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PubMed1990

Identification of antiarrhythmic drugs and their metabolites in urine.

Identification of the antiarrhythmic drugs ajmaline, aprindine, diltiazem, disopyramide, flecainide, gallopamil, lidocaine, lorcainide, mexiletine, phenytoin, prajmaline, propafenone, quinidine, sparteine, tocainide and verapamil and their metabolites in urine is described. After acid hydrolysis of the conjugates, extraction and acetylation, the urine samples were analysed by computerized gas chromatography-mass spectrometry. Using ion chromatography with the selective ions m/z 58, 72, 84, 86, 136, 224, 266, and 426, the possible presence of antiarrhythmic drugs and/or their metabolites was indicated. The identity of positive signals in the reconstructed ion chromatograms was confirmed by a visual or computerized comparison of the stored full mass spectra with the reference spectra. The ion chromatograms, reference mass spectra and gas chromatographic retention indices (OV-101) are documented. The method presented is integrated in a general screening procedure (general unknown analysis) for several groups of drugs.

Acetylation↗
PubMed1983

Do evacuated blood collection tubes interfere with therapeutic drug monitoring?

The influence of various brands of evacuated blood collection systems (the old type, red stoppered Vacutainer; the new type, blue stoppered Vacutainer; Monoject and Venoject) on therapeutic drug monitoring was investigated. No interferences were found in the assay of ethosuximide, phenobarbital, phenytoin, valproic acid, digitoxin, digoxin, procainamide, gentamicin and theophylline. Using Monoject and old type Vacutainer tubes, lower levels were found in the disopyramide assay: 91.3 +/- 4.6% (p less than 0.05) and 91.7 +/- 7.0% (not significant) respectively, and in the quinidine assay: 82.8 +/- 6.7% (p less than 0.02) and 83.9 +/- 4.4% (p less than 0.001) respectively as compared with glass tubes. In the carbamazepine assay a decrease was found in the Monoject tubes only: 93.7 +/- 1.7% (p less than 0.01). The stoppers of Monoject tubes and the old type Vacutainer tubes contained the plasticizer tris-(2-butoxyethyl)phosphate (TBEP), which has been shown to be a potent inhibitor of the binding of several drugs to alpha 1-acid glycoprotein. Using the new type Vacutainer and the Venoject, no interferences were found.

Blood Specimen Collection↗
PubMed1988

Calcium channel antagonists. Part III: Use and comparative efficacy in hypertension and supraventricular arrhythmias. Minor indications.

The major antihypertensive mechanism of calcium antagonists is by decreasing the systemic vascular resistance, modified by the counter-regulatory responses of the baroreflexes and the renin-angiotensin-aldosterone system. In severe hypertension, the concept that calcium overload of the vascular myocyte could precipitate or aggravate peripheral vasoconstriction provides a logical basis for the use of these agents as first choice therapy; nifedipine, especially, has been well tested. As monotherapy for mild to moderate hypertension each of the three first-generation agents compares well with beta-blockers. Calcium antagonists may have a special role in the therapy of certain patient groups (elderly, black) or in those subjects whose life style involves intense physical or mental exertion (hemodynamics better maintained than with beta-blockade) or in patients with early end-organ damage such as left ventricular hypertrophy or renal insufficiency. However, the goal blood pressure may not be reached during monotherapy so that drug combinations may be required. Further indications for these compounds are as follows. Verapamil and diltiazem are frequently used in supraventricular tachycardias including acute and chronic atrial fibrillation. In the arrhythmias of the Wolff-Parkinson-White syndrome, there is the potential danger of provocation of anterograde conduction. Further indications for calcium antagonists, still under evaluation, include congestive heart failure (controversial), hypertrophic cardiomyopathy (verapamil), primary pulmonary hypertension (high doses required), Raynaud's phenomenon (nifedipine and diltiazem effective), peripheral vascular disease (proof not yet documented), cerebral insufficiency and subarachnoid hemorrhage (nimodipine promising), migraine, exertional bronchospasm, renal disease, atherosclerosis (experimental), and primary aldosteronism (nifedipine inhibits aldosterone release). Second-generation agents include dihydropyridines, such as nitrendipine, nicardipine, felodipine, amlodipine, nisoldipine, nimodipine, and isradipine. From these will be selected agents that are longer acting and provide higher vascular selectivity. New preparations of existing agents include slow-release formulations of nifedipine, verapamil, and diltiazem. Minor side effects include those caused by vasodilation (flushing and headaches), constipation (verapamil), and ankle edema. Serious side effects are rare and result from improper use of these agents, as when intravenous verapamil is given to patients with sinus or atrioventricular nodal depression from drugs or disease, or nifedipine to patients with aortic stenosis. The potential of a marked negative inotropic effect is usually offset by afterload reduction, especially in the case of nifedipine. Yet caution is required when calcium antagonists, especially verapamil, are given to patients with myocardial failure unless caused by hypertensive heart disease. Drug interactions of calcium antagonists occur with other cardiovascular agents such as alpha-adrenergic blockers, beta-adrenergic blockers, digoxin, quinidine, and disopyramide.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1991

