Pulmonary Arterial Hypertension Flashcards
Pulmonary Hypertension (PH)
- higher than normal BP in the ___ that carry blood away from the heart into the ___
- mean pulmonary artery pressure (mPAP) greater than or equal to ___ mmHg at rest
- more common
- arteries
- lungs
- 20
Pulmonary Arterial Hypertension (PAH)
- progressive disease involving ___ dysfunction = elevated pulmonary arterial ___ and pulmonary vascular ___
- more rare
- endothelial
- pressure, resistance
PAH Causes
- unknown ( ___ )
- genetic
- ___ and ___ exposure
- disease associated with PAH: CHD, HIV, ___ tissue disorders
- idiopathic
- drug, toxin
- connective
PAH Treatment
- medications specifically for PAH
- ___ in responders
- ___ transplantation
- CCB
- lung
Hemodynamic Definitions
PH:
- mPAP > ___ mmHg
PAH:
- mPAP > ___ mmHg
- pulmonary artery wedge pressure (PAWP) < ___ mmHg
- pulmonary vascular resistance (PVR) > 2 ___
dont need to know
- 20
- 20
- 15
- wood units
Pulmonary arterial wedge pressure (PAWP) - estimates ___ atrial pressure
- normal = ___ - ___ mmHg
- elevated numbers signal ___ failure or ___ stenosis
Pulmonary vascular resistance (PVR)
- calculated using formula based on mPAP and PAWP
- left
- 4-12
- LV, mitral
PAH Epidemiology
rare
- mean age: 50 +/- ___ years
- 4x more common in ___
- median survial of ___ years
- prognosis is poor
Underrecognized
- median 1.1 years to diagnostic right heart catheterization
- 1/5 symptomatic > 2 years before diagnosis
- 14
- women
- 6
PAH Epidemiology
negative predictors
- advanced functional ___
- poor ___ capacity
- high ___ atrial pressure
- ___ ventricular dysfunction
- low ___
- class
- exercise
- right
- right
- CO
Signs and Symptoms
- ___ (27%)
- fainting or light headed (15%)
- ___ pain (22%)
- ___ (86%)
- palpitations
- __ (21%)
- fatigue
- chest
- SOB
- edema
Diagnosis
echocardiogram
- useful for evaluating potential ___ , RV function, estimating ___ and ___
right heart catheterization
- Confirms ___ and estimates ____
- assess response to pulmonary ___ before starting therapy (AVT)
exercise testing
- distance walked in 6 min
biomarkers
- ___ and NTproBNP
- causes, PAP, PVR
- diagnosis, severity
- vasodilators
- BNP
BNP = brain natriuretic peptide
Effects of PAH
- ____ side of heart has difficulty pumping against high ___ pressures
- leads to ___ ventricular failure
- right, pulmonary
- right
PAH Disease Progression
- risk factors and associated conditions
vascular injury (endothelial dysfunction)
- ___ nitric oxide synthase
- ___ prostacyclin production
- ___ thromboxane production
- ___ endothelin 1 production
disease progression
decreased
decreased
increased
increased
WHO Functional Classes
Class I
- symptom ___ when physically active or resting
Class II
- slight ___ of physical activity
- ordinary activity may cause ___
- ___ at rest
Class III
- marked ___ in physical activity
- less than ___ activity causes symptoms
- ___ at rest
Class IV
- significant symptoms with __
- symptoms at ___
- free
- limitation
- symptoms
- comfortable
- limitation
- ordinary
- comfortable
- activity
- rest
Treatment of PAH - PCOL
- CCB
- direct pulmonary vasodilators ( ___ )
- ___ inhibitors
- ___ receptor antagonists
- prostacyclins
- ___ guanylate cyclase stimulator ( ___ )
- iNO
- PDE-5
- endothelin
- soluble, riociguat
CHEST Guidelines
after diagnosis with right heart catheter
1) acute ___ testing (AVT)
2) if they respond positive, they get a ___
3) if negative, have RV failure, or CCB contrainidcation, do NOT do ___
vasoreactivity
CCB
CCB
Acute Vasoreactivity Test (AVT)
- done in cath lab during initial hemodynamic evaluation
- acute response to ___ -specific vasodilators predicts response to ___
- agents include (inhaled ___ , IV ___ )
- positive test = drop in mPAP > ___ mmHg with PAP less than ___ mmHg with stable improved ___
- pulmonary, CCBs
- NO, epoprostenol
- 10, 40, CO
CCBs
- only 5-8% of patients are responders; long term response is rare
- consider CCBs in positive responders without ___ sided failure
- do not use without ___ AVT
Recommended drugs
- long acting ___ 120-240 mg daily
- long acting ___ 240-720 mg daily
- ___ 20 mg daily
NO ___ due to negative inotropic effects
if pts do not improve to functional class ___ or ___ after CCB initiation, start additional or alternative PAH therapy
- right
- positive
- nifedipine
- diltiazem
- amlodipine
- verapamil
- I, II
WHO FC I
treatment naive PAH with WHO FC I
- continue monitoring for disease progression (dyspnea on exertion, fatigue, weakness)
- do not necesarily require immediate drug therapy; consider ___ if responder
CCB
WHO FC II
treatment naive PAH WHO FC II
Tolerate combo therapy?
