Drug Interactions in the Treatment of ED, LUTS and BPH: Clinically Significant Drug-Drug Interaction
The English-language medical literature, from 1986 to the present, was searched via the computer-based Medline system of the National Library of Medicine. The search focused on drug interaction data for the following agents: alfuzosin, doxazosin, dutasteride, finasteride, sildenafil, tamsulosin, tadalafil, terazosin, and vardenafil. Data were limited to information derived from studies of human subjects or actual patients and included premarketing and postmarketing observations. Articles reviewed included original studies, meta-analyses, and systematic reviews. Drug interactions were grouped into either pharmacodynamic interaction or pharmacokinetic interaction based on the mechanism.
Pharmacodynamic Drug-Drug Interactions With Selective Alpha-1-Adrenergic Receptor Blockers
As a class, these agents potentiate hypotension when given concurrently with other antihypertensive agents. However, tamsulosin and alfuzosin do not cause a greater hypotensive effect when given concurrently with antihypertensive agents because tamsulosin and alfuzosin are highly selective for alpha-1-adrenergic receptors in the prostate. To evaluate the safety of a highly selective alpha-1-adrenergic blocker, Lowe studied 36 hypertensive men ages 45 years or older whose blood pressure was being controlled with maintenance doses of nifedipine (study 1), enalapril (study 2), or atenolol (study 3). All 36 subjects were treated with placebo for five days, then randomly assigned to either placebo (control group) or tamsulosin therapy (0.4 mg/day for seven days followed by 0.8 mg/day for seven days) in addition to continuing their maintenance antihypertensive therapy. Blood pressure and pulse rate were monitored over a 24-hour period on study days 4, 11, and 19. Coadministration of tamsulosin in these small studies had no clinically significant effects on the pharmacodynamic action of nifedipine, enalapril, or atenolol. It produced no clinically significant differences in pulse rate and blood pressure, did not alter electrocardiographic or Holter monitoring results, and did not cause increased side effects. Lowe concluded that a highly selective alpha-1-adrenergic blocker can be safely coadministered with the three antihypertensive agents studied and produce a favorable safety profile without having to reduce the dosage of the preexisting regimens of nifedipine, enalapril, or atenolol in patients with benign prostatic hyperplasia (BPH).
Immediate-release alfuzosin has been shown to potentiate the negative chronotropic and the vasodilatory effects of atenolol. Administration of a single dose of atenolol 100 mg with a single dose of immediate-release alfuzosin 2.5 mg in eight healthy young male subjects increased both the maximum plasma concentration (Cmax) and AUC values by 28% and 21%, respectively. Alfuzosin increased atenolol Cmax and AUC values by 26% and 14%, respectively. The combination of alfuzosin with atenolol caused significant reductions in mean blood pressure and in mean heart rate in this study. However, the immediate-release preparation used in this study bears no pharmacokinetic resemblance to the extended-release that is commercially available in the United States.
Studies show that hypertension in the elderly can be safely controlled with low-dose diuretic therapy. According to Maruenda and colleagues, men with benign prostatic hyperplasia may benefit from peripheral alpha-blocking drugs. However, drugs such as doxazosin or terazosin may further lower blood pressure and at times may be associated with orthostatic hypotension, especially if diuretics are given concomitantly. The newer, highly selective alpha-1-adrenergic receptor blockers (i.e., tamsulosin and alfuzosin) achieve relaxation of the smooth muscle of the prostate, as do terazosin and doxazosin, but without provoking changes in blood pressure, particularly orthostatic hypotension. There appears to be no adverse interaction with any other antihypertensive medication or with low-dose diuretics. In summary, when compared to doxazosin and terazosin, tamsulosin and alfuzosin produce fewer vascular side effects including dizziness, vertigo, and orthostasis, and tamsulosin and alfuzosin may be coadministered with agents such as calcium channel blockers or angiotensin-converting enzyme (ACE) inhibitors without precipitating a hypotensive response. This level of enhanced tolerability with tamsulosin and alfuzosin is attributed to the specificity of these highly selective alpha-1-adrenergic blockers for prostatic alpha1A receptors.
Pharmacokinetic Drug-Drug Interactions With Selective Alpha-1-Adrenergic Receptor Blockers
Because the alpha-1-adrenergic receptor blockers, irrespective of their prostate-receptor selectivity, are metabolized by the CYP 450 system, there is the always potential for pharmacokinetic drug interaction. For example, studies show that cimetidine decreases the clearance of tamsulosin by 26% and increases AUC by 44%, and repeated administration of ketoconazole 400 mg produced a threefold increase in the AUC following a 10-mg single dose of extended-release alfuzosin. Although alfuzosin is highly selective for prostate gland alpha-1-adrenergic receptors, the safety and selectivity of this medication may be overshadowed by the exaggerated increase in its AUC as the result of decreased drug clearance by coadministration of potent inhibitors of CYP3A4 (e.g., amiodarone, azole antifungals, protease inhibitors, and macrolide antibiotics). Diltiazem, a moderate inhibitor of CYP3A4, increased the alfuzosin AUC by 1.5-fold but did not produce any changes in blood pressure. As tamsulosin is primarily excreted via the kidney, inhibition of hepatic mixed function oxidase enzymes is less likely to produce clinically significant drug interactions. Neither tamsulosin nor alfuzosin affect the mixed function oxidase enzyme system in the liver, and these drugs may be given concurrently with warfarin or digoxin. The recommended oral dose of tamsulosin for the treatment of mild to moderate benign prostatic hyperplasia is 0.4 mg once daily. In patients who fail to respond to the 0.4-mg dose after two to four weeks of dosing, the dose may be increased to 0.8 mg once daily. Dosage escalation does not increase the risk of pharmacokinetic interactions.
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