Treatment of Benign Prostatic Hyperplasia in Hypertensive Men

Abstract

As the proportion of the US population over the age of 65 continues to rise, it is likely that the number of individuals with concomitant benign prostatic hyperplasia and hypertension will also increase. To reduce morbidity and mortality, it is important to treat patients with hypertension optimally. Evidence from outcome trials suggests that α₁ blockers should not be used as first‐line antihypertensive therapy. Although some clinicians previously recommended α₁ blocker monotherapy for patients with both hypertension and benign prostatic hyperplasia, the most recent American Urologic Association and Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines recommend independent treatment with the most appropriate pharmacologic agents for each condition. When treating patients with benign prostatic hyperplasia, clinicians should be aware of the potential impacts that α₁ blockers may have on blood pressure and potential adverse events in patients who are normotensive as well as in patients with treated hypertension.

Benign prostatic hypertrophy (BPH) and hypertension are common comorbidities; approximately 25%–30% of all men over 60 years of age have concomitant BPH and hypertension. ¹ One hypothesis to explain the high incidence of concomitant BPH and hypertension is that the two conditions may have underlying pathophysiologic mechanisms in common. Increased sympathetic activity has been implicated in the development of both hypertension and BPH; sympathetic activity is also known to increase with advancing age. ² Mediated through the release of norepinephrine, sympathetic activity raises blood pressure (BP) by increasing heart rate (via cardiac β‐adrenergic receptors) and by increasing total peripheral resistance (via α₁‐adrenergic receptors on vascular smooth muscle cells). ³ , ⁴ In addition to its role in hypertension, sympathetic nerve activity is known to cause contraction of prostatic smooth muscle. Prostatic outflow obstruction mediated by the sympathetic component of the autonomic nervous system constitutes the dynamic component of lower urinary tract symptoms (LUTS) and is believed to account for approximately 50% of outflow obstruction.5

Several authors have reported that α₁‐adrenergic blocker therapy targets the pathophysiology of clinical BPH and improves LUTS through reductions in α₁‐adrenoceptor‐associated contractions of prostatic smooth muscle.6, 7, 8 Molecular cloning studies have identified three subtypes of α₁ adrenoreceptors: α_1A, α_1B, and α_1D 6. The α_1A subtype predominates in the prostate and bladder neck where it regulates smooth muscle tone. In contrast, the α_1B subtype regulates vascular smooth muscle contraction.9, 10 The α_1D subtype is believed to be associated with bladder muscle contraction and sacral spinal cord innervation. Evidence also indicates that as men age, α_1B adrenoreceptors become predominant in some vascular beds11. The evidence suggests the hypothesis that this age‐related change could lead to a shifting difference in the effect that BPH agents such as nonselective α blockers and selective α blockers have on BP levels, particularly in older patients.9

USE OF α₁‐ADRENERGIC RECEPTOR BLOCKERS IN HYPERTENSION

In the arterial wall, α₁‐adrenergic stimulation causes constriction of vascular smooth muscle cells. ¹² Although α₁ blockers lower BP, as monotherapy they are relatively less effective than other antihypertensives. ¹² , ¹³ In the Veterans Affairs Cooperative Trial, ¹³ a comparison of the efficacy of diltiazem, hydrochlorothiazide, atenolol, captopril, clonidine, and prazosin in 1292 men with diastolic BP (DBP) readings of 95–109 mm Hg demonstrated that diltiazem had the highest rate of success at reducing BP to <90 mm Hg for at least 1 year, followed by atenolol, clonidine, hydrochlorothiazide, captopril. The α blocker prazosin had the lowest success rate.

In January 2000, based on the results of an interim data safety analysis, an independent review committee recommended discontinuation of the doxazosin arm in the Antihypertensive and Lipid‐Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). ¹⁴ Median follow‐up was 3.3 years for the 24,335 patients who had been receiving chlorthalidone 12.5–25 mg/d (n=15,268) or doxazosin 2–8 mg/d (n=9067). Although the risk of overall coronary heart disease or nonfatal myocardial infarction and total mortality did not differ between the two groups, patients in the doxazosin arm had a higher risk of stroke and combined cardiovascular disease, and double the risk of developing congestive heart failure, compared with patients in the chlorthalidone treatment group. Additionally, the mean systolic BP (SBP) was 2–3 mm Hg higher in the doxazosin group compared to the chlorthalidone group, suggesting that BP levels played a role in the increased cardiovascular event rate on the α blocker. ¹⁴ Thus, the results of ALLHAT have challenged the appropriateness of using α₁ blockers as first‐ or even second‐line treatment for hypertension. Clinical trial data have demonstrated that it is more appropriate to use thiazide diuretics, calcium channel antagonists, angiotensin‐converting enzyme inhibitors, β blockers, or angiotensin receptor blockers alone or in combination for first‐ and second‐line hypertension therapy. ¹⁵ , ¹⁷

In response to these recent findings, the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) ¹⁵ does not include α₁ blockers among agents for initial therapy (which include thiazide‐type diuretics, followed by angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers, (β blockers, and calcium channel antagonists).