The pharmacologic treatment of atrial fibrillation.

The pharmacologic treatment of atrial fibrillation (AF) is aimed at controlling the ventricular response, restoring sinus rhythm, and preventing or delaying relapses. In the control of ventricular response, digitalis maintains a primary role when the arrhythmia is accompanied by heart failure. In ischemic, hypertensive, and degenerative (whose number is increasing at present) cardiopathies without evident ventricular dilatation, treatments with calcium antagonists (such as verapamil, gallopamil, or diltiazem) or beta-blocking agents must be preferred. In order to control the ventricular response in patients with chronic AF during physical activity, the association of digitalis with beta-blocking agents or calcium antagonists seems to provide satisfactory results. The drugs of the IC class, especially flecainide, represent a certain therapeutical progress in the restoration of sinus rhythm in the treatment of paroxysmal atrial fibrillation affecting subjects without evident alterations of ventricular function, particularly in subjects with Wolff-Parkinson-White syndrome, with forms of vagal origin, or with atrial fibrillation alone. A therapeutic combination of digitalis and quinidine may produce resolution of the arrhythmia in the presence of altered ventricular function or when AF is of an uncertain onset. In patients with hypertensive, ischemic, and/or degenerative cardiopathy without evident ventricular or advanced heart failure, the verapamil-quinidine association may also be effective and even quicker. The combination of drugs of the I and III class for restoration of the sinus rhythm in particularly resistant forms of AF without evident structural heart alterations is promising but must be verified in a greater number of patients. In the prevention of relapses amiodarone appears to have the widest spectrum of advantages from an electrophysiologic point of view; however, because of its many side effects, amiodarone represents a late therapeutical choice. The promising results obtained with flecainide are disputed by the results of the CAST, which limit the possibilities of using this drug to a low number of cases (W.P.W. syndrome, AF of vagal origin, atrial fibrillation alone). In the past, quinidine and disopyramide have been the drugs most widely used in the prophylaxis of AF. These drugs have a similar efficacy, and both of them provided some positive results. However, because of untoward side effects (especially for quinidine) during chronic treatment, the use of these drugs has been questioned. Perhaps in the majority of patients, the less dangerous therapeutic choice after the termination of the fibrillation is a combination of drugs slowly down AV node activity (digitalis or calcium antagonists and beta blockers) with class IA antiarrhythmics.

Adrenergic beta-Antagonists↗
PubMed2000

Effects of antiarrhythmic drugs on cloned cardiac voltage-gated potassium channels expressed in Xenopus oocytes.

