Phosphodiesterase Inhibitors by Ray Sahelian, M.D.

A phosphodiesterase (PDE) is an enzyme that catalyzes the hydrolysis of phosphodiester bonds. There are 11 families of phosphodiesterases, namely PDE1-PDE11. Phosphodiesterases are responsible for the degradation of the cyclic nucleotides cAMP and cGMP. They are therefore important regulators of signal transduction mediated by these molecules. Consider Passion Rx for herbal sexual enhancement.

Phosphodiesterase and impotence

The oral phosphodiesterase type 5 (PDE5) inhibitors have become quite popular for the treatment of erectile dysfunction. Phosphodiesterase type 5 inhibitors enhance cavernosal smooth muscle relaxation, vasodilatation and penile erection. However, phosphodiesterase type 5 inhibitors are not always effective. Decreased efficacy, cost, incorrect administration, lack of sexual stimulation, vascular risk factors associated with ED and vascular or neurogenic diseases are causes of phosphodiesterase type 5 inhibitor failure.

Tolerance to Phosphodiesterase Inhibitors

Tolerance is defined as reduced tissue responsiveness to a drug in the presence of a constant concentration of this drug. Phosphodiesterase inhibitor treatment failure may cause considerable distress.

Alternative treatment to Phosphodiesterase Inhibitors

These include sublingual apomorphine, intracavernosal/intraurethral pharmacotherapy, vacuum devices, the insertion of a prosthesis and penile vascular surgery. Another option is to use natural sexual enhancement herbs.

     Combination therapy like prostaglandin E(1) (PGE(1)) with doxazosin (dox; an alpha-1-blocker) or ketanserin (ketan; a 5-HT(2) antagonist) as well as other pro-erection agents, like Endothelin-1 antagonists, angiotensin II antagonists (valsartan/losartan), adrenomedullin, Rho kinase inhibitors and nitric oxide donors may be beneficial in the treatment of ED. However, these combination therapies need to be validated. Adding an androgen to a PDE5 inhibitor may help when circulatory testosterone levels are low. The early use of phosphodiesterase type 5 inhibitors in patients with hypertension, hyperlipidaemia or diabetes with concomitant ED and treating these risk factors may improve corporeal blood flow and lead to long-term preservation of cavernosal function. Therefore, the efficacy of phosphodiesterase type 5 inhibitors may be maintained.

Choosing a Phosphodiesterase Inhibitor

Of the current options available to treat erectile dysfunction, oral phosphodiesterase type 5 (PDE5) inhibitors are the recommended first-line treatment. There are three currently licensed PDE5 inhibitors: sildenafil citrate (sildenafil), vardenafil HCl (vardenafil) and tadalafil. All three phosphodiesterase type 5 (PDE5) inhibitor drugs have similar efficacy and toxicity profiles. Sildenafil and vardenafil have similar molecular structures, but tadalafil is structurally different. With regard to the onset of action, achievement of an erection that leads to successful intercourse has been reported for 35% of patients treated with sildenafil within 14 min, 21% of patients treated with vardenafil within 10 min and 16% of patients treated with tadalafil within 16 min. Sildenafil and vardenafil both have half-lives of approximately 4 h but the half-life of tadalafil is 17 h. Another difference between the PDE5 inhibitors is that food, especially fatty food, affects the pharmacokinetic profiles of sildenafil and vardenafil, but not that of tadalafil. These pharmacokinetic differences among the PDE5 inhibitors may underlie patient preference, an important and emerging aspect of ED therapy.

Early phosphodiesterase inhibitor use after brachytherapy aids erectile function
After brachytherapy for prostate cancer, use of a phosphodiesterase inhibitor such as sildenafil within a year, rather than later, may restore and preserve erectile function. Dr. Jonathan D. Schiff and colleagues from Mount Sinai Medical Center, New York studied 210 men who underwent brachytherapy and subsequently used a phosphodiesterase inhibitor ( sildenafil or vardenafil ) -- 85 within 1 year of treatment (mean 191 days) and 125 who started after 1 year (mean 595 days). Baseline and 12-month Sexual Health Inventory for Men (SHIM) scores were not significantly different between the two groups. However, SHIM scores at 18-36 months after brachytherapy were significantly different. The men in the early group had earlier and sustained improvements in erectile function that were not apparent in the late group. The researchers say, "We think that using oral phosphodiesterase inhibitors after brachytherapy helps to preserve the endothelium of the erectile tissue, and to preserve penile blood flow," the investigators write. "This should decrease the corporal fibrosis that is often seen after radiotherapy. Preventing fibrosis should lead to better erectile function, as was apparently the case in the present patients." BJU Int 2006;98:1255-1258.
   Comments: It is possible that the use of natural herbs for erectile function may also provide such benefits.

Oxytocin release in rats?
Viagra, made by Pfizer Inc., is an inhibitor of an enzyme called phosphodiesterase type 5. Related drugs such as Eli Lilly and Co.’s Cialis, known generically as tadalafil, and Levitra or vardenafil, sold by GlaxoSmithKline, Bayer AG and Schering-Plough, are also PDE-5 inhibitors. They block this enzyme, which in turn breaks down other compounds. This increases blood flow in the muscles but it also affects a brain structure known as the posterior pituitary. This, in turn, boosts oxytocin in rats.