Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

66. Erectile Dysfunction

Mary Lee


KEY CONCEPTS

 Images The incidence of erectile dysfunction is low in men younger than 40 years of age. The incidence increases as men age, likely as a result of concurrent medical conditions that impair the vascular, neurologic, psychogenic, and hormonal systems necessary for a normal penile erection.

 Images Many commonly used drugs have sympatholytic, anticholinergic, sedative, or antiandrogenic effects that may exacerbate or contribute to the development of erectile dysfunction. Clinicians should be familiar with these agents and be prepared to make adjustments in drug regimens to minimize adverse effects of these drugs on a patient’s erectile function.

 Images The first step in clinical management of erectile dysfunction is to identify and, if possible, reverse the underlying causes. Risk factors for erectile dysfunction, including hypertension, diabetes mellitus, smoking, and chronic ethanol abuse, should be addressed and minimized.

 Images Specific treatments for erectile dysfunction include vacuum erection devices (VEDs), pharmacologic treatments, psychotherapy, and surgery. Of these, phosphodiesterase inhibitors are the medications of first choice.

 Images The ideal treatment of erectile dysfunction should have a fast onset, be effective, be convenient to administer, be cost effective, have a low incidence of serious adverse effects, and be free of serious drug interactions.

 Images Specific treatment is first initiated with the least invasive forms of treatment, including VEDs or oral phosphodiesterase inhibitors, followed by intracavernosal injections or intraurethral inserts, and finally by surgical insertion of a penile prosthesis.

 Images VEDs can have a slow onset of action (30 minutes) and are not discreet; therefore, they are most effective for a couple in a stable relationship.

 Images Although phosphodiesterase inhibitors are convenient and effective regardless of the etiology of erectile dysfunction, they fail in 30% to 40% of patients. Also, phosphodiesterase inhibitors are contraindicated in patients taking any dosage formulation of nitrate.

 Images Testosterone supplementation should be reserved for patients with primary or secondary hypogonadism who have erectile dysfunction as a consequence of a decreased libido. Testosterone supplementation should not be used by patients with erectile dysfunction who have normal serum testosterone levels.

 Images Although intracavernosal injections and intraurethral pellets of alprostadil are effective independent of the etiology of erectile dysfunction, they fail in one third of patients. To self-administer medication by these routes, patients require training to minimize administration-related adverse effects.


The National Institutes of Health Consensus Development Panel on Impotence defines erectile dysfunction as the persistent failure to achieve a penile erection to allow for satisfactory sexual intercourse.1 A persistent failure refers to erectile dysfunction for a minimum of 3 months.2 Patients may refer to it as impotence.

Erectile dysfunction must be distinguished from disorders of libido, ejaculatory disorders, and infertility, which are caused by different pathophysiologic mechanisms and are treated with alternative agents (Table 66-1). A patient may suffer from one or more disorders of sexual dysfunction. For example, an elderly man with primary hypogonadism may suffer from decreased libido and erectile dysfunction. Diagnosis of the type of sexual disorder that a patient has is a key to initiating the most appropriate treatment.

TABLE 66-1 Types of Sexual Dysfunction in Men

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EPIDEMIOLOGY

Images The incidence of erectile dysfunction is low in men younger than 40 years of age but increases as men age.35 The Massachusetts Male Aging Study, a cross-sectional survey of a random sample of 1,290 men in the Boston area, was conducted during the period from 1987 to 1989. The study reported an overall prevalence of 52% for any degree of erectile dysfunction in men aged 40 to 70 years, with an age-related increase in incidence ranging from 12.4% in men aged 40 to 49 years, up to 46.4% in men aged 60 to 69 years.1,3 In the more recent Health Professional Follow-Up Study of more than 31,000 male health professionals aged 53 to 90 years, the prevalence of erectile dysfunction was 33%.4 Interestingly, although the prevalence of erectile dysfunction increases with patient age, many patients fail to seek medical treatment.5

Erectile dysfunction is sometimes assumed to be a symptom of the aging process in men. However, more likely it results from concurrent medical conditions of the patient (e.g., hypertension, arteriosclerosis, hyperlipidemia, diabetes mellitus, or psychiatric disorders) or from medications that patients may be taking for these diseases.6,7 For example, up to 50% of patients with diabetes mellitus develop erectile dysfunction, and medications such as β-blockers are associated with a high incidence of erectile dysfunction.

PHYSIOLOGY OF A NORMAL PENILE ERECTION

A normal penile erection requires full functioning of several physiologic systems: vascular, nervous, and hormonal. The patient also must be psychologically receptive to sexual stimuli.8,9

Vascular System

The penis comprises two corpora cavernosa on the dorsal side and one corpus spongiosum on the ventral side. The corpus spongiosum surrounds the urethra and forms the glans penis. The corpora are composed of multiple interconnected sinuses, which can fill with blood to produce an erection. The corpora cavernosa are encased by the tunica albuginea, a fibrous tissue membrane, which has limited distensibility. In the flaccid state, arterial flow into and venous outflow from the corpora are balanced. During the erectile phase, arterial blood flow increases and blood fills the sinusoids within the corpora, which causes penile swelling and elongation. The erection is prolonged by a decrease in venous outflow from the corpora, which is caused by compression of subtunical venules against the tunica albuginea by the swollen corpora (Fig. 66-1).

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FIGURE 66-1 Microanatomy of and vascular changes in the penis in flaccid and erect states. In the flaccid state, arterial flow into and venous outflow from the corpora are balanced. During the erectile phase, arterial blood flow increases and blood fills the sinusoids within the corpora, causing penile swelling and elongation. The erection is prolonged by a decrease in venous outflow from the corpora, which is caused by compression of subtunical venules by the swollen corpora. (From Walsh PC, ed. Campbell’s Urology, 8th ed. Philadelphia, PA: WB Saunders; 2002:1595, 1697.)

Arterial flow into the corpora is enhanced by acetylcholine-mediated vasodilation. Acetylcholine indirectly enhances arterial flow to the corpora and increases sinusoidal filling of the corporal tissue. That is, acetylcholine is a coneurotransmitter, which works along with other nonpeptidergic intracellular neurotransmitters—including cyclic guanosine monophosphate (cGMP), cyclic adenosine monophosphate (cAMP), or vasoactive intestinal polypeptide—to produce vasodilation. In effect, cGMP and cAMP are secondary messengers that direct desired effects in target tissues.

Specifically, acetylcholine produces an erection probably through two different pathways. Through one pathway, in the presence of sexual stimulation to genital tissue, acetylcholine enhances the production of nitric oxide by endothelial cells and-nonadrenergic–noncholinergic neurons. Nitric oxide enhances the activity of guanylate cyclase, which increases the conversion of cyclic guanosine triphosphate to cGMP. cGMP decreases intracellular calcium concentrations in smooth muscle cells of penile arteries and cavernosal sinuses. As a result, smooth muscle relaxation occurs, which enhances arterial blood flow to and blood filling of the corpora.9 An erection results.

In an alternative pathway, acetylcholine or prostaglandin E enhances the activity of adenyl cyclase, which increases the conversion of cyclic adenosine triphosphate to cAMP, a potent muscle relaxant. Similar to cGMP, cAMP decreases intracellular calcium concentrations to produce smooth muscle relaxation in cells of the arteries and cavernosal sinuses. Arterial blood flow to and blood filling of the corpora are enhanced, and a penile erection results.9

Nervous System and Psychogenic Stimuli

Some erections are mediated by a sacral nerve reflex arc (e.g., erections can occur while the patient is sleeping). However, in the conscious patient, sensory sexual stimulation mediates erections via the CNS. That is, when a patient sees an attractive partner, hears sweet words, smells a particular scent, or tastes or touches a pleasant object, these situations can result in an erection. In this case, the patient’s brain processes this information and the nervous impulse is carried down the spinal cord to peripheral cholinergic nerves that innervate the vascular supply to the corpora, resulting in an erection.

The medial preoptic area of the hypothalamus is thought to be that portion of the brain responsible for integrating external stimuli. Here dopamine exerts a proerectogenic effect, whereas, α2-adrenergic stimulation causes the penis to become and/or remain flaccid. After moving down the spinal cord, stimulatory nerve impulses travel to the penis by efferent peripheral nerves, including inhibitory sympathetic neurons (T11–L2), proerectogenic parasympathetic neurons (S2–S4), and proerectogenic somatic neurons (S2–S4).

In summary, acetylcholine produces an erection by working along with other coneurotransmitters, including cGMP and cAMP. Thus, an erection is mediated neurologically, maintained by arterial blood filling of the corpora, and sustained by occlusion of venous outflow from the corpora.

Detumescence, or the progression of an erect penis to a flaccid state, results from the actions of norepinephrine, which contracts vascular smooth muscle to decrease arterial inflow to the corpora and contracts sinusoidal tissue in the corpora. As a result, venous outflow from the corpora increases.

Hormonal System

Testosterone is principally produced by the testes at a daily rate of 4 to 8 mg. Production follows a circadian pattern with highest blood levels in the morning and lowest levels in the evening. Physiologically active (free) testosterone comprises only 2% of circulating blood levels. About 50% to 60% of testosterone in the bloodstream is tightly bound to sex hormone-binding globulin and is inactive. The rest of circulating testosterone is reversibly bound to albumin; this portion of testosterone is in equilibrium with the free fraction.

Testosterone stimulates libido (sexual drive) and increases muscle mass in males. In some target cells with 5-α reductase, testosterone is activated to dihydrotestosterone. Dihydrotestosterone, which is more potent than testosterone, stimulates prostate gland growth, increases facial and body hair, induces baldness, and causes acne. In adipose tissue, a small portion of testosterone is converted to estradiol which can lead to gynecomastia.

