And saw palmetto berry extract, listed by Consumer Reports in the US as a potentially helpful herb, could be just what the doctor ordered.

As many as a third of all men over 50 may suffer from benign prostate hyperplasia, experts estimate. The condition is not cancerous and simply means that the tissue of the prostate is inflamed and swollen.

Saw palmetto berry extract can help the tissue to shrink, allowing for more regular urination patterns – and with few side effects, as long as you use it with a doctor’s help, experts say.

How does it work? No one is exactly sure, but herbalists have an idea.

“It seems to affect the hormone levels in the genital area,” says Kara Dinda, director of education for the American Botanical Council in Austin, Texas.

And while the effects of the herb on men’s prostates seem fairly well documented, its effect on women is not known. Since hormones may be affected, it’s especially important that pregnant and lactating women not use the herb.

Use of this herb, which derives from the berries of the dwarf palmetto tree which is grown largely in Florida, dates back to the 1700s among Native Americans. Rigorous studies supporting use of the herb are far more recent.

According to an article in the Minneapolis Star Tribune, for example, a 1996 study of 1,098 men in the US showed that saw palmetto berry extract is at least as effective as a popular prescription drug – and produces fewer side effects, including impotence. And The Daily Telegraph reports that close to 90 per cent of men in Germany with benign prostate hyperplasia are treated with plant extracts, and saw palmetto berry extract tops the list.

One concern among doctors has been that use of the herb or a product containing it might affect PSA levels, by which prostate cancer can be diagnosed. But an editorial in Urology said that US herb specialist Varro Tyler and a UCLA urologist showed that use of the herb did not affect any tests of the prostate, including the PSA.

Side effects? They’re relatively minor: stomach problems, headaches and, with large doses, diarrhea.

One caveat: A Boston Globe story reported that a 1998 review of the herb suggested that other new prostate medications may in fact be more effective than saw palmetto berry extract.

What To Do

This herb sounds promising. Men should ask their GP for further information, however. “Herbs produce chemicals,” says Erica Kipp, manager of the Plant Research Laboratory for the New York Botanical Garden. “I think people have the misconception that anything from a plant is natural and good and benign – and this is not necessarily the case.”

According to researchers from the University of Texas Southwestern Medical Center at Dallas, prostate-specific antigen test results can predict the risk of acute urinary retention (AUR) and the need for prostate surgery in men with benign prostatic hyperplasia (BPH). Benign prostatic hyperplasia refers to a non-cancerous enlargement of the prostate gland and is commonly found in men over age 50. Although not life-threatening, an enlarged prostate may block the urethra and make the passage of urine difficult. It can also lead to acute urinary retention, a condition in which urination becomes nearly blocked.

In this study, investigators compared the prostate-specific antigen test results of over 3,000 older men with their incidence of AUR and BPH. They found that up to 20 percent of men with high PSA levels experienced either AUR or BPH-related surgery. However, in men with low prostate-specific antigen values, fewer than eight percent experienced either of those conditions. They also noted that when patients with high PSA scores are treated with finasteride, a drug used in benign prostatic hyperplasia to shrink the prostate gland, their risk for developing acute urinary retention or requiring surgery was reduced by up to 60 percent.

The authors concluded that a patient’s prostate-specific antigen values can help doctors predict the risk of BPH-related outcomes and identify appropriate therapy for benign prostatic hyperplasia.

Note: Benign prostate hyperplasia is an enlargement of the prostate; the condition is characterized by the frequent need to urinate and difficulty in urinating.

Researchers at the Harvard School of Public Health analyzed data from the 30,000-male-participant Health Professionals Follow-up Study to reach their conclusions. The study found that men who consumed moderate amounts of alcohol (about two drinks per day of beer or liquor) were at lower risk of benign prostate hyperplasia. The study notes that, contrary to previous reports, cigarette smoking was not associated with a reduced risk of benign prostate hyperplasia, but rather that heavy cigarette smoking (35 or more cigarettes per day) was associated with an increased risk. Authors suggest that this benefit of alcohol consumption could be due to a resulting reduction in concentrations of testosterone in the blood.

The following article is briefly presented

The effect of finasteride on the risk of acute urinary retention and the need for surgical treatment among men with benign prostatic hyperplasia. McConnel, J., Bruskewitz, R., Walsh, P. et al.
N Engl J Med, 338: 557-563, 26 Feb. 1998.

This was a 4-year randomized double-blind placebo-controlled trial involving around 3000 men who had BPH with moderate to severe lower urinary tract symptoms, decreased maximal urine flow rates and an enlarged prostate. They were randomized to receive either finasteride at 5 mg/day or placebo for 4 years.

The authors found the following:

• Those who had received finasteride had significantly greater decreases in symptom scores. Significantly fewer men in the finasteride group had surgery or acute urine retention.

•There was a significantly higher incidence of side effects in the finasteride group.

Commentary

The commentator suggests that patients should make an informed choice concerning treatment for BPH, as neither treatment option is particularly risky. The Veterans Affairs study (N Engl J Med, 1996) found terazosin to be superior to finasteride. A combination of ct-blocker and finasteride may work well for the long-term conservative management of BPH.

