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Priapism

Priapism is a very uncommon adverse event; however, due to its serious consequences of corporal scarring and possible irreversible damage, the patient is instructed to seek immediate medical attention for a painful erection lasting longer than 4 hours. Pharmacologic reversal of a prolonged erection less than 24 hours duration may be accomplished with phenylephrine solution, a vasoconstricting agent. An intermittent injection of 200 mcg/mL phenylephrine is administered to the side of the shaft of the penis every 10 minutes or until the erection has subsided (maximum of 10 injections). According to an impotent diabetes patient, another method to treat priapism is to use a nasal decongestant such as Neo-Synephrine. The action of Neo-Synephrine through the mucous membrane of the nasal passages also affects the penis, causing the erection to shrink. Blood pressure and heart rate should be monitored every 30 minutes since vasoconstrictors can increase blood pressure and heart rate. For priapism over 24 hours, corporal irrigation and aspiration is indicated. If the patient is concerned about a prolonged erection after 3 1/2 to 4 hours several other techniques can be employed that may prevent priapism. These include having the patient put a cold washcloth on the erect penis. Another approach: have the patient ejaculate an additional time or two and do mild exercise by walking around the block once or twice. Erections that last longer than 4 hours are a concern and pharmacological reversal should be seriously considered.

Patient Evaluation

Evaluation of the patient with erectile dysfunction should begin with a history and physical exam. Patients with psychological or neurological impotence will respond to lower doses of vasoactive agents. Psychological erectile dysfunction usually is sudden in onset and occurs in specific situations. Organic erectile dysfunction is gradual in onset and is consistently present. The history should establish onset, how long the problem has been present, and whether the erectile dysfunction is complete or partial. Risk factors should be identified such as current medications, tobacco and alcohol use, evidence of vascular, endocrine or neurologic disease, hypertension, hyperlipidemia, and surgery or trauma to the genital or pelvic region.

The physical exam should include evaluation of the penis for fibrous nodules or Peyronie’s disease, the perineum, rectum and testes. Neurologic dysfunction is assessed by squeezing the glans penis and performing perineal scratch, which causes the anus to tighten. A scratch near the scrotum should cause the testicles to contract. The prostate also should be assessed. Laboratory tests include morning free and total testosterone concentrations. In some patients with partial erectile dysfunction, testosterone replacement may improve erectile dysfunction; however, patients should be warned that it may improve libido without affecting potency. Decreased potency may also be a feature of hyperprolactinemia caused by drug use, renal failure or pituitary tumor; thus, prolactin also should be measured.

Future Treatment

Several companies are developing methods of administering prostaglandin E1 through intra-urethral administration or via topical gels that penetrate the skin to administer the smooth muscle relaxant. Clinical testing is now being performed to see if these formulations will result in an erection without the patient having to inject the smooth muscle relaxants. The Medicated Urethral System for Erection (MUSE) has concluded clinical trials and market clearance has been granted by the FDA. This product uses alprostadil administered by a novel transurethral delivery system. Sixty-five percent of the patients treated using the MUSE system achieved penile rigidity and/or full enlargement.

Doses between 125, 250, 500 and 1000 mcg were studied. The efficacy of alprostadil was similar regardless of age or the cause of erectile dysfunction, including vascular disease, diabetes, surgery, and trauma (P<0.001 for all comparisons with placebo). The most common side effect was mild penile pain, which occurred after 10.8% of alprostadil treatments, but the pain rarely resulted in refusal to continue in the study. Hypotension occurred in the clinic in 3.3% of men receiving alprostadil. Hypotension-related symptoms were uncommon at home. No men had priapism or penile fibrosis. Other treatments are also being investigated including a topical treatment using a cream containing aminophylline, isosorbide dinitrate, and codergocrine mesylate.

There is a great deal of excitement about the use of the oral agents milrinone and sildenfal, which are phosphodiesterase inhibitors. They are currently under investigation and are showing much promise in treating erectile dysfunction. These agents may prove a good alternative to penile injection.

Conclusion

New methods to improve the quality of life of those affected by erectile dysfunction have been developed. The role of the pharmacist in identifying patients at high risk of erectile dysfunction and beginning a positive dialog with them can have a significant impact in developing treatments that will overcome the problem. The pharmacist also has an important role in educating the patients about the proper use of medication or devices and in understanding possible problems and how to prevent or treat them.

