Sweatman Restrictive Lung Dz and PAH Flashcards
name the surfactant agents
- Poractant
- calfactant
- beractant
name the PDE-5inhibitors
- sildenafil (revatio)
2. tadalafil (adcirca)
Name the immunosupressants for PAH and RLD
rituximab, azathioprine, cyclphosphamide and corticosteroids, methotrexate
Name the long chain fatty acid-derived eicosanoids
iloprost, triprostinil, epoprostenol
name the ET-1 antagonists
bosentan and ambrisentan
Name the CCB’s
Diltiazem (NONDHP), Nefdipine (DHP), Amlodipine (DHP)
prostacyclin analog
treprostinil, iloprost, epoprostenol
name the three diagnostic categories of restrictive lung disease
- pneumoconisis
- ARDs, NRDS
- Idiopathic
name the 4 types of pneumoconiosis
- silicosis
- beryllosis
- CWP
- asbestosis
* review what the inhalant is that cuases the disease in each
silicosis predisposes to
TB
CWP predisposes to
Pulmonary HTN/ right sided heart failure
mesothelioma predisposes to
primary carcinoma of the lung and melignant mesothelioma
beryllosis predisposes to
multi-organ granuloma formation mimicking sarcoidosis
Drugs that can cause ARDS
aspirin, opiates, cocaine, phenothiazines, tricyclic antidresessants
*also idiosyncratic reactions with contrast dye and chemotherapeutic agents
alcohol and ARDS
does not directly cause ARD but increases the chanes of ARDS from other causes (sepsis and trauma)
most common cause of ARDS
Sepsis, Pneumonia, Aspiration, Trauma–> in that order
current tx of ARDS (terrible data nothing proven to work)
> Beta2 agonists (albuterol), NO–> vasodil. increase perfusion of functioning alveoli
corticosteroids–> antinflamm
prostacycline (PGI2)
Dietary oil supplementation –> antiinflamm..modulate arachadonic acid metabolism
tx of NRDS in at risk mothers < 34 weeks
antenatal corticosteroids–> increases surfactant production and release in the fetus pre-birth, increasing lung function
Aditional tx of NRDS after birth
exogenous surfactant to preterm neonates to reduce pulmonary surface tension and improve lung function
name the exoenous sufactants
poractant alfa
calfactant
beractant
*purified animal derivatives rich in surfactant B and C and neutral lipids as well as surface active PL’s (dipalmitoylphosphatidylcholine DPPC)
surface active agent that lowers surface tension
dipalmitoyldiphoshatidylcholine DPPC or Lecithin
multi organ inflammatory dz characterized by non-aseating granulomas in an unspecified foreign body reaciton and peri-hilar bilateral infiltrates
sarcoidsosis
tx of sarcoidsosis
glucocorticoids to control inflamm.
