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Flashcards in Physiology Deck (25):
1

Pulmonary Hypertension

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

2

Pulmonary Arterial Hypertension

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 (

3

What is the difference between PH and PAH?

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

4

what are the main vascular changes of PAH?

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

5

Physical Presentation symptoms

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)

6

Idiopathic (40%) Heritable PAH

BMPR2 gene 70-75% of people (+) polymirphism
ALK1 gene

7

Drug and toxin-induced PAH

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

8

Conditions associated with PAH

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

9

Prostacyclin Drug target

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

10

Thromboxane A2 Drug target

- vasoconstrictor
- platelet agonist

11

Endothelin-1 drug target

= 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

12

NO & Serotonin drug target

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

13

Non-selective ETa/ETb endothelin receptor antagonist

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

14

Selective ETa endothelin receptor antagonist

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

15

Adverse Effects of Endothelin receptor antagonist

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

16

Prostanoids

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

17

Side effects of Prostanoids

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

18

Nitric Oxide

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

19

Adverse effects of Nitric oxide

Headache, hypotension

20

Phosphodiesterase Inhibitors

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

21

Phosphodiesterase inhibitors cross reactivity

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

22

Adverse Drug reactions of PDE inhibitors

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)

23

PDE-5 Inhibitor & NAION

- 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

24

Soluble Guanylyl Cyclase

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

25

Adverse side effects of Soluble Guanylyl Cyclase

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