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Therapeutics 2 Final Exam > Pulmonary Arterial Hypertension > Flashcards

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

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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

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3
Q

What is the mean pulmonary artery pressure at rest in pulmonary hypertension?

A

> or = 20 mmHg

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4
Q

What is pulmonary arterial hypertension?

A

Progressive disease involving endothelial dysfunction

-leads to elevated pulmonary arterial pressure and pulmonary vascular resistance

*rare

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5
Q

What WHO PH group is pulmonary arterial hypertension?

A

Group 1

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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

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7
Q

What is considered an elevated mean pulmonary artery pressure (mPAP)?

A

> 20 mmHg

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8
Q

What is pulmonary arterial wedge pressure?

A

-Estimate of left atrial pressure

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9
Q

What is a normal pulmonary arterial wedge pressure?

A

4-12 mmHg

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10
Q

What is the median age that PAH gets diagnosed at?

A

50

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11
Q

Which gender is PAH more common in?

A

Women (4x more common)

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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)

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13
Q

What is the prognosis for patients diagnosed with PAH?

A

Poor (but improving)

15% mortality in 1 year

Mean survival: 6 years

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14
Q

What is the mean survival time for patients diagnosed with PAH?

A

6 years

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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

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16
Q

What are the signs/symptoms of PAH?

A

Shortness of breath
-Fatigue
-Chest Pain
-Edema
-Fainting/Light-headedness
-Palpitations

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17
Q

In children, what is PAH normally misdiagnosed as?

A

Asthma

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18
Q

What is the gold standard for diagnosis of PAH?

A

Right Heart Catheterization

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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

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20
Q

Besides catheterization, what 3 other tests can be used to diagnose PAH?

A

-Echocardiogram
-Exercise testing
-Biomarkers

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21
Q

What can an echocardiogram tell us in regard to PAH?

A

-Useful to evaluate potential causes
-RV function
-Estimating PAP and PVR

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22
Q

What does exercise testing measure?

A

Distance walked in 6 minutes

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23
Q

What biomarkers indicate PAH?

A

BNP

NTproBNP

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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

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25
Q

Vascular injury and endothelial dysfunction caused by PAH affect 4 things, what are they?

A

Nitric Oxide Synthase
Prostacyclin Production
Thromboxane Production
Endothelin 1 Production

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26
Q

What affect does PAH have on Nitric Oxide Synthase?

A

Decreases function

-nitric oxide is a vasodilator so decreased synthesis leads to vasoconstriction

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27
Q

What affect does PAH have on Prostacyclin Production?

A

Decreases production

-prostacyclin is a vasodilator so decreased production leads to vasoconstriction

-prostacyclin also prevents proliferation so this occurs in PAH when levels decrease

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28
Q

What affect does PAH have on Thromboxane Production?

A

Increases production

-thromboxane is a vasoconstrictor so increasing production leads to more vasoconstriction

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29
Q

What affect does PAH have on Endothelin 1 Production?

A

Increases production

-endothelin 1 is a vasoconstrictor so increasing production leads to more vasoconstriction

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30
Q

What are the characteristics of PAH Class I?

A

Symptom-free when physically active or resting

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31
Q

What are the characteristics of PAH Class II?

A

-Slight limitation of physical activity (ordinary activity may cause symptoms)

-Comfortable at rest

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32
Q

What are the characteristics of PAH Class III?

A

-Marked limitation in physical activity (less than ordinary activity causes symptoms)

-Comfortable at rest

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33
Q

What are the characteristics of PAH Class IV?

A

-Significant symptoms with activity

-Symptoms at rest

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34
Q

Which functional class of PAH has the highest mortality risk?

A

Class IV

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35
Q

What are the treatment goals of PAH?

A

-Alleviate symptoms
-Improve quality of life
-Prevent or delay disease progression
-Reduce hospitalization
-Improve survival

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36
Q

When a patient is diagnosed with PAH, what should the first recommendation be?

A

To undergo acute vasoreactivity testing at a center with experience

(to determine if CCB are an option or not)

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37
Q

If a newly diagnosed patient tests positive for acute vasoreactivity, what should the treatment recommendation be?

A

Oral CCB

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38
Q

If a newly diagnosed patient tests negative for acute vasoreactivity, what should the treatment recommendation be?

A

Do not treat with CCB

-determine treatment based on class

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39
Q

For a treatment naive patient with Class I PAH, what should the next steps be?

A

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)

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40
Q

For a treatment naive patient with Class II PAH, what should the next steps be?

A

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)

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41
Q

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)

A

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

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42
Q

For a treatment naive patient with Class III PAH with evidence of rapid disease progression or poor prognosis, what should the next steps be?

A

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

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43
Q

For patients with Class IV PAH, what should the next steps be?

A

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

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44
Q

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?

A

Addition of a second class of PAH therapy

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45
Q

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?

A

Addition of a third class of PAH therapy

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46
Q

For Class III and IV PAH patients with inadequate response to maximal pharmacotherapy, what should the next steps be?