methotrexate (OFF-LABEL USE)
SIDE EFFECTS OF CHRONIC CORTICOSTEROIDS USE
inhibition of hypothalamic-pituitary axis, oseoporosis, pancreatitis, steroid-induced DM, cataracts, glaucoma, pyschosis, oral candidiasis, immunosupression, weight gain, skin atrophy
Immune effect of chronic steroids
IMMUNE SUPPRESSION-> promote apoptosis of dedritic cells, t cells and macrophages (diminished CMI)
methotrexat MOE
DHFRinhibitor-> increase in adenosine mediated immunosupression
MTX and adenosine
MTX increases adenosine and causes immunosupresion via adenosine receptors
mechanism of MTX and adenosine immunosupression
inhibits AICAR–>FAICAR…AICAR accumulates and inhibits AMP deaminase and Adenosine deaminase–> icnreases adenosine 5’-P and adenosine–> this results in an increase in these products in the extracellular millieu, extracellular adenosine acting via the A2 pathway activated Adnylate cylase, resulting in increased cAMP production in the cell and thus IMMUNOSUPRESSION
POTENTIALLY FATALA DVERSE EFFECTS OF METHOTREXATE
ACUTE OR CHRONIC INTERSTITIAL PNEUMONITIS AND PULMONARY FIBROSIS
MTX CONTRAINDIATED IN
PT.’S WITH EXISITING IMMUNOSUPRESSION, LUNG DISEASE
CAN CAUSE BIRTH DEFECTS AND MALIGNANT LYMPHOMA
IS IPF A chronic inflammatory disease
NO–> EVEN THE MOST POTENT ANTI-INFLAMMATORY DRUGS WILL HAVE LITTLE TO NO EFFECT
*15% of interstitial lung disease to which no other cause can be attributed
HISTOPATH OF IPF
TEMPORAL HETEROGENEITY
SATISFACTORY TX FOR IPF
NONE AT THE MOMENT COMPARED TO PLACEBO (IN FACT SOME DID WORSE)
*PATIENTS WITH IPF DO NOT GET THE BENEFIT FROM OTHER DRUGS FOR OTHER FORMS PAH
HOW DOES IPF LEAD TO PAH
SHORT-LIVED INFLAMMATORY PRIOCESS LEADS TO PROLIFERATION AND MOBILIZATION OF FIBROLYSIS, apoptosis and a return to normal organ function–>
MESNchmye is now altered and leads to altered stromal cell type and activated epithelium– rlease of TGFb and PDGF–> if capillaries remodeled, PAH will ensue
good pasture syndrome is caused by
type II hypersensitivity against alpha3 chain of type IV collagen (anti-GBM disease) of the glomeruli and alveoli
anti IgG and anti Igm autoantibodies
tx of goodpastures
plasmaphoresis (IVIg)
define wegener’s
C-ANCA associated autoimune vasculitis of small-medium sized vessels of the upper respiratory tract, lungs and kidney
ANCA in wegner’s
C anca–> anti-proteinase-3 Anti-neutrophil cytoplasmic antibody
Rituximab
minoclonal anti-CD20 antibody
MOA for rituximab
induces plasma cell apoptosis via
- ADCC (recruits macrophages and NK cells by binding to FC receptors of phagocytes and FAB fragement of CD20)
- CDCC–> generates MAC’s on plasma cells
- INduction of apoptosis directly
side effects of rituximab
HTN, asthenia, pruritis, urticaria, rhinitis, arthralgia
azathioprine MOA
DNA and RNA synthesis inhibitor–> induces apoptosis in T cell populations
azithioprine side effects
neoplastic, mutagenic, leukopenic and thrombocytopenic oxicities, CAN INCREASE RISK OF INFECTION
CYCOPHOSPHAMIDE MOA
alkylating agent that also produces B and T cell lymphopenia, selective supression of B lymphocytes activity and decreased Ig secretion
side effects of cyclophosphamide
hemorrhagic cystitis–> MESNA is prophylacitc
neutro thrombocytopenias
bladder cancer
myeloproliferative or lymphoproliferative malignancies
Only drug used for systemic HTn that also works partially in PAH
CCB’s
pathogenesis of PAH
decrease in production of PGI2 and NO
increase in production of Endothelin 1 and TXA2 (more pronounced presence)
*leading to smooth muscle and endothelial cell proliferation, propagation and hypertrophy (thanks to growth inhibitors and mitogenic factors–> eventually fibrosis and thrombosis
resultant of PAH and sheer stress
pexiform lesions (more common in females)
