C. S. Reilly

Ultra‐short‐acting beta‐blockade: A comparison with conventional beta‐blockade

Esmolol is a β1‐selective adrenoceptor blocker that is rapidly metabolized by blood and liver esterases. The β‐receptor and hemodynamic effects of esmolol were determined in a group of 12 healthy men and were compared with those induced by both oral and intravenous propranolol. Esmolol was rapidly effective in inducing at least 90% of steady‐state β‐blockade within 5 minutes of either initiating or changing the esmolol infusion rate. More importantly, when esmolol infusion was discontinued the β‐blockade had totally disappeared by 18 minutes after esmolol, 300 µg/kg/min, and had been reduced by 50% after 750 µg/kg/min. In contrast, 30 minutes after discontinuation of a propranolol infusion, there was no change in the level of β‐blockade. Propranolol was much more potent at blocking isoproterenol‐induced tachycardia (dose ratio 33.5 ± 2.5) than was even the highest dose (750 µg/kg/min) of esmolol (dose ratio 13.1 ± 1.0). The same dose of intravenous propranolol was approximately equipotent to oral propranolol, 40 mg every 8 hours (dose ratio 33.5 ± 2.5 and 34.5 ± 3.6, respectively). In contrast, propranolol, 40 mg every 8 hours, and esmolol, 300 µg/kg/min, were equipotent in antagonizing exercise‐induced tachycardia (40.1% ± 2.3% and 42.7% ± 3.2%, respectively). Esmolol had striking hypotensive effects. Systolic blood pressure fell by 20 mm Hg during esmolol infusions of 750 µg/kg/min. Esmolol appears to be a potent β1‐selective adrenoceptor antagonist with a particularly strong hypotensive effect. It is likely to be very useful in the treatment of hemodynamically unstable patients and may be useful in the emergency treatment of hypertension.

The Effect of Halothane on Drug Disposition: Contribution of Changes in Intrinsic Drug Metabolizing Capacity and Hepatic Blood Flow

Several studies have shown that halothane may influence drug disposition in animals and humans, but the mechanism remains unclear. The relative contributions of changes in metabolizing capacity and hepatic blood flow to altered drug disposition were investigated during halothane anesthesia, using propranolol as a model compound. The studies were performed on six dogs on three separate days; first, the day before anesthesia, second, during halothane (2.0 MAC) anesthesia, and third, 24 h after anesthesia. Each dog simultaneously received 40 mg unlabeled propranolol directly into the portal vein and 200 mCi of 3H-propranolol intravenously via chronically implanted catheters. Blood samples were taken every 5 min for the first hour and then every 15 min for a further 3 h for the measurement of unlabeled and 3H-propranolol concentrations. During halothane anesthesia, intra-portal–intrinsic clearance was decreased by 62% (P < 0.05) from 2,110 ± 298 to 799 ± 233 ml/min, while systemic clearance was decreased (P < 0.05) from 470 ± 33 ml/min preanesthesia to 280 ± 38 ml/min during halothane anesthesia. The intravenous elimination half-life was increased (P < 0.05) from 87 ± 12 to 155 ± 23 min during anesthesia. Although halothane anesthesia tended to lower liver plasma flow from 642 ± 80 to 473 ± 47 ml/min, this change was not significant. The large change in portal or intrinsic clearance indicates that halothane anesthesia markedly inhibits drug-metabolizing ability. The authors therefore conclude that the alterations in drug disposition observed during halothane anesthesia are mainly due to inhibition of drug-metabolizing capacity in the liver.

Variability of fentanyl pharmacokinetics in man. Computer predicted plasma concentrations for three intravenous dosage regimens.

