents have a degree of negative inotropic effect at some concentration, and patients with reduced myocardial reserve are especially vulnerable to these effects. Some of the newer agents (such as tocainide, mexiletine, and encainide) appear to cause only minimal myocardial depression. Potential complications during therapy with all antiarrhythmic agents that are of special concern in patients with CHF include diuretic-induced hypokalemia, proarrhythmia, and possible interactions with cardiac glycosides and other drugs. Therapy for patients with CHF should be initiated with low doses of the agent selected, and the dosage carefully titrated while the patient is monitored, to confirm both efficacy and the absence of adverse effects. During subsequent outpatient therapy the patient should be carefully observed for sign of unexpected reactions, toxicity, or electrolyte imbalance.
Ventricular tachycardia (VT) or ventricular fibrillation is the most frequently documented mechanism of sudden cardiac death (SCD) in patients with coronary heart disease. There is no definitive proof that the abolition of complex ventricular ectopy, accomplished conventionally by pharmacologic therapy, results in the prevention of SCD; in the recent Cardiac Arrhythmia Suppression Trial (CAST), patients treated with encainide or flecainide demonstrated a greater incidence of cardiac death and arrhythmic death than a placebo group. Traditionally, the role of invasive electrophysiologic testing has been reserved for the evaluation of patients with complex ventricular ectopy associated with unexplained syncope, presyncope, or SCD, and for those patients who have sustained VT or ventricular fibrillation. Management of patients with complex ventricular arrhythmias by noninvasive methods (such as the 24-hour ambulatory ECG and exercise testing) has been the approach implemented for most patients thought to be at risk of SCD who have not experienced syncope, presyncope, or sustained VT. The CAST results, coupled with the fact that ambulatory ECG may lack sensitivity and overpredict successful therapy, warrant a discussion of noninvasive and invasive methods currently available for the evaluation and management of patients with complex ventricular arrhythmias. Among some of the relatively new techniques are programmed electrical stimulation and signal-averaged electrocardiography, both of which have been shown to be valuable in delineating high- and low-risk SCD groups.
Methods of documenting the efficacy of antiarrhythmic drugs are controversial because of wide inter- and intrasubject variability of the arrhythmias treated. In patients with symptomatic arrhythmias, clinical benefit can be inferred when symptoms are reduced or abolished, but the response cannot be quantitated. Multiple ambulatory monitoring periods before and during treatment permit determination of reductions of arrhythmia to levels of statistical significance but are costly and time-consuming. Programmed electrophysiologic induction study may be helpful in determining efficacy of some antiarrhythmic agents because of its high specificity, but its use is limited because of a low sensitivity. Titrating patients with multiple dosing into accepted plasma level therapeutic ranges may be helpful for individual patient care but does not allow quantitation. Recently, a statistical model based on linear regression analysis with established 95 and 99% confidence intervals has been used to compare efficacy of quinidine and encainide with success. Wider application of this model is suggested for determining antiarrhythmic drug efficacy.
The proarrhythmic potential and electrophysiologic effect of flecainide acetate, a potent class IC anti-arrhythmic agent, are considered in this report. Although the definition of a proarrhythmic effect is arbitrary, several such definitions are discussed and applied to data on flecainide. In patients with chronic ventricular arrhythmias, an increase in VPC frequency developed in 0 to 4% of patients, compared with 1 to 8% of patients who received quinidine and 2% who received encainide, another class IC agent. In patients with acute hemodynamically significant ventricular arrhythmias, the proarrhythmic effects were noted in 5 to 12%. Proarrhythmic effects appear to be more common in patients with left ventricular dysfunction and life-threatening ventricular arrhythmias. The depression of atrioventricular conduction produced by flecainide is similar to that seen with other class IC agents. Increases in PR and QRS intervals are related to dose and plasma concentration and are approximately 25% at therapeutic levels. These changes in the electrocardiographic intervals do not appear to carry important clinical implications and do not require discontinuation of flecainide. QT prolongation is absent or minimal with flecainide. Guidelines for management of patients with flecainide are suggested.
