Kjell Haglund

Plasma levels and effects of metoprolol on blood pressure, adrenergic beta receptor blockade, and plasma renin activity in essential hypertension

The effects of metoprolol, a selective beta adrenergic receptor antagonist, on blood pressure, beta receptor blockade (antagonist of isoproterenol and exercise tachycardia), and plasma renin activity (PRA) have been compared with those of placebo in 16 patients with essential hypertension. The dose of metoprolol was 25 mg three times daily for 1 wk and thereafter 100 mg three times daily for 5 wk. The mean decrease in blood pressure during treatment with metoprolol was 24 ± 3.8 (SEM)/10 ± 2.1 mm Hg in the lying position and 23 ± 4.419 ± 3.1 mm Hg after 1 min in the standing position. At a dose of 2.9 to 5.4 mg/kg, steady‐state plasma concentrations of metoprolol varied 17‐fold (from 20 to 341 ng/ml) between patients and correlated with the interindividual variability in isoproterenol antagonism (r = 0.58, p < 0.05) and decrease in exercise tachycardia (r = 0.65, p < 0.01). By contrast, neither of these variables correlated with the dose of metoprolol in mglkg. Metoprolol decreased PRA by 67 ± 1.9 and 71 ± 1.2% in the lying and standing positions, respectively. The decrease in the mean arterial blood pressure in the lying position was significantly correlated to the PRA during the placebo period (r = 0.61, p < 0.05) but not to the plasma steady‐state levels ofmetoprolol, the degree of beta receptor blockade, and the decrease in PRA.

Prazosin kinetics in hypertension

Prazosin kinetics were studied after single doses (intravenous and oral, 0.5 mg) and after increasing multiple doses (0.5 to 5 mg three times daily) in eight patients with hypertension. After intravenous administration the kinetics could be described by a linear two‐compartment open model. Terminal half‐life (t½β) was about 3 hr and apparent volume of distribution (Vdβ) about 0.6 l/kg. After oral doses bioavailability ranged between 55% and 82%. Since total plasma clearance was low (0.14 l/kg x hr) incomplete bioavailability was the result of incomplete absorption rather than of first‐pass liver metabolism. The estimated extraction ratio was about 14%. Renal clearance was negligible; only 1% to 2% of the dose was recovered unchanged in urine. Binding to plasma proteins to both albumin and abatid glycoprotein was substantial (97%), with albumin being most important. Increasing multiple doses showed that prazosin followed first‐order kinetics with a linear correlation between dose and steady‐state plasma concentration (P < 0.001). There were substantial variations in plasma concentrations between patients and there were also day‐to‐day variations in concentration within the same patient.

Pharmacokinetics and pharmacodynamics of alprenolol in the treatment of hypertension

SummaryMean steady-state plasma concentrations of alprenolol were studied in relationship to the degree of beta-blockade, in sixteen patients receiving 600 mg daily in divided doses. Steady-state alprenolol concentrations were determined from the area under the plasma concentration-time curve during one eight-hour dosage interval after treatment for six weeks. Beta-blockade during alprenolol treatment was assessed from the chronotropic response to intravenous isoprenaline compared to the response after six weeks of placebo therapy. Although there was interindividual variability in the mean steady-state alprenolol concentration (range 11 — 141 ng/ml), and in the degree of beta-blockade (7-fold), the correlation between the two variables was highly significant (r=0.80, p<0.001). The prescribed dose of alprenolol (mg/kg) was not significantly correlated with the plasma level of alprenolol or the β-blockade. The chronotropic effects of isoprenaline during placebo and alprenolol were significantly interrelated (r=0.79, p<0.001).

Plasma levels and effects of metoprolol after single and multiple oral doses

Five patients with moderate hypertension were given placebo and at least 3 single oral doses (25, 50, 75, 100, or 150 mg) of metoprolol as well as multiple doses at at least 2 dose levels (25, 50, or 100 mg thrice daily). Blood pressure, pulse rate at rest, plasma renin activity, and drug plasma concentration were intensively monitored during 7.5 hr after each dose. Pulse rate, systolic blood pressure, and plasma renin activity decreased after the single oral doses, but diastolic blood pressure did not decrease consistently. The correlation coefficients between percentage decrease in systolic blood pressure and pulse rate and total plasma concentrations were higher individually than in the group. The corresponding regression equations were different between individuals and for systolic blood pressure there was a 700% difference in regression coefficients. The acute changes in diastolic blood pressure and plasma renin activity were not related to metoprolol plasma concentrations. The decrease in systolic blood pressure and pulse rate on multiple doses could not be predicted from the response after single doses.

Influence of pentobarbital on metoprolol plasma levels

Induction of microsomal enzymes with barbiturates in rats has little effect on the metabolism of metoprolol, compared with propranolol and alprenolol, which undergo extensive hepatic extraction in animals and man. Our study was designed to examine whether the metabolism of metoprolol is inducable by barbiturate in man. In 8 healthy subjects the area under the plasma concentration/time curve after 0.1 gm metoprolol was reduced by a mean of 32% after treatment with 0.1 gm pentobarbital at bedtime for 10 days. There was considerable interindividual variability in the reduction after pentobarbital treatment (2% to 46%).

Prazosin dynamics in hypertension: relationship to plasma concentration.

The antihypertensive effects of prazosin in relation to its kinetics were studied after single doses (intravenous and oral, 0.5 mg) and during increasing multiple doses (0.5 to 5 mg three times a day). There was a fall in systolic and diastolic blood pressures of 10% to 14%, which was greater in the standing than in the sitting position. Prazosin plasma concentrations correlated with dose (P < 0.001). After intravenous prazosin the fall in systolic and diastolic blood pressure and prazosin plasma concentration correlated (P < 0.01) during the β‐elimination phase in all patients. In only five of eight patients, however, did mean plasma concentration and antihypertensive effect during continuous treatment with different doses correlate. The maximal fall in systolic blood pressure correlated (P < 0.01) with that after the first oral steady‐state dose (0.5 mg three times daily), which indicates limited possibility of early identification of prazosin responders. There were no signs of overshoot of blood pressure when prazosin was withdrawn for a week. On rechallenge with a single oral dose of 2.5 mg prazosin there were no signs of enhanced hypotensive effect.

Influence of pentobarbital on effect and plasma levels of alprenolol and 4-hydroxy-alprenolol.

Six healthy subjects were given placebo and a single oral 0.2‐gm dose of alprenolol (Aptin) before and after 0.1 gin pentobarbital at bedtime for 10 days. The plasma concentrations of alprenolol and its metabolite 4‐hydroxy‐alprenolol and the inhibition of exercise tachycardia were studied for 7 hr after the alprenolol. Alprenolol and 4‐hydroxy‐alprenolol plasma levels were decreased by about 40% by pentobarbital but plasma half‐lives were unchanged. The inhibition of exercise tachycardia during a 7‐hr period was reduced from 14.0% to 10.7% by pentobarbital. The reduction was proportional to the decreased drug plasma levels. There was a significant contribution of the metabolite to alprenolol effect. The estimation of relative potency of metabolite against parent compound was 0.9 before pentobarbital and 1.9 after pentobarbital.

Monoamine metabolites in cerebrospinal fluid during treatment of hypertension with prazosin

SummarySix hypertensive patients were treated with prazosin up to a final dose of 3–4.5 mg/day. There was a significant reduction of blood pressure. The cerebrospinal fluid (CSF) concentrations of the major metabolites of noradrenaline, dopamine and serotonin were unchanged. This indicates that the antihypertensive effect is not mediated via central monoaminergic neurons as suggested by animal studies.