cystic fibrosis

what is cystic fibrosis?

a genetic condition caused by a mutation in the gene that encodes for the cystic fibrosis transmembrane conductance regulator (CFTR) protein

cystic fibrosis inheritance pattern is ______

autosomal recessive meaning needs both parents inheritance

The CFTR protein is a protein found on secretory epithelial cells, which organ systems will be effects in CF?

• Sweat glands

• Pancreas

• Liver

• Respiratory system

• GI system

• Reproductive system

what is the gold standard test for cystic fibrosis?

sweat test

a sweat test of <30 mmol/L is interpreted as ______

CF unlikely

a sweat test of < 30-59 mmol/L is interpreted as ______

intermediate

a sweat test of > 60 mmol/L is interpreted as ______

diagnosis for Cystic Fibrosis

explain the pulmonary manifestation of Cystic Fibrosis

1. Impaired transport of Chloride across pulmonary epithelium

2. Dehydration of airway lumen surface liquid (mucus)

3. Ineffective mucociliary clearance due to increased viscosity of mucus

4. Mucus obstruction, Inflammation, and Infection

5. Pulmonary scarring (FIbrosis) - increased lung compliance (overly stretchy or floppy with reduced elastic recoil)

what is a clinical pearl of Albuterol used for airway clearance in cystic fibrosis?

can help prevent bronchospasms with other inhaled medications

_______ is common with hypertonic saline which loosens mucus

Bronchospasms

what is the age cutoff for Hypertonic saline?

Age > 6 years old

what is the age cut off for Dornase alfa?

age > 5 years old

______ is a macrolide antibiotic that may be prescribed to patients with cystic fibrosis as a three times weekly regimen

Azithromycin

what is the dose of Azithromycin in CF for 18 to 36kg patient? What about >36kg?

18 to 36kg → 250mg MWF

>36kg → 500mg MWF

what is the purpose of using Azithromycin in patients with CF

• prevents formation of chronic psuedomonas aeruginosa biofilm formation

• anti-inflammatory activity

CF foundation recommends use of Azithromycin in:

1. patients > 6yrs old with chronic P. aeruginosa infection

2. patients > 6yrs old not chronically infection with P. aeruginosa

_______ are given as part of maintenance regimen to eradicate or suppress the growth of bacterial organisms of concern (especially Pseudomonas aeruginosa)

Inhaled Antibiotics

Inhaled antibiotics are only if patient has no ______

symptoms

inhaled antibiotics in cystic fibrosis are used for Eradication and Suppression. What are the indications and regimens in both?

• Eradication:

  • Indication: First-time or new P. aeruginosa growth

  • Regimen: 28-day treatment course x1

• Suppression:

  • Indication: Repeated growth of P. aeruginosa

  • Regimen: cycled 28-day treatment course followed by 28-day off-treatment period

What are the two FDA approved inhaled antibiotics for cystic fibrosis?

Tobramycin

Aztreonam

________ is the preferred inhaled antibiotic FDA approved for ages > 6 yrs old and is most commonly used for BOTH eradication and suppression

Tobramycin

_______ is an inahaed antibiotic that requires a specialized nebulizer, used more often for suppressive therapy than eradication, and is FDA approved for >7 years old

Aztreonam

Acute pulmonary exacerbations are characterized by acute worsening of respiratory symptoms such as:

• cough

• sputum production/quality change

• shortness of breath

• decline in FEV1****

what is the therapeutic goal of acute pulmonary exacerbation management?

return to baseline FEV1

**remember because there is a decline in FEV1

what are the 3 guideline directed managements for Acute Pulmonary Exacerbation

• Temporarily INCREASE maintenance airway therapies

  • Airway clearance and Albuterol increased to FOUR times a day

  • Dornase alfa increased to TWO times a day

• Initiate combination antibiotic therapy (for systemic treatment)

• Treat with antibiotics for 10 - 14 days

In patients with cystic fibrosis, what happens to the Volume of Distribution and the Clearance?

• Vd is Increased

• Clearance is increased (renal and non-renal)

**So higher doses and more frequent dosing are often required to achieve goal concentrations

beta lactams (time dependent) antibiotics require ______ doses and ______ frequent dosing

lower doses and more frequent dosing (Ex: extend infusion)

Aminoglycosides (concentration dependent) antibiotics require ______ doses and ______ frequent dosing

higher doses and less frequent dosing

what is the gold standard for Pseudomonal coverage in cystic fibrosis? why?

DOUBLE coverage

Ex: Anti-pseudomonal beta-lactam + IV Aminoglycoside

WHY? → adds a synergistic effect; attacks Pseudomonas and helps avoid resistance

what is the role of pancreatic exocrine gland cells?

secrete digestive enzymes

what are the functions of the alkaline pancreatic fluid?

solubilize the digestive enzymes and transport digestive enzymes to the duodenum

the creation of alkaline pancreatic fluid is reliant on the secretion of ______

chloride

In cystic fibrosis, the secretion of ______ is impaired and the thick sticky mucus replaces the free flowing pancreatic fluid normally produce

chloride

Pancreatic duct obstruction prevents digestive enzymes from reaching the duodenum which results in what?

inability to break down carbs, proteins, and fats in the diet

What are symptoms of pancreatic insufficiency?