- yes: combo treatment - ___ + ___
- no: monotherapy - ___ , ___ , or ___
- ambrisentan, tadalafil
- ERA, riociguat, PDE-5i
WHO FC III
Treatment naive PAH WHO FC III without rapid progression/poor prognosis
Tolerate combo?
- yes: combo therapy - ___ + ___
- no: monotherapy - ___ , ___ , or ___
ambrisentan, tadalafil
Therapeutic Pathways
Nitric Oxide Pathway
- PDE-5i: ___, ___
- ___ GC stimulator: ___
- sildenafil, tadalafil
- soluble, riociguat
Therapeutic Pathways
Endothelin Pathway
3 drugs:
___ , ___ , ___
bosentan
ambrisentan
macitentan
Therapeutic Pathways
Prostacyclin Pathway
- for high risk class ___ and ___
- prostacyclins: ___ (IV) , ____ (inh), ___ (IV, subQ, inh, PO)
- IP prostacyclin receptor agonist: ___
- III, IV
- epoprostenol, iloprost, treprostinil
- selexipag
PDE-5i
- decreases conversion of ___ to GMP
- increased levels of ___ lead to ___ vasodilation
- sildenafil and tadalafil: improved ___ functional capacity
- may be used as ___ or in combination with other classes
- considered ___ in many cases (. FC ____ , FC ___ without rapid progression)
- cGMP
- cGMP, pulmonary
- 6MWD
- monotherapy
- first line, II, III
PDE5-i
tadalafil (Adcirca)
- dosing: ___
- t1/2: ___ - ___ hrs
- dose adjustments for ___ impairment
- avoid use with ___ or nitrates (hypotension)
AE
- flushing, headache, dyspepsia, visual disturabances ( ___ -tinged vision), priapism, tinnitus, ___ loss, sudden vision loss, ___
- daily
- 15-35
- renal
- riociguat
- blue
- hearing
- hypotension
PDE5-i
sildenafil (Revatio)
- dosing: ___ daily
- t1/2: ___ hrs
- avoid use with ___ or nitrates (hypotension)
- ___ administration available for pt that is NPO. (Dosing differs from PO and must be given as a slow ___ to avoid hypotension) $$$
AE
- flushing, headache, dyspepsia, visual disturabances ( ___ -tinged vision), priapism, tinnitus, ___ loss, sudden vision loss, ___
- thrice
- 4
- riociguat
- IV, infusion
- blue
- hearing
- hypotension
Endothelin Receptor Antagonists
ET receptors on vascular smooth muscle mediate ___
- overexpression of ET-1 in PH pts correlated with ___
- blocking ET = ___
Option in classes ___ - ___
- tadalafil + ___ combo is firstline for class ____ and ___ without rapid progression
improve ___, pro- ___, delay time to clinical worsening, and optimize ___
- vasoconstriction
- remodeling
- vasodilation
- II-IV
- ambrisentan
- II, III
- 6MWD, BNP, hemodynamics
ET Receptor Subtypes: A vs B
A receptors
- located on ___ smooth muscle walls
- promote ___ , proliferation, and ___
B receptors:
- located on ___: promote ___ , stimulate ___ and ___ production
- located on __ cells of vascular walls: cause ___ and cell proliferation
In PAH, expression of ___ receptors is ___ in the media of blood vessels (vasoconstriction)
___ = selective for A
___ and ___ are mixed
unclear how selectivity impacts clinical outcomes
- pulmonary
- vasoconstriction, inflammation
- endothelium, vasodilation, NO, prostacyclin
- muscle, vasocontriction
- B, upregulated
- ambrisentan
- bosentan, macitentan
ERA
Bosentan (Tracleer)
- mixed
