Antidysrhythmic Drugs Research Articles

The genetic basis for cardiac dysrhythmias and the long QT syndrome.

Cardiac muscle excitation is the result of ion fluxes through cellular membrane channels. Any alterations in channel proteins that produce abnormal ionic fluxes will change the cardiac action potential and the pattern of electrical firing within the heart. The idiopathic long QT syndrome (LQTS) is an inherited cardiac pathology localized to mutated genes encoding for myocardial, voltage-activated sodium and potassium ion channels. The expression of abnormal sodium and potassium channels results in aberrant ionic fluxes that produce a prolonged ventricular repolarization. This prolonged time to repolarization is the electrophysiologic basis for prolongation of the QT interval. Individuals with LQTS are at significant risk for developing lethal ventricular dysrhythmias due to an abnormal pattern of cardiac excitation. Identification of a genetic basis for LQTS has had significant implications for genetic counseling, the development of effective antidysrhythmic drug therapies, and nursing interventions.

Cocaine-induced wide complex dysrhythmia

Cocaine is a local anesthetic with the potential to induce dysrhythmia due to direct myocardial sodium channel antagonism similar to class I antidysrhythmic drugs. The hallmark of myocardial sodium channel poisoning is wide complex dysrhythmia, and the current accepted treatment is intravenous bicarbonate. Wide complex dysrhythmia due to cocaine in the absence of myocardial infarction is rare, and optimum management is undefined. We report three cases of acute cocaine intoxication during which patients developed wide complex dysrhythmia consistent with sodium channel poisoning. In one case, wide complex tachycardia resolved without direct treatment. In the other cases, wide complex dysrhythmia resolved following intravenous bicarbonate therapy directed at reversing sodium channel blockade.

Therapy of dysrhythmias

Antidysrhythmic drug research has recently focused on developing agents whose primary electrophysiological action is to selectively prolong repolarization. The major impetus for the development of these ‘pure’ class III agents was the assumption that their smaller effects on conduction velocity and contractility would make them safer drugs than class I agents. In this article, we will review some recently discovered electrophysiological properties of class III drugs that may markedly limit their clinical utility. Lastly, a novel therapeutic approach that exploits the antidysrhythmic properties of endogenous adenosine is described.

Additive Cardiac Depression by Volatile Anesthetics in Isolated Hearts After Chronic Amiodarone Treatment

Some patients undergoing general anesthesia may be chronically receiving the antidysrhythmic drug amiodarone. The half-life of this drug is very long and it may not be advisable or possible to discontinue its administration prior to anesthesia. We examined depressant effects of three volatile anesthetics in hearts isolated from guinea pigs chronically treated with amiodarone. Hearts were isolated and perfused retrogradely through the aorta with oxygenated Krebs-Ringer solution at 37 degrees C at constant pressure. Variables measured in 26 hearts were heart rate (HR), atrioventricular, intraatrial, and intraventricular conduction times (AVCT, IACT, IVCT) during pacing at 240 bpm, coronary flow, and left ventricular pressure (LVP). Amiodarone (20 mg intraperitoneally) or placebo (Group 1) was given once daily for 1 (Group 2) or 4 (Group 3) wk. Cardiac tissue concentrations of amiodarone were similar (12.1 micrograms/g wet weight) in hearts in Groups 2 and 3 but serum levels were twice as high in hearts in Group 3 as in Group 2 (0.33 vs 0.17 microgram/mL). Before anesthetic exposure, all variables for hearts in Group 2 were not significantly different from those in Group 1. Significantly, for hearts in Group 3, compared to those in Group 1, HR was slower (-14%), conduction times were longer (IACT + 5 ms, IVCT + 4 ms, AVCT + 9 ms), coronary flow was higher (+23%), and LVP was lower (-12%). After control measurements, hearts were exposed to 0.5 and 1 minimum alveolar anesthetic concentration (MAC) halothane, enflurane, and isoflurane in random order.(ABSTRACT TRUNCATED AT 250 WORDS)

RECENT ADVANCES IN CARDIAC PHARMACOLOGY

Summary The general surgical population has become increasingly complex. In caring for these patients with advanced cardiac failure and ischemic myocardial disease, new inotropic, anti-ischemic, and antidysrhythmic drugs are becoming available. The potency and rapidity of action of the new cardiac drugs described in this article make them attractive for use in the perioperative period. Milrinone, a new phosphodiesterase inhibitor, is an inodilator with potentially fewer side effects than its congener amrinone. Dopexamine's unique advantages of inotropism and renal protection need further elucidation but may potentially be useful in major vascular surgery. Enalaprilat has enjoyed success as an IV arterial vasodilator in hypertension and congestive heart failure states. Lastly, adenosine is currently widely used to treat SVT and has the benefit of an extremely short half-life and relatively few adverse effects.

