Alfuzosin dosing

Alfuzosin is considered to be functionally and clinically urose-lective in that usual doses used to treat BPH are less likely than other second-generation agents to cause cardiovascular adverse effects in animal or human models. This clinical observation has more often been seen with the once-daily, extended-release formulation of alfuzosin, which is the only commercially available formulation in the United States, as compared to the immediate-release formulation that is dosed three times a day that is available in Europe. It has been postulated that this may be due to higher concentrations of alfuzosin achieved in the prostate versus serum after usual doses, decreased blood-brain barrier penetration of alfuzosin, and the absence of high peak serum levels with the extended-release formulation." Extended-release alfuzosin dosing is EDA-approved for 10 mg daily, with no titration increase." " This is convenient for physician prescribers and patients who are started on the medication. 

Among the a-adrenergic antagonists, alfuzosin is considered functionally uroselective because in usual therapeutic doses, it produces relaxation of the bladder neck and prostatic smooth... 

Requirement for up-titration of dose Yes (for terazosin and doxazosin immediate-release) no (for alfuzosin possibly for doxazosin extended-release and tamsulosin) No... 

Need for up-titration of daily dose. Up-titration is required for terazosin and immediate-release doxazosin. It is minimally required for extended-release doxazosin and tamsulosin. It is not required for extended-release alfuzosin. 

Dosage formulation. Immediate-release formulations of terazosin and doxazosin are quickly absorbed and produce high peak plasma levels. Modified- or extended-release formulations of doxazosin, alfuzosin, and tamsulosin produce lower peak levels, but more sustained therapeutic plasma levels, than immediate-release formulations and have less potential for producing hypotensive episodes, thereby allowing initiation of treatment with a therapeutic dose and once daily dosing.25-27... 

Alfuzosin is a selective alpha-blocker, which relaxes smooth muscle, thereby increasing urinary flow rate. Because of its alpha-blockade effect, alfuzosin tends to lower the blood pressure and the first dose of the drug may lead to a hypotensive effect. 

First-dose effect Prazosin, terazosin, doxazosin, alfuzosin, and tamsulosin,... 

ALPHA-BLOCKERS BETA-BLOCKERS t efficacy of alpha-blockers t risk of first-dose 1 BP when alfuzosin, prazosin or terazosin is started in patients already taking beta-blockers Additive hypotensive effect may be used therapeutically Monitor BP at least weekly until stable. Warn patients to report symptoms of hypotension (lightheadedness, dizziness on standing, etc.). Watch for first-dose 1 BP... 

Second-generation agents include prazosin, terazosin, doxazosin, and alfuzosin. These differ in terms of duration of action and dosing schedule. Whereas prazosin requires dosing two to three times a day, terazosin, doxazosin, and alfuzosin offer more convenient once-daUy dosing. Prazosin, terazosin, and doxazosin antagonize peripheral vascular ai-adrenergic receptors, in addition to those in the prostate, at the usual doses used to treat BPH. As a result, first-dose syncope, orthostatic hypotension, and dizziness are... 

The most recently introduced a, antagonist for BPH, tamsulosin, has selectivity for a and adrenoceptors, vs. a,0 (Table 2). Tamsulosin shows either no selectivity (Kenny et al., 1994 Blue et al., 1997) or slight urethral selectivity (Brune et al., 1996 Testa et al., 1997) in conscious or anesthetized dogs. A small study comparing tamsulosin and terazosin showed a lower incidence of side effects with tamsulosin (Lee and Lee, 1997), although a similar comparison between tamsulosin and alfuzosin showed a similar incidence (Wilde and McTavish, 1996). Unlike most of the a [-antagonists, tamsulosin does not require dose-titration, since blood pressure is not significantly reduced at doses effective for BPH. However, this may be a consequence of the delayed-release preparation used, since early studies with standard formulations in normal volunteers showed a hypotensive effect (Tsunoo et al., 1990). 

