Erectile dysfunction (ED) is the failure to achieve a penile erection suitable for sexual intercourse. Patients often refer to it as impotence.
ED can result from an abnormality in one of the four systems necessary for a normal penile erection or from a combination of abnormalities. Vascular, nervous, or hormonal etiologies of ED are referred to as organic ED. Abnormality of the fourth system (i.e., patient’s psychological receptivity to sexual stimuli) is referred to as psychogenic ED.
The penis has two corpora cavernosa, which have many interconnected sinuses that fill with blood to produce an erection. The penis also has one corpus spongiosum, which surrounds the urethra and forms the glans penis.
Acetylcholine works with other neurotransmitters (i.e., cyclic guanylate monophosphate [cGMP], cyclic adenosine monophosphate [cAMP], vasoactive intestinal polypeptide) to produce penile arterial vasodilation and ultimately an erection.
Causes of organic ED include diseases that compromise vascular flow to the corpora cavernosum (e.g., peripheral vascular disease, arteriosclerosis, essential hypertension), impair nerve conduction to the brain (e.g., spinal cord injury, stroke), and are associated with hypogonadism (e.g., prostate or testicular cancer, hypothalamic or pituitary disorders).
Causes of psychogenic ED include malaise, reactive depression or performance anxiety, sedation, Alzheimer’s disease, hypothyroidism, and mental disorders. Patients with psychogenic ED generally have a higher response rate to interventions than patients with organic ED.
Social habits (e.g., cigarette smoking, excessive ethanol intake) and medications (Table 81-1) can also cause ED.
Signs and symptoms of ED can be difficult to detect. The patient’s mate is often the first to report ED to the health care provider.
Emotional manifestations include depression, performance anxiety, or embarrassment.
Nonadherence to drugs thought to cause ED can be a sign of ED.
The diagnostic workup should be designed to identify underlying causes of ED.
Key diagnostic assessments include ED severity, medical history, concurrent medications, physical examination, and laboratory tests (i.e., serum blood glucose, lipid profile, thyroxine level, testosterone level).
A standardized questionnaire can be used to assess the severity of ED.
The goal of treatment is to improve the quantity and quality of penile erections suitable for intercourse.
The first step in management of ED is to identify and, if possible, reverse underlying causes. Psychotherapy can be used as monotherapy for psychogenic ED or as an adjunct to specific treatments.
Treatment options include medical devices, drugs (Table 81-2), and surgery. Although no option is ideal, the least invasive options are chosen first.
Vacuum erection devices (VEDs) are first-line therapy for older patients. VEDs should be limited to patients who have stable sexual relations, because the onset of action is slow (i.e., approximately 30 minutes).
To prolong the erection, the patient can also use constriction bands or tension rings, which are placed at the base of the penis to retain arteriolar blood and reduce venous outflow from the penis.
VEDs can be used as second-line therapy after failure of oral or injectable drugs. Adding alprostadil to a VED improves the response rate.
VEDs are contraindicated in patients with sickle cell disease. VEDs should be used cautiously in patients on warfarin because, through a poorly understood and idiosyncratic mechanism, it can cause priapism.
Phosphodiesterase decreases catabolism of cGMP, a vasodilatory neurotransmitter in the corporal tissue.
Unless otherwise stated, general information applies to the entire class of phosphodiesterase inhibitors. Sildenafil is highlighted because it was the first to be marketed and is the most thoroughly studied. The newer agents tadalafil and vardenafil have different pharmacokinetic profiles (Table 81-3), drug-food interactions, and adverse effects.
Phosphodiesterase inhibitors are selective for isoenzyme type 5 in genital tissue. Inhibition of this isoenzyme in nongenital tissues (e.g., peripheral vascular tissue, tracheal smooth muscle, and platelets) can produce adverse effects.
Phosphodiesterase inhibitors are first-line therapy for younger patients. Sildenafil, 25-100 mg, induces satisfactory erections in 56% to 82% of patients. Approximately half of the remaining patients can have satisfactory responses after being instructed on proper use of phosphodiesterase inhibitors.
For the best response, patients must engage in sexual stimulation (foreplay).
For the fastest response, patients should take sildenafil on an empty stomach, at least 2 hours before meals. The other two agents can be taken without regard to meals.
For maximal absorption, patients should avoid taking sildenafil or vardenafil with a fatty meal. A fatty meal does not affect absorption of tadalafil.
If the first dose is not effective, patients should continue trying for 5 to 8 doses. Some patients benefit from titration up to 100 mg of sildenafil, 20 mg of vardenafil, or 20 mg of tadalafil.
Sildenafil and vardenafil have similar pharmacokinetic profiles with a rapid onset of action and short duration. Tadalafil has a delayed onset of action and prolonged duration. All three are metabolized by cytochrome P450 enzymes, primarily 3A4.
Patients should avoid exceeding prescribed doses because higher doses do not improve response. Depending on the phosphodiesterase inhibitor, the dose should be reduced if the patient is elderly, has renal or hepatic impairment, or receives an inhibitor of cytochrome P450 3A4 (see Table 81-3).
In usual doses, the most common adverse effects are headache, facial flushing, dyspepsia, nasal congestion, and dizziness.
Sildenafil and vardenafil decrease systolic/diastolic blood pressure by 8-10/5-6 mm Hg for 1 to 4 hours after a dose. Although most patients are asymptomatic, multiple antihypertensives, nitrates, and baseline hypotension increase the risk of developing adverse effects. Although tadalafil does not decrease blood pressure, it should be used with caution in patients with cardiovascular disease because of the inherent risk associated with sexual activity.
