Oral Drugs for Erectile Dysfunction: PDE-5 Inhibitors
Drugs for ED fall into two major groups: oral agents and nonoral agents. The oral agents—PDE-5 inhibitors—are by far the most common treatments for ED. These will constitute our primary focus. The nonoral agents—papaverine plus phentolamine, alprostadil—are considered briefly. These drugs are summarized in Table 51.2.
TABLE 51.2
Drugs for Erectile Dysfunction: Preparation, Dosage, and Administration
| Drug Class and Drug | Preparation | Dosage for ED | Administration |
| PDE-5 INHIBITORS | |||
| Avanafil [Stendra] | Tablets: 50 mg, 100 mg, 200 mg | 100 mg taken ± 15 minutes before sexual activity. May be increased to 200 mg, if needed. Decrease to lowest effective dose. | May be taken with or without food, but avoid grapefruit juice. High fat foods delay double the time to onset. Do not take over once a day. |
| Sildenafil [Viagra] | Tablets: 25 mg, 50 mg, 100 mg | 50 mg once daily ± 60 minutes before sexual activity. May be increased to 100 mg, if needed. Decrease to lowest effective dose. | May be taken with or without food, but avoid grapefruit juice. High fat foods may delay onset by as much as 60 minutes. Do not take over once a day. |
| Tadalafil [Cialis] | Tablets: 2.5 mg, 5 mg, 10 mg, 20 mg | PRN use: 10 mg before sexual activity. May be increased to 20 mg, if needed. Decrease to lowest effective dose. Daily use: 2.5 mg orally once daily; timing unrelated to sexual activity. May increase to 5 mg if needed. | May be taken with or without food, but avoid grapefruit juice. Do not take over once a day. If administered for daily use, take at the same time each day. |
| Vardenafil [Levitra, Staxyn] | Tablets (Levitra): 2.5 mg, 5 mg, 10 mg, 20 mg Orally Disintegrating Tablets (Staxyn): 10 mg | Levitra: 10 mg taken ± 60 minutes before sexual activity. May be increased to 20 mg, if needed. Decrease to lowest effective dose. Decrease starting dose to 5 mg for patients age 65 and older. Staxyn: 10 mg taken ± 60 minutes before sexual activity. Do not increase dosage. | Levitra: May be taken with or without food, but avoid grapefruit juice and fatty foods. Staxyn: Place tablet on tongue and allow to disintegrate. To not take with food or drink. Both: Do not take over once a day. |
| PROSTAGLANDIN E1 | |||
| Alprostadil intracavernosal injection [Caverject, Caverject Impulse, Edex] | Intracavernosal Kit (Caverject Impulse): 10 mcg, 20 mcg Intracavernosal Kit (Edex): 10 mcg, 20 mcg, 40 mcg Solution for Intracavernosal Injection (Caverject): 20 mcg, 40 mcg | Typical dosages range from 5–40 mcg. Dosing is individualized; determination is made in the health care setting. Maximum dosing is 60 mcg for Caverject and 40 mcg for Edex. | Patients self-administer injection into the penis. Do not take more than once in 24 hours. Limit total dosing to three times a week. |
| Alprostadil intraurethral insertion [Muse] | Urethral Pellets (Muse): 125 mcg, 250 mcg, 500 mcg, 1000 mcg | Intraurethral insertion: Initial dosing is 125–250 mcg 5–10 minutes before sexual activity. (Effect lasts 30–60 minutes.) Increase, if needed, to lowest effective dose. | Patients self-insert the pellet into the urethra. Limit use to twice daily. |
| VASODILATOR + ALPHA-ADRENERGIC ANTAGONIST | |||
| Papaverine with phentolamine | Papaverine 30 mg/mL with phentolamine 1 mg/mL | Dosing is individualized; determination is made in the health care setting. As little as 0.1 mL may be sufficient | Patients self-administer injection into the penis. |
Four PDE-5 inhibitors are available: sildenafil, tadalafil, vardenafil, and avanafil. All are considered first-line therapy for ED. Current guidelines recommend that, in the absence of a specific contraindication, all men with ED be offered one of these drugs. Which drug is preferred? Only a few trials have compared them head-to-head, so there is insufficient evidence to recommend one over the others. Accordingly, selection among them should be based on patient preference and prescriber judgment.
Sildenafil
Sildenafil [Viagra] was introduced in 1998 as the first oral treatment for ED. The drug is reliable and easy to use. Benefits derive from enhancing the natural response to sexual stimuli; sildenafil does not cause erection directly. Although sildenafil is generally well tolerated, it can be dangerous for men taking certain vasodilators, specifically alpha-adrenergic blockers, nitroglycerin, and other nitrates used for angina pectoris.
The erection-enhancing effects of sildenafil were discovered by accident. The drug was developed as a cardiac medicine, but benefits were minimal. However, in the course of testing, some men noticed a surprising side effect: their ED had been cured! The rest, as they say, is history. Sildenafil has been wildly popular. First-year sales were the hottest in pharmaceutical history. By now, tens of millions of men in more than 100 countries have used the drug. In addition to ED, sildenafil is approved for pulmonary arterial hypertension (PAH). When used for this purpose, sildenafil is sold as Revatio.
