Phosphodiesterase 5 Inhibitors in Pulmonary Hypertension

Phosphodiesterase 5 inhibitors (sildenafil and tadalafil) prevent breakdown of cyclic GMP in pulmonary vascular smooth muscle, causing vasodilation and reducing proliferation. They are oral first-line drugs for pulmonary arterial hypertension, and sildenafil is also used in persistent pulmonary hypertension of the newborn.

Mechanism. Nitric oxide raises cyclic GMP, and phosphodiesterase 5 is abundant in pulmonary arteries. Inhibition lowers pulmonary vascular resistance and improves exercise capacity and haemodynamics.

Pharmacokinetics. Sildenafil has bioavailability of about 40 percent, a half life of 3 to 5 hours and is cleared by CYP3A4 and CYP2C9, so dosing is three times daily. Tadalafil has a half life of about 35 hours, is cleared by CYP3A4 and allows once daily dosing.

Sildenafil. 20 mg orally three times daily, taken 6 to 8 hours apart. Intravenous bolus 10 mg three times daily when the patient cannot swallow, equal to 20 mg orally. Higher doses add little benefit and more adverse effects.

Tadalafil. 40 mg orally once daily, taken as 2 tablets of 20 mg. Some practice starts 20 mg once daily for 2 to 4 weeks, then increases.

Children. Sildenafil 10 mg three times daily under 20 kg and 20 mg three times daily at 20 kg or more. Higher doses were linked with excess mortality in children, so do not exceed these doses.

Newborns. Sildenafil 0.5 to 1 mg/kg orally every 6 to 8 hours is used in persistent pulmonary hypertension of the newborn when nitric oxide is unavailable.

Differences. Tadalafil gives once daily dosing, which helps adherence. Sildenafil is cheaper and more widely available.

PAH. Used with an endothelin receptor antagonist as initial combination, or alone when combination is not possible. Add to an endothelin receptor antagonist when response is inadequate. Used with prostacyclin in high risk disease.

Group 2 and 3. Not advised, because benefit is unproven and gas exchange can worsen. Do not use in left heart failure with preserved ejection fraction for pulmonary hypertension alone.

Switching to riociguat. Stop sildenafil at least 24 hours, or tadalafil at least 48 hours, before the first dose of riociguat.

Region. Generic sildenafil is cheap, widely available and often the first and only specific drug in East Africa. Confirm pre-capillary disease before prescribing, because the same drug may be used for erectile dysfunction in the same patient, and avoid duplicate prescriptions.

Contraindications. Any nitrate, nicorandil or riociguat (profound hypotension). Recent stroke or myocardial infarction, severe hypotension, and loss of vision from non-arteritic anterior ischaemic optic neuropathy.

Adverse effects. Headache, flushing, dyspepsia, nasal congestion, epistaxis, myalgia and visual disturbance. Rare effects are sudden loss of vision, sudden hearing loss and priapism needing urgent care.

Interactions.

• Ritonavir and other strong CYP3A4 inhibitors raise levels, so start tadalafil at 20 mg once daily or alternate days, and avoid sildenafil with ritonavir.
• Rifampicin and bosentan lower sildenafil levels, and rifampicin lowers tadalafil levels, so avoid or monitor response.
• Alpha blockers and antihypertensives add hypotension.

Monitoring. Functional class, 6 minute walk distance, blood pressure and visual or hearing symptoms.

Special groups. Pregnancy: limited data, used under specialist care in high risk PAH. Breastfeeding: small amounts in milk, specialist decision. Hepatic impairment: tadalafil 20 mg once daily in mild to moderate impairment and avoid in Child-Pugh C. Renal impairment: tadalafil start 20 mg once daily when creatinine clearance is 31 to 80 mL/min, and avoid under 30 mL/min. Older adults: start low.

Referral and escalation. Any sudden loss of vision, priapism over 4 hours or syncope needs urgent assessment. Worsening functional class despite treatment needs escalation in a specialist centre.