Sweatman/Zaman - RLD, CF, PAH Flashcards
1
Q
What are the drug treatment for ARDS?
A
- Intubation and mechanical ventilation may be necessary
- # of drug txs have been examined (see table), but none has demonstrated a consistent and unequivocal benefit
- May be due to heterogeneous nature of participants in clinical trials (in terms of severity of condition, genetic make up, previous drug exposure, etc.) that may confound definitive data
2
Q
What are the classes for PAH disease severity (table)?
A
3
Q
Endothelin-1 receptor antagonists: summary, route, AE’s (2)
A
- Block smooth mm proliferation and pulm arterial vaso-constriction produced by this vasoactive molecule binding to endothelin-1 type A (ETA; smooth muscle) and type B (ETB; endo cells) receptors
- Advantage over prostacyclins: orally active drugs.
-
Disadvantage: expensive drugs
1. Both are teratogenic (Cat. X), and bosentan is also associated with liver and blood toxicities -> program limits access to bosentan and ambrisentan, so pts on this drug who are hospitalized encouraged to bring med w/them to ensure availability during residence
4
Q
What is the treatment for the pneumoconioses? What other diseases are these patients at risk of?
A
- NO curative treatment for deposited material
- Patients should avoid further exposure
- Patients may be at INC risk of other diseases, as a result of the exposure:
1. Tuberculosis (S)
2. Pulmonary HTN/right-sided heart failure (CWP)
3. Carcinoma or malignant mesothelioma (A)
4. Multi-organ granuloma formation, mimicking sarcoidosis (B)
5
Q
Prostanoids: summary, route, and AE’s (3)
A
- Induce pulmonary artery vasodilation, retard smooth muscle growth, and disrupt platelet aggregation
- Gemfibrozil used to tx high chol and TG levels in blood
-
Bottom line: several drugs available to tx PAH, but no oral drug means that e/pt must be capable of storing the drug and reconstituting it correctly -> limited “shelf life” once reconstituted, room temperature < refrigerated
1. Back up pump is necessary in case of malfunction
2. Annual drug costs: >$35,000
6
Q
How does MTX help in sarcoidosis? Harm?
A
- MTX is a DHFR inhibitor, but also increases adenosine-mediated immunosuppression (see attached image)
1. Accumulation of AICAR -> inhibits ADA and AMP deaminase -> INC adenosine (and ““-5’-P) IC and EC
2. EC adenosine-5′-P to adenosine, binds A1, A2a, and A2b -> INC cAMP in cell = immunosuppression - NOT front-line therapy -> severe and sometimes fatal dermatologic rxns, birth defects and malignant lymphoma, INC risk of infection (contraindicated in pts with preexisting immunosuppression), potentially fatal pulmonary AE’s, incl acute or chronic interstitial pneumonitis & pulm fibrosis
7
Q
Rituximab
A
- Immunosuppressing MAb that binds CD20 cell surface Ag on B-cell precursors and mature B-lymphos (mech below)
1. Used to treat Wegener’s - Depletion lasts long (6-9mo after 1 drug course; 3 doses)
- AE’s: HTN, asthenia, pruritis, urticaria, rhinitis, arthralgia all reported when drug used for immunosuppressive purpose
-
Induces cell death through 3 mechanisms:
1. Ab-dependent cell-mediated-cytotoxicity -> recruits macros and NK cells by binding Fc receptors
2. Complement-mediated cytotoxicity -> activates complement and generates MAC complexes
3. Induction of apoptosis
8
Q
Dornase alfa
A
- Employed to “break up” viscous mucus
- Recombinant human (rh)DNAase taken by nebulizer, this drug cleaves and depolymerizes extracellular DNA, separating DNA from proteins and thus facilitating proteolytic enzyme activity
- Net result is a substantial reduction in the viscoelasticity and surface tension of the purulent sputum
9
Q
Ivacaftor (Kalydeco)
A
- Oral drug approved to tx pts w/G551D mutation
1. Ineffective in pts who are homo for F508del mut, which is present in at least 1 copy in ~90% of CF pts - Improves Cl- transport through mutated channels
- Extensively metabolized in liver by CYP3A4/5 (drug-drug interactions) and is an inhibitor of CYP3A and P-gp
- AE’s: URT symptomatology, incl infections, oropharyngeal pain, and nasal congestion, GI symptoms, and rash (about 8% of pts reported AE’s in clinical trials)
- Major issue (aside from limited pt pool based on mut freq) is high cost -> 1-year supply (150 mg bid) is $294,000
- Care was palliative for this disease until recently
10
Q
Azathioprine
A
-
DNA, RNA syn INH that produces immunosuppression, possibly by facilitating apoptosis of T cell populations
1. Used to treat Wegener’s - Associated with neoplastic, mutagenic, leukopenic & thrombocytopenic toxicity
- Increases risk of infection
11
Q
Goodpasture’s syndrome? Tx?
