Lecture 3: Cystic Fibrosis

Question 1

CF is an autosomal recessive disease. What does this mean?
A. Only mom carries the mutation
B. Only dad carries the mutation
C. Mom and dad both carry the mutation
D. Neither mom nor dad carries the mutation

Answer 1

CF is Progressive, life-shortening, genetic
disorder, Autosomal recessive.. originally from Europe/ whites (most common in white as well but effects all race!). orginally thought to be ped disease but can happen in all ages!
.
C! both mom and dad have to have that mutation but they do not have to have the disease..for each preg? 25%!

Question 2

CF Pathophysiology

Answer 2

• Mutation of the cystic fibrosis transmembrane
  conductance regulator (CFTR) gene causes CFTR protein to dysfunction
• Regulates chloride, sodium, bicarbonate transport across the cell membrane… dysfunction? mucus becomes thick and sticky
• Over 2000 mutations: Different mutations result in different levels of CFTR function! not everyone will look the same! There are difference variance based on different gene mutation
  – F508del: Most common mutation… Protein misfolded, doesn’t reach cell surface

Question 3

Diagnosis of CF

Answer 3

• Newborn screening
  – Immunoreactive trypsinogen
• produced by pancreas
• Sweat test
  – Sample of sweat is collected, and concentration of
  chloride is determined
  – Positive test is ≥ 60 mmol/L in children and adults
• Chromosomal analysis

Question 4

Involved Organ Systems of CF… (general)

Answer 4

• Gastrointestinal system
• Hepatic system
• Pulmonary system
• Reproductive system
• Musculoskeletal system
  .
  Involve of organs is related to where the CFTR gen is located!

Question 5

Possible Patient Signs and Symptoms for CF

Answer 5

• Poor growth or weight gain (due to the GI involvement! lack of nutrition absorbed)
• Meconium ileus
• Frequent, greasy, bulky stools or difficulty in bowel
  movements (due to not absorbing food well)
• Frequent lung infections
• Wheezing or shortness of breath
• Persistent coughing, at times with sputum
• Chronic sinusitis
• Very salty-tasting skin (due to CFTR reg of salt!)
• Male infertility
• Nasal polyps

Question 6

Pharmacological Therapy (2 main class)

Answer 6

• Chronic therapy
• Acute exacerbation therapy

Question 7

Gastrointestinal System: Goals of therapy

Answer 7

– Control pancreatic insufficiency by providing adequate enzyme supplementation (cant absorb food and fat soluble vit!)
– Optimize growth and nutritional status
– Promote healthy bowel habits
– Maintain normal vitamin levels

Question 8

Gastrointestinal Tract Manifestations

Answer 8

• Insufficient secretion of pancreatic enzymes
• Fat-soluble vitamin malabsorption
• Insulin deficiency
• Intestinal obstruction
  – Meconium ileus
  – Distal intestinal obstruction syndrome (DIOS)

Question 9

Pancreatic Insufficiency: Maldigestion of nutrients (symp)? - a Gastrointestinal Tract Manifestation

Answer 9

• Symptoms: steatorrhea (greasy stool), 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

Question 10

Pancreatic Insufficiency: Treatment?

Answer 10

Pancreatic enzyme replacement therapy (PERT)!
.
– Creon®, Zenpep®, Pancreaze®, Ultresa™,Pertzye®, Viokace™
……. ALL Contain lipase, protease, amylase!
.
– Enzyme brands are not interchangeable
– Delayed release capsules: Containing enteric-coated microspheres or minitablets
– Products are porcine (pig) derived
.
- Delayed release capsule administration: Do not crush or chew contents, Capsules may be opened and added to small amount of room temperature, acidic food like applesauce. Consume immediately, follow with water, juice, formula, breast milk
- Regular release tablet administrations: Swallow tablets whole with sufficient liquid

Question 11

Pancreatic Insufficiency: Treatment dosing

Answer 11

Dosing (no need to calc for exam! )
– Based on total body weight or fat ingested
– 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

Question 12

Pancreatic Insufficiency: Treatment Adverse events and monitoring

Answer 12

– Mucusal irritation
– Fibrosing colonopathy and colonic strictures reported at high doses (>6,000 lipase units/kg/meal): Diarrhea, Constipation, Abdominal pain
.
Monitoring parameters
– Stool fat content
– Abdominal symptoms
– Nutritional intake
– Growth

