Pulmonary Arterial Hypertension Flashcards
1
Q
What is pulmonary hypertension?
A
Higher than normal blood pressure in the arteries that carry blood away from the heart into the lungs
*umbrella term
-any situation where the pressure in the pulmonary artery increases
2
Q
What side of the heart normally has higher pressure?
A
Left side
-in pulmonary hypertension the right side of the heart is not equipped to deal with the higher pressure produced
3
Q
What is the mean pulmonary artery pressure at rest in pulmonary hypertension?
A
> or = 20 mmHg
4
Q
What is pulmonary arterial hypertension?
A
Progressive disease involving endothelial dysfunction
-leads to elevated pulmonary arterial pressure and pulmonary vascular resistance
*rare
5
Q
What WHO PH group is pulmonary arterial hypertension?
A
Group 1
6
Q
What are the causes of pulmonary arterial hypertension?
A
Unknown -most common
Genetic
Drug + toxin exposure
Disease associated with PAH: CHD, HIV, connective tissue disorder
7
Q
What is considered an elevated mean pulmonary artery pressure (mPAP)?
A
> 20 mmHg
8
Q
What is pulmonary arterial wedge pressure?
A
-Estimate of left atrial pressure
9
Q
What is a normal pulmonary arterial wedge pressure?
A
4-12 mmHg
10
Q
What is the median age that PAH gets diagnosed at?
A
50
11
Q
Which gender is PAH more common in?
A
Women (4x more common)
12
Q
What is a reason why PAH often takes a long time to diagnose?
A
Only 1 in 5 patients are symptomatic >2 years before diagnosis
(most are asymptomatic)
13
Q
What is the prognosis for patients diagnosed with PAH?
A
Poor (but improving)
15% mortality in 1 year
Mean survival: 6 years
14
Q
What is the mean survival time for patients diagnosed with PAH?
A
6 years
15
Q
What are some negative predictors of PAH?
(give patient a worse diagnosis state)
A
-Advanced functional class
-Poor exercise capacity
-High right atrial pressure
-Right ventricular dysfunction
-Low cardiac output
16
Q
What are the signs/symptoms of PAH?
A
Shortness of breath
-Fatigue
-Chest Pain
-Edema
-Fainting/Light-headedness
-Palpitations
17
Q
In children, what is PAH normally misdiagnosed as?
A
Asthma
18
Q
What is the gold standard for diagnosis of PAH?
A
Right Heart Catheterization
19
Q
What is right heart catheterization used to determine during diagnosis of PAH?
A
-Confirms diagnosis
-Estimates severity
-Assesses response to pulmonary vasodilators before starting therapy
-Determines if patient is eligible for calcium blockers
20
Q
Besides catheterization, what 3 other tests can be used to diagnose PAH?
A
-Echocardiogram
-Exercise testing
-Biomarkers
21
Q
What can an echocardiogram tell us in regard to PAH?
A
-Useful to evaluate potential causes
-RV function
-Estimating PAP and PVR
22
Q
What does exercise testing measure?
A
Distance walked in 6 minutes
23
Q
What biomarkers indicate PAH?
A
BNP
NTproBNP
24
Q
What effects can PAH have on the heart?
A
-Pulmonary artery wall and small vessels become damaged which restricts blood flow to the lungs
-Left heart becomes smaller and right heart becomes larger
-Right side of heart has difficulty pumping against high pulmonary pressure
-This leads to right ventricular failure
25
Vascular injury and endothelial dysfunction caused by PAH affect 4 things, what are they?
Nitric Oxide Synthase
Prostacyclin Production
Thromboxane Production
Endothelin 1 Production
26
What affect does PAH have on Nitric Oxide Synthase?
Decreases function
-nitric oxide is a vasodilator so decreased synthesis leads to vasoconstriction
27
What affect does PAH have on Prostacyclin Production?
Decreases production
-prostacyclin is a vasodilator so decreased production leads to vasoconstriction
-prostacyclin also prevents proliferation so this occurs in PAH when levels decrease
28
What affect does PAH have on Thromboxane Production?
Increases production
-thromboxane is a vasoconstrictor so increasing production leads to more vasoconstriction
29
What affect does PAH have on Endothelin 1 Production?
Increases production
-endothelin 1 is a vasoconstrictor so increasing production leads to more vasoconstriction
30
What are the characteristics of PAH Class I?
Symptom-free when physically active or resting
31
What are the characteristics of PAH Class II?
