Pulmonary Arterial Hypertension

Question 1

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

Answer 1

• arteries
• lungs
• 20

Question 2

Pulmonary Arterial Hypertension (PAH)

• progressive disease involving ___ dysfunction = elevated pulmonary arterial ___ and pulmonary vascular ___
• more rare

Answer 2

• endothelial
• pressure, resistance

Question 3

PAH Causes

• unknown ( ___ )
• genetic
• ___ and ___ exposure
• disease associated with PAH: CHD, HIV, ___ tissue disorders

Answer 3

• idiopathic
• drug, toxin
• connective

Question 4

PAH Treatment

• medications specifically for PAH
• ___ in responders
• ___ transplantation

Answer 4

• CCB
• lung

Question 5

Hemodynamic Definitions

PH:
- mPAP > ___ mmHg

PAH:
- mPAP > ___ mmHg
- pulmonary artery wedge pressure (PAWP) < ___ mmHg
- pulmonary vascular resistance (PVR) > 2 ___

dont need to know

Answer 5

• 20
• 20
• 15
• wood units

Question 6

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

Answer 6

• left
• 4-12
• LV, mitral

Question 7

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

Answer 7

• 14
• women
• 6

Question 8

PAH Epidemiology

negative predictors
- advanced functional ___
- poor ___ capacity
- high ___ atrial pressure
- ___ ventricular dysfunction
- low ___

Answer 8

• class
• exercise
• right
• right
• CO

Question 9

Signs and Symptoms

• ___ (27%)
• fainting or light headed (15%)
• ___ pain (22%)
• ___ (86%)
• palpitations
• __ (21%)

Answer 9

• fatigue
• chest
• SOB
• edema

Question 10

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

Answer 10

• causes, PAP, PVR
• diagnosis, severity
• vasodilators
• BNP

BNP = brain natriuretic peptide

Question 11

Effects of PAH

• ____ side of heart has difficulty pumping against high ___ pressures
• leads to ___ ventricular failure

Answer 11

• right, pulmonary
• right

Question 12

PAH Disease Progression

• risk factors and associated conditions

vascular injury (endothelial dysfunction)
- ___ nitric oxide synthase
- ___ prostacyclin production
- ___ thromboxane production
- ___ endothelin 1 production

disease progression

Answer 12

decreased
decreased
increased
increased

Question 13

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 ___

Answer 13

• free
• limitation
• symptoms
• comfortable
• limitation
• ordinary
• comfortable
• activity
• rest

Question 14

Treatment of PAH - PCOL

• CCB
• direct pulmonary vasodilators ( ___ )
• ___ inhibitors
• ___ receptor antagonists
• prostacyclins
• ___ guanylate cyclase stimulator ( ___ )

Answer 14

• iNO
• PDE-5
• endothelin
• soluble, riociguat

Question 15

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 ___

Answer 15

vasoreactivity
CCB
CCB

Question 16

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 ___

Answer 16

• pulmonary, CCBs
• NO, epoprostenol
• 10, 40, CO

Question 17

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

Answer 17

• right
• positive
• nifedipine
• diltiazem
• amlodipine
• verapamil
• I, II

Question 18

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

Answer 18

CCB

Question 19

WHO FC II

treatment naive PAH WHO FC II

Tolerate combo therapy?
- yes: combo treatment - ___ + ___
- no: monotherapy - ___ , ___ , or ___

Answer 19

• ambrisentan, tadalafil
• ERA, riociguat, PDE-5i

Question 20

WHO FC III

Treatment naive PAH WHO FC III without rapid progression/poor prognosis

Tolerate combo?
- yes: combo therapy - ___ + ___
- no: monotherapy - ___ , ___ , or ___

Answer 20

ambrisentan, tadalafil

Question 21

Therapeutic Pathways

Nitric Oxide Pathway
- PDE-5i: ___, ___
- ___ GC stimulator: ___

Answer 21

• sildenafil, tadalafil
• soluble, riociguat

Question 22

Therapeutic Pathways

Endothelin Pathway
3 drugs:
___ , ___ , ___

Answer 22

bosentan
ambrisentan
macitentan

Question 23

Therapeutic Pathways

Prostacyclin Pathway
- for high risk class ___ and ___
- prostacyclins: ___ (IV) , ____ (inh), ___ (IV, subQ, inh, PO)
- IP prostacyclin receptor agonist: ___