Beginning at age 40 years, men experience a gradual decrease in testicular production of testosterone, with an associated decrease in muscle mass and sexual function.10 The Massachusetts Male Aging Study reported that 6% to 12% of elderly males had symptoms of hypogonadism.11

Within the normal physiologic serum total testosterone concentration range (normal, 300–1,100 ng/dL; 10.4–38.2 nmol/L), sexual drive is usually normal. However, because of variability in circulating levels of sex hormone-binding globulin, a patient’s serum concentration of testosterone should always be interpreted in the context of the patient’s symptoms and physical exam findings. To confirm hypogonadism when the serum total testosterone concentration is equivocal, the clinician should obtain a serum-free (bioavailable) testosterone level.

The relationship between erectile dysfunction and serum testosterone levels is complicated. Patients with normal serum testosterone levels may have erectile dysfunction, and patients with subnormal serum testosterone levels may have normal sexual function.5 When a patient has hypogonadism and libido is decreased, a patient may not develop erections. In this case, erectile dysfunction is considered secondary to a decreased libido.

PATHOPHYSIOLOGY

Erectile dysfunction can result from any single abnormality or combination of abnormalities of the four systems necessary for a normal penile erection. Vascular, neurologic, or hormonal etiologies of erectile dysfunction are collectively referred to as organic erectile dysfunction. Approximately 80% of patients with erectile dysfunction have the organic type. Patients who do not respond to psychogenic stimuli and have no organic cause for dysfunction have psychogenic erectile dysfunction.

Diseases that compromise vascular flow to the corpora cavernosum (e.g., peripheral vascular disease, arteriosclerosis, and essential hypertension) are associated with an increased incidence of erectile dysfunction. Diseases that impair nerve conduction to the brain (e.g., spinal cord injury or stroke) or conditions that impair peripheral nerve conduction to the penile vasculature (e.g., diabetes mellitus) can result in erectile dysfunction.7

Diseases associated with hypogonadism, primary or secondary, result in subphysiologic levels of testosterone, which cause diminished sexual drive (decreased libido) and secondary erectile dysfunction. Primary hypogonadism can be associated with the normal aging process in men or surgical removal of the testes for treatment of prostate or testicular cancer. Secondary hypogonadism may result from hypothalamic or pituitary disorders of luteinizing hormone–releasing hormone or luteinizing hormone, respectively; or elevated prolactin levels, which can be associated with pituitary tumors or can occur in patients with chronic renal failure.

Patients must be in the proper mental frame of mind to be receptive to sexual stimuli. Patients who suffer from malaise, have reactive depression or performance anxiety, are sedated, have Alzheimer’s disease, have hypothyroidism, or have mental disorders commonly complain of erectile dysfunction. In most studies, patients with psychogenic erectile dysfunction generally exhibit a higher response rate to various interventions than do patients with organic erectile dysfunction because the former have less severe disease.

Social habits of patients have been linked to erectile dysfunction. The vasoconstrictor effect of cigarette smoking may compromise blood flow to the corpora and decrease cavernosal filling. Excessive ethanol intake may lead to androgen deficiency, peripheral neuropathy, or chronic liver disease, all of which can contribute to erectile dysfunction.

Images Medications may cause erectile dysfunction through similar pathophysiologic mechanisms (Table 66-2).1214 Medications are estimated to be responsible for approximately 10% to 25% of cases of erectile dysfunction.

TABLE 66-2 Medication Classes That Can Cause Erectile Dysfunction

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DIAGNOSIS

With the availability in the late 1990s of effective medications for erectile dysfunction independent of the etiology, diagnostic evaluation of erectile dysfunction became streamlined. Key assessments include a description of the severity of erectile dysfunction, complete medical, psychosocial, and surgical histories, review of concurrent medications, physical examination, and selected clinical laboratory tests.8,15

To assess the severity of erectile dysfunction, the patient should be asked about the quality of sexual intercourse for the past 4 weeks to 6 months. A self-administered standardized questionnaire, such as the International Index of Erectile Dysfunction (IIEF), is often used. It is administered before initiation of any treatment and repeated at regular intervals during treatment. It includes 15 questions about the quality of sexual function and satisfactoriness of sexual intercourse.16 Questions include the following: How often were you able to maintain an erection? How difficult was it to sustain an erection? How satisfied are you with your sexual life? The physician should carefully assess the expectations for erectile function of the patient and the partner to ensure that expectations are reasonable. Shorter versions of the IIEF and other self-reporting questionnaires are also used in clinical practice. For example, the IIEF-EF comprises the six questions from the IIEF that focus on erectile function. The patient responds to each question, each response is scored on a range of 1 to 5. A score of 26 to 30 is considered normal function, 22 to 25 is mild erectile dysfunction, 17 to 21 is mild-to-moderate erectile dysfunction, 11 to 16 is moderate erectile dysfunction, and 10 or less is severe erectile dysfunction.

A medical history should be obtained to identify concurrent medical illnesses (e.g., hypertension, atherosclerosis, hyperlipidemia, diabetes mellitus, and depression) or surgical procedures (e.g., perineal or pelvic) that are risk factors for or are associated with organic or psychogenic erectile dysfunction. Underlying diseases that do not optimally respond to treatment should be addressed before specific treatment for erectile dysfunction is initiated. If the patient smokes cigarettes, drinks excessive amounts of ethanol, or uses recreational drugs, these social habits should be discontinued before specific treatment for erectile dysfunction is started.


CLINICAL PRESENTATION Erectile Dysfunction

General

    • Men are affected emotionally in many different ways

    • Depression

    • Performance anxiety

    • Marital difficulties and avoidance of sexual intimacy (patients are often brought to a physician by their partners)

    • Nonadherence to medications patient believes are causing erectile dysfunction

Symptoms

    • Erectile dysfunction or inability to have sexual intercourse

Signs

    • If completing an International Index of Erectile Dysfunction survey, results are consistent with low satisfaction with the quality of erectile function

    • Medical history may identify concurrent medical illnesses, past surgical procedures that interfere with good vascular flow to the penis or damage nerve function to the corpora, or mental disorders associated with decreased reception of sexual stimuli

    • Medication history may reveal prescription or nonprescription medications that could cause erectile dysfunction

    • Physical examination may reveal signs of hypogonadism (e.g., gynecomastia, small testicles, decreased body hair or beard, and decreased muscle mass), which may contribute to erectile dysfunction. The patient may have an abnormally curved penis when erect, decreased pulses in the pelvic region (suggesting impaired vascular flow to the penis), or decreased anal sphincter tone (suggesting impaired nerve function to the corpora). Men older than 50 years should undergo a digital rectal examination to determine whether an enlarged prostate is contributing to the patient’s erectile dysfunction

Laboratory Tests

    • If the patient has signs of hypogonadism and complains of decreased libido, a serum testosterone concentration may be below the normal range, which would be consistent with a hormonal cause of erectile dysfunction

    • If the patient has an enlarged prostate noted on digital rectal examination, a blood sample for prostate-specific antigen should be obtained. If elevated, the patient should be evaluated for a prostate disorder, which could contribute to erectile dysfunction

A complete listing of the patient’s prescription and nonprescription medications and dietary supplements should be reviewed by the clinician, who should identify drugs that may be contributing to erectile dysfunction. If possible, causative agents should be discontinued or the dose should be reduced.

A physical examination of the patient should include a check for hypogonadism (i.e., signs of gynecomastia, small testicles, and decreased beard or body hair). The penis should be evaluated for diseases associated with abnormal penile curvature (e.g., Peyronie’s disease), which are associated with erectile dysfunction. Femoral and lower extremity pulses should be assessed to provide an indication of vascular supply to the genitals. Anal sphincter tone and other genital reflexes should be checked for the integrity of the nerve supply to the penis. A digital rectal examination in patients 50 years or older is needed to rule out benign prostatic hyperplasia, which may contribute to erectile dysfunction.

Selected laboratory tests should be obtained to identify the presence of underlying diseases that could cause erectile dysfunction. They include a fasting serum blood glucose and lipid profile. Serum testosterone levels should be checked in patients older than 50 years and in younger patients who complain of decreased libido and erectile dysfunction. At least two early morning serum testosterone levels on different days are needed to confirm the presence of hypogonadism.17

Finally, erectile dysfunction is a potential marker for arteriosclerosis. Therefore, older patients and those at intermediate and high risk for cardiovascular disease should undergo a cardiovascular risk assessment before starting on drug treatment for erectile dysfunction. By doing so, patients will be categorized into low-, intermediate-, or high-risk groups for cardiovascular morbidity related to sexual intercourse. Patients in the intermediate-risk group should undergo additional testing to reclassify them into the low- or high-risk group. The high-risk group should defer sexual activity. Patients in the low-risk group may start specific treatment for erectile dysfunction.8,1820

TREATMENT

Erectile Dysfunction

Desired Outcomes

The goal of treatment is improvement in the quantity and quality of penile erections suitable for intercourse and considered satisfactory by the patient and his partner. Simple as this may sound, healthcare providers must ensure that patients and their partners have reasonable expectations for any therapies that are initiated. Furthermore, only patients with erectile dysfunction should be treated. Patients who have normal sexual function should not seek—or be encouraged to seek—treatment in an effort to enhance sexual function or enable increased activity. In addition, treatment should be well tolerated and be of reasonable cost.

General Approach to Treatment

Images The Third Princeton Consensus Conference is a widely accepted multidisciplinary approach to managing erectile dysfunction that maps out a stepwise treatment plan.2022 The first step in clinical management of erectile dysfunction is to identify and, if possible, reverse underlying causes. Risk factors for erectile dysfunction, including hypertension, coronary artery disease, dyslipidemia, diabetes mellitus, smoking, or chronic ethanol abuse, should be addressed and minimized. Patients should follow a heart-healthy lifestyle, which includes physical fitness, weight loss to achieve a normal body mass index, low cholesterol diets, no excessive ethanol intake, and no smoking.23 In some cases, these types of interventions are sufficient to restore erectile function.24 However, if erectile dysfunction does not respond to these measures, specific treatment is indicated.

