Ramaswamy Kannan

Antiarrhythmic efficacy and electrophysiologic actions of amiodarone in patients with life-threatening ventricular arrhythmias: Potent suppression of spontaneously occurring tachyarrhythmias versus inconsistent abolition of induced ventricular tachycardia

The antiarrhythmic efficacy and the electrophysiologic effects of amiodarone were determined in 13 consecutive patients with symptomatic life-threatening ventricular arrhythmias resistant to conventional agents. Amiodarone was initially given in high doses (1000 to 1800 mg/daily); electrophysiologic effects including induction of ventricular tachycardia (VT) by programmed electrical stimulation (PES) was undertaken before and after a mean period of 28 (range 14 to 56) days of amiodarone therapy. Plasma drug levels determined by high pressure liquid chromatography were within the “therapeutic” range (0.92 to 11.99 mg/L). Antiarrhythmic efficacy was determined on the basis of the quantitative analysis of 24-hour Holter recordings. Amiodarone reduced heart rate (HR) (−17.6%, p < 0.001), lengthened PR interval (+15%, p < 0.05), AH interval (+19.8%, P < 0.01), and the QTo by 13.3% (p < 0.01), without effect on the QRS or HV intervals. The atrial effective refractory period (ERP) increased by 31.3% (p < 0.001) and the ventricular ERP by 22.5% (p < 0.001); ERP of the AV node also increased but could not be determined in all patients because of the longer refractory period of the atrium. Before amiodarone, AV Wenckebach during atrial pacing developed at HR of 150 ± 13 bpm and at 117 ± 7.6 bpm during amiodarone therapy (p < 0.01). In all 13 patients, amiodarone reduced the total counts of premature ventricular beats (PVCs) by 95% to 98% and eliminated complex ventricular ectopic activity (VEA) and runs of VT. The effect has been sustained during a mean follow-up period of 12 months and there have been no symptoms. Before amiodarone was given, VT could be induced by PES in 12 of 13 patients (seven sustained, five nonsustained). On amiodarone, VT was provoked in four (three sustained, one nonsustained). Side effects have included photosensitivity, proximal muscle weakness, elevation of hepatic enzymes, halo vision, and corneal deposits but without impaired vision; these could be reduced in severity or avoided by reduction in drug dosage. These data indicate that amiodarone is highly potent in suppressing symptomatic life-threatening ventricular tachycardias (PVCs, VEA, VTVF) without always being able to prevent the induction of VT by PES of the heart. The drug can be used in this context without the need for invasive electrophysiologic studies.

Electrophysiologic effects of the levo- and dextrorotatory isomers of sotalol in isolated cardiac muscle and their in vivo pharmacokinetics

Dl-sotalol is a specific beta-adrenergic blocking agent that markedly lengthens cardiac action potential duration. To determine whether d-sotalol, with little or no beta-blocking effect, also lengthens repolarization, standard microelectrode studies were used to determine the electrophysiologic properties of dl-sotalol and its stereoisomers in isolated rabbit and canine myocardial fibers. D- and l-sotalol produced concentration-dependent increases in action potential duration to 50% (APD50) and 90% (APD90) repolarization, respectively, and in the effective refractory period without changes in the maximal rate of rise of action potential. In rabbit sinoatrial node, d- and l-sotalol produced concentration-dependent increases in spontaneous sinus cycle length (29 and 35%, respectively) by lengthening the action potential duration (by 58 and 55%) without effect on phase 4 depolarization. At the highest concentration (27.2 micrograms/ml), d- and l-sotalol prolonged APD90 (by 38 and 54%, respectively, in Purkinje fibers and by 32 and 34% in ventricular muscle) and effective refractory period (by 49 and 49% in Purkinje fibers and 29 and 40% in ventricular muscle). The effects of the two isomers were not significantly different. At the middle concentration (2.7 micrograms/ml), d-sotalol, unlike l-sotalol, had no beta-adrenergic blocking effect, but the electrophysiologic effects of dl-, d- and l-sotalol were indistinguishable. The data indicate that d-sotalol is equipotent with l-sotalol in lengthening the action potential duration and effective refractory period in cardiac muscle, an action unrelated to adrenergic antagonism or pharmacokinetic differences between the stereoisomers.

