PAH Flashcards
moreland-head
blood flow of oxygen-poor blood through the heart
superior/inferior vena cava –> right atrium –> tricuspid valve –> right ventricle –> pulmonary valve –> pulmonary arteries
blood flow of oxygen-rich blood through the heart
pulmonary veins –> left atrium –> mitral valve –> left ventricle –> aorticle valve –> aorta
pathophysi of PAH
pulmonary arterioles narrow –> RV dilates –> pulmonary edema and damage –> thrombi and/or plexiform lesion formation
pulmonary HTN (PH)
higher than normal BP in the arteries that carry blood away from the heart into the lungs
levels of PH
mean pulmonary artery pressure (MPAP) equal to or greater than 20 mmHg at rest
what is PAH?
pulmonary arterial HTN
progressive disease involving endothelial dysfunction
characterized by elevated pulmonary arterial pressure and pulmonary vascular resistance
what are the classifications of WHO PH?
1 – PAH
2 – left heart disease
3 – lung disease
4 – chronic thromboembolic PH
5 – PH resulting from unclear mechanisms
what are the causes of PAH?
idiopathic/unknown
genetic
drug and toxin exposure
CHD
HIV
connective tissue disorders
what are the causes of PH secondary to left heart disease?
CAD
HTN
heart valve disease
what are the causes of PH secondary to lung disease?
COPD
interstitial lung disease
what are the causes of chronic thromboembolic PH?
old, disorganized blood clots in the lungs create a physical barrier to blood flow
how should chronic thromboembolic PH be treated?
surgical removal of clot
medication
what are the causes of PH resulting from unclear mechanisms?
sarcoidosis, blood diseases (anemia), history of spleen remove, metabolic disease
what is the incidence of PH by WHO classification?
unknown causes > lung disease > left heart disease and PAH > chronic thromboembolic PH
what are the risk factors of PAH?
older age
female
poor exercise capacity
high right atrial pressure
right ventricular dysfunction
low CO
what is need in the diagnosis of PAH?
right heart catheterization
echocardiogram
exercise testing
biomarkers (BNP)
what are some early signs and symptoms of PAH?
dizziness
SOB
palpitations
fatigue
edema (non-specific)
what are the late signs and symptoms of PAH?
syncope
jugular venous distension
SOB
chest pain
hepatomegaly
swollen abdomen
low BP (signs of right-sided HF)
what levels are indicative of PAH?
over 20 mmHg mPAP
under 15 PAWP
over 2 wood units PVR
what is PAWP?
pulmonary arterial wedge pressure
reflects left atrial pressure
what is normal PAWP?
4-12 mmHg
what are the indicators of elevated PAWP?
left ventricular failure or mitral stenosis
what is PVR?
pulmonary vascular resistance
calculated by mPAP and PAWP
what is WHO-FC 1?
no limitation of physical activity
ordinary physical activity does not cause undue dyspnea, fatigue, chest pain, or near syncope
what is WHO-FC II?
slight limitation of physical activity
comfortable at rest, but ordinary physical activity causes undue dyspnea, fatigue, chest pain , or near syncope
what is WHO-FC III?
marked limitation of physical activity
comfortable at rest but less than ordinary physical activity causes undue dyspnea, fatigue, chest pain, or near syncope
what is WHO-FC IV?
inability to carry out physical activity without symptoms (increased discomfort)
signs of right HF
dyspnea or fatigue at rest
what drugs are available to treat PAH?
CCB
PDE-5i
sGC stimulator
ERAs
prostacyclins
direct pulmonary vasodilator (NO, inpatient only)
what is the recommended treatment of PAH with cardiopulmonary comorbidity?
oral monotherapy with PDE5i or ERA
what is the treatment of PAH in class II or III, low-intermediate risk patients?
- ERA + PDE-5i therapy
- evaluate risk at follow up
at treatment follow up, how should an intermediate risk of PAH be treated?
add PRA or switch from PDE-5i to sGC
at treatment follow up, how should an intermediate-high or high risk of PAH be treated?
add IV or SQ prostacyclins
evaluate lung transplantation
how should PAH in class II or III, high risk be treated?
- ERA + PDE5-i therapy + IV/SQ prostacyclins
- evaluate risk
what test should be conducted following PAH diagnosis?
vasoreactivity rest in cath lab to predict the response to CCBs
what does a positivity vasoreactivity test mean?
drop in mPAP over 10 mmHg with PAP under 40 mmHg and stable-improved cardiac output
CCBs can be used (but guaranteed to have a response)
when should CCB therapy be assessed in PAH?
3-6 months after initiation then every 6-12 months after
what CCBs should be used to treat PAH?
long acting nifedipine
long acting diltiazem,
amlodipine
why can verapamil not be used in PAH?
has negative inotropic effects
what drugs used to treat PAH act in the nitric oxide pathway?
PDE5-i
sGC stimulators
how does the nitric oxide pathway influence the body?
vasodilation
antiproliferation
what is the MOA of PDE-5i
increase the levels of cGMP to promote muscle relaxation and vasodilation
reduce conversion of cGMP to GMP
what drugs are PDE-5i?
sildenafil
tadalafil
what are the benefits of PDE-5i in PAH treatment?
improved 6MWD and functional capacity
what is 6mwd?
