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Epidemiology of CF
- Most common life limiting disorder in Caucasians
- Current life expectancy of ~36 years
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Pathophysiology of CF
- Autosomal recessive
- Mutation in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)
- → Most common mutation: ΔF508
- CFTR regulates Na+ and Cl- ion transport and salt homeostasis in sweat glands
- → Mutated: sweat contains large amounts of salt and leads to a negatively charged lumen
- ¤ Water follows salt, mucous membranes become dry, no longer nice and stretchy mucous
- → Results in organ damage
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Organ: Reproductive
Abnormality:
Result:
- Organ: Reproductive
- Abnormality:
- → Obstruction in male reproductive tract
- Result:
- → Azospermia
- → Infertility
- ¤ Harder to get pregnant
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Organ: Pancreas
Abnormality:
Result:
- Organ: Pancreas
- Abnormality:
- → Lack of pancreatic enzymes
- → Poor insulin function
- Result:
- → Poor absorption
- → Malnutrition
- → CF Diabetes
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Organ: Sweat glands
Abnormality:
Result:
- Organ: Sweat glands
- Abnormality:
- → Unable to absorb sodium
- Result:
- → Hyponatremia
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Organ: Liver
Abnormality:
Result:
- Organ: Liver
- Abnormality:
- → Cirrhosis
- → Fatty infiltration
- Result:
- → Portal hypertension
- → Esophageal varices
- ¤ Need liver transplant
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Organ: Intestines
Abnormality:
Result:
- Organ: Intestines
- Abnormality:
- → Thick secretions
- Result:
- → Obstruction
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Organ: Pulmonary
Abnormality:
Result:
- Organ: Pulmonary
- Abnormality:
- → Thick (hard) secretions
- → Infection
- Result:
- → Chronic obstruction
- → Chronic infections
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Germs Found in the lungs of CF patients: S. aureus
- 2-4 years old have a lot
- Decreased amount in the lungs as they get older
- Not treated
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Germs Found in the lungs of CF patients: P. aeruginosa
- Must be treated
- Amount in lungs increases w/age
- Leads to decreased lung function
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Germs Found in the lungs of CF patients: Achromobacter
- Not treated in the US
- Treated everywhere else (Europe: France)
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Germs Found in the lungs of CF patients: S. maltophilia
Treated
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Germs Found in the lungs of CF patients: Burkholderia cepacia
- Leads to decreased mortality/morbidity
- Not allowed to be near other non-cepacia CF patients (be on a different floor, no interaction, completely isolated)
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Sinus/Lung Pathophysiology of CF
- Sinus cavity polyps
- Shortness of breath
- Cough
- Sputum production
- Barrel chest (air trapping)
- Decreased FEV1
- Bacterial growth in the lungs
- → Exacerbations
- → Increased cough
- → Reduction in pulmonary function
- → Increased sputum production
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¤ Sepsis from a bacterial lung infection
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GI Pathophysiology of CF
- Steatorrhea (greasy stools)
- Failure to thrive
- Malnutrition
- → Fat soluble vitamin deficiency, decreased pancreatic enzyme, fat malabsorption
- Infants/Small children
- → Increase frequency of small stools
- → Meconium ileus (newborns)
- ¤ 1st stool passed after birth being blocked
- Older patients
- → Constipation
- → Abdominal cramping/flatulence
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Endocrine Pathophysiology of CF
- Insulin deficiency
- Weight loss
- Increase in blood glucose levels
- Failed oral glucose tolerance test (OGTT)
- Cystic Fibrosis Related Diabetes (CFRD)
- → Seen in 20% of adolescents and 50% of adults
- → Shares features of Type 1 and Type 2
- → Primarily caused by insulin insufficiency
- → Fluctuating insulin resistance also seen
- → Treated with insulin
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Reproductive Pathophysiology of CF
- Azoospermia
- → Blockage of vas deferens
- → Absence of vas deferens
- Females may have lower fertility due to decreased water content of the cervical fluid
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Dx of CF
- All infants receive newborn screening (NBS)
- → Identifies high levels of immunoreactive trypsinogen (IRT)
- → If abnormal, DNA test preformed for known mutations
- Sweat Chloride Test
- → Pilocarpine administered transdermally to stimulate sweat gland secretion
- → If sweat chloride ≥60 mmol/L diagnostic for CF
- ¤ If positive then you test for every gene mutation
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Respiratory Therapy/”Pulmonary Toilet” for CF
- 1) Albuterol
- 2) Hypertonic Saline
- 3) Dornase alfa
- 4) Airway Clearance
- 5) Inhaled ABx
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Step One for CF
- Albuterol (ProAir®, Ventolin®, Proventil®)
- Drug Class: Beta2 Agonist
- Mechanism of Action
- → Relaxes bronchial smooth muscle
- → Opens up airways to allow for better delivery of respiratory medications
- Dose: 2 puffs prior to therapy (2 – 4 times daily)
- Adverse Effects: May increase blood pressure/heart rate
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Step Two for CF
- Hypertonic Saline (HyperSal®)
- Drug Class: Mucolytic
- Mechanism of Action:
- → Water distribution
- → Hydrates airway mucus secretions
- → Increases overall lung function
- Dose: 4 mL nebulized 2 – 4 times daily
- → 3%, 5% (not commercially available), 7%
- Adverse Effects:
- → Bronchospasm
- → Irritation (7% more burning than 3% or 5%)
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Step Three for CF