A
- Autoimmune disease arises from a type II hypersensitivity against the α3-chain of type IV collagen in basement membranes of lungs and kidney
- Most appropriately treated by plasmapheresis, which reduces the burden of autoantibodies
12
Q
What is PAH? Four primary causes?
A
- Pulmonary arterial HTN: distinct pathophys from that in systemic arterial HTN -> few drugs (w/exception of CCB’s) used for systemic arterial HTN work in PAH
-
Four primary causes:
1. Imbalance b/t vasoconstriction and dilation (relative DEC in prostacyclin and NO production, INC production of endothelin-1, more presence of TXA2)
2. Smooth muscle and endothelial cell proliferation, propagation, and hypertrophy (due to production of growth inhibitors and mitogenic factors)
3. Thrombosis
4. Fibrosis
13
Q
What is idiopathic pulmonary fibrosis? Treatment?
A
- 15% of chronic interstitial lung disease, but NOT a chronic inflam disease -> antiinflam drugs yield little or no tx effect
1. Some clinicians use response and/or non-response to corticosteroid treatment as a differential diagnosis from other lung inflammatory fibrotic diseases - Initial inflam process -> prolif and mobilization (fibrolysis), apoptosis of repair cells, return to normal organ function
1. Altered mesenchymal cell phenotype and blockade of apoptosis -> altered stromal cell pop and activated epi release a series of profibrogenic factors, TGF-β and PDGF, that interact w/deposited matrix at site of abnormal repair
2. New microenvironment in patchy areas (o/areas normal in structure and envo) can lead to remodeling of blood vessel walls, and pulm artery HTN (PAH)
14
Q
What is NRDS? Treatment?
A
- Most common cause of respiratory failure in newborns, and the most common cause of death in premature infants
- Surfactant deficiency in immature lung tissue, leading to increased surface tension, V/Q mismatch, and shunting
-
Treatment: antenatal corticosteroids for all women at risk of delivery ≤34 weeks -> enhance maturational changes in fetal lung architecture and biochemistry to INC synthesis and release of surfactant, improving neonatal lung fun
1. Exogenous surfactant for preterm (<30 weeks) neonates to reduce pulm surface tension -> natural products (Poractant alfa, Calfactant, & Beractant) are purified animal-derived products rich in surfactant proteins B and C, neutral lipids, and surface-active phospholipids (PL) such as dipalmitoylphosphatidyl-choline (DPPC), the primary surface-active component that lowers alveolar surface tension
15
Q
What is sarcoidosis? What are the 2 primary treatments?
A
- Non-caseating granulomas are the hallmark of this inflammatory disease, which often involves multiple organs
- Treatment with anti-inflammatory glucocorticoids or immunosuppressive methotrexate (off label) depends upon the degree of functional impairment in the individual patient
16
Q
Lumacaftor/Ivacaftor (Orkambi)
A
- Combo product adds conformation stabilizer drug to the action of ivacaftor -> both improves delivery of more fully functional protein to the apical surface of the cell and also potentiates the effect of the protein produced
- Lumacaftor minimally metabolized, but does function as a strong inducer of CYP3A4
- Elimination half-life 3-fold greater than that of Ivacaftor (27 hr vs. 9 hr)
- AE’s: URT symptomatology, incl infections, oropharyngeal pain, and nasal congestion, GI symptoms, and rash (about 8% of pts reported AE’s in clinical trials)
- Care was palliative for this disease until recently
17
Q
Cystic fibrosis
A
- Caused by muts in CFTR -> morbidity and mortality mainly determined by COPD that evolves from early onset mucus plugging in small airways, chronic neutrophilic airway inflammation and bacterial infection
-
CFTR is expressed in airway surface epi, submucosal glands, and many other epi organs, and func as an anion channel regulated by PKA-dependent phosphorylation of its regulatory domain and binding of ATP to the nucleotide binding domains -> conducts Cl- and bicarbonate
1. In airways, CFTR also regulates the amiloride-sensitive ENaC that constitutes the limiting pathway for Na+ absorption - Most common mutation, a deletion of phenylalanine at position 508 (DF508) in NBD1, impairs protein folding, plasma membrane expression, function and stability of CFTR, and is present on at least one allele in 90% of patients with CF in Europe and North America
18
Q
What are the categories of restrictive lung disease?