Oftentimes, antihypertensive α₁ blocker doses that are initially efficacious lose their BP‐reducing effect; this requires doses to be increased to maintain efficacy. However, higher doses needed to maintain efficacy may be poorly tolerated. Since α₁‐adrenergic stimulation is an important physiologic homeostatic mechanism that restores and maintains BP during orthostasis, exercise, and the postprandial state, pharmacologic α₁ blockade inhibits this compensatory mechanism that attempts to maintain BP during these periods of hypotension. ¹²

BP reduction is also subject to homeostatic counter‐regulation, which is reflected by an increased efferent (β‐adrenergic stimulation leading to tachycardia, palpitations, and increased myocardial oxygen demand. With α₁ blockade, the compensatory rise in total peripheral resistance following postural challenge (e.g., standing up from a seated or recumbent position) is inhibited, and maintenance of BP depends upon an increase in heart rate. In addition, the blockade of α₁‐adrenergic vasoconstriction leads to an unopposed β‐adrenergic vasodilatation due to β₂ receptors in the vascular wall; this amplifies the lack of vascular compliance. ¹² Older patients may be particularly prone to adverse effects related to these impairments of homeostatic mechanisms. ¹⁸ Older individuals tend to rely more on vasoconstriction for BP homeostasis ¹⁹ , ²⁰ , ²¹ and therefore have reduced compensatory mechanisms to counteract their impaired cardiac response to vagal stimulation. ²²

APPROACHES TO BPH PHARMACOTHERAPY

BPH can lead to bothersome LUTS, which include urgency, frequency, nocturia, and weak urine stream. ⁶ , ²³ , ²⁴ These symptoms can have a deleterious effect upon a patient's quality of life. More serious complications may also be associated with BPH, including urinary retention, renal insufficiency, urinary tract infection, gross hematuria, and bladder stones. These complications may be exacerbated by failure to treat or inadequate treatment of BPH. ⁶ , ²³

Alpha₁‐adrenergic antagonists (terazosin, doxazosin, and alfuzosin) are quinazoline derivatives currently used to treat LUTS associated with BPH, although they were originally developed to treat hypertension, terazosin and doxazosin (but not alfuzosin) are still used as antihypertensive therapies. ¹² These agents are vasodilators and in some patients can produce significant decreases in BP, especially upon standing. ²⁵ When administered for control of BPH symptoms, the nonselective α₁‐adrenergic antagonists also antagonize α₁adrenergic receptors in vascular tissue.

Terazosin is effective in the management of patients with BPH, but the combination of terazosin and other antihypertensive agents has been shown to cause clinically significant hypotension. Thus, when these are used concomitantly, dosage reduction and re‐titration of either agent may be necessary. ²⁷

A retrospective analysis of the results of terazosin therapy reviewed BP changes and BP‐related side effects in 1896 patients with BPH randomized to terazosin or placebo. A subgroup analysis was performed on terazosin patients receiving no antihypertensive treatment who were either normotensive or hypertensive as well as on patients receiving antihypertensive treatment who were either well controlled (normotensive) or not well controlled (hypertensive). Both SBP and DBP reductions occurred in all treatment arms. In the group with well‐controlled hypertension (baseline SBP, 136.0 mm Hg; DBP, 77.7 mm Hg) the systolic reduction of 5.2 mm Hg was statistically significant (p<.001) compared with placebo, as were BP changes in the normotensives not receiving more specific antihypertensive treatment.

