Kinetics and cardiac effects of propranolol in humans.

Six healthy volunteers received single 20-mg intravenous (IV) and 80-mg oral doses of propranolol on two occasions in random sequence. Serum propranolol concentrations were determined by gas chromatography in multiple samples drawn during 24 h after each dose. Mean (+/- SE) kinetic variables for IV propranolol were: elimination half-life (t 1/2 beta), 5.3 (+/- 0.6) h; volume of distribution, 2.3 (+/- 0.3) l/kg; total clearance, 4.9 (+/- 0.3) ml/min/kg; predicted extraction ratio, 0.23 (+/- 0.02). After single oral doses, t 1/2 beta (3.8 +/- 0.2 h) tended to be smaller than after the IV dose, and actual systemic availability (0.60 +/- 0.07) was less than that based on the predicted extraction ratio. During multiple oral dosage (80 mg every 12 h), observed steady state serum levels (47 +/- 5 ng/ml) tended to be less than those predicted based on the single oral dose (61 +/- 5 ng/ml), thus providing no evidence for reduced propranolol clearance at steady-state. Echocardiographic measurements of left ventricular performance (posterior wall velocity, diastolic dimensions) made during the single-dose oral study indicated significant impairment of function; impairment was maximal at 3 h post-dosage, and corresponded to the time of the peak serum propranolol concentration (341 ng/ml).

[Effect of digitalis on hemodynamics during rest in patients with arterial occlusive diseases, stage II, without cardiac insufficiency]. / Digitaliseffekt auf die Ruhedurchblutung nicht herzinsuffizienter Kranker mit arterieller Verschlusskrankheit Stadium II.

In 6 patients without clinical symptoms of myocardia insufficiency and with stage II occlusive disease of the femoral artery, blood flow volume at rest, arterial blood pressure and heart rate were measured before, during and for two hours after an iv. infusion of 1.0 mg desacetyl-lanatoside. Blood flow at rest decreased by 23% and peripheral vascular resistance increased by 34%. The increase in the blood pressure amplitude was compensated by a decrease in heart rate. The mechanism of action is discussed. It is concluded that patients suffering from stage II arterial occlusive disease do not benefit at rest from the prophylactic administration of digitalis.

Impairment of digoxin clearance by coadministration of quinidine.

Seven healthy volunteers received a single 1.0-mg dose of intravenous digoxin in a drug-free control trial and again during concurrent therapy with therapeutic doses of quinidine. Digoxin kinetics were determined from multiple serum digoxin concentrations measured during 72 hours after dosage. Compared to the control state, quinidine coadministration reduced mean digoxin volume of distribution (15.1 vs. 12.4 l./kg), prolonged its elimination half-life (47.7 vs. 75.7 hours), and significantly reduced total clearance (6.06 vs. 2.18 ml/min.kg). Both renal and extrarenal digoxin clearances were impaired by quinidine. In nine cardiac patients receiving long-term digoxin therapy (0.25 mg twice daily), quinidine coadministration elevated mean morning digoxin levels from 1.37 to 2.0 ng/ml (P less than 0.001) and evening levels from 1.44 to 1.97 ng/ml (N.S.). If digoxin concentrations at the site of action are increased by quinidine, the interaction is likely to be of clinical importance in many patients.

Clinical implications of serum digoxin concentrations.

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.

Effect of dose on bioavailability of oral digoxin.

Nine healthy volunteers received single 0.25, 0.5, 1.0, 1.5, and 2.0 mg doses of oral digoxin tablets in random sequence on five occasions separated by at least 4 weeks. Urinary excretion of immunoassayable digoxin was determined from 8 consecutive 24 h urine samples collected after each dose. Mean values of cumulative urinary excretion of digoxin at the 5 doses were: 40.9, 35.6, 36.4, 34.1, and 33.5% of the dose (F = 0.64; d.f. = 4.32; N.S.). Mean values of urinary excretion half-life were: 2.48, 2.03, 2.20, 2.07, and 1.87 days (F = 2.87; d.f. = 4.32; p = 0. 05). Thus, the bioavailability of orally administered digoxin tablets in healthy volunteers is dose-independent over an 8-fold range of doses.