A
19
Q
Cyclophosphamide
A
-
Alkylating agent that produces (B & T cell) lymphopenia, selective suppression of B-lymphocyte activity and DEC immunoglobulin secretion
1. Used to treat Wegener’s - Assoc. w/neutro- & thrombocytopenia, bladder cancer, myeloproliferative, lymphoproliferative malignancies
20
Q
What are the histological characteristics and imbalances of PAH?
A
-
Plexiform lesions (thickened arterioles from shear stress; triggered from pulm artery endo cell damage)
1. Result in proliferation of monoclonal endo cells, sm muscle cells, and accumulation of circulating cells (e.g., macros and progenitor cells) -> significant obstruction of blood flow - Neurohormonal imbalances b/t prostacyclin, nitric oxide (NO), and endothelin-1 production significant beyond their hemodynamic effects:
1. Prostacyclin and NO INH platelet activation and smooth m. growth; lack of prostacyclin allows for INC presence of TXA2 (propagator of platelet aggregation)
2. Endothelin-1 induces smooth muscle proliferation - Imbalances are basis of current pharmacotherapy
21
Q
Phosphodiesterase Type 5 inhibitors: summary, route, AE’s (2)
A
- Perpetuate endogenously generated cGMP leading to vasodilation and reduce cellular proliferation
- NOT to be used in patients taking organic nitrates
22
Q
How does the CFTR mutation affect airway secretions?
A
- Epithelial ion transport defects and impaired host defense
1. Healthy airways: coordinated secretion of salt and water driven by CFTR with the alternative chloride channels TMEM16A and SLC26A9, and absorption by the epithelial sodium channel ENaC -> proper hydration of airway surface layer (ASL) essential for effective mucociliary clearance
2. CF airways, CFTR malfunction impairs secretion of chloride/fluid and bicarbonate, so dehydrated, acidic ASL and hyper-concentrated mucus. ASL dehydration aggravated by INC ENaC- mediated sodium and fluid absorption. Mucociliary clearance, bacterial killing impaired -> airways vulnerable for infection, inflam
23
Q
CCB’s: summary, route, AE’s (3)
A
- Prevent access of Ca in cells during mem depolarization, blocking the key mediator of smooth muscle contraction, and permitting vasodilation to endure
- Small-scale trials -> significant short-term benefit and improved 5-year survival (no large-scale RCT’s yet)
1. Not all pts respond to these drugs -> some devo potentially fatal hemodynamic decompensation, so pts may need to have a “vasodilator challenge” - Agents used for vasodilator challenge of pulm circulation include IV epoprostenol, IV adenosine, and inhaled NO
1. Pts get carefully escalated dosing rate and pulm arterial pressure (PAP) and cardiac output (CO) are monitored for 2-3 hr -> pt who responds positively to a vasodilator challenge (i.e., DEC PAP w/o DEC CO) can be prescribed certain CCB’s
24
Q
How do glucocorticoids help in sarcoidosis? Harm?
A
- MOST potent anti-inflammatory agents; bind to GC receptors & modulate transcriptional regulation in nucleus
- Act on immune cells both directly & indirectly to suppress induction of pro- inflammatory responses -> INH production of pro-inflammatory cytokines, like interleukin-1β (IL-1 β) and TNF, & promote production of anti-inflam cytokines (IL-10)
- Promote apoptosis of macros, dendritic cells and T cells
-
AE’s: suppress hypothalamic-pituitary-adrenal (HPA) axis
1. Chronic, supra-physiologic doses: osteoporosis, pancreatitis, steroid-induced DM, cataracts, glaucoma, psychosis, oral candidiasis, o/opportunistic infections, immunosuppression, weight gain, skin atrophy
27
Q
What is the difference between these three sets of lungs?
A
- Obstructive: hyper-inflated lungs w/depression of the diaphragm and hyper-expansion of the chest cavity
- Normal, i.e. PAH
- Restrictive: reduced lung volume
- All lung diseases can be placed in one of these categories
28
Q
How does this image help you categorize lung disease?
A
- Obstructive diseases affect the conducting airways (air can come in, but cannot get out -> lung hyper-inflation)
- Inflammatory disease of lower respiratory tract: interstitial fibrosis -> diseases in the alveolar structure
1. Will cause reduction of lung volume - PAH belongs to NEITHER of these categories -> it is in the circulatory system (does not cause hyper-inflation or restriction)
30
Q
How can we sub-classify RLD?
A
- Parenchymal (image on the left): right lung smaller than the left in the image on the left, and the trachea is shifted to the right (interstitial, intrinsic lung disease)
- Extra-parenchymal (image on the right): large pleural effusion/tumor (white-out) of the right thorax compressing the lung on the right in the right image
32
Q
What is the lung interstitium?