Pharmacologic Agents

Pharmacologic treatment using vasoactive agents is now coming to the forefront as one of the most effective means of treating impotence. These agents, directly administered into the corpora cavernosum, mimic the vascular phenomenon of erection, eliciting a response within 5–10 minutes that lasts 30 minutes to one hour. The dose of the drug varies depending on the cause of the impotence, therefore a careful evaluation should be obtained before instituting treatment. Patients with arterial insufficiency, neurological or psychological erectile dysfunction generally respond to lower doses than those with veno-occlusive disease. It is important that both the patient and his partner be included in discussion and instruction regarding erectile dysfunction treatment.

Papaverine, phentolamine and alprostadil are currently used in practice. Papaverine, a smooth muscle relaxant, results in vasodilation; and alprostadil, a synthetic prostaglandin E1, relaxes the corporal smooth muscle leading to engorgement of the corpus cavernosum. Phentolamine, an a-blocker, opposes arterial constriction, increasing arterial inflow. Adverse effects of these drugs include priapism, fibrosis, penile pain and hematoma at the injection site. Papaverine carries a higher incidence of priapism than alprostadil (4% vs. 2.6%) but alprostadil has a higher rate of penile pain (41% vs. 12.5%).Fibrosis in the cavernosum occurs more frequently with papaverine than alprostadil (25.4% vs. 7.8%), however, it has been suggested that fibrosis may be prevented by careful injection technique and 3–5 minutes of compression at the injection site. These agents work synergistically and allow a smaller dose of each agent to be used, thereby decreasing side effects.Informed consent needs to be obtained since these drug combinations are not FDA approved specifically for treatment of impotence. Alprostadil, available as Caverject, is the only agent with FDA marketing approval to treat erectile dysfunction. It is packaged as a 10 or 20 mg disposable kit containing a syringe, lyophilized powder and diluent the patient mixes before injecting. Caverject is convenient but costly, approximately $17 for the 10 mcg dose and $22 for the 20 mcg dose, for each single-use kit.

Two formulations commonly used are 1) alprostadil with phentolamine and 2) alprostadil, phentolamine and papaverine combined (Table 3). Our clinic experience is that the three-drug combination produces a better erection in erectile dysfunction of vascular origin than the two-drug mixture. However, the latter is preferred in patients with purely neurogenic or psychologic erectile dysfunction, which requires much smaller doses. The patient and his partner are educated on the causes of erectile dysfunction, informed how the medication works and told of potential side effects. They are given instruction on injection technique and what to do in case of an adverse event. After signing an informed consent, the patient undergoes an in-office titration beginning with a dose of 0.01 to 0.03 mL (using a 1/2“ 29-gauge 1/2 cc insulin syringe, which corresponds to 1–3 units). The patient or his partner is instructed on injection technique and performs the titration dosing under supervision. Injections are given on the side of the shaft of the penis, in the first one-half area closest to the body, taking care to avoid visible blood vessels and alternating sides with each injection. Following injection, pressure is applied to the injection site for five minutes. This minimizes the chance of hematoma formation and may decrease fibrosis. If the response is partial, an additional 0.01 to 0.03 mL is given after approximately 15 minutes. A maximum of two doses per visit is given until a satisfactory erection is achieved. The patient is advised that he may require a lower dose at home in a more relaxed setting. No more than three injections per week may be administered no sooner than 24 hours apart. The cost of these formulations is approximately $5 per injection. After an appropriate dose is determined, the patient is given a prescription and instructed to report any adverse event with at-home use. Patients are advised not to inject if the penis is partially erect since this increases penis outflow and medication is carried away and thus less effective in developing and sustaining an erection. Follow-up is at two weeks and every 2–6 months thereafter.

Other pharmacological interventions for the treatment of erectile dysfunction include yohimbine hydrochloride, an alpha-2-adrenergic blocking agent. Yohimbine has long been considered an aphrodisiac. In a prospective double-blind placebo-controlled study in patients with predominately organic disease, including patients with diabetes related impotence, yohimbine did not show a statistically significant response rate over placebo control. Twenty-one percent of patients did have some response with yohimbine. Treatment of erectile dysfunction due to diabetes with hormones is effective only if the patient also suffers from hypogonadal disorders or hyperprolactinemia. Testosterone replacement therapy in treating diabetes related erectile dysfunction should only be prescribed if a proper workup of the patient has been done. Oral administration of testosterone is unpredictable and therefore, parenteral administration is often prescribed as testosterone enanthate, which is administered intramuscularly in doses of 200–300 mg every 2–3 weeks.

