Biomedical subjects
BN Singh
Publications and source records attributed to BN Singh.
Effects of Sotalol on the Circadian Rhythmicity of Heart Rate and QT Intervals With a Noninvasive Index of Reverse-Use Dependency.
BACKGROUND: The effects of sotalol on the 24-hour profile of the QT interval relative to that of the heart rate (HR) may be helpful in determining the time course of the drug's action in controlling cardiac arhythmias. This has not been previously determined. Thus, the objective of the current study was to evaluate the influence of the drug on the circadian rhythmicity of HR and QT intervals from Holter recordings in ambulatory patients. Reverse-use dependency (RUD) of sotalol was also studied noninvasively from Holter recordings. METHODS AND RESULTS: Holter recordings of 18 patients with ventricular arrhythmias were analyzed before and after 3-7 days of treatment with sotalol. We developed and used a signal processing system. A new noninvasive index to evaluate RUD was defined and applied to sotalol as a test agent. Sotalol significantly reduced HR from 76.9 +/- 3.2 to 60.0 +/- 1.1 (P <.001). The mean QT interval increased from 393 +/- 11 ms to 489 +/- 9 ms, whereas the mean normalized QT (QTc) interval increased from 415 +/- 5 ms to 487 +/- 5 ms (P <.001) during the drug treatment. Circadian rhythmicity of RR interval was abolished, but the circadian rhythms of the QT and QTc intervals were maintained during continuous treatment with sotalol. This finding is in contrast to amiodarone, which abolished the circadian rhythmicity of QTc interval while maintaining that of RR interval. RUD index was increased from 0.13 +/- 0.08 to 0.24 +/- 0.10 (P <.001) after sotalol, consistent with increased RUD with sotalol. CONCLUSIONS: The effects of sotalol on the circadian rhythmicity of HR and QTc interval are dissociated. They are in direct contrast to those reported for amiodarone, a difference that may be of clinical significance. The RUD index introduced here provides a noninvasive parameter for comparing short-term as well as long-term effects of class III antiarrhythmic drugs on RUD.
Sotalol: Current Status and Expanding Indications.
BACKGROUND: The role of antiarrhythmic drug therapy continues to undergo major changes. The change is necessitated by the advent of invasive interventional procedures, such as catheter ablation of arrhythmias and the use of implantable devices for sensing and terminating life-threatening ventricular arrhythmias and symptomatically traublesome supraventricular arrhythmias. Many conventional and time-honored drugs, such as sodium channel blockers, have been found either to be ineffective or to have the potential to produce serious proarrhythmic reactions. Attention is therefore focused on compounds that prolong repolarization and reduce sympathetic stimulation. Two compounds, amiodarone and sotalol, have emerged as prototypes of drugs of the future. METHODS AND RESULTS: This review focuses on sotalol for controlling supraventricular and ventricular tachyarrhythmias. Sotalol is a major antiarrhythmic agent that combines potent class III action with nonselective beta-blocking properties. The drug's pharmacokinetics is simple. Its elimination half-life is 10-15 hours, the drug being excreted almost exclusively by the kidneys. Sotalol's pharmacokinetics allows development of optimal dosing for initiation of therapy relative to changes in creatinine clearance with further dose adjustment by monitoring the QT interval on the surface electrocardiogram. The compound exerts broad-spectrum antiarrhythmic actions in supraventricular and ventricular arrhythmias. It prevents inducible ventricular tachycardia (VT) and ventricular fibrillation (VF) in approximately 30% of patients with a higher figure for the suppression of spontaneously occurring arrhythmias documented on Holter recordings. CONCLUSIONS: The major role of sotalol is in the management of VT/VF often in conjunction with an implantable cardioverter/defibrillator, in which context it lowere the defibrillation threshold. Sotalol is superior to class I agents, especially in VT/VF and in survivors of cardiac arrest. Sotalol has emerged as a major antifibrillatory compound for the control of life-threatening ventricular arrhythmias as the main indication. Data have indicated its potential for the maintenance of stability of sinus rhythm in patients with atrial fibrillation and flutter after electrical conversion and in preventing their occurrence in a variety of clinical settings.
Recurrent Torsades de Pointes After Sotalol Therapy for Symptomatic Paroxysmal Atrial Fibrillation in a Patient with End-Stage Renal Disease.
BACKGROUND: In recent years there has been ain increase in the use of class III antiarrhythmic drugs such as sotalol, amiodarone, and the so-called pure class III compound for the control of cardiac arrhythmias. It appears there has been a corresponding increase in the frequency of torsades de pointes (TdP). METHODS AND RESULTS: The case reported here, a patient on daily renal dialysis for end-stage renal disease, has important implications for class III agents, which are excreted largely by the kidneys. A relatively low dose of sotalol administered for the prevention of recurrences of atrial fabrillation, with a fast ventricular response producing angina, led to modest increases in the QT interval and moderate bradycardia. This culminated in the development of TdP, which deteriorated into ventricular fibrillation, from which the patient could be resuscitated with considerable difficulty. Dialysis after the occurrence of TdP led to further and striking prolongation of the QT interval associated with numerous episodes of TdP for several days before control was achieved. The atrial fibrillation and recurrences of TdP were eventually controlled with oral amiodarone. CONCLUSIONS: This case emphasizes that in the absence of significant renal function, use of sotalol may not be safe because drug accumulation may not be controlled adequately with renal dialysis. In view of this, in patients with end-stage renal disease, the use of sotalol for arrhythmia control appears contraindicated and alternative agents, the excretion of which does not occur by the renal route, should be used.