Antiarrhythmic drugs have been recognized to possess 1 or more classes of antiarrhythmic action. This classification scheme is useful, but has major limitations because the available drugs and their metabolites have multiple actions. This report presents an overview of the distinguishing features of the most frequently used agents having class I or III actions. Agents with class I actions are local anesthetic agents that depress the fast inward depolarizing sodium current and thereby slow the rate of the rise of the action potential (phase 0). This category is further divided into classes IA, IB, and IC according to the degree of potency as sodium channel inhibitors, and the individual effects of the drug on action potential, conduction velocity and repolarization. Included in the spectrum of agents with class I action are quinidine, procainamide, disopyramide, lidocaine, tocainide, mexiletine, flecainide, amiodarone, encainide and lorcainide. The antiarrhythmic drugs that exert class III action lengthen repolarization and refractoriness; included in this category are amiodarone, quinidine, bretylium and sotalol. Because of the broad range of effects that antiarrhythmic agents may exert, safe and effective therapy requires a thorough familiarity with the pharmacologic profile of each drug administered and a careful evaluation of the presenting condition and the patient history. In some cases, a multiple drug regimen may be most appropriate. Various combinations such as class IA and IB agents, have been shown to slow conduction synergistically and increase refractoriness while keeping adverse effects to a minimum.
The Cardiac Arrhythmia Pilot Study (CAPS) was a randomized, double-blind trial of antiarrhythmic drugs (encainide, flecainide, moricizine, imipramine and placebo) in 502 patients with at least 10 ventricular premature complexes/hour, 6 to 60 days after acute myocardial infarction. CAPS tested the feasibility of performing a larger study to determine if suppression of ventricular ectopic activity after acute myocardial infarction could improve survival. Patients in CAPS were followed for 1 year. All death or cardiac arrest events were evaluated by at least 2 investigators using a classification scheme that characterized the underlying mechanism as cardiac arrhythmic, cardiac nonarrhythmic or noncardiac. Forty-five patients (9%) died or had cardiac arrest during the 1-year follow-up, 29 (64%) within 1 hour from the onset of symptoms and 16 greater than 1 hour from the onset of symptoms. Twenty-three deaths (51%) were classified as arrhythmic, 19 (42%) as nonarrhythmic and 3 (7%) as noncardiac. Acute myocardial ischemia or infarction was associated with the death/cardiac arrest event in 16 patients (36%), 8 in the arrhythmic death group. Discrepancies in classification among reviewers were particularly common in patients with long-standing symptoms of congestive heart failure, in whom it was frequently difficult to identify the precise moment of the onset of symptoms in the death/cardiac arrest event. Using only the temporal relation of symptoms to categorize deaths or cardiac arrests, the mechanism of 12 (27%) of the 45 patients was in disagreement with the classification based on the Events Committee review. Classification of death as sudden or nonsudden is not equivalent to the classification of death as arrhythmic or nonarrhythmic.
Clinical failure of antiarrhythmic drugs often occurs in practice. Therefore, there is a need for new, effective and long-acting drugs with a wide therapeutic range and a low level of toxicity. Most new class I compounds block the fast sodium ion inward current of myocardial cells. According to their effects on the recovery kinetics of the sodium ion channel, these drugs are classified into 3 groups: IA (intermediate--cibenzoline, pirmenol, hydroxy-3-S-dihydroquinidine, quinacainol); IB (fast--tocainide, moricizine); IC (slow--flecainide, encainide, propafenone, lorcainide, indecainide, recainam and penticainide). Class IC drugs greatly depress intracardiac conduction and are the most potent antiarrhythmic compounds able to suppress ventricular premature beats. However, it is doubtful that long-term suppression of ventricular arrhythmias will improve survival of the patients. Some new drugs have been developed belonging to other classes: class II, esmolol, a new ultrashort-acting beta blocker; class III, N-acetyl-procainamide and sotalol, which prolong duration of the action potential and increase ventricular refractoriness; class IV, the mixed sodium ion-calcium ion-potassium ion antagonist, bepridil. The pharmacologic properties and the clinical effects of these new antiarrhythmic drugs are reviewed. However, future therapeutic trends will depend on the results of large multicenter clinical secondary prevention trials such as the Cardiac Arrhythmia Suppression Trial. New antiarrhythmic drugs with original electrophysiologic profiles and minimal adverse effects must prove their ability not only to suppress arrhythmias but also to reduce sudden cardiac death rate.
