Pulmonary Arterial Hypertension

Question 0

Five classifications of pulmonary hypertension

Answer 0

1. Pulmonary arterial hypertension (idiopathic, heritable, drug and toxin induced, HIV infection, portal hypertension and persistent pulmonary hypertension of a newborn)
2. Pulmonary HTN owing to left heart disease
3. Pulmonary HTN owing lung dx and/or hypoxia
4. Chronic thromboembolic pulmonary HTN
5. Pulmonary HTN with unclear mechanism

Question 1

Pulmonary arterial hypertension (PAH)

Answer 1

Characterized by continuous high blood pressure in the pulmonary artery. The average blood pressure in a normal pulmonary artery is about 14 mmHg when a person is resting. Mean pulmonary artery pressure PHP >25 in the setting of normal fluid status defines PAH

Question 2

Persistent pulmonary hypertension of the newborn

Answer 2

Can be caused by SSRI use during pregnancy

Question 3

Chronic thromboembolic PH

Answer 3

Occurs in a minority of PE survivors. Warfarin anticoagulation too and I love all of 2–3 is recommended given the history of a clot and for patients who are not thrombectomy candidates

Question 4

Pathology of PAH

Answer 4

An imbalance of vasoconstrictors/vasodilator substances and an imbalance of proliferation and apoptosis

Increase in vasoconstrictors (endothelin-1 and thromboxane)

Decrease in vasodilators (prostacyclins)

As a result the Hartmus work harder to push blood and thus heart failure can ensue (most common cause of death for PAH patients)

Biochemical changes mentioned in vasodilators/vasoconstrictors lead to a pro thrombotic state and anticoagulation is suggested to prevent blood clots. Warfarin, titrated to an INR of 1.5–2.5, is recommended in PAH

Question 5

Symptoms of PAH

Answer 5

Fatigue, dyspnea, chest pain, syncope, Enedina, tachycardia and/or Raynolds phenomena (discoloration and coldness in the fingers, toes and occasionally other areas)

Question 6

Nonpharmacologic treatment

Answer 6

1. Sodium restricted diet of less than 2.4 g per day
2. Manage fluid status
3. Immunizations: influenza and pneumococcal pneumonia are advised
4. May need oxygen

Question 7

Pharmacologic treatment

Answer 7

Some patients will respond to a calcium channel blocker therapy (long-acting nifedipine, diltiazem and amlodipine)

Other options: parenteral prostacyclin therapy, prostacyclin analogues, and endothelin receptor antagonist, PDE-5 inhibitors, and soluble granulate cyclase stimulators

NOTE: NSAIDS SHOULD NOT BE USED IN PATIENTS WITH PAH

Question 8

Prostacyclin analogues

Answer 8

MOA: potent vasodilators that also inhibit platelet aggregation (needed as prostacyclin is not produced enough in PAH patients

Drugs: Epoprostenol (Flolan), treprostinil (Remodulin-SC/IV, Tyvaso-inhaled), Iloprost (Ventavis)

Side effects:

1. During dose titration: vasodilation leads to hypotension, headache, Flushing; nausea/vomiting, diarrhea, anxiety, chest pain, tachycardia, edema and jaw claudication
2. Chronic use: anxiety, flulike symptoms, jaw pain, thrombocytopenia, neuropathy

Notes: avoid interruptions to therapy; avoid large, sudden reductions in those, Flolan needs to be on ice for stability, parenteral agents are considered the most potent of all PAH medications

Question 9

Endothelin Receptor Antagonists

Answer 9

MOA: block these receptors on pulmonary artery smooth muscle and therefore block vasoconstriction by endothelin

Drugs: Bosentan (Tracleer), ambrisentan (Letairis), Macitentan (Opsumit)

Question 10

Bosentan (Tracleer)

Answer 10

REMS DRUG (Tracleer Access Program (TAP)) must have a negative pregnancy test and two forms of protection

Blackbox warning: hepatotoxicity, pregnancy category X

Contraindications: pregnancy; concurrent use with cyclosporine or glyburide

Warning: avoid in mod./severe hepatic impairment

Side effect: headache, dec. hgb, inc. LFTs, URTIs, Edema, spermatogenesis inhibition may lead to male infertility (Bosentan only)

Question 11

Ambrisentan (Letairis)

Answer 11

REMS DRUG: LEAP PROGRAM

Blackbox warning: pregnancy category X

Contraindication: pregnancy

Side effects: peripheral edema, headache, decreased Hgb, Flushing, palpitations and nasal congestion

Notes: Monitor LFTs and patient should have a negative pregnancy test prior to initiation and monthly thereafter

Question 12

Macitentan (Opsumit)

Answer 12

REMS DRUG: OPSUMIT REMS PROGRAM

Blackbox warning: pregnancy category X

Contraindication: pregnancy

Side effects: decreased Hgb, headache, pharyngitis, bronchitis

Notes: should have a negative pregnancy test prior to and monthly thereafter

Question 13

Phosphodiesterase 5 inhibitors (PDE-5 inhibitor)

Answer 13

MOA: inhibit PDE-5 in smooth muscle of pulmonary vasculature thus preventing the degradation of cyclic granosine monophosphate, an agent that is used for pulmonary vascular relaxation and vasodilation.

Drugs: sildenafil (Revatio), Tadalafil (Adcirca)
NOTE DIFFERENT BRAND NAMES THAN ERECTILE DYSFUNCTION

Contraindication: concurrent use of nitrates or PI based HAART regimen

Side effects: dizziness, sudden drop in blood pressure, headache, Flushing, dyspepsia, prior prism, sudden vision loss and one or both eyes, other visual problems, hearing problems

Notes: avoid use and severe hepatic Impairment (and renal impairment for tadalafil); do not take a nitrate for 24 hours with sildenafil or 48 hours for tadalafil

Question 14

Soluble granulate cyclase stimulator (sGC)

Answer 14

MOA: increases conversion of GTP to cGMP leading to increased relaxation and anti-proliferative effects and the pulmonary artery smooth muscle cells

Indication: pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension

Drug: Rioguat (Adempas)

REMS DRUG: ADEMPAS REMS PROGRAM

Blackbox warning pregnancy category X

contraindication: pregnancy; concomitant use PDE-5 inhibitors or nitrates

Side effects: headache, dyspepsia, dizziness, hypertension, nausea/vomiting, and diarrhea

Interactions: smoking increases drug clearance (may need to decrease dose if patient stop smoking)