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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)
What is the cause of IPAH?
- Shear stress (congenital Heart abnormality)
- Viruses, Drugs
- Autoimmunity (CREST, SLE
- All cause Endothelial dysfunction and proliferation
What are the pathological responses to IPAH?
- Smooth muscle hypertrophy (collapses onto vessel)
- Intima hyperplasia (narrowing)
- In-situ thrombosis (plaques)
What is the Goal of therapy for IPAH?
Prolong life, ↓progression and ↑ QOL = no hemodynamic goals
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)
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
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
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
Is IPAH progressive?
Progressive, can be temporarily revert with treatment, but will eventually progress
What are the Non-pharma treatments for IPAH?
avoid strenuous activity(walking OK), pregnancy, ↑elevation (↓O2), infection
What drugs should be avoided w/ IPAH?
- Vasoactive decongestants (phenyl-pseudoephrine)
- Cardiodepressant antihypertensives (BBs)
- Warfarin/Anticoag interacting drugs
How do the doses for IPAH pharmacological treatment compare to normal doses?
Usually much higher doses
How do you deal with Tolerance to IPAH drugs?
Increase dose or switch medication
What drug has a mortality benefit for IPAH?
What is the Goal INR for Warfarin use in IPAH?
Why is Warfarin used in IPAH and not new anticoags Riva, Apix and Daba?
Have not been studied but could be used
Why do we need to anticoagulate IPAH patients?
Risk of thrombus/emboli from catherter(w/ epoprostenol) or physical inactivity, venous stasis/slowing
How is a vasodilator challenge performed?
Small doses of epoprostenol, adenosine or inhaled NO while under RH cath
What indicates in a Positive vasodilator challenge?
- Decreased mPAP by 10mmHg
- Increased or unchanged CO or CI
- Unchanged Systemic Pressure
- Unchanged O2 sat.
What drugs would you try to use if you had a positive vasodilator challenge result?
Vasodilators like Nifedipine and Diltiazem = higher likelihood of success
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
What drugs would you avoid if you had a positive vasodilator challenge result?
Vasodilators like Nifedipine and Diltiazem = lower likelihood of success
What Vasodilators are available for IPAH?
Diltizem, Nifedipine, Epoprostenol, Treprostinil, Bosentan (Tracleer), Macitentan (Opsumit), Ambrisentan (Letairis), Sildenafil (Revatio), Tadalafil (Adcirca)
What class is Nifedipine & Diltiazem useful for treating?
Class II: useful in 25-30% of patients
How does tolerance develop to Nifedipine & Diltiazem in IPAH?
High doses leads to tolerance
Epoprostenol (Flolan) is what type of drug?
What is the major con to Epoprostenol (Flolan)?
t1/2 = 3-5 min, Continuous IV, Judicious education required
How do you titrate Epoprostenol (Flolan)?
Titrate 3-7 days, then each month
What are the dose limiting SEs of Epoprostenol (Flolan)?
Jaw pain, Hypotension, HA, N/V, Flushing (titrate to these, then reduce)
Treprostinil (Remodulin) is what type of drug?
What is the benefit of Treprostinil (Remodulin) over Epoprostenol (Flolan)?
t1/2 = 3-4 hrs, stable at RT (no ice packing), Neutral pH
What is the Dose for Treprostinil (Remodulin)?
1.25 ng/kg/min to 40 ng/kg/min, IV or SQ
What are the Endothelin-receptor antagonists:
- Bosentan (Tracleer)
- Macitentan (Opsumit)
- Ambrisentan (Letairis)
What is the route of administration for Bosentan (Tracleer)?
What is CI/NR for Bosentan (Tracleer)?
Liver failure, CYP3A4 & 2C9 Inducer
What testing is required prior to Bosentan (Tracleer) use?
Requires baseline liver test
What is the Dose for Bosentan (Tracleer)?
62.5mg BID for 4 weeks followed by 125mg BID
What is the route of administration for Macitentan (Opsumit)?
What is CI/NR for Macitentan (Opsumit)?
- Pregnancy X (REM = restricted entity medical)
- CYP3A4 substrate
What is eth dose for Macitentan (Opsumit)?
What is CI/NR for Ambrisentan (Letairis)?
- Liver failure
- CYP3A4 & 2C19 substrate
What is the dose for Ambrisentan (Letairis)?
5mg QD ↑ to 10mg QD
What are the Phosphodiesterase type 5 inhibitors for IPAH?
- Sildenafil (Revatio)
- Tadalafil (Adcirca)
What is the route of administration for Sildenafil (Revatio)?
Which IPAH drugs are FDA approved for PAH?
- Sildenafil (Revatio)
- Tadalafil (Adcirca)
What class is Tadalafil (Adcirca) and Sildenafil (Revatio) used for?
What is the dosae for Sildenafil (Revatio)?
20 mg TID, useful in combo
What are the SEs for Sildenafil (Revatio)?
HYPOtension, don’t use w/ Nitrates
What is the route of administration for Tadalafil (Adcirca)?
What is the dose for Tadalafil (Adcirca)?
40 mg QD (Better than Sildenafil, which is TID), useful in combo
Iloprost is mainly used for what?
Neonates b/c requires constant inhalation
At what point would you consider Combos for IPAH?
- Stage III or IV
- Single drugs not effective anymore
What is the first thing all IPAH patients should be placed on?
1st: Oral anticoagulant
After an oral anticoagulant has been given, what is the second thing IPAH patients should have done?
2nd: Vasodilator challenge
What would you give an IPAH patient after a Positive Response?
What would you give an FC II IPAH patient after a Negative Response?
Ambrisentan, Bosentan, Sildenafil, Tadalafil
What would you give an FC III IPAH patient after a Negative Response?
Ambrisentan, Bosentan, Epoprostenol IV, Iloprost Inh, Sildenafil, Tadalafil
What would you give an FCIV IPAH patient after a Negative Response?
Epoprostenol IV, Iloprost Inh, Treprostinil SC, Treprostinil IV, Ambrisentan, Bosentan, Sildenafil, Tadalafil
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