pulmonary hypertension drugs - endothelin receptor antagonists

endothelin is secreted by what cells in response to what

Endothelin-1 is secreted by endothelial cells in response to stress (mechanical, hormonal, hypoxic)

Endothelin-1 effect and receptors

potent vasoconstrictor that mediates vessel contraction & remodeling via activation of the G- protein coupled receptors, ETA and ETB

ETA receptor binding effects

vasoconstriction, proliferation

ETB receptor binding effects

vasodilation, anti-proliferation, endothelin-1 clearance, but can take on

characteristics of ETA as PH progresses

plasma levels of endothelin-1 in PH pt’s

10-fold elevated

ETa/ETb receptor antagonists (ERAs) names and what group of PH are they approved

bosentan, macitentan, ambrisentan for group 1 PH

bosentan dosage form (2) and therpeutic use

Oral (tablet, liquid suspension) formulation for the treatment of Group I (Class II & III) PH

bosentan moa

Dual ETA/ETB receptor antagonist

bosentan selectivity for ETa vs ETb

20:1

bosentan dosing frequency

twice daily

bosentan induces its own…

metabolism

wht cyps does bosentan induce

CYP3A4, CYP2C9 resulting in 50% less exposure after 2 weeks dosing

major metabolite of bosentan? activity?

hydroxy bosentan (provides 10-20% of efficacy)

bosentan BBB’s (2)

1) BBB for elevations of liver aminotransferases (ALT, AST) and liver failure

Patients must be continuously monitored

2) potential to cause birth defects if taken during pregnancy

bosentan adverse effects (7)

Fluid retention, pulmonary edema, anemia, decreased sperm count, palpitations, flushing, constipation

bosentan ddi with what type of inhibitors

Co-administration with drugs that inhibit CYP3A or CYP2C9 will increase bosentan plasma levels

what class of drugs can’t be taken with bosentan

Hormonal contraceptives, including oral, injectable, transdermal, and implantable forms, may not be reliable when bosentan is co-administered because (metabolized faster bc bosentan an inducer)

macitenan and ambrisentan daily dose

10mg

bosentan vs macitentan vs ambrisentan liver toxicity differences

BBB for b, lower liver toxicity risk for M, minimal/no liver toxicity risk for A

(decreased toxicity down the line)

what risk does macitentan have that the other 2 don’t

edema risk

what risk does ambrisentan have that the other 2 don’t

anemia

trend of cyp3a4 inhibitor ddi from bosentan vs macitentan vs ambrisentan

decreases down the line, ambrisentan does not have a ddi with cyp3a4 inhibitors

macitentan was designed to have a higher pka/log D compared to bosentan for what reason

decrease liver tox, insurmountable antagonist (hence potent once daily dose)

all 3 ERA’s are approved for the tx of (what group /class as well)

the treatment of Group I (Class II & III) pulmonary hypertension

all 3 ERAs have side effects for

All carry risks for headache, nasal congestion/nasopharyngitis, flushing

all 3 ERA’s require what type of monitoring

monitoring for fluid retention and liver enzyme elevation

macitentan metabolite half life/ activity

long lived (t1/2 longer than macitentan) and contributes to efficacy

bosentan

macitentan

ambrisentan

pka trend from bosentan, macitentan, ambrisentan

3.9, 4.6, 1.2

M > B > A