Etiology of Impotence

Vascular: The most common cause of erectile dysfunction is vascular — an impaired blood flow into (arterial insufficiency) or excess blood flow out of (veno-occlusive disease) the penis. Hypertension, hyperlipidemias, diabetes and excessive cigarette smoking are factors known to contribute to vascular impotency (Table 1).

Neurological: Nerve impulses travel from the brain down the spinal cord through the lower back and sacrum to the genital region. Nerve signals cause substances such as nitric oxide and prostaglandins to be released into the blood stream; these substances stimulate the smooth muscle in the cavernosa to relax and an erection follows. Injury to the spinal cord or groin, prostate surgery, multiple sclerosis, and neuropathy associated with diabetes or alcoholism may interrupt these nerve impulses.

Hormonal: Impotence also may be associated with hormonal imbalance. Testosterone levels normally decline with age and are associated with decreased sexual interest and fewer nighttime erections. Prolactin appears to antagonize testosterone; hyperprolactinemia may be caused by medications, such as buspirone, cimetidine, estrogens, haloperidol, enalaparil, methyldopa, metoclopramide, phenytoin, ranitidine, SSRIs and some phenothiazines, kidney failure or pituitary tumor. In these patients, restoring testosterone levels usually does not restore sexual function and the underlying cause of high prolactin levels must first be treated.

Psychological: Stress and anxiety also induce impotency by raising blood catecholamine levels which oppose smooth muscle relaxation. Fear of sexually transmitted disease, pregnancy, conflict in relationships or performance anxiety are common causes. Purely psychological erectile dysfunction is most often seen in young men, but contributes to erectile dysfunction in men whose impotence is of organic origin. Failure to achieve an erection increases anxiety with each subsequent attempt, perpetuating and compounding the problem.

Medications in certain classes such as antihypertensives, some antihistamines, antidepressants, H₂ antagonists, anorexiants, sedatives and anxiolytics have been reported to cause erectile dysfunction (Table 2). If medication is believed to be causing or contributing to the problem, an alternative drug that has a low propensity for causing impotence should be substituted when possible.

Treatment Options

Treatments for erectile dysfunction have been slow to develop, but within the past two decades major advances have been made. It is important to keep in mind when counseling your patients with diabetes to understand that successful treatment requires a patient who is willing to admit that a problem exists. The patient then needs to be willing to be counseled, have the treatment options explained and then select a treatment method to see its effect. It is very important that the patient’s partner also be educated about the erectile dysfunction treatment options and counseled about how to be helpful and supportive.

Vacuum Devices

Vacuum constriction devices are a noninvasive alternative for treatment of erectile dysfunction. A plastic cylinder is placed over the flaccid penis and the air in the cylinder is pumped out, either manually or with a battery operated pump. Negative pressure created in the cylinder draws blood into the penis by passively dilating arteries and engorging the corpus cavernosa, resulting in an erection. A constriction band is then placed at the base of the penis to prevent blood drainage and maintain the erection. Penile rigidity is improved using a double pumping technique; applying the vacuum for 1–2 minutes, then releasing it for a minute and reapplying it for 3–4 minutes. It is recommended that the constriction band be left on no longer than 30 minutes. This form of therapy is successful in erectile dysfunction of organic origin, and the majority of patients and their partners report satisfaction. Complaints include the lack of spontaneity using a mechanical device, the time involved in using the device, coldness and lifelessness of the penis, and difficulty and discomfort with ejaculation. Petechiae may develop on the skin of the penis, but no serious injury has been reported. These devices range from pumps that can be purchased from the back of sex oriented magazines for $35-$50 to battery operated devices requiring an Rx that retail for $500–$700.

Penile Prostheses

Penile prostheses are generally considered when other treatment options have failed. A semi-rigid or inflatable prosthesis that simulates an erection is surgically implanted in the penis. The patient should understand that both the appearance of the flaccid penis and the erection produced by these devices is different than normal. Mechanical failure, migration of the device, infection and scarring are complications that usually require reoperation. Improvements in the design of prostheses and in surgical techniques have reduced the incidence of complications, and patient satisfaction is usually high.