Question 13

Another issue in CF (Gastrointestinal Tract Manifestations): Fat Soluble Vitamins and Nutritional Intake and Insulin Deficiency

Answer 13

1.) Fat soluble vitamin replacement
– A, D, E, K
– Doses higher compared to people without CF
.
2.) Energy intakes can be greater than standard for general population
– BMI >50-85% for age (need to take extra calories! healthy fat! )
– May require nutritional supplementation (Enteral feedings)
* Promotes healthy pulmonary function
.
3.) Cystic fibrosis-related diabetes
– Prevalence increases with age
– Associated with worse lung function, poorer nutritional status and increased pulmonary infections
– Distinct from type 1 and type 2 diabetes
– Treatment: Insulin

Question 14

Another issue in CF: DIOS (intestine is obstructed): symp and therapy?- a Gastrointestinal Tract Manifestation

Answer 14

• Symptoms
  – Cramping abdominal pain, poor appetite, abdominal distention
  .
• Therapy
  – Electrolyte lavage solutions
• Endpoint is passage of stool, symptom resolution

Question 15

Another issue in CF: Hepatic System/ Hepatic Manifestations. symp and tx?

Answer 15

• Bile duct obstruction can lead to cirrhosis, portal hypertension
  .
• Ursodeoxycholic acid
  – Controversial
  – Thought to reduce liver injury
  – 15-20 mg/kg/day; divided BID

Question 16

CF issues (biggest reason why CF ppl die) : Pulmonary System manifestation, consequences, and goal?

Answer 16

• Manifestations result from impaired mucociliary clearance resulting in accumulation of viscous mucus in airways
• Consequences: Obstruction, Inflammation, Infection
• Chronic rhinitis, sinusitis, nasal polyps
  .
  GOAL:
  Goal is to decrease the long-term rate of lung function decline
  – Airway clearance techniques (ACT)
  – Anti-inflammatory agents
  – Mucus alteration
  – Bronchodilators
  – Chronic antibiotics

Question 17

Pulmonary System: Airway clearance techniques (ACT)

Answer 17

– Improve ventilation, reduce accumulation of secretions
– Done at least BID
– Include: Chest/back percussion (you need someone else to pound on your back), Exercise, Percussion vest
– Bronchodilator pre-treatment

Question 18

Pulmonary System: Anti-inflammatory agents

Answer 18

1.) 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 (v high dose! SE: GI issue)
- IT’S AN OPTION BUT WE DO NOT USE IT OFTEN AT ALL DUE TO SIDE EFFECT PROFILE!
.
2.) 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!

Question 19

Pulmonary System: Mucus Alteration: 1. Pulmozyme

Answer 19

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 (overall it is very well tolerated)
– Use select nebulizer, compressor
– Don’t mix with other medications in nebulizer

Question 20

Pulmonary System: Mucus Alteration: 2. Nebulized hypertonic saline

Answer 20

Nebulized hypertonic saline (3% - 7% salt water! like the ocean ! surfer does better cuz salt water!)
– 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®, PulmoSal (v expensive! but works better for more severe cases!)™, Nebusal®
( PulmoSal™ buffered with sodium bicarb (pH 7.4))
-patient may be on both hyper-sal and pulmosal to help them! may switch to hyper-sal sometimes cuz it’s cheaper!)

Question 21

Pulmonary System: Mucus Alteration: 3. Mannitol inhalation powder (Bronchitol ®)

Answer 21

• 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 (faster than neb but a lot of work!)
• Bronchospasm, hemoptysis

Question 22

Chronic Therapy - Pulmonary … other misc med

Answer 22

1.) Inhaled corticosteroids
– If patient also has asthma, not routinely used (do not use inhaled steroid for CF! does not work! it is used for asthma)
2.) Inhaled short-acting beta2-agonist
– Pre-treat with SABA for irritating inhaled
therapies

