Pulmonary Hypertension Pharmacology

WHO Classification of Pulmonary HTN

Treatment for PAH Group 1

all meds discussed in lecture

Nitric Oxide Pathway - Drugs

• Sildenafil & Tadalafil

• Riociguat

Sildenafil & Tadalafil - Mechanism of Action

Nitric Oxide Pathway

Phosphodiesterase-5 (PDE5) Inhibitors

→ Prevent degradation of cGMP.

→ Smooth muscle relaxation and vasodilation.

• Sildenafil has a short half-life 4 hours.

• Tadalafil has a long half-life 35 hours.

Sildenafil & Tadalafil - Therapeutic Use

• Pulmonary hypertension

• Erectile dysfunction

Sildenafil & Tadalafil - Side Effects

• Headache, gastrointestinal upset, flushing, and muscle and joint pains.

• Visual disturbance (green/blue), epistaxis (nosebleed), erythema, hypotension, angina.

Riociguat - Mechanism of Action

Nitric Oxide Pathway

Soluble Guanylate Syclase (sGC) agonist

- Sensitizes sGC to endogenous NO.

- Directly stimulates sGC independently of NO.

→ Increased generation of cGMP.

Riociguat - Therapeutic Use

Treatment of adults with pulmonary arterial hypertension. (Group 1 and 4)

Riociguat - Side Effects

• Hypotension, angina, bleeding, acute pulmonary edema.

• Teratogenicity: exclude pregnancy prior initiation of treatment and contraception.

Endothelin Receptor Antagonists - Drugs

Bosentan, Ambrisentan, Macitentan

Bosentan, Ambrisentan & Macitentan - Mechanism of Action

Endothelin Receptor Antagonists

Bosentan and Macitentan

• Non-Selective ET-1 Receptor Antagonist (ERA)

Ambrisentan is an ET-A Receptor Antagonist

→ Prevent vasoconstriction and reduce cell proliferation of vascular smooth muscle and endothelium.

Bosentan, Ambrisentan & Macitentan - Therapeutic Use

BAM use: Pulmonary arterial hypertension (WHO Group 1).

Bosentan, Ambrisentan & Macitentan - Side Effects

• Hepatotoxicity and peripheral edema.

• Headache, hypotension, arthralgia, anemia.

• Decrease sperm count, respiratory and urinary tract infection.

*Warning: hepatotoxicity and teratogenicity

- Bosentan: Control serum aminotransferase before initiation of treatment and monthly.

- All ERA: Double method contraception.

Ambrisentan and macitentan appears to be the least hepatotoxic compared to bosentan.

Macitentan is less associated with edema.

Prostaglandin & Leukotriene Synthesis and Actions

Decr platelet aggregation + promotes vasodilation

Prostacyclin Pathway - Drugs

Epoprostenol (IV and inhaled) – prostacyclin (PGI2)

Treprostinil (IV, subQ, inhaled and oral)

Iloprost (inhaled)

Selexipag

Epoprostenol, Treprostinil & Iloprost - Mechanism of Action

Prostacyclin Pathway

Increase cAMP and potassium.

Decrease PDGF and thromboxane A2.

→ Inhibit platelet activation

→ Cause vasodilation.

→ Inhibits smooth muscle cell proliferation.

Epoprostenol, Treprostinil & Iloprost - Therapeutic Use

ETI use: Pulmonary arterial hypertension (WHO Group 1).

Epoprostenol, Treprostinil & Iloprost - Side Effects

Jaw pain, diarrhea, flushing, and arthralgias.

Selexipag - Mechanism of Action

Prostacyclin Pathway

Oral selective non-prostanoid prostacyclin receptor AGONIST; stimulates Prostacyclin IP receptor

Selexipag - Therapeutic Use

• Inhibits platelet activation and proliferation

• Causes vasodilation

Selexipag - Side Effects

• Diarrhea/nausea, jaw pain, headache, decrease hemoglobin

• Hyperthyroidism (still need observations to confirm)

TGF β-Pathway Inhibitor - Drugs

Sotatercept

Sotatercept - Mechanism of Action

TGF β-Pathway Inhibitor

• Recombinant dimer of the activin receptor IIA fusion protein with FC domain.

• Act as a decoy and sequestrant for TGF-β superfamily ligands: activin A and growth differentiation factor 11 (GDF11)

- Prevent the activation of the Smad pathway.

→ Reduced inflammation and inhibited the proliferation of endothelial and smooth muscle cells in diseased vasculature.

Sotatercept - Therapeutic Use

New drug: Treatment of adults with pulmonary arterial hypertension.

Sotatercept - Side Effects

• Thrombocytopenia and bleeding

• Headache, dizziness

• Based on animal studies may impair fertility and may cause fetal harm (contraception)

SOTAT: skin (spider veins); O (open bleeding); Thrombocytopenia; ab/gi/ teratogenic

which meds should you not mix?

Do not mix

• NO activator

• * PDE inhibitor

• guanylyl cyclase agonist!

• Major SE of hypotension = could cause an MI