Sildenafil, Bosentan, Ambrisentan, Epoprostenol and Riociguat

Mechanism

Molecular pathways of vascular intervention

Pulmonary hypertension is characterized by severe pathological vasoconstriction, proliferative remodeling of the endothelium and in situ thrombosis of the small pulmonary arteries.

1. The Nitric Oxide Pathway (Vasodilatory):
   • Sildenafil / Tadalafil: They are potent and selective inhibitors of the enzyme phosphodiesterase type 5 (PDE-5), which physiologically degrades cyclic GMP (cGMP) in vascular smooth muscle cells. By blocking PDE-5, sildenafil maintains elevated concentrations of intracellular cGMP, inducing membrane depolarization, profound pulmonary vasodilation, and reduction of intimal hypertrophy.
   • Riociguat (Soluble Guanylate Cyclase Stimulator - GCs): It acts independently of basal nitric oxide levels. It binds directly to the GCs enzyme in the muscle cell, sensitizing it to endogenous nitric oxide and directly stimulating cellular cGMP production.
2. The Endothelin (Vasoconstrictor) Pathway:
   • Endothelin 1 (ET-1) is a peptide synthesized by damaged endothelium that stimulates prolonged vasoconstriction and vascular proliferation through ET_A (smooth muscle) and ET_B (endothelium) receptors.
   • Bosentan: It is a dual competitive antagonist of ET_A and ET_B receptors.
   • Ambrisentan / Macitentan: They are selective antagonists with high affinity for the ET_A receptor, blocking vasoconstriction and muscle hypertrophy without altering endothelin clearance mediated by the ET_B receptor.
3. The Prostacyclin Pathway (Vasodilatory and Antithrombotic):
   • Prostacyclin (PGI₂) stimulates the G protein-coupled IP receptor_s, activating the cAMP pathway in vascular muscle and inhibiting platelet aggregation.
   • Epoprostenol: It is a synthetic prostacyclin with a very short half-life (< 6 minutes), which requires continuous intravenous infusion through a permanent venous catheter.
   • Selexipag: It is a selective non-prostanoid IP receptor agonist that is administered orally, with a long half-life.

Indicators and dose

Dosage and Clinical Adjustment

• Sildenafil (Revatio): 20 mg orally three times a day in a fixed manner.
• Bosentan: 62.5 mg orally twice a day for the first 4 weeks, with progressive escalation to 125 mg twice a day according to tolerance and transaminases.
• Ambrisentan: 5 mg to 10 mg orally once a day.

Security

Absolute Critical Interaction: PDE-5 and Nitrate Inhibitors

The co-administration of PDE-5 inhibitors (Sildenafil, Tadalafil) or GC stimulators (Riociguat) with nitric oxide donor drugs or organic nitrates (such as nitroglycerin, isosorbide dinitrate or amyl nitrite) is strictly contraindicated. The extreme synergy of cGMP accumulation at the systemic level causes massive and uncontrollable arterial vasodilation, triggering refractory profound arterial hypotension, cardiovascular collapse and death.

Pharmacokinetics and Safety

• Bosentan (Risk of Hepatotoxicity): Its chronic administration induces severe increases in hepatic transaminases (>3 times the normal limit) in 10% of patients due to competitive inhibition of bile salt excretion pumps. *Mandatory:* Perform monthly liver function tests throughout treatment. In addition, it is a potent enzyme inducer of CYP3A4 and CYP2C9.
• Epoprostenol (Device Risks): Abrupt interruption of the infusion due to infusion pump failure or catheter displacement can cause a rebound pulmonary hypertension crisis with life-threatening acute right ventricular failure.