Amiodarone kinetics after oral doses

Amiodarone serum kinetics after single oral doses and after long‐term therapy were investigated in patients with ventricular tachyarrhythmias. When amiodarone was given as a single oral dose (1400 to 1800 mg, n = 6), serum levels of amiodarone and its metabolite, measured by high‐performance liquid chromatography, correlated (r = 0.69, P < 0.01). Peak concentrations (amiodarone, 3 to 14 μg/ml; metabolite, 0.7 μg/ml) were attained in 4.9 ± 1.2 hr. Using computer fits to the data, amiodarone mean elimination rate constant and half‐life (t½e) were 0.128 ± 0.063 hr−1 and 7.2 ± 5.0 hr. In 12 patients given a mean dose of 1327 ± 338 mg/day of amiodarone for 4.1 ± 2.3 wk, mean serum amiodarone level was 3.84 ± 2.92 μg/ml (range 0.92 to 11.99); in three patients simultaneous determination of concentrations of amiodarone and its metabolite revealed that concentration of the latter was about 50% of that of the parent drug during long‐term therapy. In four patients on maintenance therapy (400 to 800 mg/day, serum level 1.08 ± 1.13 μg / ml) drug was discontinued and serum amiodarone levels were determined serially. Serum drug disappearance followed a single exponential function with an elimination rate constant of 0.030 ± 0.012 day−1 and t½e of 29 ± 19 days. Our kinetic data are consistent with the long therapeutic amiodarone tl/2 noted in the treatment of cardiac arrhythmias.

Electrophysiologic effects of amiodarone: Experimental and clinical observation relative to serum and tissue drug concentrations☆

Oral amiodarone is a potent antiarrhythmic agent with a slow onset of action. Its electrophysiologic properties following chronic administration are well known, but its acute electrophysiologic actions are poorly defined. The objectives of the present study were to correlate the electrophysiologic actions of intravenous amiodarone in humans with the acute and chronic effects of the drug relative to plasma and tissue concentrations of the drug. In humans (n = 10), 5 mg/kg intravenous amiodarone (serum concentration 6.50 +/- 3.34 micrograms/ml at 10 minutes; 2.13 +/- 0.71 micrograms/ml at 20 minutes, n = 7) increased the AH interval by 16.4% (p less than 0.005), the antegrade effective refractory period (ERP) of the atrioventricular (AV) node by 14.4% (p less than 0.025), and the functional refractory period (FRP) of the AV node by 15.5% (p less than 0.005). The ERP or FRP of the atrium of the right ventricle was not significantly changed; there was no effect on the HV interval or the QT and R-R intervals of the ECG. In rabbits (n = 11) given 10 mg/kg intravenous amiodarone (mean +/- SD serum concentration 0.49 +/- 0.17 micrograms/ml; mean myocardial concentration 7.0 +/- 1.9 micrograms/gm, n = 3), there were no significant effects on the ECG intervals. In isolated rabbit sinoatrial (SA) node, atria, and AV node (three preparations) superfused with 5 X 10(-6)M amiodarone (3.41 micrograms/ml), there was no effect on the action potential duration (APD) or other parameters of the transmembrane potential.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiodarone-digoxin interaction: Clinical significance, time course of development, potential pharmacokinetic mechanisms and therapeutic implications

Administration of amiodarone (600 to 1,600 mg/day) to 28 patients during long-term digoxin therapy (0.25 +/- 0.05 mg/day) increased serum digoxin level from 0.97 +/- 0.45 to 1.98 +/- 0.84 ng/ml (p less than 0.001). Gastrointestinal side effects occurred in nine patients, central nervous system reactions occurred in five and cardiovascular reactions occurred in four. Pharmacokinetic studies in six patients with a 1 mg intravenous digoxin dose before and during amiodarone therapy increased serum digoxin level at 30 minutes from 8.59 +/- 1.68 to 10.07 +/- 1.70 ng/ml (p less than 0.05). Amiodarone caused a 31% prolongation of digoxin elimination half-life from 49.5 +/- 8.8 to 65.0 +/- 28.8 hours, but the increase in half-life was not statistically significant. Total body clearance was reduced significantly (29%, p less than 0.05) from 2.05 +/- 0.76 to 1.46 +/- 0.64 ml/min per kg. Nonrenal clearance also showed a significant decrease (33%, p less than 0.05) from 1.20 +/- 0.46 to 0.80 +/- 0.30 ml/min per kg. The renal clearance decreased by 22% and the volume of distribution decreased by 11% after amiodarone therapy, but these changes were not significant. The data show that the mechanism of digoxin-amiodarone interaction is multifactorial and emphasize the need for close monitoring of serum digoxin levels and clinical features during concurrent digoxin-amiodarone therapy.

