Therapeutics Pulmonary Lubsch – Flashcards

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Genetics of Cystic Fibrosis
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  • Autosomal Recessive  -- must have two copies of faulty alleles
  • Defect on chromosome 7 that codes for Cystic Fibrosis Transmembrane Conductance Regulator
  • Base pair deletion -- ΔF508

 

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Pathophysiology of Cystic Fibrosis
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  • Mediated by cAMP in epithelial cells, CFTR normally regulates Na+, Cl-, and secondarily H2O across cell membranes
  • In patients with Cystic Fibrosis, the transporter is defected or is not at the apical membrane at all
  • Na+ and Cl- is not transported into the lumen and hence H2O is reabsorbed
  • Dehydrated and viscous secretions are ineffectively cleared and cause luminal obstruction, scarring, and dysfunction
  • This defect occurs in the cells of the respiratory, hepatobiliary, gastrointestinal, and reproductive tracts, along with the pancreas and sweat glands
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Clinical Presentation of Cystic Fibrosis
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  • 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
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Cystic Fibrosis Diagnosis
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Neonatal Screening

Increased immunoreactive trypsinogen (IRT)

 

Clinical Features of CF plus:

  • Sweat chloride test -- positive > 60 mEq/L, need two positive tests to confirm CF

OR

  • Genotyping -- need two known CFTR mutations to confirm CF
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Pathophysilogy of Cystic Fibrosis: Respiratory Tract
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  • Obstruction of airway with thick mucus results in air trapping, bronchiectasis, atelactasis
  • Increased infection risk due ot thick mucus acting as an excellent growth medium for microorganisms
  • Bacterial progression leads to elevated levels of inflammatory mediators such as TNFα, IL-1 and IL-2, and Neutrophil elastase
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Common Respiratory Findings in Cystic Fibrosis
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  • Cough/sputum production
  • Wheeze/air trapping
  • Radiographic abnormalities
  • Evidence of obstruction on pulmonary function tests
  • Digital clubbing
  • Nasal polyps
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Cystic Fibrosis Disease Severity
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Mild

FEV1 > 70-89% predicted

 

Moderate

FEV1 40-69% predicted

 

Severe

FEV1 < 40% predicted

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Cystic Fibrosis Infectious Pathogens
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Initial

  • Staphylococcus aureus
  • Haemophilus influenzae
  • Streptococcus pneumoniae

Colonization

  • Pseudomonas aeruginosa
  • Burkholderia cepacia
  • Stenotrophomonas maltophilia
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Presentation of Acute Pulmonary Exacerbation in Cystic Fibrosis
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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 respiratory rate
  • Intercostal retractions
  • Decrease in pulmonary function consistent with obstructive airway
  • Fever and leukocytosis
  • Weight loss
  • New infiltrate
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Airway Clearance Therapy
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  • Exercise
  • Hydration
  • Breathing techniques
  • Conventional Chest Physiotherapy (percussion with cupped hand/vibrator, postural drainage)
  • Oscillating positive expiratory pressure devices
  • High-frequency chest wall oscillation
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Antimicrobial Therapy for Initial Infection
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  • Oral penicillins, cephalosporins
  • Ex: dicloxacillin, cephalexin
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Antimicrobial Therapy Targeted Against Pseudomonas aeruginosa
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  • Combo therapy
  • Duration: 14-21 days
  • For synergistic activity and to prevent resistance
  • Ex: ceftazidime + Aminoglycoside, Piperacillin + Aminoglycoside
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Common Antipseudomonal Agents in Cystic Fibrosis
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  • Aztreonam
  • Ceftazidime
  • Ciprofloxacin
  • Meropenem
  • Pipercillin
  • Ticarcillin/Clavulanate
  • Tobramycin

Limit use of fluoroquinolones to prevent resistance

 

Tobramycin can be used with:

  • Ticarcillin+clavulanate
  • Pipercillin+tazobactam
  • Ceftazadime
  • Cefepime
  • Meropenem
  • Imipenem/cilastatin
  • Aztreonam

 

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Common MRSA Agents in Cystic Fibrosis
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  • Vancomycin
  • Linezolid
  • Bactrim
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Benefits of Aerosolized Antimicrobial Therapy
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  • Role -- adjunct to antibiotics for treatment, home maintenance therapy
  • Improved drug delivery to site of infection
  • Reduced systemic exposure
  • However, concern of emerging resistance
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Aerosolized Antimicrobial Therapy: ADE
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  • Bronchospasm -- some require SABA prior
  • Increased cough
  • Hoarseness
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Criteria for Aerosolized Antimicrobial Therapy
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  • > 6 yr
  • + P. aeruginosa
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Aerosolized Antimicrobial Therapy: Agents
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TOBI (Tobramycin)

  • BID, alternating months
  • Increases FEV1 ~10%, decreases hospital days and use of IV antibiotics

Cayston (Aztreonam)

  • TID, alternating months, takes less than 5 min to use
  • Increases FEV1 ~ 10%, decreases symptoms
  • Only available at CF specialty pharmacies

