Download Pulmonary arterial hypertension -previously primary pulmonary

Pulmonary arterial hypertension
-previously primary pulmonary hypertension (PPH)
-disorder of pulmonary circulation
-characterized by right-sided heart failure (afterload increases due to vasoconstriction, hypertrophy)
-mean pulmonary artery pressure (mPAP > 25 mmHg) (high)
-pulmonary capillary wedge pressure (PCWP < 15 mmHg (low)
-fix by increasing preload – right ventricle “muscles up” & eventually decreases in size & decreases preload
-incidence:
-higher in women 2:1; median survival 2.8 years; mean age diagnosis is 36 yo
-Classification:
(1) Idiopathic PAH
(2) PAH associated with other dx processes: congenital heart dx, connective tissue disorders, portal HTN, HIV, drugs and toxins
-WHO Functional Status:
I. No limitation of usual physical activity – 5 yr survival
II. Mild limitation of physical activity – 5 yr survival
III. Marked limitation of physical activity – 2.5 yr survival
IV. Symptoms at rest and may have signs of right ventricular failure – 6 month survival
Pathophysiology:
vasoconstriction + vascular hypertrophyPA obstruction and elevated PVR [pulm vasc resistance = RV afterload]RV failuredeath
Pathogenesis:
-genetic predisposition [BMPR2]
-elastase
-potassium “channelopathies”
-serotonin
Predisposing Factors:
-portal HTN
-pregnancy
-obesity
-HIV (30%)
-genetics (1°)
-hepatic cirrhosis
-anorexic agents (aminorex, fenfluramine, dexfenfluramine, phentermine)
-endothelin
-platelets
-cocaine use
-oral contraceptives (?)
-connective tissue disorders [scleroderma]
Signs:
Initial: accentuated pulmonary component of S2, early systolic ejection click, midsystolic murmur
Advanced: diastolic murmurs, heptaojugular reflux, hepatomegaly, peripheral edema, ascites, severe hypotension
--murmur = blood passes back through valve – reverse direction
Symptoms:
Initial: dypsnea, fatigue, exertional intolerance, weakness
Advanced: dypsnea at rest, chest pain, syncope, leg swelling, abdominal bloating and distension, anorexia, profound fatigue
Management:
medical: CCB, prostacyclin anaglogues, endothelian-receptor antagonists, phosphodiesterase inhibitors
surgical: transplantation, pulmonary thromboendarectomy, atrial septostomy
Calcium Channel Antagonists:
-counteracts vasoconstriction
-vasoreactivity test- small dose of IV epoprostenol or inhaled NO; must have ↓mPAP at least 10mmHg to < 40 mmHg (mild dx)
-agents: nifedipine, diltiazem, amlodipine
---pts w/ IPAH or PAH associated with scleroderma or congenital heart dx in absence of right HF w/ favorable response to vasodilation
test should be candidates for CCB---
Prostacyclin Analogues:
▪Epoprostenol: first prostacyclin analogue
-Administration: continuous IV infusion via CVC using abulatory infusion pump (1-2ng/kg/min) t ½ = 6 min
-reconstituted sol’n: 8 hr at room temp; 24 hr at 45 F
-conc ranges 3,000-15,000 ng/ml
-ADE: acute-flushing, HA, N/V, hypotension, anxiety, CP; chronic-line infection, venous thrombosis
-Avoid Abrupt Withdrawal (severe rebound PAH)
-Patient Implications: reconstitution, administration, equipment (CADD pumps, cold pouches, spare cassettes & pumps), CVC care,
long term/ lifelong therapy
-FDA: longterm tx of IPAH in functional class III or IV & long term tx of PAH assoc. with scleroderma spectrum of disease
-ACCP: All pts with PAH in WHO Class III/IV who are not candidates for, or who have failed CCB
▪Treprostinil: similar pharmacologic actions and HD effects
-Administration: continuous SQ infusion via surgically inserted SQ catheter and ambulatory infusion pump (1.25 ng/kg/min)
-3 hr t ½ + neutral pH + stable at room temp = SQ
-ADE: similar SE of epoprostenol except less thrombosis and infection; infusion site pain and erythema
