PAH- Kearns

based on study guide - focus on the 3 pathways :)

What is PAH? FYI

• “Pulmonary Arterial Hypertension”

• rare disease of the small pulmonary blood vessels resulting in vasoconstriction and scarring

In a patient with PAH what could happen to each of the following?

• endothelin-1

• TxA2

• prostacyclins

increased endothelin-1

increased TxA2

Decreased prostacyclins

In our body is endothelin a vasoconstrictor or vasodilator?

vasoconstrictor

In our body is prostacyclin a vasoconstrictor or vasodilator?

vasodilator

In our body is nitric oxide a vasoconstrictor or vasodilator?

vasodilator

A pt. with PAH takes an acute vasoreactivity test and their results indicate they are a non-responder. What drug classes would be their options for tx?

• prostacyclin analogues

• endothelin receptor antagonists

• PDE-5 Inhibitors

When treating PAH, we can target 3 different pathways. What are those 3 pathways?

• prostacyclin pathway

• endothelin pathway

• nitric oxide pathway

How is vasodilation accomplished in the prostacyclin pathway?

increase prostacyclin

• How?

  • inhibit phospholipase C—> which inhibits vasoconstriction OR

  • activate adenyl cyclase, increasing cAMP, increase vasodilation

How is vasodilation accomplished in the endothelin pathway?

inhibit endothelin

• How?

  • Block ET-1(endothelin receptor)

  • Results in decrease phospholipase C, IP3, Ca2+, and myosin light chain kinase

  • causes vasodilation

How is vasodilation accomplished in the nitric oxide pathway with PDE-5 Inhibitors?

increase nitric oxide

• How? Inhibit PDE5 which is responsible for breaking down cGMP—> increase in cGMP leads to relaxation and vasodilation

What drugs are associated with the prostacyclin pathway? (prostacyclin analogues)

• Epoprostenol

• Trepostinil

• Iloprost

• Selexipag

What drugs are associated with the endothelin pathway? (endothelin receptor antagonists)

“BAM”

• Bosentan

• Ambrisentan

• Macitentan

What drugs are associated with the nitric oxide pathway? (PDE-5 Inhibitors and sGC stimulators)

PDE-5- Sildenafil, Tadalafil

sGC stimulator- Riociguat

This structure belongs to what prostacyclin analogue?

a. Epoprostenol

b. Selexipag

c. Treprostinil

d. Iloprost

a

This structure belongs to what prostacyclin analogue?

a. Epoprostenol

b. Selexipag

c. Treprostinil

d. Iloprost

b

This structure belongs to what prostacyclin analogue?

a. Epoprostenol

b. Selexipag

c. Treprostinil

d. Iloprost

c

This structure belongs to what prostacyclin analogue?

a. Epoprostenol

b. Selexipag

c. Treprostinil

d. Iloprost

d

What 3 PAH drugs have active metabolites?

• selexipag

• Sildenafil

• Macitentan

How is Selexipag converted to its active metabolite?

through hydrolysis

• (sulfonamide is cut off)

How is Sildenafil converted to it’s active metabolite?

Through N-demethylation using the CYP3A4 enzyme

This is the structure of what nitric oxide pathway drug?

a. Sildenafil

b. Tadalafil

c. Riociguat

d. Daffodil

a

How does Riociguat differ from the PDE-5 Inhibitors?

acts independently of NO, stimulates guanyl cyclase directly