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GI/Pulmonary EXAM 3 - Lubsch
GI/Pulmonary EXAM 3 - Lubsch CF
46
Pharmacology
Graduate
04/10/2011

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Term
an autosomal recessive genetic disease that results in faulty transport of salt in organs

multi-system disease:
respiratory system - cycle of lung infection or exacerbation and inflammation which slowly damages lungs, eventually impairing ability to provide O2 to the body
digestive system - pancreas is affected, causes problems with digestion, making it difficult to grow normally and keep a healthy body weight
endocrine system
bone and joint
reproductive system
CFRD (CF related diabetes) - pancreas unable to secrete insulin and insulin resistant
depression

leads to thick, sticky mucus that blocks the ducts of these organs, disrupting their normal functions
Definition
what is cystic fibrosis?
Term
Caucasians > Hispanic, African American

most common life shortening genetic disorder in Caucasians

female = male
Definition
epidemiology of CF
Term
2 copies of abnormal gene must be present for disease

inherited through the non-sex chromosomes from both parents that are carriers:
25% chance of disease, 50% chance of carrier, 25% chance of non-carrier

1 parent = child carrier
Definition
what does autosomal recessive mean?
Term
improved survival in CF

[image]
Definition
survival rates of CF
Term
2 base pair deletion on chromosome 7

this sequence codes for CFTR (CF transmembrane conductase receptor)

there are over 1800 known mutations of the CF gene
Definition
etiology of CF
Term
CFTR regulates Na, Cl, and water transport in epithelial cells

this protein acts as a cAMP mediator of Cl channel conductance in epithelial cells

it regulates Na, Cl, and secondarily water transport across cell membranes which are responsible for creating airway surface liquid necessary for effective mucociliary clearance

in CF, genetic mutations lead to defective CFTR production, processing, conductance, and/or regulation

as a result of the CFTR mutation, epithelial cells are unable to secrete Na and Cl, and water is reabsorbed into the cell

this defect occurs in epithelial cells of the respiratory, hepatobiliary, gastrointestinal, and reproductive tracts along with the pancreas and sweat glands

dehydrated and viscous secretions are ineffectively cleared and cause luminal obstruction, scarring, and dysfunction
Definition
role of CFTR
Term
CF PANCREAS

Chronic cough
Failure to thrive
Pancreatic insufficiency
Alkalosis
Neonatal intestinal obstruction/Nasal polyps
Clubbing/CXR findings
Rectal prolapse
Electrolyte abnormalities
Absence of vas deferens/pulmonary cilia
Sputum
Definition
clinical presentation of CF
Term
neonatal screenings: increased immunoreactive trypsinogen (IRT)

clinical features of CF PLUS:

1) sweat chloride test - need 2 positive tests to confirm CF

OR

2) genotyping - +1500 CFTR mutations identified; need 2 known CFTR mutations to confirm CF

5 months is median age at diagnosis, 60% are diagnosed by 1 year of age and 90% by 5 years, but trend will likely continue to decrease

these tests do not identify severity
Definition
diagnosis of CF
Term
defective Cl transport and enhanced sodium absorption
Definition
CF results from a defect on chromosome 7 that affects the gene that codes for the protein known as CFTR in the lungs, impaired CFTR function causes:
Term
defective CF gene

defective/deficient CFTR

abnormal airway surface:
treated with hypertonic saline

bronchial obstruction:
thick mucus results in air trapping, bronchiectasis, atelectasis (results in COPD-like disease)
treated with airway clearance, dornase alfa, hypertonic saline

infection:
increased risk due to thick mucus acting as an excellent growth medium for microorganisms
treated with TOBI, azithromycin, oral/IV antibiotics

inflammation:
bacterial progression leads to elevated levels of inflammatory mediators (TNF-a, IL-1, IL-2, neutrophil elastase); further thickening of mucus and reduced efficacy of antibiotics; progressive airway and lung damage
treated with corticosteroids, ibupofen

bronchiectasis:
treated by lung transplantation
Definition
pathogenesis of lung disease in CF
Term
cough/sputum production

wheeze, air trapping

radiographic abnormalities

evidence of obstruction on PFTs (FEV1 will decrease)

digital clubbing

nasal polyps
Definition
common respiratory findings in CF
Term
MILD
FEV1 > 70-89% predicted

MODERATE
FEV1 40-69% predicted

SEVERE
FEV1 < 40% predicted
Definition
CF disease severity: pulmonary impairment
Term
[image]

major improvement in lung function of people with CF since 1990

[image]

The rising number of people with mild disease and the dropping number with severe disease show that the lungs of people with CF are healthier now than 20 years ago
Definition
CF lung function comparison from 1990s to current
Term
initial infections:
Staphylococcus aureus
Haemophilus influenzae
Streptococcus pneumoniae

colonization:
Pseudomonas aeruginosa
Burkholderia cepacia
Stenotrophomonas maltophilia

age 0-17 years most common pathogen = Staph

age 18 and up most common pathogen = P. aeruginosa
Definition
CF infection etiologies

initial infections, colonizations, and most prevalent organisms by age
Term
symptoms:

increased frequency and duration of cough
increased sputum production
change in appearance of sputum
shortness of breath
decreased exercise
decreased appetite
increased congestion in chest

signs:

increased RR
intercostal retractions
decrease in pulmonary function consistent with obstructive airway
fever and leukocytosis
weight loss
new infiltrates

