One of the most dramatic changes in urology has been the introduction of intracavernous injection of vasoactive drugs for the diagnosis and treatment of ED. A list of drugs that have been used clinically is presented in

Table 37-5.

A. Papaverine
Papaverine is an alkaloid isolated from the opium poppy. Its molecular mechanism of action is through its inhibitory effect on phosphodiesterase, leading to increased cAMP and cGMP in penile erectile tissue and thus relaxing cavernous smooth muscle and penile vessels. Papaverine is metabolized in the liver, and the plasma half-life is about 1-2 h.

The average dose for papaverine injection ranges from 15 to 60 mg. Papaverine has been shown to be effective in psychogenic and neurogenic ED (Virag, 1982). The advantages are its low cost and stability at room temperature. The major disadvantages are the higher incidence of corporal fibrosis (1-33%), thought to be a result of low acidity (pH 3-4), and occasional elevation of liver enzymes.

B. Phentolamine Methylate (Regitine)
Phentolamine methylate is a competitive alpha-adrenoceptor antagonist with equal affinity for alpha-1 and alpha-2 receptors. Systemic hypotension, reflex tachycardia, nasal congestion, and gastrointestinal upset are the most common systemic side effects. It has a short plasma half-life (30 min). When injected intracorporally alone, it increases corporal blood flow but does not result in a significant rise in intracorporal pressure.

C. Alprostadil (Prostaglandin E1)
Alprostadil is the synthetic form of a naturally occurring unsaturated 20-carbon fatty acid (ie, alprostadil refers to the exogenous form; prostaglandin E1 to the endogenous compound). It causes smooth-muscle relaxation, vasodilation, and inhibition of platelet aggregation through elevation of intracellular cAMP. Alprostadil is metabolized by the enzyme prostaglandin 15-hydroxydehydrogenase, which has been shown to be active in human corpus cavernosum (_{Roy et al, 1989}). After intracavernous injection, 96% of alprostadil is locally metabolized within 60 min and no change in peripheral blood levels has been observed (_{van Ahlen et al, 1994}).

In the United States, 2 formulations of alprostadil have been approved by the FDA for intracavernous therapy: Caverject (_{Pharmacia & Upjohn, Peapack, NJ}) and Edex (_{Schwarz Pharma, Milwaukee, WI}). Caverject is a lyophilized alprostadil powder developed for intracavernous injection. Edex is lyophilized alprostadil contained in an alpha cyclodextrin inclusion complex.

At a dosage of 10-20 ug, alprostadil produced full erections in 70-80% of patients with ED (_{Stackl, Hasun, and Marberger, 1988}). The most frequent side effects were pain at the injection site or during erection (occurring in 16.8% of patients), hematoma/ecchymosis (1.5%), and prolonged erection/priapism (1.3%). Systemic side effects occurred rarely (_{Linet and Ogrinc, 1996}).

D. Drug Combinations
Various drug combinations have been used for intracavernous injection therapy. The most commonly used are bimix (papaverine/phentolamine) and trimix (papaverine/phentolamine/alprostadil) in various concentrations. A study comparing papaverine or phentolamine alone with a papaverine/phentolamine combination in men with organic ED found that full erection occurred in 40% with papaverine alone, in 7% with phentolamine alone, and in 87% with papaverine/ phentolamine (_{Zorgniotti and Lefleur, 1985; Stief and Wetterauer, 1988}). Prolonged erection has been reported in 1-23% and fibrosis in 1.4-16% of patients receiving bimix therapy. The most commonly used formula contains 30 mg of papaverine and 1 mg of phentolamine per milliliter.

Regarding papaverine/phentolamine/alprostadil combinations, theoretically, because each of the 3 drugs has a different mechanism of action, the combination should take advantage of the synergism among them and permit a much lower dose of each to be used, avoiding the side effects of high dosages. In the study by Bennett, Carpenter, and Barada (1991), 89% of the patients tested had adequate erection and went on to home injection therapy. Overall, 74% of the 78 patients were maintained at a dose of <  0.25 mL per injection with a frequency averaging 3.1 uses per month. Two patients had a prolonged erection that required treatment. In another report from the same group of patients with 12-28 months of follow-up, 65% were continuing injection therapy and, of these, 89% were satisfied with the drug combination. Seven (5.6%) had prolonged erections >  3 h. No patient had fibrosis or nodules.

In a randomized crossover study of 228 patients, McMahon (1991) compared the triple-drug combination with papaverine/phentolamine and alprostadil alone. Statistically, the triple-drug combination was more effective in patients with severe arteriogenic or mild veno-occlusive dysfunction. The incidence of prolonged erection was lower when compared with papaverine/phentolamine but not significantly different from that in alprostadil alone. The triple-drug combination has been shown to be very effective in patients with organic ED (up to 89% response rate), but has a much lower incidence of painful erection.

E. Patient Acceptance and Dropout Rate
In several studies, the percentage of patients accepting injection therapy when offered in the office ranges from 49% to 84% (_{Gerber and Levine, 1991}). The reasons for declining include penile pain, inadequate response, fear of the needle, unnaturalness, and loss of sex drive. In long-term studies, 13-60% of patients drop out for a number of reasons. These include loss of interest, loss of the partner, poor erectile response, penile pain, concomitant illness, recovery of spontaneous erection, and ultimate choice of other therapy.

F. Serious Adverse Effects
Priapism and fibrosis are the 2 more serious side effects associated with intracavernous injection therapy. Linet and Ogrinc (1996) calculated that priapism occurred in 1.3% of 8090 patients in 48 studies with alprostadil. The incidence was found to be about 5 times lower with alprostadil than with papaverine or the combination of papaverine and phentolamine (1.5% vs 10% vs 7%). Fibrosis can occur as a nodule, diffuse scarring, plaque, or curvature. The incidence is about 10 times lower with alprostadil than with papaverine or papaverine/phentolamine (1% vs 12% vs 9% of patients), although one study reported a 12% incidence with alprostadil.

G. Dosage and Administration
Patients must have the first injection performed by medical personnel and receive appropriate training and education before home injection. For alprostadil, an initial dose of 2.5 ug is recommended. If the response is inadequate, increases in 2.5-ug increments can be given until a full erection is achieved or a maximum of 60 ug is reached.

For drug combinations, one should start with a small dose (eg, 0.1 mL) and titrate the amount according to erectile response. The goal is to achieve a full erection of less than 1-h duration to avoid priapism. Compression of the needle puncture site for at least 5 minutes is recommended to prevent bleeding and fibrosis.

H. Treatment of Prolonged Erection or Priapism
The best treatment is prevention; patient should be warned not to increase the dose or repeat the injection without consulting the physician. If the erection lasted more than 4 h, the patient should either call the physician or go to the emergency room for treatment. The best regimen for averting priapism is intracavernous injection of diluted phenylephrine 250 to 500 ug every 3-5 min until detumescence. In patients with cardiovascular disease, monitoring blood pressure and pulse is recommended.

I. Contraindications
The use of intracavernous injection therapy is contraindicated in patients with sickle cell anemia, schizophrenia or a severe psychiatric disorder, or severe venous incompetence. In patients taking an anticoagulant or aspirin, compressing the injection site for 7-10 min after injection is recommended. In patients with poor manual dexterity, the sexual partner can be instructed to perform the injection.