PH

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  1. Class I: PAH
    • Idiopathic vs. Familial
    • Associated with connective tissue diseases, Portal HTN, and HIV
    • Pulmonary HTN of newborn
    • Drug and toxin induced (vasoconstrictors)
    • → Fenfluramine
    • → Amphetamines/Cocaine
    • → Chemotherapy (etoposide, bleomycin)
    • Pulmonary venoocclusive disease
  2. Class II: PH Associated w/Left Heart Disease
    • Left ventricular dysfunction (systolic or diastolic)
    • Valvular disease
    • → Underlying valve disease (HF)
  3. Class III: PH Associated w/Respiratory Disorders
    • COPD
    • → Significant COPD, not early stages
    • Interstitial lung disease
    • Mixed restrictive and obstructive disease
    • Sleep-disordered breathing
    • Alveolar hypoventilation
    • Chronic high altitude exposure
  4. Class IV: PH Associated w/Chronic Thromboembolism
    • Thromboembolic obstruction
    • Obstruction of distal arteries
  5. Class V: PH Resulting from Unclear Multifactorial Mechanisms
    • Hematologic
    • Systemic
    • Metabolic
    • Everything else
  6. PAH Sx
    • Exertional dyspnea
    • Fatigue
    • Weakness
    • General exertion intolerance
    • Looks like HF, Kidney disease
  7. PAH Sx of Disease Progression
    • Lower extremity edema
    • Dyspnea at rest
    • Exertional chest pain
    • Syncope
    • Abdominal distention
    • Anorexia
    • Profound fatigue (worse RV dysfunction /valvular regurg)
  8. PAH Signs
    • Physical features
    • Audible S2 at apex of heart
    • Early systolic ejection click
    • Midsystolic ejection murmur
    • S4 gallop
  9. PAH Signs of Advanced Disease
    • Diastolic murmur (worsening)
    • → Pulmonary regurgitation
    • → Tricuspid regurgitation
    • Hepato-jugular reflux
    • Pulsatile liver
    • Peripheral edema
    • Hypotension/cool extremities
    • Diminished pulse pressure
    • Cyanosis
    • Digital clubbing
  10. Functional Classification in PH: Class I
    • No Sx
    • No limitation in ordinary physical activity
    • Median survival: 6 years
  11. Functional Classification in PH: Class II
    • Mild Sx
    • Slight limitation during ordinary activity
    • Comfortable at rest
    • Median survival: 6 years
  12. Functional Classification in PH: Class III
    • Marked limitation in activity due to Sx even during less-than-ordinary activity
    • Comfortable ONLY at rest
    • Median survival: 2.5 years
  13. Functional Classification in PH: Class IV
    • Sx w/any activity, even while at rest
    • Severe limitations
    • Median survival: 6 months
  14. Diagnostic Testing
    • Right heart catheterization
    • → Definitive Gold Standard, invasive test
    • Establishes diagnosis of PH
    • Evaluates pulmonary vasoreactivity
    • Guides therapy
  15. Vasoreactivity testing
    • Identifies candidates for calcium channel blocker (CCBs) therapy
    • Use short acting vasodilator during test:
    • → Epoprostenol (IV)
    • → Nitric oxide (Inhaled)
    • → Adenosine (IV)
    • Goal: reduction in mPAP of ≥ 10 mmHg to < 40 mmHg without decreasing CO
    • → Positive test- can use CCBs
    • Do NOT use CCBs if patient does not respond (negative test)
    • Contraindications
    • → Low systemic blood pressure
    • → Low cardiac output (EF, cold extremities)
    • → Presence of WHO FC IV symptoms (Stage III, IV)
    • Adverse events: Hypotension
  16. Non-pharmacological Tx (Lifestyle Modifications)
    • Low grade aerobic exercise: Walking
    • → Improves PH functional class and peak oxygen consumption
    • → Does NOT improve hemodynamic abnormalities
    • → Helps day to day function
    • Avoid high altitudes: Supplemental oxygen on commercial aircraft
    • Sodium restricted diet
    • → Less than 2400mg/day
    • → Can cause right heart failure
    • Immunizations
    • → Influenza
    • → Pneumococcal
    • Avoid pregnancy
    • → 30-50% maternal mortality
    • → Meds increase teratogenicity
    • Avoid cold and sinus medications: Vasoconstriction
  17. Monitoring for PH
    • Right heart catheterization
    • → “Gold standard” for diagnosis
    • → AKA: Swan-ganz catheter or pulmonary catheter (ICU)
    • Exercise capacity
    • → 6-min walk test every 3-6 mos
    • Functional class
    • → Every 3 months
    • Doppler echocardiography
    • → Non-invasive determination of pulmonary pressures
    • Serologic markers
  18. Management of all PH Groups
    • Oxygen
    • Anticoagulation
    • Digoxin
    • Diuretics
    • Exercise
  19. Diuretics for PH
    • Treat fluid retention
    • Decrease hepatic congestion and peripheral edema