A Case of Amiodarone-induced Interstitial Lung Disease

Amiodarone has a potent suppressive effect on supraventricular and ventricular dysrhythmias, so has widely used as a class III antiarrhythmic agent. However, significant side effects were noted in over 50% of patients treated. Pulmonary toxicity represents the most serious adverse raeaction limiting the clinical efficacy of this new antidysrhythmic drug. A 66-year-old male had received amiodarone 200mg/day for 7 months to control high grade ventricular premature contraction and was admitted due to dyspnea on exertion for 1 week. At the time of admission end-inspiratory crepitant rale was heard on auscultation. The roentgenogram of his chest revealed reticular and granular radioopaque densities on both lower lung fields and high resonance CT revealed interstitial fibrosis and pneumonic consolidations on the periphery of the both middle and lower lobes. Trans-bronchoscopic lung biopsy revealed nonspecific intersitial fibrosis. The laboratory findings were non-specific. We present a case of amiodarone-induced interstitial pulmonary disease clinically improved by cortico-steroid therapy.

Additive Depressant Effects of Amiodarone Given With Halothane in Isolated Hearts

The antidysrhythmic drug amiodarone may be given during general anesthesia. We examined the single and combined direct cardiac effects of amiodarone and halothane in the isolated guinea pig heart. Guinea pig hearts were isolated and perfused retrogradely through the aorta with oxygenated Krebs-Ringer solution at 37 degrees C at constant pressure (55 mm Hg). Variables measured in 61 hearts included spontaneous heart rate (HR), atrioventricular conduction time (AVCT), isovolumetric left ventricular pressure (LVP), and coronary flow (CF). Amiodarone was administered as a single bolus into the retrogradely perfused aortic root and halothane was vaporized into the perfusing solution. Mean control values of pooled data before treatment were as follows: HR, 228 +/- 4 (SEM) beats/min; AVCT (during atrial pacing at 240 beats/min), 82 +/- 2 ms; LVP, 97 +/- 4 mm Hg; and CF, 6.1 +/- 0.2 mL.min-1.g-1. Amiodarone, 100 micrograms and 200 micrograms, decreased HR by 8% +/- 2% and 8% +/- 2%, increased AVCT by 5 +/- 2 and 15 +/- 3 ms, decreased LVP by 22% +/- 3% and 27% +/- 3%, and increased CF by 20% +/- 1% and 40% +/- 2%, respectively; all these changes were sustained for 60 min and, except for HR, were dose dependent. Halothane, 0.5% and 1%, transiently and dose-dependently decreased HR by 6% +/- 2% and 12% +/- 2% increased AVCT by 4 +/- 2 and 8 +/- 2 ms, decreased LVP by 15% +/- 3% and 31% +/- 3%, and increased CF by 2% +/- 1% and 6% +/- 2%.(ABSTRACT TRUNCATED AT 250 WORDS)

Measurement of the class III antidysrhythmic drug, UK-68,798, in plasma by radioimmunoassay

A sensitive radioimmunoassay (RIA) for the specific determination of 1-(4-methanesulphonamidophenoxy)-2-[N-(4-methanesulphonamido -phenethyl)-N- methylamino]ethane (UK-68,798), a novel class III antidysrhythmic agent, in human plasma is described. Specific antisera were raised in sheep using desmesyl-UK-68,798-succinate-ovalbumin conjugate as the antigenic hapten carrier protein. The antisera produced exhibited high specificity for UK-68,798 compared with known metabolites from animals, other antidysrhythmic agents and co-administered drugs. Good correlation was found in a comparison of the RIA method with a high-performance liquid chromatography (HPLC) method (r = 0.997) and a 10-fold lower limit of determination was observed for the RIA method compared with the HPLC method (0.05 and 0.5 ng ml-1, respectively). The RIA method was applied to the analysis of UK-68,798 in plasma obtained from human volunteers receiving the compound.

