Cystic Fibrosis

Where does cystic fibrosis manifests

muscosal obstruction of exocrine glands caused by defective ion transport within epithelial cells

Cystic fibrosis race

white populations

CF gene

-found on chromosome 7

-autosomal recessive inheritance pattern

codes for the CFTR protein

-membrane ion channel prevalent in secretory epithelial cells of airway, GI tract, sweat glands and GU system

-functions as a chloride channel

Dysfunctional CFTR protein

-decreased chloride secretion

-increased sodium reabsorption

70% of cases caused by the

F508 deletion

Early Pathogens

staph aureus, h flu., pseudomonas aerugionsa

Pancreatic insufficiency

85-90% of pts with CF

Obstruction prevents proper excretion of _______ and ______ into digestive tract

pancreatic enzymes; sodium bicarbonate

Pancreas

-Impaired Na+ and Cl- transport results in viscous epithelial secretions and obstruction

-Malabsorption of fat, protein and fat soluble vitamins: poor growth, FTT, fat soluble vitamin deficiency

PERT

-dosing is based on the amount of lipase per product

-products contain lipase, amylase, protease

multivitamins with ADEK

Lipase

catalyze cleavage of fats

Amylase

catalyze breakdown of starches to sugars

Protease

catalyzes the breakdown of proteins into amino acids

Cystic Fibrosis Related Diabetes

• affects more than 35% of adults with CF

• decrease in pancreatic islet cell function and increase in amyloid deposition leads to insulin deficiency

Pulmonary symptoms

tachypnea, dyspnea, chronić cough, sputum production, decreased exercise tolerance, wheezing, crackles, digital clubbing

GI Symptoms

steatorrhea, flatulence, abdominal pain

Nutritional Symptoms

Failure to thrive, poor weight gain, voracious appetite

<39 mmol/L

CR unlikely

40-59 mmol/L

possible CF

>60 mmol/L

Diagnosis of CF

>70% of diagnoses are made by ______; almost all are made by age _____

12 months; 12 yo

Newborn screening- tests for IRT levels

screens for risk only (NOT diagnostic)

Prognosis of CF

• median survival age 66 yo

• pt needs appropriate psychological support

• transitioning care from childhood to adult is important

Problems that need to be treated

viscous epithelial secretions, chronic colonization with bacteria, inflammation

Treatment Goal

delay disease progression and optimize QOL. Reduce airway inflammation and infection (acute exacerbation). Maximize nutritional status.

Maintenance airway clearing technique

1-2 times a day

Acute Exacerbation airway clearance techniques

3-4 times a day

Purpose of non-pharm treatment

-Loosen thick, sticky mucus

-help with expectoration

Bronchodilators should be used ______

before or with ACT

Aerosolized antibiotics activity against

pseudomonas aeruginasa

TOBI spectrum

gram negative bacilli

directions for use for tobi

-300 mg q12 h (reduce to once daily in renal impairment)

-each dose takes about 15-20 minutes otherwise administer

-28 days on, 28 days off

-do not mix with other drugs in nebulizer

-adverse reactions: bronchospasm, hoarseness, tinnitus

TOBI Podhaler

-112 mg every 12 hours

-each dose takes about 5 minutes to administer

Cayston Directions

administer using only an alteration nebulizer system

-75 mg tid via nebulizer (at least 4 hours between doses; 2-3 minutes per dose)

-28 days on and 28 days off

-speciality pharmacy

Cayston adverse reactions

bronchospasm, sore throat, nasal congestion, fever

Colistin

-parenteral formulation used by aerosolized administration

-75-150 mg BID

-pre-treat w/ SABA and use immediately after reconstitution

Colistin AE

bronchospasm

Mucolytics

• decrease viscosity of pulmonary secretions

• increase clearance of sputum

Pulmozyme MOA

-CF lungs contain purulent airway secretions composed primarily of highly polymerized DNA from the nuclei of degenerating neutrophils

-The presence of DNA produces a viscous mucous. Decreased mucocilinary transport and infection.

-Dornase alfa selectivity cleave DNA. Reduces mucous viscosity. Results improved air flow. Decreased risk of bacterial infection.

Dose Pulmozyme

-2.5 mg inhaled once daily via nebulizer

-Patients >21 years with FVC >85% (may benefit from BID dosing)

-do not mix with any other drugs in nebulizer

-can decrease tobramycin

Adverse reactions pulmozyme

-change in or loss of voice,, rhinitis, sore throat, red watery eyes, runny nose

-angina, dyspnea, rash

Short term benefit Pulmozyme

studies showed improvement in lung function after 8 days

Long term benefit of Pulmozyme

preserves lung function

Hypertonic saline

7% saline solution delivered via nebulizer

Hypertonic saline MOA

Increases volume of fluid on epithelial lining go the airway to maintain normal ciliary flow and increased sputum expectoration

Hypertonic Saline Directions

inhale twice daily via nebulizer

AE Hypertonic saline

bronchospasm, increased cough, first dose administered at physicians office to ensure no problems

Inhaled corticosteroids

Used for reactive airways and decrease inflammation. Consider administration following airway clearance. Clear benefit not established in CF patients without reactive airway disease.

