John C. Somberg

Intravenous lidocaine versus intravenous amiodarone (in a new aqueous formulation) for incessant ventricular tachycardia

The effectiveness of intravenous amiodarone for the treatment of incessant (shock resistant) ventricular tachycardia (VT) has not been established. This study evaluated the efficacy of a water-soluble amiodarone preparation or lidocaine for the treatment of shock-resistant VT. The trial was a double-blinded parallel design. Patients were randomized to receive up to 2 boluses of either 150 mg intravenous amiodarone or 2 boluses of 100 mg lidocaine followed by a 24-hour infusion. If the first assigned medication failed to terminate VT, the patient was crossed over to the alternative therapy. Twenty-nine patients were randomized to the study (18 received amiodarone and 11 received lidocaine). There were no significant differences between groups with regard to baseline characteristics. Immediate VT termination was achieved in 14 patients (78%) with amiodarone versus 3 patients (27%) on lidocaine (p <0.05). After 1 hour, 12 patients (67%) on amiodarone and 1 patient (9%) on lidocaine were alive and free of VT (p <0.01). Amiodarone had a 33% drug failure rate, whereas there was a 91% drug failure rate for lidocaine. The 24-hour survival was 39% on amiodarone and 9% on lidocaine (p <0.01). Drug-related hypotension with aqueous amiodarone was less frequent than with lidocaine. This study found that amiodarone is more effective than lidocaine in the treatment of shock-resistant VT.

Relation of left ventricular mass and QT dispersion in patients with systematic hypertension

This study evaluated the correlation of left ventricular hypertrophy and QT dispersion in patients with systemic hypertension. QT dispersion, determined using the standard electrocardiogram, showed an increase as left ventricular mass determined by echocardiography increased in hypertensive patients.

Pharmacology and Pharmacokinetics of Amiodarone

Amiodarone is a unique antiarrhythmic agent originally developed as a vasodilator. Classified electrophysiologically as a Type III antiarrhythmic, it also has both nonspecific antisympathetic and direct, fast channel‐membrane effects. Hemodynamic effects of orally administered amiodarone (a negative inotropic agent) are usually negligible, and are usually compensated for by induced vasodilation. Effects on thyroid and hepatic function may help to explain some of the unique pharmacologic as well as toxicologic effects of the drug. Amiodarone is poorly bioavailable (20–80%) and undergoes extensive enterohepatic circulation before entry into a central compartment. The principal metabolite, mono‐n‐desethyl amiodarone is also an antiarrhythmic. From this central compartment, it undergoes extensive tissue distribution (exceptionally high tissue/plasma partition coefficients). The distribution half‐life of amiodarone out of the central compartment to peripheral and deep tissue compartments (t1/2α) may be as short as 4 hours. The terminal half‐life (t1/2β) is both long and variable (9–77 days) secondary to the slow mobilization of the lipophilic medication out of (primarily) adipocytes. A pharmacokinetically based loading scheme is described, and data suggesting a role for routine amiodarone plasma levels are presented.

QT prolongation and the antiarrhythmic efficacy of amiodarone

Amiodarone is an antiarrhythmic agent known to cause prolongation of action potential duration which is reflected in the electrocardiogram as a prolongation of the QT interval. Prolongation of the QT interval in patients dying suddenly was compared with that in patients who remained alive to determine whether a difference existed between these two groups. The electrocardiogram and amiodarone levels were evaluated in 33 patients who presented with cardiac arrest and symptomatic ventricular tachycardia in whom no other antiarrhythmic agent was found effective in preventing induction of ventricular tachycardia during electrophysiologic studies. There were 30 men and 3 women (mean age 52 +/- 10 years). Twenty-three are alive after a mean follow-up period of 12 +/- 7 months. Ten died: six suddenly, three of non-cardiac causes and one of congestive heart failure. Using a two-way analysis of variance, the percent change in QT, QTc, JT and JTc intervals before and after amiodarone therapy was analyzed. Marked prolongation in the QT interval was present in patients who remained alive with amiodarone therapy. A significant difference in percent QT prolongation was seen between the latter patients and those who died suddenly (p less than 0.005). No difference was observed in the percent change in QRS interval between the two groups. The levels of amiodarone (2.5 versus 3.2 micrograms/ml) and its metabolite (desethylamiodarone) were not significantly different between the living patients and those who died suddenly. These findings suggest that a prolongation of the QT interval may be a marker for the therapeutic antiarrhythmic effect of amiodarone.

