Cystic Fibrosis Flashcards
Cystic fibrosis is what type of disease?
autosomal recessive genetic disease
each time they have offspring - 25% chance of having one with CF, 50% chance they’ll be a carrier
What is the basic problem of CF?
CF is caused by a mutation in a gene that encodes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein
The gene is located on chromosome 7
Most common mutation is F508del
Normal lung vs CF lung
w/o CF there’s a nice equilibrium between Cl- and Na+ and water
in CF: CFTR channel is absent or reduced –> chloride can’t get into mucus or airway surface liquid like it normally would –> sodium gets draw from airway –> thick viscous mucus; bacteria, DNA, and immune cells also contribue to a thick mucus
What is a newborn screen?
Blood spot obtained from the infant:Used to test for a variety of diseases including
CF
Immunoreactive trypsinogen (IRT) - measure of pancreatic function
Positive test not diagnostic: Further testing required for diagnosis
Earlier diagnosis and treatment of CF has increased patient weight and decreased hospitalizations
Diagnosis of CF
One or more sign/symptom + evidence of CFTR dysfunction
Sweat chloride test: Pilocarpine iontophoresis > 60 mEq/L (diagnostic for CF)
Genetic testing
Pancreatic function: Stool fat quantitation; Quantitation of trypsin activity
What are the classes of CFTR mutations?
Class I, II, III, IV, and V
What are class I CFTR mutations?
protein doesn’t get made at all (non-sense/stop codon mutations)
no CFTR protein reaches the membrane; due to absence of CFTR at the membrane chloride transportation doesn’t occur
What are class II CFTR mutations?
protein not made correctly
little or no CFTR protein reaches the membrane; CFTR that reaches the membrane does not transport chloride properly
What are class III CFTR mutations?
protein doesn’t open –> gating mutration gate stuck shut
normal number of CFTR proteins at the membrane; the CFTR that reaches the membrane does not transport chloride properly
What are class IV CFTR mutations?
doesn’t always open/function as well as it should
normal number of CFTR proteins at the membrane; some of the CFTR that reaches the membrane can transport chloride
What are class V CFTR mutations?
more turnover
a reduced amount of CFTR proteins at the membrane; CFTR that reaches the membrane transport chloride appropriately
What are the CFTR modulators?
kalydeco, orkambi, symdeko, trikafta, alyftrek
Kalydeco
generic name - ivacaftor
it is a cystic fibrosis transmembrane conductance regulator potentiator (for class 3 and 4 mutations, help open door to let Cl- flow)
approved in age >/= 1mo
Kalydeco key points
Take with fatty foods (helps increase the amount of the modulator getting in body)
LFTs q3 month for 1 year then yearly
Eye exam – baseline and yearly (peds) - rare risk of cataracts
Dose adjustment for hepatic impairment Ivacaftor CYP3A substrate (DDI &Food) Approved for responsive mutations
Orkambi
generic name - ivacaftor/lumacaftor
ivacaftor helps “door” open, lumacaftor helps “door” get to cell wall
for F508del homozygous mutation
approved in age >/=1yr
Orkambi key points
Take with fatty foods
AST/ALT/Bil q3month for 1 year and then yearly
Eye exam baseline and then yearly – pediatrics
Dose adjust in hepatic impairment
only small increase in lung function, get stabilization over time
Orkambi interactions
Birth control drug interaction!
Lumacaftor CYP3A strong inducer
Ivacaftor CYP3A substrate
Side effect of chest tightness and shortness of breath with initiation in some patients
Symdeko
generic name - tezacaftor/ivacaftor
Approved for F508del/F508del
Or people with a responsive mutation
approved for in age >/= 6yr
Symdeko key points
AST/ALT/Bil q3month for 1 year and then yearly
Eye exam baseline and yearly - pediatrics
Dose adjustment for liver disease
Ivacaftor CYP3A substrate (DDI &Food)
Trikafta
generic name - elexacaftor/tezacaftor/ivacaftor
has 2 drugs get to the wall, one to help open
Approved for patients with at least one F508del (covers large % of pop)
Or one of the other responsive mutations
approved for use in age >/=2yr
Trikafta key points
Take with fatty foods
AST/ALT/Bil/Alk Phose qmonth for 6 months and then q3 months
for 12 additional months and then yearly
Eye exam baseline and yearly - pediatrics
Dose adjustment for liver disease
Ivacaftor CYP3A substrate (DDI &Food)
What to do if you miss the orange tablet with trikafta?