-Slight limitation of physical activity (ordinary activity may cause symptoms)
-Comfortable at rest
32
What are the characteristics of PAH Class III?
-Marked limitation in physical activity (less than ordinary activity causes symptoms)
-Comfortable at rest
33
What are the characteristics of PAH Class IV?
-Significant symptoms with activity
-Symptoms at rest
34
Which functional class of PAH has the highest mortality risk?
Class IV
35
What are the treatment goals of PAH?
-Alleviate symptoms
-Improve quality of life
-Prevent or delay disease progression
-Reduce hospitalization
-Improve survival
36
When a patient is diagnosed with PAH, what should the first recommendation be?
To undergo acute vasoreactivity testing at a center with experience
(to determine if CCB are an option or not)
37
If a newly diagnosed patient tests positive for acute vasoreactivity, what should the treatment recommendation be?
Oral CCB
38
If a newly diagnosed patient tests negative for acute vasoreactivity, what should the treatment recommendation be?
Do not treat with CCB
-determine treatment based on class
39
For a treatment naive patient with Class I PAH, what should the next steps be?
Continue monitoring for disease progression
Eventually determine when to start therapy
(no need to start therapy at this point) (monitor for dyspnea on exertion, fatigue, and weakness)
40
For a treatment naive patient with Class II PAH, what should the next steps be?
First: Determine if patient is willing/able to tolerate combination therapy
If yes: Ambrisentan + Tadalafil
If no: Monotherapy with: bosentan, macitentan, ambrisentan, riociguat, sildenafil, or tadalafil
(pick any based on preference)
41
For a treatment naive patient with Class III PAH without evidence of rapid disease progression or poor prognosis, what should the next steps be?
(Good Prognosis Class III Patients)
First: Determine if patient is able/willing to receive combination therapy
If yes: Ambrisentan + Tadalafil
If no: Monotherapy with: bosentan, macitentan, ambrisentan, riociguat, sildenafil, or tadalafil
*same as Class II
42
For a treatment naive patient with Class III PAH with evidence of rapid disease progression or poor prognosis, what should the next steps be?
First: Determine if patient is able/willing to manage parenteral prostanoids
If yes: Continuous IV Epoprostenol, IV Treprostinil, or SC Treprostinil
If no: Consider addition of inhaled or oral prostanoid
43
For patients with Class IV PAH, what should the next steps be?
First: Determine if patient is able/willing to manage parenteral prostanoids
If yes: Continuous IV Epoprostenol, IV Treprostinil, or SC Treprostinil
If no: Inhaled Prostanoid in combination with an Oral PDE-5 Inhibitor and an Oral Endothelin Receptor Antagonist
44
For Class III or IV PAH patients with an inadequate response to initial therapy, (who have unacceptable clinical status despite established monotherapy) what should the next steps be?
Addition of a second class of PAH therapy
45
For Class III or IV PAH patients with inadequate response to initial therapy (with unacceptable or deteriorating status despite dual [two agent] therapy), what should the next steps be?
Addition of a third class of PAH therapy
46
For Class III and IV PAH patients with inadequate response to maximal pharmacotherapy, what should the next steps be?
First: Is patient a candidate for lung transplant?
If yes: List for lung transplant
If no: Incorporate palliative care services in the management of patient
47
What is acute vasoreactivity testing?
-PAH patient is given a vasodilator to see what happens to pulmonary arterial pressures
-This test is done to see if patient qualifies for CCBs
*done in cath lab
48
If a patient is a positive responder to acute vasoreactivity testing, what does this mean?
The patient can receive CCBs
49
If a patient is a negative responder to acute vasoreactivity testing or has right ventricular (RV) failure, what does this mean?
The patient cannot use CCBs
(also applies to patients with CCB contraindication)
50
What signifies a positive test result for an Acute Vasoreactivity test (AVT)?
Drop in mPAP > 10 mmHg with PAP less than 40 mmHg and stable-improved cardiac output
51
What percent of PAH patients respond to CCBs?
5-8%
*long-term response is rare
52
What patients can we use CCBs in?
Positive Acute Vasoreactivity Test (AVT) responders WITHOUT right-sided failure or other contraindications to CCBs
53
What Calcium Channel Blockers are recommended for PAH treatment?
Long-acting Nifedipine
Long-Acting Diltiazem
Amlodipine
54
Which CCB can absolutely not be used for PAH treatment?