For patients with psychogenic erectile dysfunction, psychotherapy can be used as monotherapy or as an adjunct to specific treatments for the disorder. To enhance the relevance of psychotherapy, both the patient and the partner should be included in the counseling sessions. Treatment should be individualized and should address immediate factors that may be causing performance anxiety or depression. The effectiveness of psychotherapy is generally low, and long-term psychotherapy is often necessary.

Images Images Images Specific treatments of erectile dysfunction include vacuum erection devices (VEDs), pharmacologic treatments, and surgery. The ideal treatment of this disorder should have a fast onset, be effective, be convenient to administer, be cost-effective, have a low incidence of serious adverse effects, and be free of serious drug interactions (Table 66-3). Generally, when choosing from among treatment approaches, those that are least invasive are selected first; more invasive therapies are reserved for patients who do not respond to first-line agents.

TABLE 66-3 Dosing Regimens for Selected Drug Treatments for Erectile Dysfunction

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The American Urological Association Guideline on the Management of Erectile Dysfunction,15 the 2009 International Consultation of Sexual Medicine,25 and the American College of Physicians2 clearly identify oral phosphodiesterase inhibitors for first-line treatment. VEDs, intracavernosal injection of erectogenic agents, or intraurethral prostaglandin inserts are second-line treatments; prescribing of a particular agent for a patient should be individualized. Surgical intervention should be reserved for patients who fail to respond to first- and second-line treatments. A sample algorithm that guides selection of treatment is shown in Figure 66-2.

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FIGURE 66-2 Algorithm for selecting treatment for erectile dysfunction.

Vacuum Erection Device

A VED has two parts: a pump, which generates a negative vacuum pressure; and a cylinder, which is closed at one end and into which the penis is inserted. The patient inserts his penis into the open end of the cylinder, which is then pushed up flush against his lower abdomen to create a vacuum chamber. Then the patient activates the pump to produce a vacuum pressure, which draws arteriolar blood into the corpora cavernosa. To prolong the erection, the patient can use constriction bands or tension rings, which are placed at the base of the penis, to keep the arteriolar blood in and reduce venous outflow from the penis. With the assistance of loading cones to protect the glans, these bands or rings can be rolled over the glans penis and up the erect penile shaft. Alternatively, they can be first threaded onto the plastic cylinder before the penis is inserted. Once the penis is erect, the band or ring can be rolled off the cylinder onto the base of the penis (Fig. 66-3). However, some patients prefer to apply the band or ring before the penis is erect.26,27

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FIGURE 66-3 Technique for using a vacuum erection device. (From Osbon Erec Aid Esteem Vacuum Therapy System User Guide. Eden Prairie, MN: TIMM Medical Technologies, http://www.timmmedical.com/_l/pdf/timm-brochure-2012.pdf. Reprinted with permission.)

Images The onset of action of the VED is 3 to 20 minutes. VEDs are not discreet. That is, a patient’s use of a VED is evident to the partner. For this reason, VEDs appear to work best in older patients who are married or who have stable sexual relationships. In this group, VEDs could be considered first-line therapy, and the overall satisfaction rate can be as high as 60% to 80% (range, 27–94%).26,27 VEDs may be used as second-line therapy in patients who do not respond to oral phosphodiesterase inhibitors, which includes patients who have had radical prostatectomy26 or those who do not respond to injectable drug treatments for erectile dysfunction. The combination of a VED with intracavernosal or intraurethral alprostadil26 or a phosphodiesterase inhibitor28 is associated with a higher efficacy rate than use of the VED alone. As a result, combination therapy sometimes is attempted before penile prosthesis surgery is considered in the patient who fails VED monotherapy.

Patients may discontinue using VEDs because they are inconvenient and or not discreet. It has been reported that 20% to 50% and 50% to 64% of initial users continue with VEDs after 1 year and 5 years, respectively.26,29 Also, 6% to 11% of partners complain that the penis is cool to the touch or is discolored (bluish) in appearance, particularly when constriction bands are used.

VEDs are available with battery-operated pumps, which offer convenience, particularly in patients with arthritis of the hands. The American Urological Association recommends the use of commercially available VEDs by prescription only. These have safety mechanisms that minimize the likelihood of excessively high vacuum pressures which can cause penile discomfort and injury.15

Pain or injury from VEDs most often is caused by the constriction bands used to sustain an erection. Because these rings trap blood in the corpora and reduce arteriolar flow into the penis, the penile shaft may feel cold and numb. If the constriction bands are applied for longer than 30 minutes, the penile shaft may turn blue and hurt. Patients may complain that a hinge-like erection is produced in that the penis pivots on the rubber ring or tension band. Patients sometimes fail to ejaculate.

VEDs are contraindicated in patients with sickle cell disease. These patients are prone to priapism, which can be exacerbated by the use of constriction bands with VEDs. The devices also should be used cautiously by patients taking oral anticoagulants because warfarin, through a poorly understood and idiosyncratic mechanism, can cause priapism.

Phosphodiesterase Inhibitors

Mechanism

In the presence of sexual stimulation, nitric oxide is released by neurons and endothelial cells in cavernosal tissue, thereby enhancing the activity of guanylate cyclase, the enzyme responsible for conversion of guanylate triphosphate to cGMP (Fig. 66-4).30 cGMP is a vasodilatory secondary messenger that upregulates the response to nitric oxide by activating protein kinase G. This decreases intracellular calcium levels, resulting in smooth muscle relaxation, enhanced arterial flow to the corpora cavernosa, and enhanced blood filling of cavernosal sinuses.30 Catabolism of cGMP in cavernosal tissue is mediated by phosphodiesterase isoenzyme type 5.

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FIGURE 66-4 Mechanism of action of phosphodiesterase inhibitors. All inhibit catabolism of cGMP, a vasodilatory secondary messenger. (cGMP, cyclic guanosine monophosphate; NANC, nonadrenergic noncholinergic.)

Four competitive, reversible inhibitors of the phosphodiesterase isoenzyme type 5 found in genital tissue are marketed for erectile dysfunction in the United States (Table 66-4). Chemically, they are nonhydrolyzable analogs of cGMP and they act by decreasing catabolism of cGMP. However, phosphodiesterase isoenzyme type 5 is also found in peripheral vascular tissue, tracheal smooth muscle, and platelets. Inhibition of phosphodiesterase in these nongenital tissues can produce unwanted effects.30

TABLE 66-4 Pharmacodynamics and Pharmacokinetics of Phosphodiesterase Inhibitors

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The four marketed phosphodiesterase inhibitors differ in their degree of selectivity in inhibiting phosphodiesterase isoenzyme type 5 and other phosphodiesterase isoenzymes, pharmacokinetic profiles, drug–food interactions, and adverse effects (see Table 66-4).

Efficacy

Because of their apparent effectiveness, convenient route of administration, and comparatively low incidence of serious adverse effects, phosphodiesterase inhibitors are considered first-line therapy for erectile dysfunction, particularly in younger patients. They allow for discreet use. Although not based on direct comparison trials, all four commercially available phosphodiesterase inhibitors are considered to be equally effective.31,32 Patient preference studies show that some patients may prefer one agent over another based on the preferences of the patient or partner; or the onset, duration, or cost of treatment.33Usual starting and maintenance dose regimens are included in Table 66-3.

In the presence of sexual stimulation and in doses of 25 to 100 mg, sildenafil produces satisfactory erections in 56% to 82% of patients, independent of the etiology of erectile dysfunction. Similar results are documented in the product labeling for the other agents in this class (65–80% for vardenafil, 62–77% for tadalafil, and 50–55% for avanafil). Response rates in the lower range for phosphodiesterase inhibitors have been documented in patients with diabetes mellitus or after radical prostatectomy, or those with severe vascular disease, probably due to neuropathy or surgery-related nerve damage, respectively, in which nitric oxide availability is compromised.6,15,34 The effectiveness of the drugs appears to be dose related.

Images Approximately 30% to 40% of patients do not respond to phosphodiesterase inhibitors.15 At least half of nonresponders can benefit from education on proper use of the drugs.34,35 Therefore, follow-up is always recommended after a phosphodiesterase inhibitor is initiated. Education of patients should include the following points: (a) patients must engage in sexual stimulation (foreplay) for the best response; (b) sildenafil and vardenafil should be taken on an empty stomach, at least 2 hours before meals, for the fastest response, but tadalafil and avanafil can be taken without regard to meals; (c) patients who do not respond to the first dose should continue with the phosphodiesterase inhibitor for at least five to eight doses before failure is declared, as increasing success rates are reported with sequential dose administration; (d) some patients require dosage titration up to 100 mg sildenafil, 20 mg vardenafil, 20 mg tadalafil, or 200 mg avanafil for a response; (e) patients should avoid excessive alcohol intake, which can cause drowsiness and hypotension and worsen erectile dysfunction; (f) involvement of the sexual partner can help improve the patient’s response to treatment; and (g) treatment of concomitant medical illnesses which contribute to erectile dysfunction (e.g., diabetes mellitus, hypertension, and hypogonadism) should be optimized. If the patient has depression because of divorce or loss of a sexual partner, or has performance anxiety, psychologic counseling may be helpful.21

The phosphodiesterase inhibitors should not be used by patients with normal erectile function. Also, according to FDA-approved labeling, the drugs should not be used in combination with other forms of therapy for erectile dysfunction because prolonged erections (which may lead to priapism) may result.15,36 Also, phosphodiesterase inhibitors should be avoided in patients predisposed to developing priapism, including men with sickle cell anemia, leukemia, or multiple myeloma.