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.

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.

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.

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.

Benign prostatic hyperplasia (BPH) is highly prevalent among middle aged and elderly males. Although BPH is rarely life-threatening, it is associated with bothersome lower urinary tract symptoms (LUTS) that affect quality of life by interfering with normal daily activities and predispose to erectile dysfunction (ED). The prevalence of these genitourinary disorders is age dependent, with initial development beginning around age 40. Thereafter, approximately 50% of males 60 years old and 90% of males older than 85 will suffer from BPH. Unfortunately, 50% of males with benign prostatic hyperplasia will suffer from moderate to severe LUTS. Recent studies show that LUTS may affect erectile and ejaculatory function and diminish the ability to have pleasurable intercourse. Recent studies found that lower urinary tract symptoms interferes with sexual pleasure in about 90% of patients and LUTS produces sexual dysfunction in 50% of males.

Because sexuality is one of the most important aspects of quality of life in males, the widespread prevalence of BPH and LUTS makes these conditions the targets of pharmacotherapy. The vasoactive drugs used to treat BPH, LUTS, and ED raise the specter of clinically significant adverse drug­drug interactions. This article examines the mechanisms and prevalence of clinically relevant drug interactions in patients treated for these genitourinary conditions.

Introduction

Lower urinary tract symptoms is a descriptive term rather than a pathological term because LUTS may involve BPH, benign prostatic obstruction, or a combination of these conditions. Patients with LUTS often seek medical help for complaints of urinary frequency, hesitancy, weakening stream, urgency, or nocturia. The etiology of lower urinary tract symptoms varies with the individual; in some, LUTS may result from an enlarged prostate exerting pressure on the urethra and obstructing urinary outflow. In others, LUTS may result from increased contraction of prostatic smooth muscle and from bladder dysfunction. Urinary flow rates and prostate size do not correlate with the frequency or severity of lower urinary tract symptoms.

Although LUTS may wax and wane, severity of symptoms increases over time as the prostate enlarges with aging. Studies indicate that lower urinary tract symptoms influences sexual pleasure in approximately 90% of patients, and LUTS produces sexual dysfunction in 50% of males. Sexuality is significant to the quality of life in males; therefore, prevailing benign prostatic hyperplasia and LUTS are targets for medical attention and drug therapy. The use of vasoactive drugs indicated for BPH, LUTS, and ED elevates the clinically significant adverse drug­drug interactions, especially in patients with coexisting hypertension or heart disease. Today, the lifetime risk of patients ages 55 to 65 years to receive antihypertensive drugs approaches 60%. Yet, recent trials suggest that hypertension is not adequately controlled in the majority of patients. The prevalence of hypertension increases with advancing age, as does the prevalence of comorbid conditions and total number of medications taken. Multidrug therapy, advancing age, and comorbid conditions are also key risk factors for adverse drug reactions and drug interactions. As the spectrum of drugs prescribed is constantly changing, safety in the past does not imply safety today, and safety today does not imply safety tomorrow.

By virtue of the mechanisms of action of the medications used to treat benign prostatic hyperplasia, lower urinary tract symptoms, and erectile dysfunction, along with the prevalence of heart and hypertension conditions in these males, drug interactions are of paramount concern in these patients. However, therapeutic efficacy should not be neglected over concerns regarding drug interactions. Many patients are at risk of clinically relevant drug intera ctions involving antihypertensive drugs but, presently, even more patients may be at risk of suffering from the consequences of their inadequately treated hypertension. Therefore, informed decision-making by clinicians regarding the risk-to-benefit ratio of potential drug­drug interactions could enhance the quality of life of patients with bothersome, yet non­life-threatening, genitourinary tract problems. This article examines the mechanisms and potential clinical relevance of drug interactions with medications used commonly to treat BPH, LUTS, and ED, i.e., selective alpha-1-adrenergic receptor blockers, 5-alpha-reductase inhibitors, and selective inhibitors of cyclic guanosine monophosphate (cyclic GMP)-specific phosphodiesterase 5 (PDE-5) enzymes.

Drug interactions are a major factor in the etiology of common and potentially fatal adverse drug reactions. Frequent use of complex drug regimens increases the likelihood of multiple drug interactions in the same individual. Furthermore, the significance of an interaction depends on the effect of a given drug in a specific patient. Drug interactions that cause noticeable side effects (e.g., hypotension with subsequent syncope or myocardial ischemia [MI]) are readily detectable and potentially life-threatening. Other interactions that might alter the bioavailability or the pharmacokinetics may be more subtle or insidious (e.g., effect of food on oral bioavailability). Because drug interactions should be viewed as preventable side effects, clinicians must be proactive and vigilant. This requires a thorough understanding of the potential interactions and their mechanism of interaction. However, before we proceed with a detailed discussion of clinically relevant, potential drug­drug interactions, it is important to review the mechanisms of action and pharmacokinetic profiles of the drugs commonly used to treat benign prostatic hyperplasia, lower urinary tract symptoms, and erectile dysfunction to better appreciate the potential for clinically relevant drug interactions.