Answer 23

• III, IV
• epoprostenol, iloprost, treprostinil
• selexipag

Question 24

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)

Answer 24

• cGMP
• cGMP, pulmonary
• 6MWD
• monotherapy
• first line, II, III

Question 25

# 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, ___

Answer 25

- daily - 15-35 - renal - riociguat - blue - hearing - hypotension

Question 26

# 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, ___

Answer 26

- thrice - 4 - riociguat - IV, infusion - blue - hearing - hypotension

Question 27

# 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 ___

Answer 27

- vasoconstriction - remodeling - vasodilation - II-IV - ambrisentan - II, III - 6MWD, BNP, hemodynamics

Question 28

# 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**

Answer 28

- pulmonary - vasoconstriction, inflammation - endothelium, vasodilation, NO, prostacyclin - muscle, vasocontriction - B, upregulated - ambrisentan - bosentan, macitentan

Question 29

# 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

Answer 29

- BID - 5hrs - edema - LFT - REMs, hepatotoxicity - hepatic - pregnancy - LFT - hemoglobin

Question 30

# 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)

Answer 30

- A - once - 9-15 - edema, congestion - REMS, reproductive - LFT - hepatic - pregnancy - LFT - hemoglobin

Question 31

# 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")

Answer 31

- once - 14-19 - edema - LFT - REMs, reproductive - hepatic - pregnancy - LFT hemoglobin

Question 32

# ERA Clinical Effects improves - ___ capacity (6MWD) - ___ capacity - ___ parametes - time to clinical ___ - WHO FC improvement not likelt seen for ___ - ___ weeks

Answer 32

- exercise - functional - hemodynamic - worsening - 8-10

Question 33

# 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 ___

Answer 33

riociguat - PDE5-i - sildenafil, tadalafil - antiproliferative, antiremodeling - exercise, worsening

Question 34

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)

Answer 34

- ambrisentan, tadalafil - hypotension

Question 35

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

Answer 35

- tadalafil, selexipag, macitentan - triple

Question 36

# 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 ___ + ___ )

Answer 36

- treprostinil, treprostinil, epoprostenol - inh, ERA, PDR-5i

Question 37

# WHO FC IV candidate for parenteral prostanoids? - Yes: SC ___ , IV ___ , IV ___ - No: consider ___ or oral prostanoid + ___ + ___

Answer 37

- treprostinil, treprostinil, epoprostenol - inh, ERA, PDR-5i

Question 38

# 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

Answer 38

- cAMP, vasodilation, platelet, antiproliferative - treprostinil

Question 39

# 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

Answer 39

III, IV - ERA, PDE-5i

Question 40

# 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

Answer 40

- jaw - thrombocytopenia - hypotension - anemia - line

Question 41

# Oral Prostacyclins treprostinil (Orenitram) - dosing: __ daily or every __ hrs; titrate to effect - t1/2 ~ ___ hrs - if more than 2 doses are missed; must ___

Answer 41

- twice, 8 - 4 - re-titrated

Question 42

# 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)

Answer 42

- twice - 0.8-2.5, 13.5 - re-titration - 2C8

Question 43

# 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

Answer 43

- 9 - 2-30 - 9

Question 44

# Inhaled Prostacyclins treprostinil (Tyvaso) - more common - dosing: ___ times daily - t1/2 = ___ hrs - 1 ampule = ___ hrs of therapy - special inhaler; battery powered

Answer 44

- 4 - 4 - 24

Question 45

# 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

Answer 45

- same - 4 - 1-3 - 50-80 - co-infuse

Question 46

# 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

Answer 46

- infection - portable - undiluted, diluted

Question 47

# 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

Answer 47

- 1-3 - back-ip - ice - co-administer

Question 48

# 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

Answer 48

- PDE-5i, prostacyclin - lung

Question 49

# 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

Answer 49

anticoagulation, antiplatelet - 1.5-2.5 - diuretics

Question 50

# Supportive Therapy - immunizations: flu, pneumococcal, covid - supplemental ___ (pulmonary ___ ) - ___ supplementation - avoid ___ travel - palliative care

Answer 50

- oxygen, vasodilation - Fe - air

Question 51

# Pregnancy Considerations avoid pregnancy - __ containing contraceptives may increase ___ risk - ___ can decrease efficacy - ___ and ___ are category X (REMS program)

Answer 51

- estrogen, VTE - Bosentan - ERAs, riociguat