Tamsulosin is the first subtype-selective (α1A) α1 adrenoceptor antagonist with specificity for prostatic α1 adrenoceptors (α1A adrenoceptors are thought to be involved in prostatic smooth muscle contraction) to become available for the treatment of patients with symptomatic benign prostatic hyperplasia (BPH).
With tamsulosin, the incidence of adverse events commonly associated with α1 adrenoceptor antagonism is similar to that with placebo (except for ejaculation disorders) and alfuzosin. The incidence of other adverse events is similar with tamsulosin and placebo. Furthermore, blood pressure and heart rate are not significantly affected by tamsulosin in patients with symptomatic BPH. In contrast, blood pressure is significantly reduced by alfuzosin compared with tamsulosin.
Tamsulosin is available as a controlled release formulation suitable for once-daily administration; dose titration is not required. The overall efficacy of this agent administered at a dosage of 0.1 to 0.4 mg/day in Japan, 0.4 mg/day in Europe and 0.4 to 0.8 mg/day in the US to patients with symptomatic BPH is greater than that of placebo and was similar to that of alfuzosin or prazosin in the 2 available studies. Efficacy was primarily assessed by changes in maximum and average urinary flow rates, residual urinary volume and total symptom scores. Improvements in these parameters in short term trials (≤13 weeks) appear to be maintained in the longer term (≤60 weeks). Quality-of-life effects also appear to be similar with tamsulosin and alfuzosin.
In conclusion, the pharmacodynamic properties of this agent appear to translate into tolerability and administration advantages over other α1 adrenoceptor antagonists. If future investigations confirm its promising efficacy and tolerability, tamsulosin will be ideally placed as a valuable therapeutic option for patients with symptomatic BPH and in patients awaiting surgery or in those unable to undergo surgery.
The α adrenoceptor antagonist activity of tamsulosin has been demonstrated in vitro (human prostatic tissue) and in vivo. The antagonistic activity of tamsulosin against epinephrine-induced contraction of the canine prostate was greater than that of terazosin and at least the same as with prazosin.
In contrast to other clinically available α1 adrenoceptor antagonists, tamsulosin has greater affinity (7- to 38-fold) for α1A adrenoceptors than for α1B adrenoceptors, α1A Adrenoceptors are thought to be the predominant α1 adrenoceptor in the prostate and to mediate prostatic smooth muscle contraction; α1B adrenoceptors are also found in the prostate. Evidence suggests that am and α1D adrenoceptors are involved in vascular smooth muscle contraction.
Tamsulosin has greater affinity for α1 adrenoceptors in the prostate than in the vasculature. The affinity of tamsulosin for [ 3H]prazosin binding sites was approximately 12 times greater in human prostatic than aortic tissue. Tamsulosin was approximately 6 times more potent than prazosin in prostatic tissue in this study. Results of 4 of 5 in vivo animal studies have shown tamsulosin to have a greater effect on intraurethral pressure than blood pressure; the remaining study showed tamsulosin to have similar effects on these 2 parameters.
Blood pressure and heart rate were not significantly changed from baseline by multiple doses of tamsulosin 0.4mg in 10 healthy volunteers. The effects of tamsulosin on finger skin and dorsal hand vein constrictor responses to appropriate stimuli were similar to those with placebo and less than those with doxazosin.
A significant reduction in maximum urinary flow rate (Qmax) compared with placebo has been observed after one dose of tamsulosin 0.4mg in patients with symptomatic benign prostatic hyperplasia (BPH). No single-dose studies addressing the effects of tamsulosin on other urodynamic parameters in humans have been reported.
Tamsulosin is available as a controlled release (modified release) once-daily oral formulation with almost 100% bioavailability. The extent and rate of absorption of this agent are reduced when it is given with food.
Steady-state plasma concentrations of tamsulosin are achieved by day 5 of multiple dose (0.4mg once daily) administration. Mean maximum plasma concentration was 17 μ/L after a mean time of approximately 6 hours and elimination half-life was about 13 hours in elderly patients (aged >65 years) with symptomatic BPH who received tamsulosin 0.4mg once daily for 8 days.