- Dornase alfa (Pulmozyme®)
- Drug Class: Mucolytic
- Mechanism of Action
- → Cleaves neutrophil DNA found in airway secretions (~10% of mucous)
- → Reduces mucous viscosity
- → Improved lung function
- Dose: 2.5 mg nebulized daily
- → Can’t be mixed with other products
- → Must be protected from light and refrigerated
- → Must be used with specific nebulizers
- Adverse Effects: Chest pain, cough, fever, voice alteration
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Step Four for CF
- Percussion
- Loosens mucus so it can be cleared by coughing/huffing
- Past therapies
- → Chest Physical Therapy (CPT) and Postural Drainage
- Current therapies
- → Oscillating Positive Expiratory Pressure (Oscillating PEP)- not ideal (depends on amount of work you put into it)
- ¤ Examples: Flutter™, Acapella™, Cornet™
- → High frequency Chest Wall Oscillation
- ¤ Vest vibrates at high frequency- not ideal
- → Nebulizer with oscillating PEP
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Step Five: Inhaled ABx (I) for CF
- Tobramycin (Tobi®)
- Drug Class: Aminoglycoside Antibiotic
- Mechanism of Action:
- → Binds to 30S and 50S ribosomal subunits of bacterial cell membrane
- → Improves pulmonary function
- → Decreases density of P. aeruginosa in sputum
- Dose: 300 mg nebulization every 12 hours for 28 days followed by 28 days off (combat resistance)
- → Can’t be mixed, refrigerate, use with specific nebulizers, light protected
- Adverse Effects: Cough, voice alteration, sputum color change
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Step Five: Inhaled ABx (II) for CF
- Azetreonam (Cayston®)
- Drug Class: Monobactam Antibiotic
- Mechanism of Action
- → Inhibits bacterial cell wall synthesis by binding to penicillin binding proteins (PBPs)
- → Improves pulmonary function
- → Decreases density of P. aeruginosa in sputum (reserved for resistance to Tobi)
- Dose: 75 mg nebulized three times daily for 28 days with 28 days off
- → Must use with specific nebulizer, do not mix, store in fridge before reconstituted
- → Severe patients can skip off block or switch b/w Tobi and Cayston every month
- Adverse Effects: Cough, congestion, wheezing, sore throat, fever
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Airway Inflammation for CF
- Azithromycin (Zithromax®)
- Drug Class: Macrolide Antibiotic
- Mechanism of Action
- → Inhibits protein synthesis, binds to 50s subunit
- → Inhibits neutrophil migration
- → Decreases production of pro-inflammatory mediators
- → Improves lung function
- Dose: 250 mg – 500 mg on Monday, Wednesday, and Friday
- Adverse Effects: Diarrhea, nausea, QT prolongation, increased risk for mycoplasma infections
- → Azithromycin is used to Tx mycoplasma, but mycoplasma will become resistant
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Fat Absorption for CF
- Pancreatic Enzymes (Creon®, Pancreaze®, Zenpep®)
- Drug Class: Pancreatic enzyme (no product is interchangeable)
- Mechanism of Action:
- → Contains lipase, amylase and protease
- → Break down fats, proteins and starch
- Dose: 500 units of lipase/kg/meal (500 – 2500 units/kg/meal)
- → take with all meals and with snacks
- Adverse Effects: Abdominal pain (dose is too high, need to decrease)
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Fat Soluble Vitamins for CF
- Vitamin A, D, E and K (AquaADEKs®)
- Drug Class: Vitamins
- Mechanism of Action
- → Provides fat soluble vitamins to patients who have decreased absorption
- → Vitamins enclosed in hydrophilic spheres
- Typical Dose: 1 softgel twice daily with food
- → usually need more Vit. D & has been reformulated with more Vit. D
- Adverse Effects: GI Upset
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Gene Modulation (I) for CF
- Ivacaftor (Kalydeco™)
- Drug Class: Cystic Fibrosis Transmembrane Conductance Regulator Potentiator
- Mechanism of Action:
- → Restores function of the defective CFTR protein
- → Improves salt and water absorption
- → Approved for 10 rare mutations: G551D, G551S, G178R, G1244E, G1349D, S549N, S549R, S1251N, S1255P and R117H (flaps don't work- open/close properly)
- Dose: 150 mg PO every 12 hours with high fat foods
- → Makes flap work
- → Can stop all CF meds
- Adverse Effects: Headache, rash, URI, oropharyngeal pain, congestion, nasopharyngitis
- → Heavy CYP 3A4 inducer, decrease dose if decreased liver function, expensive ($3,000/year)
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Gene Modulation (II) for CF
- Lumacaftor and Ivacaftor (Orkambi®)
- Drug Class: Cystic Fibrosis Transmembrane Conductance Regulator Potentiator
- Mechanism of Action:
- → Increased processing and trafficking of mature protein to the cell surface (lumacaftor)
- → Ivacaftor MOA on previous slide
- → Approved for homozygous ΔF508 mutation
- Dose: 400/250 mg every 12 hours with high fat foods
- Adverse effects: GI, changes in respiration, chest discomfort, dyspnea, nasopharyngitis
- → $3,000/year, CYP 3A4 inducer, decreased dose in poor liver function
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IV Antibiotics for CF
- Must be given
- Recommend to be given as an inpatient versus home health
- No recommendations on whether to continue inhaled antibiotics on admission
- → Continue all other home treatments
- On every admission will treat for pseudomonas infections with double coverage
- Admissions typically last for multiple weeks
- Other antibiotics will be based on sputum growth
- Lung transplant is a possibility
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IV Antibiotics for Pseudomonas for CF
- Piperacillin-Tazobactam (Zosyn®)
- Ceftazidime (Fortaz®)
- Cefepime (Maxipime®)
- Meropenem (Merrem®)
- Levofloxacin (Levaquin®)
- Gentamicin (once daily dosing)
- Tobramycin (once daily dosing)
- Amikacin (once daily dosing)
- Colistimethate (Coly-Mycin M®)
- Patients are rapid metabolizers and may need higher doses than average population
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