Doxazosin Mesylate (Page 2 of 7)

B. Hypertension

The mechanism of action of Doxazosin mesylate is selective blockade of the alpha1 (postjunctional) subtype of adrenergic receptors. Studies in normal human subjects have shown that doxazosin competitively antagonized the pressor effects of phenylephrine (an alpha1 agonist) and the systolic pressor effect of norepinephrine. Doxazosin and prazosin have similar abilities to antagonize phenylephrine. The antihypertensive effect of Doxazosin mesylate results from a decrease in systemic vascular resistance. The parent compound doxazosin is primarily responsible for the antihypertensive activity. The low plasma concentrations of known active and inactive metabolites of doxazosin (2-piperazinyl, 6′- and 7′-hydroxy and 6- and 7-O-desmethyl compounds) compared to parent drug indicate that the contribution of even the most potent compound (6′-hydroxy) to the antihypertensive effect of doxazosin in man is probably small. The 6′- and 7′-hydroxy metabolites have demonstrated antioxidant properties at concentrations of 5 µM, in vitro.

Administration of Doxazosin mesylate results in a reduction in systemic vascular resistance. In patients with hypertension, there is little change in cardiac output. Maximum reductions in blood pressure usually occur 2–6 hours after dosing and are associated with a small increase in standing heart rate. Like other alpha1 -adrenergic blocking agents, doxazosin has a greater effect on blood pressure and heart rate in the standing position.

In a pooled analysis of placebo-controlled hypertension studies with about 300 hypertensive patients per treatment group, doxazosin, at doses of 1–16 mg given once daily, lowered blood pressure at 24 hours by about 10/8 mmHg compared to placebo in the standing position and about 9/5 mmHg in the supine position. Peak blood pressure effects (1–6 hours) were larger by about 50–75% (i.e., trough values were about 55–70% of peak effect), with the larger peak-trough differences seen in systolic pressures. There was no apparent difference in the blood pressure response of Caucasians and blacks or of patients above and below age 65. In these predominantly normocholesterolemic patients, doxazosin produced small reductions in total serum cholesterol (2–3%), LDL cholesterol (4%), and a similarly small increase in HDL/total cholesterol ratio (4%). The clinical significance of these findings is uncertain. In the same patient population, patients receiving Doxazosin mesylate gained a mean of 0.6 kg compared to a mean loss of 0.1 kg for placebo patients.


After oral administration of therapeutic doses, peak plasma levels of Doxazosin mesylate occur at about 2–3 hours. Bioavailability is approximately 65%, reflecting first-pass metabolism of doxazosin by the liver. The effect of food on the pharmacokinetics of Doxazosin mesylate was examined in a crossover study with twelve hypertensive subjects. Reductions of 18% in mean maximum plasma concentration and 12% in the area under the concentration-time curve occurred when Doxazosin mesylate was administered with food. Neither of these differences was statistically or clinically significant.

Doxazosin mesylate is extensively metabolized in the liver, mainly by O-demethylation of the quinazoline nucleus or hydroxylation of the benzodioxan moiety. Although several active metabolites of doxazosin have been identified, the pharmacokinetics of these metabolites have not been characterized. In a study of two subjects administered radiolabelled doxazosin 2 mg orally and 1 mg intravenously on two separate occasions, approximately 63% of the dose was eliminated in the feces and 9% of the dose was found in the urine. On average only 4.8% of the dose was excreted as unchanged drug in the feces and only a trace of the total radioactivity in the urine was attributed to unchanged drug. At the plasma concentrations achieved by therapeutic doses, approximately 98% of the circulating drug is bound to plasma proteins.

Plasma elimination of doxazosin is biphasic, with a terminal elimination half-life of about 22 hours. Steady-state studies in hypertensive patients given doxazosin doses of 2–16 mg once daily showed linear kinetics and dose proportionality. In two studies, following the administration of 2 mg orally once daily, the mean accumulation ratios (steady-state AUC vs. first-dose AUC) were 1.2 and 1.7. Enterohepatic recycling is suggested by secondary peaking of plasma doxazosin concentrations.

In a crossover study in 24 normotensive subjects, the pharmacokinetics and safety of doxazosin were shown to be similar with morning and evening dosing regimens. The area under the curve after morning dosing was, however, 11% less than that after evening dosing and the time to peak concentration after evening dosing occurred significantly later than that after morning dosing (5.6 hr vs. 3.5 hr).