Oral corticosteroids long term use

Benefit lost shortly following discontinuation. Safety concerning.

Oral corticosteroids Short Term Use

Helpful in acute exacerbations. Used in patients with ABPA. Limit dose and duration to lest necessary.

Oral NSAIDs (Ibuprofen)

-Benefit not seen immediately

-Requires daily use for years to see full benefit

-Studies show slow rate of pulmonary decline

-Does not improve lung function

Ibuprofen dose

20-30 mg/kg twice daily

High doses Ibuprofen

inhibit lipoxygenase pathway leading to decreased neutrophil migration and lysosomal enzymes

Lower does Ibuprofen

neutrophil migration increases, potentially increasing inflammation

Azithromycin Use

anti-inflammatory properties, decrease sputum production, preserve lung function and decrease pulmonary exacerbations, contraindicated in macrolide resistant nontuberculous mycobacteria

Dose in Azithromycin

-25-39 kg=-14 kg 250 mg

->40 kg=88.185 lb 500 mg

-do not exceed 10 mg/kg in children

-long tissue half life leads to dosing 3 days per week

Leukotriene modifiers

-Cysteinyl LT have been found in increased concentrations in airway secretions of patients with CF

-Montelukast: used in patients with reactive airway disease and useful in allergic rhinitis

Short acting beta agonist albuterol

-Use in combination with airway clearance to stimulate mucociliary clearance.

-Used in combination with other inhaled therapies to prevent bronchospasm.

-May see benefit if recurrent wheeze or dyspnea exists

Long acting Beta agonist salmeterol

benefit if recurrent wheeze or dyspnea

Inhaled anticholinergic agents Ipratropium

-Administered via nebulizer. Act to decrease bronchospasm.

CFTR Potentiator

compound the increases CFTR transporter function

Ivacaftor MOA

-Potentiates epithelial cell Cl- ion transport defective 97 CF gene mutations cell-surface CFTR protein. Improves the regulation of salt and water absorption and secretion in various tissues.

Ivacaftor Indications

patients 1 month and older who have one mutation in the CFTR gene that is responsive to ivacaftor potentiation based on clinical and/or in vitro assay data

Adult Dosing of Ivacaftor

150 mg q12h

what foods to avoid with ivacaftor

grapefruit and oranges

what to monitor Ivacaftor

FEV1, ophthalmological examinations, ALT/AST

Adverse Effects of Ivacaftor

headache, skin rash, abdominal pain, upper respiratory tract infections

corrector

lumacaftor

potentiator

ivacaftor

What following can be used for f508 del?

ivacaftor/lumacaftor and ivacaftor/tezacaftor

Cystic fibrosis has a mutation in CTFRs which severe as ____ channels. The mucus will then contain decreased levels of ____ and have ____viscosity.

Cl, H20, increased

Which of the following respiratory conditions is associated with amiodarone therapy

What medications are used to decrease inflammation associated with CF lung diseases

ibuprofen and azithromycin

MOA of lumacaftor

Lumacaftor improves the conformational stability of F508 resulting in increased processing and trafficking of mature protein to the cell surface.

Indication for lumnacaftor/ivacaftor

treatment of CF in patients 1 yr older who are homozygous for the F508 deletion mutation in the CFTR gene

Dose Lumnacaftor and ivacaftor

Lumacaftor 400 mg/ ivacaftor 250 mg every 12 hours

Tzeacaftor

corrector

MOA for tezacaftor

Tezacaftor facilitates the cellular processing and trafficking of normal and select mutant forms of CFTR to increase the amount of mature CFTR protein delivered to the cell surface

Indication for tezacaftor/ivacaftor

treatment of CF in patients 6 years older who are homozygous for the F508 deletion mutation or who have at least one mutation the CFTR gene that is responsive to teacaftor/ivacaftor based on in vitro

What order should patients administer medications

open airways/prevent bronchospasm, clear mucus, treat pseudomonas

Open Airways/Prevent bronchospasm

SABA short acting B agonists

Clear mucus

Mucolytics

1) Dornase Alpha

2) hypertonic saline

Treat Pseudomonas

Inhaled antibiotics

tobramycin, aztreonam, colistin

Pulmonary exacerbations mild symptoms

oral and inhaled outpatient antibiotic treatment for 14-21 days

Pulmonary exacerbation severe infections

Iv antibiotic treatment for 2-3 weeks

Pulmonary exacerbations corticosteroids

• not recommended for chronic management in most patients

• short course of systemic corticosteroids may offer benefit

PK considerations- enhanced total body clearance

increased renal clearance, increased GFR, decreased protein binding, increased tubular secretion, decreased tubular reabsorption, extra renal elimination, increased metabolism

PK considerations-large vd for many antibiotics

• increased ratio of lean body mass to total body mass

• decreased fat stores