A

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
Q

What is acute vasoreactivity testing?

A

-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
Q

If a patient is a positive responder to acute vasoreactivity testing, what does this mean?

A

The patient can receive CCBs

49
Q

If a patient is a negative responder to acute vasoreactivity testing or has right ventricular (RV) failure, what does this mean?

A

The patient cannot use CCBs

(also applies to patients with CCB contraindication)

50
Q

What signifies a positive test result for an Acute Vasoreactivity test (AVT)?

A

Drop in mPAP > 10 mmHg with PAP less than 40 mmHg and stable-improved cardiac output

51
Q

What percent of PAH patients respond to CCBs?

A

5-8%

*long-term response is rare

52
Q

What patients can we use CCBs in?

A

Positive Acute Vasoreactivity Test (AVT) responders WITHOUT right-sided failure or other contraindications to CCBs

53
Q

What Calcium Channel Blockers are recommended for PAH treatment?

A

Long-acting Nifedipine

Long-Acting Diltiazem

Amlodipine

54
Q

Which CCB can absolutely not be used for PAH treatment?

A

Verapamil

-due to negative inotropic effects

55
Q

After CCB initiation, when should we consider starting an additional or alternative therapy?

A

If patients do not improve to functional class I or II after initiation

56
Q

What is the gold standard of care for PAH?

A

Ambrisentan + Tadalafil

57
Q

What are some reasons a patient may want to start with monotherapy and not Tadalafil + Ambrisentan?

A

-Combination therapy increases cost and risk of ADRs

-May have comorbidities requiring caution

58
Q

Which pathways do we want to target in “Good Prognosis Class III Patients”?

A

NO/sGC/cGMP Pathway (nitric oxide)

Endothelin Pathway

(not prostacyclin pathway)

59
Q

Which drugs target the Nitric Oxide Pathway?

A

PDE-5 Inhibitors (sildenafil, tadalafil)

Soluble Guanylate Cyclase Stimulator (riociguat)

60
Q

Which drugs target the Endothelin Pathway?

A

Endothelin Receptor Antagonists
(bosentan, ambrisentan, macitentan)

61
Q

Which drugs target the Prostacyclin Pathway?

A

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
Q

What drugs are PDE-5 Inhibitors?

A

Sildenafil

Tadalafil

63
Q

What drug is a Soluble Guanylate Cyclase Stimulator?

A

Riociguat

64
Q

What drugs are Endothelin Receptor Antagonists?

A

Bosentan

Ambrisentan

Macitentan

“entan” drugs

65
Q

What drugs are prostacyclins?

A

Epoprostenol (IV)

Iloprost (inh)

Treprostinil (IV, SQ, inh, oral)

“prost” drugs

66
Q

What drug is a IP Prostacyclin Receptor Agonist?

A

Selexipag

67
Q

What is the mechanism of action for PDE-5 Inhibitors?

A

*Phosphodiesterase Inhibitors

-Decrease conversion of cGMP to GMP

-Increased levels of cGMP lead to pulmonary vasodilation

68
Q

What is the brand name for Sildenafil when used for PAH?

A

Revatio

69
Q

What is the brand name for Tadalafil when used for PAH?

A

Adcirca

70
Q

What is a benefit to Tadalafil vs Sildenafil?

A

Sildenafil has a short half-life: TID

Tadalafil has a long half-life: Daily

71
Q

What benefit may sildenafil have for pediatric patients?

A

Comes in liquid form which makes administration easier

72
Q

Why do we rarely use sildenafil for PAH?

A

-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
Q

What are the side effects of PDE-5 Inhibitors?

A

-Flushing
-Headache
-Dyspepsia
-Visual disturbance (blue-tinged vision)
-Priapism
-Tinnitus
Hearing Loss
Sudden vision loss
Hypotension -main worry

74
Q

What is the substrate of PDE-5 inhibitors?

A

CYP 3A4

75
Q

What is the mechanism of action of Endothelin Receptor Antagonists?

A

Endothelin receptors on vascular smooth muscle mediate vasoconstriction

-Overexpression of ET-1 in PAH patients correlates with remodeling

-Blocking endothelin receptors causes vasodilation

76
Q

Which endothelin receptor antagonist is the most toxic and has the highest risk of hepatic dysfunction?

A

Bosentan

77
Q

With what disease state do we generally not want to use Endothelin Receptor Antagonists?

A

Hepatic dysfunction

78
Q

Arrange the Endothelin Receptor Antagonists from shortest to longest half-life

A

Bosentan (5 hours)
Ambrisentan (9-15 hours)
Macitentan (14-19 hours)

79
Q

What are the adverse effects associated with Endothelin Receptor Antagonists?

