http://evolve.elsevier.com/Edmunds/NP/
Top 100 drug; 
Key drug. Key drug because it was the first on the market and is in common use. Drugs listed in general order of use within class.
The drugs used for benign prostatic hyperplasia (BPH) and those given for erectile dysfunction (ED) are discussed in separate sections of this chapter.
Benign Prostatic Hyperplasia
Therapeutic Overview
BPH is a benign neoplasm of the prostate gland that, if large enough, causes voiding dysfunction. BPH, which is extremely common in the aging male, occurs in less than 10% of men aged 31 to 40 years. However, by age 60, nearly half of men will develop BPH, and by age 85, more than 80% will have it. Prostatism has three components: histologic prostatic hyperplasia, an increase in outflow resistance, and response of the bladder (detrusor) muscle to obstruction. The prostate depends on the androgen 5α-dihydrotestosterone (DHT) for growth. The enzyme 5α-reductase metabolizes testosterone to DHT in the prostate gland, liver, and skin. DHT induces androgenic effects by binding to androgen receptors in the cell nuclei of these organs.
The medical history focuses on the urinary tract and on overall health problems that could affect the urinary system such as diabetes, Parkinson’s disease, and stroke. It is important to rule out the possibility of prostatic cancer. Medications that can affect bladder function include anticholinergics and sympathomimetics. The American Urological Association (AUA) symptom score for BPH is commonly used to assess symptom severity but not for diagnosis. A patient’s symptom score is calculated from the answers to seven questions on a scale of 0 (not present) to 5 (almost always present). These questions address urinary frequency, nocturia, weak urinary stream, hesitancy, intermittence, incomplete bladder emptying, and urgency. A symptom score of 0 to 7 (mild), 8 to 19 (moderate), or 20 to 35 (severe) is given. The AUA symptom score has also been shown to be effective in visually impaired and illiterate patients.
Physical examination emphasizes the digital rectal examination (DRE) and the neurologic system. The DRE is used to estimate the size of the prostate gland, to evaluate anal sphincter tone, and to raise suspicion of prostate or rectal malignancy.
Laboratory tests required to assess renal function include urinalysis, serum creatinine, and BUN. PSA is considered optional under some guidelines. Other tests that may be performed are uroflowmetry, postvoid residual, and pressure flow studies. Tests that are not recommended are filling cystometry, urethrocystoscopy, and imaging of the urinary tract, unless these are indicated by prostatism complicated by additional disease or symptoms.
Mechanism of Action
The nonspecific α1-adrenergic receptor blockers (terazosin, doxazosin, and prazosin) reduce sympathetic tone and relax urethral stricture that causes BPH symptoms. Prazosin has a shorter duration of action than the others and generally is not used first line. These drugs also lower blood pressure by blocking α1-adrenergic receptors on arterioles, causing vasodilation. Newer selective agents such as tamsulosin and alfuzosin are specific for the α1A-adrenoceptor in the prostate and have little effect on blood pressure.
Finasteride reduces the size of the prostate gland, but 6 to 12 months may be required for improvement of symptoms. It is a 5α-reductase enzyme inhibitor that blocks the conversion of testosterone to dihydrotestosterone, the potent androgen upon which the development of the prostate gland is dependent. Dutasteride is a second-generation 5α-reductase inhibitor. It inhibits both type I and II 5α-reductase.
Treatment Principles
Cardinal Points of Treatment
The goals of treatment are to alleviate symptoms and to maintain kidney function. Surgery is the primary treatment for BPH. Watchful waiting is a common plan; symptoms are monitored and treatment is initiated when symptoms become problematic. One review found that 38% of symptoms actually improved and 16% stabilized over a period of 2.6 to 5 years. Surgery is indicated when the patient has refractory urinary retention, recurrent UTIs, hematuria, bladder stones, or renal insufficiency. Medical treatment for BPH is designed to address the impact these symptoms have on the patient’s quality of life, or to provide treatment when the patient is reluctant or unable to have surgery, or when the symptoms are mild enough that surgery is not warranted. Treatment decisions generally are made when the patient discusses his options with a urologist. Primary care providers often provide prescriptions and watchful waiting.