A
- Extra-vascular and extra-alveolar compartment of the lung parenchyma
- Interstitial lung diseases predominantly involve the connective tissue of the alveolar wall
1. B/t the epithelium and the endothelium, there are connective tissue cells, fibers and ground substances - What is left after the air and the blood is the interstitium
- Interstitium should be very thin, but will get larger in interstitial disease
33
Q
What is interstitial lung disease?
A
- Diffuse inflammatory processes involving the lung parenchyma
- Results in excess growth of connective tissue with dysfunction of lungs
- Non-neoplastic, non-vascular
34
Q
What are the 3 structural components of the interstitium?
A
-
Parenchymal cells:
1. Epithelial cells: type I & type II (image attached)
A. 90% of surface area covered by Type I cells
B. Distance b/t air and blood INC on the right -> growth of CT in this space, and increased wall thickness (makes alveolar capillary mem wider)
- Endothelial cells
- Inflammatory cells: - Alveolar macrophages (90%): most represented WBC in the lung (in contrast to the neutro in most o/parts of the body)
- Lymphocytes (10%)
- Neutrophils (<1%)
- Connective tissue elements: - Cells (fibroblast, progenitor cell)
- Fibers (collagen, elastin)
- Ground substance (proteoglycans)
35
Q
What is the tissue model of lung fibrosis?
A
- Coal dust, for example, can affect the lining of the cells in this way
36
Q
What is the difference b/t these two lung tissue samples?
A
- Fibrosis is the one on the right -> increased thickness for gas exchange
1. Also can’t expand this because it is too thick
2. Causes tachypnea, shallow breathing, hyper-ventilation, hypocapnia, hypoxemia, and exercise-induced desaturation
37
Q
What are the etiologies of the various RLD’s?
A
-
Known Etiology
1. Granulomatous
A. Inorganic dust: berylliosis
B. Organic dusts: hypersensitivity pneumonitis
- Non-granulomatous
A. Inorganic dusts: asbestos, coal, silica
B. Drugs: bleomycin, amioderone (interstitial fibrosis), nitrofurantion
C. External radiation
-
Unknown Etiology
1. Granulomatous: Sarcoidosis
2. Non-granulomatous: 1) Idiopathic interstitial pneumonias, 2) ILD w/connective tissue diseases - Granulomatous diseases not as bad as non-granuloma because granulomas are reversible, but fibrosis is not
38
Q
The hypoxemia in ILD is most due to what?
A
- V/Q mismatch
- Ventilation DEC due to smaller size of the lumen in acini, out of proportion to perfusion (V/Q mismatch the most common cause of all lung disease)
41
Q
What is the difference between these three bars? What do they represent?
A
- 1st: restrictive; 2nd: normal; 3rd: obstructive
1. RLD is defined by reduction of total lung capacity (below 80%) -> THIS MIGHT BE TESTED - TLC = FVC + RV
44
Q
What is this?
A
- This is clubbing from pulmonary fibrosis (one of the causes of clubbing)
47
Q
What do you see here?
A
- Ground glass
- Pneumococcal pneumonia: multi-lobar involvement: RML, superior segment RLL, and LLL infiltrates
- You can still see the background blood vessels: this is the hallmark of ground glass appearance (with consolidation, you would not see this)
1. Reversible inflammatory state -> potential target for treatment
48
Q
What is going on here?
A
- Reticulo-nodular (intermediate stage)
- Darker structures are nodules and white lines are reticular
- This is a very common presentation -> may have reticular, nodular, or both predominance
49
Q
What is this?
A
- Honeycombing: thick alveolar walls (late-stage)
51
Q
What is this for?
A
- BAL: helps you determine the distribution of inflammatory cells
1. Only necessary in 1/3 or less of ILD cases (due to advancement of radiology, CT scan) - Attached image shows the “normal” distribution of inflammatory cells in the lung
52
Q
What are these cell types? When might you see them?
A
- UL: macrophages -> normal
- UR: lymphocytes -> sarcoidosis (CD4), hypersensitivity pneumo (CD8)
- LL: neutrophils -> pneumonia, ARDS
- LR: eosinophils
53
Q
How often will you do a biopsy to diagnose ILD?
A
- Needed in about 1/3rd or less patients: gives you all you need for the diagnosis
54
Q
What is an example of a pleural disease?
A
Mesothelioma
55
Q
What is this?
A
- Kyphoscoliosis -> can cause RLD
- This can cause reduction of lung volume
