Phosphodiesterase type-5 (PDE-5) inhibitors are used in the management of erectile dysfunction (ED), pulmonary arterial hypertension (PAH), and digital ulcers. Common examples include sildenafil, tadalafil, vardenafil, and avanafil. Additionally, tadalafil is licensed for use in benign prostatic hyperplasia (BPH). This article outlines their mechanism of action, pharmacokinetic parameters, cautions and contraindications, adverse effects, and clinically significant drug interactions, focusing primarily on sildenafil and tadalafil. Mechanism of Action Erection occurs when nitric oxide (NO) is released in the corpus cavernosum during sexual stimulation. NO activates guanylate cyclase, which increases cyclic guanosine monophosphate (cGMP), leading to smooth-muscle relaxation and increased blood flow to the penis. Phosphodiesterase (PDE) type 5 is an enzyme found in the corpus cavernosum smooth muscle, vascular and visceral smooth muscle, skeletal muscle, platelets, kidneys, lungs and cerebellum. PDE type-5 degrades cGMP, therefore PDE type-5 inhibitors increase cGMP levels and enhance the relaxant effect of NO. NO is only released during sexual stimulation, therefore sexual activity must occur for PDE type-5 inhibitors to be effective. Generally they are taken 15-60 minutes prior to sexual activity. Sildenafil, tadalafil, avanafil and vardenafil are selective for type 5 PDE which is the phosphodiesterase involved in the erection process. PDE-6 (involved in retinal phototransduction) and PDE-3 (involved in cardiac contractility) may also be affected to a small extent, explaining certain side effects such as visual disturbances and cardiac effects. PDE type 5 inhibitors can also be used in pulmonary arterial hypertension, a rare condition where blood pressure in the lung is abnormally high. PDE type 5 inhibitors cause the blood vessels to relax thus increasing blood flow to the lungs and lowering blood pressure. Furthermore, PDE type 5 inhibitors can play a role in the treatment of digital ulcers (open sores that can appear on the fingers or toes). Digital ulcers can be caused by conditions such as Raynaud’s syndrome or systemic sclerosis (scleroderma), usually due to poor blood flow to the fingertips or toes. PDE type-5 inhibitors have vasodilatory effects thereby increasing blood flow to fingertips and toes. Created in BioRender. Boucher, M. (2025) https://BioRender.com/dp3rq7b Fig 1: mechanism of action of PDE type-5 inhibitors Pharmacokinetic Parameters Parameter Sildenafil Tadalafil Formulations Tablets (PK described below), oral suspension, IV solution Tablets Absorption F ≈ 41%; Tmax 30–120 min; delayed by food (≈ 1 h) F unknown; Cmax ≈ 2 h Distribution Vd = 105 L; 96% protein-bound Vd = 63 L; 94% protein-bound Metabolism CYP3A4 (major), CYP2C9 (minor); active metabolite ≈ 50% potency CYP3A4 (primary); inactive metabolites Elimination Half-Life 3–5 h 17.5 h Excretion Mainly faecal; reduced clearance in renal/hepatic impairment If CrCl <30ml/min or hepatic impairment such as cirrhosis, then consider dose reduction on initiation and monitor for efficacy and tolerability Mainly faecal; exposure ↑ in hepatic/renal impairment (avoid once-daily use in severe renal disease) Cautions and Contraindications Cautions Contraindications Active peptic ulcer or bleeding disorders (sildenafil, vardenafil, avanafil) Anatomical penis deformation Autonomic dysfunction Cardiovascular disease Left ventricular outflow obstruction Predisposition to priapism (e.g. ,sickle-cell disease, multiple myeloma, or leukaemia) Hypotension/intravascular volume depletion/pulmonary veno-occlusive disease when used for pulmonary arterial hypertension Susceptibility to prolongation of QT interval or older age (vardenafil) Hereditary degenerative retinal disorders (sildenafil, vardenafil, avanafil) History of non-arteritic anterior ischaemic optic neuropathy Recent history of myocardial infarction (within 90 days for tadalafil) or stroke Hypotension (systolic BP <90mmHg) Heart failure (mild to severe, tadalafil, and avanafil) Uncontrolled hypertension or arrhythmias (avanafil and tadalafil) For pulmonary arterial hypertension: sickle-cell disease Erectile dysfunction: For patients whom sexual activity is inadvisable (e.g. unstable angina, angina during intercourse or severe cardiac failure) Severe hepatic impairment (sildenafil, vardenafil film coated tablets and avanafil), moderate to severe (vardenafil orodispersible tabs) Adverse Effects Very common adverse effects for sildenafil include gastrointestinal disorders and vision disorders. Sildenafil rarely causes acute coronary syndrome, priapism, optic neuropathy (discontinue if sudden visual impairment occurs) and sudden cardiac death. Tadalafil causes prolonged erections (uncommon) and priapism (rare). Decreased or sudden hearing loss has been reported with tadalafil (rare); patients should stop taking tadalafil immediately if either is experienced. Vasodilation occurs likely due to increased cGMP levels in vascular smooth muscle. When being used for erectile dysfunction, the vasodilatory effect of PDE type-5 inhibitors should be considered, as alongside sexual activity (degree of cardiac risk), this may adversely affect patients with underlying cardiac conditions. Interactions Metabolism: All PDE-5 inhibitors are primarily metabolised by CYP3A4. CYP3A4 inducers (e.g. rifampicin) may decrease effectiveness. CYP3A4 inhibitors (e.g. ketoconazole, ritonavir, erythromycin, grapefruit juice) increase exposure and risk of toxicity. Ritonavir + sildenafil: ↑ exposure x10-fold – contraindicated. Other key Interactions: Alpha-1 blockers (e.g. doxazosin): risk of postural hypotension – stabilise patient before co-administration; start PDE-5 inhibitor at the lowest dose, Tadalafil + doxazosin: combination not recommended. Nitric oxide donors (amyl nitrite), nitrates and guanylate cyclase stimulators (riocigut): potentiation of hypotensive effect via effects on cGMP pathway: contraindicated References https://www.medicines.org.uk/emc/product/7141/smpc#gref https://bnf.nice.org.uk/drugs/sildenafil/#medicinal-forms https://www.medicines.org.uk/emc/product/13431/smpc https://bnf.nice.org.uk/drugs/tadalafil/ https://www.phauk.org/about-ph-2/treatment-for-pulmonary-hypertension/oral-therapies/phosphodiesterase-5-inhibitors/#:~:text=PDE5%20helps%20control%20blood%20flow,lungs%20and%20lowers%20blood%20pressure. https://cks.nice.org.uk/topics/erectile-dysfunction/prescribing-information/phosphodiesterase-5-pde-5-inhibitors/#contraindications-cautions Do you think you’re ready? Take the quiz below Pro Feature - Quiz Phosphodiesterase Type-5 Inhibitors Question 1 of 3 Submitting... 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