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What does IPAH stand for?
- Idiopathic Pulmonary Arterial Hypertension
- What qualifies a patient as having IPAH?
- mPAP >25 mmHg at rest or 30 mmHg under stress
- Determined by Right heart catheterization (pulmonary vessels exit right heart)
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What is the cause of IPAH?
- Shear stress (congenital Heart abnormality)
- Viruses, Drugs
- Infalmmation
- Mutation
- Autoimmunity (CREST, SLE
- All cause Endothelial dysfunction and proliferation
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What are the pathological responses to IPAH?
- Smooth muscle hypertrophy (collapses onto vessel)
- Intima hyperplasia (narrowing)
- In-situ thrombosis (plaques)
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What is the Goal of therapy for IPAH?
Prolong life, ↓progression and ↑ QOL = no hemodynamic goals
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What is the Focus of treatment for IPAH?
- Open constricted vessels in the pulmonary system
- What are the three general methods of treating IPAH?
- Avoidance = reduce circulating mediatiors (Thromboxane, Serotonin, Platelets)
- Endothelial-dependent factors = ↑ NO and prostacyclin, ↓endothelin and Thromboxane
- Smooth muscle ion channel activity = Ca balance in cells (use CCBs to treat)
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What are the 5 WHO classes for PAH?
- Group 1: idiopathic (IPAH), HIV, Portal Hypertension, congenital, newborn, drug/toxin induced
- Group 2: Left heart disease = treat underlying disease
- Group 3: lung disease or hypoxemia = treat underlying disease
- Group 4: Chronic thromboembolic pulmonary hypertension = often recurrent PE = prevent PEs
- Group 5: Unclear multifactorial = treat underlying diseases
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What are the general treatment focuses for the 5 WHO classes for PAH?
- Group 1: Vasodilation
- Group 2: Treat underlying disease
- Group 3: Treat underlying disease
- Group 4: Prevent PEs
- Group 5: Treat underlying diseases
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What are the IPAH function Classes?
- Class 1: w/o physical limitation of dyspnea, fatigue, chest pain or presyncope
- Class 2: Mild physical limitation during ordinary or excessive activity
- Class 3: Marked limitation of physical activity, fine at rest.
- Class 4: Inability to perform any activity w/o symptoms, symptoms at rest, signs of Right heart failure, JVD, accentuated heart sounds, edema
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Is IPAH progressive?
Progressive, can be temporarily revert with treatment, but will eventually progress
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What are the Non-pharma treatments for IPAH?
avoid strenuous activity(walking OK), pregnancy, ↑elevation (↓O2), infection
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What drugs should be avoided w/ IPAH?
- Vasoactive decongestants (phenyl-pseudoephrine)
- Cardiodepressant antihypertensives (BBs)
- Warfarin/Anticoag interacting drugs
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How do the doses for IPAH pharmacological treatment compare to normal doses?
Usually much higher doses
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How do you deal with Tolerance to IPAH drugs?
Increase dose or switch medication
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What drug has a mortality benefit for IPAH?
Warfarin
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What is the Goal INR for Warfarin use in IPAH?
1.5-2
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Why is Warfarin used in IPAH and not new anticoags Riva, Apix and Daba?
Have not been studied but could be used
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Why do we need to anticoagulate IPAH patients?
Risk of thrombus/emboli from catherter(w/ epoprostenol) or physical inactivity, venous stasis/slowing
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How is a vasodilator challenge performed?
Small doses of epoprostenol, adenosine or inhaled NO while under RH cath
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What indicates in a Positive vasodilator challenge?
- Decreased mPAP by 10mmHg
- Increased or unchanged CO or CI
- Unchanged Systemic Pressure
- Unchanged O2 sat.
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What drugs would you try to use if you had a positive vasodilator challenge result?
Vasodilators like Nifedipine and Diltiazem = higher likelihood of success
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What indicates in a Negative vasodilator challenge?
- Increased or unchanged mPAP
- Decreased CO or CI or O2 sat.
- Decreased Systemic Pressure
- Increased R atrial pressure
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What drugs would you avoid if you had a positive vasodilator challenge result?
Vasodilators like Nifedipine and Diltiazem = lower likelihood of success
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What Vasodilators are available for IPAH?
