All patients were successfully repleted using the described protocol without any significant adverse effects. This repletion regimen may have widespread applicability in the ICU setting.
In a study designed to determine the influence of renal dysfunction on the disposition of amiodarone and its metabolite, desethylamiodarone (DEA), 30 subjects received a single 5 mg/kg intravenous dose of amiodarone over 15 minutes. Of the 30, 11 had normal renal function (group I; mean +/- SD glomerular filtration rate [GFR] = 118 +/- 20 mL/min/1.73 m2), 9 had renal impairment (group II; GFR = 23 +/- 10 mL/min/1.73 m2), and 10 were long-term hemodialysis patients (group III; 4 of these patients were studied during dialysis). Total and free concentrations of amiodarone and DEA were measured by high-performance liquid chromatography. There were no significant differences between the three groups in mean systemic clearance, steady state volume of distribution, or mean residence time of amiodarone. However, the area under the concentration-time curve (AUC) for amiodarone was significantly higher in group I than in group II, and this finding was related to total body weight. Free fraction was similar in groups I and III. The disposition of amiodarone and its metabolite DEA was similar in patients with normal renal function, moderate renal dysfunction, and end-stage renal disease. Thus, dosage adjustment in patients with renal impairment is not necessary based on this pharmacokinetic analysis.
To evaluate the potential need for modification of dose regimens of intravenous amiodarone in patients with left ventricular dysfunction, the pharmacokinetics of amiodarone and its active metabolite, desethylamiodarone (DEA), were examined after a single 15-minute intravenous infusion of amiodarone 5 mg/kg. Three parallel groups of otherwise healthy volunteers with normal (n = 12), moderately impaired (ejection fraction > 30 but < or = 45%; n = 6), or severely impaired (ejection fraction < or = 30%; n = 6) left ventricular function were enrolled in the study. Serial blood samples were obtained over a 76-day period for estimation of pharmacokinetic parameters. With the exception of the half-life (t1/2) of DEA, statistical comparisons revealed no significant between-group differences in pharmacokinetic parameters or correlations between pharmacokinetic parameters and ejection fractions. The t1/2 of DEA was increased by approximately 60% in patients with severe left ventricular dysfunction compared with that in patients with moderately impaired and normal left ventricular function. The rate of DEA formation is slow, however, and its concentration relative to amiodarone is low. Therefore, it is unlikely that concentrations of DEA in serum would reach levels that contribute significantly to the pharmacologic activity of amiodarone during short-term (up to 2 weeks) intravenous amiodarone therapy. Single doses of amiodarone were well tolerated. The results of this study suggest that intravenous amiodarone can be used with appropriate observation to control arrhythmias, regardless of the degree of left ventricular dysfunction.
A 40-hour age- and weight-adjusted lidocaine infusion administered after an initial 8-hour infusion provoked more congestive heart failure than placebo. In view of the absence of ventricular fibrillation episodes with both infusions, caution should be used when lidocaine is administered for longer than 8 hours in patients with uncomplicated myocardial infarction.
Although propafenone is a known substrate and inhibitor of the cytochrome P450 4-hydroxylation pathway of debrisoquin (CYP2D6 isozyme), its effects on other hepatic mixed- function oxidative isozymes have not been extensively evaluated. We studied the influence of propafenone on the disposition of continuously infused lidocaine in 12 healthy male volunteers. Placebo or propafenone (225 mg every 8 hours) was orally administered for 4 days before and during lidocaine administration (2 mg/kg/hr for 22 hours). In the 11 (92%) subjects phenotyped as extensive metabolizers, propafenone significantly increased the lidocaine area under the plasma concentration time curve (81.7 +/- 16.2 versus 76.3 +/- 15.6 micrograms.hr/ml; p < or = 0.05) and reduced systemic lidocaine clearance (9.53 +/- 1.77 versus 10.27 +/- 2.24 ml/min/kg; p < or = 0.05), but did not significantly affect volume of distribution at steady state (2.48 +/- 0.33 versus 2.64 +/- 0.45 L/kg; p = 0.10) or mean residence time (4.37 +/- 0.92 versus 4.47 +/- 0.87 hours; difference not significant) compared with placebo, respectively. Adverse central nervous system effects were significantly worse in severity and duration during the propafenone phase (p < or = 0.05). Propafenone minimally inhibits the metabolism of lidocaine. This suggests that the ability of propafenone to inhibit metabolic pathways exclusive of the CYP2D6 isozyme may be limited. In addition, potentiation of disturbing central nervous system adverse effects may occur during combination therapy of propafenone and lidocaine.
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