Doxazosin mesylate is used alone or in combination with other classes of antihypertensive agents for the management of hypertension. Doxazosin's efficacy in hypertensive patients appears to be similar to that of other α1-adrenergic blocking agents, thiazide diuretics, β-adrenergic blocking agents, angiotensin-converting enzyme (ACE) inhibitors, and calcium-channel blocking agents. However, in one randomized and double-blind clinical study (the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial [ALLHAT]), doxazosin was shown to be less effective in lowering mean systolic blood pressure (by about 2-3 mm Hg) than chlorthalidone, a thiazide-like diuretic. In order to achieve target blood pressure in hypertensive patients, use of doxazosin required additional hypotensive therapy more frequently than chlorthalidone. In addition, interim analysis (median follow-up: 3.3 years) of this study indicates that use of doxazosin in high-risk (at least 2 risk factors for coronary heart disease) hypertensive patients 55 years of age and older was associated with a higher risk of stroke and incidence of combined cardiovascular disease events (including twice the risk of congestive heart failure) than use of chlorthalidone. Study investigators concluded that such increased risk of congestive heart failure could not have been caused by the relatively small difference in the mean target systolic blood pressure observed in patients receiving doxazosin compared with those receiving chlorthalidone. Therefore, based on these findings, the trial's Data Safety and Monitoring Board recommended that the doxazosin treatment arm be terminated prematurely. The remaining antihypertensive arms (e.g., calcium-channel blockers, ACE enzyme inhibitors, diuretics) and lipid-lowering (pravastatin vs usual care) components of the study subsequently were completed and reported.
Because of established clinical benefits (e.g., reductions in overall mortality and in adverse cardiovascular, cerebrovascular, and renal outcomes), ACE inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide diuretics generally are considered the preferred drugs for the initial management of hypertension in adults. Although in the past α1-blockers such as doxazosin were recommended as one of several classes of first-line antihypertensive therapy or as initial therapy in selected hypertensive patients (e.g., those with symptomatic prostatic hyperplasia), current antihypertensive and urology guidelines no longer recommend α1-blockers as preferred first-line therapy for any patients with hypertension, principally because of negative findings observed in ALLHAT. However, α1-blockers are effective antihypertensive drugs and many experts still consider their use appropriate for the management of resistant hypertension as a component of combination therapy. Therapy with an α1-blocker is most effective when used in combination with a diuretic. Although some experts state that an α1-blocker may be a useful component of antihypertensive treatment regimens in older men with coexisting benign prostatic hyperplasia (BPH), the American Urology Association (AUA) states that monotherapy with these drugs is not optimal in hypertensive patients with lower urinary tract symptoms (LUTS) or BPH and that such conditions should be managed separately .
The beneficial effects of α1-blockers on blood glucose and lipid concentrations may mitigate some of the adverse metabolic effects of diuretics, and α1-blockers may offer some advantage in patients with underlying lipoprotein disorders (e.g., hypercholesterolemia) or in those with lipoprotein abnormalities induced by other antihypertensive agents (e.g., thiazide diuretics). The possibility that geriatric patients may be more susceptible than younger patients to the postural hypotensive effects of α1-blockers should be considered in the selection of therapy. Blood pressure response to α1-blockers appears to be comparable in white and black patients.
Benign Prostatic Hyperplasia
Doxazosin is used to reduce urinary obstruction and relieve associated manifestations in hypertensive or normotensive patients with symptomatic benign prostatic hyperplasia (BPH, benign prostatic hypertrophy). For patients who can tolerate the potential cardiovascular and other effects of α1-adrenergic blockade, doxazosin can effectively relieve mild to moderate obstructive manifestations (e.g., hesitancy, terminal dribbling of urine, interrupted or weak stream, impaired size and force of stream, sensation of incomplete bladder emptying or straining) and improve urinary flow rates in a substantial proportion of patients and may be a useful alternative to surgery, particularly in those who are awaiting or are unwilling to undergo surgical correction of the hyperplasia (e.g., via transurethral resection of the prostate [TURP]) or who are not candidates for such surgery.
Therapy with α1-blockers appears to be less effective in relieving irritative (e.g., nocturia, daytime frequency, urgency, dysuria) than obstructive symptomatology. In addition, therapy with the drugs generally can be expected to produce less subjective and objective improvement than prostatectomy, and periodic monitoring (e.g., performance of digital rectal examinations, serum creatinine determinations, serum prostate specific antigen [PSA] assays) is indicated in these patients to detect and manage other potential complications of or conditions associated with BPH (e.g., obstructive uropathy, prostatic carcinoma). While symptomatic improvement has been maintained for at least up to 2 years of doxazosin therapy in some patients, the long-term effects of α-blockers on the need for surgery and on the frequency of developing BPH-associated complications such as acute urinary obstruction remain to be established.