Poisoning By Antidysrhythmic Drugs

This article discusses the management of antidysrhythmic drug overdoses in children and adolescents.

Potassium channel blockade: A mechanism for suppressing ventricular fibrillation.

The suppression of ventricular fibrillation by antidysrhythmic drugs is well correlated with their ability to block potassium channels in nerve and cardiac membranes. Blockade of potassium channels reduces electrical inhomogeneities in action potential and conduction parameters that lead to ventricular fibrillation. These actions tend to effectively decrease the electrical size of the heart, which suggests a mechanism for antifibrillatory drug action. The receptor sites for antifibrillatory drug action (IK blockade) appear to be on the outside of the cardiac membrane whereas receptors for antiarrhythmic drug action (INa blockade) appear to be on the inside of the cardiac membrane.

The Effects of Indecainide, a New Antidysrhythmic Drug, on Nodal Tissues in the Isolated Rabbit Heart

The effects of indecainide, previously shown to be a class 1c antiarrhythmic drug restricting fast inward current, have been studied on rabbit sinoatrial (SA) node and atrioventricular (AV) node. Indecainide at concentrations up to 2.9 mumol/L in 5 preparations did not produce a sinus bradycardia, nor reduce the maximum rate of rise of the intracellular action potential of sinus node cells, but it did antagonize the tachycardia induced by increasing the extracellular calcium concentration. Indecainide slightly prolonged AV conduction time [from 49.07 +/- 4.43 ms to 57.37 +/- 0.90 ms at 2.9 mumol/L (means +/- SEM in four preparations)], but this small delay could be attributed to slowing of conduction in atrial fibres leading to the node, rather than to an effect on the AV nodal cells themselves. It is concluded that indecainide does not block channels carrying inward calcium current in nodal tissues.

376 AGE-DEPENDENT VERAPAMIL KINETICS AFFECT PEDIATRIC ORAL DOSE REQUIREMENTS

Although intravenous verapamil effectively terminates supraventricular tachycardia (SVT) in children, its utility as a chronic oral antidysrhythmic drug has been disappointing. To assess whether drug kinetics contribute to this problem, we measured serum concentrations before and for 24 hours after a maintenance oral dose of verapamil (mean dose 1.36 mg/kg, range 0.4-2.9 mg/kg) in 7 children with a median age of 10.8 yrs (range 2.8-15.3 yrs). All had SVT controlled by chronic oral verapamil at mean serum peak and trough concentrations of 248±117 and 64±38 ng/ml, respectively. We found several clearly age-dependent kinetic parameters: younger children demonstrated faster drug uptake “Tmax” (p <.005), lower relative bioavailability “F” (p<.01), smaller volume of distribution “Vd” (p <.005) and slower elimination half-life “t ½ β” (p <.001). Younger children also exhibited a possible diurnal variation in drug kinetics. There was no significant age-relationship in distribution half-life “t½α” or drug clearance rate. Although these changes have opposing effects on serum concentrations, their net effect in young children is for a greater dosage requirement, and perhaps a shorter dosage interval, than are currently recommended. *Supported in part by G.D. Searle & Co. of Canada, Ltd., and the Ontario Heart and Stroke Foundation.

Development of a severe model of early coronary artery ligation-induced dysrhythmias in the anaesthetized rat.

1. The potential use of catecholamines to increase the severity of dysrhythmias evoked by coronary artery ligation in the anaesthetized rat was investigated. Drugs were given intravenously prior to ligation. 2 Pressor doses of adrenaline (5 microgram/kg) noradrenaline (1 microgram/kg) phenylephrine (5-10 microgram/kg), and angiotensin (0.25 microgram/kg) conferred protection against the development of dysrhythmias. 3 Atropine (1 mg/kg) increased mortality from ventricular fibrilloflutter (VF) and abolished the protective effects of phenylephrine (10 micrograms/kg). 4 Administration of isoprenaline (10 microgram/kg) significantly increased the incidence of and the mortality from VF. 5 The order of antidysrhythmic drug potency of Org 6001 (1-10 mg/kg), disopyramide (2-10 mg/kg) and practolol (2-10 mg/kg) was similar in both the standard (without isoprenaline) and modified (with isoprenaline) models. 6 Use of the modified method for antidysrhythmic screening purpose allows demonstration of statistically meaningful results with the use of relatively few animals. 7 Comparison of the pattern of VF in the rat heart induced by various means suggests that the diagnosis of ventricular fibrillation can be made with more confidence in the modified method compared to the standard method.

