Alfuzosin

Abstract

Synopsis

Alfuzosin, a new quinazoline derivative, acts as a selective and competitive antagonist of α₁-adrenoceptor-mediated contraction of prostatic, prostatic capsule, bladder base and proximal urethral smooth muscle, thereby reducing the tone of these structures. Consequently, urethral pressure and resistance, bladder outlet resistance, bladder instability and symptoms associated with benign prostatic hyperplasia are reduced.

A limited range of clinical studies have shown oral alfuzosin to be more effective than placebo (in studies of ⩽6 months’ duration), to have sustained effects on long term administration (⩽30 months), and to be comparable with the α₁-adrenoceptor antagonist prazosin, in the symptomatic treatment of benign prostatic hyperplasia. This is reflected in increases in urinary flow rate and decreases in symptom score and residual urinary volume. The most marked improvements occur in patients with severe pretreatment urinary flow abnormalities. Furthermore, preliminary results suggest a beneficial effect of alfuzosin on quality of life in patients with benign prostatic hyperplasia.

The overall incidence of adverse effects appears similar to that with placebo, and the incidence of vasodilatory-related adverse effects appears lower than that with prazosin. The relative selectivity of alfuzosin for α₁-adrenoceptors in the genitourinary tract compared with receptors in the vasculature is a potential advantage over other α-adrenoceptor antagonists, including prazosin, as the symptoms of benign prostatic hyperplasia may be reduced by alfuzosin at doses that have minimal vasodilatory effects, thereby minimising postural hypotension and syncope. However, vasodilatory-related adverse effects are the most common adverse effects that occur with alfuzosin, and dose and first-dose hypotensive relationships, especially in the elderly, cannot be excluded at this stage in the clinical use of alfuzosin.

The full potential of alfuzosin in the symptomatic treatment of benign prostatic hyperplasia will be clarified by further long term comparative studies (with large patient numbers) against placebo and other α₁-adrenoceptor antagonists. Nevertheless, oral alfuzosin 7.5 to 10 mg/day in divided doses appears to be a promising first-line agent for symptomatic treatment of noncomplicated mild to moderate benign prostatic hyperplasia in patients with a high dynamic component to their obstruction. In addition, alfuzosin offers an alternative to prostatectomy (the current ‘gold standard’) in patients who require surgery but are unfit for this treatment, and in patients requiring symptomatic relief while awaiting surgery.

Pharmacodynamic Properties

Alfuzosin has high in vitro affinity for post-junctional α₁-adrenoceptors in human prostatic adenoma as seen by the potent displacement of [³H]prazosin (a specific radioligand at the α₁-adrenoceptor) by alfuzosin. The IC₅₀ value of alfuzosin in this model was 0.035 μmol/L compared with 3.5 μmol/L for idazoxan, an α₂-adrenoceptor antagonist.

Alfuzosin displaces the concentration-contractile response curve to phenylephrine (an α₁-adrenoceptor agonist) in rabbit trigone muscle and urethral ring preparations in parallel to the right, thus demonstrating competitive antagonism at the α₁-adrenoceptor. In in vivo animal models, alfuzosin is more selective for α₁-adrenoceptors in the genitourinary tract than prazosin and terazosin as reflected in the ratios of the dose required to reduce blood pressure by 20%: the dose required to reduce urethral pressure by 50% being 3.2 and 11 (with intravenous and oral administration, respectively) for alfuzosin, 1 (with either route) for prazosin and 1 to 3.5 (with intravenous and oral administration, respectively) for terazosin. Thus, these models suggest that alfuzosin may decrease urethral resistance at doses that have only minimal effects on blood pressure and heart rate.

Alfuzosin has been shown to reduce urethral hypertonia (50% reduction in urethral pressure) in patients with urethral hypertonia of neurological origin, and to increase urinary flow rate and decrease residual urinary volume in patients with benign prostatic hyperplasia after single and multiple doses.

Although generally minor, reductions in blood pressure accompanied by reflex tachycardia have been observed with alfuzosin 1 to 10 mg/day in healthy volunteers and patients with benign prostatic hyperplasia.

