Tamsulosin

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Abstract
Tamsulosin is a selective α1a- and α1D-adrenoceptor antagonist. These α1-receptors are predominant in the prostate, prostatic capsule, prostatic urethra and bladder. The relaxation of prostate and bladder smooth muscles may result in improvement in maximum urine flow (Qmax) and reduction of lower urinary tract symptoms (LUTS). Tamsulosin 0.4 and 0.8 mg/day in a modified-release formulation was significantly more effective than placebo in large (n >250) double-blind, randomised, multicentre, 12- to 13-week clinical trials in patients with LUTS. A greater increase in Qmax from baseline was seen in patients receiving tamsulosin 0.4 or 0.8 mg/day (1.4 to 1.79 ml/sec from a baseline of 9.46 to 10.7 ml/sec) than in placebo recipients (0.4 to 0.93 ml/sec from a baseline of 9.75 to 10.4 ml/sec); the between-group difference was significant in two of three studies. Tamsulosin 0.4 or 0.8 mg/day improved total Boyarsky symptom scores from baseline by a significantly greater extent (by 3.0 to 5.2 points from a baseline of 9.5 to 11.1 points) than placebo (1.9 to 3.2 points from a baseline of 9.3 to 11.0 points). In non-comparative extension studies, the improvement in efficacy parameters with tamsulosin treatment was maintained for up to 4 years. Tamsulosin is effective in patients with mild to severe LUTS, patients with diabetes mellitus or those aged ≥65 years and does not interfere with the antihy-pertensive action of nifedipine, enalapril or atenolol. Tamsulosin 0.4 mg/day for 12 weeks and tamsulosin 0.2 mg/day for 4 weeks were as effective as alfuzosin 2.5mg three times daily and terazosin 2 mg/day, respectively, in improving Qmax and symptom scores in randomised comparative trials. With the exception of a numberically greater incidence of abnormal ejaculation, dizziness and rhinitis, the incidence of adverse events with tamsulosin 0.4 mg/day was similar to that seen with placebo in randomised, double-blind studies. The overall incidence of symptoms indicative of orthostasis was 1.4% with tamsulosin 0.4 or 0.8 mg/day treatment. Tamsulosin had less effect on blood pressure than alfuzosin or terazosin. Conclusion: Tamsulosin, an α1-adrenoceptor antagonist, has a well established place in the treatment of LUTS and has a tolerability profile similar to that of placebo (apart from a higher incidence of abnormal ejaculation, dizziness and rhinitis). Comparative data have shown tamsulosin to be as effective as other α1-adrenoceptor antagonists at increasing Qmax and improving symptom scores. However, tamsulosin is unlikely to produce orthostatic hypotensive adverse effects or interfere with concomitant antihypertensive drug therapy. Therefore, tamsulosin is a useful therapeutic option in the management of patients with moderate to severe LUTS. Tamsulosin is an α1-adrenoceptor antagonist, available as a modified-release formulation, that is selective for α1A- and α1D-receptors which are predominant in the prostate, prostatic capsule, prostatic urethra and bladder. The relaxation of prostate and bladder smooth muscles caused by tamsulosin may result in improvement in maximum urine flow (Qmax) and reduction of lower urinary tract symptoms (LUTS). A placebo-controlled, single-blind, randomised, crossover study using ex vivo radioreceptor assays demonstrated that the α1-adrenoceptor subtype selectivity of single-dose tamsulosin 0.4mg in healthy volunteers was α1a > α1d ≈ α1b. Tamsulosin has a greater affinity for α1-adrenoceptors in the prostate than in the vasculature. In in vitro studies, tamsulosin showed a 10-fold selectivity for human prostate tissue over mesenteric arteries, as measured by the ratio of molar affinities, and an approximately 12-fold greater affinity for [3H]prazosin binding sites in human prostatic tissue than in aortic tissue, based on inhibition constants. Modified-release tamsulosin has a low potential to cause vasodilation and associated cardiovascular adverse effects. A single dose of tamsulosin 0.4mg inhibited phenylephrine-induced elevations in diastolic blood pressure to a lesser extent than a clinically equi-effective dose of terazosin 5mg in healthy volunteers. Using fingertip and dorsal hand vein vasoconstrictor response tests, the vascular α1-adrenoceptor antagonistic activity of tamsulosin 0.2mg was similar to that of placebo and less than that of doxazosin 1mg or terazosin 1mg in randomised, placebo-controlled studies in healthy individuals. In a similar study, tamsulosin 0.6mg had greater α1-adrenoceptor antagonist activity on blood vessels than tamsulosin 0.2 mg. The modified-release formulation of tamsulosin is given once daily and has a bioavailability of 100% under fasting conditions. When given with food, the extent and rate of absorption of tamsulosin are reduced, and the time to maximum plasma concentration (tmax) is increased. The mean steady-state volume of distribution of intravenous tamsulosin (0.125 mg over 4 hours) was 16L in healthy individuals. Tamsulosin is ≈ 99% plasma protein bound to primarily α1-acid glycoprotein. The pharmacokinetics of the drug are linear following single and multiple doses. Steady-state plasma concentrations of the drug were achieved by the fourth day of administration of tamsulosin 0.1 to 0.6mg once daily. Cmax (5.7 μg/L) occurred at 8 hours in healthy volunteers who received single oral doses of tamsulosin 0.2mg. When single-dose tamsulosin 0.4mg was taken with a light breakfast by healthy volunteers, the mean maximum plasma concentration of the drug was 10.1 μg/L and tmax was 6 hours. The elimination half-life (t½) of a single-dose of modified-release tamsulosin 0.2mg is 9 hours and the t½ of tamsulosin 0.4mg is estimated to be 14 to 15 hours in elderly patients based on the absorption rate-controlled pharmacokinetics of tamsulosin (t½ was 5 to 7 hours following intravenous or oral administration of immediate-release tamsulosin in healthy volunteers). The systemic clearance of tamsulosin is 2.88 L/h and is reduced in elderly patients resulting in a slightly prolonged pharmacokinetic disposition. Unchanged tamsulosin accounts for most of the drug in the plasma as it is metabolised slowly in the liver by cytochrome P450 enzymes. The parent drug and metabolites are 76.4% excreted in the urine and 21.4% in the faeces; 8.7% are excreted as unchanged drug. The pharmacokinetic profile of tamsulosin is not significantly altered in patients with moderate to severe renal impairment or mild to moderate hepatic impairment. There are no pharmacokinetic data on the drug in patients with a creatinine clearance of 1-adrenoceptor antagonists. The manufacturer recommends caution with the concomitant administration of tamsulosin and antihypertensive drugs (Japan), cimetidine (US), warfarin (US and Europe) and diclofenac (Europe).