Endothelin Antagonists

Question 1

MOA of Endothelin?

Answer 1

• can act on the endothelium (ETB) –> ↑ NOS –> L-arg –> release of NO –> causes ↑ cGMP in vascular sm m –> CONTRACTION of vascular sm muscle
• also directly works on vascular sm m via Gq (ETA & ATB)–> PIP to IP3 –> CONTRACTION

Question 2

MOA of bosENTAN?

Answer 2

• nponspecifically blocks ETA and ETB endothelin receptors

Question 3

Effects of bosENTAN & ambrisENTAN?

Answer 3

• Improves exercise tolerance and slows sx progression

Question 4

PKs of bosENTAN?

Answer 4

• hepatotoxicity, teratogenesis (no preggers)
• HA, flushing, peripheral edema, nasal congestion, anemia & ↓ sperm production
• Drug interactions: accelerates metabolism of warfarin, OCs (use 2 forms) & ↑ levels of many other drugs including cyclosporine or glyburide

Question 5

MOA of ambrisENTAN?

Answer 5

• Selectively blocks ETA receptors, the receptors that cause vasoconstriction and promote cell proliferation

Question 6

PK of ambrisentan?

Answer 6

• oral drug

Question 7

Toxicities of ambrisentan?

Answer 7

• no preggers; does not damage liver
• peripheral edema, nasal congestion, anemia, and ↓ sperm production
• Drug interactions: does not accelerate warfarin metabolism and OCs, but still must use 2 forms of birth control

Question 8

MacitENTAN?

Answer 8

non-selective agent distinguished by ~18 hr half life that permits 1x daily dosing; cyto P450 effects similar to bosENTAN