Bepridil is an antianginal agent with multiple therapeutic actions. It decreases calcium influx through potential-dependent and receptor-operated sarcolemmic calcium channels and acts intracellularly as a calmodulin antagonist and calcium sensitizer. Thus, in cardiac muscle it enhances the sensitivity of troponin C to calcium, stimulates myofibrillar adenosine triphosphatase activity, removes calmodulin's inhibitory effect on sarcoplasmic reticulum calcium release, and inhibits sodium-calcium exchange--actions that tend to offset the effects of calcium influx blockade on cardiac contractile force. However, in vascular smooth muscle where the calcium-calmodulin complex promotes muscle contraction by activating myosin light-chain kinase phosphorylation of contractile proteins, calmodulin antagonism, coupled with bepridil's blockade of calcium influx, leads to vasorelaxation. In animal models of ischemia, bepridil and other calmodulin inhibitors show antiarrhythmic efficacy following reperfusion. Additionally, interfering with calmodulin's role in sympathetic nerve terminal function may help to limit the ischemia-induced catecholamine release that contributes to arrhythmogenesis. Bepridil shows a lidocaine-like fast kinetic block of inward sodium current (as distinct from the slow or intermediate kinetic inhibition expressed by encainide or quinidine, respectively). This inhibition is pH-dependent; activity is expressed to a greater degree at lower pH levels. This, this potentially antiarrhythmic mechanism is activated by conditions of ischemia. Bepridil's blockade of outward potassium currents and its inhibition of sodium-calcium exchange increase action potential duration and ventricular refractoriness, prolong the QT interval, and form the basis for a class III antiarrhythmic mechanism. Because hypokalemia also prolongs the QT interval, the addition of bepridil in the presence of hypokalemia can lead to excessive prolongation. Bepridil both increases myocardial oxygen supply through coronary vasodilation and decreases myocardial oxygen demand through mild heart rate and afterload reduction, and shows potential antiarrhythmic activity through class IB, III, and IV mechanisms.(ABSTRACT TRUNCATED AT 250 WORDS)
Serial testing of antiarrhythmic drugs by programmed electrical stimulation can be costly in time, expense and risk. The purpose of this study was to evaluate the results of serial electropharmacologic tests for similarities that might obviate the need for protracted drug testing. Serial electropharmacologic testing was performed in 283 patients with coronary artery disease and clinical sustained ventricular tachycardia (VT) or fibrillation (VF). Drug tests were defined as concordant if sustained VT or VF could be consistently induced, or failed to be consistently induced during all such trials in a given patient. The following drugs were included for testing: procainamide, quinidine and disopyramide (class IA); phenytoin, mexiletine and tocainide (class IB); and flecainide and encainide (class IC). All patients were serially tested with > or = 2 (mean and median, 3) antiarrhythmic agents regardless of results from drug-free testing or initial acute drug testing. Overall, the results of serial drug trials directed by programmed stimulation were concordant in more than two thirds of patients. Concordance was comparably high whether patients were serially tested with drugs within the same antiarrhythmic class, or with drugs from differing classes, and was not related to patients' clinical or electrophysiologic characteristics. Protracted serial electropharmacologic testing does not appear necessary for predicting successful or unsuccessful antiarrhythmic drug therapy in survivors of clinical VT or VF. Single drug testing can identify most patients whose arrhythmia will or will not respond to medications.
Great advances have been made in our understanding of cardiac arrhythmias and the effect of drugs on these arrhythmias. Several new types of antiarrhythmic drugs have been introduced. For example, encainide, flecainide, or lorcainide are new type I drugs that exert their major effects on depressing cardiac conduction. These drugs appear to be very effective for suppression of premature ventricular contractions. The introduction of verapamil (a calcium antagonist) allows for rapid control of supraventricular arrhythmias by virtue of its effects on the slow-channel (predominately Ca++) receptors. New beta-blocking drugs have been introduced which may prove beneficial in certain clinical situations since they exert more selective blockade of the cardiac receptors (beta1) as opposed to smooth muscle receptors (beta2). Amiodarone is an extremely potent drug which is effective for both supraventricular as well as ventricular arrhythmias. The major cellular electrophysiologic effect of this drug is to prolong the action potential duration. Its major clinical drawback is the rather formidable long-term side effects which include corneal opacities, thyroid dysfunction, neurologic toxicity, and pulmonary fibrosis.
