Pharmacokinetic studies of quinidine in patients with arrhythmias.

The absorption and disposition of quinidine were measured in nine patients following single oral and intravenous dosing. A new specific chromatographic method was used to measure the drug in plasma and urine. After intravenous administration, the plasma half-life (t1/2beta) was 7.8+/-0.7 h, the volume of distribution (Vd) was 3.0+/-0.5 liters/kg, and the total body clearance was 4.8+/-0.8 ml/min/kg. After oral administration, 87+/-7% (mean+/-SEM) was available to the systemic circulation. Quinidine was removed primarily by hepatic metabolism, with the renal clearance averaging only 1.0+/-0.2 ml/min/kg. Mean quinidine concentrations were estimated in 42 patients on chronic therapy by averaging blood levels during a dosing interval. In patients without heart failure, these corresponded well to mean drug levels predicted from the pharmacokinetic parameters measured after a single intravenous dose, but in patients with heart failure, the values for mean quinidine concentrations were higher than predicted. This suggests that impaired elimination of the drug or a decreased volume of its distribution, or both, may develop in heart failure.

Minoxidil reduces pulmonary vascular resistance in dogs and cattle.

Minoxidil has a direct dilator effect on the systemic arterial smooth muscle. It is potentially an important drug in the treatment of systemic hypertension, especially when combined with beta blockade, which is used to control the associated tachycardia and increase in cardiac output. However, recent observations have suggested that minoxidil might cause pulmonary hypertension. Consequently, we examined the acute effect of monoxidil and propranolol, separately and in combination, on the pulmonary vasculature of the anesthetized dog and the awake calf during normoxia and hypoxia. In both species minoxidil reduced pulmonary vascular resistance. In the dogs this appeared to be the result of a direct action on the pulmonary vascular smooth muscle and in the cattle it was secondary to beta-receptor stimulation. Propranolol alone in the cattle increased the pulmonary pressor response to hypoxia. While we have not examined the possibility that chronic administration of minoxidil might cause pulmonary hypertension by some other mechanism, our acute studies suggest that it reduces, rather than increases, pulmonary vascular resistance. Furthermore, there seems to be a species difference in the mode of its action in dogs and cattle.

Intravenous aminophylline dosage. Use of serum theophylline measurement for guidance.

A practical method for monitoring serum theophylline concentrations has been used to investigate intravenous aminophylline dosage requirements. Initial serum theophylline concentrations were found to vary widely and correlate poorly with drug history. Aminophylline loading doses determined from these values more frequently resulted in drug concentrations in the therapeutic range (10 mug to 20 mug/ml) than when therapy was given without knowledge of serum theophylline concentrations. Continuous intravenous aminophylline therapy administered in a standardized dosage (0.9 mg/kg/hr in adults and 1.0 mg/kg/hr in children) produced variable and often excessive serum concentrations. This resulted from variable drug clearance rates, which in adults averaged 0.64 +/- 0.38 ml/kg/min (mean +/- SD), only half that previously reported. These observations suggest that it is not possible to achieve optimal therapeutic aminophylline dosage without monitoring serum theophylline concentrations.

Correlation of plasma propranolol concentration with therapeutic response in patients with angina pectoris.

The therapeutic response to propranolol was evaluated in patients with documented coronary artery disease at doses varying from 40 to 320 mg/day. Therapeutic response was quantified by evaluating exercise performance on a treadmill and then related to plasma propranolol concentration. Plasma propranolol was defined in terms of beta-adrenergic blockade by comparison with dose (concentration) response curves in normal subjects. Individual therapeutic benefit occurred at doses which averaged 144 +/- 21 mg/day and at concentrations which averaged 30 +/- 7 ng/ml. There was a wide variation between both dose and concentration among the patients at maximum therapeutic response, but when the plasma propranolol was related to pharmacologic activity, the maximum therapeutic response was observed between 64 to 98% of total blockade. Despite the increased exercise performance in these patients, the double product of heart rate and systolic blood pressure was always less, suggesting either an alteration of the relation between myocardial oxygen consumption and the double product during propranolol or a reduction on oxygen delivery to the myocardium as the result of beta-adrenergic blockade of the coronary vasculature.

Studies of the absorption and removal of propranolol in hypertensive patients during therapy.

The variability of plasma propranolol concentrations has been determined in a large group of patients being treated with the drug. Although the average patient achieved a therapeutic plasma level with 160 mg/day, there was marked interpatient variation. This was found to be primarily the result of differences in effective absorption of the drug, which averaged 46% of the oral dose but ranged from 20 to 80%. Propranolol disappeared from plasma with a half-life of 4.7 hours and its removal appeared to follow dose independent kinetics with no evidence of saturation of hepatic metabolism. The derived pharmacokinetic values of volume of distribution and clearance rate have been used to provide guidelines for initiating propranolol therapy intravenously, and the schedule of 8 mg as a loading dose and 0.02 mg/min as a sustaining dose has been suggested.

Hypotensive and renin-suppressing activities of propranolol in hypertensive patients.

1. In patients with mild or moderate essential hypertension, oral propranolol, given in incremental doses, produced a moderate but significant lowering of blood pressure which was correlated with the concentration of propranolol in plasma. 2. Propranolol also reduced plasma renin activity (PRA) in the supine posture, on standing and after intravenous frusemide. However, 'supine' and 'frusemide' PRA values were markedly reduced at a plasma concentration of propranolol that had little effect on blood pressure. 3. On administration of propranolol there was little correlation between blood pressure decrease and PRA suppression, and even less between pretreatment PRA values and hypotensive response. 4. It is concluded that in patients with mild and moderate hypertension and low or normal plasma renin activity, suppression of PRA is not an important determinant of the hypotensive response to propranolol.

Pharmacodynamic studies of beta adrenergic antagonism induced in man by propranolol and practolol.

The pharmacodynamic activities of two beta adrenergic antagonists, propranolol and practolol, were compared in eight hypertensive patients. The activity of each antagonist was established in relation to its blood concentration at maximal and submaximal adrenergic blockade defined by inhibition of exercise tachycardia. Maximal inhibition of exercise tachycardia was comparable with both drugs and averaged 74+/-7% of the control value during drug treatment. This inhibition was achieved with a blood concentration of 2.5+/-0.4 mug/ml practolol and 0.10+/-0.08 mug/ml propranolol. The antagonist activities of these drugs against adrenergic stimulation with isoproterenol infusion indicated a much greater relative potency of propranolol against this stimulus, and in vivo estimates of PA(2) values differed by more than 600-fold. Relative antagonist activity of practolol during isoproterenol stimulation was equivalent both at cardiac (inotropic and chronotropic) and at vascular adrenergic receptors, whereas greater antagonist activity of propranolol was observed at vascular receptors than at cardiac receptors. Thus, the activity of practolol was not limited to cardiac receptors as previously suggested. Practolol did not reduce cardiac output at any dose level and the effect on resting blood pressure was small. Both practolol and propranolol had much greater hypotensive activity during exercise. These studies have defined the differing pharmacodynamic activities on the cardiovascular system of two effective beta adrenergic receptor antagonists and have established the blood levels of these antagonists necessary to achieve effective adrenergic blockade.