PAH- Pharmacology

Question 1

Physical Presentation of PAH

Answer 1

Exertional dyspnea – helps categorize severity
Fatigue (right side is working exceptionally hard)
Weakness
Exertional chest pain – inadequate O2 supply
Complaints of general exertion intolerance
Dyspnea at rest as disease progresses
Syncope – unable to provide enough blood/O2 back to the brain
Lower extremity edema – gravity dependent

Question 2

Contributing Factors to PAH

Answer 2

Idiopathic (40%)
Heritable
BMPR2 gene
ALK1 gene

Drug- and toxin-induced
Aminorex*
Dexfenfluramine*
Fenfluramine*
Amphetamines
L-tryptophan
Methamphetamines
Chemotherapeutic agents 
Drug- and toxin-induced (continued)
Cocaine
Phenylpropanolamine* 
Selective serotonin reuptake inhibitors 

Conditions associated with PAH
Chronic hemolytic anemia
Congenital heart disease
Connective tissue disease
Human immunodeficiency virus infection 
Portal hypertension
Schistosomiasis
Persistent pulmonary hypertension of the newborn

Question 3

Regulation of Pulmonary Arterial Tone

Answer 3

Everything must be in balance – disease states often occur because one is greater than the other
Constriction: endothelin, TxA2
Relaxation: NO, PGI2
Endothelin – potent vasoconstrictor – produced and released from endothelium - prohormone, once it is cleaved it is extremely vasoactive
- Excessive endothelin1 results in increase in vascular tone
NO – potent vasodilator – increase cGMP (inhibits Ca+ influx – relaxation) – works through direct and indirect pathways, also reduces platelet activation
PGI2 – responsible for dilation – arachidonic acid pathway (from breakdown of cell membrane) – blocking prostaglandins may lead to an increase in vascular tone,
TxA2 - can contribute to vasoconstriction, increase coagulability, can contribute to additional problems – increase vascular tone

Question 4

Prostacyclin

Answer 4

• Vasodilator
• Inhibits platelet activation
• Antiproliferative properties

Question 5

Thromboxane A2

Answer 5

• Vasoconstrictor

- Platelet agonist

Question 6

Endothelin-1

Answer 6

• potent vasoconstrictor
• stimulates proliferation of smooth muscle cells
• plasma levels increased in PHT
• level inversely proportional to pulmonary blood flow and CO

Question 7

NO

Answer 7

Vasodilator & inhibitor of platelet activation & vascular SM proliferation
NO –> cGMP–> decrease Ca++–>smooth muscle relaxation of smooth muscle cells

Question 8

Serotonin

Answer 8

Vasoconstrictor promoting SM hyperplasia & hypertrophy (narrowing of the vessel)