[image]

frequent exacerbation more common in adolescents/young adults
Definition
signs and symptoms of an acute pulmonary exacerbation in CF
Term
exercise

hydration

breathing techniques - belly breathing; "huff" breathing

conventional chest physiotherapy (CPT) - percussion with cupped hand/vibrator; postural drainage

oscillating positive expiratory pressure devices

high-frequency chest wall oscillation
Definition
airway clearance therapy for CF
Term
oral penicillins and cephalosporins

dicloxacillin, cephalexin
Definition
antimicrobial therapy for an initial infection in CF
Term
COMBINATION anti-pseudomonal therapy

duration: 14-21 days
synergistic activity
slow development of resistance

ceftazedime PLUS AG (tobramycin)
piperacillin PLUS AG (tobramycin)

other anti-pseudomonals:
aztreonam
CIPROFLOXACIN
meropenem
ticarcillin/clavulanate

FQs are the ONLY ORAL ANTIBIOTIC TO TREAT PSEUDOMONAS!

can use FQs in children (ciprofloxacin) in cases of CF
Definition
antimicrobial therapy for a pseudomonal infection in CF
Term
vancomycin
linezolid
bactrim

clindamycin not effective in CF b/c MRSA is similar to hospital acquired
Definition
antimicrobial therapy for MRSA infection in CF
Term
adjunct to antibiotics for treatment
home maintenance therapy

improved drug delivery to site of infection

reduced systemic exposure

ADRs: increased cough, hoarseness

no products approved for exacerbation treatment, usually used as maintenance; chronic therapy every other month

concern for emerging resistance?
Definition
role of aerosolized antimicrobial therapy in CF
Term
TOBI (tobramycin)

criteria: >/= 6 years + P. aeruginosa
dosed: BID alternating months
benefits: increases FEV1 ~10%, decreases hospital days/IV antibiotics

Cayston (aztreonam)

same criteria
dosed: TID alternating months
benefits: increases FEV1 ~10%, decreases symptoms
only available at CF specialty pharmacies
Definition
examples of aerosolized antimicrobial therapy
Term
prevent/delay colonization with CF pathogens:

Staphylococcus aureus
Pseudomonas aeruginosa: TOBI, macrolides
Stenotrophomonas maltophila: SMX/TMP

PROPHYLAXIS NOT ROUTINELY RECOMMENDED AT THIS TIME
Definition
antimicrobial prophylaxis in CF
Term
MOA:
reduces sputum viscosity
cleaves DNA in sputum reducing sputum viscosity and/or its adherence to epithelial airways improving mucociliary sputum clearance and lung function

Critera: >/= 6 years

Dosing: given after SABA

benefits:
decreases pulmonary exacerbations
decreases IV antibiotic use
increases FEV1 by 5%

ADRs:
hoarseness
pharyngitis
Definition
Pulmozyme (dornase alfa)

MOA, criteria, benefits, ADRs
Term
osmotic agent that increases the water content of the airway surface liquid and improves clearance of mucus

thins mucus

induces expectoration

FEV1 increased from baseline by 7%

routine use not recommended
Definition
Mucomyst (N-acetylcysteine)

MOA
Term
mobilize sputum

controversial benefits

adjunct therapy to conventional chest physiotherapy (CPT)

use prior to/during airway clearance with saline

ADRs: jitteriness, dose dependent

recommended for patients >/= 6 years with + bronchodilator response
Definition
role of SABAs in CF
Term
used for reactive airway disease

concern for toxicity

reserved ONLY for patients with documented improvement
Definition
role of theophylline in CF
Term
glucocorticoids:
little role in long-term therapy
concern for ADRs

high dose ibuprofen:
ADRs - GI, nephrotoxicity
concern for intermittent low dose

macrolides:
azithromycin
criteria - >/= 6 years, weight > 25 kg, FEV1 > 30% predicted, no B. cepacia present, no liver disease
benefits - increases FEV1 ~6%, decreases hospital stays/IV antibiotics, weight gain
Definition
anti-inflammatory agents used in CF
Term
increases mucociliary clearance

criteria: >/= 6 years

dosed after SABA

benefits: increase sputum clearance to increase lung function, decreases exacerbations, decreases IV antibiotics

ADRs: coughing, sore throat, chest tightness
Definition
role of hypertonic saline in CF
Term
A: Strong recommendation for:

inhaled tobramycin - moderate to severe disease
dornase alfa - moderate to severe disease

B: recommended for:

inhaled tobramycin - asymtpomatic to mild disease
dornase alfa - asymtpomatic to mild disease
hypertonic saline
ibuprofen
macrolides
inhaled B-agonists

