IP850-Cystic Fibrosis Flashcards
Cystic Fibrosis
- Progressive, life-limiting, genetic disorder
- Autosomal recessive
- More than half of CF population is greater than or equal to 18 years
CF Pathophysiology
- Mutation of the cystic fibrosis transmembrane conductance regulatory (CFTR) gene causes CFTR protein to dysfunction
- Regulates chloride transport across the cell membrane
- Without Chloride, mucus becomes thick and sticky
F508 del
- Most common mutation
- Protein misfolded, doesn’t reach cell surface
-Over 2000 mutations (Different mutations result in different levels of CFTR function)
Diagnosis
- Newborn screening
- NM measures immunoreactive trypsinogen (chemical made by pancreas) - Sweat test
- Sample of sweat is collected, and concentration of chloride is determined
- Positive test is greater than or equal to 60 mmol/L in children and adults - Chromosomal analysis
Ivolved Organ Systems
- Gastrointestinal system
- Hepatic system
- Pulmonary System
- Reproductive System
- Bone disease
Possible Patient Signs and Symptoms
- Poor growth or weight gain
- Meconium ileus
- Frequent, greasy, bulky stools or difficulty in bowel movements
- Frequent lung infections
- Wheezing or shortness of breath
- Persistent coughing, at times with sputum
- Chronic sinusitis
- Very salty-tasting skin
- Male infertility
- Nasal polyps
Pharmacological Therapy
- Chronic therapy
2. Acute exacerbation therapy
Gastrointestinal System (Goals of therapy)
- Control pancreatic insufficiency by providing adequate enzyme supplementation
- Optimize growth and nutritional status
- Promote healthy bowel habits
- Maintain normal vitamin levels
Gastrointestinal Tract Manifestations
- Insufficient secretion of pancreatic enzymes
- Fat-soluble vitamin malabsorption
- Insulin deficiency
- Intestinal obstruction
• Meconium ileus
• Distal intestinal obstruction syndrome (DIOS)
Pancreatic Insufficiency
- Maldigestion of nutrients
• Symptoms: steatorrhea, frequent loose stools, flatulence, cramping, bloating, poor weight gain, sometimes constipation
• Below age-related norms for both weight and height - Result of pancreatic enzymes deficiency
Pancreatic Insufficiency: Pancreatic enzyme replacement therapy (PERT)
- Creon®, Zenpep®, Pancreaze®, UltresaTM, Pertzye®, ViokaceTM
• Contain lipase, protease, amylase - Enzyme brands are not interchangeable
- Delayed release capsules
• Containing enteric-coated microspheres or minitablets - Products are porcine derived
Pancreatic Insufficiency: Dosing
- Based on total body weight or fat ingested
2. Dosed on lipase units • 500-2,500 units/kg/meal • 10,000 units/kg/day • 4,000 units/gram of dietary fat/day • Take with every meal and snack
Pancreatic Insufficiency: Delayed release capsule administration
- Delayed release capsule administration
– Do not crush or chew contents
– Capsules may be opened and added to small amount of room temperature, acidic food
• Applesauce
• Consume immediately, follow with water, juice, formula, breast milk - Regular release tablet administrations
– Swallow tablets whole with sufficient liquid
Pancreatic Insufficiency: Adverse Events
- Mucusal irritation
- Fibrosing colonopathy and colonic strictures reported at high doses (>6,000 lipase units/kg/meal)
– Diarrhea
– Constipation
– Abdominal pain
Pancreatic Insufficiency: Monitoring parameters
- Stool fat content
- Abdominal symptoms
- Nutritional intake
- Growth
Fat Soluble Vitamins
• Fat soluble vitamin replacement
– A,D,E,K
– Doses higher compared to people without CF
Nutritional Intake
• Energy intakes can be greater than standard for general population
– BMI >50-85% for age