Some medical centers are now doing vascular bypass surgery to improve the flow of blood to the penis. In properly selected patients this procedure can be beneficial.

A penile support sleeve has been developed by American medtech that enables a man with a flaccid penis to enter the woman’s vagina. This enhances sexual pleasure and allows the couple to strive for intimacy whenever they choose. The product, called the Rejoyn support sleeve, fits over the penis and straps around the scrotum to provide support to the penis in order to engage in sexual intercourse.

Pharmacists can have a significant impact on the quality of life of men who suffer from erectile dysfunction. To impact the care of these patients one must first recognize that there is a potential problem and then develop sensitive communication skills to stimulate discussion with the patient and/or his significant other. This approach can help the patient understand the various treatment options that can be utilized to overcome impotence. Since pharmacists see patients more than any other health-care provider and are respected and trusted by patients, pharmacists can impact the patient’s life in a very positive way. With the baby-boomer generation reaching their middle years, erectile dysfunction (ED) will be a major concern for a high percentage of the U.S. population.

The history of treating erectile dysfunction is fascinating. At one time impotence was considered a result of witchcraft or evil-doers’ handiwork. Some church groups considered sexual problems as externally imposed disturbances of the individual. In the 19th century the medical profession began to regard sexual functioning as potentially a medical problem, but it has only been in recent decades that this subject has been confronted in a scientific manner and treatment options developed. Determining the actual frequency of erectile dysfunction is difficult, though studies have suggested a prevalence of 7%–8% of the male population. Conservative estimates are that at least 20 million American men may be unable to achieve or maintain a penile erection. The prevalence of impotence in men with diabetes is particularly high and is estimated to range from 35%–50%.

Understanding the Problem

Impotence is often referred to as erectile dysfunction, and is defined as an inability to achieve or maintain an erection sufficient for satisfactory sexual intercourse. Male sexual dysfunction may also be classified as diminished libido, dysfunction of emission, ejaculation, or orgasm; erectile dysfunction and priapism. Erectile dysfunction is a multi-factorial disorder comprising organic and psychological aspects. The likelihood of erectile dysfunction increases with age, but it is not an inevitable consequence of aging. The etiology of erectile dysfunction can be vasculogenic, neurogenic, endocrinologic, psychogenic, drug-induced or a combination of the above. Certain groups of patients have been found to have a particularly high prevalence of erectile dysfunction. In the Massachusetts Male Aging Study, aging, hypertension, heart disease and diabetes were among several physiologic variables found to predict impotence strongly. Men with diabetes had three times the probability of developing impotence than men without diabetes. Prevalence of erectile dysfunction in men with diabetes is 15% at age 30 and more than 55% by age 60. The onset of erectile dysfunction occurs earlier in the diabetes population regardless of insulin dependency status.

Physiology of Erectile Dysfunction

Impotence occurs in various degrees, and may range from an erection not rigid enough for sexual intercourse to an erection that cannot be sustained or the complete inability to achieve an erection. More recent studies estimate that between 20 and 30 million American men are affected by some degree of impotence, constituting a major health problem. Impotency is largely due to organic causes but in some cases may be psychological.Diabetes, hypertension, multiple sclerosis, and medications are but a few causes of erectile dysfunction. From progress in this field over the past decade, pharmacologic treatment has emerged as a highly successful alternative to a surgically implanted penile prosthesis or vacuum device. Depression, anger, and lack of self-esteem and self-confidence are often seen in men with erectile dysfunction. Few treatments can so greatly improve quality of life for both men with erectile dysfunction and their partners as the treatment of impotence.

A pair of long tubular-shaped structures called the corpus cavernosa originate in the body cavity and extend the length of the penis. The cavernosa is composed of thousands of tiny sacs, much like miniature balloons, each surrounded by smooth muscle. When the penis is flaccid, the tone of the muscles around these sacs is increased and keeps the sacs collapsed. With stimulation, either physical or from the brain, these muscles are signaled to relax, allowing blood to fill the tiny sacs. Encircling the cavernosa is the tunica, a tough and rather inelastic membrane just under the skin of the penis. Veins beneath the tunica normally drain blood away from the penis. As the cavernosa fill and expand against the rigid tunica, these veins are squeezed shut, keeping the sacs filled with blood and resulting in an erection. Adequate blood supply, nerve function, and hormones work in harmony to produce an erection. Disruption in one or more of these factors can cause impotence.