Long-term use of phosphodiesterase inhibitors for five to six consecutive years continues to be effective and is not associated with tachyphylaxis. The voluntary discontinuation rate among patients who respond to phosphodiesterase inhibitors is less than 2% per year.3638


Clinical Controversy…

Whether tachyphylaxis develops with long-term use of phosphodiesterase inhibitors is unclear. Some patients continue to respond to the medication even after many years of regular use. Other patients eventually become nonresponsive to treatment. This lack of response could be due to tachyphylaxis, or it could be due to worsening erectile dysfunction.

Despite the initial effectiveness of phosphodiesterase inhibitors and the measures to salvage patients with re-education, some patients will show minimal or no response to maximum doses of a phosphodiesterase inhibitor. Various strategies have been attempted in this subgroup of patients, including the following:

   1. The effectiveness of switching from one phosphodiesterase inhibitor to another when the patient does not respond to an initial agent is controversial. In one study, vardenafil was beneficial in patients who did not respond to sildenafil.39 However, less than 5% of patients who fail to respond to a phosphodiesterase inhibitor experience benefit from switching to another phosphodiesterase inhibitor.34 Controlled clinical trials in larger patient groups are needed before this strategy is used as routine treatment.

   2. High-dose phosphodiesterase inhibitor treatment (e.g., sildenafil 200 mg) has been used anecdotally. However, such doses are also associated with a higher frequency of adverse effects.40

   3. In patients with primary hypogonadism and erectile dysfunction, correcting the former with testosterone supplementation improves the response to a phosphodiesterase inhibitor.41

   4. Phosphodiesterase inhibitors have been combined with intracavernosal or intraurethral alprostadil in selected patients.42,43


Clinical Controversy…

For patients who fail to respond to a particular phosphodiesterase inhibitor, a common strategy employed is to switch the patient to another phosphodiesterase inhibitor. Although a low percentage of patients respond to the switch, most patients do not. The benefit of switching from one agent to another is controversial.

Selectivity of Other Phosphodiesterase Isoenzymes

More than 25 different phosphodiesterase isoenzymes have been identified; however, the physiologic effects of stimulation and inhibition of some of these isoenzymes remain to be elucidated. Of note, phosphodiesterase isoenzyme type 6 is localized to the rods and cones of the eye. Inhibition of this isoenzyme has been associated with blurred vision and cyanopsia. Sildenafil is the most potent inhibitor of phosphodiesterase isoenzyme type 6, vardenafil and avanafil are intermediate inhibitors, and tadalafil is the least potent inhibitor.32 Likewise, phosphodiesterase isoenzyme type 11 is localized to striated muscle. Inhibition of this isoenzyme has been associated with myalgia and muscle pain. Tadalafil exerts the greatest inhibitory activity against phosphodiesterase type 11.9

Pharmacokinetics and Drug–Food Interactions

Pharmacokinetic parameters of the phosphodiesterase inhibitors are listed in Table 66-4.

Sildenafil and the conventional oral formulation of vardenafil have similar pharmacokinetic profiles. Both drugs have a 1-hour onset of action and short duration of action. Oral absorption is significantly delayed by 1 hour when either drug is taken within 2 hours of a fatty meal. In contrast, tadalafil has a slower onset of action of 2 hours, has a prolonged duration of action up to 36 hours, and food does not affect its rate of absorption. Thus, tadalafil offers greater spontaneity for patients, as one dose can last through an entire weekend and allows for multiple acts of sexual intercourse over multiple days with a single dose.31,32 An oral disintegrating tablet formulation of vardenafil, which dissolves on the tongue, has 1.2- to 1.4-fold higher bioavailability than the conventional oral tablet. The oral disintegrating tablet formulation is not susceptible to the drug–food interaction of the conventional oral tablet, which is an advantage for some patients.44 Avanafil has an onset and duration similar to sildenafil and vardenafil, but food does not significantly affect its rate or extent of absorption.

The onset of action of these agents has undergone reexamination to assess how soon after drug administration patients can expect to have an erection suitable for intercourse. Although up to 50% of patients may develop an erection within 20 to 30 minutes of sildenafil 100 mg, vardenafil 20 mg, tadalafil 20 mg, or avanafil 200 mg, the rest of the patients may require a full hour to achieve an adequate erectile response.45 Therefore, patients should be instructed to allow adequate time for the drug to work. In addition, sildenafil and vardenafil have been reported to be effective in some patients up to 12 hours after dosing, which is long after plasma concentrations have declined. It has been hypothesized that this may be due to the continued intracellular action of the phosphodiesterase inhibitor.4649

Concomitant ingestion of ethanol with phosphodiesterase inhibitors can result in orthostatic hypotension and drowsiness. Therefore, the manufacturer recommends that patients avoid ethanol when taking these medications.

All four phosphodiesterase inhibitors are hepatically catabolized principally by the cytochrome P450 3A4 microsomal isoenzyme and by other P450 isoenzymes (minor routes) and/or other hepatic enzymes (Table 66-4). Sildenafil has an active metabolite, which is excreted primarily in the urine. Tadalafil has a clinically insignificant active metabolite; however, 36% of the parent drug is renally eliminated. Thus, both sildenafil and tadalafil doses should be reduced in patients with significant renal impairment. Vardenafil and avanafil have active metabolites that are largely excreted in feces; no dosage reduction of vardenafil is required in patients with renal impairment (see Table 66-3).

Dosing

The usual oral doses of the phosphodiesterase inhibitors are listed in Table 66-3. Sildenafil, vardenafil, and avanafil should be taken on demand at least 30 to 60 minutes before sexual intercourse. Tadalafil should be taken at least 2 hours before sexual intercourse. The durations of action for sildenafil, vardenafil, and avanafil are 4 to 5 hours, whereas the effects of tadalafil last for 36 hours. The agents vary as to whether doses must be adjusted for patients 65 years and older and those with compromised hepatic or renal function. Patients should be advised to take not more than the amount prescribed and to use only one dose per day (or less often in the case of most patients taking tadalafil). Doses higher than those recommended have been described in the published literature (e.g., sildenafil 200 mg40); however, such dosing regimens have not consistently produced improved erectile responses.

For patients who do not respond to an adequate course of on-demand phosphodiesterase inhibitors for erectile dysfunction, daily low dosing of these agents may improve endothelial function in cavernosal tissue. That is, regular use of phosphodiesterase inhibitors may activate endothelial nitric oxide synthase, increase local concentrations of cGMP, which may lead to increased oxygen tension, improved blood flow, and reduced endothelial damage and cavernosal fibrosis. A preliminary clinical trial of daily use of tadalafil 2.5 or 5 mg showed a 58% frequency of successful sexual intercourse compared with conventional on-demand use of tadalafil 5 to 20 mg, which produced a 21% frequency of success.48,50 Other potential advantages of daily low dosing regimens include a lower potential for dose-related adverse effects, lower cost, and increased spontaneity of sexual intercourse.51 However, a disadvantage of the daily low-dose regimen is that patients with more severe erectile dysfunction, who may require higher doses of a phosphodiesterase inhibitor, may not respond.51 Although clinical trials of daily dosing of tadalafil 10 and 20 mg,51 and sildenafil 50 and 100 mg52,53 have been published, the only FDA-approved labeling is for daily dosing of tadalafil 2.5 or 5 mg.

Adverse Effects

Most adverse effects of the phosphodiesterase inhibitors are mild or moderate and are self-limited, and patients often become tolerant to them with continued use.54,55 The rates of drug discontinuation caused by adverse effects are low, ranging from 2.1% to 25%, and are similar for all four agents. In usual doses, the most common adverse effects are headache (11%), facial flushing (12%), dyspepsia (5%), nasal congestion (3.4%), and dizziness (3%),56 all of which are dose-related and result from vasodilation or smooth muscle relaxation secondary to inhibition of phosphodiesterase isoenzyme type 5 in extragenital tissues.

Sildenafil and vardenafil produce an 8- to 10-mm Hg decrease in systolic and a 5- to 6-mm Hg decrease in diastolic blood pressure starting approximately 1 hour after a dose is taken and lasting for 4 hours. Most patients are asymptomatic as a result of these blood pressure changes, but some patients, particularly those taking multiple antihypertensives or nitrates or those with baseline hypotension, may develop clinical symptoms as a consequence of these peripheral vascular effects. Avanafil can produce similar decreases in blood pressure, especially when used along with other antihypertensives or α-adrenergic antagonists. Tadalafil does not produce decreases in blood pressure, but it must be used with caution in patients with cardiovascular disease because of the cardiac risk inherent to sexual activity. A management approach for such patients, developed based on an analysis of deaths in men who were using sildenafil and commonly referred to as the recommendations of the Princeton Consensus Guideline Conference III,20 should be applied to all the phosphodiesterase inhibitors (Table 66-5).

TABLE 66-5 Recommendations of the Third Princeton Consensus Conference for Cardiovascular Risk Stratification of Patients Being Considered for Phosphodiesterase Inhibitor Therapy

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Sildenafil, vardenafil, and avanafil cause increased sensitivity to light, blurred vision, or loss of blue–green color discrimination in 2% to 3% of patients. The adverse effect is dose-related with the incidence increasing to 40% to 50% in patients taking sildenafil 200 mg.57 These effects result from inhibition of phosphodiesterase type 6 in the photoreceptor cells of in retinal rods and cones. Visual adverse effects commonly occur at the time of peak serum concentrations. Although visual adverse effects are mild and reversible, caution regarding use is recommended for airplane pilots, who rely on green and blue lights for landing planes. Avanafil has moderate and tadalafil has minimal to no inhibitory activity against type 6 phosphodiesterase, and a lower incidence of visual adverse effects (less than 1%) has been reported.31,58 Nevertheless, according to current product labeling, all phosphodiesterase inhibitors should be used cautiously in patients at risk for retinitis pigmentosa, a genetic disease associated with retinal phosphodiesterase deficiency.