Electrophysiologic effects of desethylamiodarone, an active metabolite of amiodarone: Comparison with amiodarone during chronic administration in rabbits

During acute superfusion studies by means of the standard microelectrode technique, we previously showed that both amiodarone and its major metabolite, desethylamiodarone, had a modest effect on the lengthening of the action potential duration (APD) at high drug concentrations and produced a rate-dependent block of the sodium channel in cardiac muscle. In this study the comparative electrophysiologic effects of the two compounds in rabbits treated chronically with these compounds were determined with particular reference to repolarization and sinus node automaticity. The changes were correlated with those in serum and tissue drug levels and in thyroid hormone indices. After 1 week neither compound had a significant effect on atrial or sinus nodal potentials; after 3 weeks, amiodarone increased the atrial APD at 90% repolarization time by 10.5% (p less than 0.05) and the effective refractory period (ERP) by 6.7% (p less than 0.05). The corresponding figures for desethylamiodarone were 13% (NS) and 18% (NS). The sinus cycle length was increased 12% (NS) by amiodarone and 27.9% (p less than 0.05) after the metabolite. In animals treated for 6 weeks, amiodarone increased the ventricular APD at 90% repolarization by 58.8% (p less than 0.01) and desethylamiodarone by 42.0% the corresponding figures for the ERP were 63.4% (p less than 0.01 and 47.4% (p less than 0.01), respectively. At the stimulation frequency used, neither compound exerted a significant effect on Vmax. Both amiodarone and desethylamiodarone significantly decreased serum triiodothyronine and increased reverse triiodothyronine levels but had no effect on thyroxine.(ABSTRACT TRUNCATED AT 250 WORDS)

Amiodarone efficacy in a young population: Relationship to serum amiodarone and desethylamiodarone levels

Serum amiodarone and desethylamiodarone levels were measured in children and young adults receiving chronic amiodarone therapy. The study population consisted of 34 children and young adults with ventricular tachycardia (36%), atrial flutter (36%), and recurrent supraventricular tachycardia (27%). The mean age was 12.9 +/- 8.6 years (range 4 months to 23 years) and the mean daily dose of amiodarone was 6.6 +/- 3.7 mg/kg/day (range 2.5 to 25 mg). Serum amiodarone and desethylamiodarone levels after 10.1 months (range 1 to 40 months) were 0.85 +/- 0.63 microgram/ml and 0.67 +/- 0.42 microgram/ml, respectively. In three patients for whom amiodarone therapy was unsuccessful, serum amiodarone levels were 0.27, 0.85, and 1.18 micrograms/ml. There was no significant correlation between serum amiodarone or desethylamiodarone levels and dosage of amiodarone. Four patients, all 13 years or older, developed toxicity (skin rash [one patient], keratopathy [two patients], and hyperthyroidism [one patient]). There was no correlation between serum amiodarone and desethylamiodarone levels and toxicity; although there was a trend toward elevated reverse serum triiodothyronine levels in patients who developed toxicity, the values fell within the range of those patients without toxic side effects. Serum amiodarone levels do not appear to be of great value in predicting efficacy and toxicity of amiodarone in children and young adults receiving chronic drug therapy.

Hypertriglyceridemia in ehrlich ascites carcinomatous mice. Tumor and mouse strain differences.

