The effects of chronic phosphodiesterase-5 inhibitor use on different organ systems

Abstract

Phosphodiesterase-5 (PDE-5) inhibitors selectively inhibit PDE-5 enzymes that are present in various tissues like penile tissue, platelets, vascular, and smooth muscle tissue. The drug's actions on these tissues have lead to the successful therapeutic use in patients suffering from conditions such as erectile dysfunction (ED) and pulmonary hypertension. PDE-5 inhibitors (PDE-5i) act on the erectile tissue causing penile smooth muscle relaxation and vasodilatation leading to penile erection. In addition, in particular when used in conjunction with prostaglandin inhibitors, PDE-5i cause vasodilatation in pulmonary vasculature hence decreasing both the pulmonary arterial pressure and resistance. PDE-5i have also shown to mildly decrease blood pressure, increase cardiac index, and increase coronary blood flow in experimental animals as well as in human studies. The Food and Drug Administration (FDA) has approved three PDE-5i for the treatment of ED: sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) and one for pulmonary hypertension: sildenafil (Revatio). These agents are highly selective for PDE-5 enzymes as compared to other subclasses of PDE enzymes and have the almost identical pharmacological action but slightly different pharmacokinetics. Only little data exist about long-term use of PDE-5i and their effects on different organ system. This paper reviews the current information available on chronic PDE-5 inhibitor use.

Expression of the PDE5 enzyme on human retinal tissue: new aspects of PDE5 inhibitors ocular side effects

“…PDE5 enzyme on human retinal tissue C Foresta et al the corpora cavernosa of the penis, but many other organs express the PDE5 enzyme such as pulmonary and coronary vasculature, sympathetic nervous system, and Purkinje neurons, [11][12][13] where its influence is less known. Minor adverse effects of PDE5 inhibitors administration such as headache, flushing, hypotension, dyspepsia, and visual disturbances may be due to this influence and inspired many studies.…”

Phosphodiesterase inhibitors in vascular ischemia: A case report and review of their use in ischemic conditions

“…Relative contraindications to the use of PDE5 inhibitors include alpha-blockers and antihypertensive medications. The concurrent use of potent cytochrome P450-3A4 inhibitors (such as erythromycin, ketoconazole or itraconazole) or the nonspecific CYP inhibitor, cimetidine, has been associated with increased plasma levels of PDE5 inhibitors; however, the clinical relevance of these observations remains controversial (11). A recent review (24) on the effects of sildenafil on fatal cardiac events seem to indicate that sildenafil, in fact, may confer a protective effect in the absence of coadministration with alpha-blockers or NO donors.…”

“…In particular, PDE type 5 (PDE5) is located in vascular tissue such as blood vessels, platelets and vascular smooth muscle. Pfizer in the United Kingdom originally developed sildenafil with the intent of augmenting the nitric oxide (NO)/ cyclic GMP (cGMP) pathway for the treatment of angina pectoris in coronary artery disease patients (11 (12), and have become blockbuster drugs with annual sales in the $3 billion range.…”

“…Its effects on blood flow are noticeable in the alleviation of disorders associated with decreased blood flow. As a result, in addition to its established role in the treatment of erectile dysfunction, these drugs have been used successfully for other conditions, such as primary and secondary pulmonary hypertension, congestive heart failure and diabetic neuropathy (11,(15)(16)(17). There is also mounting evidence that sildenafil may be beneficial in the treatment of Raynaud's phenomenon, joint stiffness and fibrosis in systemic sclerosis, and digital ischemia (18)(19)(20).…”

Anti-ischemic effects of sildenafil, vardenafil and tadalafil in heart

“…Unfortunately, none has produced any notable clinical applications. Considering the safety of PDE-5 inhibitors and their overwhelmingly reproducible protective effects in the heart and their potential benefits in other organ systems, 6 it is logical to expect that this class of drugs may be promising therapeutic agents to treat IHD, similar to the recently approved use of sildenafil for treating pulmonary hypertension. Clearly, future clinical trials are required to fully exploit the cardioprotective potential of PDE-5 inhibitors in patients.…”