Although the etiology of benign prostatic hyperplasia currently is unclear, age-associated changes in circulating hormones (e.g., androgens, estrogens) appear to be involved; approximately 40% of men have been reported to have clinical evidence of BPH by age 70. Hyperplasia of the prostatic tissue encircling the urethra produces narrowing of the bladder neck and prostatic urethra, leading to both obstructive (e.g., urinary hesitancy, slow/weak stream, straining, incomplete voiding) and irritative (e.g., urinary frequency, urgency, nocturia) manifestations; progressive obstruction of urinary flow eventually may lead to urinary retention and subsequent complications (e.g., urinary tract infection, bladder calculi, hydronephrosis).
In addition to the mechanical component of urethral obstruction caused by the enlarged gland, a dynamic component of obstruction may be prominent in some patients; current evidence suggests that approximately 50% of prostate outflow obstruction is caused by reversible α-adrenergic (principally α1) receptor-mediated contractions of smooth muscle in the prostatic capsule, prostatic adenoma, and bladder neck. While nonselective α-adrenergic blockers such as phenoxybenzamine have been used successfully to treat BPH, such nonselective blockade has been associated with adverse effects such as postural hypotension, dizziness, and tachycardia because blockade of α2-adrenergic receptors interferes with the negative feedback mechanism controlling norepinephrine release from presynaptic nerve terminals. As a result, nonselective α-blocker therapy currently is not recommended for BPH; instead, therapy with selective α1-blockers, which can relieve α1-adrenergic-mediated bladder outflow obstruction, is recommended.
Patients with mildly symptomatic BPH and those with moderate to severe symptoms that are not bothersome (i.e., that do not interfere with daily activities of living) generally should simply be followed rather than actively treated. Active therapy (e.g., drug therapy; minimally invasive therapies such as transurethral microwave heat; surgery such as TURP) should be considered for patients with moderate to severe BPH that is bothersome; the potential benefits and possible risks of various therapeutic options, including watchful waiting, should be discussed with the patient. Although drug therapy usually is not as effective as surgical therapy, it may provide adequate symptomatic relief with fewer and less serious adverse effects compared with surgery. Most experts currently consider therapy with an α1-adrenergic blocker such as doxazosin to be an appropriate option for symptomatic treatment of bothersome lower urinary tract symptoms in patients with BPH. With the exception of prazosin (for which there are insufficient data to compare), currently available α1-adrenergic blockers are considered comparably effective. Therapy with an α1-adrenergic blocker generally is more effective in relieving lower urinary tract symptoms than that with a 5α-reductase inhibitor (e.g., finasteride), and 5α-reductase inhibitors are ineffective in patients without prostatic enlargement.
Although studies of up to 1 year in duration generally have found combination therapy with an α1-blocker and 5α-reductase inhibitor (e.g., finasteride) to be no more effective than α1-adrenergic blocker monotherapy in providing symptomatic relief of BPH, a long-term (mean follow-up: 4.5 years), double-blind study (Medical Therapy of Prostatic Symptoms [MTOPS]) found that combined therapy with doxazosin (4-8 mg daily) and finasteride (5 mg daily) was more effective than therapy with either drug alone in preventing symptom progression (defined as an increase from baseline of at least 4 points in the American Urological Association [AUA] symptom score, acute urinary retention, urinary incontinence, renal insufficiency, or recurrent urinary tract infection). The percent reduction in the risk of symptom progression (generally manifested as an increase in AUA symptom score) relative to placebo was 34% with finasteride, 39% with doxazosin, and 67% with combination therapy. The risks of long-term acute urinary retention and the need for invasive therapy were reduced by combination therapy and by finasteride monotherapy but not by doxazosin monotherapy. Combination therapy or doxazosin or finasteride monotherapy each were effective in providing improvement in symptom scores, with combination therapy providing greater improvement than either drug alone.
Most experts state that combined therapy with an α1-adrenergic blocker and 5α-reductase inhibitor can be considered for men with bothersome moderate to severe BPH and demonstrable prostatic enlargement, weighing the benefit of preventing progression of BPH with the risks and cost of the combination. Men at risk for BPH progression are most likely to benefit from combination therapy. Although the benefit of combination therapy was not as substantial in men with low baseline prostate-specific antigen (PSA) levels compared with those with high baseline values in the MTOPS study, the potential benefit appears to be greatest in those in whom baseline risk of progression generally is high rather than specifically in those with larger prostates or higher PSA levels at baseline.
Adverse effects associated with combined α1-adrenergic blocker and 5α-reductase inhibitor therapy generally reflect the combined toxicity profile of each drug alone, although certain adverse effects (e.g., effects on sexual function and libido, postural hypotension, peripheral edema, dizziness, asthenia, rhinitis) may be more common with combined therapy.