QT Interval Dispersion in Healthy Subjects and Survivors of Sudden Cardiac Death: Circadian Variation in a Twenty- Four-Hour Assessment

Twenty-four-hour acquisition of QT dispersion (QTd) from the Holter and the circadian variation of QTd were evaluated in 20 survivors of sudden cardiac death (SCD), in 20 healthy subjects, and in 14 control patients without a history of cardiac arrest who were age, sex, diagnosis and therapy matched to 14 SCD patients. Computer-assisted QT measurements were performed on 24-hour Holter recordings; each recording was divided into 288 5-minute segments and templates representing the average QRST were generated. QTd was calculated as the difference between QT intervals in leads V1 and V5 for each template on Holter. The 24-hour mean QTd was significantly greater in SCD patients (40 +/- 28 ms) than in healthy subjects (20 +/- 10 ms) and control patients (15 +/- 5 ms) (p <0.05). There was a circadian variation in QTd with greater values at night (0 to 6 A.M.) than at daytime (10 A.M. to 4 P.M.) in healthy subjects (25 +/- 13 vs 15 +/- 8 ms, p <0.001) and control patients (18 +/- 10 vs 12 +/- 4 ms p <0.05), whereas in SCD patients there was no significant difference between night and day values (45 +/- 31 vs 37 +/- 28 ms, p = NS). It is concluded that QTd measured by Holter was greater in SCD patients than in healthy subjects and matched control patients during the entire day. QTd has a clear circadian variation in normal subjects, whereas this variation is blunted in SCD patients. QTd measured on Holter differentiates survivors of cardiac arrest and may be a useful tool for risk stratification.

Multicenter Trial of Sotalol for Suppression of Frequent, Complex Ventricular Arrhythmias: A Double-Blind, Randomized, Placebo-Controlled Evaluation of Two Doses

Sotalol is a unique beta-adrenergic blocking agent with additional actions characteristic of Vaughn-Williams class III antiarrhythmic agents in experimental models. To test the efficacy of sotalol to suppress ventricular arrhythmias, a 6 week parallel, placebo-controlled out-patient study of two doses (320 and 640 mg/day, in two divided doses) was performed in four hospitals in 56 patients with chronic premature ventricular complexes at a frequency of 30/h or more (mean +/- SE, 528 +/- 60/h) on 48 hour ambulatory electrocardiographic recording. During a placebo week, no change occurred in arrhythmia frequency (532 +/- 76/h). Subsequent sotalol therapy significantly reduced median arrhythmia frequency in patients receiving both low (n = 19) and high (n = 18) doses compared with that in patients receiving placebo (by 77 and 83%, respectively, versus 6%; p less than 0.001). Twenty-two (59%) of 37 sotalol-treated patients, 11 in each group, reached the prospectively defined criterion of efficacy (greater than or equal to 75% arrhythmia reduction) versus 2 (11%) of 19 placebo control patients (p less than 0.001). Sotalol reduced the median frequency of couplets by 94% (p less than 0.0001) and that of runs by 89% (p less than 0.0007). The electrocardiographic effects of sotalol included reductions in heart rate (by 17 to 27%) and increases in the QTc (by 6 to 9%) and PR (by 6%) intervals. Ejection fraction was unchanged. The most common adverse side effect was fatigue, but drug discontinuation was required in only three patients taking 640 mg/day. No proarrhythmic events or biochemical abnormalities were observed. In summary, sotalol displays significant antiarrhythmic activity of moderately high degree with good tolerance in doses of both 320 and 640 mg/day. Its antiarrhythmic actions are distinguished from those reported for other beta-blockers by its effects on the QTc interval and its moderately high degree of antiarrhythmic activity.

The Cimetidine-Lidocaine Interaction

Lidocaine is a widely used antiarrhythmic agent whose plasma clearance varies with changes in hepatic blood flow. Cimetidine, an H2-receptor antagonist, has been shown to decrease hepatic blood flow. To ascertain whether cimetidine affected serum lidocaine concentration, we studied 21 patients receiving lidocaine infusions and divided them into two groups. Fifteen patients received cimetidine, 300 mg every 6 hours, in addition to lidocaine; six patients received only lidocaine. In 14 of the 15 patients receiving both lidocaine and cimetidine, a rise in serum lidocaine levels was seen, whereas no change was noted in the control group. Six of the 15 patients were found to have levels in the toxic range and two had symptoms. An additional three patients on lidocaine received diphenhydramine, an H1-receptor antagonist. No elevation in serum lidocaine levels was noted after administration of diphenhydramine. We conclude that there exists an interaction between lidocaine and cimetidine and that the rise in serum lidocaine levels may be mediated by cimetidines inhibition of the H2 receptor.

