Brainscape's Knowledge GenomeTM


Top Flashcards (Certified)
All Flashcards

PHRM 844 Module #2 > Pulmonary Aterial Hypertension > Flashcards

Pulmonary Aterial Hypertension Flashcards

1
Q

Cardiac Anatomy

A

Normally pressures higher on left side of heart, goes all throughout body; right side just goes to lungs, lower pressure
PAH we’re focused on pulmonary artery –> have elevated pressures in this vessel and the right side of the heart not equipped to pump high pressures

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Pulmonary Hypertension

A
  • Pulmonary hypertension is higher than normal blood pressure in the arteries that carry blood away from the heart into the lungs
  • Pulmonary Hypertension (PH)
    – Mean pulmonary artery pressure (MPAP) ≥ 20 mmHg at rest
    – More common
  • Pulmonary Arterial Hypertension(PAH)
    – Progressive disease involving endothelial lung dysfunction –> elevated pulmonary
    arterial pressure and pulmonary vascular resistance
    – Rare
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

WHO Classification

A

Group 1: pulmonary arterial hypertension
causes:
- Unknown (idiopathic) - more common in adults
- Genetic
- Drug and toxin exposure
- Disease associated with PAH: CHD, HIV, connective tissue disorders
treatment:
Medications specifically for treatment of PAH
CCB in responders
Lung transplantation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Hemodynamic definitions

A

PH: mean pulmonary artery pressure: > 20mmHg
PAH: mean pulmonary artery pressure: > 20mmHg; pulmonary artery wedge pressure: </= 15mmHg; pulmonary vascular resistance: > 2 wood units

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Hemodynamic Definitions

A
  • Pulmonary arterial wedge pressure
    – Estimates left atrial pressure
    – Normal = 4-12 mmHg
    – Elevated numbers signal LV failure or mitral stenosis
  • Pulmonary vascular resistance
    – Calculated using formula based on mPAP and PAWP
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

PAH Epidemiology (Group 1)

A
  • Rare
    – 2-7.6 cases per million adults/year
    – prevalence 10-26 per one million adults
  • Variable age @ diagnosis
    – Mean 50 ± 14 years
    – 4 x more common in women
  • Underrecognized
    – Median 1.1 years to diagnostic right heart catheterization (gold standard for diagnosing)
    – 1 in 5 symptomatic > 2 years before diagnosis
  • Prognosis is poor but improving
  • Approx 15% mortality within 1 year * Median survival 6 years
    Negative predictors:
  • Advanced functional class
  • Poor exercise capacity
  • High right atrial pressure
  • Right ventricular dysfunction
  • Low cardiac output
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Signs & Symptoms

A

27% reported fatigue
15% reported fainting or light-headedness
22% reported chest pain
86% reported shortness of breath
13% reported palpitations
21% reported edema
frequently misdiagnosed as asthma

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Diagnosis

A

echocardiogram: Useful for evaluating potential causes, RV function, estimating PAP and PVR (ultrasound of heart)
right heart catheterization: Confirms diagnosis and estimates severity; Assess response to pulmonary vasodilators before starting therapy (AVT); acute vasoreactivity test to see if candidates for CCBS
exercise testing: Distance walked in 6 minutes
biomarkers: BNP and NTproBNP

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

PH Centers

A
  • If PH suspected, guidelines suggest early evaluation at PH Center
  • Accreditation for adult and pediatric programs through Pulmonary Hypertension Association
  • Access to specialty physicians, allied health, diagnostics, active research program
  • Approx. 9 pediatric centers nationwide (Riley = closest)
  • IN Adult Centers: St. Vincent, IU Health
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Effects of PAH

A
  • Right side of heart has difficulty pumping against high pulmonary pressures
  • Leads to right ventricular failure
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

PAH Disease Progression

A

Vascular injury: endothelial dysfunction - decrease nitric oxide synthase, decrease prostacyclin production, increase thromboxane production, increase endothelin 1 production
where the drugs act; want to try to slow this vascular injury process