Comparative pharmacodynamics and plasma levels of beta-adrenoceptor blocking drugs.

1. Metoprolol (ME), pindolol (PI) and propranolol (PR) were studied in nine subjects at different doses and at 'maximum beta-adrenoceptor blockade' at a defined exercise load. Exercise tests were performed after each dosing period; isoprenaline stimulation was studied at the highest dose level. 2. ME and PR reduced heart rate at rest with most doses tested, while PI had no effect on resting heart rate. 3. Exercise heart rate was reduced with the smallest daily doses (ME 75 mg; PI 7.5 mg; PR 60 mg), and maximum reduction was from 163 to 116 beats/min (ME), 124 (PT) and 115 (PR) beats/min with daily doses of 242, 23 and 233 mg, respectively. 4. Resting blood pressure was not significantly affected by any beta-adrenoceptor blocker dose, but exercise induced blood pressure decreased from 166 to 130 (ME), 138 (PI) and 131 (PR) mm Hg, respectively. 5. Mean plasma concentrations at 'maximum beta-adrenoceptor blockade' were 158 (ME), 24 (PI) and 159 (PR) ng/ml without significant differences in the plasma level variation between beta-adrenoceptor blockers. 6. Isoprenaline doses required to increase heart rate by 30 beats/min were 3.8 microgram (control), 22 microgram (ME), 458 microgram (PI) and 200 microgram (PR), respectively. The differences may be due to different ratios of beta 1, beta 2 activity of the beta-adrenoceptor blockers tested.

Single- and multiple-dose kinetics of intravenous digoxin.

Nine healthy men received 0.5, 1.0, and 1.5 mg digoxin intravenously in random sequence on occasions separated by at least 4 wk. Digoxin concentrations were measured in serum samples drawn during 36 hr after each dose, and a mean across-dose kinetic profile was determined for each subject. After a 6-mo washout period, the same subjects received 0.25 mg digoxin intravenously every 24 hr for 10 consecutive days. Samples were drawn every 12 hr during the first 9 days and at multiple points during 72 hr after the last dose. Mean kinetic variables for the single- and multiple-dose trials were as follows: elimination half-life (t1/2), 27.9 and 38.0 hr (r = 0.62); volume of distribution, 5.5 and 7.4 l/kg (r = -0.56); total clearance, 2.50 and 2.49 ml/min/kg (r = 0.19); urinary excretion t1/2, 40.9 and 37.9 hr (r = -0.14). Mean observed and predicted predose steady-state serum concentrations were 0.59 and 0.79 ng/ml (r = -0.02). Mean values of accumulation and elimination t1/2 were nearly identical (27.8 and 27.9 hr), but were not positively correlated (r = -0.64). Multiple-dose digoxin therapy leads to no systematic change in digoxin clearance. Single-dose kinetics is poorly predictive of the rate and extent of drug accumulation and of washout kinetics during and after multiple-dose therapy.

[Biological availability of digoxin from a combination drug]. / Biologische Verfügbarkeit von Digoxin aus einem Kombinationspräparat.

In a randomized cross-over study with 14 voluntary test persons the absolute biological availability of digoxin in Card-Dusodril 1/8 and 1/4 respectively was investigated. 6 test persons received 4 drag. Card-Dusodril 1/8 (= 0.5 mg digoxin), 8 test persons 4 drag. Card-Dusodril 1/4 (= 1 mg digoxin) orally, in comparison to the corresponding group with intravenously applied digoxin as standard. Based on the cumulative digoxin excretion in the urine an absolute biological availability of Card-Dusodril 1/8 of 79%, of Card-Dusodril 1/4 of 76% could be demonstrated. With regard to an average resorption of oral digoxin preparations of approx. 70%, the present values, which correspond in direct comparison to those of acetyl digoxin, can be considered good. Maximum serum levels were achieved after 86 +/- 6.8 minutes which also indicates a quick resorption.