All α-blockers used in the treatment of BPH are considered equally efficacious. This was the conclusion of a meta-analysis in which 6333 patients reported that symptom scores improved by an average of 30% to 40%. Selection of one agent over another was based largely on their side effect profiles. The selective α-blockers, tamsulosin and alfuzosin, were found to be better tolerated than their nonselective counterparts in that rates of discontinuation due to side effects were comparable with those of placebo. In contrast, 8% to 20% of patients discontinued treatment with nonspecific α-blockers because of orthostatic hypotension and headache. In elderly patients, tamsulosin was found to have less effect on blood pressure than alfuzosin. Nonspecific α-blockers should be considered in patients with concomitant BPH and hypertension. If the patient does not have hypertension, tamsulosin is probably the first choice. These drugs have an onset of action of approximately 2 to 4 weeks.
Although α-blockers are best for quick symptom relief, 5α-reductase inhibitor finasteride can prevent growth of the prostate over the long term. Treatment for 1 year led to a reduction in AUA symptom scores of 23% and has been shown to reduce the need for surgery by 55% in men treated for 5 years. In general, patients with larger prostates (>40 g) at presentation have been found to derive greatest benefit from treatment with a 5α-reductase inhibitor. Dutasteride has shown to be efficacious and safe for the treatment of BPH and to have side effects comparable with those of finasteride.
The FDA has issued a warning that there is an increased risk of being diagnosed with a high-grade prostate cancer while taking 5α-reductase inhibitors. These drugs have been investigated for prostate cancer prevention in men at high risk. While there was an overall reduction in prostate cancer, there was an increase in high-grade prostate cancer. 5α-reductase inhibitors cause an about 50% reduction in prostate-specific antigen (PSA) by 6 months. Proscar also now carries a warning that some sexual adverse effects persist after discontinuing treatment, although it remains effective and safe for approved indications.
Combination therapy with finasteride and doxazosin was shown to lower the risk of clinical progression of BPH by 66%. This was evident in patients treated for longer than 4 years.
Herbal treatment with saw palmetto is popular. It acts as a 5α-reductase inhibitor and should not be used in combination with other β-α-reductase inhibitors. The longest and most clinically useful trial to date failed to demonstrate after 1 year any improvement in AUA symptom scores vs. placebo in 225 men. Research studies are inconsistent in demonstrating efficacy. Saw palmetto appears to be well tolerated and safe.
Finasteride and dutasteride are teratogenic. Tablets must not be touched by a woman who may be pregnant because the product may be absorbed through the skin. A pregnant woman should not come in contact with the semen of a man who is taking finasteride.Specific Drugs
tamsulosin (Flomax)
Hypersensitivity; concurrent use with PDE5 inhibitors such as sildenafil (>25 mg), tadalafil (if tamsulosin dose exceeds 0.4 mg/day), or vardenafil
Orthostatic hypotension with syncope, priapism, patients with severe sulfonamide allergies; may affect pupils of the eyes during cataract surgery
See Table 33-1. The short-acting drugs have an increased incidence of adverse effects because of the rapid increase in drug levels.
See Table 33-2.
TABLE 33-2
Adverse Effects of Drugs That Affect the Urinary Tract
| Drug | Adverse Effects |
| tamsulosin | Orthostasis (7%-16%), dizziness (15%-17%), somnolence, rhinitis (13%-18%), diarrhea, abnormal ejaculation (8%-18%), fatigue, headache (19%-21%) |
| alfuzosin | Dizziness (6%), syncope (rare), hypotension (rare), abnormal ejaculation has not occurred, QT interval increase (dose higher than 40 mg), fatigue (3%), headache (3%) |
| silodosin | Retrograde ejaculation (28%), orthostatic hypotension (3%), dizziness, headache, insomnia, diarrhea, abdominal pain, PSA increased, weakness, elevated liver enzymes |
| doxazosin, terazosin | Orthostatic hypotension (0.3%-2%), syncope, arrhythmias, priapism (rare), dizziness (5%-19%), headache (5%-14%), fatigue (8%-12%), edema, rhinitis, diarrhea |
| finasteride, dutasteride | Impotence (19%), decreased libido (10%), orthostasis (9%), decreased volume of ejaculate (7%), breast tenderness and enlargement, hypersensitivity reactions, including lip swelling and skin rash, testicular pain |
| sildenafil, tadalafil, vardenafil | Headaches (16%-46%), flushing (10%), dyspepsia (7%-17%), rhinitis, myalgia, abnormal vision, temporary vision loss, diarrhea, dizziness, rash, hypotension. arrhythmia, cerebrovascular hemorrhage, photosensitivity, blood dyscrasias, priapism, seizures, hearing loss |
| alprostadil injection | Penile pain (>10%), urethral burning (>10%), headache (2%-10%), dizziness (2%-10%), vaginal pain (partner; 2%-10%), increased heart rate (<2%) |
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