PHARM: PAH

Question 1

True or False: most drugs used against systemic HTN work for pulmonary HTN.

Answer 1

FALSE: only CCBs have been shown to help pulmonary as well as systemic HTN

Question 2

What are the 4 main “causes” of PAH?

Answer 2

1) Impalance between vasoconstriction and vasodilation
2) SM/Endothelial cell proliferation, propogation, and hypertrophy
3) Thrombosis
4) Fibrosis

Question 3

What is the “sine qua non” of patient with IPAH or heritable PAH?

Answer 3

plexiform lesions (thickened arteroiles as a result of sheer stress)

Question 4

What does prostacyclin do in pulmonary arteries?

Answer 4

inhibits platelet activation and smooth muscle growth

also vasodilates

Question 5

What does NO do in pulmonary arteries?

Answer 5

increases cGMP which leads to inhibition of platelet activation and smooth muscle activity (so vasodilation)

Question 6

What does TXA2 do in pulmonary capillaries?

Answer 6

activates platelets

Question 7

What does endothelin-1 do in pulmonary vessels?

Answer 7

induces smooth muscle growth

Question 8

What are the 4 classes of drugs used to treat PAH?

Answer 8

Prostanoids
Endothelin-1 Receptor Antagonists
Phosphodiesterase Type 5 Inhibitors
CCBs

Question 9

What is a prostanoid?

Answer 9

prostacyclin derivative that induces pulmonary artery vasodilation, retards smooth muscle growth and disrupts platelet aggregation

Question 10

List the prostanoids used to treat PAH.

Answer 10

Epoprostenol
Iloprost
Treprostinil

Question 11

What are the disadvantages of prostanoids?

Answer 11

Very expensive and NONE of them are oral (Epoprostenol is IV, Iloprost is inhaled, Treprostinil is SC or IV)

Question 12

Why does epoprostenol have to be IV infused?

Answer 12

it has a 3-5 minute half-life (very short)

Question 13

What are the dose limiting toxicities of epoprostenol?

Answer 13

Hypotension
Muscle pains
HA
Flushing

Question 14

What are the AEs of iloprost?

Answer 14

Cough
Flushing
Hemoptysis* (rarely)

Question 15

What are the AEs of treprostinil?

Answer 15

Injection site erythema, rash, pain.
Jaw pain
CYP2C8 drug interactions

Question 16

What is the MOA of endothelin-1 receptor antagonists?

Answer 16

block the smooth muscle proliferaiton and pulmonary arterial vasoconstriction produced by endothelin-1 upon binding to its Type A (smooth muscle) and Type B (endothelial cell) receptors

Question 17

What is the advantage of endothelin-1 receptor antagonists over prostacyclins?

Answer 17

they are all orally active!

Question 18

What are the disadvantages of endothelin-1 receptor antagonists?

Answer 18

Expensive

TERATOGENIC

Question 19

What are the 2 endothelin-1 receptor antagonists used to treat PAH?

Answer 19

Bosentan

Ambrisentan

Question 20

What are the AEs of Bosentan?

Answer 20

Liver and Blood toxicities

CYP interactions

Question 21

What are the AEs of Ambrisentan?

Answer 21

Peripheral Edema
HA

*Less likely to cause liver problems and have CYP interactions

Question 22

What is the MOA of phosphodiesterase Type 5 inhibitors?

Answer 22

perpetuate endogenously generated cGMP leading to vasodilation and reduce cellular proliferation

Question 23

Who should NEVER talk a phosphodiesterase Type 5 inhibitor?

Answer 23

someone taking organic nitrates

Question 24

List the 2 phosphodiesterase Type 5 inhibitors used to treat PAH.

Answer 24

Sildenafil

Tadalafil

Question 25

What are phosphodiesterase Type 5 inhibitors also used for?

Answer 25

erectile dysfunction | benign prostatic hyperplasia

Question 26

What are some AEs of Sildenafil?

Answer 26

HA Epistaxis Dizziness with sudden hearing loss CYP interactions

Question 27

What are some AEs of tadalafil?

Answer 27

headache back pain change in color vision (NAION) CYP interactions

Question 28

What is the MOA of CCBs?

Answer 28

prevent access of Ca2+ into cells during membrane depolarization (block the key mediator of SM contraction, permitting a vasodilation to endure)

Question 29

True or false: all patients with PAH respond well to CCBs.

Answer 29

FALSE: some can even get worse

Question 30

How do you test to see if patient will respond to CCBs?

Answer 30

"vasodilator challenge"

Question 31

What is involved with a vasodilator challenge?

Answer 31

IV epoprostenol,IV adenosine, or inhaled NO are received at escalated dosing rates while PAP and CO are monitored for 2-3 hours

Question 32

What is considered to be a positive vasodilator challenge?

Answer 32

Decreased pulmonary arterial pressure with NO decrease in CO

Question 33

What CCBs have been used to treat PAH?

Answer 33

Diltiazem (immediate release) Nifedipine (extended release) Amlodipine

Question 34

What are the AEs of diltiazem?

Answer 34

``` bradycardia hypotnesion HA edema cyp interactions ```

Question 35

What are the AEs of nifedipine?

Answer 35

``` Flushing edema hypotension heartburn cyp interactions ```

Question 36

What are the AEs of amlodipine?

Answer 36

edema fatigue hypotension cyp interactions

Question 37

Why is verapamil NOT used in PAH treatment?

Answer 37

it has strongly negative inotrophic properties which make it more likely to cause bradycardia

Question 38

What percent of tested patients are positive for the vasodilator challenge?

Answer 38

15%

Question 39

What is the goal of CCB therapy for PAH patients?

Answer 39

to reach NYHA-FC 1 or II after 3-4 months: meaning mild symptoms and/or slight limitation during normal physical activity or less