John Vincent

Clinical Pharmacokinetics of Prazosin — 1985

SummaryPrazosin is a selective α1-adrenoceptor antagonist which is useful alone or in combination for the treatment of hypertension and heart failure. Unlike many other antihypertensive drugs, the action of prazosin appears to be closely related to its concentration in plasma or whole blood. Prazosin is variably absorbed, is subject to first-pass metabolism, and is eliminated almost entirely as metabolites of much lower hypotensive activity than the parent drug. Prazosin is highly bound to plasma and tissue proteins.The influences of renal, hepatic and cardiac disease on the disposition of prazosin are reviewed, as are the effects of pregnancy and ageing. The optimum use of prazosin in clinical practice depends on an understanding of the pharmacokinetic properties of the drug.

Vascular reactivity to phenylephrine and angiotensin II: comparison of direct venous and systemic vascular responses.

The objective of this study was to determine the relationship between peripheral venous responsiveness (use of the dorsal hand vein compliance technique) and systemic vascular responsiveness (measurement of blood pressure changes) to phenylephrine and angiotensin II in humans. There was a significant correlation (r = 0.70, p < 0.02) between the dose causing a 20 mm increase in mean arterial pressure and the dose producing half‐maximal response in the hand vein (log ED50) for phenylephrine but not for angiotensin II. There was no correlation between the systemic responses to angiotensin II and phenylephrine, but there was a significant correlation (r = 0.70, p < 0.02) between the log ED50 measurements for phenylephrine and angiotensin II in the hand vein experiments. These findings suggest that systemic and hand vein responsiveness to phenylephrine are similar. Consequently, in evaluating a‐adrenergic receptor mediated responses, the dorsal hand vein compliance approach offers a satisfactory alternative to the use of systemic hemodynamic changes.

The alpha adrenoceptor antagonist properties of idazoxan in normal subjects

The imidazoline derivative idazoxan, which has been shown to be a potent, selective α2‐adrenoceptor antagonist, was injected intravenously to eight men with normotension. There was a transient small increase in blood pressure and a decrease in heart rate within 20 min of injection, with a slight increase in plasma norepinephrine levels. These effects are consistent with antagonism of prejunctional α2‐adrenoceptors. In response to infusions of the relatively selective α2‐adrenoceptor agonist α‐methylnorepinephrine, the pressor dose‐response curve shifted to the right with idazoxan. These data provide evidence for receptors with α2‐adrenoceptor characteristics on resistance vessels in man. In vitro platelet aggregation studies provide further evidence of selective α2‐adrenoceptor antagonism by idazoxan, with greater potency and affinity than α‐yohimbine. These observations are consistent with both pre‐and postjunctional peripheral α2‐adrenoceptors in man and provide further support that idazoxan is a selective α2‐adrenoceptor antagonist.

Pharmacological tolerance to alpha 1-adrenergic receptor antagonism mediated by terazosin in humans.

Chronic administration of alpha 1-receptor antagonists is associated with loss of clinical efficacy, especially in congestive heart failure, although the mechanism is uncertain. To evaluate changes in venous alpha 1-adrenoceptor responsiveness during chronic alpha 1-adrenoceptor blockade, dose-response curves to phenylephrine and angiotensin II were constructed in 10 healthy subjects before, during, and after administration of terazosin 1 mg orally for 28 d. Terazosin initially shifted the dose-response curve of phenylephrine to the right, with a significant increase in ED50 for phenylephrine from a control value of 102 to 759 ng/min on day 1 of terazosin (P < 0.001). However, by day 28, the dose-response curve had shifted back towards baseline with an ED50 of 112 ng/min. After discontinuing terazosin, the ED50 for phenylephrine remained near the baseline value, indicating no evidence of supersensitivity to phenylephrine. There was no change in responsiveness to angiotensin II during the course of treatment with terazosin. Plasma terazosin concentrations were stable throughout the period of drug administration. The mean Kd of terazosin was estimated as 11 +/- 15 nM in the first few days of treatment. This study demonstrates that pharmacological tolerance to the alpha 1-adrenoceptor blocking action of terazosin occurs in man and may be responsible for loss in efficacy with chronic therapy.