Electrophysiologic and Antiarrhythmic Effects of Propafenone: Focus on Atrial Fibrillation.
Explore the source record for details and available documents.
Atrial Fibrillation: Defining Some Unanswered Questions.
Explore the source record for details and available documents.
Different Effects of Amiodarone and Quinidine on the Homogeneity of Myocardial Refractoriness in Patients With Intraventricular Conduction Delay.
BACKGROUND: Increases in QT and JT dispersion have been suggested as indicative of a proarrhythmic potential as a result of heterogeneity in myocardial refractoriness, the reduction of which by antiarrhythmic agents might be associated with a beneficial effect on the development of serious ventricular arrhythmias. METHODS: To test the hypothesis that amiodarone reduces the heter-ogeneity of ventricular refractoriness to a significantly greater extent than quinidine in patients with intraventricular conduction defects under treatment for ventricular arrhythmias, the corrected and uncorrected QT and JT intervals and dispersions from 12-lead surface electrocardiograms were determined in 120 patients with intraventricular conduction defects with cardiac arrhythmias before and during treatment with amiodarone (n = 60) and quinidine (n = 60). RESULTS: Amiodarone increased QT from 403 +/- 50 ms to 459 +/- 47 ms (P <.001), with a similar increase in the corrected QT interval (QTc) (P <.001). Amiodarone reduced QT dispersion by 40% (P <.001), whereas quinidine increased by 18% (P <.001). The net effects of both drugs were similar for OTc. Amiodarone, but not quinidine, reduced heart rate significantly; amiodarone had no effect on the QRS; but quinidine increased if (P <.001). Quinidine as well as amiodarone increased the JT and JTc intervals significantly, but the effect of quinidine was qualitatively less striking. Amiodarone decreased the JT dispersion by 33% (P <.001) and JTc dispersion by 37% (P <.001). On the other hand, quinidine increased the corresponding values for JT and JTc by 18% (P <.001) and 21% (P <.001), respectively. The overall data on QT and JT dispersion indicate an improvement in the homogeneity of myocardial refractoriness with amiodarone treatment and the converse with quinidine treatment; this observation is consistent with a lower proarrhythmic propensity and mortality with amiodarone than with quinidine. Quinidine increased the QRS interval more than amiodarone, and the data indicate that in patients with intraventricular conduction defects, the monitoring of the JT interval might more accurately reflect changes in myocardial repolarization. CONCLUSIONS: Amiodarone and quinidine both increased the corrected and uncorrected QT and JT intervals; amiodarone decreased and quinidine increased the dispersion of these intervals, and these results suggested an improvement in the homogeneity of myocardial refractoriness as a result of amiodarone treatment and the converse as a result of quinidine treatment. Quinidine increased the QTS interval more than amiodarone, and the data indicate that in patients with intraventricular conduction defects, the monitoring of the JT interval might more accurately reflect changes in myocardial repolarization.
Significance and Prevention of Atrial Fibrillation Occurring After Cardiac Surgery: A Time for Fundamental Change in Strategy?
Explore the source record for details and available documents.
Class III Antiarrhythmic Drugs: Simple versus Complex Molecules for Controlling Cardiac Arrhythmias.
Explore the source record for details and available documents.
Antiarrhythmic and Arrhythmogenic Actions of Varying Levels of Extracellular Magnesium: Possible Cellular Basis for the Differences in the Efficacy of magnesium and Lidocaine in Torsade de Pointes.
