Concentration‐effect relationships and individual responses to doxazosin in essential hypertension.

Abstract

1. This study investigates aspects of the pharmacokinetics, pharmacodynamics and concentration‐effect relationships in 10 patients with essential hypertension during acute and chronic treatment with doxazosin, an alpha 1‐adrenoceptor antagonist. 2. Following the first dose of doxazosin (2 mg) there were significant reductions in blood pressure, increases in heart rate and in plasma noradrenaline, and parallel rightward shifts of the phenylephrine pressor response curves, consistent with alpha‐adrenoceptor antagonism. There was no significant change in the pressor response to angiotensin II. 3. Using an integrated kinetic‐dynamic model, individual blood pressure responsiveness was characterised as the fall in blood pressure (mm Hg) per unit drug concentration. Responsiveness to the first dose of doxazosin was directly correlated with the responsiveness after 1 and 6 weeks treatment although there was a systemic reduction (of approximately 30%) which occurred during the first week of treatment. 4. Neither the acute nor long‐term responsiveness to doxazosin was related to age, plasma renin activity, plasma noradrenaline or the pretreatment sensitivity to phenylephrine. There was a significant relationship between responsiveness and the height of the initial (pretreatment) blood pressure. 5. Integration of pharmacokinetic and pharmacodynamic data provides a reproducible index of responsiveness which can be used to investigate the consistency of the long‐term anti‐ hypertensive response, to identify factors which influence the magnitude of the response, and to optimise the choice of dose and dose interval.

Concentration-effect analysis of antihypertensive drug responses.

“…As earlier, with normotensive subjects, the blood pressure response to acute and chronic prazosin and doxazos was adequately described by a linear model. 27 - 28 Response to the first dose of doxazosin in individual patients correlated well with the response after 1 and 6 weeks of treatment, although the magnitude of response systematically diminished by about 30%.…”

“…It is thus important to be able to characterize the concentration-response relation in patients with essential hypertension after acute oral administration and also at steady state to validate single dose predictions of response. Such an evaluation has been undertaken in a series of parallel placebocontrolled studies with a variety of antihypertensive drugs including prazosin, 27 doxazosin, 28 ketanserin, 51 nifedipine, 26 verapamil, 25 and enalapril. 17 All studies followed essentially the same design.…”

“…- 28 When a similar approach was used with verapamil, despite a significant decrease in drug clearance between acute and steady-state therapy, the response in terms of blood pressure fall per unit drug concentration was the same. 25 Similar findings were obtained with nifedipine 26 and enalapril 17 with good agreement between the response on first dosing and at steady state.…”

α₁-Adrenoceptor Selectivity: The North American Experience

“…It is recognized, however, that theoretically this may not be entirely representative of the degree of blockade of the endogenous neurotransmitter, noradrenaline. Reassuringly, however, the effective doses of doxazosin versus both cardiovascular and urethral responses were identical to the doses used in treating hypertension and the lower urinary tract symptoms of BPH [15, 18]. Likewise there was no evidence that doxazosin had a selective effect on either of the parameters measured.…”

Cardiovascular Effects of Alpha-Blockers Used for the Treatment of Symptomatic BPH: Impact on Safety and Well-Being

“…The counter-regulation is reflected by an increased efferent β-adrenergic stimulation leading to tachycardia, palpitation and increased myocardial oxygen demand, and by the activation of the renin-angiotensin-aldosterone cascade which results in fluid retention and weight gain. This counter-regulation, along with adrenoceptor upregulation, is responsible for the development of tachyphylaxis [3, 4, 5]. Initially, highly efficacious doses of most antihypertensive α-blockers rapidly lose their BP-reducing effect, requiring doses to be increased progressively over the first few weeks in order to maintain efficacy.…”