Pharmacokinetic and pharmacodynamic studies with two α‐adrenoceptor antagonists, doxazosin and prazosin in the rabbit

1 The cardiovascular effects of doxazosin, a quinazoline derivative related to prasozin were investigated and compared to prazosin in the rabbit. 2 Radioligand binding studies using rabbit cerebral membranes showed that both doxazosin and prazosin were roughly equipotent at displacing [3H]‐prazosin from specific binding sites. However, the lower pA2 value for doxazosin at α1‐adrenoceptors in isolated thoracic aorta preparations suggests a lower potency compared to prazosin. 3 The dose‐related pressor effects of intravenous phenylephrine were used to assess vascular α1‐adrenoceptor antagonism in vivo. There was a close agreement between α1‐adrenoceptor antagonist potency and maximum hypotensive effects with both doxazosin and prazosin. The α1‐adrenoceptor antagonist effects of doxazosin were more prolonged than those of prazosin. 4 Studies using either radioligand binding or pressor responses to B‐HT 920 showed that doxazosin did not show any significant affinity for the α2‐adrenoceptor. Similarly, no direct vasodilator effects were observed either in animals administered angiotensin II or in isolated thoracic aorta spiral strip preparations contracted with potassium. 5 Doxazosin has a longer terminal elimination half‐life than prazosin. The pharmacokinetics of doxazosin were linear over the dose range examined. 6 Following pharmacological ‘autonomic blockade’ and treatment with prazosin, doxazosin did not cause any further fall in blood pressure. 7 These observations suggest that doxazosin, like prazosin, appears to exert its hypotensive action through α1‐adrenoceptor antagonism. The prolonged fall in blood pressure and well sustained α1‐adrenoceptor antagonism after doxazosin raise the possibility of an active metabolite which also has α1‐adrenoceptor blocking properties.

Relationship between plasma prazosin concentrations and α‐antagonism in humans: Comparison of conventional and rate‐controlled (Oros) formulations

A single‐dose comparative evaluation in young normotensive men of the plasma concentrations and α‐adrenoceptor antagonism after conventional prazosin and a new slow‐release formulation (Oros) is described. Whereas conventional prazosin (2 mg) produced a maximum reduction in erect blood pressure at 3 hours (80/46 mm Hg compared with 110/65 mm Hg with placebo), the lowest blood pressure of 94/48 mm Hg with Oros prazosin (5.5 mg) was not observed until 8 hours after administration. Twenty‐four hours after Oros prazosin, prazosin was still detectable in plasma and erect blood pressure was reduced to 107/58 mm Hg compared with 110/71 mm Hg after placebo. α1‐Antagonism (assessed by the pressor responses to intravenous phenylephrine) was maximal, with a 4.8‐fold shift in dose‐response 24 hours after Oros prazosin, and persisted at least until 30 hours after administration, with a 2.3‐fold shift. There were significant correlations between α1‐antagonism and plasma prazosin concentrations for both Oros and conventional prazosin. The slopes of these relationships were significantly different, but this is thought to be consistent with the differences in the rates of drug release from the two formulations. Overall this study provides further evidence in humans that the duration and extent of the α1‐antagonism and the blood pressure response reflect the plasma prazosin concentrations. Additionally these data suggest the potential suitability of this type of a slow‐release formulation for single daily administration.

Desensitization of Nitrate-induced Venodilation: Reversal with Oral N-acetylcysteine in Humans

Summary: The objective of this study was to determine whether the dorsal hand vein could be used as a model to study tolerance to oral nitrates, and whether oral N-acetylcysteine (NAC) could reverse tolerance if present. Dose–response curves to nitroglycerin were constructed for 11 normotensive volunteers before and during treatment with a sustained-release formulation of isosorbide dinitrate, 80 mg, three times daily for 7 days and followed by concurrent treatment with NAC at a mean dose of 150 mg/kg/day, in divided doses, for 2 days. In separate studies, dose–response curves were constructed for seven normotensive volunteers before and after treatment with oral NAC at the same dose for 2 days. Nitroglycerins Emax was significantly attenuated from 115 ± 36 to 77 ± 22% after treatment with isosorbide dinitrate alone (p < 0.009). Concurrent treatment with NAC reversed this decrease, as nitroglycerins Emax of 108 ± 26% during coadministration of isosorbide dinitrate and NAC was not different from its Emax in the control period. There was also no difference in the dose of phenylephrine required to cause 80% of maximal venoconstriction throughout the study. These studies demonstrate that smooth muscle tolerance to nitrates can be demonstrated in medium-sized veins in humans. In addition, high-dose oral NAC can reverse existing tolerance to oral nitrates in human veins. These results indicate that the dorsal hand vein compliance technique is a good model for the clinical investigation of tolerance to nitrates in humans.