-FDA: tx of PAH in pts with functional class II-IVsymptoms
-ACCP: 3rd line agent in pts with functional class III/IV who are not candidates for or who have failed CCB therapy
▪Iloprost: synthetic prostacyclin analogue available via aerosol administration
-Administration: 2.5 mcg/d divided into 6-9 daily doses via jet nebulizer
-ADE: HA, flushing, jaw pain
-FDA: tx of PAH with functional class III-IV sxs
-ACCP: 4th line agent in pts with class III or optional adjunct after epoprostenol/treprostinil in functional class IV, who are not candidates
or have failed CCB
▪Beraprost: orally active prostacyclin analogue
-NOT approved for use by FDA in US
-Administration: 80-120mcg PO QID
-ADE: HA, flushing, jaw pain
Endothelin: potent vasoconstrictor and smooth muscle mitogen
-effects mediated through 2 receptors:
-ETA: vasoconstriction and vascular SMC proliferation
-ETB: endothelin clearance and vasodilation
-expression, production and concentration elevated in PAH patients
Endothelian Antagonists:
▪Bosentan (Tracleer): antagonism of both ETA and ETB receptors
-prevents/reverses development of PAH, vascular remodeling, and RV hypertrophy
-PO 62.5 mg bid x 4 weeks, then 125 mg PO bid
-SE: increased LFTs/hepatotoxic, anemia, male infertility
-CI: pregnancy, concominant use of glyburide or cyclosporine A, hormonal contraceptives as only contraception
-FDA: tx of PAH with functional class III or IV
-ACCP: 1st line in class III or 2nd line in class IV who are not candidates or failed CCB
▪Sitaxsentan (thelin): 6,000 fold more selective for ETA
-PO 100mg/day
-FDA approved
▪ Ambrisentan: highest selectivity for ETA
-PO 5mg/ day
-orphan drug status
Phosphodiesterase Inhibitors:
-phosphodiesterase (PDE): enzyme that hydrolyzed cGMP & cAMP, PDE 5 elevated in PAH
-Sildenafil (Revatio): potent inhibitor of PDE 5, indicated in ED, role management of long-term PAH
-FDA approved for tx of PAH in pts with class II-III sxs
-should be considered who have failed or are not candidate for other therapy
Surgical Tx:
-Atrial Septostomy: palliative measures for severe PAH unresponsive to meds
-Pumonary Thromboendarectomy: potential cure resulting from chronic
thromboemoblic PAh (CTEPH)
-Transplantation: when prognosis remains poor despite med therapy
Future direction:
agents: advances in administration, selectivity, and drug target sites
studies: combo of drugs with differing mechanism, long term data
Hemodynamics:
PAP
20-23/10-15 mmHg
mPAP
10-20 mmHg
RAP
0-6 mm Hg
PVR
120-250 dyne/s/cm-5
PCWP
6-12 mmHg
CO
3-7 L/min
Screening:
-genetic testing, EKG, chest radiography, doppler echocardiography, right-heart catheterization
-others: HIV testing, V/Q & CT scans, sleep studies
ACCP Health and Science Policy Grading System: quality of evidence + net benefit  strength of recommendation
Quality: good (large RCT or meta-analysis); fair (other control trials or RCT w/ minor flaws); low (nRCT, case control, observational);
EO (selected panel of experts in topic)
Net benefit: substantial, intermediate, small/weak, none, conflicting, negative
Strength of recommendation: A=strong, B=moderate, C=weak, D=negative, I=inconclusive
+
Epoprostenol
-
-
RCT’s:
exercise
capacity and
QOL
Long term
survival data
-
$/yr
-Delivery/Administration
-Lifelong therapy
-Complications
75000
Treprostinil
-RCT’s: exercise
capacity and QOL
-SQ formulation
-Data not impressive
-Long term survival data
-Injection site pain
90000
Bosentan
-RCT’s: exercise
capacity and QOL
-Oral formulation
No survival data
Limited class IV
pts
- LFT’s/Pregnancy risk
36000
Sildenafil
-Limited SE’s
-Oral formulation
-Strong Potential
-Lack of adequately
powered RCT’s
12000
-