Liquid-Chromatographic Determination of Antidysrhythmic Drugs

We present a method for the analysis of antidysrhythmic drugs [procainamide, acecainide (NAPA), lidocaine, quinidine, disopyramide, N-desisopropyl disopyramide, and propranolol] in serum. The drugs, together with an internal standard, are extracted from 0.2-1.0 ml of serum, separated on an octyl-bonded reversed-phase column using a mobile phase consisting of acetonitrile/phosphate buffer, and monitored by either ultraviolet or fluorescence spectrophotometry. The proposed method offers good reproducibility, sensitivity, linearity, and accuracy. Of more than 50 drugs and metabolites, tested for possible interference, only diazepam, flurazepam, and the N-oxide metabolite of quinidine interfere with quinidine analysis, while meperidine coelutes with disopyramide. However, diazepam and flurazepam do not interfere with quinidine analysis with fluorescence detection.

The effects of prolonged oral administration of a new antidysrhythmic drug (Org 6001) on coronary artery ligation dysrhythmias in conscious and anesthetized rats.

We determined the antidysrhythmic activity of acute or prolonged administration of Org 6001 on dysrhythmias following coronary artery ligation in conscious and anesthetized rats. Intravenous doses of 5 and 10 mg/kg of Org 6001 markedly protected against postligation dysrhythmias in anesthetized rats, whereas a single oral dose of 10 mg/kg given 1 hr prior to ligation did not. Prolonged oral administration of Org 6001, 10 mg/kg twice daily for 10 days, the last dose given 1 hr before ligation, reduced the incidence of ventricular fibrillation and increased survival in both conscious and anesthetized animals. This effective antidysrhythmic dose regimen resulted in drug concentrations of 335 +/- 68 ng/ml in plasma and 2,940 +/- 408 ng Org 6001/g in the whole heart. At 24 hr after the last dose no protection against the dysrhythmias remained, and drug levels in both plasma and heart tissue were low. A good correlation was observed between the levels of Org 6001 in the heart and the reduction in the rate of rise of phase zero of cardiac action potentials obtained from drug-pretreated animals. It is concluded that prolonged administration of Org 6001 is effective against postligation dysrhythmias and that this effect may be associated with the drug's Class I activity.

Antidysrhythmic and electrophysiological effects of a new antianginal agent, bepridil.

The antidysrhythmic effects of a new antianginal agent, bepridil, were compared with those of disopyramide, a known antidysrhythmic drug. Bepridil (20, 50, and 100 mg/kg, i.p.) conferred little protection against aconitine-induced dysrhythmias in mice, whereas similar doses of disopyramide exerted a marked dose-dependent antidysrhythmic effect. Intravenous administration of either bepridil (2 mg/kg) or disopyramide (10 mg/kg) significantly reduced the number of ventricular extrasystoles and completely abolished the occurrence of ventricular fibrillation following coronary artery ligation in the rat. Local anesthetic and electrophysiological effects in vitro of bepridil were also investigated. A marked but slowly developing reduction in action potential height of desheathed frog sciatic nerves was observed at concentrations of 0.01-0.05 mM. In sheep Purkinje fibres, a similar decrease in action potential height, associated with a pronounced reduction in the maximum rate of depolarization of phase zero of the action potential (MRD) was seen with bepridil (0.5-2 X 10(-5) M). Higher concentrations (2-8 X 10(-5) M) were required to reduce MRD of guinea pig ventricular muscle. The antidysrhythmic actions of bepridil may at least in part be explained by the electrophysiological effects observed.

