Pulmonary HTN

Question 1

Definition of pulmonary arterial hypertension

Answer 1

Pulmonary Hypertension (PH): mean pulmonary artery pressure > 25 mmHg (leads to Right HF)

–> Diagnosed by invasive monitoring with a pulmonary artery catheter

Question 2

Normal Pathophysiology:

Answer 2

High flow, low-pressure circulation

Has less resistance as compared to systemic circulation

Question 3

Normal Pathophysiology:

Mediators

Answer 3

Endothelin- Vasoconstrictor; stimulate smooth muscle growth

o Prostacyclin- vasodilator; decrease platelet activation

o Nitric oxide-Vasodilator

o Serotonin- Vasoconstrictor

o Other: Thromboxiane: promotes clotting and increases cell proliferiation

Question 4

PH Pathophysiology:

Answer 4

Imbalance of vasoconstrictors and vasodilators

Increased resistance:
->Thickening of the smooth muscle cells

->Growth of endothelial cells due to
cellular proliferation

->Thrombosis block the lumen of the
vessel

*Leads to enlarged right ventricle and HF

Question 5

WHO

Causes/ Classification of pulmonary hypertension
Group I: Pulmonary arterial hypertension

Answer 5

Idiopathic

Familial

Related to HIV, drugs, congenital,
connective tissue disease

Question 6

Causes/ Classification of pulmonary hypertension

Group II

Answer 6

Pulmonary hypertension with left heart disease

Question 7

Causes/ Classification of pulmonary hypertension

Group III

Answer 7

Associated with hypoxemia

Question 8

Causes/ Classification of pulmonary hypertension

Group IV

Answer 8

Due to chronic thromboembolic

For those who constantly have have pulmonary embolism.

Question 9

Causes/ Classification of pulmonary hypertension

Group V

Answer 9

Miscellaneous

Question 10

Group I: Pulmonary arterial hypertension

Drug Induced:

Answer 10

Definite: aminorex, fenfluramine, dexfenfluramine, phentermine (diet pills)

Possible: Amphetamines, cocaine, chemotherapy

Question 11

Symptoms and Functional Classification

Common symptoms

Answer 11

Exertional dyspenea, Fatigue/weakness, Leg swelling, Angina, syncope

Question 12

Symptoms and Functional Classification

Progressing disease

Answer 12

Worsening dyspenea, Abdominal fullness, increased edema, Profound fatigue, Anorexia

Question 13

Symptoms and Functional Classification

Advance disease

Answer 13

Tricuspid regurgitation, peripheral edema, Hypotension, cool extremities, Cyanosis

Question 14

Functional Classification:

Answer 14

I: often Asymptomatic
II:Slight limitation
III:marked limitation with physical activity
IV: Symptoms at rest (late stage)

Question 15

Non-Pharmacologic treatment

Answer 15

Avoid pregnancy + contraceptive (avoid hormone )

Excercise

Question 16

Supportive therapy

Answer 16

• Prophylactic oral anticoagulants (goal INR 1.5-2.5)

o Idiopathic PAH/inherited PAH/due to anorexigens

• Diuretics
• Oxygen
• Digoxin (target concentration 0.5-0.8ng/ml)
• Vaccines
• ->Influenza
• ->Pneumococcal

Question 17

Targeted therapy: List

Answer 17

• Calcium channel blockers
• Synthetic prostacyclin and prostacyclin analogs
• Endothelin receptor antagonists
• Phosphodiesterase inhibitors
• Guanylate cyclase activator

Question 18

Targeted therapy:

Calcium channel blockers

Answer 18

Nifedipine extended release (Procardia/ Adalat CC)
tablet

Diltiazem (Cardia XT, Cardizem CD, etc.) capsule-
Avoid diltiazem in patients with left ventricular systolic
dysfunction

Amlodipine (Norvasc) tablet

Question 19

Targeted therapy: Prostacyclins

All dispensed from specialty pharmacies only (Accredo and Curascript)