PLEXIFORM LESION ETIOLOGY
PULMONARY ARTERY ENDOTHELIAL DAMAGE–> proliferation of monoclonal endothelial cells smooth muscles and accumulation of circulating cells (macrophages)–> lead to SIGNIFICANT OUTFLOW OBSTRUCTION
PGI2 CAUSES WHAT normally
inhibits platelet activation and smooth muscle growth
endothelin also causes what normally
smooth muscle growth
absence of PGI2 has what effect on TXA2
now allows TXA2 to act unchecked leading to improper platelet aggregation
NO usually has what effect in the lungs
inhibits platelet activation and inhibits smooth muscle cell growth
PGI2 causes what effect on blood vessels
increase cAMP and causes vasodilation
NO is made from what precursor and turns into what
L-arginine–> cGMP
effect of NO on blood vessels
turns L-arginine into NO–> increase cGMP–> leading to vasodilaiton and antiproliferaiton
endothelin ahs what effect on the pulmonary blood vessels
vasoconstriction and muscle cell proliferaiton
depletion of B cells by rituximab lasts how long
6-9 mos following 3 doses
MOA for all prostanoids
induce PAvasodilation, retard smooth muscle growth and disrupts platelet aggregation
rout of epoprostenol
requires constant IV infusion (half life=5 minutes)
epoprosternol AE’s
hypotension, flushing, headaches, bleeding if anticoagulated, catheter infection
Iloprost route
6-9 inhaled doses daily (half life 25 minutes) 10 minutes per dose
Iloprost AE’s
hemoptysis (MUST MONITOR), flushing, cough, headaches-most common
*hypotension, tongue/back pains, minotor for bleeding
Treprostinil route
continuous SC infusion half life 4 hours or IV infusion (more stable
AE associated with treprostinil
injection site erythema, rash headache, nasue/ diarrhea, –> MONITOR FOR BLEEDING
- -> CYP 2C8 D-D INTRXNS
- ->DEC CLEARANCE WITH GEMFIBROZIL
- -> INCREASED CLEARANCE WITH RIFAMPIN
ET1 ANTAGONISTS MOA
block smooth muscle proliferation signal and pulmonary arterial vasocnstriction produced by ET1 binding to ET-1 TYPE A RECEPTORS AND TYPE B RECEPTORS
ET1-A RECEPTORS ARE LOCATED WHERE
SMOOTH MUSCLE
ET1-B RECEPTORS ARE LOCATED WHERE
ENDOTHELIAL CELLS (BLOOD VESSELS)
ADVANTAGE OF ET1 ANTAGONISTS
ORALLY AVAILABLE, EASIER DOSING
DISDVANTAGES OF ET1 ANTAGONISTS
EXPENSIVE AND CATEGORY X (MAJOR TERATOGENS)
BOSENTAN ALSO ASSOCIATED WITH
LIVER AND BLOOD TOXICITIES
HALF LIVES OF ET1 ANTAGS
BOSENTAN –> 5-8HRS BID *HEPATOTOXICITY
AMBRISENTAN–> 15 HOURS QD
CYPS INVOLEVED WITH ET1 ANTAGS
CYP 3a4 and CYP 2c9
ambrisenten is a substrate and inhibitor if pgp as well as OATP
PDE 5 inhibitors–> MOA
perpetuate endogenous cGMP leading to vasodilation and reduce deulluar proliferation
PDE5 inhibitors should not be taken in pt.’s taking
organic nitrates such as NITROGLYCERINE FOR ANGINA
name the PDE5 inhibitors
sildenafil (3-4 hours), tadalafil (17 hours)
major side effects of sildenafil and tadalafil
S–> epistaxis, dizziness, hearing loss
T–> change in color vision,back pain dyspepsia,
CCB MOA
prevent calcium from entering cell and inhibit SM vasoconstrcition–> cause vasorelaxation–> dec blod pressure
vasodilation challenge–> ONLY 15% of patient are candiates for CCB therapy due to negative vasodilaiton challeneg
IV epoprostenol, IV adenosine, and inhaled NO–> measure CO and PAP for 3 hours…if PAP goes down without a decrease in CO
do CCB’s improve mortality
yes–> but dont work in everyone and can lead to CV collapse
name the ccb’s and their major side effects
diltiazem-> bradycard, hypotension
nefedipine–> flushing, edema, hypotension, heartburn
amlodipine–> edema, fatigue, hypotension
CCB avoided in PAH
verapamil–> negative inotropic effect
goal of CCB therapy…
get the pt. back to functional class 1 or 2 by 3-4 mos…if not achieved..consider alternative therapy