Diltizem, Nifedipine, Epoprostenol, Treprostinil, Bosentan (Tracleer), Macitentan (Opsumit), Ambrisentan (Letairis), Sildenafil (Revatio), Tadalafil (Adcirca)
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What class is Nifedipine & Diltiazem useful for treating?
Class II: useful in 25-30% of patients
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How does tolerance develop to Nifedipine & Diltiazem in IPAH?
High doses leads to tolerance
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Epoprostenol (Flolan) is what type of drug?
Prostacyclin
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What is the major con to Epoprostenol (Flolan)?
t1/2 = 3-5 min, Continuous IV, Judicious education required
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How do you titrate Epoprostenol (Flolan)?
Titrate 3-7 days, then each month
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What are the dose limiting SEs of Epoprostenol (Flolan)?
Jaw pain, Hypotension, HA, N/V, Flushing (titrate to these, then reduce)
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Treprostinil (Remodulin) is what type of drug?
Prostacyclin analogue
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What is the benefit of Treprostinil (Remodulin) over Epoprostenol (Flolan)?
t1/2 = 3-4 hrs, stable at RT (no ice packing), Neutral pH
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What is the Dose for Treprostinil (Remodulin)?
1.25 ng/kg/min to 40 ng/kg/min, IV or SQ
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What are the Endothelin-receptor antagonists:
- Bosentan (Tracleer)
- Macitentan (Opsumit)
- Ambrisentan (Letairis)
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What is the route of administration for Bosentan (Tracleer)?
Oral
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What is CI/NR for Bosentan (Tracleer)?
Liver failure, CYP3A4 & 2C9 Inducer
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What testing is required prior to Bosentan (Tracleer) use?
Requires baseline liver test
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What is the Dose for Bosentan (Tracleer)?
62.5mg BID for 4 weeks followed by 125mg BID
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What is the route of administration for Macitentan (Opsumit)?
Oral
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What is CI/NR for Macitentan (Opsumit)?
- Pregnancy X (REM = restricted entity medical)
- CYP3A4 substrate
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What is eth dose for Macitentan (Opsumit)?
10 mg/day
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What is CI/NR for Ambrisentan (Letairis)?
- Liver failure
- CYP3A4 & 2C19 substrate
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What is the dose for Ambrisentan (Letairis)?
5mg QD ↑ to 10mg QD
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What are the Phosphodiesterase type 5 inhibitors for IPAH?
- Sildenafil (Revatio)
- Tadalafil (Adcirca)
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What is the route of administration for Sildenafil (Revatio)?
Oral
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Which IPAH drugs are FDA approved for PAH?
- Sildenafil (Revatio)
- Tadalafil (Adcirca)
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What class is Tadalafil (Adcirca) and Sildenafil (Revatio) used for?
Class II-III
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What is the dosae for Sildenafil (Revatio)?
20 mg TID, useful in combo
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What are the SEs for Sildenafil (Revatio)?
HYPOtension, don’t use w/ Nitrates
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What is the route of administration for Tadalafil (Adcirca)?
Oral
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What is the dose for Tadalafil (Adcirca)?
40 mg QD (Better than Sildenafil, which is TID), useful in combo
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Iloprost is mainly used for what?
Neonates b/c requires constant inhalation
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At what point would you consider Combos for IPAH?
- Stage III or IV
- Single drugs not effective anymore
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What is the first thing all IPAH patients should be placed on?
1st: Oral anticoagulant
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After an oral anticoagulant has been given, what is the second thing IPAH patients should have done?
2nd: Vasodilator challenge
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What would you give an IPAH patient after a Positive Response?
Oral CCB
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What would you give an FC II IPAH patient after a Negative Response?
Ambrisentan, Bosentan, Sildenafil, Tadalafil
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What would you give an FC III IPAH patient after a Negative Response?
Ambrisentan, Bosentan, Epoprostenol IV, Iloprost Inh, Sildenafil, Tadalafil
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What would you give an FCIV IPAH patient after a Negative Response?
Epoprostenol IV, Iloprost Inh, Treprostinil SC, Treprostinil IV, Ambrisentan, Bosentan, Sildenafil, Tadalafil
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What would you give a patient with no improvement at FCIII or FCIV after all treatment options have been tried?
Combo therapy of Prostanoid, ERA or PDE-5 Inhibitor
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