The pharmacokinetics of Doxazosin mesylate in young (<65 years) and elderly (≥65 years) subjects were similar for plasma half-life values and oral clearance. Pharmacokinetic studies in elderly patients and patients with renal impairment have shown no significant alterations compared to younger patients with normal renal function. Administration of a single 2 mg dose to patients with cirrhosis (Child-Pugh Class A) showed a 40% increase in exposure to doxazosin. There are only limited data on the effects of drugs known to influence the hepatic metabolism of doxazosin [e.g., cimetidine (see PRECAUTIONS, Drug Interactions)]. As with any drug wholly metabolized by the liver, use of Doxazosin mesylate in patients with altered liver function should be undertaken with caution.

In two placebo-controlled studies of normotensive and hypertensive BPH patients, in which doxazosin was administered in the morning and the titration interval was two weeks and one week, respectively, trough plasma concentrations of Doxazosin mesylate were similar in the two populations. Linear kinetics and dose proportionality were observed.


A. Benign Prostatic Hyperplasia (BPH)

Doxazosin mesylate is indicated for the treatment of both the urinary outflow obstruction and obstructive and irritative symptoms associated with BPH: obstructive symptoms (hesitation, intermittency, dribbling, weak urinary stream, incomplete emptying of the bladder) and irritative symptoms (nocturia, daytime frequency, urgency, burning). Doxazosin mesylate may be used in all BPH patients whether hypertensive or normotensive. In patients with hypertension and BPH, both conditions were effectively treated with Doxazosin mesylate monotherapy. Doxazosin mesylate provides rapid improvement in symptoms and urinary flow rate in 66–71% of patients. Sustained improvements with Doxazosin mesylate were seen in patients treated for up to 14 weeks in double-blind studies and up to 2 years in open-label studies.

B. Hypertension

Doxazosin mesylate is also indicated for the treatment of hypertension. Doxazosin mesylate may be used alone or in combination with diuretics, beta-adrenergic blocking agents, calcium channel blockers, or angiotensin-converting enzyme inhibitors.


Doxazosin mesylate is contraindicated in patients with a known sensitivity to quinazolines (e.g., prazosin, terazosin), doxazosin, or any of the inert ingredients.


Syncope and “First-dose” Effect

Doxazosin, like other alpha-adrenergic blocking agents, can cause marked hypotension, especially in the upright position, with syncope and other postural symptoms such as dizziness. Marked orthostatic effects are most common with the first dose but can also occur when there is a dosage increase, or if therapy is interrupted for more than a few days. To decrease the likelihood of excessive hypotension and syncope, it is essential that treatment be initiated with the 1 mg dose. The 2, 4, and 8 mg tablets are not for initial therapy. Dosage should then be adjusted slowly (see DOSAGE AND ADMINISTRATION), with evaluations and increases in dose every two weeks to the recommended dose. Additional antihypertensive agents should be added with caution.

Patients being titrated with doxazosin should be cautioned to avoid situations where injury could result should syncope occur, during both the day and night.

In an early investigational study of the safety and tolerance of increasing daily doses of doxazosin in normotensives beginning at 1 mg/day, only 2 of 6 subjects could tolerate more than 2 mg/day without experiencing symptomatic postural hypotension. In another study of 24 healthy normotensive male subjects receiving initial doses of 2 mg/day of doxazosin, seven (29%) of the subjects experienced symptomatic postural hypotension between 0.5 and 6 hours after the first dose, necessitating termination of the study. In this study, 2 of the normotensive subjects experienced syncope. Subsequent trials in hypertensive patients always began doxazosin dosing at 1 mg/day, resulting in a 4% incidence of postural side effects at 1 mg/day with no cases of syncope.

In multiple-dose clinical trials in hypertension involving over 1500 hypertensive patients with dose titration every one to two weeks, syncope was reported in 0.7% of patients. None of these events occurred at the starting dose of 1 mg, and 1.2% (8/664) occurred at 16 mg/day.

In placebo-controlled clinical trials in BPH, 3 out of 665 patients (0.5%) taking doxazosin reported syncope. Two of the patients were taking 1 mg doxazosin, while one patient was taking 2 mg doxazosin when syncope occurred. In the open-label, long-term extension follow-up of approximately 450 BPH patients, there were 3 reports of syncope (0.7%). One patient was taking 2 mg, one patient was taking 8 mg, and one patient was taking 12 mg when syncope occurred. In a clinical pharmacology study, one subject receiving 2 mg experienced syncope.

If syncope occurs, the patient should be placed in a recumbent position and treated supportively as necessary.

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