ERECTILE DYSFUNCTION (ED) is the inability to achieve and maintain penile erection sufficient to complete satisfactory sexual intercourse. It varies from occasional and minimal to permanent and complete. ED can result from psychological, vascular, neurologic, or hormonal disorders. It's estimated to affect up to 30 million men in the United States.
Previous therapies for ED have included penile implants, intrapenile injections of alprostadil, and intraurethral suppositories of alprostadil. However, because of their efficacy, ease of use, and safety, oral phosphodiesterase (PDE) inhibitors are now considered to be first-line therapy for men with ED. Three PDE-5 inhibitors, sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis), are approved for the treatment of ED.
How they work
Sildenafil, vardenafil, and tadalafil are equally effective in treating ED, and the adverse reaction profiles of the drugs are similar. However, the duration of action of PDE-5 inhibitors differ, as do the effects of food on the rates of drug absorption.
Sexual stimulation results in smooth muscle relaxation of the corpus cavernosum, increasing the inflow of blood (see Penile erection). The mediator of this response is nitric oxide, which activates guanylyl cyclase to form cyclic guanosine monophosphate (cGMP) from guanosine triphosphate. cGMP produces smooth muscle relaxation through a reduction in the intracellular Ca2+ concentration. The duration of action of cyclic nucleotides is controlled by the action of PDE. At least 11 isozymes of PDE have been characterized; sildenafil, vardenafil, and tadalafil inhibit PDE-5, the isozyme responsible for termination of cGMP in the corpus cavernosum. PDE-5 inhibitors increase the flow of blood into the corpus cavernosum at any given level of sexual stimulation (at recommended doses). They have no effect in the absence of sexual stimulation. All three PDE-5 inhibitors are metabolized by the cytochrome P450 3A4 enzyme.
Sildenafil and vardenafil have similar pharmacokinetic properties. Both drugs should be taken approximately 1 hour before anticipated sexual activity; erectile enhancement is observed up to 4 hours after administration. Administration of sildenafil and vardenafil must be timed so sexual activity occurs within 1 to 6 hours. The absorption of both drugs is delayed by consumption of food, particularly high-fat meals.
Tadalafil has a slower onset of action but a significantly longer half-life of approximately 18 hours, resulting in enhanced erectile function for at least 36 hours. The absorption of tadalafil isn't clinically influenced by food or alcohol consumption. The timing of sexual activity is less critical for tadalafil because of its prolonged duration of effect.
What can go wrong?
The most frequent adverse reactions of PDE inhibitors are headache, flushing, dyspepsia, and nasal congestion. These effects are generally mild, and men with ED rarely discontinue treatment because of adverse reactions. Disturbances in color vision (loss of blue/green discrimination) occur with sildenafil, probably because of inhibition of PDE-6 (a PDE found in the retina that's important in color vision). The incidence of these reactions appears to be dose-dependent. Treatment with a PDE doesn't increase the incidence of myocardial infarction. PDE-5 inhibitors shouldn't be used more than once per day.
Because of the ability of PDE inhibitors to potentiate the activity of nitrous oxide, they shouldn't be used with concurrent organic nitrates in any form. Concomitant treatment with alpha-adrenergic antagonists (used to alleviate symptoms associated with benign prostatic hyperplasia) is contraindicated because of the potential for hypotension with combination therapy. One exception is tamsulosin (Flomax), which may be used safely with tadalafil.
Patient teaching
Tell your patient to report all of the medications he's taking to his healthcare provider prior to prescription of these drugs. Advise him to take these drugs only as prescribed and to notify his healthcare provider if he experiences any adverse reactions such as vision or hearing changes. Remind your patient that taking these drugs with nitrates such as nitroglycerin may cause a serious drop in BP and that these medications will not protect him against sexually transmitted diseases.
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