Health and Prostate

Clinically Relevant Drug­-Drug Interactions With the 5-Alpha-Reductase Inhibitors

Neither dutasteride nor finasteride have any clinically significant pharmacodynamic or pharmacokinetic adverse drug interactions. Studies show that the 5-alpha-reductase inhibitors do not affect the CYP 450 enzyme system. However, agents that inhibit the CYP 450 3A4 may, in theory, interfere with metabolism of these medications. Therefore, until more data are available, cautious monitoring should follow the concurrent administration of a 5-alpha-reductase inhibitor with an agent known to alter the activity of the hepatic mixed function oxidase enzyme system.

Pharmacodynamic Drug-Drug Interactions With PDE-5 Inhibitors

Pharmacodynamic drug interactions leading to precipitous hypotension and MI are clinically relevant with PDE-5 inhibitors. All selective inhibitors of cyclic GMP-specific PDE-5 are prone to clinically significant pharmacodynamic interactions with agents that produce vasodilation. The concurrent use of nitrate preparations is a contraindication to treatment with selective inhibitors of cyclic GMP-specific PDE-5. The selective inhibitors of cyclic GMP-specific PDE-5 differ with regard to the warning against concurrent use of with alpha-1-adrenergic blockers. For example, sildenafil in doses above 25 mg should not be used within four hours after ingestion of an alpha-1-adrenergic blocker. Vardenafil is contraindicated in patients treated with alpha-1-adrenergic blockers. Tadalafil is contraindicated in patients receiving an alpha-1-adrenergic blocker, with the exception of those taking tamsulosin 0.4 mg once daily. Extreme caution should be employed when any PDE-5 inhibitors are used in patients receiving antihypertensive medications (e.g., nitroprusside, nitroglycerin, phentolamine, amyl nitrate, ACE inhibitors, angiotensin receptor blockers, hydralazine, and nitrates) because the vasoactive effects of the combination may be exaggerated. Lastly, the concurrent administration of PDE-5 inhibitors and opiates (e.g., dihydrocodeine) results in exaggerated release of cyclic GMP and has been reported to produce priapism. An increased risk of cardiac events has been suspected with these agents when given concurrently with vasoactive agents that may steal blood from the cardiac collateral circulation.

Pharmacokinetic Drug­-Drug Interactions With PDE-5 Inhibitors

There are increasing numbers of patients with ED who are taking concurrent medications that can affect the metabolism of PDE-5 inhibitors. Medications that inhibit CYP3A4 (e.g., protease inhibitors, azole antifungals, erythromycin, and grapefruit juice) will significantly alter the metabolism and raise the bioavailability of PDE-5 inhibitors. These clinically significant pharmacokinetic interactions require that the dose or dosage interval of the PDE-5 inhibitor be modified to prevent drug accumulation and precipitous hypotension. Table 4 lists the drugs that may produce potentially life-threatening drug­drug interactions if used concurrently with a PDE-5 inhibitor.Although medications that induce CYP3A4 may increase the metabolism of PDE-5 inhibitors, no specific dosage adjustments are required. Lastly, studies show that PDE-5 inhibitors may be given safely with theophylline, digoxin, warfarin, antacids, glyburide, tolbutamide, and ranitidine.

Conclusions

Currently, the scientific literature is skewed in its content of useful information regarding potential drug interactions with alpha-1-adrenergic blockers and PDE-5 inhibitors. Most of the information on drug­drug interactions is with the older non­prostate-selective alpha-1-adrenergic blockers. The limited data available with tamsulosin and alfuzosin show that these agents are less likely to have pharmacodynamic interactions with alpha-1-adrenergic blockers than doxazosin or terazosin. Regarding pharmacokinetic interactions, tamsulosin has the lowest potential for clinically significant interactions because it undergoes minimal hepatic metabolism and is primarily eliminated via the kidneys. Fortunately, neither dutasteride nor finasteride have any clinically significant pharmacodynamic or pharmacokinetic adverse drug interactions. Because clinicians see an increasing number of patients being prescribed PDE-5 inhibitors who also have cardiovascular disease, clinicians must be vigilant about the potential for clinically significant pharmacodynamic interactions with medications that produce vasodilation or increase the release of NO. Furthermore, PDE-5 inhibitors are prime targets for clinically important drug interactions with agents that inhibit CYP3A4. Currently, there is insufficient information with which to judge the pharmacodynamic drug interaction liability of alfuzosin and of tamsulosin relative to PDE-5 inhibitors. Until such data are available, patients receiving alfuzosin or tamsulosin should be advised about the potential dangers of concomitant therapy with any of the PDE-5 inhibitors.

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 alpha_1A 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.