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

WHO Functional Classes

A

class 1: Symptom-free when physically active or resting (at risk, don’t receive tx)
class II: Slight limitation of physical activity – ordinary activity may cause symptoms; Comfortable at rest
class III: Marked limitation in physical activity – less than ordinary activity causes symptoms; Comfortable at rest
class IV: Significant symptoms with activity; Symptoms at rest
worse functional class, your mortality is worse

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Risk Assessment in PAH

A
  • Stratification in European guidelines based on low (<3%), intermediate-low (2-7%), intermediate-high (9-19%), or high (>20%) risk of 1-year mortality
    – Registry data suggest risk model helps predict mortality
    – Use additional criteria as needed (age, renal function, comorbidities, etc)
  • US guidelines focus on WHO functional class, but clinician discretion will shape treatment
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

Treatment of PAH

A
  • Goals of therapy
    – Alleviate symptoms
    – Improve quality of life
    – Prevent or delay disease progression
    – Reduce hospitalization
    – Improve survival
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Pharmacotherapy

A
  • Calcium channel blockers (CCB)
  • Direct pulmonary vasodilator (inhaled nitric oxide - iNO)
  • Phosphodiesterase 5 (PDE-5) inhibitors
  • Endothelin receptor antagonists (ERAs)
  • Prostacyclins (oral, inhaled, parenteral)
  • Soluble guanylate cyclase (sGC) stimulator (riociguat)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

Things to Remember

A
  • Head-to-head comparisons of therapies still emerging
  • Different drugs have different safety profiles/ADRs
  • Consider patient values/preferences/goals
  • Cost/insurance
    rare disease state makes it harder to study
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Guideline Recommendation: AVT

A

acute vasoreactivity testing –> positive responder –> CCB
acute vasoreactivity testing –> negative responder, RV failure, or CCB contraindication –> do not use CCB

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Acute Vasoreactivity Test (AVT)

A
  • Done in cath lab during initial hemodynamic evaluation
  • Acute response to pulmonary-specific vasodilators predicts response to
    calcium channel blockers
  • Agents used include – Inhaled nitric oxide – IV epoprostenol
  • Positive test = drop in mPAP > 10 mmHg w/PAP less than 40 mmHg w/stable-improved cardiac output
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Calcium Channel Blockers

A
  • Only 5-8% of patients are responders; long-term response is rare
  • Consider CCBs in positive responders without right-sided failure or other
    contraindication to CCB; do not use w/out positive AVT
  • Recommended drugs
    – Long-acting nifedipine 120-240 mg daily – Long-acting diltiazem 240-720 mg daily – Amlodipine 20 mg daily
  • NO verapamil due to negative inotropic effects
  • If patients do not improve to functional class I or II after CCB initiation,
    start additional or alternative PAH therapy
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

Guideline Recommendation: WHO FC I

A

treatment naive PAH patients w/ WHO FC I –> continued monitoring for disease progression –> determine when to start therapy
* PAH FC I patients do not necessarily require immediate drug therapy; consider CCB if responder
* Monitor closely and consider initiation if worsening symptoms (dyspnea on exertion, fatigue, weakness) or concern for disease progression

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Guideline Recommendation: WHO FC II

A

treatment naive PAH with WHO FC II –> tolerate combo therapy –> yes: combo treatment –> ambrisentan + tadalafil
treatment naive PAH with WHO FC II –> tolerate combo therapy –> no: monotherapy –> ERA, riociguat, or PDE-5 inhibitor
* PAH FC II patients who fail/are not candidates for CCBs should receive targeted PAH therapy
* Combination therapy may increase costs and risk of ADRs – Some patients may prefer to start with monotherapy
– May have comorbidities that require caution

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

Guideline Recommendation: WHO FC III

A

treatment naive PAH with WHO FC III w/o rapid progression or poor prognosis –> tolerate combo therapy? –> yes: combo therapy –> ambrisentan + tadalafil
treatment naive PAH with WHO FC III w/o rapid progression or poor prognosis –> tolerate combo therapy? –> no: monotherapy –> ERA, riociguat, or PDE-5 inhibitor