Doxazosin is also an effective α blocker for the management of patients with BPH but, must be titrated to relatively high doses (≥8 mg daily) to achieve symptomatic relief of LUTS. ²⁴ However, the controlled‐release gastrointestinal therapeutic system formulation of doxazosin does reduce, but does not eliminate, the need for dose titration. ²⁹

Doxazosin has been reported to have minimal hypotensive effects in normotensive patients with BPH, though, Fulton et al. ³⁰ noted that hypotensive events occurred in 17% of 665 patients with LUTS (with and without hypertension) treated with doxazosin compared with 0% of 300 patients with LUTS treated with placebo. In clinical trials of patients with hypertension or LUTS, doxazosin has been associated with significant reductions in sitting and standing BP compared with placebo. ³¹ , ³²

Alfuzosin (Uroxatral; Sanofi‐Synthelabo, Inc., New York, NY), a newer α₁ blocker, is also effective in the management of patients with BPH. The results of two double‐blind, placebo‐controlled phase III studies of similar design evaluating 983 patients with LUTS suggestive of BPH demonstrated that alfuzosin 10 mg once daily is an effective treatment for both symptoms and urinary flow rates. ³³

A safety analysis of two placebo‐controlled trials (a 1‐month study and a 3‐month study) of alfuzosin 10 mg once daily included a subgroup analysis of patients with both treated and untreated hypertension. In those patients, alfuzosin was associated with reductions in SBP and DBP of 6.0 mm Hg and 5.0 mm Hg, respectively, compared with placebo‐associated reductions of 2 mm Hg for both SBP and DBP (Table). ³⁴

Tamsulosin (Flomax; Boehringer Ingelheim Corp., Ridgefield, CT) is an α₁‐adrenoceptor blocker that is selective for the α_1A‐ and α_1D‐adrenoceptor subtypes, while showing far less affinity for the α_1B subtype. Tamsulosin is thus subtype‐selective; it has a 20:1 α_1A/α_1B selectivity ratio. ²⁸ , ³⁴ , ³⁵ , ³⁶ Binding studies have shown that tamsulosin is 12 times more selective for α₁ adrenoceptors in human prostate tissue than for α₁ adrenoceptors in human aortic tissue. ³⁷

In clinical trials in men with BPH, tamsulosin (0.4 mg/d) improved urinary flow rates and BPH symptoms without resulting in clinically significant effects on BP or heart rate. ⁴ , ³⁵ , ³⁶ , ³⁸ In a phase III, placebo‐controlled study, clinically significant orthostatic hypotension occurred in two patients in the 0.8 mg tamsulosin group, one patient in the 0.4 mg tamsulosin group, and but none in the placebo group. At study end point, the mean BP changes for controlled hypertensives in the tamsulosin 0.4 mg group and in the placebo group were 0.1/2.4 mm Hg and 2.6/4.4 mmHg, respectively (Table). The mean BP changes for normotensives in the tamsulosin 0.4 mg group and in the placebo group were −2.7/0.0 mm Hg and 1.3/1.2 mm Hg, respectively. ³⁹ In another placebo‐controlled study that evaluated tamsulosin 0.4 mg and 0.8 mg, or placebo, the percentages of patients with decreases of ≥20 mg Hg in SBP on standing there were no statistically significant differences among the two treatment groups, but a difference between the tamsulosin 0.8 mg and placebo groups at one point in the trial. ²⁵

In a number of smaller trials in which men with BPH and controlled hypertension were treated with tamsulosin or placebo, coadministration of this medication and three antihypertensive drugs (nifedipine, enalapril, and atenolol) produced no clinically significant changes in BP or heart rate. ⁴⁰

Thus, these safety analyses suggest that the addition of α₁ blockers for the management of patients with BPH whose hypertension is well controlled by medication—and perhaps even in patients whose hypertension is treated but not well controlled—may be problematic.

Cardiovascular α₁‐adrenoceptor blockade is inherent to the pharmacologic profile of nonselective α₁ blockers. Consequently, clinically desirable α₁‐adrenoceptor antagonism in prostatic smooth muscle of patients with BPH is unavoidably linked to the possibility of clinically undesirable α₁adrenoceptor antagonism and its effects (e.g., disturbance of BP homeostasis). Cardiovascular α₁ blockade in normotensive patients with BPH, although without an important impact on unchallenged BP, carries the risk of impaired BP control and homeostasis in situations where BP may be challenged—e.g., stress, postural change, and age‐related cardiovascular changes such as reduced vascular compliance and an age‐related decline in maximum achievable heart rate. Vascular α₁ blockade in patients with BPH with comorbid untreated hypertension, treated hypertension not well controlled, and well controlled treated hypertension may precipitate clinically relevant BP changes. ¹² , ³⁴

The subtype selectivity and tissue affinity demonstrated by tamsulosin, as opposed to that of nonselective α₁ blockers, which show little subtype preference, may explain why tamsulosin therapy has shown little effect on blood vessels and vasodilation. ³⁶