Guidelines are available for stratifying patients on the basis of their cardiovascular risk.
Sildenafil is contraindicated in patients at risk of ophthalmologic problems (e.g., retinitis pigmentosa) and should be used with caution by pilots who rely on blue and green lights to land airplanes. Sildenafil should be used cautiously in patients taking aspirin or other antiplatelet agents and in patients with bleeding tendencies.
Tadalafil inhibits type 11 phosphodiesterase, which is thought to account for the dose-related back and muscle pain seen in 7% to 30% of patients.
Testosterone-replacement regimens restore serum testosterone levels to the normal range (300 to 1100 ng/dL). These regimens are indicated for symptomatic patients with hypogonadism as confirmed by low testosterone concentrations.
Instead of directly correcting ED, testosterone-replacement regimens correct secondary ED by improving libido. Usually within days or weeks of starting therapy, they restore muscle strength and sexual drive and improve mood.
Testosterone can be replaced orally, parenterally, or topically (see Table 81-2). Injectable regimens are preferred because they are effective, are inexpensive, and do not have the bioavailability problems or adverse hepatotoxic effects of oral regimens. Testosterone patches and gel are more expensive than other forms and should be reserved for patients who refuse injections.
Before starting testosterone replacement, patients 40 years and older should be screened for benign prostatic hyperplasia (BPH) and prostate cancer. To ensure an adequate treatment trial, the patient should continue treatment for 2 to 3 months.
Testosterone replacement can cause sodium retention, which can cause weight gain or exacerbate hypertension, congestive heart failure, and edema; gynecomastia; deleterious serum lipoprotein changes; and polycythemia. Exogenous testosterone can also exacerbate BPH and enhance prostate cancer growth.
Oral testosterone-replacement regimens can cause hepatotoxicity, ranging from mildly elevated hepatic transaminases to serious liver diseases (e.g., peliosis hepatitis, hepatocellular and intrahepatic cholestasis, and benign or malignant tumors).
Alprostadil, or prostaglandin E1, stimulates adenyl cyclase to increase production of cAMP, a neurotransmitter that ultimately enhances blood flow to and blood filling of the corpora.
Alprostadil is approved as monotherapy for the management of ED. It is generally prescribed after failure of VEDs and phosphodiesterase inhibitors and for patients who cannot use these therapies. Of the available routes, the intracavernosal route is preferred over the intraurethral route because of better efficacy.
Intracavernosal alprostadil is effective in 70% to 90% of patients. However, a high proportion of patients discontinue its use because of perceived ineffectiveness; inconvenience of administration; unnatural, nonspontaneous erection; needle phobia; loss of interest; and cost of therapy.
Intracavernosal alprostadil has been used successfully in combination with VEDs or vasoactive agents (e.g., papaverine, phentolamine, atropine) that act by different mechanisms. Phosphodiesterase inhibitors should not be added to intracavernosal alprostadil because the combination can cause prolonged erections and priapism.
Intracavernosal alprostadil acts rapidly with an onset of 5 to 15 minutes. The duration of action is dose related and, within the usual dosage range, lasts less than 1 hour.
The usual dose of intracavernosal alprostadil is 10 to 20 mcg up to a maximum of 60 mcg. Patients should start with 1.25 mcg, which should be increased by 1.25 to 2.50 mcg at 30-minute intervals to the lowest dose that produces a firm erection for 1 hour and does not produce adverse effects. In clinical practice, however, most patients start with 10 mcg and titrate quickly.
To minimize the risk of complications, patients should use the lowest effective dose.
Intracavernosal alprostadil should be injected 5 to 10 minutes before intercourse using a 0.5-inch, 27- or 30-gauge needle or an autoinjector. The maximum number of injections is one per day and three per week.
Intracavernosal alprostadil is most commonly associated with local adverse effects, usually during the first year of therapy. Adverse events include cavernosal plaques or fibrosis at the injection site (2% to 12% of patients), penile pain (10% to 44%), and priapism (1% to 15%). Penile pain is usually mild and self-limiting, but priapism (i.e., painful, drug-induced erection lasting more than 1 hour) necessitates immediate medical attention.
Intracavernosal injection therapy should be used cautiously in patients at risk of priapism (e.g., sickle cell disease or lymphoproliferative disorders) and bleeding complications secondary to injections.
Intraurethral alprostadil, 125 to 1000 mcg, should be administered 5 to 10 minutes before intercourse. Before administration, the patient should empty his bladder and void completely. The maximum number of doses is one per day.
Intraurethral administration is associated with pain in 24% to 32% of patients, which is usually mild and does not require discontinuation of treatment. Prolonged painful erections are rare.
Female partners may experience vaginal burning, itching, or pain, which is probably related to transfer of alprostadil from the man’s urethra to the women’s vagina during intercourse.
Many other remedies are used, which may or may not be effective.
Examples of other agents include trazodone (50 to 200 mg/day), yohimbine (5.4 mg three times daily), papaverine (7.5 to 60 mg [single agent therapy] or 0.5 to 20 mg [combination therapy] intracavernosal injection), and phentolamine (1 mg [combination therapy] intracavernosal injection).
Surgical insertion of a penile prosthesis, the most invasive treatment for ED, is used after failure of less invasive treatments and for patients who are not candidates for other treatments.
After a penile prosthesis is inserted, the corporal tissue is destroyed and the patient will no longer have a response to oral or intracavernosal vasoactive therapies or VEDs.