Ehrlich ascites carcinoma growth in mice induces hypertriglyceridemia. The degree of hypertriglyceridemia found in one laboratory (Spector’s) was much greater than we observed in our laboratory. Moreover, major differences were reported with respect to fasting (no effect on tumor extracellular fluid triglyceride levels in Spector’s tumor-bearing mice; marked decrease in ours). We have obtained tumorous CBA mice from Spector’s laboratory and have studied them simultaneously with our Swiss-Webster mice. Triglyceride levels of the above two groups and from two controlled crossover groups, included to evaluate the influence of mouse and tumor strains on hypertriglyceridemia, were determined. The CBA mice had intense hypertriglyceridemia and high triglyceride levels in tumor extracellular fluid regardless of the subline source of ascites tumor. On the other hand, only mild hyperlipidemia was induced with both strains of tumor in Swiss-Webster mice. Thus, the variations in plasma and tumor extracellular fluid triglyceride levels probably arise from the mouse strains and not from variations in the tumor subline. Fasting caused a decrease in both plasma and tumor extracellular fluid triglyceride concentrations in CBA, as well as in Swiss-Webster mice. A mouse strain difference was also evident from a significant decrease in wet weights of adipose tissues like epididymal fat, inguinal fat, and intermuscular fat with tumor growth in the CBA strain which was not observed in the Swiss-Webster strain at the corresponding stage of tumor growth. Study of these strain differences may lead to an understanding of factors that regulate hyperlipidemia.

Fatty acid synthesis in vivo and hepatic contribution to whole-body lipogenic rates in obese zucker rats

We have re-examined the claim by Godbole and York, based on the effect of surgical hepatectomy (Diabetologia14∶191, 1978), that liver contributed more than 90% of the newly synthesized FA found in adipose tissue of obese rats at the end of a 1-hr pulse of3H2O. The amount of newly synthesized FA transported via plasma VLDL from liver to adipose tissue was estimated in lean and obese Zucker rats by determining the effects of Triton WR-1339, which blocks the uptake of VLDL-TGFA into tissues. Triton treatment was found not to cause any significant change in the amount of radioactive FA found in subcutaneous/perimetrial fat tissues, carcass or liver in either chow-fed or high-glucose, fed-refed lean or obese rats, although in the fed-refed dietary state the proportion found in the liver was increased over that in the chow-fed groups. Furthermore, the amounts of newly made FA which accumulated in the plasma of Triton-treated, chow-fed and glucose-fed refed animals during this period constituted only a few percentages of those found in the adipose tissue of these animals. Thus, in contrast to the claims of Godbole and York, no significant transfer of newly made FA from liver to adipose tissue occurs during a 1-hr experiment; it follows that the amounts of these FA found in different tissues at the end of that period are valid measurements of their actual lipogenic activities in situ. It is suggested that the Godbole and York results are artifacts of their surgical hepatectomy procedure.

Beneficial effects of amiodarone pretreatment on early ischemic ventricular arrhythmias relative to infarct size and regional myocardial blood flow in the conscious dog.

The effects of chronic preireatment with amiodarone on ischemic ventricular arrhythmias were evaluated in fully conscious instrumented dogs. In control dogs (n = 14) with large myocardial infarcts, early (first 30 min) ventricular arrhythmias occurred in a bimodal distribution with peaks at 3–5 min and at 12–25 min, with only the former associated with epicardial conduction delay. Ventricular fibrillation occurred equally frequently during each peak of early ventricular arrhythmias. Amiodarone (30 mg/kg daily) for 3–4 weeks had no significant effect (n = 11) on anatomic infarct size (28 ± 6 vs. 30 ± 5% of left ventricular weight) nor on collateral blood flow in the center of the infarct (19 ± 11 vs. 15 ± 7 ml/min/100 g of tissue) or on the ratio of endocardial/epicardial perfusion (0.23 ± 0.19 vs. 0.28 ± 19). Despite significant lengthening of peak epicardial conduction delay (191 ± 20 to 239 ± 81 ms, p < 0.05), the frequency of early ventricular arrhythmias, especially during the second peak of ectopic activity, were markedly attenuated, by amiodarone pretreatment, with the extrasystole-free intervals often being as long as 6 h. The incidence of ventricular fibrillation was 9% in the treated animals compared with 29% in the controls. In the control animals, arrhythmias always supervened when epicardial fractionation was significant, and no ectopy-free interval was present in the first 6 h following coronary occlusion. The data indicate that chronic amiodarone pretreatment exerts a beneficial effect on the frequency and severity of such ventricular tachyarrhythmias, with reduction in the incidence of ventricular fibrillation and ectopic activity in the early phases following coronary occlusion.