Pharmacokinetic Properties

The pharmacokinetics of oral and intravenous alfuzosin are linear and nonsaturable over the dose range 1 to 10mg; however, there is large interindividual variation due to elimination of alfuzosin being almost entirely metabolic. The mean oral bioavailability of alfuzosin is 64% and absorption is unaffected by concomitant food intake. The volume of distribution of alfuzosin is 2.5 L/kg and it is 90% protein bound.

Alfuzosin undergoes extensive metabolism by the liver with only 11 % of the parent compound being excreted unchanged in the urine. The majority of the metabolites (which are inactive) are excreted in the faeces (75 to 91%). The mean elimination half-life (t_½) of alfuzosin is 4.8h and total clearance is 0.36 L/h/kg.

Absorption is more rapid, and maximum plasma concentration (C_max) and area under the concentration-time curve (AUC) are increased, in elderly patients. Also, volume of distribution may be decreased and oral bioavailability may be increased in this patient group; therefore a reduced initial dose is recommended. Dosage modifications are also required in patients with hepatic insufficiency as C_max, t_½ and AUC are increased. In contrast, dosage modification does not appear necessary in patients with renal insufficiency.

Therapeutic Potential

Although only a small number of controlled clinical studies have been reported, oral alfuzosin 7.5 to 12 mg/day appears to be more effective than placebo and comparable with prazosin (and possibly better tolerated) in the treatment of symptomatic benign prostatic hyperplasia, as reflected in reductions in symptom severity (Boyarsky scale) and residual urinary volume and increases in urinary flow rate. The most marked improvements in urinary flow rate occurred in patients with severe urinary flow abnormalities (pretreatment peak urinary flow rate < 10 ml/ sec).

In the largest double-blind, placebo-controlled study of alfuzosin performed to date in patients with benign prostatic hyperplasia (n = 518), alfuzosin 7.5 to 10 mg/day was significantly more effective than placebo in reducing mean total Boyarsky score (by 42 vs 32%) and residual urinary volume (by 38 vs 9%), and in increasing mean but not peak urinary flow rate (by 14 vs 10%) at 6 months. These beneficial clinical effects were maintained at 18 months, and symptomatic improvement was sustained for up to 30 months on long term administration.

Alfuzosin 7.5 to 10 mg/day appears to be of comparable efficacy to prazosin 2 to 4 mg/day in reducing the total Boyarsky score (by 28–32 vs 23–34%) and increasing peak and mean urinary flow rates (by 24–26 vs 24–28% and 26–30 vs 20–27%, respectively) in patients with symptomatic benign prostatic hyperplasia. It also appears to be superior to serenoa repens, a plant extract, in the treatment of this disorder.

Tolerability

Oral alfuzosin 7.5 to 10 mg/day is generally well tolerated in the medium and long term (up to 30 months) in patients with benign prostatic hyperplasia, with an overall incidence of adverse effects similar to that with placebo (approximately 30%), and an incidence of vasodilatory-related adverse effects that may be less than that with prazosin. Nevertheless, the most common adverse effects with alfuzosin are related to vasodilation (dizziness, headache, tachycardia and postural hypotension) and usually occur within the first 4 weeks of treatment, are transient, and resolve spontaneously after drug withdrawal.

Although the relative selectivity of alfuzosin for α₁-adrenoceptors in the genitourinary tract compared with receptors in the vasculature may allow for effective symptomatic control of benign prostatic hyperplasia with minimal effects on blood pressure, dose and first-dose hypotensive relationships cannot be excluded at this stage in its clinical use. Hypotensive-related adverse effects appear to be more common in the elderly, in patients with hypertension and in patients receiving other α-adrenoceptor antagonists, diuretics, calcium antagonists or β-adrenoceptor antagonists.

Dosage and Administration

The recommended oral daily dosage of alfuzosin for the symptomatic treatment of benign prostatic hyperplasia is 7.5 to 10 mg/day in 3 divided doses, with an initial daily dose of 5mg in 2 divided doses in the elderly (>65 years) and patients with hypertension. Dosage modification appears necessary in patients with hepatic dysfunction but not in patients with renal dysfunction.

Concomitant administration of alfuzosin with a calcium antagonist or another α-adrenoceptor antagonist is not advised as the risk of hypotension is increased.