Aphosphodiesterase type 5 inhibitor (PDE5 inhibitor) is a vasodilatingdrug that works by blocking the degradative action ofcGMP-specific phosphodiesterase type 5 (PDE5) oncyclic GMP in thesmooth muscle cells lining the blood vessels supplying various tissues. These drugs dilate thecorpora cavernosa of thepenis, facilitating erection with sexual stimulation, and are used in the treatment oferectile dysfunction (ED).Sildenafil was the first effective oral treatment available for ED. Because PDE5 is also present in the smooth muscle of the walls of thearterioles within thelungs, two PDE5 inhibitors, sildenafil andtadalafil, are FDA-approved for the treatment ofpulmonary hypertension. As of 2019, the widercardiovascular benefits of PDE5 inhibitors are being appreciated.[1]
Phosphodiesterase-5 (PDE5) inhibitors such assildenafil (Viagra),tadalafil (Cialis),vardenafil (Levitra), andavanafil (Stendra) are clinically indicated for the treatment oferectile dysfunction.[2] Sildenafil and tadalafil are also indicated for the treatment of some subtypes ofpulmonary hypertension, while tadalafil is also licensed for the treatment ofbenign prostatic hyperplasia.[1]
PDE5 inhibitors have been used as a second line therapy in severe cases ofRaynaud phenomenon when it is related tosystemic sclerosis per The European Society for Vascular Medicine guidelines.[3]
Sildenafil, the prototypical PDE5 inhibitor, was originally discovered during the search of a novel treatment forangina. Studies in 2002 explored its potential for increasingneurogenesis afterstroke,[4] but clinical evidence for benefit in cerebrovascular diseases is currently lacking.[1]
PDE5 inhibitors are contraindicated within 24 hours (or 48 hours with tadalafil) of takingalpha-blockers,soluble guanylate cyclase stimulators, ornitrate medications such asisosorbide mononitrate orisosorbide dinitrate.[1] Concurrent use of these medications can lead to life-threateninglow blood pressure.[5] PDE5 inhibitors are also contraindicated in patients with previous nonarteriticanterior ischaemic optic neuropathy and hereditary eye diseases.[1]
Despite initial concerns of adverse cardiovascular events in patients prescribed PDE5 inhibitors, several long-term studies have established the safety of the drugs in both healthy patients and patients with cardiovascular risk factors.[1]
All PDE5 inhibitors are generally well tolerated.[1] The occurrence of side effects, oradverse drug reactions (ADRs), with PDE5 inhibitors depends on the dose and type of agent.[1]Headache is a very common ADR, occurring in >10% of patients. Other common ADRs include: dizziness, flushing,dyspepsia, nasal congestion or rhinitis.[6] Back pain and muscle aches are also more common in patients taking tadalafil.[1]
In 2007, theU.S. Food and Drug Administration (FDA) announced that a warning about possiblesudden sensorineural hearing loss would be added to drug labels of PDE5 inhibitors.[7]
Since 2007 there has been evidence to suggest that PDE5 inhibitors can cause ananterior optic neuropathy,[8] although theabsolute risk increase is small.[1]
Finally, there are concerns that PDE5 inhibitors may increase the risk ofneonatal mortality in pregnant women, and trials investigating use of the drugs forfetal growth restriction have been suspended.[1]
PDE5 inhibitors are primarily metabolized by thecytochrome P450 enzyme system, particularlyCYP3A4. The potential exists for adverse drug interactions with other drugs which inhibit or induce CYP3A4, includingHIV protease inhibitors,ketoconazole, anditraconazole,[6] although coadministration has not been linked to changes in the safety or efficacy of either agent.[1] Combination withnitrovasodilators such asnitroglycerin andPETN is contraindicated because potentially life-threateninghypotension may occur.[9] PDE5 inhibitors do not interactsynergistically with otherantihypertensive drugs.[1]
The PDE5 inhibitor story begins with the work of the British physician and physiologist Henry Hyde Salter who, in 1886, noticed that his asthma symptoms eased after drinking a strong cup of coffee. We now know that this was due to thebronchodilator properties ofcaffeine, a non-selective, albeit weak, PDE5 inhibitor.[10] In 1986,Pfizer scientists atSandwich, UK, started preclinical work on the development of a PDE5 inhibitor (later known assildenafil citrate) for the treatment ofangina.
Sildenafil,tadalafil,vardenafil andavanafil are the main agents marketed globally, althoughsimmerafil,mirodenafil,udenafil,gisadenafil [d],yonkenafil (tunodafil) andlodenafil are available in some countries.[1] Other agents with weak PDE5 inhibitory properties includefenspiride,MBCQ,zaprinast andicariin.[11]
Although all PDE5 inhibitors share the same mechanism of action, each agent has differentpharmacokinetics andpharmacodynamics which affect how quickly it acts, how long its effects last, and its side effects.[1] Notably, although all PDE5 inhibitors preferentially inhibit PDE5, the degree to which they also inhibit otherphosphodiesterases influences their side effect profile.[1] For example, sildenafil also inhibitsPDE6 which is present in theretina of the eye; this reaction is thought to be responsible for the temporary visual changes which some patients using sildenafil experience. Similarly tadalafil also inhibitsPDE11 which is present in the prostate, although no effects on fertility have been reported.[1] Although agents more selective for PDE5 were in development, these trials have been suspended, likely due to the saturation of the market with the introduction of agents with broad cardiovascular benefits, such asSGLT2 inhibitors andendothelin receptor antagonists.[1]
Nevertheless, PDE5 inhibitors already marketed forerectile dysfunction andpulmonary arterial hypertension are undergoing research in several conditions such asresistant hypertension,myocardial infarction,heart failure,intermittent claudication,Raynaud's phenomenon,chronic kidney disease, anddiabetes mellitus due to our greater appreciation of their broad physiological properties.[1]
There are some PDE5 inhibitors, generally not approved by any health regulatory agency, that have been found as undeclared ingredients or adulterants in a variety of supplements which are sold as "natural" or "herbal" sexual enhancement products. Examples areacetildenafil,aildenafil,homosildenafil,nitrosoprodenafil, andsulfoaildenafil, andthioquinapiperifil [d].[citation needed]
Part of the physiological process of vasodilatation involves the release ofnitric oxide (NO) by vascular endothelial cells which then diffuses to nearby vascular smooth muscle cells. There, NO activates solubleguanylate cyclase which convertsguanosine triphosphate (GTP) tocyclic guanosine monophosphate (cGMP), the main effector of the system. For example, in the penis, NO release at high levels from endothelial cells and penile nerves duringsexual stimulation leads to relaxation of the smooth vasculature of thecorpus cavernosum, causingvasocongestion and a sustained erection.[1]
PDE5 inhibitors prolong the action of cGMP by inhibiting its degradation by the enzyme PDE5, which is found throughout the body. In the penis, PDE5 inhibitors potentiate the effects of cGMP to prolong erections and increase sexual satisfaction.[12] However, PDE5 inhibitors do not cause erections without sexual stimulation.
As well as their haemodynamic effects, PDE5 inhibitors have also been shown to have anti-inflammatory, antioxidant, antiproliferative, and metabolic properties in several experiments.[1] However, larger and longer-term studies are needed to establish their effectiveness and safety compared to other medications in other diseases.