If miss orange tablet dose by more than 6 hours take orange tablets when remember and skip evening blue tablet (blue tab only has ivacaftor)
Alyftrek
generic name - vanzacaftor/tezacaftor/deutivacaftor (helps it last longer)
Approved for if one F508del or another responsive mutation
once a day!
efficacy non inferior to trikafta
Alyftrek key points
Take with fatty foods
AST/ALT/Bil/Alk Phose qmonth for 6 months and then q3 months for
12 additional months and then yearly
Eye exam baseline and yearly - pediatrics
Ivacaftor CYP3A substrate (DDI &Food)
What is CF lung disease?
Cause of ~ 85% of CF deaths
Due to CFTR dysfunction CF patients
have thickened mucus
This mucus is hard to clear and creates a good environment for bacteria to grow
Respiratory exacerbations are common
What are methods of airway clearance?
Recommended for all CF patients
No method proven better than another
Method based on patient: Manual airway clearance techniques (P&PD); Therapy Vest; Flutter, acapella; Huff coughing; Meta neb
What are the different types of maintenance lung treatment?
dornase alfa, hypertonic saline, inhaled mannitol
Dornase alfa
◦ MOA: Cleaves the extracellular DNA from expended neutrophils and other inflammatory cells in the CF mucus, thus reducing viscosity and promoting clearance (chops up mucus to help it get out easier)
◦ Nebulized solution
◦ Generally well tolerated but $$$
◦ Recommended for daily use in CF patients ≥ 6 years old; Can use in select cases < 6 years old
Hypertonic saline
◦ MOA: Exact MOA unclear
Proposed MOA: NaCl in the airway creates an osmotic gradient, this osmotic gradient draws water into the airway, Increased water in the airway helps to reduce mucus thickness, Thinner mucus is easier for the patient to expectorate (helps draw water into airway, mucus can slide out easier)
◦ Can reduce the percent of saline if intolerance
occurs (3% or 3.5%)
◦ Recommended in all CF patients ≥ 6 years; Can also use in select cases in patients < 6 years old
bronchospasm issue - use bronchodilator (albuterol) prior
Inhaled mannitol
◦ MOA: Exact MOA unclear
Proposed MOA: Draws water into the airways to hydrate the mucus
◦ Approved 18 years and older
◦ Dry powder inhaler
◦ Requires tolerance test before use
◦ Alternative to hypertonic saline
◦ Side effects: main one bronchospasm, hemoptysis - Administer albuterol 5-15 min before use
What are anti-inflammatory agents used?
azithroymcin, ibuprofen
Azithromycin
◦ MOA: Immunomodulating effects
◦ May not be tolerated due to GI side effects – dose can be reduced
◦ Recommended in patients with chronic pseudomonas
◦ Consider in patients without chronic pseudomonas
Ibuprofen
◦ MOA: anti-inflammatory NSAID
◦ Check levels: Goal peak > 50 mcg/mL and <100 mcg/mL
◦ Not well tolerated due to GI side effects; kidney injury risk
NOT recommended therapies
inhaled corticosteroids - flovent, asthmanex
leukotriene modifiers - montelukast
oral corticosteroids
What are bronchodilators?
Albuterol
◦ MOA: Short acting beta agonist
◦ Used to open up airways prior to airway clearance therapy and to decrease bronchoconstriction prior to inhaled hypertonic saline; Theoretically increases cilliary beating
Ipratropium: Not recommended by current guidelines
What are the pulmonary function tests?