- dosing: ___ daily
- t1/2: ___ hrs
- strong CYP2C9/3A4 substrate/inducer (++++)
AE
- peripheral ___
- ___ abnormalities
- anemia
- ___ program due to black box warning for reproductive harm and ___
- avoid use in ___ impairment (3x > LFT)
Monitoring
- ___ test (baseline + monthly)
- ___ (baseline + monthly)
- ___ (baseline, 1st month, 3rd month, quartlerly)
this drug sucks
- BID
- 5hrs
- edema
- LFT
- REMs, hepatotoxicity
- hepatic
- pregnancy
- LFT
- hemoglobin
ERA
ambrisentan (Letairis)
- selective for ___ receptor
- dosing: ___ daily
- t1/2: ___ - ___ hrs
- substrate for CYP3A4 (+)
AE
- strong peripheral ___ with headache and nasal ___ (+++)
- ___ program due to blackbox warning for ___ harm
- ___ abnormalities
- avoid use in ___ imapairment (3x > LFT)
Monitoring
- ___ test (baseline + monthly)
- ___ testing not required, but good idea to check baselie, first 1-2 months, then periodically
- ___ monitoring (baseline, after first month, then periodically)
- A
- once
- 9-15
- edema, congestion
- REMS, reproductive
- LFT
- hepatic
- pregnancy
- LFT
- hemoglobin
ERA
macitentan (Opsumit)
- dosing: ___ daily
- t1/2: ___ - ___ hrs (metabolite 46-56 hrs)
- substrate for CYP3A4 (++)
AE
- peripheral ___ (+)
- ___ abnormalities (++)
- ___ program due to blackbox warning for ___ harm
- do not use in pts with ___ impairment (3x > LFT)
Monitoring
- ___ test (baseline, monthly)
- ___ monitoring (baseline, “as indicated”)
- ___ monitoring (baseline, “as indicated”)
- once
- 14-19
- edema
- LFT
- REMs, reproductive
- hepatic
- pregnancy
- LFT
hemoglobin
ERA Clinical Effects
improves
- ___ capacity (6MWD)
- ___ capacity
- ___ parametes
- time to clinical ___
- WHO FC
improvement not likelt seen for ___ - ___ weeks
- exercise
- functional
- hemodynamic
- worsening
- 8-10
Soluble GC Stimulator
___ (Adempas)
- may be used as alternative to ___
- cannot be used in combo with ___ or ___ due to risk of hypotension
- demonstrate ___ and ___ activity in animal models
- improves ___ capacity, WHO FC, and time to clinical ___
riociguat
- PDE5-i
- sildenafil, tadalafil
- antiproliferative, antiremodeling
- exercise, worsening
AMBITION
- subjects were treatment naive patients with FC II or III
- tested combo therapy of ___ and ___ vs these drugs by themselves with placebo
TAKEAWAY:
- combo therapy more effective than mono
- however SE were more common ( rates of ___ were similar)
- ambrisentan, tadalafil
- hypotension
TRITON
evaluating efficacy of triple vs dual therapy in lowering PVR in newly diagnosed, treatment naive pts.
___ , ___ , ___ vs placebo
Results
- triple therapy = 54%
- dual therapy = 52%
TAKEAWAY: no significant difference; not much benefit/evidence for ___ therapy
- tadalafil, selexipag, macitentan
- triple
WHO FC III with rapid progression or poor prognosis
candidate for parenteral prostanoids?
- Yes: SC ___ , IV ___ , IV ___
- No: consider ___ or oral prostanoid (likely in combo with ___ + ___ )
- treprostinil, treprostinil, epoprostenol
- inh, ERA, PDR-5i
WHO FC IV
candidate for parenteral prostanoids?
