Kenneth A. Conrad

Effects of ketorolac tromethamine on hemostasis in volunteers

Ketorolac tromethamine, an analgesic agent with prostaglandin synthetase–inhibiting activity, is more active than aspirin in vitro in inhibiting collagen– or arachidonic acid–induced platelet aggregation. In this randomized, double‐blind study, 26 volunteers received ketorolac, 30 mg intramuscularly four times a day for 5 days, and placebo, two capsules orally four times a day for at the last 2 study days. The effects of this treatment were compared with those of intramuscular placebo and oral aspirin, two 325 mg capsules, given on the same schedule to eight volunteers. Aspirin at a mean serum concentration of 84 μg/ml did not affect prothrombin time, partial thromboplastin time, platelet count, or bleeding time. Ketorolac produced a modest prolongation of the bleeding time, from 4.9 ±1.1 minutes (mean ± SD) to 7.8 ± 4.0 minutes (p < 0.005). Ketorolac did not affect the prothrombin time or partial thromboplastin time but was associated with clinically insignificant change in the platelet count from 303 ± 57 × 103/m3 to 277 ± 56 × 103/mm3.

Effects of metoprolol and propranolol on theophylline elimination

The effects of beta adrenergic blockade on theophylline elimination were studied in nine normal subjects. Oral propranolol. 40 mg every 6 hr, induced a fall in theophylline clearance from 0.0464 ± 0.0216 to 0.0294 ± 0.0129 l/kg/hr (p < 0.001). Oral metoprolol, 50 mg every 6 hr, did not reduce theophylline clearance in the group as a whole but had a reducing effect intermediate to that of propranolol on theophylline clearance in some smokers whose theophylline clearance was high initially. Beta adrenergic blockade may reduce theophylline clearance, particularly in subjects whose theophylline metabolism has been induced by cigarette smoking.

Lidocaine elimination: Effects of metoprolol and of propranolol

The effects of administration of metoprolol and propranolol on lidocaine elimination were studied in six healthy young men who did not smoke. Each received three single intravenous doses of lidocaine (2.5 to 3.0 mg/kg injected over 10 min): one alone, one after 1 day pretreatment with propranolol (40 mg orally every 6 hr), and one after 1 day pretreatment with metoprolol (50 mg orally every 6 hr). Lidocaine clearance was 0.88 ± 0.28 l · hr−1 · kg−1 before beta blockade, 0.61 ± 0.20 l · hr−1 · kg−1 during metoprolol dosing, and 0.47 ± 0.16 l · hr−1 · kg−1 during propranolol dosing. There was no correlation between the change in lidocaine elimination and the steady‐state concentrations of metoprolol or propranolol, nor between the change in lidocaine clearance and the change in resting heart rate produced by either beta blocker. Metoprolol and propranolol reduce lidocaine elimination significantly.

Phenobarbital Pharmacokinetics and Bioavailability in Adults

Abstract: The pharmacokinetics and bioavailability of phenobarbital were examined in six healthy adult subjects after a 2.6 mg/kg intravenous and a 2.9 mg/kg oral dose. Serum concentrations of phenobarbital were followed by means of a high pressure liquid chromatographic assay for 21 days after drug administration. After the intravenous dose, the mean distribution half‐life was 0.18 hour and the mean elimination half‐life was 5.8 days. Mean total body clearance and mean renal clearance were 3.0 ml/hr/kg and 0.8 ml/hr/kg, respectively. The apparent volume of distribution was 0.60 liter/kg. After administration of phenobarbital tablets, the maximum phenobarbital serum concentration was 5.5 mg/liter at 2.3 hours after the dose. Adjusted absolute availability of phenobarbital from the tablets studied was 94.9 per cent (range 81–111.9 per cent). The elimination half‐life averaged 5.1 days for the oral dose. There was no evidence of autoinduction of phenobarbital elimination over the study period.

Clodronate kinetics and dynamics

Clodronaie disodium (C12MDP) was given intravenously in doses of 3, 6, and 10 mg/kg to six men (aged 23 to 30 yr). Volume of distribution was 0.2720 ± 0.0255 l/kg (x̄ ± SD) after 3 mg/kg dose, 0.3037 ± 0.0445 l/kg after 6 mg/kg, and 0.2528 ± 0.0417 l/kg after 10 mg/kg. The elimination rate constant was 0.3787 ± 0.0546 hr−1, 0.3492 ± 0.0616 hr−1, and 0.3962 ± 0.0358 hr−1 after 3, 6, and 10 mg/kg. Corresponding total body clearances were 0.1026 ± 0.0149, 0.1049 ± 0.0159, and 0.0998 ± 0.0172 1/kg/hr. Renal clearance accounted for 73% of total body clearance; 73% of the drug was excreted unchanged in the urine in 24 hr. After Cl2MDP serum phosphate decreased approximately 13%; this was associated at the 10 mg/kg dose with a transient fall in fractional phosphate excretion. There were no significant changes in the serum concentration or fractional excretion of calcium, sodium, or uric acid. Creatinine clearance and renal concentrating ability were not altered by Cl2MDP. After short‐term administration Cl2MDP is excreted primarily by the kidney but has no significant effects on renal function.