FEVI, FVC, FEF25-75
What is a CF exacerbation?
Not well defined
Typical clinical features
◦ Increased cough
◦ Increased sputum production
◦ Shortness of breath
◦ Chest pain
◦ Loss of appetite
◦ Loss of weight
◦ Decreased lung function
Cover past and current bacteria – the big players
What are the causative pathogens of CF?
S. aureus (MSSA, MRSA)
P. aeruginosa
H. influenza, K. pneumonia
E. Coli
Stenotrophomonas maltophilia
Burkholderia cepacia
Aspergillus fumigatus
Achromobacter
What is the antibiotic empiric IV therapy for CF?
MRSA (only single coverage needed) example: bactrim, clinadmycin, vancomycin, tetracycline, linezolid
MSSA (only single coverage needed) cefazolin, unasyn, coverage by anti- pseudomonal beta lactam
Pseudomonas for IV therapy
Double coverage
Two different MOA (typically beta-lactam with aminoglycoside)
Piperacillin-tazo, imipenem-cilast, ceftazidime, meropenem, cefepime with aminoglycoside (tobra, amikacin)
Gentamicin no longer recommended
If history of pseudomonas typically cover even if doesn’t grow in current culture
What antibiotics have altered kinetics to take into consideration?
beta-lactams, aminoglycosides, and quinolones
Beta-lactams altererd kinetics
increased renal and non-renal Cl - max dose at shortest interval or prolonged infusion at higher doses
Aminoglycosides altered kinetics
icnreased Cl and Vd; higher doses
Quinolones altered kinetics
no significant change
higher doses to penetrate thick, sticky mucus
What are the inhaled antibiotics?
tobramycin, aztreonam
Tobramycin
◦ Recommended for initial pseudomonas
eradication – One 28 day course
◦ Suppression therapy in 28 days cycle for patients with chronic pseudomonas
Tobramycin administration
Administration time 15-20 minutes
Premade solution
Aztreonam
Used in patient with chronic pseudomonas
Patients that can’t tolerate tobramycin
Can be used in off months
Treatment time: 5 minutes per treatment X 3 = 15 minutes per day
Cleaning time: 15 minutes per day (depending on number of hand sets)
Aztreonam administration
Administration time 2-3 minutes Bronchodilator pretreatment
Extensive cleaning required
Why nebulization?
Delivery of the drug to the site of infection
Reduced systemic exposure
Decreased risk of systemic side effects
Route allows for chronic administration of antipseudomonal antibiotics without IV
Ability to get higher concentrations of the drug to the site
Pancreas in CF
Exocrine insufficiency 85%
◦ Mucus obstructs exocrine ducts
◦ Decreased enzymes (amylase, lipase, protease) and HCO3 output
Pancreatic enzymes
help pts absorb their food
◦ Do not exceed 10,000 units of lipase/kg/day
Pancreatic enzymes are adjusted based on number of stools per day, fat content of stools, and growth/weight
creon, pancrease, zenpep, pertzye, viokace
What is an immobilized lipase cartridge?
used in pts with tube feeds, secretes enzymes into tube feeds
What vitamins do you need to monitor in CF?
Vitamin D: 25-OH – goal > 30; preferred supplement cholecalciferol (vitamin D3)
Vitamin A Level
Vitamin E Level
Vitamin K: PT/INR
(all fat soluble vitamins)
Combination CF vitamins
◦ Aquadeks
◦ MVW complete
◦ DEKA essentials or plus
Cystic fibrosis related diabetes
Diagnosis
◦ Fasting plasma glucose ≥ 126 mg/dL
◦ 2 hour plasma glucose ≥ 200 mg/dL
Screening
◦ OGTT annually in CF patients > 10 years
◦ HgbA1c – not reliable for diagnosis
Ketoacidosis rare (treat with insulin)
Macrovascular effects rare