The effects of 17 commonly used antiarrhythmic drugs on the rapidly activating cardiac voltage-gated potassium channels (Kv1.1, Kv1.2, Kv1.4, Kv1.5, Kv2.1 and Kv4.2) were studied in the expression system of the Xenopus oocyte. A systematic overview on basic properties was obtained using a simple and restricted experimental protocol (command potentials 10 mV and 50 mV positive to the threshold potential; concentration of 100 micromol/l each). The study revealed that 8 of 17 drugs yielded significant effects (changes >10% of control) on at least one type of potassium channel in the oocyte expression system. These drugs were ajmaline, diltiazem, flecainide, phenytoin, propafenone, propranolol, quinidine and verapamil, whereas the effects of adenosine, amiodarone, bretylium, disopyramide, lidocaine, mexiletine, procainamide, sotalol and tocainide were negligible. The drug effects were characterized by reductions of the potassium currents (except for quinidine and ajmaline). A voltage-dependence of drug effect was found for quinidine, verapamil and diltiazem. The different effect of the drugs was not related to the fast or slow current inactivation of the potassium channels (except for verapamil). Profiles of the individual drug effects at the different potassium channel types were identical for propafenone and flecainide and differed for all other substances. The study demonstrates marked differences in sensitivity to antiarrhythmic drugs within the group of voltage-operated cardiac potassium channel types. Taking the restrictions of the oocyte system into consideration, the findings suggest that several antiarrhythmic drugs exert significant effects at rapidly activating cardiac potassium channels.

Animals↗
PubMed1997

The role of serotonin re-uptake inhibitors in preventing recurrent unexplained childhood syncope -- a preliminary report.

UNLABELLED: To assess the efficacy of a serotonin re-uptake inhibitor, sertraline hydrochloride, in preventing recurrent neurocardiogenic syncope, we studied 15 patients (10 female; mean age 12.9 +/- 2 years) with positive head-upright tilt test and resistant to standard pharmacotherapy, atenolol or disopyramide. The patients were given 50 mg oral sertraline hydrochloride daily for 6 weeks. Intolerance to the drug was seen in 3 patients and 2 had syncopal episodes during the therapy. A head-upright tilt table test was then repeated in 10 patients. Six were tilt negative and asymptomatic over a mean follow up period of 7 +/- 3 months while four remained tilt positive: two experienced marked hypotension and bradycardia, characterized as mixed type syncope, and two had cardiac asystole, lasting > 10 s, during tilting, thereby exhibiting a cardio-inhibitory response. CONCLUSION: Sertraline hydrochloride may be useful in preventing recurrent neurocardiogenic syncope resistant to standard pharmacotherapy but careful clinical studies are essential before such a treatment strategy can be recommended since serious asystole could develop.

1-Naphthylamine↗
PubMed2004

A patient responding to combined therapy with pirmenol and midodrine for refractory neurally mediated syncope complicated by prostatic hypertrophy.

A 67-year-old man with neurally mediated syncope (NMS) complicated by prostatic hypertrophy responded well to combined therapy with pirmenol and midodrine. In 2003, syncope occurred while the patient was driving a car. Results of head-up tilt-table testing (HUT) suggested a mixed type of NMS. Oral administration of disopyramide provided severe urinary obstruction. Pirmenol treatment was not associated with syncope during ordinary HUT, but nausea, sweating, and syncope occurred during HUT with provocative administration of isosorbide dinitrate. Combined therapy with pirmenol and midodrine avoided syncope during HUT, and has prevented attacks since discharge from the hospital.

Aged↗
PubMed2006

Effects of cardioactive medications on retrograde conduction: continuing relevance for current devices.

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.

Adrenergic beta-Agonists↗
PubMed2002

Maintaining stability of sinus rhythm in atrial fibrillation: antiarrhythmic drugs versus ablation.

In managing atrial fibrillation, the main therapeutic strategies include rate control, termination of the arrhythmia, and pr vention of recurrences and thromboembolic events. Rate control with digoxin, b-blockers, verapamil, and diltiazem may be preferred in drug refractory and sedentary patients with markedly dilated left atrium and atrial fibrillation of long duration. Drugs useful in the maintenance of sinus rhythm include quinidine, procainamide, disopyramide, sotalol, amiodarone, dofetilide, flecainide, and propafenone. In patients with structural heart disease, the class III antiarrhythmics are the initial drugs of choice, given their neutral effects on survival in a post-myocardial infarction and congestive heart failure population. Due to high recurrence rates with pharmacologic therapy, nonpharmacologic options of therapy include atrioventricular junction ablation, atrial defibrillators, catheter ablation of pulmonary vein foci, and attempts to perform an atrial Maze procedure using catheters. Hybrid therapy using drugs in combination with nonpharmacologic approaches will be used more frequently in the future for refractory patients.

