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The Three PDE-5 Inhibitors for Erectile Dysfunction: How Do They Compare?

Internal Medicine World Report, August 2005,

The Three PDE-5 Inhibitors for Erectile Dysfunction: How Do They Compare?

Dr Randrup is a urologist, Ochsner Clinic Foundation, and Dr Baum is Clinical Associate Professor of Urology, Tulane Medical School, New Orleans, La.

Although sexual potency is maintained in some men into the late decades of life, the myth that potency is the norm with aging is exactly that—a myth. The Massachusetts Male Aging Study (Feldman HA, et al. J Urol. 1994;151:54-61) found that nearly 50% of men >40 years old complained of sexual dysfunction. The same study estimated that between 20 and 30 million men in America, and more than 150 million worldwide, suffer from erectile dysfunction (ED). Chronic diseases (ie, diabetes, kidney disease, alcoholism, atherosclerosis) account for as many as 70% of these, and up to 50% of diabetic men have ED.

Comparing the 3 PDE-5 Inhibitors

Since the approval of sildenafil citrate (Viagra) in 1998 as the first phosphodiesterase (PDE)-5 inhibitor for the treatment of ED, 2 additional PDE-5 inhibitors became available—vardenafil HCl (Levitra) in 2003 and tadalafil (Cialis) in 2004. The question facing primary care physicians is how to make an evidence-based decision regarding which of these 3 would be best for an individual patient?

All 3 agents (Table) inhibit the conversion of cyclic guanosine monophosphate (cGMP) to GMP, allowing more cGMP to accumulate and prolonging the vasodilatory effects of nitric oxide (NO) on smooth muscle cells within the corporal bodies of the penis. Adverse event profiles are similar; differences in the pharmacokinetic and pharmacodynamic properties exist, but the clinical impact of these differences has not yet been fully defined.

Efficacy

The 3 PDE-5 inhibitors are similarly efficacious. Because no thorough head-to-head study has compared the 3 drugs, a sensible comparison criterion would appear to be a change in erectile function versus the baseline value compared with placebo.

In separate, placebo-controlled studies, treatment with vardenafil, 20 mg, improved the ability to achieve an erection in 80% of patients with ED; sildenafil, 100 mg, successfully treated 84% of patients; and tadalafil, 25 mg, improved the ability to achieve an erection in 81% of patients. This suggests a similar level of efficacy among these drugs.

In addition, compared with placebo, treatment with sildenafil, 100 mg, leads to a 20-fold improvement in achieving an erection adequate for vaginal penetration, 7.5-fold improvement with 20 mg of vardenafil, and 1.4-fold improvement with 25 mg of tadalafil.

Drug interactions

Nitrates. All PDE-5 inhibitors act via the NO/cGMP mechanism, which potentiates the hypotensive effect of nitrates. They are, therefore, contraindicated in patients taking nitrates or those who have unstable angina and may need to use nitrates (Package Insert, tadalafil). In men who develop angina while taking tadalafil and the situation is considered life-threatening, nitrates should not be administered until at least 48 hours after the tadalafil dose, and then only with close monitoring.

Alpha-blockers. Alpha-blockers are used for the treatment of benign prostatic hyperplasia, which is often associated with ED. Product labeling warns that sildenafil in doses >25 mg should not be administered within 4 hours of taking an alpha-blocker.

Vardenafil is contraindicated in men taking alpha-blockers, based on a study in which some patients taking vardenafil with terazosin HCl (Hytrin) or tamsulosin HCl (Flomax) developed symptomatic hypotension. Tadalafil is contraindicated in patients receiving alpha-blockers, except for the 0.4-mg dose of tamsulosin. Some patients who combined tadalafil with the alpha-blocker doxazosin mesylate (Cardura) have developed hypotension (Kloner RA, et al. Abstract presentation. American Urological Association; May 2004; San Francisco, Calif).

Drugs Metabolized by the CYP450 Pathway

Elimination of the PDE-5 inhibitors takes place overwhelmingly via the liver, primarily, the cytochrome (CY)P450 3A4 pathway. Thus patients who use drugs that inhibit this pathway will need to make dose adjustments to prevent increased serum levels of PDE-5 inhibitors. Sildenafil’s dose should be reduced to 25 mg in patients using potent CYP450 3A4 inhibitors, such as protease inhibitors, erythromycin (eg, E-Base, E-Mycin, Ery-Tab), or itraconazole (Sporanox). According to the package insert, vardenafil dose should be limited to 2.5 mg, used at ³72 hours intervals, in patients taking ritonavir (Norvir).

Those receiving indinavir sulfate (Crixivan), ketoconazole (Nizoral), or itraconazole, vardenafil dose is either 2.5/d or 5.0/d, depending on the dose of the CYP3A4 inhibitor. Tadalafil’s package insert recommends dose adjustments in patients using potent CYP3A4 inhibitors and a maximum of 10 mg every 72 hours.

High-Risk Patients

The PDE-5 inhibitors are safe in patients with a history of coronary artery disease (CAD) (DeBusk RF, et al. Am J Cardiol. 2004;93:147-153). Age-standardized mortality/ morbidity rates show no evidence of increased risk of events or death caused by CAD from PDE-5 inhibitors (Shakir SAW, et al. BMJ. 2001;322:651-652).

All 3 agents have slightly hypotensive effects in the supine position. Systolic/diastolic blood pressure (BP) decreases by about 8/16 mm Hg with sildenafil and 7/8 mm Hg with vardenafil, but by only 2/1 mm Hg with tadalafil. In men using antihypertensive medications (including calcium channel blockers, diuretics, beta-blockers, or angiotensin-converting enzyme inhibitors), sildenafil has resulted in small additive decreases in BP from baseline that were similar to changes observed in patients not taking antihypertensives (Zusman RM, et al. J Hypertens. 2000;18:1865-1869).

Candidates for PDE-5 therapy must undergo a proper cardiovascular risk assessment even though all 3 agents have a favorable cardiac safety profile. There is even a suggestion of cardioprotective properties, but further research is needed to support this conclusion (Kukreja RC, et al. J Mol Cell Cardiol. 2004;36;165-173).

Dose adjustments may be needed when PDE-5 inhibitors are taken by patients with impaired hepatic or renal function. Consult package insert for each drug.

Practical Tips

A quick inquiry into the functional status of a man’s sexual health should be a routine part of every clinical evaluation.

If a sexual problem is identified, ask questions such as:

  • “Is the problem partner-specific?”
  • “Do you have erections at night or upon awakening in the morning?”
  • “Do you have erections with masturbation or self-stimulation?”

Absence of nocturnal erections, or lack of erections with self-stimulation strongly suggests an organic cause of ED; investigate other comorbid conditions associated with endothelial dysfunction. The presence of ED is a barometer of endothelial dysfunction and is often associated with comorbid conditions (eg, diabetes, dyslipidemia, hypertension, or cardiovascular disease).

Disappointed Patients

Patients who are disappointed with the results of PDE-5 inhibitors may have been expecting that erection would occur spontaneously rather than by active sexual involvement in foreplay. Other patients have had poor results but subsequently admit to having had a heavy meal with a high fatty content before taking vardenafil or sildenafil, and thus absorption of the drug was delayed and more time would be needed for blood levels to reach peak values.

Given the complexity of the human sexual response and the many emotional as well as physiologic factors that can influence it, if a patient does not do well with an initial low dose, it is worth giving the medication a second chance by doubling the dose and making an earnest second try.