Answer 19

Agents used:
Epoprostenol - IV continuous infusion

Treprostinil - IV, SC continuous infusion

Treprostinil - inhaled four times daily

Treprostinil ER - tablet 2-3 times daily

Iloprost -inhaled 6-9 times daily

Question 20

Targeted therapy:
Special

Epoprostenol - IV continuous infusion

Answer 20

IV epoprostenol considered the most effective therapy

Question 21

Targeted therapy:

Special

IV/SC formulations:

Epoprostenol - IV continuous infusion

Treprostinil - IV, SC continuous infusion

Answer 21

Mixed by the patient at home and administered
through a central line by a special IV/SC pump

NOT compatible with other medications

** Abrupt withdrawal or interruption of infusion may lead to rebound pulmonary hypertension and possibly death!**

Question 22

Targeted therapy:

Endothelin receptor antagonists (ERAs)

PO ONLY

Answer 22

Bosentan (Tracleer) oral tablet

Ambrisentan (Letairis) oral tablet

Macitentan (Opsumit) oral tablet

Question 23

Calcium channel blockers

MOA

Answer 23

vasodilation but sustained response is rare

Question 24

Calcium channel blockers

Major adverse effects/warnings:

Answer 24

Peripheral edema, headache, fatigue, constipation

Question 25

Calcium channel blockers Drug interactions:

Answer 25

Known inhibitors of CYP 3A4: e.g. amiodarone, erythromycin, azole antifungals, HIV medications Known inducers of CYP 3A4: e.g. rifampin, carbamazepine, phenytoin, St. John’s wort Simvastatin: 10mg diltiazem, 20mg amlodipine

Question 26

Prostacyclins MOA

Answer 26

Potent vasodilator that affects the pulmonary and systemic circulations Known to cause a decrease in platelet aggregation

Question 27

Prostacyclins Major /most common adverse effects:

Answer 27

Flushing, jaw pain, severe headache, hypotension, thrombocytopenia (ALL) Pain at injection site- (treprostinil SC) Infection with IV continuous infusion due to central line - Epoprostenol and Treprostinil Throat irritation, cough, hemoptysis (Iloprost and Treprostinil)

Question 28

Endothelin receptor antagonists (ERAs) o Major/most common adverse effects:

Answer 28

Headache, flushing, peripheral edema, increase in | liver enzymes, reduced hemoglobin

Question 29

Endothelin receptor antagonists (ERAs) Drug interactions:

Answer 29

Avoid with cyclosporine, glyburide, rivaroxaban and apixaban Bosentan: metabolized by CYP2C9, 3A4, inducer of 2C9, 3A4 Ambrisentan & macitentan: substrate of 2C19, 3A4 p-glycoprotein (ambrisentan only) Inducers of CYP 2C9 (e.g. carbamazepine, azole antifungals, phenytoin, rifampin) Inhibitors of CYP 2C9 (e.g omeprazole, voriconazole) Substrates of CYP3A4 (with bosentain only) Substrates of 2C9 (e.g. warfarin, tamoxifen, glyburide) (with bosentan only) Inhibitors of CYP 2C19 (e.g. cimetidine, efavirienz) (with ambrisentan/macitentan only)

Question 30

Bosentan (Tracleer) oral tablet

Answer 30

! Substrates of CYP3A4 (with bosentain only) Substrates of CYP3A4 (with bosentain only) ! Substrates of 2C9 (e.g. warfarin, tamoxifen, glyburide) (with bosentan only) Bosentan and macitentan blocks ETA and ETB receptors FDA requires LFT monitoring monthly (Bosentan ONLY)

Question 31

Ambrisentan (Letairis) oral tablet

Answer 31

Inhibitors of CYP 2C19 (e.g. cimetidine, efavirienz) (with ambrisentan/macitentan only) Ambrisentan & macitentan: substrate of 2C19, 3A4, p-glycoprotein (ambrisentan only) Ambrisentan blocks ETA receptors only Ambrisentan can be initiated in patients that experienced asymptomatic LFT elevations to bosentan

