Chapter 40. Pulmonary Arterial Hypertension

Select Drugs that can cause PAH

• Cocaine

• Fenfluramine

• Methamphetamine/amphetamine

• SSRI use during pregnancy (increased risk of persistent pulmonary hypertension of a newborn [PPHN])

• Weight-loss drugs (diethylpropion, phendimetrazine, phentermine)

Pathophysiology of PAH

Imbalance in vasoconstrictors (endothelin-1, TXA2) being increased and decreased vasodilators substances (e.g. prostacyclins)

• PAH characterized by continuous high BP in pulmonary arteries

  • Results in reduced blood flow and high pressure within pulmonary vasculature

What is the most common cause of death in those who have PAH?

Heart failure

• Why?

  • walls thicken and scar → arteries more narrower → harder for right ventricle to pump blood through pulmonary arteries → develops right HF

Is there a cure for PAH

No - lung or heart transplant may be an option (drugs reduce sx and improve exercise tolerance)

• Sx: fatigue, dyspnea

What is non-drug treatment for PAH?

• sodium restriction of < 2.4 g/day (for volume status)

• Avoid NSAIDs (sodium and water retention)

• Immunizations against influenza and pneumococcal

What is performed to confirm PAH diagnosis?

• Right heart catheterization

• During this, IV vasodilators that are short-acting are given to perform vasoreactivity testing

Who should be treated with a CCB?

A responder (this is what pt is called)

• Their mPAP (mean pulmonary pressure) is falling by at least 10 to an absolute value less than 40.

Treatment Options:

• Oral CCBs: Long-acting nifedipine, diltiazem, and amlodipine

  • Verapamil NOT recommended (d/t negative inotropic effects related to diltiazem)

What should non-responders to vasoreactivity testing or has failed CCB tx be given?

Treat w/ more potent vasodilating drugs: (remember, this is for those who did not have a sustained response to oral CCB or are non-responders to acute vasoreactivity testing)

• Prostacyclin analogues and receptor agonists

• Specifically, IV epoprostenol = decreased mortality (for Prostacyclin analogues)

• Endothelin receptor antagonists (ERAs)

• PDE-5 inhbitors

• Soluble guanylate cyclas (sCG) stimulator and/or sotatercept (Winrevair)

Supportive therapies for PAH

• Loops for volume overload

• Digoxin to improve CO or control HR in AF

• Warfarin preferred if pro-thrombotic

• Why Warfarin?

  • Biochemical changes (inc. TXA2, dec. Prostacyclin = pro-thrombotic state)

  • INR goal set to a specific individualized goal with other comorbidities

Prostacyclin analogue effects (prostanoids)

• Potent vasodilators

• Inhibitors of platelet aggregation

• In PAH, prostacyclin synthases reduced causing lower prod. of prostacyclin I2

Epoprostenol and Treprostinil are prostacyclin analogues that can be administered....

Continuous IV at home

Epoprostenol brand name

Flolan

• AKA this is prostacyclin

• MUST ADMINISTER CONTINUOUS IV INFUSION VIA CENTRAL VENOUS CATH

Epoprostenol (flolan) dosing vs Treprostinil Dosing

Epoprostenol (Flolan): 2 ng/kg/min IV

Treprostinil (Remodulin): 1.25 ng/kg/min

Warnings/Side effects of Prostacyclin analogues

Warnings:

• Vasodilation rxns (hypotension, flushing)

• Rebound PH (w/ interruption or large dec. in dose)

• Chronic IV infusions = sepsis and bloodstream infections (use sterile technique and educate pt)

Side effects:

• Jaw pain, hypotension

• Infusion site pain (IV/SC injections) - Especially SC Remodulin

Important notes on Prostacyclin analogue administration

• Parenteral agents (Flolan, Veletri, Remodulin) are very potent vasodilators - avoid interruptions and sudden, large dose reductions

• Epoprostenol must be protected from light in storage AND during infusion

• Reconstituted Flolan requires ice packs for stability

Boxed Warning associated with Endothelin recpetor antagonists (i.e. Bosentan, ambrisentan)

• Teratogenic, must have. anegative pregnancy test prior to initiation of therapy and monthly therafter

• Bosentan only: hepatotoxic

• All drugs available only through individual REMS programs

Warnings/Side effects of endothelin receptor antagonists

Drugs = Bosentan, Ambrisentan, Macitentan

Contraindications: Pregnancy

Warnings:

• hepatotoxicity (bosentan BW)

• decreased Hgb, Hct

• fluid retention

Side effects:

• headache

• decreased effectiveness of hormonal contraceptives with Bosentan (use 1 barrier method contraception recommended)

How do PDE-5 inhibitors improve PAH?

PDE-5 degrades cGMP, so using PDE-5 inhibitors Increase cGMP leading to pulmonary vasculature relaxation and vasodilation

Sildenafil brand name for PAH

Revatio

(Viagra for ED)

Tadalafil brand name for PAH

Adcirca

(Cialis for ED, BPH)

Contraindications to PDE-5 inhibitors

Concurrent use of nitrates or riociguat

• high risk of hypotension

Warnings/side effects of PDE-5 inhibitors

Warnings:

• hearing loss

• vision loss

• NAION (neuropathy) - non-arteritic anterior ischemic optic neuropathy

• hypotension

• priapism (seek medical care if erection > 4 hrs)

Side Effects: headache

Which medication for PAH sensitizes soluble guanylate cyclase (sGC), which is a receptor for endogenous nitric oxide?

Riociguat (sensitizes sGC to nitric oxide and directly stimulates receptor, which Leads to increased cGMP and relaxation and antiproliferative effects)

• DO NOT USE with PDE-5 inhibitor

DDIs for PDE-5 inhibitors

• No Nitrates please! (Excessive hypotension) absolute contraindication

• Use of other Alpha-1 blockers or other HTNs with PDE-5 inhibitor = hypotension

• also a substrate of CYP3A4 (avoid inhibitor/inducers)

Boxed Warnings for Riociguat

• Teratogenic (must have negative pregnancy test) prior and monthly thereafter

• REMS program (brand = Adempas; Adempas REM program)

Contraindications, Warnings, and Side effects to Riociguat

CI: • Pregnancy, use of nitrates or PDE-5 inhibitors (severe hypotension)

Warnings: • Hypotension

SEs: • Headache

Key Drugs causing Pulmonary Fibrosis

PF = scarred and damaged lung tissue (sx. exertional dyspnea with non-productive cough)

• Amiodarone/Dronedarone

• Bleomycin

• Busulfan

• Carmustine

nitrofurantoin, sulfasalazine