PDE-5 Inhibitors

Phosphodiesterase type 5 (PDE-5) inhibitors are oral medications used to treat pulmonary hypertension and erectile dysfunction.

They are currently being investigated as an alternative to the calcium channel blockers used to manage Raynaud’s phenomenon and pulmonary arterial hypertension (PAH), both of which are often associated with systemic scleroderma.

Examples of PDE-5 inhibitors include sildenafil, tadalafil, udenafil, and vardenafil.

How PDE-5 inhibitors work

Pulmonary arterial hypertension and Raynaud’s phenomenon result from the constriction of blood vessels. In PAH, blood vessels that supply the lungs tighten and become narrower, resulting in high blood pressure. This leads to the heart working harder to pump blood to the lungs and, in the long-term, may result in heart failure.

In Raynaud’s, the small blood vessels of the fingers and/or toes are narrowed, reducing blood flow and causing ulcers and possibly gangrene (tissue death). Up to 90 percent of people with systemic scleroderma develop Raynaud’s phenomenon.

PDE-5 is an enzyme found in vessel walls that breaks down a molecule known as cyclic guanine monophosphate (cGMP). cGMP relaxes the muscles in the walls of the blood vessels, dilating or opening the vessels.

PDE-5 inhibitors work by preventing the break down of cGMP, leading to increased concentrations of the molecule. This, in turn, relaxes blood vessels and improves blood flow — lowering blood pressure and heart strain in scleroderma patients with PAH, and increasing blood flow to the digits affected by Raynaud’s.

Studies on PDE-5 inhibitors

Sildenafil, tadalafil, and vardenafil taken orally have been shown in several studies to lower pressure in the blood vessels of the lungs and improve exercise capacity in people with PAH.

A systematic review of studies that investigated oral sildenafil, tadalafil, and vardenafil to treat secondary Raynaud’s found these medications to be moderately effective in reducing the severity, duration, and frequency of Raynaud’s episodes.

A Phase 2/3 clinical trial (NCT01280266), involving 29 people with secondary Raynaud’s in Korea, reported that 100 mg of udenafil each day showed comparable efficacy to 10 mg of daily amlodipine (a calcium channel blocker) in terms of its ability to reduce the severity and frequency of Raynaud’s episodes. Moreover, udenafil was superior to amlodipine in improving blood flow to the fingers.

An observational study (NCT03393325), set to open in October 2018, plans to investigate the efficacy of 2 percent tadalafil cream in treating Raynaud’s phenomenon. About 30 patients with primary or secondary Raynaud’s and using tadalafil cream under prescription at two rheumatology clinics in Ontario, Canada, will be followed for four to eight weeks to determine charges in digital ulcers and other measures.

Further details

Some common side effects associated with the use of PDE-5 inhibitors are headaches, facial flushing, nose blocks, and an upset stomach. More serious but rarer side effects include problems with vision, painful erections lasting more than six hours (priaprism), and sudden hearing loss.


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