Lack of relationship between debrisoquine oxidation phenotype and the pharmacokinetics and first dose effect of prazosin.

The relationship between debrisoquine oxidation phenotype and the pharmacokinetics and pharmacodynamics of a single oral dose of prazosin has been studied in eight hypertensive patients (four extensive and four poor metabolisers). No significant differences between the two phenotypes were observed in either the area under the plasma prazosin concentration-time curve, the terminal half-life or the first-dose effect of prazosin.

Metoprolol metabolism and debrisoquine oxidation polymorphism--population and family studies.

The metabolism of metoprolol was studied in 143 unselected hypertensive patients and in 10 families. The log10 metoprolol to alpha-hydroxymetoprolol urinary ratio was bimodally distributed and was correlated with the debrisoquine oxidation phenotype (rs = 0.81, P less than 0.001). The results of the pedigree study were compatible with poor hydroxylation of metoprolol being inherited as an autosomal recessive trait. The major urinary metabolite of metoprolol metabolism was H117-04, the end-product of O-dealkylation. The distribution of the log10 metoprolol to H117-04 (M/H117-04) urinary ratio was unimodal. However, there was a significant correlation between this ratio and the debrisoquine oxidation phenotype (rs = 0.68, P less than 0.001) and poor metabolisers of debrisoquine (PMs) were concentrated at the upper end of the range of M/H117-04 values. These results indicate that both the alpha-hydroxylation and O-dealkylation of metoprolol are under polymorphic control of the debrisoquine type. Plasma concentrations of metoprolol were about three times higher in PMs than in extensive metabolisers of debrisoquine (EMs) at 3 h after dosing. In a sub-group of 24 subjects, all seven PMs but only two EMs showed more than a 10% reduction in post-exercise heart rate at 24 h after dosing.

Pharmacokinetics and beta-blocking effects of timolol in poor and extensive metabolizers of debrisoquin.

We studied the pharmacokinetics and beta-blocking effects of a single, oral 20 mg dose of timolol in six poor metabolizers (PMs) and six extensive metabolizers (EMs) of debrisoquin. The plasma timolol concentration was significantly higher in PMs than in EMs. There was a fourfold difference in mean AUC (1590 +/- 1133 vs. 394 +/- 239 ng X hr/ml; P less than 0.01) and a twofold difference in mean t1/2 (7.5 +/- 3 vs. 3.7 +/- 1.7 hours; P less than 0.01), reflecting differences in oral clearance (13.1 +/- 7.8 vs. 48.5 +/- 23.2 L/hr; P less than 0.01). The degree of beta-blockade was greater in PMs than in EMs at 12 hours (30.9% vs. 18.2%; P less than 0.05) and at 24 hours (28.3% vs. 13.1%; P less than 0.05). In the group as a whole the metabolic ratio correlated positively with both kinetic data and beta-blockade, but some overlap was observed. Hence timolol metabolism appears to be subject to debrisoquin-type polymorphism, which results in interphenotypic variation in plasma concentration and beta-blocking effect.

Controlled trial of ketanserin in hypertension.

We have completed a double-blind parallel group comparison of the 5-HT2 receptor antagonist ketanserin with placebo in 22 hypertensive patients. Ketanserin (20-40 mg twice daily) lowered sitting blood pressure more than placebo by 6.9 mm Hg systolic (NS), 13.1 mm Hg diastolic (P less than 0.05) and by 11.4 mm Hg mean arterial pressure (P less than 0.02). The fall in standing blood pressure was similar and we observed no first dose hypotensive effect. Ketanserin lowered the sitting heart rate by 11.1 beats/min (P less than 0.01). The drug was well tolerated.

Tolerability of combined treatment with verapamil and beta-blockers in angina resistant to monotherapy.

We have used a combination of a beta-blocker and verapamil to treat 42 consecutive patients with angina resistant to either agent alone. Patients with heart failure, heart block or uncontrolled hypertension were excluded. The mean duration of follow-up was 6.5 months. Thirty-six patients (81%) reported an improvement and the number of angina attacks was reduced from 17/week to 5/week. Side effects necessitated withdrawal of one or both drugs in 6 patients, 2 of whom developed bradyarrhythmias not solely related to drug treatment. The most common complication was mild left ventricular failure (6) treated by reducing or stopping the beta-blocker. The data suggest that the combination of verapamil and a beta-blocker may be used in a relatively unselected group of patients with difficult angina. However, as dosage adjustment and close observation may be necessary to minimise side effects, the use of this combination should be limited to hospital practice.

Comparison of once daily endralazine with placebo in the treatment of hypertension uncontrolled by a beta-blocker and diuretic.

We report the first placebo controlled parallel group study of once daily endralazine (5-20 mg) in hypertension uncontrolled by a beta-blocker plus a diuretic. Following a 4-week run-in period 22 patients with a sitting mean arterial pressure (MAP) greater than 110 mm Hg were entered into the study and received either endralazine 5 mg or placebo. Blood pressure was measured 2 h and 24 h after dosing and the drug dose doubled at 2 and 4 weeks if the 24-h MAP remained greater than 110 mg Hg. The final blood pressure assessment was made after 6 weeks treatment in the 19 patients who completed the study. Three patients withdrew from the study because of side effects. The hypotensive effect (sitting) was in excess of placebo at 2 h by 15.8 mm Hg systolic (NS), 15.4 mm Hg diastolic (p less than 0.01), 15.5 mm Hg MAP (p less than 0.02) and at 24 hours by 7.7 mm Hg systolic (NS), 8.9 mm Hg diastolic (p less than 0.02) and 11.1 mm Hg MAP (p less than 0.02). This study suggests that endralazine should be prescribed twice daily.

Polymorphic metabolism of metoprolol: clinical studies.

After a single 200 mg oral dose of metoprolol tartrate the mean metoprolol AUC was found to be six-fold higher in poor metabolizers (PMs) of debrisoquine than in extensive metabolizers (EMs). This was associated with impaired metabolic clearance via alpha-hydroxylation and O-dealkylation. A population study (n = 143) has shown a bimodal distribution in the ratio of metoprolol: alpha-hydroxymetoprolol recovered in urine which was correlated highly with the debrisoquine metabolic ratio. Nine per cent of the population were PMs. Plasma metoprolol concentrations three hours after a 100 mg oral dose of metoprolol were greater than 200 ng/ml in PMs but were lower than this in most EMs. This dose of metoprolol given once daily provided a clinically significant reduction (16%) in exercise heart rate in PMs after 24 hours. EMs require conventional doses (100 mg b.d.) to achieve the same degree of beta-blockade. Preliminary data from family studies support the view that the defect in metoprolol oxidation is inherited. In 12 hypertensive patients who were EMs we compared the beta-blocking activity and antihypertensive effect of chronic treatment with metoprolol 200 mg once daily (conventional and long-acting formulations), with those of atenolol 100 mg once daily and placebo. The effects of all active preparations were similar at 3.5 hours but atenolol was superior to all metoprolol formulations at 24 hours after dosing. It is concluded that for the majority of patients metoprolol should be prescribed twice daily when using currently available dosage forms. Relationships between oxidation phenotype and side-effects should be examined.