COMPARATIVE ELECTROPHYSIOLOGICAL EFFECTS OF Org 6001, A NEW ORALLY ACTIVE ANTIDYSRHYTHMIC AGENT, AND LIGNOCAINE ON HUMAN VENTRICULAR MUSCLE

1 The electrophysiological effects of Org 6001, a new orally active antidysrhythmic agent, have been compared with those of lignocaine on the human ventricular action potential in vitro.2 Org 6001 (4 to 16 mg/l) greatly reduced the maximum rate of depolarization (MRD) of the human ventricular action potential but had no effect on resting membrane potential or action potential amplitude.3 The action potential duration at the 50% repolarization level, but not at the 90% repolarization level, was significantly reduced by Org 6001. The absolute refractory period was unchanged.4 Lignocaine, at a concentration (4 mg/l) within the therapeutic range, had no significant effect on any measured parameter, either in muscle exposed to a normal (4.0 mM) or high (5.4 mM) extracellular potassium concentration ([K(+)](o)).5 Higher concentrations of lignocaine (8 to 16 mg/l) did, however, reduce MRD at both [K(+)](o) without changing resting membrane potential or action potential amplitude. The action potential duration was decreased slightly by these higher concentrations of lignocaine whilst the absolute refractory period was lengthened.6 Org 6001 was found to be more potent than lignocaine in reducing MRD but, unlike lignocaine, the absolute refractory period was not prolonged. These compounds, therefore, differed in their electrophysiological effects on human ventricular muscle although both are characterized as being class 1 antidysrhythmic drugs.

Electrophysiologic Properties of Antidysrhythmic Drugs as a Rational Basis for Therapy

The often emergent nature of life-threatening cardiac dysrhythmias, the frequent seeming "resistance" of the abnormal heart rhythm to therapy, and the commonly encountered toxicity of antidysrhythmic agents combine to make treatment of cardiac dysrhythmias one of the strictest challenges to the practicing physician. Although electrophysiologic studies have markedly increased out understanding of dysrhythmogenesis and the actions of anti-dysrhythmic drugs, these numerous investigations have provided but little assistance to the practicing physician either as an intellectual framework or as a guide to patient care. The electrophysiologic classification of the antidysrhythmic drugs presented in this paper should be acceptable both to the electrophysiologist and the clinician since it is based on alterations in basic membrane properties and correlates well with clinical realities. It serves as a guide to initial drug selection, anticipated bioelectric complications, the use of alternative drugs, and combination antidysrhythmic therapy.

Mechanism of action of antidysrhythmic drugs on ventricular conduction as studied with intramural electrodes.

Using the Dürrer electrode needle to record the intramural electrogram and a standard peripheral electrocardiogram (ECG) lead as reference, the authors studied the action of 9 different drugs in the conduction system of dogs. The authors concluded that diphenylhydantoin and lignocaine would be useful in dysrhythmias related to increased excitability and perhaps increased automatism. Ajmaline and quinidine may be some of some interest in dysrhythmias due to conduction disturbances; and, finally, ajmaline, diphenylhydantoin, di-isopyramide and quinidine may be useful in dysrhythmias due to focal re-entry.

Cardiac arrhythmias. 6. Present status of electroversion in the management of cardiac dysrhythmias.

The theoretical and practical considerations of electrical reversion of cardiac dysrhythmias are reviewed and a comparison made between AC and DC defibrillation, indicating the superiority of DC under all circumstances. The indications for, immediate and late results of DC shock for atrial and ventricular dysrhythmias are presented, the complication of such treatment reviewed, and the need for anticoagulant cover, anesthesia, and drug therapy preceding and following the electrical treatment discussed. Each patient requires individual assessment, particularly those with chronic rhythm disturbances, especially atrial fibrillation, in whom electrical energy settings in excess of 300 joules are rarely indicated for the risk of complications becomes progressively higher as the energy setting is increased and the length of time sinus rhythm persists in this group of patients may be short. Patients with acute rhythm disturbances, however, with potentially serious hemodynamic consequences should be treated with maximum electric energies if needed. Caution is also advised in patients with coronary heart disease, atrial fibrillation, and a slow ventricular rate, even in the absence of digoxin, patients with rapidly changing rhythm disturbances, those who cannot maintain sinus rhythm for a significant period of time despite drug therapy, patients with the "sick sinus syndrome," those with atrial fibrillation of more than 5 years standing with a cardiothoracic ratio exceeding 55%, and patients in lone atrial fibrillation. Heavily digitalized patients in general should have their electroversion postponed if possible, but if not, they should be protected against serious ventricular rhythm disturbances immediately after the shock by an intravenous dose of lidocaine, phenylhydantoin, or procaine amide immediately before and the initial energy setting should be reduced to 5 joules. Quinidine or some other antidysrhythmic drug may be needed in an attempt to maintain sinus rhythm after successful electroversion, but even when controlled with adequate blood levels, results are poor.