The effectiveness of masking in the Cardiac Arrhythmia Suppression Study (CAPS) was assessed by surveying investigators and study coordinators. CAPS patients were assigned one of five treatments: encainide, flecainide, imipramine, moricizine, or placebo. Had all treatments appeared identical and equal numbers of patients been assigned to each, 20% of guesses of treatment assignment would be correct by chance alone. Since neither was possible in CAPS, higher rates of correct guessing were expected. Overall, respondents correctly identified treatment 39% of the time. Investigators identified the drug 30% of the time with rates of 20%, 24%, 37%, 20%, and 55% for the five treatment groups, respectively, whereas coordinators identified the treatments 47% of the time with scores of 42%, 45%, 50%, 40%, and 60%. Side effects and a suboptimal masking design detracted from masking; electrocardiographic changes did not imipramine, which caused characteristic side effects, was the most frequently identified active treatment. Scores were higher for investigators who had prior experience with the drugs, but scores did not improve over the course of the trial. Findings suggest that to improve masking all drugs should have been matched in appearance or persons evaluating treatments should not have been allowed to see the drugs.
Antiarrhythmic medications are widely used either at the ventricular or supraventricular level. However, those drugs can induce severe side effects. Actually, antiarrhythmic drugs are paradoxically able to favour the occurrence of new arrhythmias or aggravate the preexisting arrhythmia for which they were indicated. These proarrhythmic effects have been found in 10 to 20% of patients, as evidenced by literature. Moreover, the CAST study showed a significant increase in mortality in patients with non sustained ventricular arrhythmias after myocardial infarction who were treated with either flecainide or encainide, compared to the placebo group. This overmortality seems to be due, in large, to the proarrhythmic effects of antiarrhythmic drugs. Several mechanisms have been evoked, related to the type of antiarrhythmic drug and to the presenting arrhythmia: early post-depolarization due to slow calcium and sodium inward currents in the case of torsades de pointes, facilitation of intraventricular reentries in the case of class 1c antiarrhythmic drugs, facilitation of the ventricular response of atrial arrhythmias. These deleterious effects, that can be very serious, are unpredictable, not toxicity-related and all antiarrhythmic drugs are involved. Their detection appears to be difficult and is based upon ECG, Holter monitoring, treadmill test and possibly electrophysiologic study. The use of antiarrhythmic drugs requires the knowledge of their proarrhythmic effects, the analysis of the benefit-risk ratio--particularly if left ventricular function is impaired--and careful monitoring.
Antiarrhythmic therapy in 506 consecutive patients undergoing 1,268 antiarrhythmic drug trials for ventricular tachycardia or ventricular fibrillation was reviewed for evidence of arrhythmogenic drug effect defined as the occurrence of a new form of ventricular tachyarrhythmia temporally associated with initiation of drug therapy or dosage increase. Arrhythmogenic effects occurred in 6.9% of patients and 3.4% of drug trials. This ranged from a high of 11.8% caused by encainide to none occurring with procainamide, tocainide or beta-adrenergic blocking drugs. The incidence of arrhythmogenesis was significantly greater in patients whose presenting arrhythmia was sustained ventricular tachycardia than it was in those who presented with nonsustained ventricular tachycardia or ventricular fibrillation (p = 0.02). Decreased systolic function measured echocardiographically at the base of the left ventricle was associated with an increased incidence of arrhythmogenic effects (p = 0.006) whereas global left ventricular ejection fraction was not. Age, gender, cardiac diagnosis, location of prior myocardial infarction and New York Heart Association functional class for heart failure were not related to the occurrence of drug-induced arrhythmias. These findings emphasize the need for in-hospital cardiac monitoring during initiation of antiarrhythmic drug therapy for ventricular tachyarrhythmias.