Anti-Arrhythmia Agents↗
PubMed2002

Hypertrophic Cardiomyopathy.

When an individual is diagnosed with hypertrophic cardiomyopathy (HCM), all relatives potentially affected by Mendelian autosomal-dominant inheritance should be evaluated with an electrocardiogram (ECG) and echocardiogram. Genetic testing should be considered in high-risk mutations where there are diagnostic uncertainties. Symptom relief depends on beta-blockers as first-line therapy. If the disease is nonobstructive, then calcium channel blockers can be added or used alone. If there is a significant left ventricular outflow tract (LVOT) gradient then disopyramide can be used, ideally in combination with a beta-blocker. Verapamil should be used with care due to potential exacerbation of the LVOT gradient. Nonmedical therapy for obstructive disease consists of surgical myectomy, alcohol septal ablation, or dual-chamber pacing. Surgery is the gold standard, although in experienced hands and directed appropriately, septal ablation achieves good results. Pacing is generally less effective. The development of atrial fibrillation (AF) or left atrial enlargement carries a significant risk of thromboembolism. All patients should be closely observed for AF and thromboembolic risk, and the threshold for initiation of anticoagulation should be low in patients with sustained palpitations, atrial enlargement, and nonsustained supraventricular arrhythmia on Holter. All patients with HCM should be assessed for their risk of sudden death regardless of severity of symptoms or morphology. The factors predictive of risk are 1) previous cardiac arrest; 2) unexplained syncope; 3) family history of premature sudden death; 4) abnormal blood pressure response to exercise; 5) nonsustained ventricular tachycardia; and 6) severe left ventricular hypertrophy >/= 30 mm.

Journal Article↗
PubMed1980

Tocainide for drug-resistant ventricular arrhythmias: efficacy, side effects, and lidocaine responsiveness for predicting tocainide success.

Tocainide therapy has been evaluated in 38 patients with ventricular arrhythmias. Thirty-one had recurrent sustained ventricular tachycardia and/or fibrillation and 29 required prior cardioversions. These arrhythmias could not be managed with quinidine, procainamide, disopyramide, or propranolol. Tocainide doses averaged 1,500 mg/day (range 600 to 2,400) and the majority of patients had plasma concentrations from 6 to 12 micrograms/ml. Twenty-two patients (61%) had their arrhythmias controlled with tocainide and 16 (39%) did not. Tocainide dose and plasma concentrations were similar for responders and nonresponders. Lidocaine was effective in 26 patients and 16 (63%) of these had their arrhythmias controlled with tocainide. Of 12 patients in whom lidocaine was known to be ineffective or who had not been previously treated, only two (17%) had arrhythmias controlled with tocainide (P < 0.02). Side effects occurred in approximately two thirds of patients but required discontinuation of long-term tocainide in only three patients.

Aged↗
PubMed1985

A review of the uses and limitations of tocainide--a class IB antiarrhythmic agent.

In conclusion, it appears that tocainide will be an extremely important new antiarrhythmic agent in the armamentarium of the clinical cardiologist (Table V). Its similarity to lidocaine and the predictability of its efficacy in patients responsive to lidocaine is an important note. Its lack of interaction with beta blockers and digoxin is also a promising feature. While tocainide has proven to be effective in the prophylaxis and treatment of patients with both refractory and chronic ventricular arrhythmias, its efficacy is in the approximate range of other class I agents, such as quinidine, procainamide, and disopyramide. Its side effect profile appears to be similar in percentage to the adverse effects of quinidine, but often these side effects are milder, better tolerated, and respond to dosage alteration. Thus, tocainide will undoubtedly prove to be a useful new antiarrhythmic agent, particularly when compared to the currently available antiarrhythmic agents.

Animals↗
PubMed1985

How the university cardiologist treats ventricular premature beats: a nationwide survey of 65 University Medical Centers.

