The Three Pharmacological Pathways in Pulmonary Hypertension Treatment

Two mechanisms operate together. Viral proteins cause stiffness in the lung's interstitial tissue, which physically compresses the pulmonary blood vessels. At the same time, the immunocompromised state associated with HIV promotes smooth muscle hyperplasia within the vessel walls, narrowing the lumen from within. It's the combination of external compression and internal luminal narrowing that drives HIV-associated pulmonary hypertension.

The pulmonary valve opens against a high-pressure circuit, so when it closes, it's slammed shut by that elevated pressure — a forceful, rapid closure that produces the loud P2. It isn't the size of the valve that determines the loudness, it's the closing pressure. That's why even in conditions like tetralogy of Fallot, where pulmonary stenosis would normally produce a soft P2, elevated pulmonary arterial pressure from collateral flow can still produce a loud P2 despite the outflow obstruction.

After the first trimester, amlodipine and other calcium channel blockers are reasonably safe. For eclampsia or hypertension specifically during pregnancy, the preferred agent is a direct alpha agonist, such as prazosin.

Any mean pulmonary artery pressure greater than 20 mmHg combined with a pulmonary vascular resistance greater than 2 Wood units should be started on therapy — at minimum, a PDE5 inhibitor plus an endothelin receptor antagonist as double therapy. If the patient remains symptomatic, we add a prostacyclin analog to complete triple therapy. Escalating beyond triple therapy to sotatercept should only be considered after at least six months to a year of adequate triple therapy without sufficient response.

First, PDE5 inhibition, to promote vascular relaxation via the cGMP pathway. Second, soluble guanylate cyclase stimulation, to address back-pressure and encourage vasodilation. Third, endothelin receptor blockade, to retard smooth muscle cell hypertrophy and reduce pulmonary vascular resistance. Sotatercept adds a fourth, distinct pathway — anti-proliferative inhibition of activin signalling — which addresses the underlying vascular remodelling rather than just haemodynamics.

Tadalafil is the preferred starting agent, dosed at 2.5 mg once daily for patients under 60 kg and 5 mg once daily for patients 60 kg or above.

Younger male patients should be counselled specifically on the risk of prolonged erections, a side effect that should be addressed directly, with psychological support offered if needed, and one that tends to lessen as the dose is escalated.

Macitentan, taken at 10 mg once daily, is preferred because it has been shown to reduce composite endpoints and clinical worsening events at one, three, and five years, compared with alternatives such as bosentan and ambrisentan.

Iloprost is given by inhalation multiple times a day and commonly causes severe pruritus, dry mouth, and allergic reactions, so dose titration is essential.

Selexipag is typically dosed at 200 micrograms twice daily for most adults, reduced to 100 micrograms twice daily for patients under 50 kg.