The derived pharmacokinetic data for the intravenous administration of fentanyl obtained from seven previous studies were compared using computer simulation of predicted plasma concentrations following three intravenous dosage regimens. There was wide discrepancy between the reported calculated pharmacokinetic constants from the various studies, such that the volume of distribution ranged from 4.4 to 59.7 litres, estimates of terminal elimination half‐life ranged from 141 to 853 minutes while total body clearance values ranged from 160 to 1530 ml/minute. The differences in predicted plasma concentrations were marked. The peak concentration following a bolus of 500 pg ranged from 8.4–113.6 ng/ml and took from 2.9 to 18.9 hours to fall to 0.5 ng/ml. The steady state plasma concentration reached with an infusion of 0.3 μg/kg/minute varied from 12.2–119.9 ng/ml and the plateau level attained with a two‐rate infusion (2.7 μg/kg/minute for 20 minutes then 0.3 μg/kg/minute) ranged from 10.6–50.8 ng/ml. The aim of descriptive pharmacokinetics is to allow the clinician to predict the plasma concentration achieved by a given dose and to facilitate dosage choice and adjustment. Recent interest has centred on the use of pharmacokinetics to calculate continuous intravenous infusion dosage regimens. The clinical application of current pharmacokinetic data for fentanyl is questionable.

Suppression of ventricular arrhythmias in man by d-propranolol independent of beta-adrenergic receptor blockade.

To investigate the mechanisms of ventricular arrhythmia suppression by propranolol, we determined the antiarrhythmic efficacy of d-propranolol in 10 patients with frequent ventricular ectopic depolarizations (VEDs) and nonsustained ventricular tachycardia. After an initial placebo phase, 40 mg d-propranolol was administered orally every 6 h with dosage increased every 2 d until arrhythmia suppression (greater than or equal to 80% VED reduction), intolerable side effects, or a maximal dosage (1,280 mg/d) was reached. Response was verified by documenting return of arrhythmia during a final placebo phase. Arrhythmia suppression occurred in six patients while two more had partial responses. Effective dosages were 320-1,280 mg/d (mean 920 +/- 360, SD) of d-propranolol with corresponding plasma concentrations of 60-2,280 ng/ml (mean 858 +/- 681). For the entire group, the QTc interval shortened by 4 +/- 4% (P = 0.03). Arrhythmia suppression was accompanied by a reduction in peak heart rate during exercise of 0-29%. To determine whether arrhythmia suppression could be attributed to beta-blockade, racemic propranolol was then administered in dosages producing the same or greater depression of exercise heart rate. In 3/8 patients, arrhythmias were not suppressed by racemic propranolol indicating that d-propranolol was effective via a non-beta-mediated action. By contrast, in 5/8 patients racemic propranolol also suppressed VEDs. We conclude that propranolol suppresses ventricular arrhythmias by both beta- and non-beta-adrenergic receptor-mediated effects.

Enprostil, in contrast to cimetidine, does not inhibit propranolol metabolism

Enprostil, an orally active prostaglandin E2 analog, is undergoing clinical trials in the treatment of peptic ulcer disease. Because results of animal studies suggested that prostaglandins might affect both hepatic drug metabolizing ability and hepatic blood flow, the effects of enprostil on drug elimination were studied and compared with those of the standard antiulcer drug Cimetidine in a double‐blind, randomized, crossover study of nine normal subjects. Cimetidine reduced the oral clearance of propranolol by 50%, consistent with the inhibition of drug metabolism reported in previous studies. On the other hand, enprostil had no effect on propranolol elimination. Neither drug altered liver blood flow as assessed either by the clearance of indocyanine green or by the technique of dual route of administration of propranolol. Thus in contrast to cimetidine, enprostil had no effect on hepatic drug metabolism.

Pharmacokinetics of fentanyl

thetics on drug metabolism and d i s p o s i t i ~ n . ~ ~ However, as we stated in our paper, although within study differences in fentanyl kinetics between healthy controls and surgical patients have been described, these did not explain our findings. For example, the normal volunteer studies quoted yielded values that were amongst both the highest and the lowest in our simulations. Thus, we remain convinced that there is considerable inconsistency in the plasma fentanyl concentrations which would be predicted from the various published studies describing fentanyl pharmacokinetics.