A

-Peripheral Edema
-LFT Abnormalities
-Anemia

80
Q

Rank the Endothelin receptor Antagonists in order from most to least likely to cause peripheral edema

A

Most: Ambrisentan (also more headache + nasal congestion)

Bosentan

Least: Macitentan

81
Q

Rank the Endothelin Receptor Antagonists in order from most to least likely to cause Liver Function test (LFT) abnormalities

A

Most: Bosentan
Ambrisentan
Macitentan

82
Q

True or False: Endothelin Receptor Antagonists often have to be discontinued due to anemia and transfusions often have to be given

A

FALSE
-anemia is a side effect but treatment discontinuation and transfusions are not common

83
Q

What black box warning is associated with Endothelin Receptor Antagonists?

A

Embryo-Fetal Toxicity

Bosentan: Hepatotoxicity

84
Q

What parameters need to be monitored with Endothelin receptor Antagonists?

A

-Pregnancy testing required monthly for all!

-LFTs (bosentan=monthly, macitentan= as indicated)

-Hemoglobin

85
Q

How long does it take for improvement to be seen with Endothelin Receptor Antagonists?

A

8-10 weeks

86
Q

When would we use Riociguat?

A

Asan alternative to PDE-5i

(used when patients cannot take PDE-5 inhibitors)

**RARELY USED

87
Q

True or False: Riociguat can be used in combination with PDE-5 inhibitors

A

FALSE
-do not use in combination with tadalafil or sildenafil due to risk of hypotension

88
Q

What did the AMBITION trial show?

A

-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
Q

What did the TRITON trial show?

A

Evaluated triple vs dual therapy

-Showed little difference between triple and dual therapy groups
(why we do not recommend triple therapy)

90
Q

What is the mechanism of action of prostacyclins?

A

-Stimulate cAMP pathway to increase pulmonary vasodilation

-Induce vasodilation in all vascular beds
-Inhibit platelet aggregation
-Cytoprotective and antiproliferative effects

91
Q

What is the standard treatment for severe PAH with right ventrivular failure?

A

Prostacyclins

-subQ treprostinil becoming most common

92
Q

What dosage forms are prostacyclins available in?

A

Parenteral (IV + SubQ)
Oral
Inhaled

93
Q

When does parenteral treatment become first-line?

A

Class IV or Rapidly Progressing Class III

94
Q

What drugs can prostacyclins be used in combination with?

A

Endothelin receptor agonists + PDE-5 inhibitors OR riociguat

95
Q

True or False: You can use oral, inhaled, and parenteral prostacyclins concurrently

A

FALSE
-do not use together

96
Q

How do prostacyclins affect platelet aggregation?

KNOW THIS CARD

A

All prostacyclins inhibit platelet aggregation

97
Q

What are the common side effects associated with prostacyclins?

A

Thrombocytopenia (especially epoprostenol)

Hypotension

98
Q

What is a major reason why we prefer subQ formulations of prostacyclins?

A

IV forms are likely to cause line infections

99
Q

What are common side effects of subcutaneous prostacyclins?

A

Site pain

Infusion site reactions*

100
Q

When would we use oral prostacyclins?

A

Patients who refuse or cannot manage parenteral therapy

(oral not preferred)

101
Q

What is an important thing to note about oral selexipag?

A

Dose must be titrated
-if you miss a few doses you have to start the titration over

-very expensive

102
Q

What are the 2 oral prostacyclins?

A

Treprostinil

Selexipag

103
Q

What are the two inhaled prostacyclins and which one is preferred?

A

Iloprost

Treprostinil (Tyvaso)

*treprostinil is preferred because iloprost requires 9 doses daily

104
Q

True or False: Oral and Inhaled Prostacyclins are equivalent

A

TRUE

105
Q

What is the only IV/SubQ prostacyclin

A

Treprostinil

106
Q

True or False: IV Treprostinil can be co-infused with other drugs

KNOW THIS CARD

A

FALSE

-DO NOT CO-INFUSE IV PROSTACYCLINS WITH ANYTHING ELSE

-IV requires stable access
-WILL KILL PATIENT

107
Q

True or False: SubQ and IV dosing of prostacyclins is the same

A

TRUE

108
Q

What is the half-life of IV/SubQ Treprostinil (Remodulin)?

A

4 hours

109
Q

When do we use IV Treprostinil?

A

In patients who cannot tolerate subQ

110
Q

What is the other IV prostacyclin and when do we use it?

A

Epoprostenol IV

NOT USED ANYMORE

111
Q

Why is Epoprostenol IV not used anymore?

A

-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
Q

What are some common adjunct therapies to PAH medications?

A

-Anticoagulation
(depends on cardiac function)

-Diuretics
(to maintain euvolemia)

113
Q

What are common supportive therapies with PAH treatment?

A

-Immunizations
-Supplemental oxygen
-Iron supplementation

Avoid air travel/high altitudes
(may affect oxygen saturation)

114
Q

Which endothelin receptor antagonist can decrease efficacy of hormonal contraceptives?

A

Bosentan
-not good since this is contraindicated in pregnancy

Therapeutics 2 Final Exam (3 decks)

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