• Weight loss *

• Malnourishment *

• Poor growth (in children) *

  • Normal growth is associated with improved lung fucntion in children with CF

• flatulence

• bloating

• steatorrhea

• GI upset

How is Pancreatic insufficiency diagnosed?

1. annual fecal elastase screening

2. pancreatic insufficient if fecal elastase < 200mcg/g

how is Pancreatic insufficiency managed?

• high calorie, high fat diet

• fat soluble vitamin supplements

• pancreatic enzyme replacement therapy

are Pancreatic Enzyme Replacement Therapy brands interchangeable?

NO, therapy is formulation specific and brands differ in terms of amylase/protease components

*microencapsulated (enteric coated) are most effective

what is the dose of Pancreatic Enzyme Replacement Therapy for infants vs children/adults?

• Infants: weight x 13,000 divided by number of feeds/day

  • MAXL 13,000 lipase units/kg/day

• Children/Adults: 2,500 lipase units/kg/meal

  • MAX: 10,000 lipase units/kg/day

  • Snacks = ½ mealtime dose

what are the Pancreatic Enzyme Replacement Therapy drugs?

• Zenpep

• Creon

• Pancreaze

• Pertzye

• Viokace

what is the goal Vitamin D (25-hydroxyvitamin) level ?

Goal > 30 ng/mL

** should be supplemented as Cholecalciferol

Pancreatic duct obstruction leads to chronic inflammation and intrinsic damage to pancreatic cells, including beta cells (insulin), which results in:

insulin sufficiency (cellular damage) and insulin sensitivity (inflammation)

what is the management strategy for CF related Diabetes?

• Moderate aerobic exercise 150minutes/week

• Insulin therapy *oral agents not as effective in CF related Diabetes

what is the screening and ADA criteria for CF related Diabetes?

• Screen oral glucose tolerance test annually starting at 10 yrs old

• Fasting glucose > 126 mg/dL

• 2-hour glucose > 200mg/dL

• A1c > 6.5%

________ therapy does not cure the CF disease but works at the level of the defective protein and addresses the cause of the symptoms

CFTR modulator therapy

what is CFTR Mutation Class 1?

production mutation

what is CFTR Mutation Class 2?

processing mutation

what is CFTR Mutation Class 3?

Gating mutation

what is CFTR Mutation Class 4?

conduction mutation

what is CFTR Mutation Class 5?

everything goes right but just not enough CFTR protein being produced

_______ increase the function of the CFTR channels already on the cell surface

** helps the CFTR channel work better

Potentiators

________ correct misfolded CFTR proteins and increase their processing and tracking into the cell surface

**helps CFTR get to cell surface better

Correctors

_______ is the only monotherapy CFTR therapy that is a potentiator only

Kalydeco (ivacaftor)

_______ is not active against Type 1 (synthesis) or Type 2 (processing) defects

Kalydeco (ivacaftor)

Kalydeco (ivacaftor) is a major substrate for ______

CYP3A4

what are the two combination therapy Correctors?

Orkambi (Lumacaftor + Ivacaftor)

Symdeko (Tazacaftor + Ivacaftor)

Corrector component of Orkambi (Lumacaftor + Ivacaftor) provides activity for those with ____ defects

Class 2

*specifically homozygous F508del

Orkambi is a ______ substrate and inducer

CYP3A4

Symdeko is a _____ substrate and is active against a wider range of mutations (± F508del)

CYP3A4

what are the two triple therapy CFTR modulators?

Trifakta and Alyftrek

Trifakta is a combination of what?

Elexacaftor + Tezacaftor + Ivacaftor

Alyftrek is a combination of what?

Vanzacaftor + Tezacaftor + Deutivacaftor

Trikafta and Alyftrek are ____ substrates

CYP3A4

______ leads to major increases in FEV1

Triple therapy

Trikafta is approved for ages _______ whereas Alyftrek is for ages _____

Trikafta for ages > 2 years old

Alyftrek for ages > 6 years old

Ivacaftor and Deutivicaftor are _____ only

potentiators

Ofrkambi (Lumacaftor + Ivacaftor) is approved for which age ?

Ages > 1 year old

Symdeko (Tezacaftor + Ivacaftor) is approved for which age?

Ages > 6 years old

_______ is the combination therapy CFTR modulator with greater number of mutations, fever DDIs, and lower ADE Incidnce

Symdeko

______ are have eligibility for rare mutations

Trikafta and Alyftrek (both are triple therapy CFTR modulators)

**Trifakta has 521+ eligible mutations

**Alyftrek has 564+ eligible mutations

modified _______ in Alyftrek allows for once daily dosing

Ivacaftor

**deutivacaftor is in Alyftrek along with Vanzacaftor and Tezacaftor