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

Therapeutic Pathways

A

nitric oxide pathway
endothelin pathway
prostacyclin pathway

24
Q

Nitric Oxide Pathway

A
  • PDE-5 Inhibitors: sildenafil, tadalafil
  • Soluble Guanylate Cyclase Stimulator: riociguat
25
Endothelin Pathway
Endothelin Receptor Antagonists * Bosentan * Ambrisentan * Macitentan
26
Prostacyclin Pathway
* Prostacyclins: epoprostenol (IV), iloprost (inh), treprostinil (IV, SQ, inh, oral) * IP prostacyclin receptor agonist: selexipag
27
Phosphodiesterase Inhibitors
* PDE-5 inhibition – Decreases conversion of cGMP to GMP – Increased levels of cGMP --> pulmonary vasodilation * Sildenafil and tadalafil: Improved 6MWD, functional capacity * May be used as monotherapy or in combination with other classes * Considered first line in many cases – FC II, FC III without rapid progression * May require specialty pharmacy (cost)
28
PDE-5 Inhibitors
MOA: block PDE-5 --> increase cGMP --> muscle relaxation, vasodilation sildenafil: TID tadalafil: daily avoid use with riociguat or nitrates (hypotension); substrate: CYP3A4 ADRs: Flushing, headache, dyspepsia, visual disturbances (blue-tinged vision), priapism, tinnitus/hearing loss, sudden vision loss, hypotension
29
IV sildenafil
* Available but rarely used * Restricted for patients who are strictly NPO * Dosing differs from oral * $$$ * Must be given as slow infusion to avoid hypotension
30
Endothelin Receptor Antagonists
* ET receptors on vascular smooth muscle mediate vasoconstriction – Overexpression of ET-1 in PH patients, correlates with remodeling – Blocking ET --> vasodilation * Option in Class II-IV – Tadalafil + ambrisentan combo first line for Class II and Class III without rapid progression * Improve 6MWD, pro-BNP, delay time to clinical worsening, optimize hemodynamics
31
Receptor Subtypes: A vs B
* ETA receptors – Located on pulmonary smooth muscle walls – Promote vasoconstriction, proliferation, and inflammation * ETB receptors – Receptors on endothelium: Promote vasodilation, stimulate NO and – Receptors on muscle cells of vascular walls: Cause vasoconstriction and cell proliferation * In PAH, expression of ETB receptors is upregulated in the media of blood vessels (vasoconstriction) * Ambrisentan = selective for ETA (may cause worse edema) and bosentan/macitentan = mixed * Unclear how selectivity impacts clinical outcomes
32
Endothelin Receptor Antagonists Medications
MOA: Block endothelin receptors on vascular smooth muscle --> reduced vasoconstriction/cell proliferation bosentan: BID; interactions with CYP2C9/3A4; most toxic, highest risk of hepatic dysfunction ambrisentan: daily; interaction with CYP3A4 macitentan: daily; interaction with CYP3A4 all highly protein bound
33
ERA Adverse Events
peripheral edema, LFT abnormalities, anemia (tx discontinuation/transfusion not typically necessary) bosentan black box warning: embryo-fetal toxicity, hepatotoxicity ambrisentan + macitentan black box warning: embryo-fetal toxicity REMS program for bosentan: reproductive harm and hepatoxicity REMS program for ambrisentan + macitentan: reproductive harm avoid use in hepatic impairment, do not initiate if LFT > 3x ULN
34
ERA Required Monitoring
pregnancy test monthly LFTS (except ambrisentan) hemoglobin
35
Clinical Effects of ERAs
* Improve – exercise capacity (6MWD) – functional capacity – hemodynamic parameters – time to clinical worsening – WHO FC * Note: Improvement not likely seen for 8-10 weeks
36
Soluble Guanylate Cyclase Stimulator
* Riociguat (Adempas®) is currently only drug in class * May be used as alternative to PDE-5i – Cannot be used in combination with tadalafil or sildenafil due to risk of hypotension * Demonstrate antiproliferative and antiremodeling activity in animal models * Improves exercise capacity, WHO FC, and time to clinical worsening
37
AMBITION