Question 32

Macitentan (Opsumit) oral tablet

Answer 32

macitentan: substrate of 2C19, 3A4 Inhibitors of CYP 2C19 (e.g. cimetidine, efavirienz) (with ambrisentan/macitentan only) Alternative if Bosentan elevates LFTs

Question 33

Endothelin receptor antagonists (ERAs) Other important points:

Answer 33

Pregnancy category X: pregnancy test is required prior to initiation of therapy and then monthly Women of child-bearing age should use 2 forms of contraception LFT monitoring prior to starting therapy FDA requires LFT monitoring monthly (Bosentan ONLY) Avoid in patient with pretreatment moderate to severe hepatic disease Treatment should be stopped in patients with elevated LFTs with accompanying signs of liver failure OR bilirubin levels ≥ 2 times upper limit of normal Ambrisentan can be initiated in patients that experienced asymptomatic LFT elevations to bosentan

Question 34

Endothelin receptor antagonists (ERAs) MOA

Answer 34

Endothelin is a potent vasoconstrictor ETA Receptors: activation facilitates vasoconstriction and proliferation of vascular smooth muscle cells ETB Receptors: involved in clearance of endothelin, may also cause vasodilation Bosentan and macitentan blocks ETA and ETB receptors Ambrisentan blocks ETA receptors only

Question 35

Phosphodiesterase inhibitors:

Answer 35

Sildenafil (Revatio) oral tablet, IV Tadalafil (Adcirca) oral tablet

Question 36

Phosphodiesterase inhibitors: MOA

Answer 36

Promotes accumulation of cGMP therefore enhancing nitric-oxide mediated vasodilation in the lung

Question 37

Phosphodiesterase inhibitors: Major/common adverse effects:

Answer 37

Headache, flushing, hypotension, nose bleeds, visual | disturbances, myalgia/pain in arms/legs (Tadalafil

Question 38

Phosphodiesterase inhibitors: Drug interactions:

Answer 38

Inhibitors of CYP 3A4 Inducers of CYP 3A4 Contraindicated with nitrates

Question 39

Tadalafil ORAL ONLY --DOSE ADJUSTMENTS?

Answer 39

Tadalafil: Dose adjustment in kidney and hepatic | impairment

Question 40

Soluble guanylate cyclase stimulator:

Answer 40

Riociguat (Adempas) 1st line for PH with Chronic Thromboemoblic disease (IV)

Question 41

Soluble guanylate cyclase stimulator: Mechanism of action:

Answer 41

stimulates soluble guanylate cyclase leading to increase NO and increased cGMP leading to vasodilation

Question 42

Soluble guanylate cyclase stimulator: Riociguat (Adempas) Major/most common adverse effects:

Answer 42

Hypotension, palpations, peripheral edema, dyspepsia, dizziness, headache, bleeding

Question 43

Soluble guanylate cyclase stimulator: Riociguat (Adempas) Drug interactions:

Answer 43

Riociguat is a substrate of CYP2C8, 3A4 and p- glycoprotein Contraindicated with nitrates and PDE-5 inhibitors Metabolism induced by cigarette smoking

Question 44

Soluble guanylate cyclase stimulator: Riociguat (Adempas) Other important points

Answer 44

Contraindicated in pregnancy Indicated for WHO class I PAH ``` 1st drug indicated for chronic thromboembolic pulmonary hypertension (WHO IV) ```

Question 45

Deciding on therapy

Answer 45

! Non-pharmacologic therapy (all patients) ! Start supportive therapy (if appropriate) ! All positive responders to vasodilator testing → start calcium channel blocker ! All non-responders and patients without sustained response to CCB/Class III/IV): • Start therapy according to functional class (II-IV) • Choice of therapy depends on route of administration, adverse effects, patient preference, and clinical judgment ``` • IV Epoprostenol should be first line in functional class IV ``` • Combo therapy should be used for those who do not improve or deteriorate on monotherapy (use 2 drugs from different classes)