Nonarteritic anterior ischemic optic neuropathy (NAION) is a sudden, unilateral, painless blindness, which may be irreversible. Isolated cases of NAION have been associated with phosphodiesterase inhibitor use.58 NAION has developed at variable and unpredictable times after starting a phosphodiesterase inhibitor, ranging from 6 hours to months or years after the first dose.57 Although a cause-and-effect relationship has not been definitively established, the blood pressure-lowering effects of these medications may decrease blood flow to the optic nerve and lead to a sudden unilateral decrease in vision.58Because NAION may lead to permanent vision loss, the FDA has required inclusion of warnings on the product labeling of phosphodiesterase inhibitors. Specifically, before receiving these agents, patients at risk for NAION should be evaluated by an ophthalmologist, risk factors for NAION should be addressed, and the patient should be cautioned against using a phosphodiesterase inhibitor.

Patients at risk include a wide variety of patients: those with glaucoma, macular degeneration, diabetic retinopathy or hypertension, those who have undergone eye surgery or have experienced eye trauma, patients who are age 50 years or more, or smokers. A patient who experiences sudden vision loss in one eye while taking a phosphodiesterase inhibitor should be evaluated for NAION before continuing treatment. If NAION is present, the phosphodiesterase inhibitor should be discontinued as there is a 15% to 25% risk of developing NAION in the other eye in the ensuing 5 to 10 years.57,58

Tadalafil produces lower back and limb muscle pain, which occur in a dose-related fashion in 7% to 30% of patients treated with doses of 10 to 100 mg.31 The mechanism for this is not known. It may be linked to inhibition of type 11 phosphodiesterase, a unique characteristic of tadalafil.

Vardenafil can cause prolongation of the QT interval. Therefore, it should be used cautiously in patients with this anomaly or in patients who are taking class IA or III antiarrhythmic medications that prolong the QT interval (e.g., quinidine, procainamide, amiodarone, and sotalol).

Acute unilateral hearing loss has also been reported after use of a phosphodiesterase inhibitor. A cause–effect relationship has not been established. In the cases reported, the hearing loss occurred within 1 day of starting treatment; it was variably accompanied by tinnitus or vertigo, and often resulted in residual hearing loss despite discontinuation of the phosphodiesterase inhibitor.59,60

Priapism is a rare adverse effect of phosphodiesterase inhibitors, particularly sildenafil and vardenafil, which have shorter plasma half-lives than tadalafil. Priapism has been associated with excessive doses of the phosphodiesterase inhibitor or concomitant use with other erectogenic drugs.

Recommendations for adverse effect monitoring are included in Table 66-6.

TABLE 66-6 Drug Monitoring Table

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Drug Interactions

Patients taking organic nitrates may develop severe hypotension if they are taken with phosphodiesterase inhibitors as a result of two major factors: (a) organic nitrates on their own produce hypotension, and (b) organic nitrates are nitric oxide donors, which can stimulate the activity of guanylate cyclase and increase tissue levels of cGMP. For this reason, use of phosphodiesterase inhibitors is contraindicated in patients taking nitrates given by any route at scheduled times or intermittently.20,61 Furthermore, nitrates should be withheld for 24 hours after sildenafil or vardenafil administration and for 48 hours after tadalafil administration.20,61 Finally, if a patient who has taken a phosphodiesterase inhibitor requires medical treatment of angina, non–nitrate-containing agents (e.g., calcium channel blocker, β-adrenergic antagonist, and morphine) should be used.

If severe hypotension occurs after exposure to nitrates and a phosphodiesterase inhibitor, the patient should be placed in a Trendelenburg position and aggressive fluid administration initiated. If severe hypotension continues, parenteral β-adrenergic agonists (e.g., dopamine) should be administered cautiously.

Interestingly, dietary sources of nitrates, nitrites, or L-arginine (a precursor for nitrates) do not interact with phosphodiesterase inhibitors. This is because dietary sources do not increase circulating levels of nitric oxide in humans.

The phosphodiesterase inhibitors have a low potential to interact with antihypertensive medications.62 In retrospective analyses of patients taking sildenafil in combination with α-adrenergic antagonists, β-adrenergic antagonists, diuretics, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or calcium channel blockers, the incidence of hypotension was similar to that reported in patients taking sildenafil alone.63 This finding was confirmed by a retrospective analysis of pooled data on more than 4,800 patients in 35 clinical trials.64

Small decreases in blood pressure with clinically symptomatic hypotension have been described in some patients taking phosphodiesterase inhibitors and α-adrenergic antagonists. The degree of hypotension that develops is dependent on several factors: (a) stability of patient’s blood pressure prior to taking both drugs; (b) dose of the α-adrenergic antagonist used; (c) particular α-adrenergic antagonist used; (d) particular phosphodiesterase inhibitor used; and (e) timing of administration of both drugs. The drug interaction produces less hypotension when the patient has stable blood pressure prior to taking both drugs; a low dose of α-adrenergic antagonist is taken; a uroselective (e.g., tamsulosin or silodosin) or extended-release formulation of α-adrenergic antagonist (e.g., alfuzosin, or modified-release doxazosin) is used; tadalafil is preferentially prescribed over sildenafil, vardenafil, or avanafil; and when there is an interval of 4 to 6 hours between the dosing of the α-adrenergic antagonist and phosphodiesterase inhibitor.62,6467

Hepatic metabolism of all three phosphodiesterase inhibitors can be inhibited by enzyme inhibitors of CYP 3A4, including cimetidine, erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, saquinavir, and grapefruit juice.64 Lower starting doses should be used in these patients to minimize dose-related adverse effects, including cyanopsia, hypotension, flushing, nasal congestion, and priapism (see Table 66-4).

Testosterone Replacement Regimens

Mechanism

Images Testosterone replacement regimens supply exogenous testosterone and restore serum testosterone levels to the normal range (300 to 1,100 ng/dL; 10.4 to 38.2 nmol/L). In so doing, testosterone replacement regimens correct symptoms of hypogonadism, which include malaise, loss of muscle strength, depressed mood, and decreased libido. Testosterone can directly stimulate androgen receptors in the CNS and is thought to be responsible for maintaining normal sexual drive. In addition, testosterone may stimulate nitric oxide synthase, thereby increasing cavernosal concentrations of nitric oxide, and enhancing the effects of phosphodiesterase type 5 in cavernosal tissue.68

Indications

Testosterone replacement regimens are indicated in symptomatic patients with primary or secondary hypogonadism, as confirmed by both the presence of a decreased libido and low serum concentrations of testosterone.2 Primary hypogonadism can be a characteristic of aging men who undergo andropause, in which the Leydig cells of the testes slowly and progressively decrease testosterone production.69 This is often referred to as late-onset hypogonadism, symptomatic late-onset hypogonadism andropause, or the male menopause. Symptoms include decreased libido, erectile dysfunction, gynecomastia, small testes, reduced growth of body hair and beard, decreased muscle mass, and increased body fat. If left untreated, patients develop anemia and osteoporosis.

Serum testosterone concentrations typically are measured in the early morning (approximately 8 am) because the secretion pattern of this hormone follows a circadian pattern, with highest serum concentrations in the morning hours and the lowest level at night (approximately 10 pm). A low measured serum testosterone level is confirmed with a repeat measurement on a separate day. Simultaneous serum luteinizing hormone levels help to distinguish patients with primary hypogonadism, who have elevated luteinizing hormone levels, from those with secondary hypogonadism, who have decreased luteinizing hormone levels.2,69

Testosterone replacement regimens should never be administered to men with normal serum testosterone levels, or in patients with isolated erectile dysfunction as the only sign of hypogonadism.2,6870

Efficacy

Testosterone replacement regimens restore muscle strength and sexual drive and improve mood in patients with hypogonadism. Improvements are generally observed within days or weeks of the start of testosterone replacement. Administration of testosterone will correct the serum testosterone level to the normal range. No additional benefit has been demonstrated for large doses of testosterone, which increase the serum testosterone level from the low end to the upper end of the normal range or to the above-normal range.70 Testosterone replacement regimens do not directly correct erectile dysfunction; instead, they improve libido, thereby correcting secondary erectile dysfunction.70

Testosterone replacement regimens can be administered orally, bucally, parenterally, or transdermally (Tables 66-3 and 66-7). Injectable testosterone replacement regimens are the preferred treatment for symptomatic patients with primary or secondary hypogonadism because they are effective, inexpensive, and not associated with the bioavailability problems or hepatotoxic adverse effects of oral androgens.2,6870 Although convenient for the patient, testosterone patches, gels, and sprays are much more expensive than other forms of androgen replacement; therefore, they should be reserved for patients who refuse injectable testosterone.

TABLE 66-7 Comparison of Testosterone Replacement Regimens and Ideal Testosterone Replacement Regimen

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In the ideal testosterone replacement regimen, the medication would mimic the normal circadian pattern of serum testosterone concentrations such that peak and trough concentrations occur in the early morning and late afternoon, respectively; produce serum concentrations in the normal range; produce serum concentrations of dihydrotestosterone and estradiol, which are metabolites of testosterone that mimic the normal physiologic pattern; and produce minimal adverse effects.70 Table 66-7 compares commercially available testosterone replacement regimens for these characteristics and shows that an ideal regimen has yet to be identified.

Pharmacokinetics

Natural testosterone has poor oral bioavailability because of extensive first-pass hepatic metabolism; therefore, large doses must be taken. To improve oral bioavailability, alkylated derivatives were formulated. Of these derivatives, methyltestosterone and fluoxymesterone are more resistant to hepatic catabolism and can be taken in smaller daily doses, which are potentially safer. However, oral alkylated derivatives of testosterone are not metabolized to dihydrotestosterone or estradiol, are associated with a higher incidence of serious hepatotoxicity, and therefore are not preferred for management of hypogonadism.

