Drug Therapy of Erectile Dysfunction

Basic Principles

Erectile dysfunction (ED) is divided into psychogenic causes and organic causes, with the latter constituting around 90% of cases. Organic etiologies include arteriogenic ED, veno-occlusive dysfunction, neurogenic ED, hormonal dysfunction, drug-induced causes, and anatomic causes.

Evaluation of the ED patient includes history, physical examination, basic laboratory tests, and sometimes specialized testing. The history is most important in determining whether a psychogenic or organic predominance is present. Men with organic ED tend to be older, exhibit cardiovascular risk factors, and have a consistent dysfunction that is gradually progressive. Men with psychogenic ED tend to be younger, have no vascular disease risk factors, and have abrupt onset of the ED, often with varying amounts of dysfunction, depending on the sexual situation. Psychogenic causes must be identified because organic treatments are of no benefit here. Men with psychogenic ED should be treated by appropriate psychotherapists.

Once an organic cause has been established, treatment can often be attempted without having an exact diagnosis, meaning that specialized testing is not usually needed. This goal-oriented approach is based on the idea that it might not, for example, be important if a patient’s ED is primarily of arteriogenic or of veno-occlusive origin as long as a simple treatment can alleviate the problem and potential underlying systemic causes are being attended to. This is because a specific treatment, such as penile arterial revascularization, will likely have a much lower success rate than administration of sildenafil. For a more thorough description of patient evaluation, see the selected references.

Many antihypertensive drugs have been implicated as a cause of ED. Older antihypertensive agents, such as ganglionic blockers, caused ED by the marked neurologic dysfunction they induced. However, modern blood pressure medicines do not carry the same adverse event profiles. Furthermore, some drugs implicated in the genesis of ED, such as calcium-channel blockers, actually cause an erection when injected into the penis. How a drug that induces erection when injected can cause ED when taken orally is an open question.

Patients who have newly diagnosed ED and hypertension might have small plaques in the penile arteries. With a very high perfusion pressure, a man may be able to drive enough blood into the penis through partial blockages to obtain and maintain an erection. When an antihypertensive is given, the resultant perfusion pressure may be inadequate to create an erection. Therefore, any antihypertensive can cause ED because the blood pressure is lower. That being said, it may be of benefit to switch antihypertensive drugs to see if there is less of an effect on the ED the patient is experiencing.

Phosphodiesterase 5 Inhibitors

PDE5 inhibitors constitute the first-line therapy for ED. Advantages include oral administration, safety, and effectiveness. PDE5 inhibitors were originally developed as a cardiovascular drug but were found to improve the erections of test subjects. These drugs inhibit PDE5 and thus limit the breakdown of cGMP in penile tissue, leading to accumulation of cGMP and prolonged corporal smooth muscle relaxation. PDE5 inhibitors are taken 1 to 2 hours before sexual activity to obtain adequate tissue levels for action. The reduced cGMP breakdown leads to improved and prolonged smooth muscle relaxation, resulting in both harder and longer-lasting erections.

The mechanism of action means that the drugs require sexual stimulation to initiate NO release and start cGMP production in the cavernous tissue. Without this initial induction, PDE5 inhibitors cannot work as they do not start the erectile process, but rather reinforce it and stop it from terminating. PDE5 inhibitors are highly specific for PDE5, and because this enzyme is overrepresented in the penile tissue, the erectile augmentation response is possible without major systemic side effects.

Available PDE5 inhibitors include sildenafil (25, 50, and 100 mg), vardenafil (5, 10, and 20 mg), and tadalafil (5, 10, and 20 mg for demand dosing, and 2.5 or 5 mg for daily use). In spite of differences in pharmacokinetics, the three drugs have shown equal clinical efficacy, with success rates for improvement of erection of about 70% to 80%, and with restoration of erections satisfactory for intercourse on PDE5 inhibitors alone in approximately 60% of cases. The nonresponders are primarily men with severe ED, particularly diabetics and severe vasculopaths.

Sildenafil and vardenafil are both taken about ½ to 1 hour before sexual activity because they take about an hour to reach peak plasma concentrations. Tadalafil peaks in 2 hours and is usually taken earlier than the other drugs. The half-lives of sildenafil and vardenafil are 4 to 5 hours, and for tadalafil the half-life is 18 hours in young men and longer in elderly men. This means that sildenafil and vardenafil generally augment erectile function for 4 to 12 hours, and tadalafil can have an effect up to 36 to 48 hours after administration.

The long half-life of tadalafil allows accumulation when administered in 2.5 or 5 mg daily dosing. This can allow the patient more spontaneity in his sex life, and for some patients it represents a psychological advantage because it separates sex from the need to take a pill. The frequency of sexual activity is important in making a decision about whether daily dosing is a smart option, because cost considerations arise.

Options of both on-demand and daily treatments should be presented to the patient. After this, choice of drug should depend on the patient’s preference because the treatments are similar regarding efficacy and side effects.

When administering PDE5 inhibitors, the physician needs to convey to the patient the correct recommended administration of the drugs. It must be stressed that sexual stimulation is necessary for effect, and the temporal relationship between drug administration and desired time of effect must be respected. Furthermore, sildenafil should not be taken in conjunction with food because this can lower the subsequent bioavailability of the drug.

