Nonpharmacologic Therapy

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To reduce nocturia, patients should be instructed to stop drinking fluids several hours before going to bed, and then voiding before going to sleep. During the day, patients should avoid excessive caffeine and alcohol intake, as these may cause urinary frequency. Patients should avoid taking nonprescription medications that can worsen obstructive voiding symptoms (e.g., antihistamines or decongestants) (Table 52-4). In addition, toilet mapping (knowing the location of toilets on the way to and from various destinations) may help reassure the patient that he can still continue with many of his routine daily activities. Patients are also advised to lose weight, if overweight. Because testosterone is converted to estrogen in fat tissue, an alteration in the testoster-one:estrogen ratio occurs in overweight men, similar to that which occurs in elderly males, which may contribute to the development of BPH 15-17

Although a variety of herbal agents are used for symptomatic management, including pygeum (African plum), secale cereale (rye pollen), and hypoxis rooperi (South African star grass), objective evidence of efficacy is lacking.18,19 Also, in a randomized, double-blind, and placebo-controlled clinical trial, saw palmetto was no differ-

ent than placebo in improving symptoms or increasing peak urinary flow rate. Pharmacologic Therapy

a-Adrenergic Antagonist Monotherapy

® a-Adrenergic antagonists reduce the dynamic factor causing BPH symptoms. These drugs competitively antagonize a-adrenergic receptors, thereby causing relaxation of the bladder neck, prostatic urethra, and prostate smooth muscle. A secondary mechanism of action may be that a-adrenergic antagonists induce prostatic apoptos-

is, which suggests that these agents may cause some shrinkage of an enlarged prostate. However, the clinical importance of this remains to be elucidated.

All a-adrenergic antagonists are considered equally effective in relieving symptoms.10 In various clinical trials, 30% to 80% of patients experience improvement in AUA Symptom Score by 30% to 45% and 20% to 40% of patients experience urinary flow rate increases of 2 to 3 mL/s.15 The onset of action is days to weeks, depending on the need for titration of the dose from a subtherapeutic starting dose to a therapeutic dose. An adequate clinical trial is considered to be at least 1 to 2 weeks of continuous treatment at a full maintenance dose with any of these agents.10 Durable responses have been demonstrated for up to 5 years of continuous use of terazos-

23 24 25

in, 10 years with doxazosin, and 6 years with tamsulosin. However, some patients will develop disease progression despite treatment. a-Adrenergic antagonists are hepatically catabolized. Therefore, in patients with significant hepatic dysfunction, these drugs should be used in the lowest possible dose. With the exception of silodosin, these drugs do not require dosage modification in patients with renal dysfunction. These agents can be differentiated by their adverse effect profile. Dose limiting adverse effects include hypotension and syncope, which are more common with immediate-release terazosin and doxazosin, less frequent with extended-release doxazosin and alfuzosin, and least frequent with uroselective a-adrenergic antagonists 26,27 Delayed or retrograde ejaculation has been reported most often with tamsulosin 0.8 mg orally once a day. Combined use with antihypertensives, diuretics, or phosphodiesterase inhibitors can lead to additive blood pressure-lowering effects; however, this appears to be less of a problem with tamsulosin.26,27

a-Adrenergic antagonists are recommended as first-line treatment for moderate to severe BPH. The agents in this pharmacologic class can be classified by several characteristics (Table 52-6):

• Generation of a-adrenergic antagonist. First-generation agents (e.g., phenoxyben-zamine) block presynaptic and postsynaptic a-adrenergic receptors. Whereas blockade of postsynaptic a-adrenergic receptors is desirable for BPH management, blockade of presynaptic a-adrenergic receptors is undesirable, as it results in release of catecholamines and tachycardia. Thus, first-generation a-adrenergic antagonists are not used for treatment of BPH.28 Second-generation a-adrenergic antagonists block postsynaptic a-adrenergic receptors in the bladder neck, prostate, and peripheral vasculature. Hypotensive adverse effects are dose-related and common. Examples include terazosin, doxazosin, and alfuzosin. Third-generation a-adrenergic antagonists (e.g., tamsulosin, silodosin) selectively block postsynaptic aiA-receptors, which concentrate in the prostate. As a result, hypotensive adverse effects are less common than with second-generation agents.

