PAH Pathophysiology and Pharmacology

pulmonary hypertension

Continuous high blood pressure in the pulmonary arteries

≥20 mmHg

normal mean pulmonary artery pressure (PAP)

pulmonary arterial hypertension

rare, progressive, and fatal disease characterized by vascular changes in the small arteries and arterioles leading to progressive rise in PVR and increase in PAP

cocaine

SSRI use during pregnancy

methamphetamines/amphetamines

drugs that can cause PAH

increased endothelin

decreased NO

decreased I2 (prostacyclin)

three main pathways in PAH

vasoconstriction, proliferation, and promotes thrombosis

effects of endothelin

vasodilation, antiproliferation, prevents thrombosis

effects of nitric oxide and prostacyclin

fatigue, dizziness, chest pain, shortness of breath, edema, cyanosis

symptoms of PAH

CCB (nifedipine, amlodipine, diltiazem)

treatment of PAH for treatment-naive patients

ERAs

PDE-5 Inhibitors

sGC stimulators

prostacyclin analogs and agonists

four main drug classes to use if patient is not responding to CCB treatment for PAH

bosentan

ambrisentan

macitentan

endothelin receptor antagonists

decrease vasoconstriction

decrease proliferation and remodeling

decrease situ thrombosis

pharmacologic effect of ERAs

CYP3A4 and CYP2C9 inducer

PK/DDIs of bosentan

headache

peripheral edema

anemia

hepatotoxicity

adverse effects of ERAs

bosentan

which ERA has the most hepatotoxic side effects

contraindicated in pregnancy

BBW for ERAs

fetal toxicity

hepatotoxicity

bosentan BBW

sildenafil (Revatio)

tadalafil (Adcirca)

PDE-5 inhibitors

cGMP

what to phosphodiesterase-5 inhibitors increase levels of?

vasodilation

antiproliferative

anticoagulant

positive inotrope in right ventricle

PDE-5 inhibitor pharmacologic effects

bosentan

reduces serum levels of sildenafil and tadalafil

hypotension

priapism

tinnitus

vision changes (blue-green tint)

adverse effects of PDE-5 inhibitors

organic nitrate

interaction with organic nitrate that would cause severe hypotension

erythromycin, cimetidine, protease inhibitors

drugs that interact with PDE-5 inhibitors that would increase its serum levels and increase hypertension

organic nitrates, sGC stimulators

what should PDE-5 inhibitors not be combined with

riociguat

soluble guanylate cyclase stimulator (sGC)

sensitize sGC to nitric oxide to increase production of

sCG (riociguat) MOA

vasodilation

antiproliferative

anticoagulation

pharmacologic effects of sGC stimulators (riociguat)

headache

hypotension

nausea

adverse effects of sGC stimulators

teratogenicity (no use in pregnancy)

BBW for sGC stimulators

epoprostenol

treprostinil

iloprost

prostacyclin analogs

vasodilation

antiproliferative

anticoagulatn

pharmacologic effects of prostacyclin analogs

slow dose titration

what is required for adverse effects of prostacyclin analogs to be tolerated?

nausea, GI upset, headache, tachycardia, myalgia

adverse effects of prostacyclin analogs

abrupt withdrawal

_______________ or large dose reduction of prostacyclin analog can be fatal due to rebound hypertension

treprostinil

Prostacyclin analog that has high risk for chronic infection

selexipag

prostacyclin agonist

vasodilation

antiproliferative

anticoagulation

prostacyclin agonist pharmacologic effect

strong CYP2C8 inhibitors

what should not be used with selexipag?