An alternative to oral administration is the testosterone buccal system (Striant), which is applied to the gum above the upper incisor teeth twice per day. Over time it forms a gel from which testosterone is absorbed. One advantage of this route of administration is that the drug bypasses first-pass hepatic catabolism, which allows for increased bioavailability of testosterone. Serum testosterone levels are maintained in the normal range for approximately 80% of the day.71

Several testosterone esters have been formulated for intramuscular injection, with different durations of action (see Table 66-3). The shorter-acting testosterone propionate, which requires dosing three times per week, has been replaced with testosterone cypionate or enanthate, which can be dosed every 2, 4, or 6 weeks in most patients. These testosterone formulations produce suprapharmacologic patterns of serum testosterone during the dosing interval, which have been linked to mood swings in some patients. An even longer-acting parenteral testosterone is available as a subcutaneous implant for dosing every 3 to 6 months. Although this schedule minimizes repeat visits to the clinician’s office for dosing, the implant must be administered by a physician, and the implanted pellet may be extruded after administration. This extrusion has been reported in up to 8.5% of treated patients and results in loss of drug effect.

Topical testosterone replacement regimens can be delivered as once-daily patches or gel. Testosterone patches increase serum testosterone levels into the normal range in 2 to 6 hours. Serum testosterone levels return to baseline 24 hours after patch administration. However, unlike oral or injectable supplements, transdermal testosterone patches applied at bedtime or testosterone gel applied each morning produce physiologic patterns of serum testosterone levels throughout the day. The clinical importance of this biochemical effect is unknown.68,72

The original Testoderm brand patch was formulated for scrotal application. Scrotal skin is thinner and has a richer vascular supply than does the skin on the arms or thighs. Therefore, application of Testoderm patches produced excellent absorption of the hormone. However, the patch could detach when the scrotum became damp or moist, when the patient exercised, or if the scrotum was excessively hairy.72

For improved convenience, Androderm patches were formulated for application to the upper arms, back, abdomen, or thighs. The addition of absorption enhancers and different adhesives has been linked to a higher incidence of contact dermatitis with Androderm patches compared with the original Testoderm scrotal patch.72

Testosterone gel 1% formulation (AndroGel) is applied in much larger doses (5 or 10 g each day) to the skin of the shoulders, upper arms, or abdomen. The hormone is absorbed quickly, within 30 minutes, but several hours may be required for complete absorption of the dose. For this reason, the patient should be reminded to wait at least 2 hours after application before showering. To prevent inadvertent transfer of testosterone gel to others, the patient should thoroughly wash his hands with soap and water after administration of a dose, allow the application site to dry undisturbed for several minutes before dressing or covering it, and ensure that there is no contact with clothing contaminated with the gel by children and female members of the household.

Dosing

Table 66-3 lists the usual doses for testosterone replacement regimens. Two to three months is considered an adequate treatment trial with a particular dose. Thus, a dose should not be increased until the patient has used one particular dose for at least this time period.69 The serum testosterone level should return to the normal range and symptoms of androgen deficiency should be relieved with appropriate dosing. After starting treatment, the patients should be reassessed in 1 to 3 months. If the patient is responding to treatment and serum testosterone levels have returned to normal, then the patient can be followed up annually. At each visit, the use of a validated self-assessment tool (e.g., Androgen Deficiency in Aging Men Questionnaire) can assist the physician in gauging the patient’s response to treatment.73

Before initiating any testosterone replacement regimen in patients 40 years and older, patients should be screened for breast cancer, benign prostatic hyperplasia, and prostate cancer. All are testosterone-dependent conditions and theoretically could be worsened by exogenous administration of testosterone. Untreated prostate cancer is a contraindication to androgen supplementation. To screen for prostate disorders, a prostate-specific antigen serum concentration should be obtained and a digital rectal examination of the prostate performed. These tests are generally repeated at 1-year intervals after treatment is started.6870

Adverse Effects

Testosterone replacement regimens can cause sodium retention, which can cause weight gain, or exacerbate hypertension, congestive heart failure, and edema. Gynecomastia can occur as a result of conversion of testosterone to estrogen in peripheral tissues. This has been reported most often in patients with liver cirrhosis.

Although serum lipoprotein perturbations may occur, testosterone replacement regimens have a neutral effect in that they decrease both total cholesterol and high-density lipoprotein cholesterol levels. No cases of cardiovascular disease have been reported with testosterone replacement regimens.

Large doses of parenteral testosterone can produce adverse metabolic effects. Thus, patients on long-term testosterone replacement regimens must undergo clinical laboratory testing for a serum testosterone level and hematocrit before starting treatment and every 6 to 12 months during treatment.70 Repeated serum testosterone levels that exceed the normal range require a dosage reduction or increased interval between drug doses. If the hematocrit exceeds 55% (0.55), the testosterone replacement regimen should be withheld to avoid polycythemia and its consequences.

Oral alkylated testosterone replacement regimens have caused hepatotoxicity, ranging from mild elevations of hepatic transaminases to serious liver diseases, including peliosis hepatis (hemorrhagic liver cysts), hepatocellular and intrahepatic cholestasis, and benign or malignant tumors. For this reason, parenteral testosterone replacement regimens are preferred.

Topical testosterone patches may cause contact dermatitis, which responds well to topical corticosteroids. This adverse effect has been associated with the presence of permeation enhancers, which are added to patch formulations. If the dermatitis becomes problematic, an alternative is testosterone gel formulations, which are associated with a lower incidence of contact dermatitis compared with patches.

Alprostadil

Mechanism

Alprostadil, also known as prostaglandin E1, stimulates adenyl cyclase, resulting in increased production of cAMP, a secondary messenger that decreases the intracellular calcium concentration and causes smooth muscle relaxation of the arterial blood vessels and sinusoidal tissues in the corpora. This results in enhanced blood flow to and blood filling of the corpora. Because it does not require nitric oxide to produce its clinical effects, patients with erectile dysfunction due to diseases that are associated with an impaired nitric oxide pathway (e.g., diabetes mellitus, postradical prostatectomy, and who have failed phosphodiesterase treatment) may respond to alprostadil.74 In one study, 88% of men who failed to respond to sildenafil responded to intracavernosal alprostadil.75

Alprostadil is commercially available as an intracavernosal injection (Caverject and Edex) and as an intraurethral insert (medicated urethral system for erection [MUSE]).

Indications

Both commercially available formulations of alprostadil are FDA approved as monotherapy for management of erectile dysfunction. Alprostadil is more effective by the intracavernosal route than the intraurethral route.

The enhanced efficacy of the intracavernosal injection may be related to the excellent bioavailability of the drug when injected directly into the corpora cavernosum. In contrast, intraurethral alprostadil doses generally are several hundred times larger than intracavernosal doses. This is because intraurethral alprostadil must be absorbed from the urethra, through the corpus spongiosum, and into the corpus cavernosum, where it exerts its full proerectogenic effect.

Although several other agents, including papaverine, phentolamine, and atropine, have been used off-label for intracavernosal therapy, alprostadil is preferentially prescribed. This is because intracavernosal alprostadil has been FDA approved for erectile dysfunction, it does not require extemporaneous compounding, and it has a low potential for causing prolonged erections and priapism.

Both formulations of alprostadil are considered more invasive than VEDs or phosphodiesterase inhibitors. For this reason, intracavernosal alprostadil is generally prescribed after patients do not respond to or cannot use less invasive interventions. Intracavernosal alprostadil is preferred over intraurethral alprostadil because of its greater effectiveness. Intracavernosal alprostadil may be preferred in patients with diabetes mellitus, who are accustomed to injectable drug therapy and may have peripheral neuropathies, which decrease the patient’s perception of pain upon injection. Intraurethral alprostadil is generally reserved as a treatment of last resort for patients who do not respond to other less invasive and more effective forms of therapy, and who refuse surgery.

Intracavernosal Alprostadil

Efficacy The overall efficacy of intracavernosal alprostadil is 70% to 90%.68,76 Three characteristics of intracavernosal alprostadil include the following:

   1. The effectiveness of alprostadil is dose related over the range of 2.5 to 20 mcg. The mean duration of erection is directly related to the dose of alprostadil administered and ranges from 12 to 44 minutes.

   2. A higher percentage of patients with psychogenic and neurogenic erectile dysfunction respond to alprostadil at a lower dose compared to patients with vasculogenic erectile dysfunction.

   3. Tolerance does not appear to develop with continued use of intracavernosal alprostadil at home.

Images Although 70% to 75% of patients respond to intracavernosal alprostadil, a high proportion of patients elect to discontinue its use over time. Depending on the study and the length of observation, 30% to 50% of patients voluntarily discontinue therapy, usually during the first 6 to 12 months. Common reasons for discontinuation include lack of perceived effectiveness; inconvenience of administration; an unnatural, nonspontaneous erection; needle phobia; loss of interest; and cost of therapy.15,7678

Approximately one third of patients do not respond to usual doses of intracavernosal alprostadil. In these patients, intracavernosal alprostadil has been used successfully along with VEDs. Such combination therapy can be attempted by patients before transitioning to more invasive surgical procedures.76,78 Alternatively, intracavernosal injections of synergistic combinations of vasoactive agents that act by different mechanisms have been used.77Intracavernosal drug combinations typically produce an erection that lasts longer than an erection produced by any one of the agents in the mixture. In addition, because of the low dosage of each agent in the combination, fewer systemic and local fibrotic adverse effects develop compared with high-dose monotherapy. For example, when used in low-dose combination regimens, papaverine is less likely to induce hypotension and liver dysfunction, and phentolamine is less likely to induce tachycardia and hypotension.76 However, as previously mentioned, such intracavernosal drug combinations are not commercially available and must be extemporaneously compounded.