    • Administer with CAUTION
    • → Avoid decreased CO
    • → If excessively decrease right and/or left preload
    • → Caution in over diuressing them
  20. Oxygen Therapy for PH
    • Continuous oxygen administration (>90%)
    • Cornerstone of therapy in Group 3 PH
    • → Underlying COPD
    • May also benefit other PH groups to relieve hypoxemia
    • → Resting
    • → Exercise-induced
    • → Nocturnal
  21. Anticoagulation for PH
    • ↑ risk for intrapulmonary thrombosis and thromboembolism
    • Indicated for:
    • → Idiopathic PH
    • → Hereditary PAH
    • → Drug-induced PH
    • → Group 4 PH
    • Warfarin (goal INR 1.5-2.5)
    • → Blood flow slows down- increases risk of thromboembolism
  22. Digoxin for PH
    • Improves right ventricular EF
    • → Increased risk digoxin toxicity
    • → Require close monitoring
    • Rate control: supraventricular tachycardias
    • → Verapamil preferred
    • → EXCEPT? LVEF <40% (negative inotropic effects worsening cardiac output)
  23. Endothelin-1 Pathway in PH
    • Excess production of endothelins
    • Vasoconstriction
    • Proliferation
    • Tx: Endothelin-receptor antagonists
    • → Bosentan (Tracleer) PO
    • → Ambrisentan (Letairis) PO
    • → Macitentan (Opsumit) PO
  24. Nitric Oxide Pathway in PH
    • Decreased production of NO
    • Vasodilation
    • Antiproliferation
    • Tx: PDE inhibitors
    • → Sildenafil (Revatio, Viagra) PO
    • → Tadalafil (Adcirca, Cialis) PO
    • → Vardenafil (Staxyn / Levitra)
    • → Riociguat (Adempas)
  25. Prostacyclin Pathway in PH
    • Decreased production of prostacyclins
    • Vasodilation
    • Antiproliferation
    • Tx: Prostacyclin derrivatives
    • → Epoprostenol (Flolan, Veletri) IV
    • → Iloprost (Ventavis) Inhaled
    • → Treprostinil
    •     ¤ (Remodulin, Orenitram) IV, SQ, PO
    •     ¤ (Tyvaso) Inhaled
  26. Look at
    • Slide 7
    • Slide 8
    • Slide 25
    • Slide 30
  27. CCB in PH
    • WHO FC I to IV (positive vasodilator response)
    • Dihidropyridine CCBs preferred
    • → Nifedipine (long-acting) 30 mg/day initially
    • → Titrate to 240 to 720 mg daily
    • → Do NOT use short-acting formulation (profound drops in BP, increases mortality)
    • Diltiazem may be used in patients with tachycardia
    • → Diltiazem 120 mg/day initially
    • → Inhibits myocardial contractility, AV conduction, and HR
    • Avoid non-DHP CCBs in LV systolic dysfunction <40%
  28. Primary Therapy in PH
    • PH Class I: Advanced PH Therapy
    • PH Class II: Treat underlying HF
    • PH Class III: Oxygen
    • PH Class IV: Anticoagulation
    • PH Class V: Treat underlying PH cause
  29. Bosentan (Tracleer®)
    • Dual endothelin-A (ETA) and endothelin-B (ETB) receptor antagonist
    • Delays clinical worsening and improves pulmonary vascular hemodynamics and exercise capacity
    • Mortality improved in idiopathic PAH
    • Indicated for WHO Functional class II-IV
    • Dose: 62.5mg PO BID x 4 weeks, then 125mg PO BID
    • Drug Interactions
    • → Many DIs, need to screen for DIs
  30. Macitentan (Opsumit®)
    • Dual endothelin-A (ETA) and endothelin-B (ETB) receptor antagonist
    • One randomized trial (n=250) showed fewer patients progressed or died on therapy
    • Improved exercise capacity and WHO functional class
    • Studies not powered to assess mortality benefits
    • Indicated for WHO Functional Class II-IV
    • Dose: 10 mg PO daily
    • Multiple significant drug interactions
    • → Substrate of CYP3A4 and CYP2C19
    • → DI screening
  31. Ambrisentan (Letairis®)
    • Selective endothelin-A (ETA) receptor antagonist
    • Improved exercise capacity, WHO functional class, quality of life, and pulmonary vascular hemodynamics
    • Delays disease progression and clinical worsening
    • → No mortality benefit
    • Recommended for WHO Functional Class II-IV
    • Dose
    • → Initially 5 mg once daily
    • → Increase to 10 mg once daily (if tolerated)
    • May be tried in patients with prior asymptomatic liver function abnormalities on bosentan after liver enzymes return to normal (less risk of hepatotoxicity)
  32. Adverse Effects of ERAs
    • Peripheral edema (up to 17%)
    • → Manage with diuretics
    • → Discontinue, if severe
    • Potential serious liver injury
    • → Hepatotoxicity
    • → Bosentan- monitor LFTs monthly, indefinitely Q4wks
    • → Ambrisentan, Macitentan (lesser risk)- LFTs baseline and PRN
    •     ¤ Less risk of liver toxicity
    • Pregnancy category X
    • → Teratogenecity
    • → Decrease efficacy of oral contraceptives
    • Restrictive access programs
