PDE5 inhibitor
From Wikipedia, the free encyclopedia
Cyclic nucleotide phosphodisterases are a group enzymes that hydrolyze cyclic nucleotides such as cyclic AMP and cyclic GMP. These multiple forms or subtypes of cyclic nucleotide phosphodiesterase were initially isolated from rat brain by Uzunov and Weiss in 1972 and were soon afterward shown to be selectively inhibited by a variety of drugs in brain and other tissues (Weiss,1975; Fertel and Weiss, 1976). The potential for selective phosphodisterase inhibitors to be used as therapeutic agents was predicted as early as 1977 by Weiss and Hait. This prediction has now come to pass in a variety of fields.
A phosphodiesterase type 5 inhibitor, often shortened to PDE5 inhibitor, is a drug used to block the degradative action of phosphodiesterase type 5 on cyclic GMP in the smooth muscle cells lining the blood vessels supplying the corpus cavernosum of the penis. These drugs are used in the treatment of erectile dysfunction, and were the first effective oral treatment available for the condition.
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[edit] Mode of action
Part of the physiological process of erection involves the release of nitric oxide (NO) in vasculature of the corpus cavernosum as a result of sexual stimulation. NO activates the enzyme guanylate cyclase which results in increased levels of cyclic guanosine monophosphate (cGMP), leading to smooth muscle relaxation in blood vessels supplying the corpus cavernosum, resulting in increased inflow of blood and an erection.
PDE5 inhibitors inhibit the degradation of cGMP by phosphodiesterase type 5 (PDE5), increasing bloodflow to the penis during sexual stimulation.
This mode of action means that PDE5 inhibitors are ineffective without sexual stimulation.
[edit] Clinical use of PDE5 inhibitors
[edit] Indications
PDE5 inhibitors are clinically indicated for the treatment of erectile dysfunction.
Sildenafil, the prototypical PDE5 inhibitor, was originally discovered during the search of a novel treatment for angina. Recent studies are exploring its use as a treatment for pulmonary hypertension (Kanthapillai, Lasserson & Walters, 2004), and its potential for increasing neurogenesis after stroke (Zhang, Wang et. al, 2002).
[edit] Contraindications
PDE5 inhibitors are contraindicated in those taking nitrate medication. They are also contraindicated in men for whom sexual intercourse is inadvisable due to cardiovascular risk factors. (Rossi, 2004)
[edit] Adverse drug reactions
The occurrence of adverse drug reactions (ADRs) with PDE5 inhibitors appears to be dose related. Headache is a very common ADR, occurring in >10% of patients. Other common ADRs include: dizziness, flushing, dyspepsia, nasal congestion or rhinitis. (Rossi, 2004)
Other ADRs and their incidence vary with the agent and are listed in their individual pages.
[edit] Drug interactions
PDE5 inhibitors are primarily metabolised by the cytochrome P450 enzyme CYP3A4. The potential exists for adverse drug interactions with other drugs which inhibit or induce CYP3A4, including HIV protease inhibitors, ketoconazole, itraconazole, etc (Rossi, 2006).
[edit] Examples
Sildenafil was the prototypical member of the PDE5 inhibitors. Two other agents, with their own advantages/disadvantages are also available.
[edit] References
Uzunov, P. and Weiss, B.: Separation of multiple molecular forms of cyclic adenosine 3',5'-monophosphate phosphodiesterase in rat cerebellum by polyacrylamide gel electrophoresis. Biochim. Biophys. Acta 284:220-226, 1972.
Weiss, B.: Differential activation and inhibition of the multiple forms of cyclic nucleotide phosphodiesterase. Adv. Cycl. Nucl. Res. 5:195-211, 1975.
Fertel, R. and Weiss, B.: Properties and drug responsiveness of cyclic nucleotide phosphodiesterases of rat lung. Mol. Pharmacol. 12:678-687, 1976.
Weiss, B. and Hait, W.N.: Selective cyclic nucleotide phosphodiesterase inhibitors as potential therapeutic agents. Ann. Rev. Pharmacol. Toxicol. 17:441-477, 1977.
- Kanthapillai P, Lasserson TJ, Walters EH. Sildenafil for pulmonary hypertension. Cochrane Database Syst Rev 2004;18(4):CD003562. PMID 15495058
- Rossi S, editor. Australian Medicines Handbook 2006. Adelaide: Australian Medicines Handbook; 2006.
- Zhang, R. et al. Sildenafil (Viagra) induces neurogenesis and promotes functional recovery after stroke in rats. Stroke 33, 2675-80 (2002)
