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Ten otherwise healthy cigarette smokers (mean, 31 cigarettes per day), and ten nonsmoking control volunteers matched for age, weight, and sex received single intravenous doses of diazepam (5 to 10 mg), midazolam (5 mg), and lorazepam (2 mg) on three separate occasions. Kinetics of each benzodiazepine were determined from multiple serum concentrations measured after each dose. In non-smoking vs smoking subjects, there was no significant difference in mean clearance of diazepam (0.44 vs 0.47 ml/min/kg), midazolam (9.6 vs 7.1 ml/min/kg), or lorazepam (0.96 vs 1.08 ml/min/kg). Thus, differences in pharmacokinetics are unlikely to account for altered sensitivity to benzodiazepines that may occur in cigarette smokers.

The pharmacokinetics of oral quinidine sulfate and quinidine gluconate were compared in seven healthy volunteers In a two part pharmacokinetic study. Part I was a single dose crossover trial assessing absorption and elimination of quinidine sulfate (400 mg, equivalent to 331 mg of quinidine base) and quinidine gluconate (495 mg, equivalent to 309 mg of quinidine base). Mean kinetic values for the sulfate and gluconate preparations, respectively, were: peak serum quinidine level 2.07 versus 1.24 μg/ml (P Part II evaluated steady state kinetics of both preparations in a cross-over trial in the same subjects. Maintenance dosing schedules were 200 mg of quinidine sulfate every 6 hours versus 495 mg of quinidine gluconate every 12 hours. Systemic availability of the gluconate at the steady state level was 10 percent less (based upon area under the serum concentration curve) or 7 percent less (based upon urinary excretion of quinidine) than that of the sulfate, but the differences were not significant. Interdose fluctuation in serum quinidine concentrations during the gluconate trial averaged 70 percent, which was not significantly different from the average of 67 percent during the sulfate trial. However, variation within and between subjects in minimal steady state levels with quinidine gluconate (15.6 and 16.0 percent, respectively) was greater than with quinidine sulfate (7.2 and 9.9 percent, respectively). Steady state concentrations during the multiple dose trial were not accurately predicted from single dose pharmacokinetics, either for quinidine sulfate (r = 0.45) or quinidine gluconate (r = −0.12), but deviation of observed from predicted concentrations tended to be greater with quinidine gluconate. The slow absorption of quinidine from the gluconate preparation allows maintenance therapy on a 12 hourly dosage schedule with acceptable interdose fluctuation in serum levels. Variability within and between subjects in absorption kinetics tends to be greater with quinidine gluconate than with the more rapidly absorbed sulfate salt.

The influence of age on quinidine pharmacokinetics was assessed in 22 healthy male and female volunteers; 14 of the subjects were young (aged 23 to 34 years) and 8 elderly (aged 60 to 69 years). All subjects received 180 to 300 mg of quinidine base by constant rate intravenous infusion over 10 to 15 minutes. The concentration of total and unbound quinidine in multiple serum samples and in urine collected within 48 hours after the administration of quinidine qas determined with spectrophotofluorometric assay. Mean kinetic values for total quinidine in the young subjects were: elimination half-life (t 1/2 beta), 7.3 hours; total volume of distribution (Vd), 2.39 liters/kg; total clearance, 4.04 ml/min per kg; renal clearance 1.43 ml/min per kg; and percent unbound, 24.6 In the elderly subjects, the values for Vd (2.18 liters/kg) and percent unbound (28.2) did not differ significantly from these values in the young subjects. However, in the elderly subjects t 1/2 beta was significantly longer (9.7 hours, P less than 0.05) and total quinidine clearance significantly less (2.64 ml/min per kg, P less than 0.005) than in the young subjects. Renal clearance of quinidine in the elderly was also significantly less (0.99 ml/min per kg, P less than 0.05) than in the young and was associated with lower rates of creatinine clearance in the elderly (r = 0.66). Reduced clearance of quinidine and prolongation of its elimination half-life could predispose to toxicity in the elderly unless the dose were appropriately adjusted.

infarction is not known. Moreover, the diagnosis of this arrhythmia should not be restricted to instances where delayed repolarization or extreme bradyarrhythmias are present. The therapeutic implications of this finding are unclear. Antiarrhythmic agents which potentially prolong the QT interval may be relatively contraindicated in this setting and the use of bretylium or early ventricular pacing may be preferable.

Factors influencing serum digoxin concentrations, and the relation of these levels to classical electrocardiographic (ECG) and clinical manifestations of toxicity, were assessed in a series of 463 consecutively hospitalized patients of mean age 58 years. The majority of patients were receiving beta-acetyldigoxin or beta-methyldigoxin. Age, sex, creatinine clearance, and weight-corrected dose collectively explained less than 7% of overall variability in serum digoxin concentrations; creatinine clearance, which declined significantly with age (r=-0.36, p less than 0.001) was the most important of these determinants. ST-segment depression was present in the majority of patients and became more common at higher serum digoxin concentrations. However, PR interval, QRS durations, QT interval, or the presence of AV block were not associated with serum levels. Among 75 patients with atrial fibrillation, ventricular rate did not decline with increasing digoxin concentrations. The presence of gastrointestinal, neuromuscular, or psychiatric symptoms classically attributed to digitalis toxicity was not associated with serum digoxin concentration. Serum levels of digoxin appear to be of limited value in assessing the degree of digitalization.