• Uroselectivity. Pharmacologic uroselectivity refers to preferential inhibition of aiA-and aiD-receptors, which predominate in the prostatic stroma and bladder de-

trusor muscle, respectively. Pharmacologically uroselective aiA-adrenergic antagonists have the potential to produce less hypotension, as they have a lower propensity to antagonize aiB-adrenergic receptors in the peripheral vasculature. Tamsulosin and silodosin are the only commercially available a-adrenergic antagonists with pharmacologic uroselectivity. In contrast, despite the potential of inhibiting a-adrenergic receptors in both the prostate and peripheral vasculature, functionally uroselective a-adrenergic antagonists in usually-prescribed doses, produce effective relaxation of prostatic smooth muscle with minimal vascular vasodilation. Thus, blood pressure-lowering effects are mild or absent. The only functionally urose-lective a-adrenergic antagonist is alfuzosin extended-release tablets. The mechanism of functional uroselectivity is unclear. It may be related to a drug formulation

which produces a higher concentration in target tissues than in nontarget tissues.

Both pharmacologically and functionally uroselective agents appear to be clinically uroselective, in that they improve BPH symptoms without causing cardiovascular

adverse effects in humans.

Pharmacologic and functional uroselectivity are dose-related phenomena. Large daily doses of tamsulosin or alfuzosin may cause loss of uroselectivity with resultant hypotension and dizziness in some patients.

• Need for up-titration of daily dose. Up-titration required for immediate-release terazosin and doxazosin. It is minimally required for extended-release doxazosin and tamsulosin. It is not required for extended-release alfuzosin or silodosin.

• Plasma half-life. a-Adrenergic receptors with short plasma half-lives (e.g., prazosin) require multiple doses during the day. This is challenging for most patients, and, thus, prazosin is not recommended for BPH.10

• Dosage formulation. Immediate-release formulations of terazosin and doxazosin are quickly absorbed and produce high peak plasma levels. Modified- or extended-release formulations of doxazosin, alfuzosin, and tamsulosin produce lower peak levels, but more sustained therapeutic plasma levels, than immediate-release formulations and have less potential for producing hypotensive episodes. This allows for

29_31

initiation of treatment with a therapeutic dose and once daily dosing.

• Adverse effects. Hypotensive adverse effects of a-adrenergic antagonists can range from asymptomatic blood pressure reductions to dizziness and syncope. This adverse effect is most commonly associated with immediate-release terazosin and doxazosin; is less commonly associated with extended-release alfuzosin and extended-release doxazosin, and silodosin; and least commonly associated with tamsulosin. , To minimize first-dose syncope from terazosin and doxazosin immediate-release, a slow up-titration from a subtherapeutic dose of 1 mg/day to a therapeutic dose is essential. The first dose should be given at bedtime so that the patient can sleep through the peak serum concentration of the drug when the adverse effect is most likely to occur. A 3- to 7-day interval between each dosage increase should be allowed, and the patient should be maintained on the lowest effective dose of a-adrenergic antagonist. If the patient is noncompliant with his regimen of terazosin or doxazosin, and he skips or interrupts treatment, the a-adrenergic antagonist should be restarted using the usual starting dose and then retitrated up. He should not be instructed to simply double up on missed doses or resume treatment with his currently prescribed daily dose, as this can lead to significant hypotension.

