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Doxazosin

An Update of its Clinical Pharmacology and Therapeutic Applications in Hypertension and Benign Prostatic Hyperplasia

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An Erratum to this article was published on 01 April 1995

Summary

Synopsis

Doxazosin is a long-acting α1-adrenoceptor antagonist structurally related to prazosin and terazosin. Its antihypertensive effect is produced by a reduction in the smooth muscle tone of peripheral vascular beds resulting in a decrease in total peripheral resistance without significant effect on cardiac output or heart rate. In benign prostatic hyperplasia, doxazosin’s effect of relieving bladder outflow obstruction is produced through a reduction in prostatic tone mediated via α1-adrenoceptor blockade.

In most comparative trials doxazosin has proven to be equally effective as the comparator drug in the treatment of mild to moderate hypertension. It has been used in a variety of patient populations including the elderly, Blacks, smokers, and patients with concomitant disease states such as renal dysfunction, hypercholesterolaemia, non-insulin-dependent diabetes mellitus (NIDDM) and respiratory disease. Doxazosin has also been used successfully in combination with β-adrenoceptor antagonists, diuretics, calcium channel antagonists, and angiotensin-converting enzyme inhibitors in patients with hypertension that is uncontrolled with monotherapy.

Doxazosin has a beneficial effect on some of the risk factors associated with coronary heart disease including elevated serum lipid levels, impaired glucose metabolism, insulin resistance and left ventricular hypertrophy. Modest decreases in total cholesterol, low density lipoprotein cholesterol and triglycerides are seen with doxazosin therapy while small increases in high density lipoprotein cholesterol and the high density lipoprotein cholesterol/total cholesterol ratio are consistently reported. Some studies have reported an improvement in glucose tolerance although this effect has been more consistently seen in nondiabetic patients than in patients with NIDDM. Additionally, doxazosin produces a similar reduction in left ventricular hypertrophy to other antihypertensive agents. Modelling-based calculations suggest that doxazosin significantly reduces the risk of developing coronary heart disease in patients with mild to moderate hypertension, although this remains to be confirmed in long term prospective studies.

Doxazosin appears to be a promising agent in the treatment of urinary symptoms associated with benign prostatic hyperplasia. Similar to other α1-adrenoceptor antagonists, doxazosin treatment produces increases in peak and mean urinary flow rates and improves other objective and symptomatic measures.

In acute and long term studies, doxazosin has an incidence of adverse effects and withdrawal rates similar to other α1-adrenoceptor antagonists and other classes of antihypertensive agents. The most commonly reported adverse effects are dizziness, headache, fatigue/malaise and somnolence. Of most concern is the possibility of first-dose postural effects such as syncope; however, the risk of this appears to be minimal with careful dosage titration.

Recent clinical trials have consolidated the place of doxazosin as an effective antihypertensive agent and have expanded its therapeutic potential to include treatment of benign prostatic hyperplasia. While data regarding its effect on cardiovascular mortality are still awaited, doxazosin is now well established as a first-line antihypertensive agent with metabolic properties that may be especially beneficial in patients with concomitant hypercholesterolaemia or NIDDM.

Pharmacodynamic Properties

Doxazosin is a quinazoline derivative structurally related to prazosin and terazosin, which acts through selective inhibition of α1-adrenoceptors. Blockade of these receptors in the peripheral vasculature results in vasodilation. A decrease in total peripheral resistance with a corresponding decrease in mean arterial pressure is seen both at rest and following exercise in patients with mild to moderate hypertension after short or long term use of doxazosin. No significant concomitant changes in heart rate or cardiac index are seen. α1-Adrenoceptors are also located at other sites including the prostate and bladder neck, where receptor blockade causes a decrease in resistance to urinary flow.

Results from large scale randomised, double-blind comparative trials have found that doxazosin treatment produces modest reductions in serum total cholesterol, low density lipoprotein cholesterol and triglycerides combined with small increases in high density lipoprotein cholesterol and the high density lipoprotein cholesterol/total cholesterol ratio. These effects have been reported in a variety of hypertensive patient populations including those with non-insulindependent diabetes mellitus (NIDDM) or hypercholesterolaemia, and in smokers.

Doxazosin has either a neutral or positive effect on glucose homeostasis. Numerous studies in nondiabetic patients treated with doxazosin report improvements in glucose metabolism including improvements in the insulin sensitivity index, decreases in fasting and stimulated blood glucose and insulin levels and decreases in glycosylated haemoglobin levels. In patients with NIDDM the effects on glucose metabolism have been less consistent, with some studies reporting improvements and others reporting a neutral effect.

Chronic hypertension is associated with the development of left ventricular hypertrophy resulting in functional impairments which may increase the risk of cardiovascular events. Doxazosin treatment reduces left ventricular mass by approximately 7 to 14% in patients with mild to moderate hypertension, which is similar to that seen with other antihypertensive agents.

While acute intrarenal infusion of doxazosin produces an increase in renal blood flow, long term use of doxazosin appears to have no deleterious effect on renal function.

Pharmacokinetic Properties

The oral bioavailability of doxazosin is 62 to 69%. Peak plasma doxazosin concentrations, which are proportional to the dose, occur 1.7 to 3.6 hours after oral administration. Administration of doxazosin with food reduces the rate, but not the extent, of its absorption.