* 500 treatment-naïve patients with FC II or III PAH * Randomized 2:1:1 – 10 mg ambrisentan daily + 40 mg tadalafil daily – 10 mg ambrisentan + placebo – 40 mg tadalafil + placebo * Primary composite endpoint : Death, hospitalization for PAH (including lung transplant or parenteral prostanoids), disease progression, or unsatisfactory clinical response (assessed by FC/6MWD)
38
AMBITION results
* In combination group, peripheral edema, headache, nasal congestion, dizziness and anemia were more common than either monotherapy group * Rates of hypotension were similar * Rate of discontinuation and serious ADRs were similar across all groups reason why ambrisentan + tadalafil are 1st line; longer time of being event free
39
TRITON
* Evaluating triple vs dual therapy in newly diagnosed treatment naïve PAH group 1 patients * N = 247 * Randomized 1:1 to macitentan + tadalafil + selexipag vs placebo * Primary = 26-week change in PVR – Triple therapy = 54% decrease – Dual therapy = 52% decrease – 95% CI: 0.86-1.07, p = 0.42 no difference b/w these 2 groups
40
Guideline Recommendation: WHO FC III
WHO FC III WITH rapid progression or poor prognosis --> Candidate for parenteral prostanoids? --> yes --> SC treprostinil, IV treprostinil, IV epoprostenol WHO FC III WITH rapid progression or poor prognosis --> Candidate for parenteral prostanoids? --> no --> Consider inhaled or oral prostanoid (likely in combo w/ERA + PDE- 5i)
41
Guideline Recommendation: WHO FC IV
WHO FC IV --> Candidate for parenteral prostanoids? --> yes --> SC treprostinil, IV treprostinil, IV epoprostenol WHO FC IV --> Candidate for parenteral prostanoids? --> no --> Inhaled prostanoid + ERA + PDE-5i
42
Prostacyclins
* Prostacyclins stimulate the cAMP pathway to increase pulmonary vasodilation * Parenteral prostacyclins = standard for severe PH with RV failure – subQ treprostinil is becoming most common * Available in parenteral (IV + subQ), oral and inhaled formulations * Reserved for WHO Class III and IV patients – Class II or low-risk Class III: optimize oral therapy – Parenteral: first-line if Class IV or rapidly progressing Class III * Improve symptoms, 6MWD, hemodynamics, mortality? * May be used in combination with ERA plus PDE-5 or riociguat * Do not use oral, inhaled and parenteral concurrently
43
Prostacyclins Medication
MOA: Induce vasodilation in all vascular beds, inhibits platelet aggregation, cytoprotective and antiproliferative effect ADRs: Headache, jaw pain, limb pain, flushing/skin rash, diarrhea, nausea/vomiting, thrombocytopenia (more in epoprostenol) hypotension Oral: diarrhea, anemia Inhaled: cough, throat irritation IV: line infections, erythema subQ: site pain, infusion site rxns
44
Prostacyclins: Oral
* Option for patients w/ indication for prostacyclin who refuse or cannot manage parenteral therapy treprostinil - BID; if more than 2 doses missed, must re-titrate selexipag - titrate to max tolerated dose (max dose = 1600 mcg BID); therapy interruption more than 3 days requires re-titration; contraindicated with CYP2C8 inhibitors
45
Prostacyclins: Inhaled
* Option for patients w/ indication for prostacyclin who refuse or cannot manage parenteral therapy iloprost - daily; requires up to 9 doses daily treprostinil - QID
46
Treprostinil inhaled
* Tyvaso more common due to less frequent dosing * New device can be charged (vs always plugged in) * Assembling device is complicated and done once every day * Treatments throughout the day are 2-3 minutes
47
Prostacyclin: Treprostinil IV/SQ
* Treprostinil (Remodulin®) 1-3 ng/kg/min IV or subQ (continuous), titrated as tolerated, max dose varies – t1⁄2: 4 hours – Start in hospital and titrate Q8-12 hours to ~20 ng/kg/min then weekly at home by ~2 ng/kg/min increments up to goal dose (usually 50-80 ng/kg/min) * IV infusion requires stable access, do not co-infuse with anything else; risk of line infection with continuous IV * SQ/IV dosing is the same