Pharmacokinetics Intracavernosal injection should be administered into only one corpus cavernosum. From this injection site, the drug will reach the other corpus cavernosum through vascular communications between the two corpora. Alprostadil acts rapidly, with an onset of 5 to 15 minutes. The duration is directly related to the dose. Within the usual dosage range of 2.5 to 20 mcg, the duration of erection is not more than 1 hour. Higher doses are expected to exhibit a longer duration of action. Local enzymes in the corpora cavernosum quickly metabolize alprostadil. Any alprostadil that escapes into the systemic circulation is deactivated on first pass through the lungs.76Hence, the plasma half-life of alprostadil is approximately 1 minute, and the potential for systemic adverse effects is negligible. Dose modification is not necessary in patients with renal or hepatic disease.

Dosing The usual dose of intracavernosal alprostadil is 10 to 20 mcg, with a maximum recommended dose of 60 mcg. Doses greater than 60 mcg have not produced any greater improvement in penile erection but may cause hypotension or prolonged erections lasting more than 1 hour.78 The dose should be administered 5 to 10 minutes before intercourse. The manufacturer recommends that patients be slowly titrated up to the minimally effective dosage to minimize the likelihood of hypotension. Under a physician’s supervision, patients should be started with a 1.25-mcg dose, which can be increased in increments of 1.25 to 2.50 mcg at 30-minute intervals up to the lowest dose that produces a firm erection for 1 hour and does not produce adverse effects. In clinical practice, this process is rarely done because it is time consuming. Thus, many physicians start the patient on 10 mcg and move quickly up the dosage range to identify the best dose for the patient. To avoid adverse effects, patients should receive not more than one injection per day and not more than three injections per week (Table 66-3).

Intracavernosal injections should be performed using a 0.5-inch, 27- or 30-gauge needle. A tuberculin syringe or a syringe prefilled with diluent as supplied by the manufacturer should be used to ensure precise measurement of doses. Patients with needle phobia, poor vision, or poor manual dexterity can use commercially available autoinjectors (e.g., PenInject) to facilitate administration of intracavernosal alprostadil.

Intracavernosal injections require that the patient or the sexual partner practice good aseptic techniques (to avoid infection), have good manual skills and visual ability, and be comfortable with injection techniques. When practicing self-injection, the patient should use one hand to firmly hold the glans penis against his thigh to expose the lateral surface of the shaft. The injection should be made at right angles into one of the lateral surfaces of the proximal third of the penis. The injection should never be made into the dorsal or ventral surface of the penis. This will prevent inadvertent injection of the drug into arteries on the dorsal surface or the urethra on the ventral surface. After the injection, the penis should be massaged to help distribute the drug into the opposite corpus cavernosum. Injection sites should be rotated with each dose. Finally, manual pressure should be applied to the injection site for 5 minutes to reduce the likelihood of hematoma formation (Fig. 66-5).

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FIGURE 66-5 Technique for administration of intracavernosal injections. (From Caverject [package insert]. New York, NY: Pfizer Inc.; 1999. Data from http://media.pfizer.com/files/products/uspi_caverject_powder.pdf.)

Once the optimal dosage of intracavernosal alprostadil is established, the patient should return for routine medical follow-up every 3 to 6 months. Some patients subsequently require dosage adjustment, largely attributed to worsening of the underlying disease that is contributing to the erectile dysfunction.

Adverse Effects Intracavernosal alprostadil is most commonly associated with local adverse effects, which occur most often during the first year of therapy. However, an improved administration technique with continued use is believed to account for the lower frequency of adverse effects during subsequent treatment periods.

Intracavernosal injections are associated with several local adverse effects. Cavernosal plaques or areas of fibrosis at injection sites form in approximately 2% to 12% of patients. When they occur, the patient should suspend further injections until the plaques resolve. These plaques may cause penile curvature, similar to Peyronie’s disease, which makes sexual intercourse difficult or impossible. The cause of corporal fibrosis and plaque formation is unknown. This adverse effect may be caused by poor injection technique or by alprostadil itself. Although patients have developed corporal fibrosis, alprostadil may be less likely to cause this adverse effect compared to other intracavernosal drug combinations, such as phentolamine or papaverine. Unlike cavernosal fibrosis associated with large doses and repeated administration of papaverine, penile scarring secondary to alprostadil appears to be unpredictable.

Alprostadil causes penile pain in approximately 10% to 44% of patients. The pain has been described as a burning discomfort or dull pain near the injection site or during the erection, which generally does not persist after the penis becomes flaccid. The pain usually is mild, generally does not require discontinuation of therapy, and often abates even with continued treatment. However, 2% to 5% of patients discontinue taking alprostadil because of severe pain. The pain can be managed by oral analgesics (e.g., acetaminophen), if necessary. One investigator has recommended adding procaine to intracavernosal alprostadil, but this may mask the signs of more serious adverse effects of the drug or of penile injury during intercourse and is not recommended.79 The mechanism of this adverse reaction is poorly understood. Alprostadil may intrinsically produce pain. In addition, the pain may be a result of the pH of the parenteral solution. Alprostadil is acidic, and the commercially available Caverject formulation is buffered with sodium citrate, a weak base, to reduce pain on injection.

Priapism, a prolonged, painful erection lasting more than 1 hour, occurs in 1% to 15% of treated patients. It occurs most often during the dose titration period and is rare thereafter. Blood sludging in the corpora can lead to tissue hypoxia and cavernosal fibrosis and scarring. The risk for this complication is greatest for erections that persist beyond 4 hours. Patients are advised to seek medical attention immediately when drug-induced erections last more than 1 hour, as this is considered a urologic emergency. Its management includes supportive care, including analgesics for pain and sedatives for anxiety. In addition, needle aspiration of sludged blood in the corpora or intracavernosal injection of α-adrenergic agonists (e.g., phenylephrine) has been used. These procedures facilitate venous drainage of the corpora, allowing venous outflow to “catch up” with arterial inflow.

The likelihood of prolonged erections with intracavernosal alprostadil is dose related. Therefore, to prevent this adverse effect, the lowest effective dose should be used, and the dose should be titrated to ensure that the duration of the erection is not more than 1 hour.

Other local adverse effects include injection site hematomas and bruising. These effects are largely the result of poor injection technique. To minimize the risk of injection site hematomas, patients should be advised to apply pressure to the injection site for 5 minutes after each dose. Similarly, infection at the injection site has been reported. Meticulous aseptic technique is necessary to prevent this complication.

Intracavernosal alprostadil rarely causes systemic adverse effects, owing to the agent’s local catabolism in cavernosal tissue and rapid deactivation in pulmonary tissue (if any of the drug escapes into the systemic circulation). However, large doses greater than 20 mcg are associated with dizziness and hypotension in some patients and is one reason why such large doses are not commonly used.

Intracavernosal injection therapy should be used cautiously by patients at risk for priapism, including patients with sickle cell disease, leukemia, or multiple myeloma. It should be used cautiously by patients who may develop bleeding complications secondary to injections, including patients with thrombocytopenia or those taking anticoagulants. It also should be used cautiously by patients who use poor-quality injection technique, including patients with psychiatric disorders, obese patients (who may not be able to reach or see the penile injection site), patients who are blind, and patients with severe arthritis.

Intraurethral Alprostadil

Efficacy Images Intraurethral alprostadil inserts are marketed as MUSE, which contains a medication pellet inside a prefilled urethral applicator. Multiple studies show this product has an overall effectiveness rate of 43% to 65%78compared with 70% to 90% for intracavernosal alprostadil. Its decreased effectiveness and inconvenient administration method have resulted in this product being considered a third-line treatment option for patients with erectile dysfunction. However, some patients have responded to intraurethral alprostadil even though they did not respond to intracavernosal alprostadil80 or sildenafil.81

Intraurethral alprostadil has been combined with an adjustable penile constriction band to improve treatment response.81

Pharmacokinetics Following intraurethral instillation, alprostadil is absorbed quickly through the urethra, into the corpus spongiosum, and then into the corpora cavernosum. As much as 90% of each dose is absorbed by the urethra and corpus spongiosum in less than 10 minutes, with peak absorption occurring in 20 to 25 minutes. An estimated 20% of each dose is delivered to the corpora cavernosum. As with intracavernosal injections of alprostadil, any drug absorbed into the systemic circulation is rapidly metabolized on first pass through the lungs.

The onset after intraurethral insertion is similar to that of intracavernosal injection, 5 to 10 minutes.

Dosing The usual dose of intraurethral alprostadil is 125 to 1,000 mcg. The dose should be administered 5 to 10 minutes before sexual intercourse. Not more than two doses per day are recommended. Before administration, the patient should be advised to empty his bladder, voiding completely (Table 66-3).

Similar to intracavernosal injection treatments, intraurethral insertion of alprostadil requires good manual and visual skills to minimize the risk of urethral injuries. Intraurethral alprostadil is supplied in a prefilled intraurethral applicator. The patient should void first. With one hand the patient holds the glans penis, and with the other hand the patient inserts the intraurethral applicator 0.5 inch (1.3 cm) into the urethra. The drug pellet is then pushed into the urethra. The penis should be massaged to enhance drug dissolution in the urethral fluids and drug absorption (Fig. 66-6).

Images

FIGURE 66-6 Technique for administration of intraurethral alprostadil with a medicated urethral system for erection applicator. (From Muse [package insert]. Mountain View, CA: Vivus, Inc.; 2003. Data from http://www.vivus.com.)