Sixty-five of 118 university cardiologists responded to a survey of indications for treatment of ventricular ectopy, particularly in the completely asymptomatic patient or those with palpitations as the only symptom. The percentage of cardiologists treating these patients increased as the complexity of ventricular ectopy increased, as the severity of underlying heart disease increased, as the symptoms increased from completely asymptomatic to palpitations or skipped beats, if the patient experienced dizziness or syncope, and if the patient had complex VPBs or asymptomatic VT after MI. Ninety-eight percent of respondents had patients who experienced exacerbation of arrhythmia with antiarrhythmic drugs. Of the conventional type 1 drugs, the drug of first choice was quinidine for 60%, procainamide for 37%, and disopyramide for 3%. The accepted indications for electrophysiologic testing included survivors of sudden cardiac arrest and patients with symptomatic VT.

Anti-Arrhythmia Agents↗
PubMed1991

Short-term variability of ventricular arrhythmia and rapid assessment of drug efficacy.

Statistical criteria for suppression and aggravation of ventricular arrhythmia were defined by means of 50 short-term drug tests performed in 24 patients. Each patient's spontaneous variability (SV) was evaluated by linear regression analysis of hour-to-hour changes in ectopy during 24- to 48-hour Holter monitoring. The response to a single oral dose of disopyramide, 300 mg, flecainide, 200 mg, and propafenone, 450 mg, was measured during a trial lasting 4 hours. Lidocaine was administered intravenously in incremental doses of up to 4 mg/min and was evaluated over 3 hours. Threshold values of ventricular arrhythmia corresponding to 95% confidence limits were calculated from baseline recordings and were used to ascertain the likelihood of a true drug effect. The minimum decrease in hourly ectopy indicating arrhythmia suppression averaged 90.9%, while an increase of at least 947% was required for a proarrhythmic effect. When these efficacy criteria were applied, 16 of 50 short-term tests revealed no drug effect. In contrast, when a 70% threshold derived from studies of daily variability was employed, only 7 of 50 trials were negative. Thus individual determination of hourly arrhythmia variability yields more stringent criteria than extrapolation from day-to-day spontaneous variation.

Aged↗
PubMed1994

Absence of tachycardia during tilt test predicts failure of beta-blocker therapy in patients with neurocardiogenic syncope.

Not all patients with neurocardiogenic syncope respond to beta-blockers. To determine whether differences in heart rate response to head-up tilt test with and without isoproterenol may predict drug efficacy, we evaluated 32 consecutive patients with a history of syncope, who were treated with beta-blockers after a positive tilt test. During the tilt test 21 patients (group A) with a baseline heart rate of 72 +/- 15 beats/min had tachycardia (mean 131 +/- 15) during tilt, before syncope, whereas 11 patients (group B) with a baseline heart rate of 68 +/- 13 beats/min did not (mean 86 +/- 13; p < 0.001). There were no significant differences between groups with regard to demographic and clinical characteristics or mean heart rate and mean arterial pressure in the supine position and during syncope. However, the proportion of patients requiring isoproterenol for provocation of syncope was significantly higher in group A compared with group B (15 of 21 vs 1 of 11; p < 0.001). All patients were treated with beta-blockers (propranolol or metoprolol). During a follow-up period of 18 +/- 6 months only one patient in group A had syncope and a positive tilt test compared with six patients in group B (9% vs 54%; p < 0.01). Development of tachycardia was a better predictor of drug efficacy than an isoproterenol-induced positive tilt test. The six nonresponders from group B were subsequently treated with disopyramide. During a mean follow-up period of 9 +/- 3 months, only one patient had syncope and another had a positive response to tilt test.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1983

Differentiation of septal from free wall accessory pathway location: observations during bundle branch block in reciprocating tachycardia in the presence of type I antiarrhythmic drugs.

