Week 3: Cystic Fibrosis/ Drug Induced Pulmonary Disease Flashcards
(77 cards)
Root Cause of CF
defect in cystic fibrosis transmembrane (CFTR)conductance regulator. Transports Cl- and bicarbonate.
organs typically involved in cf
skin
pancreas lung
Epidemiology
most common lethal genetically inherited disease affecting caucasions
outcome of cf dependent on ..
disease/genotype
pt mangement
compliance w. therapies
CFTR mutation classes and order of Prevalence
Class I mutation: nucleus
Class II mutation: Golgi apparatus
both effect synthesis of CTFR mutation, and cannot reach epithelial surface
Class III, IV, V, : dysfunctional CFTR proteins. little to no Cl can be transfered outside of cell
Class II»>Class I>Class III~Class IV>Class V
Classes IV and V cause milder disease because of little transport
classes I-III have no cloride transport
Most common mutation of CFTR
F508del
can either be homozygous or heterozygous
homozygous F508del=44.2%
heterozygous F08del= 40.5%
CF patho
mutated CFTR gene
loss of CFTR function
Impaird Bacterial Eradication
Infection
Inflammation
Airway Remodeling
Airway Obstruction
Broncheiectasis
Most common pathogen affecting young children and adulthhod
children: staph. Aureus
1.s.aureus
2.H. influenzae
3.ps aeruginosa
adults: psudamonas aeruginosa
1.p. aeuginosa
2.s. aureus
3. MRSA
chronic infection in CF triggers inflammation involving what mediators
tnf-a
IL-
GM-CSF
Leukotrienes
Neutrophils etc.
further worsens obstruction and creates better environment for infection
Exocrine dysfunction due to CF
occurs in 85-90% of CF pts.
results in obstruction and consequently deficient in ..
Protease, amylase, lipase
bicarbonate
causes poor absoprtion of…
*fat soluble vitamins (ADEK),vit. b12, zinc
Long term xocrine dysfunction: Acinar celldestruction->fibrosis->progressive adipose replacement of pancreatic tissue
SS of poor digestoin and complications
abdominal distention,increased stool frequency w.loose consistency/foul odor
increased fecal fat content
endocrine dysfunction: CF related diabetes (5-30% prevelance)
complication:mal nutrition and poor weightgain (predictor of mortality)
CF comorbidities
depression
anxiety
manifestations: asthma, acid reflux, CF related diabetes, sinus disease
CFTR Modulators
ex: Ivacafter (Kalydeco)
moa:
age indication:
Class mutation indications:
specific mutation indications:
ex:
moa: Facilitates opening of the chloride channel (CFTR potentiator)”
age indication: >/4 months
Class mutation indications: class III-IV when used alone
specific mutation indications: G551D, R117H, etc.
considerations: can be used as monotherapy or combo
CFTR modulators
ex: Lumacaftor/ Ivacaftor (Orkambi)
moa:
age indication:
Class mutation indications:
specific mutation indications:
pearls:
CFTR modulators
ex:
moa: fixes the defective CFTR protein so it can move to the proper place on the airway cell surface (CFTR corrector). Ivacaftor serves as potentiator
age indication: >/2 years old
Class mutation indications: Class Ii
specific mutation indications: homozygous F508del
pearls:
CFTR modulators
ex: Tezacaftor/ Ivacaftor (Symdeko)
moa:
age indication:
Class mutation indications:
specific mutation indications:
pearls:
CFTR modulators
ex:
moa:T.fixes the defective CFTR protein so it can move to the proper place on the airway cell surface (CFTR corrector). Ivacaftor serves as potentiator
age indication: >/6 y.
Class mutation indications:
specific mutation indications: homo or hetero mutation of F508del CFTR, 3849+10kbC->T
pearls:
*MUST INCLUDE A mutation that is responsive to symdeko
CFTR modulators
ex: Elexacaftor/Tezacaftor/Ivacaftor (Trikafta)
moa:
age indication:
Class mutation indications:
specific mutation indications:
pearls:
CFTR modulators
ex: Elexacaftor/Tezacaftor/Ivacaftor (Trikafta)
moa: E and T fixes the defective CFTR protein so it can move to the proper place on the airway cell surface (CFTR corrector). Ivacaftor serves as potentiator
age indication: >/6 years old
Class mutation indications:
specific mutation indications: homo or hetero F508 delta
pearls: doesnt have limitations like symdeko has as far as specific mutation response
Ivacaftor Studies
STRIVE trial: ivacaftor improved FEV1
ENVISION trial: improved fe1 at 24 and 48 wks
PERSIST study:
Lumacaftor/ Ivacaftor
TRAFFIC &TRansport trials
improved FEV1 @ 24 weeks
PROGRESS studies:
Tezacaftor + Ivacaftor trials
EVOLVE trials: improvement of fev1 @24 WEEKS
EXPAND trial:
Considerations for general CFTR modulator use
must take w. fat containing meal.
get basline ast/alt levels
ast/alt q 3 mo. first 1 year, annually therafter
dose reduction required in mod-severe hepatic dysfunction
DDIs of CFTR modulators
Ivacaftor, Tezacaftor, Elexacaftor
mechanism of DDI:
EX:
Affect on AUC and CMAX:
dose adjustment :
I, Tz, El: cyp3a4 substrates
mechanism of DDI: moderate cyp3a4 inhibitors EX: erythromycin and fluconazole
Affect onAUC and CMAX: increase
dose adjustment :
*I once daily,
* Tz, El: qod alternating btw T+I( or E/T/I) and I
mechanism of DDI: STRONG cyp3a4 inhibitors EX: clarithromycin and itroconazole
Affect onAUC and CMAX: significant increase
dose adjustment :
*I : twice weekly
* Tz, El: twice weekly T/I or E/T/I
mechanism of DDI: CYP3A4 induction
EX: rifampin, carbamezapine, phenobarbital, pheytoin, st johns wort
Affect onAUC and CMAX: significant decrease
dose adjustment :
*T : avoid concomitant use
* Tz: avoid concominant use
DDIs of CFTR modulators
Lumacaftor/ Ivacaftor: STRONG cyp3a inducer
cotreatment w. cyp3a4 inhibitors (ex itraconazole),
if L/I added to a regimen w. storng inhibitor..
decrease lumacaftor/ivacaftor dose to 1 tab daily during first week, then rsume normal dose therafter
if string inhibitor added to L/I regimen.. no dose adjustment needed
Non Pharm Treatment of CF lung disease
high frequency chest wall oscillation (HFCWO) aka “vest” therapy
postural draining (PO)
Positive Expiratory pressure (PEP)
Oscillatory PEP-devices : flutter, Acapella, AerobikA and Corney
Exercise
Annual Influenza vaccination starting at age of 6 mo.
Topical Mucolytic/ Hydrating Agents
ex: Dornase Alfa
indication:
dose:
AE:
considerations:
ex:
indication: mucolytics
dose: 2.5 mg inhalation 1-2x daily
AE: hoursenss of voice, rash
considerations:
improves FEV and decrease acute pulmonary exacerbations.
well tolerated
chronic use recommended in mild and strongly recommended in mod-severe disease to improve lung function and increase qol
more commonly used in >/ 6y.o
