PharmacologyTier 1Medical Sciences concept

Pulmonary arterial hypertension drug classes and mechanisms (endothelin antagonists, PDE5i, prostacyclin analogues, sGC stimulators)

Core concept

PAH endothelium shows three deficits and one excess; each drug class corrects one

1. Endothelin pathway - excess

Endothelin-1 acts on ET-A (vasoconstriction, proliferation) and ET-B (clearance, some NO release)
Endothelin receptor antagonists
- Bosentan, macitentan - dual ET-A/ET-B; ambrisentan - selective ET-A
- Oral; all are teratogenic and require monthly pregnancy testing

2. Nitric oxide - cGMP pathway - deficient

PDE5 inhibitors (sildenafil, tadalafil) - block cGMP breakdown
sGC stimulators (riociguat) - stimulate soluble guanylate cyclase directly, NO-independent, and sensitise it to NO
- Never combine riociguat with a PDE5 inhibitor - both raise cGMP, profound hypotension

3. Prostacyclin pathway - deficient

IP receptor agonism -> inc cAMP -> vasodilatation, antiproliferation, antiplatelet
- Epoprostenol IV continuous (half-life ~6 min, needs a permanent line and pump)
- Iloprost inhaled, treprostinil SC/IV/inhaled
- Selexipag - oral, non-prostanoid IP receptor agonist

4. Activin signalling - the new axis

Sotatercept - activin receptor type IIA-Fc ligand trap
- Scavenges activin A and GDFs -> restores the BMPR2 (anti-proliferative) vs activin (pro-proliferative) balance
- First new mechanism in over a decade; reverse remodelling, not just vasodilatation

Class	Signature toxicity
ERAs	Hepatotoxicity (bosentan - monthly LFTs), peripheral oedema, anaemia, teratogenic
PDE5i	Headache, flushing, epistaxis; contraindicated with nitrates
Riociguat	Hypotension, haemoptysis; contraindicated with PDE5i and in PH from IPF
Prostacyclins	Jaw pain, diarrhoea, flushing, line sepsis (epoprostenol); rebound PH if infusion interrupted
Sotatercept	inc Hb/polycythaemia, thrombocytopenia, telangiectasia, epistaxis

Bosentan is a CYP3A4 and CYP2C9 inducer -> dec efficacy of the oral contraceptive, warfarin, sildenafil
Treatment is stratified by ESC/ERS risk score (WHO FC, 6MWD, NT-proBNP, RAP, cardiac index, SvO2)
- Low/intermediate risk -> initial oral dual therapy (ERA + PDE5i)
- High risk -> triple therapy including a parenteral prostacyclin from the outset
- Add sotatercept in FC II-III on background therapy
Vasoreactivity testing (inhaled NO) identifies the ~5-10% of idiopathic PAH who respond to high-dose calcium channel blockers
- Positive = dec mPAP >=10 mmHg to an absolute mPAP <=40 with preserved CO
These drugs are for group 1 PAH only - in group 2 (left heart) and group 3 (lung disease) they worsen V/Q matching and outcomes

Diagnosis requires right heart catheterisation: mPAP >20 mmHg, PVR >2 Wood units, PAWP <=15 mmHg
Group 4 (CTEPH) must be excluded by V/Q scan in every case - it is surgically curable by pulmonary endarterectomy; riociguat is the licensed medical option
Background therapy: diuretics, oxygen, anticoagulation only in idiopathic PAH, avoid pregnancy
Deterioration on a stable regimen -> escalate to parenteral prostacyclin and refer for transplant assessment
All patients through a specialist PH centre - Australian access is via PBS authority with defined FC and haemodynamic criteria

Idiopathic pulmonary arterial hypertension - pathophysiology
Right heart catheterisation interpretation; pulmonary vascular resistance and lung volume
BMPR2 mutations and heritable PAH
Nitric oxide-cGMP signalling; PDE inhibitor pharmacology
Chronic thromboembolic pulmonary hypertension

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