In patients with Wolff-Parkinson-White syndrome, observations during bundle branch block (BBB) in reciprocating tachycardia are of value in accessory pathway localization. Most importantly, an increase in the ventriculoatrial (VA) interval of greater than or equal to 35 ms has indicated an ipsilateral free wall location and excluded a septal location. The present study examined whether data collected in the presence of type I antiarrhythmic drugs retained localizing value. Review of retrospective data showed that observations in the drug-free state were precluded by the need to suppress atrial arrhythmia during electrophysiologic study in 20% of patients with Wolff-Parkinson-White syndrome who underwent preoperative workup. Prospectively, in 15 patients with left free wall or posteroseptal pathways, we observed transient left BBB during tachycardia before and after administration of procainamide, disopyramide or quinidine. Serum drug levels ranged from 4.6 to 6.9 mg/liter, except in 1 patient with a serum procainamide level of 18 mg/liter. Drugs increased the VA interval during narrow QRS tachycardia by 17% (p less than 0.01). However, the change in the VA interval with left BBB was not significantly affected. The baseline and drug values averaged 73 ms (range 39 to 94) and 70 ms (range 39 to 90), respectively, for left free wall pathways (n = 8), and 19 ms (range 0 to 28) and 21 ms (range 2 to 35), respectively, for posteroseptal pathways (n = 7). Among the latter, the interval increased less than 30 ms during left BBB except in the patient with the high serum procainamide level, in whom the increase was 35 ms. Thus, the VA interval change that accompanied left BBB remained of localizing value with moderate blood levels of type I drugs, and an increase greater than or equal to 35 ms indicated a left free wall rather than posteroseptal pathway.

Adolescent↗
PubMed1983

Importance of metabolites in antiarrhythmic therapy.

The presence of metabolites with pharmacologic activity can produce unanticipated drug efficacy or toxicity. This is particularly true during treatment with drugs that have narrow therapeutic-toxic ratios, such as the antiarrhythmic agents. The presence of active metabolites can often be inferred from variability in the relation between pharmacologic effect and steady-state plasma concentrations of the parent drug. Moreover, metabolites may ordinarily be unimportant but can accumulate to therapeutic (or toxic) levels in disease states such as congestive heart failure, renal failure and hepatic failure. Further characterization of the contribution of such metabolites during treatment requires direct evaluation of their pharmacology in vitro, in animal models and, if indicated, in man. Procainamide and its active metabolite N-acetylprocainamide provide the best and most complete example of this sequence of observations. Other drugs, including quinidine, disopyramide, verapamil and the investigational agents encainide and lorcainide, have active metabolites for which pharmacologic activity is less well-defined. Further studies in this area will help reduce the frequency of antiarrhythmic drug adverse effects, make successful therapy more frequent, and perhaps allow insights into structure-activity relations.

Acecainide↗
PubMed1984

Symposium on the management of ventricular dysrhythmias. Antifibrillatory versus antiectopic therapy.

The concept of antifibrillatory action distinct from antiarrhythmic effect has recently been recognized. An antiarrhythmic (antiectopic) action leads to a decrease in the frequency of ventricular ectopic beats. In contrast, an antifibrillatory drug action increases myocardial electric stability, decreasing the propensity for ventricular fibrillation. Agents with predominant antiarrhythmic action (designated class I) include lidocaine, quinidine, procainamide and disopyramide. Bretylium is an agent with predominant antifibrillatory action (class III). Amiodarone and sotalol are experimental class III drugs. The beta-blockers (class II) also possess antifibrillatory action, particularly in ischemic heart disease. The rationale for the use of agents with antiarrhythmic (antiectopic) effects is the reduction of triggering events for more complex ventricular tachyarrhythmias. These agents act by slowing conduction, decreasing abnormal automaticity and affecting phase IV depolarization. In contrast, agents with antifibrillatory action may exert little effect on cardiac conduction and automaticity. However, they raise the energy threshold required for premature electrical discharge to initiate ventricular fibrillation (ventricular fibrillation threshold). The inhomogeneity of electrophysiologic properties and adrenergic tone in different portions of the heart may be reduced or eliminated. Direct electrophysiologic effects of agents such as bretylium include a general lengthening of the refractory period and the action potential duration in the heart and a diminution in the disparity of their durations between normal and abnormal myocardium. Clinical studies are incomplete, but they support the concept of antifibrillatory therapy. In postmyocardial infarction patients at intermediate risk of sudden death, the broad use of oral antiarrhythmic agents has not decreased the incidence of sudden death, whereas high-dose beta-blocker therapy, which exerts experimental antifibrillatory effects, may reduce sudden death by 30 to 70%.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