- Yes: SC ___ , IV ___ , IV ___
- No: consider ___ or oral prostanoid + ___ + ___
- treprostinil, treprostinil, epoprostenol
- inh, ERA, PDR-5i
Prostacyclins
- prostacyclins stimulate the ___ pathway to increase pulmonary ___ , inhibit ___ aggregation, have cytoprotective and ___ effect
- parenteral prostacyclins = standard for severe PH with RV failure
- subQ ___ is becoming most common
- cAMP, vasodilation, platelet, antiproliferative
- treprostinil
Prostacyclin
- available in parenteral (IV + subQ), oral, and inhaled formulations
- reserved for WHO Class ___ (rapidly progressing) and ___ patients
- may be used in combination with ___ plus ___ or riociguat
- do not use oral, inh, and parenterally concurrently
III, IV
- ERA, PDE-5i
Prostacyclins
ADRs
- headache, ___ and limb pain, flushing/rash, diarrhea, nausea/vomiting, ___ (more in epoprostenol), ___
- PO: diarrhea, ___
- Inhaled: cough, throat irritation
- IV: ___ infections, erythema
- subQ: sit pain, infusion site reactions
- jaw
- thrombocytopenia
- hypotension
- anemia
- line
Oral Prostacyclins
treprostinil (Orenitram)
- dosing: __ daily or every __ hrs; titrate to effect
- t1/2 ~ ___ hrs
- if more than 2 doses are missed; must ___
- twice, 8
- 4
- re-titrated
Oral Prostacyclins
selexipag (Uptravil)
- dosing: titrate to max tolerated dose (1600 mcg ___ daily)
- t1/2 = ___ - ___ hrs, active metabolite up to ___ hrs
- therapy interrupted over 3 days requires ___
- do not crush or chew
- contraindicated with strong CYP ___ inhibitors (gemfibrozil)
- twice
- 0.8-2.5, 13.5
- re-titration
- 2C8
Inhaled Prostacyclins
Illoprost (Ventavis)
- dosing: ___ times daily (bonk)
- t1/2: ___ - ___ min
- administration considerations: requires up to ___ doses daily; special inhaler requires setup prior to use
- must be plugged in
- 9
- 2-30
- 9
Inhaled Prostacyclins
treprostinil (Tyvaso)
- more common
- dosing: ___ times daily
- t1/2 = ___ hrs
- 1 ampule = ___ hrs of therapy
- special inhaler; battery powered
- 4
- 4
- 24
Prostacyclin: Treprostinil IV/SQ
treprostinil (Remodulin)
- SQ and IV dosing is the ___
- t1/2 = ___ hrs
- start at ___ - ___ ng/kg/min and titrate up to ___ - ___ ng/kg/min
- IV infusion requires stable access, do not ___ with anything else
- same
- 4
- 1-3
- 50-80
- co-infuse
Prostacyclin: SQ vs IV treprostinil
IV is reserved for patients who cannot tolerate SQ
- SQ infusion site reactions can be treated with antihistamines and topical agents
- SQ avoids risk of central line associated ___
- SQ pumps are smaller and more ___
- SQ administration typically utilizes ___ drug; IV must be prepared with ___ cassettes
- infection
- portable
- undiluted, diluted
Prostacyclin: epoprostenol IV
epoprostenol ___ - ___ ng/kg.min IV (continuous) titrated
- t1/2: ___ - ___ min
- must always have ___ prepared
- abrupt d/c may precipitate PH crisis
- Flolan (had to keep on ___ at all times - non-thermostable)
- Veletri (thermostable)
- requires permanent stable IV access, no SQ
- incompatible with everything - do not ___ with any other fluid
- inadvertent bolus can lead to CV collapse and death
no one uses this anymore; it’s poopy
- 1-3
- back-ip
- ice
- co-administer
Disease Progression Guidelines
expert consultation likely needed
- for patients who do not respond to initial therapy (mono or combo), consider adding a 2nd or 3rd class
- example: add on ERA is on ___, or add inhaled ___ if already on ERA and PDE-5i
for FC III and FC IV pateints with inadequate response to max PCOL, consider ___ transplantation
- PDE-5i, prostacyclin
- lung
Adjunct Therapy
treat underlying conditions like HTN and sleep apnea
___ or ___ therapy depending on cardiac function
- warfarin INR goal: ___ - ___
- aspirin 81 mg daily
- ___ to maintain euvolemia
anticoagulation, antiplatelet
- 1.5-2.5
- diuretics
Supportive Therapy
- immunizations: flu, pneumococcal, covid
- supplemental ___ (pulmonary ___ )
- ___ supplementation
- avoid ___ travel
- palliative care
- oxygen, vasodilation
- Fe
- air
Pregnancy Considerations
avoid pregnancy
- __ containing contraceptives may increase ___ risk
- ___ can decrease efficacy
- ___ and ___ are category X (REMS program)
- estrogen, VTE
- Bosentan
- ERAs, riociguat