Prazosin, terazosin, doxazosin, tamsulosin, and alfuzosin have been studied extensively and used widely in patients with benign prostatic hyperplasia. With the exception of tamsulosin, the comparative efficacies of each of these drugs, especially in comparison with relative adverse effects such as postural hypotension, appear similar, although direct comparisons are limited. Tamsulosin at the recommended dose of 0.4 mg daily is less likely to cause orthostatic hypotension than the other drugs. There is growing evidence that the predominant a,-receptor subtype expressed in the human prostate is the a,-receptor. Developments in this area will provide the basis for the selection of Ct receptor antagonists with specificity for the relevant subtype of aj-receptor. However, the possibility remains that some of the symptoms of BPH are due to aj-receptors in other sites, such as bladder, spinal cord, or brain. 

CALCIUM CHANNEL BLOCKERS ALPHA-BLOCKERS t efficacy of alpha-blockers t risk of first-dose 4. BP with alfuzosin, prazosin and terazosin Additive hypotensive effect may be used therapeutically Watch for first-dose i BP when starting either drug when the patient is already established on the other consider reducing the dose of the established drug and starting the new agent at the lowest dose and titrating up... 

Thus, tamsulosin and alfuzosin are first-line drugs for the treatment of BPH and have no utility in treating hypertension, because they have fewer cardiovascular effects than terazosin and doxazosin. Their clinical profiles are related to their pharmacokinetic differences (Table 45.3). Improvements in urine flow occur 4 to 8 hours after the first dose and in BPH symptoms after 1 week. 

Severe first-dose hypotension, and synergistic hypotensive effects that occurred when a patient taking enalapril was given bnna-zosin have been replicated in healthy subjects. The first-dose effect seen with other alpha blockers (particularly alfuzosin, prazosin and terazosin) is also likely to be potentiated by ACE inhibitors. In one small study tamsulosin did not have any clinically relevant effects on blood pressure that was already well controlled by enalapril. 

The manufacturers of alfuzosin and prazosin warn that patients receiving antihypertensive drugs (the manufacturers of prazosin specifically name the ACE inhibitors) are at particular risk of developing postural hypotension after the first dose of alpha blocker. 

Direct information is limited. Acute hypotension (dizziness, fainting) sometimes occurs unpredictably with the first dose of some alpha blockers (particularly, alfuzosin, prazosin and terazosin but see Alpha blockers , (p.83)), and this can be exaggerated if the patient takes or is already taking a beta blocker or a calcium-channel blocker (see Alpha blockers + Beta blockers , below, and Alpha blockers + Calcium-channel blockers , p.85). It would therefore seem prudent to apply the same precautions to ACE inhibitors, namely reducing the dose of the ACE inhibitor to a maintenance level if possible, then starting the alpha blocker at the lowest dose, with the first dose given at bedtime. Note that the acute hypotensive reaction appears to be short-lived. There is limited evidence that terazosin and tamsulosin may not cause an additional hypotensive effect in the longer term in patients with BPH who have hypertension already well-controlled with ACE inhibitors. Nevertheless, caution should be exercised in this situation, and a dose reduction of the ACE inhibitor may be required. 

No pharmacokinetic interaction occurred between alfuzosin 2.5 mg and atenolol 100 mg in a single-dose study in 8 healthy subjects. The manufacturer notes that postural hypotension may occur in patients receiving antihypertensives when they start alfuzosin, and note a study in which the combination of single doses of alfuzosin 2.5 mg and atenolol 100 mg caused significant reductions in mean heart rate and blood pressure. The AUCs of both drugs were raised up to about 20%. ... 

Not fully understood. It would seem that the vasodilatory effects of the alpha blockers and the calcium-channel blockers can be additive or synergistic, particularly after the first dose. The fall in blood pressure seen with prazosin and verapamil may, in part, result from a pliMinacokinetic interaction, as does the interaction between alfuzosin and diltiazem. Tamsulosin possibly has less effect on blood pressure since it has some selectivity for alpha receptors in the prostate (see Alpha blockers , (p.83)). 

Desager JP, Harvengt C, Bianchetti G, Rosenzweig P. The effect of cimetidine on the pharmacokinetics of single oral doses of alfuzosin. IntJ Clin Pharmacol Ther Toxicol (1993) 31,568-71. 

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