48
Prostacyclin: SubQ vs IV Treprostinil
* IV is reserved for patients who cannot tolerate subQ * SubQ avoids risk of central lines (including associated infections) * May have infusion-site reactions with subQ (may treat with antihistamines, topical agents) – Some patients do not tolerate and must be converted to IV * SubQ administration typically utilizes undiluted drug; IV must be prepared with diluent into cassettes * SubQ pums are smaller and more portable
49
Prostacyclin: Epoprostenol IV
* Epoprostenol 1-3 ng/kg/min IV (continuous), titrated as t1⁄2: 3- 5 minutes – Must always have back-up cassette prepared – Abrupt D/C may precipitate PH crisis * Flolan®: non-thermostable product * Veletri®: thermostable product * Startinhospital,titratetoeffect * Requires permanent, stable IV access (no subQ) * Incompatible with everything -- DO NOT co-administer any other fluids - could cause profound hypertension – Inadvertent bolus can lead to CV collapse and death * Used less often than treprostinil
50
PGI2 Analogs: Key Information
* Prostacyclin therapy requires significant education before initiation * $$$$ * Patients should have their own pumps and supplies * Interview patient; may need to call specialty pharmacy to confirm – Drug concentration – Diluent (if IV) – Dosing weight – Infusion rate – Infusion dose – Last syringe/cassette change
51
Prostacyclin Medication Errors
* Electronic survey of health providers at pulmonary hypertension centers (n = 95) – 68% reported serious or potentially serious errors – 29% reported serious adverse events – 9 deaths reported * Common reported errors: – Flushing of line(33%) – Calculation or concentration error(31%) – Programming error(25%) – Pump turned off(25%) – Inappropriate change in weight(3%)
52
Guideline Recommendation: Disease Progression
* Expert consultation likely needed * For patients who do not respond to initial therapy (monotherapy or combination), consider adding on a second or third class – Ex: Add on ERA if on PDE-5i, or add inhaled prostacyclin if already on ERA and PDE-5i * For FC III and FC IV patients with inadequate response to maximal pharmacotherapy, consider lung transplantation
53
Pharmacotherapy
* Guidelines provide algorithm but based largely on expert opinion – Incorporate patient specific factors and preferences when appropriate – Evaluation of disease severity, medication costs, patient preference – Compliance can be challenging and have clinical consequences *Therapeutic escalation, rebound symptoms, clinical worsening, hospitalization, death
54
Adjunct Therapy
* Treat underlying/contributing conditions like hypertension/sleep apnea * Anticoagulation – May consider anticoagulation or antiplatelet therapy depending on cardiac function *Warfarin: INR goal 1.5-2.5 - don't do if on prostacyclin *Aspirin 81 mg daily * Diuretics to maintain euvolemia
55
Supportive Therapy
* Immunizations – Influenza – Pneumococcal – SARS-CoV-2 - new RSV immunizations * Supplemental oxygen (pulmonary vasodilation) * Iron supplementation if deficiency * Avoid air travel/high altitudes if possible (altitude may effect ability to keep O2 saturations up) – May need supplemental O2 to keep saturations >91% * Consider pulmonary rehabilitation/supervised exercise program * Avoid non-essential surgical intervention * Palliative care consultation
56
Pregnancy Considerations
* Avoid pregnancy – Estrogen-containing contraceptives may increase VTE risk – Bosentan can decrease efficacy – ERAs (bosentan, ambrisentan, macitentan) and riociguat category X *REMS programs for distribution *Specialty pharmacies and provider enrollment *Monthly pregnancy tests *“Highly reliable” contraception required * If pregnancy occurs, should be cared for at PAH center ERAs contraindicated

PHRM 844 Module #2 (23 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2025 Bold Learning Solutions. Terms and Conditions