Mechanism of Action
Sildenafil causes selective inhibition of PDE-5. By doing so, it increases and preserves cGMP levels in the penis, thereby making the erection harder and longer lasting. Please note that the drug only enhances the normal erectile response to sexual stimuli (e.g., erotic imagery, fantasies, physical contact). In the absence of sexual stimuli, nothing happens.
Pharmacokinetics
Sildenafil is well absorbed after oral administration. Bioavailability is about 40%. In fasting subjects, plasma levels peak about 1 hour after dosing. A high-fat meal slows absorption, resulting in a peak plasma level in 2 hours (rather than 1) and reducing the peak concentration. Sildenafil is metabolized in the liver, primarily by the 3A4 isoenzyme of cytochrome P450 (CYP3A4). Both the parent drug and its major metabolite (N-desmethyl sildenafil) are biologically active. Both compounds are eliminated primarily in the feces (80%) and partly in the urine (13%). For both compounds, the half-life is 4 hours. Clearance of both is delayed in men older than 65 years and in men with hepatic impairment or severe renal insufficiency, causing drug levels to rise higher and persist longer.
Sexual Benefits
In Men With ED.
Sildenafil has been evaluated in several thousand men (aged 19–87 years) with ED of organic, psychogenic, or mixed-cause origin. At least some improvement in erection hardness and duration was seen in 70% of men taking the drug, compared with 20% taking placebo. Benefits were dose related and lasted up to 4 hours, although they began to fade after 2 hours. Sildenafil was able to help a wide range of patients, including those with ED resulting from diabetes, spinal cord injury, and transurethral prostate resection, as well as ED of no known physical cause.
In Men Without ED.
Despite anecdotal reports to the contrary, sildenafil has little or no effect on erection quality or duration in men who do not have ED. Any apparent benefits in healthy men are likely the result of a placebo response.
In Women.
Sildenafil is not approved for use in women and probably won’t be. Although several large-scale studies showed the drug is safe in women, they failed to show much enhancement of sexual arousal. Thus the manufacturer decided not to seek U.S. Food and Drug Administration (FDA) approval for treating female hypoactive sexual desire disorder or any other condition in women.
Adverse Effects
Patient-Centered Care Across the Life Span:
Drugs for Erectile Dysfunction
| Life Stage | Considerations or Concerns |
| Children | Safety for PDE-5 inhibitors has not been established. PDE-5 inhibitors are not indicated for children. Alprostadil is indicated for treatment of patent ductus arteriosus in neonates; however, the formulations for ED would not apply. |
| Pregnant Women | PDE-5 inhibitors are Pregnancy Category B; however, they are not indicated for women and, therefore, should not be taken by pregnant women. Alprostadil urethral pellets and injectable alprostadil or papaverine with phentolamine would not be used by people without a penis. It is recommended that men taking these drugs use a condom if their partner is a pregnant woman. |
| Breast-Feeding Women | Excretion in breast milk is unknown; however, drugs for erectile dysfunction are not indicated for use in women. |
| Older Adults | Consider lower dosing when prescribing for older adults age 65 and older. |
Hypotension.
At recommended doses, sildenafil produces a small (8.4/5.5 mm Hg) reduction in blood pressure. However, in men taking nitrates or alpha blockers, severe hypotension can develop.
Priapism.
A few cases of priapism (painful erection lasting more than 6 hours) have been reported. If an erection persists more than 4 hours, immediate medical intervention is required. Left untreated, priapism can cause permanent damage of penile tissue. If priapism persists longer than 24 hours, chances are very high that the patient will never be able to have sexual intercourse again. Persistent erection can be relieved by aspirating blood from the corpus cavernosum followed by irrigation with a solution containing a vasoconstrictor (e.g., epinephrine, phenylephrine, metaraminol). If this is unsuccessful, surgery is required.
Nonarteritic Ischemic Optic Neuropathy (NAION).
Very rarely, men taking sildenafil have developed NAION, resulting in irreversible blurring or loss of vision. The cause is blockage of blood flow to the optic nerve. In most cases, there were underlying anatomic or vascular risk factors for NAION. Also, although NAION developed during sildenafil use, a direct causal relationship has not been established. Nonetheless, patients with NAION in one eye should not use sildenafil, owing to a potential risk for developing NAION in the other eye.
Sudden Hearing Loss.
Very rarely, men taking sildenafil have experienced sudden hearing loss, usually in one ear, sometimes in association with dizziness, vertigo, and tinnitus. Hearing loss may be partial or complete. Hearing returned by the time the loss was reported in one third of cases, but had not returned in the remaining two thirds. To date, a direct causal relationship between sildenafil and hearing loss has not been established. Nonetheless, the drug is suspected because (1) sudden hearing loss is unusual and (2) it developed when sildenafil was taken. Men who experience sudden hearing loss should discontinue the drug—but only if they are taking it for ED; men taking the drug for PAH should continue treatment.
Other Adverse Effects.
