Phosphodiesterase-5 (PDE-5) inhibitors

Phosphodiesterase-5 metabolizes the nitric acid and natriuretic peptide systems’ second messenger cyclic guanosine monophosphate.

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.

PDE5 is the target of oral erectile dysfunction drugs and is a part of the signaling pathway which includes RAS-RAF-MEK-and ERK.

BRAF gene down regulates PDE5.

PDE5 is also present in the arterial wall smooth muscle within the lungs, and PDE5 inhibitors are used for the treatment of pulmonary hypertension.

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.

The occurrence of adverse drug reactions are dose related.

Adverse drug reactions include: Headache, occurring in >10% of patients, dizziness, flushing, dyspepsia, nasal congestion or rhinitis.

Use associated with modest increase in malignant melanoma and basal cell carcinoma.

Possibly associated with hearing loss and anterior optic neuropathy.

PDE5 inhibitors are primarily metabolised by the cytochrome P450 enzyme CYP3A4.

May be associated with adverse drug interactions with other drugs which inhibit or induce CYP3A4, including HIV protease inhibitors, ketoconazole, itraconazole, and other anti-hypertensive drugs.

Sildenafil is the prototypical member of the PDE5 inhibitors.

These drugs preferentially inhibit PDE5, but are not selective, especially at high doses.

Sildenafil also inhibits PDE6 and PDE9.

PDE type 4 is an enzyme that it maintains intracellular levels of cyclic adenosine monophosphate (cAMP) and mediates biological responses to extracellular stimuli in numerous cell types, including immune cells.

Phosphodiesterase inhibitors such as caffeine affect the G-coupled signal transduction cascade, inhibiting the enzyme that catalyzes the breakdown of cAMP, leading to the increased concentration of calcium ions in the cytosol.

PDE 4 has increased activity in psoriatic skin than  in healthy skin.

Inhibition of PDE 4 results in down regulation of immune modulators including TNF alpha, interferon-gamma, Interleukin-17 and interleukin 23.

Apremilast, an oral PDE 4=inhibitor is approved for the treatment of moderate to severe plaque psoriasis.

Inhibition of PDE6 in the retina thought to be responsible for the vision changes which can be a side effect of sildenafil.

An erection involves the release of nitric oxide (NO) in vasculature of the corpus cavernosum as a result of sexual stimulation.

Nitric oxide 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.


Tadalafil has a  longer half-life of 17.5 hours compared to sildenafil and vardenafil, which are both 4�5 hours.


The longer half-life is the basis for its  therapeutic use in treating pulmonary arterial hypertension.


Sildenafil and vardenafil inhibit PDE6, an enzyme found in the eye, more than tadalafil.


Some sildenafil users see a bluish tinge and have a heightened sensitivity to light because of PDE6 inhibition.


Sildenafil and vardenafil also inhibit PDE1 more than tadalafil.


PDE1 is found in the brain, heart, and vascular smooth muscle, and is thought that the inhibition of PDE1 by sildenafil and vardenafil leads to vasodilation, flushing, and tachycardia.

Regular use of phosphodiesterase type 5 inhibitors for erectile dysfunction is associated with increased risk of serious retinal detachment, retinal vascular occlusion, and ischemic optic neuropathy, among older US men in observation studies.





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