Verapamil
-due to negative inotropic effects
55
After CCB initiation, when should we consider starting an additional or alternative therapy?
If patients do not improve to functional class I or II after initiation
56
What is the gold standard of care for PAH?
Ambrisentan + Tadalafil
57
What are some reasons a patient may want to start with monotherapy and not Tadalafil + Ambrisentan?
-Combination therapy increases cost and risk of ADRs
-May have comorbidities requiring caution
58
Which pathways do we want to target in "Good Prognosis Class III Patients"?
NO/sGC/cGMP Pathway (nitric oxide)
Endothelin Pathway
(not prostacyclin pathway)
59
Which drugs target the Nitric Oxide Pathway?
PDE-5 Inhibitors (sildenafil, tadalafil)
Soluble Guanylate Cyclase Stimulator (riociguat)
60
Which drugs target the Endothelin Pathway?
Endothelin Receptor Antagonists
(bosentan, ambrisentan, macitentan)
61
Which drugs target the Prostacyclin Pathway?
Prostacyclins
(epoprostenol [IV], ilprost [inh], treprostinil [IV, SQ, inh, oral])
IP prostacyclin receptor agonist
(selexipag)
*these are reserved for Class III or IV patients
62
What drugs are PDE-5 Inhibitors?
Sildenafil
Tadalafil
63
What drug is a Soluble Guanylate Cyclase Stimulator?
Riociguat
64
What drugs are Endothelin Receptor Antagonists?
Bosentan
Ambrisentan
Macitentan
"entan" drugs
65
What drugs are prostacyclins?
Epoprostenol (IV)
Iloprost (inh)
Treprostinil (IV, SQ, inh, oral)
"prost" drugs
66
What drug is a IP Prostacyclin Receptor Agonist?
Selexipag
67
What is the mechanism of action for PDE-5 Inhibitors?
*Phosphodiesterase Inhibitors
-Decrease conversion of cGMP to GMP
-Increased levels of cGMP lead to pulmonary vasodilation
68
What is the brand name for Sildenafil when used for PAH?
Revatio
69
What is the brand name for Tadalafil when used for PAH?
Adcirca
70
What is a benefit to Tadalafil vs Sildenafil?
Sildenafil has a short half-life: TID
Tadalafil has a long half-life: Daily
71
What benefit may sildenafil have for pediatric patients?
Comes in liquid form which makes administration easier
72
Why do we rarely use sildenafil for PAH?
-Sildenafil is available in IV form
-Restricted to patients that are nothing by mouth (NPO)
-Very expensive
-Must be given as slow infusion to avoid hypotension
73
What are the side effects of PDE-5 Inhibitors?
-Flushing
-Headache
-Dyspepsia
-Visual disturbance (blue-tinged vision)
-Priapism
-Tinnitus
*Hearing Loss*
*Sudden vision loss*
*Hypotension* -main worry
74
What is the substrate of PDE-5 inhibitors?
CYP 3A4
75
What is the mechanism of action of Endothelin Receptor Antagonists?
Endothelin receptors on vascular smooth muscle mediate vasoconstriction
-Overexpression of ET-1 in PAH patients correlates with remodeling
-Blocking endothelin receptors causes vasodilation
76
Which endothelin receptor antagonist is the most toxic and has the highest risk of hepatic dysfunction?
Bosentan
77
With what disease state do we generally not want to use Endothelin Receptor Antagonists?
Hepatic dysfunction
78
Arrange the Endothelin Receptor Antagonists from shortest to longest half-life
Bosentan (5 hours)
Ambrisentan (9-15 hours)
Macitentan (14-19 hours)
79
What are the adverse effects associated with Endothelin Receptor Antagonists?
-Peripheral Edema
-LFT Abnormalities
-Anemia
80
Rank the Endothelin receptor Antagonists in order from most to least likely to cause peripheral edema
Most: Ambrisentan (also more headache + nasal congestion)
Bosentan
Least: Macitentan
81
Rank the Endothelin Receptor Antagonists in order from most to least likely to cause Liver Function test (LFT) abnormalities
Most: Bosentan
Ambrisentan
Macitentan
82
True or False: Endothelin Receptor Antagonists often have to be discontinued due to anemia and transfusions often have to be given
FALSE
-anemia is a side effect but treatment discontinuation and transfusions are not common
83
What black box warning is associated with Endothelin Receptor Antagonists?
Embryo-Fetal Toxicity
Bosentan: Hepatotoxicity
84
What parameters need to be monitored with Endothelin receptor Antagonists?
