Pharmacotherapy of Pulmonary Hypertension

Pharmacotherapy of Pulmonary Hypertension

1. Definition, haemodynamics & disease overview

• Pulmonary hypertension (PH) is defined as a mean pulmonary arterial pressure (mPAP) > 20 mmHg at rest, measured by right heart catheterization (RHC); the historic threshold of >25 mmHg has been lowered (Simonneau et al., 2019) (G&G 14e Ch.35, p.695).
• The pulmonary circulation is normally a low-pressure, low-resistance circuit; mean PAP in healthy subjects is 14.0 ± 3.3 mmHg (G&G 14e Ch.35, p.695).
• The defining haemodynamic relationship is PAP = CO × PVR (cardiac output × pulmonary vascular resistance); the pulmonary circulation runs in series with the systemic circulation and receives the entire cardiac output each cardiac cycle (G&G 14e Ch.35, pp.695–696).
• Because PVR ∝ 1/r⁴ (Poiseuille), a small fall in arteriolar radius causes a large rise in resistance — a 16% decrease in radius (to 0.84 r) doubles PVR (G&G 14e Ch.35, Fig.35–1, p.697).
• Pulmonary arterial hypertension (PAH) is the WHO Group 1 subset — a primary disorder of the small pulmonary arteries/arterioles, and the most-studied subset and principal target of available drug therapy (G&G 14e Ch.35, pp.695–696).
• The full haemodynamic definition of PAH (DiPiro): mPAP ≥ 20 mmHg at rest + pulmonary capillary wedge pressure (PCWP) or LVEDP ≤ 15 mmHg + PVR > 3 Wood units (= 24 MPa·s/m³) by RHC — the wedge/PVR criteria distinguish pre-capillary PAH from post-capillary (left-heart) PH (DiPiro 12e Ch.46, p.419).
• Idiopathic PAH (IPAH) is rare, progressive and fatal; untreated median survival ≈ 2.8 years, extended to ≈ 9 years with modern therapy (Benza et al., 2012) (G&G 14e Ch.35, p.695; DiPiro 12e Ch.46, p.419).
• Pre-therapy era survival (IPAH) was 68%/48%/34% at 1/3/5 yr; in the modern (post-epoprostenol, 1995) era, registry 1- and 3-yr survival rose to ~85%/68% (PAH) and ~91%/74% (IPAH) (DiPiro 12e Ch.46, p.419).
• Elevated RV afterload → RV dysfunction and failure, which is the major cause of morbidity and mortality in PAH (Voelkel et al., 2012) (G&G 14e Ch.35, p.695; DiPiro 12e Ch.46, p.420).
• Therapy is palliative, not curative — it improves symptoms, function, haemodynamics and survival but does not cure the underlying vasculopathy (KDT 8e Ch.37, p.547).

Epidemiology (DiPiro)

• PAH prevalence ≈ 15–26 per million; IPAH incidence ≈ 2.0–7.6 per million in North America/Europe, with female predominance (M:F ≈ 1:1.7) (DiPiro 12e Ch.46, pp.419–420).
• Historically mean age at recognition ≈ 37 yr; recent registries show diagnosis now commoner in older patients (mean 50–65 yr) (DiPiro 12e Ch.46, p.420).
• Worldwide, the commonest cause of PAH is schistosomiasis, then congenital heart disease and PH of early childhood; in US registries (REVEAL) ~46% IPAH, ~25% connective-tissue-disease–associated, ~10% congenital heart disease (DiPiro 12e Ch.46, pp.419–420).