Effects of meals on hemodynamics: Implications for antihypertensive drug studies

The ingestion of food is known to affect blood pressure and heart rate, but food is often allowed in patients under observation for antihypertensive drug effects. Seventy‐seven patients with essential hypertension were observed for 8 hours after a 16‐hour fast. Thirty‐six continued to fast, 20 ate a high‐carbohydrate meal, and 21 ate a meal of their own choice. Blood pressure and heart rate did not change during fasting, but both meals lowered mean supine and standing diastolic blood pressures during the subsequent 4 hours by 3 to 7 mm Hg (P < 0.001). The high‐carbohydrate meal reduced supine systolic blood pressure by 6 mm Hg (P < 0.0001). Both meals increased supine and standing heart rates by 5 to 8 bpm (P < 0.001). After the self‐selected meal, standing systolic blood pressure increased in younger patients but decreased in older patients. Food ingestion during antihypertensive drug studies may interfere with the interpretation of results and should be avoided whenever possible.

Effect of quinine on digoxin kinetics

Six subjects were evaluated for the effect of quinine, the 1‐isomer of quinidine, on digoxin pharmacokinetics. A 1.0‐mg intravenous digoxin dose was given before and during quinine administration, followed by the measurement of digoxin serum and urine concentrations for 96 hr after each dose. Quinine reduced digoxin total body clearance by 26% from 2.98 to 2.22 ml/min/kg (p < 0.03). Digoxin elimination half‐life (t½) was lengthened from 34.2 to 51.8 hr, reflecting a 32% decrease in digoxin elimination rate constant (p < 0.003). Quinine did not reduce digoxin renal clearance or any volumes of distribution. The amount of digoxin excreted into the urine increased from x̄ = 628.29 μg to x̄ = 772.52 μg (p < 0.02). Digoxin nonrenal clearance decreased an average of 55% from 1.2 to 0.55 ml/min/kg (p < 0.05). These results suggest that quinine alters digoxin metabolism or biliary secretion, reducing digoxin total body clearance by a mechanism that is qualitatively similar, but quantitatively different, from quinidine.

Digitoxin-quinidine interaction: pharmacokinetic evaluation.

The effect of quinidine on digitoxin single-dose pharmacokinetics was evaluated in five healthy adults. Blood was collected for 3 weeks, and a complete urine collection was obtained for 4 days, after a single intravenous dose of digitoxin. The protocol was conducted once while each subject was taking oral quinidine, for 3 weeks, and then repeated 10 days after discontinuing quinidine treatment. Quinidine induced the following changes in digitoxin pharmacokinetics: Elimination half-life was prolonged from 174 +/- 25 to 261 +/- 58 hours (p less than 0.02); total body clearance decreased from 1.54 +/- 0.40 to 1.09 +/- 0.31 mL/h . kg (p less than 0.05); renal clearance decreased from 0.65 +/- 0.07 to 0.46 +/- 0.17 mL/h . kg (p less than 0.05). Digitoxin volume of distribution and protein binding were unaltered by quinidine. Quinidine caused a rise in serum digitoxin levels. Digitoxin total body clearance was decreased by quinidine to an extent comparable to that reported for digoxin; however, the mechanism of the interaction with the two digitalis glycosides may, in part, be different.

Gastrointestinal absorption as a function of age: Xylose absorption in healthy adults

Xylose oral absorption was examined in 24 healthy male subjects ranging in age from 32 to 85 years. Absorption was evaluated from xylose plasma concentration‐time data after administration of a 25 gm po or a 5 gm iv dose. There was no relationship between various estimates of the rate of absorption and age. The absolute oral bioavailability or the extent of xylose absorption showed no relationship to age in our population. In contrast with previous suggestions, xylose absorption does not decline with age. General statements of decreased gastrointestinal absorption efficiency as a function of age may not be correct.

Doxazosin in patients with hypertension

SummaryThe antihypertensive effects and steady-state pharmacokinetics of doxazosin, as well as the bioequivalence of four dosage forms, were studied in 25 hypertensive patients.For an 8 mg daily dose mean Cmax at steady-state for all patients was 108 ng/ml; the mean tmax was 1.8 h. The mean terminal elimination half-life was 22 h. The four tablets containing 1, 2, 4, or 8 mg of doxazosin were bioequivalent in delivering the 8 mg dose.In patients with mild to moderate hypertension, 26-day treatment with doxazosin resulted in blood pressure reduction of 10/7 mm Hg in the supine and 13/18 mm Hg in the standing position. Adverse effects were generally mild and of brief duration.