Pulmonary HTN Flashcards
Definition of pulmonary arterial hypertension
Pulmonary Hypertension (PH): mean pulmonary artery pressure > 25 mmHg (leads to Right HF)
–> Diagnosed by invasive monitoring with a pulmonary artery catheter
Normal Pathophysiology:
High flow, low-pressure circulation
Has less resistance as compared to systemic circulation
Normal Pathophysiology:
Mediators
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
PH Pathophysiology:
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
WHO
Causes/ Classification of pulmonary hypertension
Group I: Pulmonary arterial hypertension
Idiopathic
Familial
Related to HIV, drugs, congenital,
connective tissue disease
Causes/ Classification of pulmonary hypertension
Group II
Pulmonary hypertension with left heart disease
Causes/ Classification of pulmonary hypertension
Group III
Associated with hypoxemia
Causes/ Classification of pulmonary hypertension
Group IV
Due to chronic thromboembolic
For those who constantly have have pulmonary embolism.
Causes/ Classification of pulmonary hypertension
Group V
Miscellaneous
Group I: Pulmonary arterial hypertension
Drug Induced:
Definite: aminorex, fenfluramine, dexfenfluramine, phentermine (diet pills)
Possible: Amphetamines, cocaine, chemotherapy
Symptoms and Functional Classification
Common symptoms
Exertional dyspenea, Fatigue/weakness, Leg swelling, Angina, syncope
Symptoms and Functional Classification
Progressing disease
Worsening dyspenea, Abdominal fullness, increased edema, Profound fatigue, Anorexia
Symptoms and Functional Classification
Advance disease
Tricuspid regurgitation, peripheral edema, Hypotension, cool extremities, Cyanosis
Functional Classification:
I: often Asymptomatic
II:Slight limitation
III:marked limitation with physical activity
IV: Symptoms at rest (late stage)
Non-Pharmacologic treatment
Avoid pregnancy + contraceptive (avoid hormone )
Excercise
Supportive therapy
• 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
Targeted therapy: List
- Calcium channel blockers
- Synthetic prostacyclin and prostacyclin analogs
- Endothelin receptor antagonists
- Phosphodiesterase inhibitors
- Guanylate cyclase activator
Targeted therapy:
Calcium channel blockers
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
Targeted therapy: Prostacyclins
All dispensed from specialty pharmacies only (Accredo and Curascript)
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
Targeted therapy:
Special
Epoprostenol - IV continuous infusion
IV epoprostenol considered the most effective therapy
Targeted therapy:
Special
IV/SC formulations:
Epoprostenol - IV continuous infusion
Treprostinil - IV, SC continuous infusion
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!**
Targeted therapy:
Endothelin receptor antagonists (ERAs)
PO ONLY
Bosentan (Tracleer) oral tablet
Ambrisentan (Letairis) oral tablet
Macitentan (Opsumit) oral tablet
Calcium channel blockers
MOA
vasodilation but sustained response is rare
Calcium channel blockers
Major adverse effects/warnings:
Peripheral edema, headache, fatigue, constipation
Calcium channel blockers
Drug interactions:
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
Prostacyclins
MOA
Potent vasodilator that affects the pulmonary and
systemic circulations
Known to cause a decrease in platelet aggregation
Prostacyclins
Major /most common adverse effects:
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)
Endothelin receptor antagonists (ERAs)
o Major/most common adverse effects:
Headache, flushing, peripheral edema, increase in
liver enzymes, reduced hemoglobin
Endothelin receptor antagonists (ERAs)
Drug interactions:
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)
Bosentan (Tracleer) oral tablet
! 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)
Ambrisentan (Letairis) oral tablet
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
Macitentan (Opsumit) oral tablet
macitentan: substrate of 2C19, 3A4
Inhibitors of CYP 2C19 (e.g. cimetidine, efavirienz)
(with ambrisentan/macitentan only)
Alternative if Bosentan elevates LFTs
Endothelin receptor antagonists (ERAs)
Other important points:
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
Endothelin receptor antagonists (ERAs)
MOA
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
Phosphodiesterase inhibitors:
Sildenafil (Revatio) oral tablet, IV
Tadalafil (Adcirca) oral tablet
Phosphodiesterase inhibitors:
MOA
Promotes accumulation of cGMP therefore enhancing nitric-oxide mediated vasodilation in the lung
Phosphodiesterase inhibitors:
Major/common adverse effects:
Headache, flushing, hypotension, nose bleeds, visual
disturbances, myalgia/pain in arms/legs (Tadalafil
Phosphodiesterase inhibitors:
Drug interactions:
Inhibitors of CYP 3A4
Inducers of CYP 3A4
Contraindicated with nitrates
Tadalafil ORAL ONLY –DOSE ADJUSTMENTS?
Tadalafil: Dose adjustment in kidney and hepatic
impairment
Soluble guanylate cyclase stimulator:
Riociguat (Adempas)
1st line for PH with Chronic Thromboemoblic disease (IV)
Soluble guanylate cyclase stimulator:
Mechanism of action:
stimulates soluble guanylate cyclase leading to increase NO and increased cGMP leading to vasodilation
Soluble guanylate cyclase stimulator:
Riociguat (Adempas)
Major/most common adverse effects:
Hypotension, palpations, peripheral edema, dyspepsia, dizziness, headache, bleeding
Soluble guanylate cyclase stimulator:
Riociguat (Adempas)
Drug interactions:
Riociguat is a substrate of CYP2C8, 3A4 and p-
glycoprotein
Contraindicated with nitrates and PDE-5 inhibitors
Metabolism induced by cigarette smoking
Soluble guanylate cyclase stimulator:
Riociguat (Adempas)
Other important points
Contraindicated in pregnancy
Indicated for WHO class I PAH
1st drug indicated for chronic thromboembolic pulmonary hypertension (WHO IV)
Deciding on therapy
! 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)
