The penis erection
Recent advances in our knowledge of the physiology of erection have facilitated understanding of the pharmacodynamics of sildenafil. Erection is initiated by dilation of the arterial bed, which increases blood flow and pressure; it is maintained by restriction of venous outflow. Previously it was believed that the parasympathetic system was critical in maintaining erection. Now we know that the major player is the nonadrenergic, noncholinergic (NA-NC) system, which was identified 50 years ago but never studied in detail until recently. The NA-NC system uses nitric oxide as a neurotransmitter. Through its second messenger, cyclic guanine monophosphate (cGMP), nitric oxide triggers relaxation of penile endothelium and smooth muscle, allowing expansion of the lacunar spaces within the corpora and the trapping of blood by compression of peripheral draining venules.
Sildenafil, a type 5 phosphodiesterase inhibitor, prevents the breakdown of cGMP, thus prolonging erection. It has no effect on libido and it does not cause erection, but it maintains an erection once it has been achieved. Although the NA-NC system is particularly prominent in the penis, it is also found in the heart, the brain, and other organs. Its presence in the eye explains the blue visual hue that some patients experience after taking sildenafil.
The most common side effects of sildenafil are headache, flushing, and dyspepsia. It can also decrease blood pressure. Because the decrease may be synergistic with the hypotensive action of nitrates, sildenafil is contraindicated in patients taking a medication that contains nitrates, such as nitroglycerin.
In addition, sildenafil alters the half-life of many other medications, and many medications change the half-life of sildenafil. The list of agents that can interact with sildenafil includes such common medications as nonselective beta-blockers, erythromycin, itraconazole, potassium-sparing diuretics, and cimetidine. It is not known whether those interactions affect the side effects of sildenafil–especially the incidence or severity of hypotension. In initial clinical trials, hypotension was reported in about 3% of patients, but those trials included a large percentage of young men with psychogenic impotence. Obviously, patients with vascular disease or diabetes have more problems with blood pressure regulation and theoretically with orthostatic hypotension. A number of deaths have occurred among patients taking sildenafil since it became available. The U. S. Food and Drug Administration (FDA) is currently investigating those deaths.
Evaluating sildenafil has been difficult because it is one of several drugs that have been approved during the past two years through a new FDA process. Previously, a drug was not approved until studies had been published. Now the FDA allows pharmaceutical companies to submit unpublished studies. With this streamlined process, a drug can be approved before clinicians have the chance to read peer-reviewed data and decide whether their patients falls into the same category as patients in the initial studies. Instead, the physician has only the drug company brochure, which does not offer the detail of a peer-reviewed journal article.
The first study of data on different patient populations taking sildenafil was published several months after the drug became available for clinical use. While the package insert indicated an overall efficacy of 82% (vs 24% for placebo), analysis showed that the efficacy was 68% in patients with hypertension, 57% in diabetes, 61% after trans-urethral prostatic resection, and 43% after radical prostatectomy. Moreover, those results were obtained in a selected patient population, not from general clinical use.
Physicians need additional information from peer-reviewed studies so that they can assess the risk-benefit ratio of sildenafil and make rational treatment decisions in individual cases. Meanwhile, third-party payers are trying to decide whether they should reimburse the cost of the drug. Arguments against coverage include the fact that erectile dysfunction is not a life-threatening condition. Also, since many third-party payers do not pay for oral contraceptives for women, they feel that they should not reimburse for a drug that enhances sexual performance in men.
In any case, newspaper reports indicate that sales of sildenafil have slowed in recent months. The decrease has been attributed to refusals for insurance coverage and increasing reports of side effects. A human element may also be involved. For example, in several studies of penile prostheses, patient interviews confirmed that the prostheses functioned well, but interviews with the patients’ wives revealed that the patients were not using it. Similar findings have been reported in studies of other treatments for erectile dysfunction; the actual frequency of use is much less than that initially described by the patient. The ability to have sex is only one element in a complicated equation that determines whether or how often a patient has sexual relations.
Future Possibilities. Other oral agents for erectile dysfunction are undergoing clinical trials and should soon be available. Apomorphine, an opiate antagonist, has shown up to 70% efficacy in patients with psychogenic impotence; it will probably be available for clinical use late this year. Also under FDA review is an oral preparation of phentolamine. This agent blocks norepinephrine, causing smooth-muscle relaxation and vasodilation. In preliminary studies, it was effective in 60% to 80% of patients and had fewer side effects than sildenafil.
For patients using intracavernosal injection, a combination of vasoactive intestinal peptide (VIP) and phentolamine is under investigation. Both agents are smooth muscle relaxants, and vasoactive intestinal peptide appears to increase production of nitric oxide.
