Alfuzosin Hydrochloride for the Treatment of Benign Prostatic Hyperplasia

Mary Lee


Am J Health Syst Pharm. 2003;60(14) 

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Pharmacology of

Three generations of α-adrenergic antagonists have been used to treat BPH. First-generation agents (e.g., phenoxybenzamine) antagonize both prostatic and vascular α1- and α2-adrenergic receptors. As a result, first-generation agents cause many dose-related adverse effects, including first-dose syncope, orthostatic hypotension, reflex tachycardia, cardiac arrhythmias, nasal stuffiness, and retrograde ejaculation.[11,12] In addition, phenoxybenzamine has been implicated as a mutagen.[13] Because of these adverse effects, first-generation agents have been replaced by second- and third-generation agents in clinical practice.

Second-generation agents selectively antagonize α1-receptors but do not antagonize α2-receptors in typical therapeutic doses. They improve urinary voiding symptoms but cause less tachycardia and cardiac arrhythmias than first-generation agents. Second-generation agents include prazosin, terazosin, and doxazosin. Of these, prazosin has the shortest half-life, producing large differences between peak and trough serum prazosin levels after each dose. These differences have been associated with a higher frequency of orthostatic hypotension, dizziness, and syncope than that which occurs with terazosin and doxazosin. Compliance with prazosin therapy is a concern as it must be administered two or three times a day, whereas terazosin and doxazosin can be administered once or twice a day.[14] However, all second-generation α1-adrenergic antagonists cause dose-related hypotensive adverse effects. To reduce the likelihood of these complications, physicians should (1) administer a subtherapeutic dose and slowly increase it to a full therapeutic maintenance dose over two to four weeks, (2) advise patients to take the first dose at bedtime to avoid first-dose syncope, (3) avoid combined use of any of these agents with other antihypertensive agents to reduce additive hypotensive adverse effects, and (4) use the lowest effective dose to treat BPH, as cardiovascular adverse effects are dose related. Other adverse effects of second-generation α1-adrenergic antagonists include asthenia and somnolence.

Alfuzosin is a second-generation α1-adrenergic antagonist. It competitively and selectively inhibits α1-adrenergic receptors in the prostatic stroma and capsule, bladder neck, and posterior urethra. Like the other agents in this group, alfuzosin was initially evaluated as an antihypertensive agent, although it is not currently approved or prescribed for this indication. It has a short half-life and requires twice- or thrice-daily administration when using the immediate-release (IR) formulation. Two extended-release (ER) formulations allow for once- or twice-daily administration. The ER formulations produce serum alfuzosin concentrations that simulate a continuous i.v. infusion of the drug, with small differences between peak and trough serum concentrations over the dosing interval. This may partly explain why fewer cardiovascular adverse effects occur when using ER versus IR alfuzosin versus other second-generation α1-adrenergic antagonists. Alfuzosin, considered to be functionally uroselective, relieves obstructive voiding symptoms in patients with BPH with less potential for causing significant reductions in systolic or diastolic blood pressure.[15]

Third-generation α1-adrenergic antagonists are pharmacologically uroselective in that they are competitive antagonists for prostatic α1A-receptors.[16,17] Blockade of these receptors relaxes the smooth muscle of the prostate and bladder neck without blocking vascular receptors. Tamsulosin is currently the only third-generation uroselective α1A-adrenergic antagonist commercially available in the United States. Pharmacologic studies have found that tamsulosin has a 40-fold greater affinity for α1A-receptors than for other α1-receptors.[17,18] Tamsulosin has a low affinity for vascular α1-receptors, which explains why hypotension is an uncommon adverse effect of tamsulosin therapy and why the drug has not been studied for use in hypertension.[19] This pharmacologic uroselectivity for prostatic α1A-receptors has multiple implications. Dosage adjustment is not necessary because first-dose syncope and hypotension do not occur. Patients can begin therapy with the usual daily maintenance dose and can take their tamsulosin dose at any time during the day, as opposed to taking doses at bedtime only. Also, the addition of tamsulosin to selected antihypertensive regimens (e.g., furosemide, enalapril, nifedipine, and atenolol) does not result in additive hypotension.[20] Tamsulosin therefore is a good choice for patients who cannot tolerate hypotension (e.g., patients with poorly controlled angina or those at high risk of stroke), patients taking multiple antihypertensives, and instances in which dosage adjustment would be too complicated for the patient or would produce an unacceptable delay in the onset of symptom relief in patients with BPH.

Pharmacologic uroselectivity should be distinguished from functional or clinical uroselectivity. Functional uroselectivity is determined from intact animal models, and clinical uroselectivity is ascertained in normal volunteers or patients with BPH. A drug that exhibits functional or clinical uroselectivity displays a greater smooth muscle contractile effect on urethral or prostatic tissue than on blood vessels. Although not pharmacologically uroselective, alfuzosin has functional uroselectivity and, in some cases, clinical uroselectivity, as it can improve urinary voiding symptoms with a low potential for causing vascular adverse effects. This clinical uroselectivity has been reported with ER alfuzosin, which is administered once or twice daily.

Functional uroselectivity is not solely attributed to selective blockade of α1A-receptors. Experimental studies have found that alfuzosin blocks a significant percentage of α1A-, α1B-, and α1D-receptors. Alfuzosin's uroselectivity may be due to its preferential binding to prostatic α1A-receptors, as opposed to vascular α1A-receptors, which has been demonstrated in intact anesthetized cat and rat models.[21,22] In these studies, the ratio of the oral alfuzosin dose needed to reduce blood pressure by 20% to the dose that reduces urethral pressure by 50% was 11:1, a ratio indicative of the functional uroselectivity of alfuzosin.[21]


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