Desensitization of β-adrenoceptor– and Prostaglandin E1 Receptor–mediated Human Vascular Smooth Muscle Relaxation

Regulation of beta-adrenoceptors in animal tissues and human cell cultures has been extensively described; on the other hand, relatively little is known about regulation of beta-adrenoceptors in human tissues in vivo. Both beta-adrenoceptors and the prostaglandin E1 (PGE1) receptors stimulate vasodilation. We wondered if prolonged infusion of isoproterenol or PGE1 would cause desensitization of smooth muscle relaxation and used the dorsal hand-vein compliance technique to investigate this question. After constructing a dose-response curve to either the beta-agonist isoproterenol or to PGE1 in a phenylephrine preconstricted vein, isoproterenol (271 ng/min), PGE1 (956 pg/min), or saline was infused for 4 h in separate experiments. There was no change in the ED50 or Emax for either isoproterenol or PGE1 after saline infusion. After a 4-h infusion of isoproterenol, the maximal vasodilator response to isoproterenol was significantly (p less than 0.01) attenuated from 61 +/- 33% to 19 +/- 10%, while the ED50 significantly increased (p less than 0.01) from a geometric mean of 37 to 197 ng/min. After infusion of isoproterenol, the mean maximum PGE1-induced venorelaxation of 129 +/- 29% was modestly but significantly (p less than 0.05) blunted to 96 +/- 35%, while the ED50 of PGE1 increased significantly (p less than 0.01) from a geometric mean of 81 to 398 pg/min. A 4-h infusion of PGE1 significantly (p less than 0.01) attenuated the maximum response to PGE1 from 73 +/- 35 to 28 +/- 16%. The maximal vasodilatory response to isoproterenol was also significantly blunted (p less than 0.05) from 62 +/- 35 to 42 +/- 41%, with no change in ED50.(ABSTRACT TRUNCATED AT 250 WORDS)

Trimazosin: relationships between hypotensive effect, vascular responsiveness, and drug and metabolite concentrations

Summary: The relationships between the effects on blood pressure and vascular responsiveness, and the whole blood concentration of the antihypertensive drug trimazosin and its major metabolite were investigated in six normotensive male volunteers following 100 mg i.v. and 200 mg p.o. administration. Pressor responses to intravenous phenylephrine and angiotensin II were evaluated 1–3 (early) and 5–7 h (late) after drug or vehicle administration. There was a fall in blood pressure in the erect position (maximum between 4 and 8 h) associated with a modest increase in heart rate. Following treatment with trimazosin, blood pressure fell to 100/63 mm Hg with intravenous administration and 92/63 mm Hg with oral treatment, compared with the placebo value of 114/83 mm Hg. Both oral and intravenous trimazosin caused a significant rightward shift of the phenylephrine pressor dose–response curve (p < 0.05). There was no significant shift of the angiotensin II pressor dose responses. Using linear regression analysis, the concentration of trimazosin in whole blood showed a significant correlation with the dose ratios from the phenylephrine pressor dose responses following treatment with both intravenous (r = 0.73, p < 0.02) and oral (r = 0.57, p < 0.05) trimazosin. There was no such correlation using dose ratios from angiotensin II pressor dose responses. There was no correlation between the concentration of the metabolite 1-hydroxytrimazosin and dose ratios from either phenylephrine or angiotensin II pressor dose responses. These observations suggest that the predominant mechanism of action of trimazosin, at doses that reduce blood pressure in humans, is through blockade of peripheral postjunctional α1-adrenoceptors.

Trimazosin in normotensive subjects

Oral and intravenous trimazosin, a quinazoline derivative, resulted in a significant reduction in blood pressure of normal subjects, particularly when the subjects rose from a supine position to standing. This hypotensive effect was maximal between 4 and 6 hr after dosing and was accompanied by a significant increase in heart rate. The responses to intravenous infusions of phenylephrine indicated that trimazosin had significant, selective, peripheral α1‐antagonist properties. Kinetic analysis showed oral bioavailability of 63%, a clearance rate of 66 ml/min, and a terminal elimination t½ of approximately 3 hr. The correlation between drug levels and hypotensive effect was significantly improved by inclusion of the concentrations of trimazosins major metabolite, 1 ‐hydroxy‐trimazosin (CP 23445), particularly for the period of maximum effect. Our data show that acute administration of trimazosin is associated with a fall in blood pressure, an increase in heart rate, and a significant degree of α1‐antagonism and that the overall hypotensive effect may in part be mediated by an active metabolite. It seems 1‐hydroxy‐trimazosin is a likely candidate for this role, but it is not clear whether this metabolite also has significant α‐adrenoceptor antagonist properties.