Physiology of erection

Before discussing drugs for ED, we need to review the physiology of erection. As indicated in Figure 66–1, the process begins with sexual arousal, which increases parasympathetic nerve traffic to the penis, causing local release of nitric oxide. Nitric oxide then activates guanylyl cyclase, an enzyme that makes cyclic guanosine monophosphate (cGMP). Through a series of steps, cGMP promotes relaxation of arterial and trabecular smooth muscle. The resultant arterial dilation increases local blood flow and blood pressure, which, in combination with relaxation of trabecular smooth muscle, causes expansion and engorgement of sinusoidal spaces in the corpus cavernosum. This, in turn, causes venous occlusion and thereby reduces venous outflow. The combination of increased arterial pressure and arterial inflow plus reduced venous outflow causes sufficient engorgement to produce erection. Erection subsides when cGMP is removed by phosphodiesterase type 5 (PDE5), an enzyme that converts cGMP into guanosine monophosphate.

Oral drugs for ED: PDE5 inhibitors

Drugs for ED fall into two major groups: oral agents and nonoral agents. The oral agents—PDE5 inhibitors—are by far the most common treatments for ED, and hence constitute our primary focus. The nonoral agents—papaverine plus phentolamine, alprostadil—are considered briefly.

Three PDE5 inhibitors are available: sildenafil, tadalafil, and vardenafil. All three 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, and hence 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, and nitroglycerin and other nitrates used for angina pectoris. In addition to ED, sildenafil is approved for pulmonary arterial hypertension (PAH) (see Chapter 107).

Sildenafil has been wildly popular. First-year sales were the hottest in pharmaceutical history. By now, tens of millions of men in over 100 countries have used the drug.

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 impotence had been cured. The rest, as they say, is history.

As discussed in Chapter 107, sildenafil, sold as Revatio, is also used for pulmonary arterial hypertension (PAH).

Mechanism of action

Sildenafil causes selective inhibition of PDE5. By doing so, it increases and preserves cGMP levels in the penis, thereby making the erection harder and more long lasting. Please note that the drug only enhances the normal erectile response to sexual stimuli (eg, erotic imagery, fantasies, physical contact). In the absence of sexual stimuli, nothing happens.

Pharmacokinetics

Sildenafil is well absorbed following oral administration. Bioavailability is about 40%. In fasting subjects, plasma levels peak about 1 hour after dosing. A high-fat meal slows absorption. As a result, plasma levels peak in 2 hours (rather than 1), and the peak concentration is reduced. Sildenafil is metabolized in the liver, primarily by the 3A4 isozyme 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 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 (ages 19 to 87) 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. After all, there’s a limit to how good an erection can get. Sildenafil cannot improve on that limit. Any apparent benefits in healthy men are likely the result of a placebo response (or perhaps wishful thinking).

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. Hence, the manufacturer decided not to seek Food and Drug Administration (FDA) approval for treating female hypoactive sexual desire disorder or any other condition in women.

Adverse effects

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 (see below), 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 damage penile tissue, thereby causing permanent loss of potency. Persistent erection can be relieved by aspirating blood from the corpus cavernosum followed by irrigation with a solution containing a vasoconstrictor (eg, epinephrine, phenylephrine, metaraminol).

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 of 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 (ringing in the ears). 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 (16%), flushing (10%), and dyspepsia (7%). Sildenafil may also cause nasal congestion (4%), diarrhea (3%), rash (2%), and dizziness (2%). 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 and/or dilating pulmonary blood vessels).

Drug interactions

Nitrates.

Both sildenafil and nitrates (eg, 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 hypertrophy (see below)—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 (eg, 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 CHD?

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)

• Heart failure

• Unstable angina

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 of 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.

Preparations, dosage, and administration

For treatment of ED, sildenafil is available in 25-, 50-, and 100-mg tablets sold as Viagra. The usual dose is 50 mg taken 1 hour before sexual activity. The dosage range is 25 to 100 mg taken 30 minutes to 4 hours before sexual activity. A low dose (25 mg) should be considered for men older than 65, men with hepatic dysfunction or severe renal dysfunction, and men taking alpha blockers or drugs that inhibit CYP3A4. Dosing should not be done more than once a day.

Vardenafil and tadalafil

Vardenafil and tadalafil are very similar to sildenafil. All three drugs inhibit PDE5, 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. Otherwise, the clinical effects of all three drugs appear about equal, although some patients may respond better to one than to the others. Properties of all three are summarized in Table 66–2.

TABLE 66–2 

Comparison of PDE5 Inhibitors

	Drug
Parameter	Sildenafil [Viagra]	Tadalafil [Cialis]	Vardenafil [Levitra, Staxyn]
Date approved	3/27/1998	11/21/2003	8/19/2003
Dosing schedule	PRN only	PRN or once daily	PRN only
Dosing with food	May be taken without regard to meals—but high-fat meals delay absorption and reduce peak levels	May be taken without regard to meals	May be taken without regard to meals—but high-fat meals delay absorption and reduce peak levels
Median time to peak level	1 hr	2 hr	1 hr
Half-life	4 hr	17.5 hr	4–5 hr
Duration of action	4 hr	36 hr	4 hr
Major mode of metabolism	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
Alpha blockers	Use with caution	Contraindicated (except for tamsulosin, 0.4 mg once daily)	Contraindicated
CYP3A4 inhibitors	Reduce sildenafil dosage	Reduce tadalafil dosage to no more than 10 mg every 72 hr	Reduce vardenafil dosage
Class I and class III antidysrhythmic drugs	No interaction	No interaction	Vardenafil prolongs the QT interval—avoid class I and class III antidysrhythmics

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