After either oral or intravenous administration the primary route of elimination is by metabolism via O-demethylation or hydroxylation with subsequent excretion in the faeces. Small amounts of the parent drug are eliminated unchanged in the urine and faeces. The terminal elimination half-life ranges from 16 to 22 hours and does not appear to be affected by age, renal function or dose.

Therapeutic Use

In the treatment of mild to moderate hypertension, recent comparative trials have confirmed the relative efficacy of doxazosin compared with other antihypertensive agents and have increased the range of populations in which it has been used. In large scale, randomised trials, treatment with doxazosin 1 to 16 mg/day for up to 4 years produced similar reductions in standing and supine blood pressure to those seen with angiotensin converting enzyme inhibitors, β-adrenoceptor antagonists, calcium channel antagonists, diuretics and other α1-adrenoceptor antagonists. In the Treatment of Mild Hypertension Study (TOMHS), long term treatment with doxazosin reduced diastolic blood pressure to a similar extent to that of acebutolol, amlodipine, chlorthalidone and enalapril, and produced results that were significantly superior to lifestyle modification alone.

In small scale, short term trials in patients with hypertension uncontrolled by monotherapy, doxazosin has proved effective in combination with ACE inhibitors, β-blockers, calcium channel antagonists and diuretics. Addition of doxazosin has resulted in further blood pressure reductions and increased response rates compared with monotherapy.

In patients with NIDDM, treatment with doxazosin produced reductions in blood pressure that were similar to those seen in other patient populations. In these patients, doxazosin produced either a neutral effect or a slight improvement in glycaemic control.

Age, race or concomitant disease do not appear to compromise the efficacy of doxazosin in the treatment of hypertension. Doxazosin has proven effective in hypertensive patients with chronic obstructive pulmonary disease, asthma, renal dysfunction or intermittent claudication, and in smokers.

Recent double-blind, placebo-controlled trials in patients with benign prostatic hyperplasia (BPH) indicate that doxazosin alleviates the urinary symptoms associated with the disease. Several studies of up to 29 weeks’ duration found doxazosin to be superior to placebo on several objective measures including peak and mean urinary flow rates and maximum voiding pressures. In some studies doxazosin also produced significant improvements in symptom scores compared with placebo when assessed by either the patient or the investigator. The improvements tended to be more pronounced in obstructive symptoms (weak stream flow, urinary hesitancy, incomplete bladder emptying and terminal dribbling) than in irritative symptoms (urinary frequency and urgency).

Tolerability

The adverse effects associated with doxazosin are related primarily to its pharmacodynamic properties. In placebo-controlled trials in the treatment of hypertension the most common adverse effects were dizziness (19% of patients), headache (14%), fatigue/malaise (12%), somnolence (5%), oedema (4%), rhinitis (3%) and nausea (3%). Most effects were mild with only 7% of patients discontinuing treatment because of intolerance. First-dose postural effects have been reported with doxazosin although the incidence is low if doses are titrated slowly. Postural effects are dose-related and most likely to occur 2 to 6 hours after a dose.

The incidence of adverse effects with doxazosin has been similar to that with other antihypertensive agents in comparative trials. In TOMHS there was no difference between doxazosin, acebutolol, amlodipine, chlorthalidone and enalapril in an overall adverse effect severity score.

In the treatment of BPH, adverse effects that were reported significantly more frequently with doxazosin than with placebo included hypotension (17%), dizziness (16%), fatigue (8%), oedema (3%) and dyspnoea (3%).

Dosage and Administration

For the treatment of hypertension, the recommended dosage range of doxazosin is 1 to 16 mg/day, initiated at dosages of 1 mg/day to minimise the risk of postural hypotension. Dosage may be titrated upwards at 1- to 2-week intervals until blood pressure goals are reached. In the treatment of BPH dosages of 2 to 12 mg/day have been used; however, most patients respond to 4 mg/day. As in hypertension, treatment should be initiated at a dosage of 1 mg/day and titrated upwards at 1- to 2-week intervals.

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Bret Fulton, Antona J. Wagstaff & Eugene M. Sorkin

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Various sections of the manuscript reviewed by: A.M. Breckenridge, Department of Pharmacology, The University of Liverpool, Liverpool, England; S.G. Carruthers, Department of Medicine, Victoria General Hospital, Halifax, Nova Scotia, Canada; E.L. Conway, Clinical Pharmacology and Therapeutic Unit, The University of Melbourne, Heidelberg, Victoria, Australia; R. Donnelly, Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow, Scotland; M.D. Feher, Department of Therapeutics, Charing Cross and Westminster Medical School, London, England; L.A. Ferrara, Istituto di Medicina Interna e Malattie Dismetaboliche, Università degli Studi di Napoli Federico II, Naples, Italy; K. Fukiyama, Third Department of Internal Medicine, University of the Ryukyus School of Medicine, Okinawa, Japan; R.A. Janknegt, Department of Urology, University Hospital Maastricht, Maastricht, The Netherlands; S. Kageyama, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan; P. Lund-Johansen, Department of Heart Disease, Haukeland Hospital, Bergen, Norway; R.W. Piepho, Department of Pharmacy, University of Missouri-Kansas City, Kansas City, Missouri, USA; M. Velussi, Centro Antidiabetico, Presidio Ospedaliero Monfalcone, Monfalcone, Italy.

An erratum to this article is available at http://dx.doi.org/10.1007/BF03259147.

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Fulton, B., Wagstaff, A.J. & Sorkin, E.M. Doxazosin. Drugs 49, 295–320 (1995). https://doi.org/10.2165/00003495-199549020-00011

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