TBL PAH

group II

pulmonary hypertension due to left heart disease

group III

pulmonary hypertension associated with lung disease

group IV

pulmonary hypertension due to chronic thrombotic disease

group V

pulmonary hypertension with unclear mechanism

pathogenesis of PAH (1-3) contributing to vasoconstriction

endothelial cell dysfunction

constricting factors

loss of relaxing factors

pathogenesis of PAH (4-5) contributing to thrombosis

platelet activation

a procoagulant state

pathogenesis of PAH (6-8) contributing to vasoconstriction

cellular proliferation

fibrosis and inflammation

hypertrophy of right ventricle

what is PAH characterized by?

remodeling of small pulmonary arteries → right ventricular hypertrophy

pulmonary endothelial dysfunction can lead to …. ?

medial hypertrophy

intimal fibrosis

what are the 3 main dysfunctional pathways

1. endothelin pathway

2. nitric oxide

3. prostacyclin pathway

sotatercept

MOA

activin signaling pathway → vascular remodeling

VSM contraction and relaxation

1. Ca²⁺ → L-type calcium channel

2. Ca²⁺ activates calmodulin

3. myosin light chain → actin filament

4. VSM cell contraction

what does preproET-1 form when its cleaved?

proendothelin-1

ET-1

vasoconstrictor/mitogen

mediated by ET-A/B

where is ET-A/B receptors found?

VSM cell

where are ET-B receptors found?

endothelial cells

ET-B effects

vasodilatory effect

enhances NO

NO pathway

1. vascular endothelial cells → activate guanylyl cyclase

2. GTP → cGMP

3. cGMP mediates VSM relaxation

prostacyclin pathway

produced and released by vascular endothelial cells

prostaglandin binds to IP → cAMP from ATP

dx of PAH

mPAP > 20 mmHg

PCWP < 15 mmHg

pulmonary vascular resistance > 2 wood units

what is PAP

pressure right ventricle → into pulmonary circulation

normal mPAP

14 ± 3 mmHg

mPAP 21-24

close monitoring

mPAP > 25 mmHg

indicative of PAH

how can mPAP be measured ?

TTE - ultrasound of the heart

right heart catheterization - (GOLD STANDARD)

clinical presentation of PAH

dyspnea

fatigue

WHO functional classification of PAH symptoms

1. no limitation

2. mild limitation, no discomfort at rest, normal activity increases

3. marked limitation of physical activity, no discomfort at rest, less than physical activity

4. unable to perform physical activity at rest

conventional therapies based on symptomatic presentation for PAH

diuretics: signs of HF

warfarin: increased risk of venous thromboemoblism

digoxin: improve cardiac output

oral calcium channel blockers

MOA

L-type calcium channel blockers decrease Ca²⁺ which causes smooth muscle relaxation

oral calcium channel blockers

amlodipine

nifedipine

diltiazem

diltiazem

contraindications

LVEF < 40%

eligibility for CCB

pts who have (+) vasoreactivity test response

CCB adverse effects

hypotension, flushing, peripheral edema

endothelium-receptor antagonists (ERA)

bosentan

ambrisentan

macitentan

what is ERA + _______ with?

PDE5i

ERA

BBW

teratogenic

ERA

route of administration

oral

which ERA can cause the most liver toxicity?

ambrisentan < bosentan = macitentan

how is ERA metabolized?

CYP450 → DDI

which medications for PAH do pts need to go through REMS?

ERA

sGC

ERA

adverse effects

fluid retention

low sperm count

decrease in Hgb/Hct

URTI

bosentan

MOA

irreversible block ET-A/B receptor

bosentan

BBW

teratogenicity

hepatotoxicity

ambrisentan

MOA

blocks ET-A receptor

macitentan

MOA

blocks ET-A/B

PDE5-i

sidenafil

tadalafil

how is sildenafil administered?

3x/day

how is tadalafil administered?

1x/day

what is PDE5-i metabolized by?

CYP3A4 and 2C9

what should PDE5-i avoided with?

nitrates

riociguat

PDE5-i

adverse effects

hearing loss

hypotension

priapism

dyspepsia

blurred vision and color discrimination

prostacyclin analogs

epoprostenol

trepostinil

iloprost

selexipag

prostaglandin analogs

use

high risk pts (IV/SC)

prostacyclin analogs

follow up: intermediate low-risk

add oral/inhaled agent

prostacyclin analogs

follow up: high-risk

add IV/SC agent

prostacyclin analog

MOA

mimic actions of PGI₂ → IP receptor → cAMP → PKA → vasodilation

epoprostenol

improved survival in PAH

epoprostenol

formulations

floan: stable 8 hrs, WITH cold pack 24 hrs

veletri: stable at room temperature

how is epoprostenol implanted?

IV infusion

• central venous catheter

• ambulatory pump

epoprostenol

½ life

3-5 mins

pts should have backup supplies → interruption may lead to pulmonary vasconstriction

epoprostenol

adverse effects

flushing

jaw pain

hypotension

central line infection

epoprostenol

BBW

preg cat B

epoprostenol

contraindication

HFrEF

treprostinal

formulations

SC/IV

powder

ER

treprostinol

½ life

longer compared to epoprostenol

treprostinol

pt counseling points

oral take w food

oral treprostinol

contraindications

hepatic impairment

iloprost

adminstration

inhalation

4-10 mins and multiple inhalation for full dose = backup supply

which prostacyclin analogs are the most stable?

treprostinil

iloprost

selexipag

dosage forms

tablet

IV infusion (temp use)

selexipag

adverse reactions

jaw pain

myalgia

vomiting

pain in extremeties

riociguat

MOA

soluble guanylate cyclase stimulator

• increases sensitivity to NO

riociguat

formulation

oral tabs

riociguat

BBW

preg x

riociguat

recommendation use in class?

class II, III, IV

riociguat

adverse reaction

dyspepsia

headache

hypotension

riociguat

contraindication

PDE5-I

riociguat

smoking

reduces riociguat concentrations by 50-60%

sotatetercept

MOA

activin signaling inhibitor

• reduce abnormal blood vessel

sotatetercept

FDA indication

group 1

sotatetercept

monitoring parameters

Hgb

platelets

what may sotatetercept cause?

erthrocytosis

thrombocytopenia

serious bleeding

embryo-fetal toxicity

impair infertility

low risk mortality

< 5%

intermediate risk mortality

5-20%

high risk mortality

> 20%

initial treatment recommendation

low or intermediate mortality risk

ERA + PDE5

initial treatment recommendation

high risk mortality

ERA + PDE5 + IV prostaglandin analog

non rx reccomendation

sodium restriction

routine immunization

oxygen > 90%

rehab

advise against pregnancy

monitoring parameters for pharmacotherapy

risk assessment 3-4 months

natruretic peptides/ electrocardiogram/ echocardiogram/ quality of life/ 6 min walk distance

• 3-6 months

what if pt still has persistent mortality risk?

may need 4 drugs

1. prostacyclin analog

2. ERA

3. PDE5 or riociguat

4. activin signaling