BACKGROUND: In recent years, there has been an increasing use of antiarrhythmic drugs that act predominantly by prolonging myocardial repolarization. An inevitable electrophysiologic consequence of these drugs is the development of torsade de pointes as a proarrhythmic reaction. Both intravenous lidocaine and magnesium sulphate have been used in the acute control of such a proarrhythmia. Their electrophysiologic mechanisms in this setting are not well defined. METHODS AND RESULTS: Using the standard microelectrode techniques, the effects of magnesium (Mg) and lidocaine on action potential duration (APD), and on barium-induced spontaneous action potentials, were studied in canine Purkinje fiber preparations. The objective was to clarify the direct and indirect effects of magnesium on triggered activities due to early afterdepolarizations. Superfusion in media with 0.1 mM Mg and 2.5 mM K produced more pronounced increases in APD measured at -20mV repolarization time [APD(20)] than those in a solution with 5 mM K. This effect was further enhanced at lower stimulation frequencies. The striking prolongation of APD(20) by solutions with low potassium concentrations diminished as the Mg concentration was increased. In solutions with 2.5 mM K, Mg produced concentration-dependent decreases in APD(20). This effect was greater at lower stimulation frequencies. Lidocaine at 4.0 x 10(_5) M produced a marked shortening of the APD in the entire firing frequency of the abnormal automaticity in a concentration-dependent manner. With 10 mM Mg, such action potentials appeared only sporadically. Magnesium also decreased the amplitude and the maximum upstroke velocity of these action potentials. In contrast, lidocaine at 4.0 x 10(-5) M exhibited no significant effects on action potentials due to barium-induced abnormal automaticity, or on additional depolarizations developing from the repolarization phase of these action potentials. CONCLUSIONS: The data indicate that (i) hypomagnesemia may be arrhythmogenic when combined with hypokalemia and bradycardia leading to a prolongation of the plateau phase of the action potential, (ii) magnesium administration may suppress triggered activities mainly by a direct inhibition of the development of triggered potentials, and (iii) lidocaine may suppress triggered potentials only indirectly by preventing the development of early afterdepolarizations due to the shortening effect on the APD. These findings are consistent with the clinical observation of a high incidence of torsade de pointes in the setting of hypokalemia and hypomagnesemia introduced by a chronic diuretic therapy. They are also consistent with the marked effectiveness of intravenous Mg relative to the inconsistent clinical effects of lidocaine in controlling torsade de pointes.
Restoring Sinus Rhythm in Patients With Atrial Flutter and Fibrillation: Pharmacologic or Electrical Cardioversion?
Atrial fibrillation and atrial flutter, the most frequently encountered tachyarrhythmias requiring treatment, have become a major focus for clinical and basic research in recent years. Restoration and maintenance of sinus rhythmn, having been shown to improve exercise capacity, alleviate symptoms, and reduce the incidence of thromboembolic events, may be the optimal management strategy. Identification of the safest, most efficacious and cost-effective means of restoring sinus rhythm is necessary prior to the institution of optimal antiarrhythmic therapy to maintain sinus rhythm. Potential advantages of pharmacologic compared with electrical cardioversion include lack of need for general anesthesia and likely lower cost. Pharmacologic conversion include lack of need for general anesthesia and likely lower cost. Pharmacologic conversion has been accomplished with drugs that prolong atrial refractorinerss, including class Ia (quinidine, procainamide, disopyramide), class Ic (flecainide, propafenone), and class II (sotalol, amiodarone) compounds. The so-called pure class III agents were created to overcome the blocker side effects of sotalol and the complex pharmacodynamic profile of amiodarone. Two such agents are dofetilide, which selectively blocks the rapid component of the delayed rectifier current (Ikr) and ibutilide, which augments the slow inward sodium current, with a smaller component of action mediated by the block of Ikr. Reported overall conversion rates for recent onset atrial fibrillation and atrial flutter were 31% and 54% for difetilide, respectively, and 29-31% and 38-63%, respectively, for ibutilide. Proarrhythmia, manifested as polymorphic ventricular tachycardia requiring cardioversion, was a significant early side effect of both agents. Data from clinical trtials with these new agents, combined with increasing nowledge of the electrophysiologic substrate for these arrhythmias, has renewed initerest in the development of safer, more efficacious class IIIdrugs for atrial fibrillation and atrial flutter conversion.
Reflections on Recent Clinical Trials in Patients With Heart Failure and Those With Reduced Ventricular Function.
Explore the source record for details and available documents.
Searching for the Ideal Class III Antiarrhythmic Agent: How Pure Should they Be?
Explore the source record for details and available documents.
Why a New Journal in Cardiovascular Pharmacology and Therapeutics?
Explore the source record for details and available documents.
Antiarrhythmic Therapy of Ventricular Arrhythmias: The Contemporary Dilemma.
Explore the source record for details and available documents.
Rise and Fall of Guided Antiarrhythmic Therapy for Ventricular Tachycardia and Fibrillation.
Explore the source record for details and available documents.
Sudden Death During Flecainide Therapy for Atrial Fibrillation Complicating Wolff-Parkinson-White Syndrome.
The Wolff-Parkinson-White syndrome can be complicated by atrial fibrillation that may increase morbidity and mortality. Different pharmacologic therapy, includes class IA, IC, and III agents, has been used in such cases with variable success. We now use less pharmacologic intervention with development of an electrode catheter ablation for accessory pathways. However, antiarrhythmic agents are still being used, especially when an electrode catheter ablation is unavailable or if a patient refuses such a procedure. Therefore, it is prudent that one understands each antiarrhythmic agents' electropharmacologic properties as well as its potential proarrhythmic effect in order to accurately assess each drug's risk-benefit ratio. We present a case that illustrates electropharmacologic properties of quinidine, flecainide, sotalol, and amiodarone on various cardiac tissues, as well as possible proarrhythmic effect of flecainide on a structurally normal heart.