PDE5 inhibitors have class-related effects and drug-specific effects. The class-related side effects result from vasodilation caused by systemic PDE5 inhibition. This can cause a small decrease in blood pressure, but more bothersome are the occurrence of headache, dizziness, facial flushing, and rhinitis. Also, effects at the gastroesophageal sphincter can cause acid reflux and dyspepsia. The drug-specific side effects include visual disturbances in the form of a bluish discoloration caused by sildenafil and back and muscular pain caused by tadalafil. The visual disturbances are caused by partial PDE6 inhibition in the retina, and the muscle pain is of unknown etiology. Mild QT interval prolongation has been reported with vardenafil treatment, and caution should be taken in patients with preexisting QT prolongation or on other medications that can cause such prolongation. Typically, adverse events are mild and uncommonly result in discontinuation of the therapy.

Finally, there have been cases of nonarteritic ischemic optic neuropathy and sporadic cases of hearing loss associated with PDE5 inhibitors. These effects need to be explored further, but even if the association does exist, it is likely caused by underlying medical conditions because cardiovascular disease and neuropathy are known causes of ED.

PDE5 inhibitors are contraindicated in patients receiving organic nitrates because these drugs have a synergic effect on lowering blood pressure. Nitrates stimulate cGMP production systemically, and PDE5 inhibitors prevent its breakdown, which sustains and attenuates the resulting smooth muscle relaxation. This can result in marked vasodilation and subsequent dramatic drops in blood pressure. Some ED patients with a cardiovascular diagnosis have a prescription for nitrates even though they do not develop ischemia. This may, for example, be the case after cardiac revascularization procedures, where nitrates are uniformly prescribed. Because these patients will likely benefit from PDE5 inhibitor treatment, a reevaluation of the need for nitrates (an exercise stress test) may be indicated. In the situation where a patient has taken a PDE5 inhibitor and subsequently develops angina, nitrates can be safely administered 24 hours after the last short-acting PDE5 inhibitor dose (sildenafil and vardenafil) and 48 hours after the last long-acting PDE5 inhibitor dose (tadalafil).

To a lesser degree, PDE5 inhibitors and α-blockers can interact and cause drops in blood pressure. Although use of α-blockers is not a contraindication for PDE5 inhibitor use, caution should be used when taking these two classes of drugs at the same time. Patients on stable α-blocker therapy should be started on the lowest dose of a PDE5 inhibitor, and side effects resulting from drops in blood pressure should be monitored closely.

PDE5 inhibitors are effective in most patients. When a patient reports that the drug is not working, it is important to examine compliance with instructions and timing of administration. The physician must make sure that the patient is taking the drug as prescribed and that sexual stimulation is taking place, because these drugs do not initiate erection by themselves. Two large studies have demonstrated that reeducation alone can increase PDE5 inhibitor success. Compliance has been shown to improve with educating the patient, managing expectations, prescribing individualized treatment, and scheduling follow-up visits. Several trials have noted that there may be a learning curve, with success only seen after several attempts with the drugs.

The dosage should be increased until the patient is using the top dose of the drug before calling it a failure. Further improvements may be achieved by asking the patient to wait longer between taking the pill and attempting sexual activity (up to about 2 hours) and to take the pill on an empty stomach. Finally, if one drug—taken correctly—does not work, evidence suggests that another might have effect in spite of the identical mechanism of action. Thus, patients should ideally have tried all three PDE5 inhibitors at their maximum dosage before continuing on to more invasive therapies.

Penile Injection Therapy

By injection of vasoactive substances into the penis it is possible to both induce and sustain erections. The first of several substances used for the purpose was the nonspecific PDE inhibitor papaverine. Alprostadil (PGE ₁ ) is the only U.S. Food and Drug Administration (FDA)-approved medication for penile injection therapy.

When injected into the corpus cavernosum, alprostadil activates the cAMP system, leading to calcium efflux and smooth muscle relaxation, as described earlier. In contrast to PDE5 inhibitor treatment, this induces an erection even without sexual stimulation, but sexual activity can augment and sustain the response. The treatment results in erections satisfactory for intercourse in 60% to 80% of patients, and it is more likely to have effect in cases of severe ED than the PDE5 inhibitors. The treatment is, however, both more invasive and more costly than the oral treatment. If treatment with alprostadil alone fails, non–FDA-approved combinations of alprostadil, papaverine, and phentolamine (a nonselective α-adrenergic antagonist) can be attempted to increase effect according to the American Urological Association (AUA) guidelines.

When introducing injection therapy to a patient, the first injection should be done under medical supervision. This is to teach the procedure and to evaluate efficacy and possible side effects.

Priapism (prolonged erection >6 hours) is the most feared adverse event. Injection therapy should not be offered to patients predisposed to this condition. When present, priapism usually occurs with the first injection, when patient sensitivity to the treatment is still unknown. It is still important to inform the patient of the risk with at-home treatment, because late cases can occur also. The priapism associated with injection therapy is usually treated easily with intracavernosal injection of sympathomimetic agents. Penile pain occurs in 35% to 40% of patients using PGE ₁ injection therapy, and it can cause the patient to abandon the treatment. Finally, fibrosis formation at the site of injection is a rare side effect of PGE ₁ treatment, which may be reduced by alternating injection sites. A higher rate of fibrosis formation is seen with the off-label use of papaverine.