ERECTILE DYSFUNCTION THERAPY AND α BLOCKERS

The prevalence of erectile dysfunction (ED) increases with advancing age and is associated with reduced perceived quality of life and depression. ⁴¹ , ⁴² , ⁴³ Moreover, epidemiologic studies indicate that aging men with ED are likely to have concomitant hypertension, diabetes, and cardiovascular disease; vascular disease is thought to be the most common organic etiology of ED. ⁴⁴ , ⁴⁵ Even though the pathogenic relationship between BPH and ED is not completely understood, a direct association between these two symptom complexes in aging men has also become evident. ⁴⁶ Pharmacologic therapies for ED include sildenafil, vardenafil, and tadalafil, all of which are selective inhibitors of cyclic guanosine monophosphate‐specific phosphodiesterase type 5.

Phosphodiesterase type 5 inhibitors are known to potentiate the BP‐lowering effects of certain members of the ocadrenergic antagonist class. Simultaneous administration of sildenafil doses >25 mg and an α blocker may lead to symptomatic hypotension in some patients. Doses of 50 mg or 100 mg of sildenafil should not be taken within 4 hours of α‐blocker administration. A 25 mg dose of sildenafil may be taken at any time. ⁴⁷

Because of augmentation of BP‐lowering effects, therapy with tadalafil and all α blockers are contraindicated, with the exception of 0.4 mg tamsulosin. In a clinical pharmacology study, the simultaneous administration of tadalafil 20 mg and tamsulosin 0.4 mg produced no significant decreases in BP. ⁴⁸ A similar study evaluating the simultaneous administration of vardenafil 10 mg and 20 mg and tamsulosin 0.4 mg also showed no significant reductions in supine and standing SBP. ⁴⁹

INDEPENDENT OR COMBINATION THERAPY RATHER THAN DUAL THERAPY

Because α₁ blocker therapy has been used independently to treat patients with hypertension and to treat patients with BPH, some clinicians have proposed using α₁ ‐blocker monotherapy for the treatment of concomitant hypertension and BPH; this strategy has been tested in a number of clinical trials. ⁵⁰ , ⁵¹ Current clinical practice guidelines, however, would not favor α₁‐blocker‐based therapy for the treatment of patients with hypertension; consequently, α₁‐blocker monotherapy should no longer be recommended as initial treatment of hypertension with comorbid BPH. The JNC 7 has proposed diuretics, angiotensin‐converting enzyme inhibitors, angiotensin receptor blockers, (β blockers, or calcium antagonists as first‐ and second‐line agents for the treatment of patients with hypertension. ¹⁵ Current American Urologic Association ²⁴ guidelines on the management of BPH recommend that use of an α₁ blocker to manage a patient's LUTS should not necessarily be assumed to constitute optimal management of that patient's concomitant hypertension.

Patients with concomitant hypertension and BPH are best treated by the separate management of each condition. Although it has been claimed that hypertension and BPH can be controlled by the administration of a single α₁ blocker, such a regimen may require dosages above levels currently in practice for the treatment of patients with BPH alone. The higher dosages of α₁‐antagonist therapy would be expected to increase the risk of hypotension. ⁵² In patients with treated but uncontrolled hypertension and concomitant BPH, non‐selective α₁ blockers, which have the potential to significantly lower BP, may have a role in treating these patients. However, the potential of vascular side effects with the use of these agents remains a concern. In patients with BPH whose concomitant hypertension is well controlled by medication, it may be impractical to introduce BPH therapy, such as nonselective α₁ blockers, that can interfere with established antihypertension therapy, as this could lead to a loss of BP control, necessitating dose adjustments of current antihypertensive(s), or provoke adverse reactions, such as hypotension. ³⁴

CONCLUSION

As the proportion (and number) of the US population over 65 years of age increases, it is likely that the number of men who present with both BPH and hypertension will also increase. To reduce morbidity and mortality, it is paramount to treat patients with hypertension optimally. The results of the ALLHAT study, ¹⁴ , ⁵³ in addition to other clinical trial data, suggest that α₁ blockers should not be used as initial antihypertensive therapy. Although some clinicians have previously proposed α₁ blocker monotherapy for patients with comorbid hypertension and BPH, the most recent American Urologic Association and JNC 7 guidelines suggest that optimal therapy for these conditions—even when comorbid—is to treat them independently with the most appropriate pharmacologic agents.