Pharmacokinetic and dynamic aspects of alpha-adrenoceptor blockade in hypertension.
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Adrenergic alpha-Antagonists↗
Biomedical subjects
P Seideman
Publications and source records attributed to P Seideman.
Prazosin first dose phenomenon during combined treatment with a beta-adrenoceptor blocker in hypertensive patients.
1 The antihypertensive effect of prazosin has been studied in three groups of hypertensive patients. 2 The drug caused a significant reduction of blood pressure both as monotherapy and combined with alprenolol. 3 The effect of prazosin on blood pressure was more marked at the first dose and especially in combination with alprenolol. 4 No pharmacokinetic interaction between prazosin and alprenolol was observed. 5 Prazosin exhibits an exaggerated first dose effect together with alprenolol. Smaller starting doses of prazosin in combination therapy with beta-adrenoceptor blockers are warranted.
Adult↗
Additive intraocular pressure reducing effect of topical timolol during systemic beta-blockade.
The effect on intraocular pressure (IOP) of topical timolol was studied in 30 patients with arterial hypertension treated with oral alprenolol, metoprolol or timolol. No patient had any known eye disorder. Topical administration of timolol induced a significant reduction of IOP regardless if the patients had systemic beta-blockade or not. Treatment with topical timolol alone was equally effective in reducing IOP as combined topical and oral therapy. Patient compliance was checked with plasma concentrations of the different beta-blockers.
Administration, Oral↗
No effect of zinc on acetylating capacity.
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Acetylation↗
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 (t1/2 beta) was about 3 hr and apparent volume of distribution (Vd beta) 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 alpha 1-acid 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 less than 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.
Adult↗
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 less than 0.001). After intravenous prazosin the fall in systolic and diastolic blood pressure and prazosin plasma concentration correlated (P less than 0.01) during the beta-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 less than 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.
Adult↗
Effect of pentobarbital on the formation of diastereomeric oxazepam glucuronides in man: analysis by high performance liquid chromatography.
Barbiturate treatment can enhance drug oxidation in man, but its effects on glucuronidation of clinically used drugs are unknown. We have studied the effect of 10 days treatment with pentobarbital on oxazepam glucuronidation in six volunteers. The diastereomeric (+ and -) glucuronides in urine were analyzed separately by high performance liquid chromatography and oxazepam in plasma by gas liquid chromatography. The area under the plasma concentration time curve for oxazepam (15 mg sod) decreased after pentobarbital treatment in all subjects, mean 10.4 before and 6.9 h X mumol/l after treatment (P less than 0.05) and oxazepam's plasma clearance increased by about 50 per cent. The glucuronides appeared more rapidly in the initial urinary fractions. The ratio between the glucuronides (+/-) appearing in urine decreased on pentobarbital treatment. Our data indicate that pentobarbital treatment increases the clearance of oxazepam by increased glucuronide conjugation, probably reflecting barbiturate induced changes of UDP glucuronyltransferase.
Adult↗
Relative bioavailability of a paracetamol suppository.
The relative bioavailability of a new paracetamol suppository (Panodil) and tablets in doses of 0.5 and 1 g was investigated in eight healthy subjects. The tablets were absorbed faster and higher peak plasma concentrations were obtained than after the suppositories. The bioavailability of the suppositories was approximately 80% of that of the tablets at both dose levels. There was no indication of capacity-limited elimination at either the two doses investigated.
Acetaminophen↗
Monoamine metabolites in cerebrospinal fluid during treatment of hypertension with prazosin.
Six 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.
Biogenic Amines↗
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 gm 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.
Adult↗
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%).
Adult↗
[Why is Mrs. Jansson coming to the emergency department and how can the situation in emergency departments be improved?].
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Emergency Service, Hospital↗
Effects of prazosin on hemodynamics and sympatho-adrenal activity in hypertensive patients.
We studied peripheral and central hemodynamics and plasma catecholamine levels in 12 previously untreated patients with essential hypertension before and during treatment with the alpha 1-adrenoceptor antagonist prazosin (9.8 +/- 1.1 mg/day for 3-6 weeks following dose titration) as a single drug. Prazosin did not alter intra-arterially recorded blood pressures in the group as a whole, in spite of adequate plasma levels (12.6 +/- 1.2 ng/ml). There were no changes in cardiac output, blood volume, systemic or forearm vascular resistance, or forearm venous tone at rest during treatment. The blood pressure response to prazosin was correlated to pretreatment systemic and forearm vascular resistances. Arterial adrenaline levels were unchanged, but noradrenaline levels increased from 1.30 +/- 0.10 to 1.85 +/- 0.20 nM (p less than 0.05). Both noradrenaline and blood pressure responses to isometric hand-grip exercise were delayed and reduced during treatment. The hemodynamic and plasma catecholamine responses to a cold pressor test and tilting (50% head-up during 10 min) were similar before and during treatment. Our results may be related to development of tolerance to the alpha-adrenoceptor blocking effect of prazosin during long-term treatment. The elevation of arterial noradrenaline levels suggests that increased sympathetic activity also may have opposed the hypotensive response to prazosin.
Adult↗
Absorption of ocular timolol.
The absorption of timolol after topical administration to the eye was studied in 11 healthy volunteers and in 5 patients with bilateral open angle glaucoma. The volunteers received 2 drops of 0.5% timolol ophthalmic solution in each eye, equivalent to 0.8 mg of timolol maleate. Overflow was absorbed by paper tissue. The patients received the same dose twice daily for 2 weeks and were then investigated. In the paper tissue, 12 to 88% of the dose administered was recovered. Plasma concentrations were never above 5 ng/ml and not always detectable (detection limit 1 to 2 ng/ml). However, timolol was absorbed as the drug was found in the urine samples from all volunteers and glaucomatous patients.
Absorption↗