Sildenafil for Pulmonary Hypertension

Sildenafil is an oral phosphodiesterase-5 inhibitor used for pulmonary arterial hypertension (PAH, group 1) at a lower dose than for erectile dysfunction, and off label for persistent pulmonary hypertension of the newborn. Start only in a PAH centre after right heart catheterisation. It is not for pulmonary hypertension from left heart disease or lung disease.

Classification. Phosphodiesterase-5 inhibitor, pulmonary vasodilator.

Mechanism. Blocks breakdown of cyclic GMP in pulmonary vascular smooth muscle, enhancing nitric oxide-mediated vasodilatation and reducing vascular remodelling.

Pharmacokinetics. Oral bioavailability about 40%. Peak at about 1 hour; fatty meals delay absorption. Metabolised by CYP3A4 (major) and CYP2C9 to an active metabolite. Half-life 3 to 5 hours. Excreted mainly in faeces.

Specialist, PAH, adults. 20 mg three times daily, 6 to 8 hours apart. Specialists sometimes titrate to 40 to 80 mg three times daily off label; higher doses add adverse effects without proven extra benefit.

Intravenous, when oral dosing is not possible. 10 mg as an injection three times daily, which matches 20 mg orally.

Children 1 to 17 years, specialist. Body weight 20 kg or less: 10 mg three times daily. Over 20 kg: 20 mg three times daily. Higher doses were linked to higher mortality in children.

Neonatal persistent pulmonary hypertension, specialist, off label. Oral 0.5 to 2 mg/kg every 6 hours, or an intravenous loading dose of 0.4 mg/kg over 3 hours then 0.07 mg/kg/hour, in neonatal intensive care.

Combination. Often combined with an endothelin receptor antagonist. Bosentan lowers sildenafil levels by about 60% and raises bosentan levels slightly.

Emergency. Not used for acute decompensation outside specialist care.

Titration and loading. No loading dose in adults. Keep to the labelled dose unless a specialist titrates.

Contraindications. All nitrates and nitric oxide donors (including nicorandil), riociguat, hypersensitivity, recent stroke or myocardial infarction, severe hypotension, and pulmonary veno-occlusive disease (risk of pulmonary oedema).

Serious adverse effects. Hypotension, non-arteritic anterior ischaemic optic neuropathy, sudden hearing loss, priapism, epistaxis and haemoptysis, vaso-occlusive pain crises in sickle cell disease.

Common adverse effects. Headache, flushing, dyspepsia, nasal congestion, diarrhoea, visual colour changes, myalgia.

Interactions.

• Nitrates: profound hypotension; contraindicated.

• Ritonavir and other strong CYP3A4 inhibitors raise levels sharply. With ritonavir, avoid. With ketoconazole, itraconazole or clarithromycin, consider 20 mg twice daily.

• Rifampicin and other inducers lower levels.

• Alpha-blockers and antihypertensives add hypotension.

Common prescribing errors. Using the erectile dysfunction strengths (25, 50, 100 mg) without matching the labelled PAH dose. Prescribing with nitrates. Using in sickle cell pulmonary hypertension. Using in left heart disease.

Special groups.

• Pregnancy: PAH carries high maternal risk. Sildenafil is used under specialist care when needed. Breastfeeding: small amounts in milk; use under specialist advice.

• Children: dosing is weight-banded.

• Older adults: start at the labelled dose and watch blood pressure.

• Kidney impairment: no adjustment in PAH; caution in severe impairment. Liver impairment: caution; not studied in severe disease.

• East Africa: sickle cell disease is common, and sildenafil increased hospitalisation for pain crises in sickle cell pulmonary hypertension, so avoid it there. Schistosomiasis-related PAH occurs. Generic 20 mg tablets may not be stocked, and mixing up erectile dysfunction strengths causes dosing errors. Rifampicin and ritonavir change exposure.

Formulations. Tablets 20 mg (PAH); tablets 25, 50 and 100 mg (erectile dysfunction); oral suspension 10 mg/mL; injection 10 mg/12.5 mL.

Administration. Three times daily with or without food, at even intervals.

Baseline. Blood pressure, right heart catheter results, functional class, 6 minute walk distance, NT-proBNP, nitrate use, eye history.

Monitoring. Blood pressure, symptoms of hypotension, visual and hearing changes, functional class and 6 minute walk distance every 3 to 6 months.

Stop and reduce rules. Stop for sudden visual or hearing loss, priapism lasting over 4 hours, or symptomatic hypotension that does not settle on dose reduction. Stop if pulmonary oedema suggests veno-occlusive disease. Therapeutic drug monitoring is not used.

Referral and escalation. Manage in a PAH centre. Refer urgently for syncope, right heart failure or visual loss.