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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 now contains large amounts of salt and leads to a negatively charged lumen
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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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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 (blockage)
- • Older patients
- → Constipation
- → Abdominal cramping/flatulence
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Endocrine Pathophysiology
- • 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
- • 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
- • 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
- ¤ Positive: test for every gene mutation
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Respiratory Therapy/”Pulmonary Toilet”
- 1) Albuterol
- 2) Hypertonic Saline
- 3) Dornase alfa
- 4) Airway Clearance
- 5) Inhaled ABx
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Step One
- 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
- 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
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Step Three
- Dornase alfa (Pulmozyme®)
- • Drug Class: Mucolytic
- • Mechanism of Action
- → Cleaves neutrophil DNA found in airway secretions
- ¤ Makes up ~10% of the weight 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
- 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)
- ¤ Examples: Flutter™, Acapella™, Cornet™
- → High – frequency Chest Wall Oscillation
- ¤ Vest vibrates at high frequency
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Step Five: Inhaled ABx (I)
- 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
- → 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)
- 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
- • 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
- • Adverse Effects: Cough, congestion, wheezing, sore throat, fever
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Airway Inflammation
- • 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
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Fat Absorption
- • 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)
- • Adverse Effects: Abdominal pain
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Fat Soluble Vitamins
- • 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
- • Adverse Effects: GI Upset
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Gene Modulation (I)
- • 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
- • Dose: 150 mg PO every 12 hours with high fat foods
- • Adverse Effects: Headache, rash, URI, oropharyngeal pain, congestion, nasopharyngitis
- → Heavy CYP 3A4, decrease dose if decreased liver function
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Gene Modulation (II)
- • 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
- → 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
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IV Antibiotics
- • 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
- • 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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