6 minute walk distance
what drugs should be avoided when taking a PDE5i?
riociguat and nitrates due to increase risk of hypotension
CYP3A4 substrates
what are the SE of PDE5i?
flushing
HA
dyspepsia
visual disturbances (blue-tinged vision)
priapism
tinnitus/hearing loss
sudden vision loss
hypotension
what is riociguat?
adempas
soluble guanylate cyclase stimulator (sGCs)
used as an alternative to PDE5i in PAH therapy
what are the benefits of riociguat in PAH treatment?
improves exercise capacity, WHO FC, and time to clinical worsening
has anti proliferative and anti-remodeling activity
what drugs are ERAs?
bosentan
ambrisentan
macitentan
what is bosentan?
mixed ETa ETb ERA
what is ambrisentan?
ETa selective ERA
what is macitentan?
mixed ETb and ETa ERA
what is the location and function of ETa receptors?
located on pulmonary smooth muscle walls
function in vasoconstriction, proliferation, and inflammation
what is the location and function of ETb receptors?
located on endothelium and muscle cells of vascular walls
on endothelium, function in vasodilation, stimulate NO and prostacyclin production
on muscle cells, function in vasoconstriction and cell proliferation
how do ETb receptors express in PAH?
up regulated in the media of blood vessels, causing vasoconstriction
what are the benefits associated with ERAs?
improved exercise capacity, functional capacity, hemodynamic parameters, time to clinical worsening, and WHO FC
how long does it take to see improvement while on ERA?
8-10 weeks
what is the MOA of ERAs?
block endothelin receptors on VSM to reduce vasoconstriction and cell proliferation
what is the AE of ERAs?
peripheral edema (A>B>M), LFT abnormalities (B>M>A), anemia
what are SE specific to ambrisentan?
HA
nasal congestion
what are the black box warnings of ERAs?
embryo-fetal toxicity (avoid in pregnancy)
hepatotoxicity (bosentan only)
what are the CI of ERAs?
hepatic impairment – dont start if LFT over 3x ULN
what should be monitored in ERAs?
pregnancy status
LFTs
hemoglobin
what are the effects of prostacyclin activation?
vasodilation and antiproliferation (stimulate cAMP)
what drug classes are involved in the prostacyclin pathway?
prostacyclins
prostacyclin IP receptor agonists
what agents are prostacyclins?
epoprostenol
treprostinil
what dosage form does epoprostenol come in?
IV
what dosage form does treprostinil come in?
IV
SQ (prefered)
inhaled
PO
what drug is a prostacyclin IP receptor agonist?
selexipag
what dosage form is selexipag?
PO
what are the indications of parenteral prostacyclins?
first line treatment of class IV PAH
first line treatment of rapidly progressing class III PAH
standard treatment of severe PH with RV failure
what are the benefits of prostacyclins?
improve symptoms, 6MWD, hemodynamics, and mortality (epoprostenol only)
what is the MOA of prostacyclins?
induce vasodilation in all vascular beds and inhibit platelet aggregation
has cytoprotective and anti proliferative effects
what are the common SE of prostacyclins?
HA
jaw and limb pain
flushing/skin rash
NVD
thrombocytopenia (more i epoprostenol)
hypotension
what are the SE of oral prostacyclins?
diarrhea
anemia
what are the SE of inhaled prostacyclins?
cough
throat irritation
what are the SE of IV prostacyclins?
line infections
erythema
what are the SE of SQ prostacyclins?
site pain
infusion site reactions
what happens if you missed a dose of oral treprostinil?
if over 2 doses are missed, you must re-titrate
dosed BID or q8h
what happens if therapy is interrupted in selexipag?
if over 3 days, titrate is required again
do not crush or chew tablets
what are the CI of selexipag?
strong CYP2C8 inhibitors (gemfibrozil)
what is unique about inhaled treprostinil?
1 ampule is 24 hour of therapy with 2-3 minute treatments
a DPI is a new cartridge with each session so no charging
what is the dosing of treprostinil?
start in hospital at 1-3 ng/kg/min
titrate q8-12h up to 10-20 ng/kg/min
then weekly at home by 2 ng/kg/min increments up to goal dose of 50-80 ng/kg/min
why is SQ preferred in treprostinil?
avoids risk of central lines compared to IV
what is flolan?
non-thermostable product of epoprostenol whose back-up cassettes must be kept on ice
what is veletri?
thermostable product of epoprostenol that is stable for 48 hours
when should epoprostenol be co-administered?
never with any other fluids due to increase in CV collapse and death risk
incompatible with everything
what is the result of abrupt d/c of epoprostenol?
accelerated PH crisis
what are the CP of epoprostenol?
always needs back-up cassette prepared
what are common medication errors of prostacyclins?
flushing of line
calculation or concentration error
programming error
pump turned off
inappropriate change in weight
what are the most common SE of combo therapy between ERA and PDE5-i?
nasal congestion
peripheral edema
headache
dizziness
anemia
is triple or dual therapy more effective in newly diagnosed PAH patients?
dual
what cardiopulmonary comorbidities?
any condition that may worsen left ventricular function or lung function (to then worsen RV function and PH)
what are cardiovascular comorbidities?
obesity
HTN
diabetes
coronary artery disease
what is a pulmonary comorbidity?
interstitial lung disease (fibrotic lungs)
what is sotatercept?
activin signaling inhibitor
when are diuretics used in PAH?
may be used with right HF symptoms
monitor kidney function and weight
when are CV drugs used in PAH?
to treat underlying (left-sided) heart disease that requires their use
what PAH agents are safe to use in pregnancy?
CCBs
PDE5i
prostacyclins
what PAH agents are to be avoided in pregnancy?
ERAs
riociguat
selexipag
how is O2 used in PAH?
use supplemental O2 if needed at sea level or an extended time at altitudes > 1500 m
when should lung transplantation?
consider in FC III or IV patients with inadequate response to maximal pharmacotherapy