Comparative study of encainide and quinidine in the treatment of ventricular arrhythmias

The antiarrhythmic efficacy and safety of oral encainide hydrochloride and quinidine sulfate were compared in a nine center double-blind crossover study in 187 outpatients with benign or potentially lethal ventricular arrhythmias. Patients with at least 30 premature ventricular complexes/h were randomized to receive either encainide, 25 mg four times/day, or quinidine, 200 mg four times/day, for 2 weeks. These doses were continued for another 2 weeks if a 75% or greater reduction in premature ventricular complexes was observed. If this reduction was not seen, encainide was increased to 50 mg four times/day or quinidine to 400 mg four times/day for an additional 2 weeks. Both drugs produced a statistically significant reduction in premature ventricular complex frequency compared with baseline values. Encainide produced a statistically significant greater mean reduction in total premature ventricular complexes than did quinidine during the initial dose phase and after dose adjustment. More patients required dose increases of quinidine (60%) than of encainide (51%). Early discontinuation of treatment resulting in advancement to the next study period occurred in 12 patients taking encainide and 38 patients taking quinidine (p less than 0.05). PR and QRS intervals increased significantly during encainide treatment, as did QTc and JT intervals during quinidine treatment. No adverse reactions resulted from these electrocardiographic changes. Adverse reactions were more common with quinidine than with encainide.(ABSTRACT TRUNCATED AT 250 WORDS)

Bioavailability and pharmacokinetics of magnesium after administration of magnesium salts to humans.

Therapeutically, magnesium salts represent an important class of compounds and exhibit various pharmacologic actions. Examples of magnesium salts are ionic magnesium and magnesium citrate in nephrolithiasis, magnesium salicylate in rheumatoid arthritis, magnesium hydroxide as an antacid as well as a cathartic, and magnesium mandelate as urinary antiseptic. Various anions attached to the cation magnesium, such as oxide, chloride, gluconate, and lactate, affect the delivery of the amounts of elemental magnesium to the target site and thereby produce different pharmacodynamic effects. This review examines the bioavailability and pharmacokinetics of various magnesium salts and correlates pharmacodynamic action with the structure-activity relationship.

Cibenzoline plasma concentration and antiarrhythmic effect

The relationship between plasma concentrations of cibenzoline and its antiarrhythmic effect was evaluated in patients receiving the drug orally as part of an ascending multiple dose efficacy and tolerance study. Twenty‐five patients participated in a 3‐day placebo period, 3 days of 32.5 mg cibenzoline every 6 hr, 3 days of 65 mg cibenzoline every 6 hr, 3 days of 81.25 mg cibenzoline every 6 hr, and 3 final placebo days. Arrhythmia frequency was monitored by 24‐hr Holter monitoring and blood samples were drawn during and after dosing. Percent reduction in baseline premature ventricular complex (PVC) frequency for the 25 subjects demonstrated considerable interpatient variability in antiarrhythmic response. Cibenzoline plasma concentrations over 300 ng/ml were associated with some decrease in PVC frequency in virtually all cases. The relationship between plasma concentration and PVC frequency was studied more rigorously in eight of the 25 patients and that for ventricular couplet (VC) frequency was studied in six. For these analyses, PVC and VC frequency data were averaged over 6‐hr intervals and plotted against trough cibenzoline concentrations. The data from each patient were fitted with a concentration‐effect function (Hill equation) by means of least squares regression. With the exception of two extreme values, the concentration corresponding to 90% reduction in PVC frequency (C90) ranged from 215 to 405 ng/ml. In five of the six patients with arrhythmia in whom VC data were also evaluated, the individual C90 for VCs were considerably less than those for PVCs. The agreement between the observed concentration‐response relationships and those predicted by curve‐fitting the data suggests that the antiarrhythmic effect of cibenzoline is proportional to its plasma concentration, and that the Hill equation provides an accurate mathematic description of the concentration‐response relationship.