D: recommendation against:

oral corticosteroids - age 6 to 18 years
inhaled corticosteroids
anti-Staph antibiotics
Definition
summary of recommendations for pulmonary treatment of CF
A, B, and D recommendations
Term
caused by Pseudomonas, H. flu, Strep, and/or anaerobes

25-50% of patients may develop nasal polyps

treat with topical steroids or antihistamines for allergic symptoms

requires surgical removal

immunization
Definition
treatment of sino-pulmonary disease in CF (pansinusitis)
Term
exocrine pancreatic insufficiency
fat-soluble vitamin deficiency

meconium ileus
distal intestinal obstruction disorder
rectal prolapse
gastrointestinal reflux
recurrent pancreatitis
hepatobiliary disease
failure to thrive
hypoproteinemia-edema
Definition
gastrointestinal/nutritional abnormalities of CF
Term
increased caloric requirements (130-150% of RDA for age)

oral supplements: Ensure, Scandishakes

enteral feedings: nocturnal feedings

pharmacologic agents: not routinely recommended
anabolic agents - growth hormone, megestrol acetate
cyproheptadine
Definition
nutritional management in patients with CF
Term
about 90% of people with CF have pancreatic insufficiency

role: achieve adequate nutrition, abolish GI symptoms, achieve normal bowel function

agents vary in amylase:lipase:protease ratios - NOT bio-equivalent, NOT interchangeable
Definition
role of pancreatic enzyme replacement therapy in patients with CF
Term
dose based on LIPASE activity

individualize dose, titrate to response

take before each meal or snack
Definition
dosing of pancreatic enzyme replacement therapy
Term
fat soluble vitamin replacement:
Vitamin A
Vitamin D
Vitamin E
Vitamin K

monitor vitamin A, D, E levels yearly

beta-carotene
calcium
iron
zinc
sodium

TAKE WITH ENZYME
Definition
vitamin/mineral/electrolyte supplementation in patients with CF
Term
decreased bicarbonate secretion, gastric acid cause decreased absorption of pancreatic enzymes

antacids
histamine-2 receptor antagonists
proton pump inhibitors

gastroesophageal reflux:
above +/- metoclopramide (Reglan)
Definition
gasterointestinal therapy for patients with CF
Term
delay the progression of lung disease

normal nutrition, growth, and development

normal bowel habits

reduce pulmonary symptoms
Definition
treatment goals of CF
Term
ursodiol

role: improves bile flow, displaces toxic bile acids that accumulate in liver disease
Definition
treatment of cholestasis/fibrosis/cirrhosis sequence in patients with CF
Term
propranolol for prophylaxis and variceal bleeding
Definition
treatment of cirrhosis induced portal hypertension in patients with CF
Term
prevalence 22%
primary cause is insulin deficiency
age of onset: 18-21 years

individualized insulin regimen:
split dose NPH/regular insulin
lispro before meals/lantus HS
insulin pump therapy

microvascular complications can occur

> 10 years should be tested for CFRD, diagnosing and treating CFRD earlier results in better outcomes
Definition
CF related diabetes
onset and therapy
Term
weight bearing exercise

avoid tobacco, alcohol, caffeinated/carbonated beverages

calcium
vitamin D
vitamin K, magnesium, zinc, copper
Definition
treatment of CF bone disease
Term
regular visits quarterly

annual visit:
multidisciplinary approach
history and physical
laboratory measurements
sputum/throat swab culture
spirometry
oral glucose tolerance test/DEXA
education
Definition
monitoring CF
Term
Increased pulmonary vascular resistance

Fixed pulmonary vascular obstruction

Cor pulmonale and CHF

Patients with FEV1 <30%, PaO2 <50mm Hg or PCO2 >50 mm Hg have about a 50% chance of surviving 2 years

Lung transplant is very risky and the supply of good lungs for transplant is limited
Definition
progression of CF lung disease
Term
gene therapy:
correction of the genetic defect by administering of right DNA sequence into airway epithelial cells
research involving appropriate vector for delivery underway - viral vectors, non-viral vectors

protein therapy:
correction of function of defected CFTR
research involving appropriate CFTR modulation underway
Definition
is there a cure for CF?
Term
absorption:
increased gastric acid secretions
lower duodenal pH
insufficient pancreatic enzymes, loss of bile acid

distribution:
increased extracellular fluid/decreased fat mass
altered protein binding
increased Vd for water soluble drugs
decreased albumin, decreased binding affinity for protein bound drugs

metabolism (hepatic)
cirrhosis, cholestasis
increased fecal loss of bile acids
increased acetylation

elimination:
increased renal clearance for impaired tubular reabsorption
enhanced tubular secretion
Definition
pharmacokinetic considerations for patients with CF
Term
albuterol -> hypertonic saline -> pulmonzyme -> TOBI/Cayston

DO NOT MIX solutions
Definition
sequence of nebulizer solutions
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