Physiology

Question 1

Pulmonary Hypertension

Answer 1

an elevation of pulmonary vascular pressure caused by an isolated increase in pulmonary arterial pressure or by increase in both pulmonary arterial and pulmonary venous pressure

Question 2

Pulmonary Arterial Hypertension

Answer 2

characterized by a sustained elevation of mean pulmonary arterial pressure (mPAP) to > 25 mmHg at rest, with normal pulmonary capillary wedge pressure (left capillary pressure–> estimated the preload on the left side) and left ventricular end-diastolic pressure (

Question 3

What is the difference between PH and PAH?

Answer 3

Pulmonary hypertension (PH) simply refers to elevation of BP in your lungs. Pulmonary arterial hypertension (PAH) is a sub-group of PH caused by narrowing of the blood vessels in the lungs. Most PH is not PAH, and in these cases, PH is usually result of other diseases

Question 4

what are the main vascular changes of PAH?

Answer 4

vasoconstriction
smooth muscle cell and endothelial cell proliferation
fibrosis
thrombosis
– severe concentric (equal on all sides) laminar intimal fibrosis
– medial hypertrophy
– in situ thrombosis of small residual lumen

Question 5

Physical Presentation symptoms

Answer 5

extertional dyspnea (right side of the heart not equipped to over come high pressures)
fatigue
weakness
exertional chest pain (heart trying to work harder and needs additional blood flow and oxygen)
complaints of general exertion intolerance
dyspnea at rest as disease progresses
syncope (fainting due to changes in vascular resistance)
lower extremity edema (backup to the left = lungs, right = periphery)

Question 6

Idiopathic (40%) Heritable PAH

Answer 6

BMPR2 gene 70-75% of people (+) polymirphism

ALK1 gene

Question 7

Drug and toxin-induced PAH

Answer 7

Aminorex
Dexfenfluramine
Fenfluramine
Amphetamines
L-Tryptophan
Methamphetamines
Chemotherapeutic agents
Cocaine
Phenylpropanolamine
Selective serotonin reuptake inhibitor (fetus more affected than the mother)

Question 8

Conditions associated with PAH

Answer 8

Chronic Hemolytic anemia
Congenital heart disease
Connective tissue disease
Human immunodeficiency virus infection
Portal hypertension
Schistosomiasis
Persisten pulmonary hypertension of the newborn

Question 9

Prostacyclin Drug target

Answer 9

• vasodilator
• inhibits platelet activation
• antiproliferative properties
• by product of arachidonic pathway

Question 10

Thromboxane A2 Drug target

Answer 10

• vasoconstrictor

- platelet agonist

Question 11

Endothelin-1 drug target

Answer 11

= potent vasoconstrictor

• stimulates proliferation of smooth muscle cells
• plasma levels increased in PHT
• level inversely proportional to pulmonary blood flow & CO
• ETa= vascular smooth muscle
• ETb= on endothelium

Question 12

NO & Serotonin drug target

Answer 12

NO: vasodilator & inhibitor of platelet activation & vascular SM proliferation. NO–>cGMP–> decrease Ca–> smooth muscle relaxation of smooth muscle cells
Serotonin: vasoconstrictor promoting SM hyperplasia & hypertrophy

Question 13

Non-selective ETa/ETb endothelin receptor antagonist

Answer 13

Bosentan (Tracleer)
Macitentan (Opsumit)
MOA: block endothelin-1 and endothelin-2 receptors in the vascular smooth muscle

Question 14

Selective ETa endothelin receptor antagonist

Answer 14

Ambrisentan (Letairis)
- at extremely high doses it becomes non-selective
MOA: block/selectively block endothelin-1 receptors in the vascular smooth muscle.
–> improve pulmonary hemodynamics, exercise capacity, functional status, & clinical outsomes

Question 15

Adverse Effects of Endothelin receptor antagonist

Answer 15

Most common: peripheral edema, nasal congestion, sinusitis, flushing (all have to deal w/some type of vasoconstriction)
Additional side effects: elevated liver enzymes (upset stomach, vomiting, fever, stomach pain)
BLACK BOX WARNING: Pregnancy category X

Question 16

Prostanoids

Answer 16

Epoprostenol (Flolan)
Ilopost (Ventavis)
Treprostinil- synthetic analog of prostacyclin
IV or SC: Remodulin
Inhaled: Tyvasco
PO: Orentitram
MOA: agonist at the prostacyclin EP receptor producing potent vasodilatory activity and inhibition of platelet aggregation

Question 17

Side effects of Prostanoids

Answer 17

flushing, headache, chest pain, skeletal pain, diarrhea, abrupt interruption of treatment can lead to worsening in PAH

Question 18

Nitric Oxide

Answer 18

MOA: stimulates soluble guanylyl cyclase, resulting in increased levels of cyclic GMP in lung smooth muscle cells producing vasodilation

Question 19

Adverse effects of Nitric oxide

Answer 19

Headache, hypotension

Question 20

Phosphodiesterase Inhibitors

Answer 20

Sildenafil (Revatio)
Tadalafil (Adcirca)
MOA: inhibition of PDE5, the predominant PDE isoform in the lung that metabolizes cGMP

Question 21

Phosphodiesterase inhibitors cross reactivity

Answer 21

PDE6 activity (retinal enzyme)--> vision abberations
PDE1 activity (vascular/cardiac enzyme)--> flushing, tachycardia, vasodilation
PDE11 activity (skeletal muscle)

Question 22

Adverse Drug reactions of PDE inhibitors

Answer 22

Sildenafil Tadalafil
HA 4% 11%
Flushing 1% 6%
Dyspepsia 2% 4%
Nasal Cong 2% 4%
Other (blue hue) (back pain,
myalgia,
pain limbs & caution
w/hepatic dysfunction)

Question 23

PDE-5 Inhibitor & NAION

Answer 23

• loss of eyesight following dosing
  –> Non-arteritic Anterior Ischemic Optic Neuropathy
  Patients at risk are: heart disease, HTN, > 50 yo, High cholesterol, DM, smokers, & eye problems

Question 24

Soluble Guanylyl Cyclase

Answer 24

Riociguat (Adempas)
MOA: increases sensitivity of soluble guanylyl cyclase to NO and independently activates soluble guanylyl cyclase. Produces ant-platelet and vasodilatory effects.

Question 25

Adverse side effects of Soluble Guanylyl Cyclase

Answer 25

Headache, GI effects, hypotension, confusion, bleeding, fatigue