-Pregnancy testing required monthly for all!
-LFTs (bosentan=monthly, macitentan= as indicated)
-Hemoglobin
85
How long does it take for improvement to be seen with Endothelin Receptor Antagonists?
8-10 weeks
86
When would we use Riociguat?
Asan alternative to PDE-5i
(used when patients cannot take PDE-5 inhibitors)
**RARELY USED
87
True or False: Riociguat can be used in combination with PDE-5 inhibitors
FALSE
-do not use in combination with tadalafil or sildenafil due to risk of hypotension
88
What did the AMBITION trial show?
-Took treatment naive patients that were Class II or Class III
-Showed the superiority of combination therapy for PAH treatment
-Risk of adverse events is higher with combination treatment
-Risk of HYPOTENSION was not shown to be higher with combination therapy *scary side effect
-Serious ADRs were similar across all groups
89
What did the TRITON trial show?
Evaluated triple vs dual therapy
-Showed little difference between triple and dual therapy groups
(why we do not recommend triple therapy)
90
What is the mechanism of action of prostacyclins?
-Stimulate cAMP pathway to increase pulmonary vasodilation
-Induce vasodilation in all vascular beds
-Inhibit platelet aggregation
-Cytoprotective and antiproliferative effects
91
What is the standard treatment for severe PAH with right ventrivular failure?
Prostacyclins
-subQ treprostinil becoming most common
92
What dosage forms are prostacyclins available in?
Parenteral (IV + SubQ)
Oral
Inhaled
93
When does parenteral treatment become first-line?
Class IV or Rapidly Progressing Class III
94
What drugs can prostacyclins be used in combination with?
Endothelin receptor agonists + PDE-5 inhibitors OR riociguat
95
True or False: You can use oral, inhaled, and parenteral prostacyclins concurrently
FALSE
-do not use together
96
How do prostacyclins affect platelet aggregation?
*KNOW THIS CARD*
All prostacyclins inhibit platelet aggregation
97
What are the common side effects associated with prostacyclins?
Thrombocytopenia (especially epoprostenol)
Hypotension
98
What is a major reason why we prefer subQ formulations of prostacyclins?
IV forms are likely to cause line infections
99
What are common side effects of subcutaneous prostacyclins?
Site pain
Infusion site reactions*
100
When would we use oral prostacyclins?
Patients who refuse or cannot manage parenteral therapy
(oral not preferred)
101
What is an important thing to note about oral selexipag?
Dose must be titrated
-if you miss a few doses you have to start the titration over
-very expensive
102
What are the 2 oral prostacyclins?
Treprostinil
Selexipag
103
What are the two inhaled prostacyclins and which one is preferred?
Iloprost
Treprostinil (Tyvaso)
*treprostinil is preferred because iloprost requires 9 doses daily
104
True or False: Oral and Inhaled Prostacyclins are equivalent
TRUE
105
What is the only IV/SubQ prostacyclin
Treprostinil
106
True or False: IV Treprostinil can be co-infused with other drugs
*KNOW THIS CARD*
FALSE
-DO NOT CO-INFUSE IV PROSTACYCLINS WITH ANYTHING ELSE
-IV requires stable access
-WILL KILL PATIENT
107
True or False: SubQ and IV dosing of prostacyclins is the same
TRUE
108
What is the half-life of IV/SubQ Treprostinil (Remodulin)?
4 hours
109
When do we use IV Treprostinil?
In patients who cannot tolerate subQ
110
What is the other IV prostacyclin and when do we use it?
Epoprostenol IV
NOT USED ANYMORE
111
Why is Epoprostenol IV not used anymore?
-Very short half-life
-Had to keep on ice
-Always had to have a second pump ready to go
-Had to live a certain distance away from an emergency room due to high risk of something going wrong
-INCOMPATIBLE WITH EVERYTHING
(NEVER CO-ADMINISTER WITH OTHER FLUIDS)
112
What are some common adjunct therapies to PAH medications?
-Anticoagulation
(depends on cardiac function)
-Diuretics
(to maintain euvolemia)
113
What are common supportive therapies with PAH treatment?
-Immunizations
-Supplemental oxygen
-Iron supplementation
Avoid air travel/high altitudes
(may affect oxygen saturation)
114
Which endothelin receptor antagonist can decrease efficacy of hormonal contraceptives?
Bosentan
-not good since this is contraindicated in pregnancy
