PDE5 Inhibitors

Content written by Irwin Goldstein MD

PDE 5 inhibitors may be helpful to men with erectile dysfunction (ED) from arterial insufficiency, bicycle riding, pelvic or perineal trauma, venous leak, cancer treatment, diabetes, metabolic syndrome, thyroid problems, or medications such as anti-depressants and SSRIs.

In the baseline flaccid state, the smooth muscles of the penis are contracted. To achieve an erection, relaxation of the smooth muscles must occur. When taken orally prior to sexual activity, PDE5 inhibitors facilitate sustained smooth muscle relaxation following sexual stimulation. With the penis muscles relaxed, more arterial blood enters the erection chambers. This blood is trapped in the erection chambers resulting in a more rigid and sustained erection.

Sildenafil (Viagra) was the first PDE5 inhibitor, followed by vardenafil (Levitra), tadalafil (Cialis) and avanafil (Stendra). The four agents taken together as a class have been studied in men of different ages and races, with diabetes, hypertension, cigarette smoking, high cholesterol, obesity, spinal cord injury, multiple sclerosis and more. The safety and efficacy of these products for erectile dysfunction are well documented.

When a man with erectile dysfunction is given a PDE5 inhibitor, not only is sexual function improved, but that of his untreated woman partner is improved as well if she was initially without sexual dysfunction. When the man with ED is given a placebo (sugar pill), the sexual function of the untreated woman partner worsens, assuming she was without sexual dysfunction before. Sexual dysfunctions and sexual treatments can affect both members of the couple even though only one member is treated.

Until 2008, the only use of PDE5 inhibitors approved by the government was for administration of PDE5 inhibitors prior to sexual activity. In 2008, the FDA approved a first-ever daily dosing schedule of the PDE5 inhibitor tadalafil (Cialis) for the treatment of men with erectile dysfunction. Daily dosing would obviously eliminate the need for men with ED to associate PDE 5 inhibitor pill administration with sexual activity. Daily dosing would be indicated in men with ED who have frequent sexual activity more than 8 times per month.

It has been shown repeatedly that daily use of low dose PDE5 inhibitors has beneficial effects on a host of medical problems including heart disease, angina, stroke recovery, Reynaud’s disease, voiding difficulties (lower urinary tract symptoms or LUTS), pulmonary hypertension, infertility, altitude sickness, unhealing wounds, premature ejaculation and anal fissures. All of these uses, other than pulmonary hypertension, are “off-label”, in that the FDA has not yet approved daily administration of PDE 5 inhibitors for their management. The basic principle underlying the medical advantages of chronic daily administration of low dose PDE5 inhibitors is that the medication improves the health of the endothelial or lining cells of arteries. Chronic use of PDE5 inhibitors is widely used by urologists for penile rehabilitation post-radical prostatectomy. There are also data showing that daily dosing of low dose PDE5 inhibitors allows men with ED the ability to recover erectile function.

Recognized side effects of PDE5 inhibitors include headache, flushing, nasal congestion and back pain. There were observational data reporting blindness, however subsequent investigation using higher-level science (double-blind, placebo-controlled trials) showed no evidence for this concern. There were recent observational data reporting hearing loss, however subsequent investigation using higher-level science (double-blind, placebo-controlled trials) showed no evidence for this concern. Strict contraindication of PDE5 use is concomitant use of nitroglycerin. Research into the use of PDE5 inhibitors in men with heart disease ironically showed that PDE5 inhibitors are actually beneficial. There is less heart muscle death when a heart attack occurs while on a PDE5 inhibitor.

How physicians will choose which of the drugs to prescribe will be much the same as electing among other classes of drugs with multiple pharmacologic treatment options. The selection process will take into account drug pharmacokinetic and pharmacodynamic profiles, physicians’ previous experiences, patient satisfaction and preferences as well as the recognition that similar drugs may have significantly different effects in the same individual.