Adverse Effects The urethra can be injured because of an improper administration technique. Injuries can lead to urethral stricture and difficulty voiding. Patients should receive complete education about optimal administration procedures before starting treatment.

Urethral pain has been reported in 24% to 32% of patients. Usually it is mild and does not require discontinuation of treatment. Female sexual partners may experience vaginal burning, itching, or pain, which probably is related to transfer of alprostadil from the man’s urethra to the woman’s vagina during intercourse.

Prolonged painful erections (priapism) have been rarely reported. Syncope and dizziness have been reported rarely (only 2–3% of patients) and likely are related to use of excessively large doses.

Intraurethral alprostadil should be avoided in patients with urethral stricture or urethritis.


Clinical Controversy…

Although not recommended by the manufacturer, combinations of erectogenic medications or use of erectogenic medications with VEDs is a common practice. Published clinical trials of good research design are often lacking. Use of such combinations must take into consideration the published data available to support the use, potential adverse effects of the combination, and cost.

Unapproved Agents

A variety of other commercially available and investigational agents have been used for management of erectile dysfunction. Although it is beyond the scope of this chapter to discuss all of them, some of the more commonly used agents are discussed here.

Trazodone

The mechanism by which trazodone produces an erection is not clear. It likely acts peripherally to antagonize α-adrenergic receptors. As a result, a predominant cholinergic effect results, which causes peripheral arteriolar vasodilation and relaxation of cavernosal tissues, enhancing blood filling of the corpora. Intracavernosal injection of trazodone in experimental studies supports this likely mechanism.82

Although some clinical trials suggested that trazodone 50 to 200 mg daily by mouth might be effective in the management of erectile dysfunction, these trials were generally poorly controlled, were nonrandomized, included small samples treated for short time periods, and did not include validated objective parameters of response.82,83

The adverse effects of trazodone, when used for erectile dysfunction, are similar to those reported with trazodone when used to treat depression and include dry mouth, sedation, and dizziness.

Yohimbine

Yohimbine, a tree-bark derivative also known as yohimbe, is widely used as an aphrodisiac. Yohimbine is a central α2-adrenergic antagonistic that increases catecholamines and improves mood. Some investigators believe that yohimbine has peripheral proerectogenic effects. Yohimbine may reduce peripheral α-adrenergic tone, thereby permitting a predominant cholinergic tone, which could result in a vasodilatory response.76,78 The usual oral dose is 5.4 mg three times per day.

A controlled clinical trial has shown that high-dose yohimbine (100 mg daily) is not more effective than placebo.84 Based on a meta-analysis of published studies that came to the same conclusion, the American Urological Association has cautioned against the use of yohimbine.15 In addition, yohimbine can cause many systemic adverse effects, including anxiety, insomnia, tachycardia, and hypertension.

Papaverine

Papaverine is a nonspecific phosphodiesterase inhibitor that decreases metabolic catabolism of cAMP in cavernosal tissue. As a result of enhanced tissue levels of cAMP, smooth muscle relaxation occurs. Cavernosal sinusoids fill with blood, and a penile erection results.

Papaverine is not FDA approved for erectile dysfunction. Intracavernosal papaverine alone is not commonly used for management of erectile dysfunction because the large doses required produce dose-related adverse effects, such as priapism, corporal fibrosis, hypotension, and hepatotoxicity.76,85 Papaverine is more often administered in lower doses combined with phentolamine and/or alprostadil. A variety of formulas have been used, but no one mixture has been proven better than other mixtures. Combination formulations are considered safer and are associated with the potential for fewer serious adverse effects than high doses of any one of these agents.

A portion of each papaverine dose is systemically absorbed, and its prolonged plasma half-life of 1 hour contributes to adverse effects. The usual dose of papaverine is 7.5 to 60 mg when used as a single agent for intracavernosal injection. When used in combination, the dose decreases to 0.5 to 20 mg.

If treated with papaverine, patients with a history of underlying liver disease or alcohol abuse should undergo liver function testing at baseline and every 6 to 12 months during continued treatment.

Phentolamine

Phentolamine is a competitive nonselective α-adrenergic blocking agent. It reduces peripheral adrenergic tone and enhances cholinergic tone. As a result, it improves cavernosal filling and is proerectogenic.

Phentolamine has most often been administered as an intracavernosal injection. Monotherapy is avoided because large doses are required for an erection, and at these large doses systemic hypotensive adverse effects would be prevalent. Most often, phentolamine has been used in combination with other vasoactive agents for intracavernosal administration. A ratio of 30 mg papaverine to 0.5 to 1 mg phentolamine is typical, and the usual dose ranges from 0.1 to 1 mL of the mixture. Such a mixture promotes local effects of phentolamine and minimizes systemic hypotensive adverse effects.

Hypotension is the most common adverse effect of intracavernosal phentolamine. It is more common and more severe with large doses or in patients with a poor injection technique who have injected into a vein (rather than the cavernosa). Prolonged erections have been reported in patients who used excessive doses of intracavernosal medications in combination.

Penile Prostheses

Surgical insertion of a penile prosthesis is the most invasive treatment of erectile dysfunction. It is reserved for patients who do not respond to or who are not candidates for less invasive oral or injectable treatments.

Prosthesis insertion requires anesthesia and skilled urologists. Two prostheses are widely used: malleable and inflatable. Malleable or semirigid prostheses consist of two bendable rods that are inserted into the corpora cavernosa. The patient appears to have a permanent erection after the procedure; the patient is able to bend the penis into position at the time of intercourse.

The inflatable prosthesis has several mechanical parts. The inflatable prosthesis produces a more natural erection. The patient develops an erection only when the device is activated. Some newer advances in inflatable prosthesis technology have resulted in devices with fewer mechanical parts. These devices can be placed during shorter surgical procedures and have a low 5-year mechanical failure rate (6% to 10%) as compared with the original inflatable prostheses (Fig. 66-7).15,76,86

Images

FIGURE 66-7 Example of surgically implanted penile prosthesis. (a, activation mechanism; b, reservoir with fluid for inflating prosthesis; c, inflatable rods in corpora.) (From http://kidney.niddk.nih.gov/kudiseases/pubs/impotence.)

Penile prostheses provide penile rigidity suitable for vaginal intercourse and are associated with a greater than 90% patient satisfaction rate, which is generally higher than that observed with any other drug treatment or VED.87The surgical success rate after insertion is 82% to 98%.76

Adverse effects of prosthesis insertion can occur early or late after the surgical procedure. The most common early complication is infection. Late complications include mechanical failure of the prosthesis, particularly when an inflatable prosthesis has been inserted. With improved technology, the mechanical failure rate has decreased to 5%.76 Other late complications include erosion of the rods through the penis or late-onset infection. Although some salvage procedures have been devised, in many cases the prosthesis requires removal.

Personalized Pharmacotherapy

For the management of erectile dysfunction, treatment selection must be individualized based on the patient’s preferences for and perception of the effectiveness of various treatment options and potential adverse effects.

In general, patients prefer a discreet form of treatment that is not obvious to the sexual partner and that does not require careful attention to timing of administration relative to sexual intercourse. Because treatment for erectile dysfunction is not included as a covered item on many insurance plans, the cost of treatment is likely to be a consideration for most patients.

For patients with both moderately symptomatic benign prostatic hyperplasia and erectile dysfunction, a reasonable approach is the use of daily tadalafil, which should be effective for both conditions.

For patients who fail treatment with a single medication, a VED, a combination drug regimen, or surgical intervention are options.

EVALUATION OF THERAPEUTIC OUTCOMES

The primary therapeutic outcomes of specific treatments for erectile dysfunction include (a) improvement in the quantity and quality of penile erections suitable for intercourse and (b) avoidance of adverse drug reactions and drug interactions.

At baseline and after the patient has completed a clinical trial period of 1 to 3 weeks with a specific treatment for erectile dysfunction, the physician should conduct assessments to determine whether the quality and quantity of penile erections has improved. A patient’s level of satisfaction is highly individualized, depending on his lifestyle and expectations. Therefore, a patient who has successful intercourse once per week might be completely satisfied, whereas another patient might judge this to be unsatisfactory. Patients with unrealistic expectations in this regard must be identified and counseled by clinicians to avoid adverse effects of excessive use of erectogenic agents.

Failure to improve the quality and quantity of penile erections suitable for intercourse after an appropriate clinical trial period with a specific treatment for erectile dysfunction occurs in a significant percentage of patients. In this case, physicians generally take the following steps in order:

   1. Ensure that the patient has been prescribed a maximum tolerated dose and has an adequate clinical trial of a specific treatment before discarding it as ineffective.

   2. Switch to another drug (see Fig. 66-2).

   3. Reserve surgical treatment for patients who do not respond to drug treatment.

CONCLUSIONS

Erectile dysfunction is a common disorder of aging men. Its incidence is higher in patients with underlying medical disorders that compromise the vascular, neurologic, hormonal, or psychogenic systems necessary for a normal penile erection. Medications are common causes of erectile dysfunction. By correcting the underlying etiology, erectile dysfunction can often be reversed without the use of specific treatments.

When treatments of erectile dysfunction are needed, the least invasive forms of treatment should be used first because they produce the lowest incidence of serious adverse effects. VEDs or phosphodiesterase inhibitors are considered first-line treatments. If these treatments fail, intracavernosal alprostadil injection therapy can be initiated. If this treatment fails, the patient can attempt a combination of intracavernosal alprostadil plus VED, combination intracavernosal therapy, or intraurethral alprostadil. If this treatment fails, the patient may require insertion of a penile prosthesis.

Some insurance companies do not reimburse for drug treatments for erectile dysfunction, so cost is an important issue for some patients.

Clinicians should provide clear and simple advice. Patient confidentiality and privacy, which are extremely important to men with erectile dysfunction, should be maintained at all times.

ABBREVIATIONS

Images

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