The most common adverse effects are headache, flushing, and dyspepsia. Sildenafil may also cause nasal congestion, diarrhea, rash, and dizziness. About 3% of patients experience mild transient visual disturbances (blue color tinge to vision, increased sensitivity to light, blurring). In addition, sildenafil may intensify symptoms of obstructive sleep apnea (perhaps by relaxing pharyngeal muscles or dilating pulmonary blood vessels).
Drug Interactions
Nitrates.
Both sildenafil and nitrates (e.g., nitroglycerin, isosorbide dinitrate) promote hypotension, and they both do so by increasing cGMP (nitrates increase cGMP formation, and sildenafil slows cGMP breakdown). If these drugs are combined, life-threatening hypotension could result. Therefore sildenafil is absolutely contraindicated for men taking nitrates. At least 24 hours should elapse between the last dose of sildenafil and giving a nitrate. If elimination of sildenafil is slowed (owing to a CYP3A4 inhibitor or hepatic or renal impairment), an even longer time should elapse before nitrate use.
Alpha Blockers.
Alpha-adrenergic antagonists—including doxazosin [Cardura] and other alpha blockers used for prostatic hyperplasia (see later discussion)—dilate arterioles and can thereby lower blood pressure. Combined use with sildenafil has caused symptomatic postural hypotension. Accordingly, these combinations should be used with caution.
Inhibitors of CYP3A4.
Inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, erythromycin, cimetidine, saquinavir, ritonavir, grapefruit juice) can suppress metabolism of sildenafil, thereby increasing its levels. These combinations should be used with caution.
Is Sildenafil Safe for Men With Coronary Heart Disease?
Reports of adverse cardiovascular events, including at least 130 cardiac deaths, raised concern about the safety of sildenafil in men with coronary heart disease (CHD). However, there was a question as to what caused the adverse events: sildenafil or the sexual activity that sildenafil permitted. When attempting to answer this question, researchers made two important observations: First, giving sildenafil to resting men with severe CHD produced no harmful effects on coronary blood flow or any other hemodynamic parameter. Second, in men with stable CHD who were performing exercise, sildenafil had no effect on CHD symptoms, exercise tolerance, or exercise-induced ischemia. Taken together, these results suggest that, in men with CHD, sexual activity—and not sildenafil—is the likely cause of ischemic events. However, even though sildenafil itself appears safe for men with CHD, sexual activity may not be. Accordingly, the drug should be used with caution by men with the following conditions:
• Myocardial infarction, stroke, or life-threatening dysrhythmia within the last 6 months
• Resting hypotension (blood pressure below 90/50 mm Hg)
• Resting hypertension (blood pressure above 170/110 mm Hg)
In addition, sildenafil should not be used at all by men taking nitroglycerin or any other drug in the nitrate family.
To reduce the risk for adverse events, candidates for sildenafil therapy should undergo a careful evaluation of cardiovascular function. Those with impaired function should be counseled about the risks posed by sexual activity and all other moderate to intense physical activity.
Vardenafil, Tadalafil, and Avanafil
Vardenafil, tadalafil, and avanafil are very similar to sildenafil. All three drugs inhibit PDE-5, and all three are approved for oral therapy of ED. Vardenafil is unique in that it prolongs the QT interval, and tadalafil is unique in that its effects last 36 hours. Avanafil is unique in that it has the fastest onset of action. Otherwise, the clinical effects of all four PDE-5 inhibitors appear about equal, although some patients may respond better to one than to the others. Properties of all four are shown in Table 51.3.
TABLE 51.3
Comparison of PDE-5 Inhibitors
| Drug | ||||
| Parameter | Sildenafil [Viagra] | Tadalafil [Cialis] | Vardenafil [Levitra, Staxyn] | Avanafil [Stendra] |
| Date approved | 3/27/1998 | 11/21/2003 | 8/19/2003 | 4/28/2012 |
| Dosing schedule | PRN only | PRN or once daily | PRN only | PRN |
| Median time to peak level | 1 hr | 2 hr | 1 hr | 30–45 min |
| Half-life | 4 hr | 17.5 hr | 4–5 hr | 5 hr |
| Duration of action | 4 hr | 36 hr | 4 hr | 4 hr |
| Major mode of metabolism | CYP3A4 | CYP3A4 | CYP3A4 | CYP3A4 |
| DRUG INTERACTIONS | ||||
| Nitrates | Contraindicated: Wait 24 hr before giving a nitrate | Contraindicated: Wait 48 hr before giving a nitrate | Contraindicated: Wait 24 hr before giving a nitrate | Contraindicated: Wait 12 hr before giving a nitrate |
| Alpha blockers | Use with caution | Contraindicated (except for tamsulosin, 0.4 mg once daily) | Contraindicated | Use with caution |
| CYP3A4 inhibitors | Reduce sildenafil dosage | Reduce tadalafil dosage to no more than 10 mg every 72 hr | Reduce vardenafil dosage | Do not take with strong CYP3A4 inhibitors; reduce dosage with moderate inhibitors |
| Class I and class III antidysrhythmic drugs | No interaction | No interaction | Vardenafil prolongs the QT interval—avoid class I and class III antidysrhythmics | No interaction |
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