    • → Bosentan: Tracleer Access Program (TAP)
    • → Ambrisentan: Letairis Education and Access Program (LEAP)
    • → Macitentan: Risk Evaluation and Mitigation Strategy (REMS)
  33. Sildenafil (Revatio®)
    • Potent and highly specific PDE-5 inhibitor
    • → ↑s intracellular concentration of cGMP → vasorelaxation and antiproliferative effects on vascular smooth muscle cells
    • → Relaxes pulmonary smooth muscle cells which leads to the dilation of pulmonary arteries
    • Improves pulmonary hemodynamics and exercise capacity
    • Mortality effects NOT adequately evaluated
    • Effective in WHO Functional Class II and III (combo in IV)
    • Dose 20 mg TID (higher doses used clinically)
    • DI- CI w/nitrates
    • → Precipitous drop in BP
    • ADR- vision changes
    • → Need to stop medication
  34. Tadalafil (Adcirca®)
    • Improves exercise capacity, time to clinical worsening, and quality of life
    • Decreased clinical worsening
    • Effective in WHO functional Class II and III (combo in IV)
    • Dose: 40 mg oral daily (longer ½ life)
    • Adverse Effects: Headache, myalgia, and flushing
  35. Riociguat (Adempas)
    • Indicated in patients with inoperable and persistent chronic thromboembolic PH (CTEPH, group IV PH)
    • Guanylate cyclase stimulant
    • → Increase sensitivity of soluble guanylate cyclase to nitric oxide (pulmonary vasodilator)
    • → Directly stimulate the receptor
    • Dose
    • → Initial 1 mg oral TID (Max: 2.5 mg oral TID)
    • → Initiate at 0.5 mg oral TID (patients intolerance to hypotensive effects)
    • → May increase by 0.5 mg oral TID if SBP > 95 mm HG
    • → Increase at intervals ≥ 2 weeks
    • Dose adjustments
    • → Concurrent strong CYP and P-gp inhibitors
    • → Smokers: may titrate over max → decrease dose may be necessary in patients who stop smoking during therapy
    • → Pulmonary edema: stop if pulmonary veno-occlusive disease
    • Pregnancy Category X
    • Prescribing and Access Restrictions- Adempas REMs program
  36. Prostacyclin Pathway
    • Relax smooth muscle by increasing intracellular cAMP
    • Inhibit platelet aggregation
    • Inhibit smooth muscle proliferation
    • Inhibit pulmonary vascular remodeling
  37. Epoprostenol (Flolan, Veletri)
    • Considered first line in severe (Class IV PAH)
    • Improves hemodynamic parameters, functional capacity, and survival (idiopathic PH)
    • Usual starting dose: 2 ng/kg/min
    • → Increase by 1 ng/kg/min every 30-60 min until dose-limiting side effects occur (every 1-2 days)
    • → Increase to maximum tolerated dose
    • Deliver dose continuously through permanently implanted central venous catheter using portable infusion pump
    • Patients develop tolerance keep titrating up
    • ADR: Flushing, jaw pain, diarrhea, nausea, rash, headache
    • → Keep titrating up until they experience jaw pain
  38. Treprostinil (Remodulin)
    • IV (continuous infusion) or SubQ
    • Improve hemodynamic parameters, symptoms, exercise capacity, and possibly survival in group 1 PAH (IV and SubQ- longer ½ life)
    • Dose Range: 15-100 ng/kg/min
    • → Smaller pump, like an insulin pump
    • Dose Adjustment:
    • → Hepatic Impairment (mild or moderate)
    • → Decrease to 0.625 ng/kg/min SubQ or IV (initially)
    • Half-life: 4 hours
    • Advantages of IV treprostinil formulation over epoprostenol
    • → Option of continuous SubQ delivery
    • → Longer half-life
    • → No need for refrigeration
    • → Patients can be transitioned without loss of efficacy
    • Can be offered as first line (over epoprostenol)
  39. Combination Therapy in PH
    • Address the multiple pathophysiologic mechanisms
    • → Improvement in hemodynamics
    • → Resolution of symptoms
    • → Increased exercise capacity
    • Simultaneous initiation of two (or more) treatments or by the addition of a second (or third) agent
    • Indications
    • → signs of right-heart failure
    • → 6-minute walk distance <380 m
    • → persistent functional class III or IV symptoms despite active treatment
    • → Inadequate response to monotherapy
    • → WHO functional class IV– prostacyclin Tx
  40. Surgical Interventions in PH
    • “When all else fails…”
    • → Atrial Septostomy
    •     ¤ Increase systemic blood flow
    •     ¤ Reduces RV preload
    • → Lung Transplantation
    • → Heart-Lung Transplantation
    •     ¤ Reserved for medication non-responders

Card Set Information

Author:
ebmalonzo
ID:
315874
Filename:
PH
Updated:
2016-02-14 19:15:10
Tags:
IT PH
Folders:
IT 2
Description:
IT 2 (MT 3): PH
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