Table 52-6 Comparison of Pharmacologic Properties of a-Adrenergic Antagonists

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Ejaculation disorders, including delayed and retrograde ejaculation, occur with all adrenergic antagonists. Although largely thought to be due to pharmacologic blockade of peripheral a-adrenergic receptors at the bladder neck (i.e., the bladder neck is unable to close during ejaculation in the presence of a-adrenergic blockade), a CNS

mechanism of action cannot be discounted. The incidence appears to be dose-related and highest with tamsulosin 0.8 mg daily, occurring in up to 26% of treated

patients. Ejaculation disorders generally do not necessitate discontinuation of treatment. Although they may decrease the patient's satisfaction with the quality of sexual intercourse, ejaculation disorders are not harmful to the patient.

Rhinitis and malaise occur with a-adrenergic antagonists and are an extension of the pharmacologic blockade of a-adrenergic receptors in the vasculature of the nasal mucosa and in the CNS, respectively. Tolerance often develops to these adverse effects and they rarely require discontinuation of treatment. Avoid use of topical or oral decongestants, as these may exacerbate obstructive voiding symptoms. Cautious use of antihistamines with anticholinergic adverse effects is also recommended in patients with BPH, as these drugs may cause acute urinary retention in patients with an obstructed bladder neck.

Floppy iris syndrome has been reported with a-adrenergic antagonists, most often with tamsulosin. In response to tamsulosin, the iris dilator muscle relaxes. As a result, in a tamsulosin-treated patient who is undergoing cataract surgery, the iris can become flaccid, billow out, or become floppy. This can interfere with the surgical procedure and increase the risk of intraoperative and postoperative complications. A patient who plans to undergo cataract surgery is advised to inform his ophthalmologist that he is taking an a-adrenergic antagonist. Although the drug will not need to be held or discontinued, the ophthalmologist can plan to use certain surgical techniques, for example, iris hooks or iris expansion rings, to deal with the drug's effect on the iris dilator muscle.34,35

Alfuzosin has been linked to two cases of hepatitis. , The cause-effect relationship remains to be elucidated.

• Potential for drug interactions. Hypotensive adverse effects of terazosin and doxazosin can be additive with those of diuretics, antihypertensives, and phosphodiesterase inhibitors (e.g., sildenafil). In patients at greatest risk for hypotension, or in those patients who tolerate hypotension poorly, including those with poorly controlled coronary artery disease or severe orthostatic hypotension, tamsulosin 0.4 mg appears to be the safest choice.38,39 In patients who cannot tolerate tamsulosin, a 5a-reductase inhibitor or prostatectomy should be considered. When initiating sildenafil, tadalafil, or vardenafil, patients who are taking a-adrenergic antagonists should be stabilized first on a fixed dose of the a-adrenergic antagonist, and patients should be instructed to allow a 4-hour interval between the a-adrenergic antagonist and the phosphodiesterase inhibitor to minimize the likelihood of hypotensive effects.

Among the a-adrenergic antagonists, tamsulosin and silodosin are unique in that they are third-generation a-adrenergic antagonists. They are pharmacologically uroselective and exert greater antagonism of aiA- and aiD-receptors, which predominate in prostatic and bladder detrusor muscle. Tamsulosin exerts comparatively low antagonism of vascular aiB-receptors. Therefore, tamsulosin can be started with a therapeutic dose, which achieves peak effects sooner than terazosin and doxazosin immediate-release, which must be up-titrated. Tamsulosin appears to have the lowest potential to cause hypotension.26,2 In various clinical trials, tamsulosin has minimal hypotensive adverse effects and is well tolerated in the elderly, as well as in patients taking diuretics, antihypertensives, or phosphodiesterase inhibitors. It is also commercially available in a modified-release dosage formulation, which is dosed at 0.4 mg orally once a day. With chronic use, tamsulosin can be taken at any time of the day and at the patient's convenience. Although the package insert states that the dose can be increased to 0.8 mg daily, no consistent improvement in clinical efficacy has been observed in patients taking the higher dose 2 It is not clear at this time whether silodosin has the same clinical cardiovascular safety profile as tamsulosin.

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