Tamsulosin is approximately 99% protein bound and has a small volume of distribution (approximately 0.2 L/kg). The drug undergoes hepatic metabolism, with most of the parent drug and metabolites excreted in the urine; up to 14% is excreted as unchanged drug.
In general, the pharmacokinetic profile of tamsulosin is not significantly altered in patients with renal impairment or mild to moderate hepatic impairment. There are no pharmacokinetic data on the drug in patients with severe hepatic impairment or in those with a creatinine clearance of <10 ml/min (0.6 L/h).
The overall efficacy of short term (≤13 weeks) controlled release tamsulosin 0.1 to 0.4 mg/day in Japanese, 0.4 mg/day in European and 0.4 to 0.8 mg/day in US patients with symptomatic BPH is greater than that of placebo. Efficacy was primarily assessed by changes in Qmax, average urinary flow rate (Qave), residual urinary volume and total symptom scores from baseline. In a meta-analysis of 2 trials involving >500 patients with symptomatic BPH, a clinically significant response (≥30% increase in Qmax or ≥25% decrease in total Boyarsky symptom score) occurred in significantly more tamsulosin than placebo recipients (32 vs 20% and 66 vs 49%, respectively). Improvements in efficacy parameters with tamsulosin in short term trials appear to be maintained with longer term therapy (≤60 weeks).
Overall efficacy of tamsulosin was similar to that of alfuzosin or prazosin in the 2 studies currently available. However, based on Qmax values, there was a tendency for tamsulosin to have a faster onset of effect than alfuzosin; this is likely to be a direct effect of the lack of need for dose titration with tamsulosin. Trials comparing tamsulosin with other long-acting α1 adrenoceptor antagonists or other pharmacological treatment options (e.g. finasteride) are awaited.
According to the Life Style Quality-of-Life questionnaire, the overall quality of life of patients with symptomatic BPH was significantly improved from baseline with tamsulosin but not with placebo. These improvements were maintained for ≤60 weeks. According to the same questionnaire, quality-of-life effects of tamsulosin and alfuzosin appear to be similar.
With the exception of ejaculation disorders, the incidence of adverse events with tamsulosin up to 0.4mg once daily in patients with symptomatic BPH is similar to that with placebo. In particular, tamsulosin does not affect blood pressure or heart rate to a clinically significant extent. The incidence of postural hypotension with this drug was similar to that with placebo in controlled trials of patients with symptomatic BPH. The most common adverse events with tamsulosin in European patients are abnormal (retrograde) ejaculation or decreased volume of ejaculate (4.5%), dizziness (3.4%), infection (3.1%), headache (2.1%) and flu-like symptoms (1.6%); the incidence of the above ejaculation problems was significantly greater than with placebo (1%). Similar results were seen when treatment was continued for ≤60 weeks.
In the 1 available comparative study, the incidence of adverse events associated with α1 adrenoceptor blockade (including dizziness, postural hypotension, headache and palpitation/tachycardia) was similar with tamsulosin and alfuzosin (9.2 vs 10.5%); abnormal ejaculation occurred in 1 and 0 patients, respectively. Tamsulosin had no significant effects on blood pressure or heart rate, whereas alfuzosin significantly reduced blood pressure compared with baseline and tamsulosin.
Dosage and Administration
In clinical trials of patients with symptomatic BPH, controlled release tamsulosin dosages of 0.1 to 0.4 mg/day in Japan, 0.4 mg/day in Europe and 0.4 to 0.8 mg/day in the US have been used. The recommended dosage in Europe is 0.4mg once daily after breakfast and the recommended dosage in Japan is 0.2mg once daily. Dosage adjustments are not required in patients with mild to moderate hepatic impairment or renal dysfunction; however, there are no available data specifically in patients with a creatinine clearance of <10 ml/min (<0.6 L/h). In Europe, tamsulosin is contraindicated in patients with severe hepatic impairment because of a lack of available data in this patient group.