Question 23

Pulmonary System: the bacterial makeup

Answer 23

1.) Staphylococcus aureus: Major pathogen first year of life
2.) Haemophilus influenzae: Major pathogen by age 3 (at this time you will see a decrease in lung function)
3.) Pseudomonas aeruginosa: Major pathogen by age 5, Colonized
4.) Burkholderia, Stenotrophomonas, Aspergillus, MRSA
.
So we treat them with- Chronic antibiotics
– Intention is to prolong time between acute
exacerbations

Question 24

Chronic Therapy - Antibiotics: TOBI and Tobi® Podhaler®

Answer 24

TOBI® , TOBI® Podhaler®
– Nebulized and dry powder inhaler formulations of tobramycin
– P. aeruginosa colonization
– Given BID; 28 days on treatment, 28 days off (vacation to prevent resistance from developing)
.
Tobi® Podhaler® - dry powder
* 4 capsules (28 mg/capsule) inhaled BID
* Inhale 2 times from each capsule
* Take doses 12 hours apart
* Store capsules in blister card until ready to use
* Do not swallow capsules

Question 25

Chronic Therapy - Antibiotics: Cayston® (nebulized aztreonam)

Answer 25

– P. aeruginosa colonization – Give TID; 28 days on treatment, 28 days off – Altera nebulizer system . NOTE: usually start with TOBI but if symp progress then you may see them on this drug and other inhaled abx as well! Can switch inhaled abx around to prevent resistance)

Question 26

Sequence of Administering Inhaled Medications

Answer 26

1. Bronchodilator (albuterol) 2. Hypertonic saline - mucus adjust 3. Pulmozyme® - mucus adjust 4. Airway clearance technique - to cleared the adjusted mucus 5. Aerosolized antibiotics

Question 27

Additional Systems the CF effects

Answer 27

Reproductive system – Majority of males have congenital bilateral absence of the vas deferens – Women are typically fertile but some have reduced fertility . Musculoskeletal system – Decreased bone mineral density – Malabsorption of vitamin D, poor nutritional status, corticosteroid use

Question 28

CFTR Modulator Class (newer promising drug!): 4 main classes - but focus on 2 of them because the other 2 are not approved in USA yet...what are they 2 approved ones and what drugs do they include? what do they do?

Answer 28

1.) Potentiators – Ivacaftor – Help open the CFTR channel and increase flux of chloride and bicarbonate 2.) Correctors – Elexacaftor, tezacaftor, lumacaftor – Help normalize folding of CFTR and movement to cell surface

Question 29

CFTR Modulator: Kalydeco™ (ivacaftor) - single potentiator: general, dosing, AE, warnings

Answer 29

– Targets the defective CFTR protein – ≥ 4 months of age – Patients with specific mutations: Not homozygous F508del aka from both mom and dad! (does not work in this but this is the most common mutation..) – Improves Lung function, growth parameters, pulmonary exacerbations, reduces Pseudomonas aeruginosa – Expensive, tablet form . Dosing – Reduce dose in... * Moderate-severe hepatic impairment * CYP3A inhibitors: inhibitors: (e.g. ketoconazole, fluconazole): Adjust dose * Avoid with strong inducer: 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) . Warnings (for all CFTR modulators!!!!) – 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

Question 30

CFTR Modulator: Orkambi® (Lumacaftor + ivacaftor).. general, drug interaction, AE

Answer 30

Orkambi® – a combination of Lumacaftor + ivacaftor – 2 copies of F508del (yay! can be used in the more general pop.), ≥ 1 year of age . Drug interactions – Lumacaftor strong inducer CYP3A: Avoid benzodiazepines, immunosuppressants – Hormonal contraceptives: Decrease effectiveness . Respiratory AEs during initiation: Chest discomfort, dyspnea . NOTE: Not as impressive as Kalydeco tho when it was used in the population it was used in.

Question 31

CFTR Modulator: Symdeko®: medication components and population it is used it?

Answer 31

– 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 - Not as expensive . NOTE: Not as impressive as Kalydeco tho when it was used in the population it was used in.

Question 32

CFTR Modulator: Trikafta™

Answer 32

– Elexacaftor + tezacaftor + ivacaftor – ≥6 years old with at least one copy of F508del or mutation that is responsive – Supplied as 2 separate products packaged together ........ Elexacaftor/tezacaftor/ivacaftor ........ Ivacaftor

Question 33

Acute Pulmonary Exacerbation: Signs and symptoms

Answer 33

– 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