– May require nutritional supplementation (Enteral feedings)
• Promotes healthy pulmonary function
Insulin Deficiency: Cystic fibrosis-related diabetes
– Prevalence increases with age – Associated with worse lung function, poorer nutritional status and increased pulmonary infections – Shares features of DM type I and II – Treatment • Insulin
DIOS
Symptoms & Therapy
- Symptoms
• Cramping, abdominal pain, poor appetite, abdominal distention - Therapy
• Electrolyte lavage solutions- Endpoint is passage of stool, symptom resolution
Hepatic System
• Bile duct obstruction can lead to cirrhosis, portal hypertension
• Ursodiol
– Controversial
– 15-20 mg/kg/day; divided BID
Pulmonary System
• Manifestations result from impaired mucociliary clearance resulting in accumulation of viscous mucus in airways
• Consequences
– Obstruction
– Inflammation
– Infection
• Chronic rhinitis, sinusitis, nasal polyps
Pulmonary System Goal:
• Goal is to decrease the long-term rate of lung function decline
- Airway clearance techniques (ACT)
- Anti-inflammatory agents
- Mucus alteration
- Restore airway surface liquid
- Bronchodilators
- Chronic antibiotics
Pulmonary ACT:
- Improve ventilation, reduce accumulation of secretions
- Done at least BID
- Include:
• Chest/back percussions
• Exercise
• Percussion vest - Bronchodilator pre-treatment
Anti-inflammatory Treatment:
- Ibuprofen
2. Azithromycin
Anti-inflammatory Treatment:
Ibuprofen
- Decreased rate of decline of FEV1
- 6-17 years with mild lung disease
• FEV1 ≥ 60% - Peak plasma concentrations of 50 -100 mg/L
- 20-30 mg/kg/dose given BID
Anti-inflammatory Treatment:
Azithromycin
– Unclear if anti-inflammatory effects are due to antimicrobial and/or immunomodulatory mechanisms
– Slows decline in FEV1 in CF patients with Pseudomonas
– Decreased pulmonary exacerbation
– Dosing
• Three times weekly
Mucus Alteration
Pulmozyme
– Aerosolized recombinant dornase alfa (DNase)
– Decreases viscosity of sputum
– Clinical trials show modest improvement
• 3.2% FEV1 improvement
• Decreased pulmonary exacerbation
– 2.5 mg nebulized once daily or BID
– AEs: hoarseness, voice alteration and pharyngitis – Use select nebulizer, compressor
– Don’t mix with other medications in nebulizer
Mucus Alteration
Nebulization Hypertonic Saline
– Draws water into airways, improve mucus clearance
– 3-7% nebulized daily-BID
– Improved lung function, decrease exacerbations requiring antibiotics
– May cause bronchospasm, pre-treat with bronchodilator
– Hyper-Sal®, PulmoSalTM, Nebusal®
• PulmoSalTM buffered with sodium bicarb (pH 7.4)
Mucus Alteration
-Mannitol inhalation Powder (Bronchiol®)
- Osmotic agent, draws water into the airways, thins mucus
- 18 years of age and older
- Dry powder inhaler
- Bronchitol ® tolerance test
- Albuterol prior to use
- Inhale contents of 10 capsules twice daily
- Bronchospasm, hemoptysis
Chronic Therapy - Pulmonary
- Inhaled corticosteroids
– If patient also has asthma, not routinely used - Inhaled short-acting beta 2-agonist
– Pre-treat with SABA for irritating inhaled therapies
Pulmonary System - Pathogens
1. Staphylococcus aureus – Major pathogen first year of life 2. Haemophilus influenzae – Major pathogen by age 3 3. Pseudomonas aeruginosa – Major pathogen by age 5 – Colonized 4. Burkholderia, Stenotrophomonas, Aspergillus, MRSA
Chronic Therapy - Antibiotics
• Chronic antibiotics
– Intention is to prolong time between acute exacerbations
- Tobi
- Cayston
Tobi Podhaler (TOBI)
– Nebulized and dry powder inhaler formulations of tobramycin
– P. aeruginosa colonization
– Given BID; 28 days on treatment, 28 days off
– Administration:
• 4 capsules (28 mg/capsule) inhaled 2 times daily
• Inhale 2 times from each capsule
• Take doses 12 hours apart
• Store capsules in blister card until ready to use
• Do not swallow capsules
Cayston® (nebulized aztreonam)
– P. aeruginosa colonization
– Give TID; 28 days on treatment, 28 days off
– Altera nebulizer system
Sequence of Administering Inhaled Medications
- Bronchodilator
- Hypertonic saline
- Pulmozyme®
- Airway clearance technique
- Aerosolized antibiotics
Additional Systems:
- Reproductive system
– Majority of males have congenital bilateral absence of the vas deferens - Bone disease
– Low bone density
– Secondary to vitamin D deficiency, systemic inflammation, corticosteroid use
CFTR Modulator: Kalydeco (ivacaftor)
- Targets the defective CFTR protein, ≥ 4 months
- Patients with specific mutations
• Not homozygous F508del - Improves
• Lung function
• Weight gain
• Quality of life - Expensive
CFTR Modulator - Dosing:
– Reduce dose
• Moderate-severe hepatic impairment
• CYP3A inhibitors
– Inhibitors: (e.g. ketoconazole, fluconazole): Adjust dose
• Avoid with strong inducers
– e.g. carbamazepine, phenobarbital, phenytoin
• Avoid grapefruit
– Give with fat containing food
– Mix granules in 5 mL of soft food or liquid at or below room temperature (stable for 1 hour)
CFTR Modulator - Warnings:
– May increase hepatic transaminases
• Monitor liver function: Baseline, every 3 months during 1st year of therapy and yearly after
– Cataracts
– CNS effects: dizziness, may impair abilities
CFTR Modulator - Orkambi:
– Lumacaftor + ivacaftor
– 2 copies of F508del, ≥ 2 years
1. Drug interactions – Lumacaftor strong inducer CYP3A • Avoid benzodiazepines, immunosuppressants – Hormonal contraceptives • Decrease effectiveness 2. Respiratory AEs during initiation – Chest discomfort, dyspnea
CFTR Modulator - Symdeko:
- Tezacaftor + ivacaftor tablet and ivacaftor tablet
- Co-packaged
• Tezacaftor 100mg/ivacaftor 150 mg fixed dose combination tablet and ivacaftor 150 mg tablet
• Combination tablet in the morning, monotherapy tablet in evening - ≥6 years old with 2 copies of F508del or at least one mutation that is responsive
CFTR Modulator - Trikafta:
- Elexacaftor + tezacaftor + ivacaftor
- ≥12 years old with at least one copy of F508del
- Supplied as 2 separate products packaged together
• Elexacaftor/tezacaftor/ivacaftor
• Ivacaftor
Acute Pulmonary Exacerbation:
Signs and symptoms
- New or increased cough
- New or increased sputum production
- Change in sputum appearance
- Decreased exercise tolerance, decreased energy
- New or increased dyspnea with exertion
- Decreased pulmonary function tests
- Decreased appetite, weight
- Increased nasal congestion or drainage
- +/- Fever
- Chest x-ray not routinely done; may not show changes over baseline
Acute Pulmonary Exacerbation:
Diagnosis of acute exacerbation & Goal of therapy
• Diagnosis of acute exacerbation
– Changes from an individual patient’s baseline
• Goal of therapy
– Decrease pulmonary signs and symptoms
– Eradication of P. aeuroginosa is unlikely
Acute Pulmonary Exacerbation:
Treatment
- Antibiotics, oral or iv
- Choice depends on culture/sensitivity reports
• S. aureus, H. influenzae
• P. aeruginosa –» based on sensitivities
- Generally, aminoglycosides in combination with an antipseudomonal penicillin - Increased nutrition
- Increased ACT
Acute Pulmonary Exacerbation:
Antibiotics
- Dosing at upper end
- CF patients have increase Vd and Cl
• As patients age, they approach normal population parameters
Investigational Therapies:
- CFTR modulators
- Antibiotics
– Inhaled levofloxacin - Non-porcine derived enzymes