Pharmacodynamics

The deficiency of 5-alpha-reductase was discovered more than 30 years ago. At this time, the role of 5-alpha-reductase inhibitors was hypothesized to be beneficial for the treatment of androgen-related diseases. Dihydrotestosterone (DHT) is the main prostatic androgen and is approximately twice as potent as testosterone; DHT binds to androgen receptors to induce androgenic effects in the prostate gland, liver, and skin. The enzyme 5-alpha-reductase is necessary to catalyze the conversion of testosterone to dihydrotestosterone. Five-alpha-reductase acts upon circulating testosterone, which when reduced to DHT accumulates in the prostate. There are two isoenzymes of 5-alpha-reductase: type 1 and type 2. The function of type 1 5-alpha-reductase is unknown. It has been found most commonly in sebaceous glands and is present in most body tissues. Type 2 5-alpha-reductase plays a role in prostate development and in the androgenic effects on the hair follicle. Finasteride inhibits mostly type 2 isoenzymes and is used for the treatment of benign prostatic hyperplasia (BPH) and alopecia. Approximately 85% to 90% of dihydrotestosterone is suppressed by the inhibition of type 2 isozymes. The remaining DHT is hypothesized to be from type 1 5-alpha-reductase. Dutasteride inhibits both type 1 and type 2 5-alpha-reductase and is also indicated for the treatment of benign prostatic hyperplasia.

Pharmacokinetics

The pharmacokinetic properties of finasteride and dutasteride are well-defined. The agents have good oral bioavailability and undergo extensive hepatic metabolism. Both agents are extensively metabolized via hepatic CYP 450 3A4 enzymes. Bioavailability is approximately 60% and is not affected by food. The half-life of both agents increases with age; however, no dosage adjustments are necessary. Biliary/fecal elimination appears to be similar, but finasteride undergoes approximately 39% renal elimination, whereas dutasteride data suggests virtually no renal elimination. Although plasma metabolites of finasteride will be higher in patients with renal impairment, the metabolites display less than 20% of the activity of the parent drug; therefore, no dosage adjustment is necessary. The effect of hepatic impairment on either agent is unknown at this time. Table 2 compares selected pharmacokinetic properties between finasteride and dutasteride.

Pharmacodynamics

Alpha₁ receptors are located in nonvascular smooth muscles (e.g., bladder trigone and sphincters, gastrointestinal tract and sphincters, prostate adenoma and capsule, and ureters) and in nonmuscular tissues (e.g., central nervous system, liver, and kidneys). Symptoms of benign prostatic hyperplasia (BPH) are related to bladder outlet obstruction, comprised of underlying static and dynamic components. The static component is associated with an increase in prostate size caused by a proliferation of smooth muscle; however, the symptoms of benign prostatic hyperplasia and degree of urinary outlet obstruction do not correlate directly with prostate size. The dynamic component is associated with the increased smooth muscle tone in the prostate and bladder neck. Administration of the alpha₁-receptor antagonist affects the dynamic component by decreasing urethral resistance, relaxing smooth muscle, and improving urine flow rates in the bladder neck and prostate. Few alpha₁ receptors are in the bladder body; most are located on the prostate capsule and adenoma and the bladder trigone. Thus, blocking these receptors reduces bladder outlet obstruction without affecting bladder contractility.

At least three alpha₁-adrenoceptor subtypes exist: alpha_1A, alpha_1B, and alpha_1D. Approximately 70% of the alpha₁ adrenoceptors located in the prostate are of the alpha_1A subtype. Both doxazosin and terazosin are nonselective alpha₁ antagonists, causing a decrease in blood pressure and urinary symptoms. Alfuzosin and tamsulosin are selective for the alpha_1A adrenoceptor and are less likely to cause peripheral alpha-1-adrenergic blockade and hypotension.

Pharmacokinetics

Table 1 lists the pharmacokinetic properties of the alpha-1-adrenergic receptor blockers. The bioavailability of alfuzosin is improved with food, whereas the bioavailability of tamsulosin is 30% higher when it is administered in a fasting state compared with administration in a fed state. Tamsulosin pharmacokinetic properties do not differ whether the drug is taken with a light breakfast or a high-fat breakfast. All the agents have similar protein binding and once-daily dosing because of their long half-life or extended-release formulation. Tamsulosin is primarily eliminated in the urine, whereas alfuzosin, doxazosin, and terazosin are primarily eliminated in the bile or feces. No dosing changes are needed when tamsulosin is given to patients with renal impairment. Blood alfuzosin concentrations are significantly increased in the presence of moderate to severe liver failure (i.e., Childs-Pugh categories B and C) as well as in the presence of potent inhibitors of CYP3A4; these changes may predispose to alfuzosin toxicity. Severe renal insufficiency (creatine clearance [CrCl] < 30 mL/minute) may alter the elimination of alfuzosin and raise the serum drug concentration by 50%, but there are insufficient data to determine the clinical relevance of renal insufficiency on the kinetics of alfuzosin.table 1 summarizes the pharmacokinetics of the alpha₁-receptor antagonists.