 

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Agents for Mucolytic Therapy
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  • Pulmozyme (Dornase Alfa)
  • Mucomyst (N-acetylcysteine)
  • Recombinant Human Deoxyribonuclease I (rhDNAse)
  • Inhaled Mannitol
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Pulmozyme (Dornase Alfa): Role, Criteria, Benefits
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Role

Mucolytic therapy, reduces sputum viscosity

 

Criteria

> 6 yrs

 

Benefits

Decreased pulmonary exacerbations, decreased need for IV antibiotics, increases FEV1 by 5%

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Mucomyst (N-acetylcysteine): Role
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Role

Mucolytic therapy, thins sputum, induces expectoration

 

Routine use not recommended

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Recombinant Human Deoxyribonuclease I (rhDNAse): MOA, AE, Disadvantages
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MOA

  • Cleaves the DNA in sputum
  • Reduces sputum viscosity and/or its adherence to epithelial airways
  • Improves mucociliary sputum clearance and lung function

AE

  • Hoarseness
  • Pharyngitis

Disadvantages

  • COSTLY
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Inhaled Mannitol: MOA, Benefits
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MOA

  • Mucolytic therapy
  • An osmotic agent that increases the water content of the airway surface liquid
  • Improves clearance of mucus

Benefits

  • FEV1 increased from baseline by 7%
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Bronchodilators for Cystic Fibrosis
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Short Acting Beta2 Agonists

  • Role: mobilize sputum
  • Scheduled albuterol vs levalbulerol
  • Controversial benefits
  • Adjunctive therapy to CPT

Theophylline

  • Role: reactive airway disease
  • Concern for toxicity
  • Reserved ONLY for patients with documented improvements


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Anti-Inflammatory Agents for Cystic Fibrosis
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Glucocorticoids

  • Little role in long term therapy
  • Limited documented benefits for pulse and inhaled therapy
  • Concern for AE

High Dose Ibuprofen

  • Plasma concentration 50-100 mcg/ml
  • AE: GI, nephrotoxicity
  • Concern for intermittent low dose

Macrolides

  • Azithromycin
  • Criteria: > 6 yr, + P. aeruginosa
  • Benefits: increases FEV1 by ~6%, decreases hospital stays and IV antibiotics, weight gain

 

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Hypertonic Saline: Role, Criteria, AE, Benefits
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Role

Increases mucociliary clearance

 

Criteria

> 6 yr with mild-mod disease

 

AE

Coughing, sore throat, chest tightness

 

Benefits

Increased sputum clearance, increased lung function, decreased exacerbations, decreased need for IV antibiotics

 

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CF Pulmonary Guidelines: Class A
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  • Inhaled Tobramycin (mod-severe disease)
  • Dornase alfa (mod-severe disease)
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CF Pulmonary Guidelines: Class B
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  • Inhaled Tobramycin (Asx - mild disease)
  • Dornase alfa (Asx - mild disease)
  • Hypertonic saline
  • Ibuprofen
  • Macrolides
  • Inhaled Beta-agonists
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CF Pulmonary Guidelines: Class D
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  • Oral Corticosteroids (age 6-18)
  • Inhaled corticosteroids
  • Anti-staph antibiotics
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Pansinusitis: Causes, Treatment
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Causes

P. aeruginosa, H. influenzae, Streptococcus, and/or Anaerobes

 

Treatment of Nasal Polyps

Topical steroids/antihistamines for allergic symptoms

Some patients require surgical removal

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Gastrointestinal/Nutritional Abnormalities
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  • Exocrine pancreatic insufficiency
  • Fat-soluble vitamin deficiencies
  • Meconium ileus
  • Distal Intestinal Obstruction Syndrome
  • Rectal prolapse
  • Gastroesophageal reflux
  • Recurrent pancreatitis
  • Hepatobiliary disease
  • Failure to thrive
  • Hypoproteinemia-edema
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Nutritional Management for GI Abnormalities
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  • Increased caloric requirements
  • Oral supplements (ensure, scandishakes)
  • Enteral feeding (nocturnal feeding)
  • Pharmacological agents -- Anabolic agents, cyproheptadine -- not recommended for routine use
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Pancreatic Enzyme Replacement Therapy
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Role

Achieve adequate nutrition, abolish GI symptoms, achieve normal bowel function

 

  • Agents vary in amylase:lipase:protease ratios
  • Generic enzymes are NOT bioequivalent/interchangeable
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Dosing of Pancreatic Enzyme Replacement Therapy
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  • Based on lipase activity
  • Individualize dosing, titrate to response
  • initiate 500-1000 lipase units/kg/meal
  • Normal requirements 1500-2000 lipase units/kg/meal
  • Avoid > 2500 lipase units/kg/meal due to increased risk of fibrosing colonopathy
  • Take before each meal/snack
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Vitamin/Mineral/Electrolyte Supplementation
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Fat Soluble Vitamin Replacement

  • Vit A 5000-10000 IU daily
  • Vit D 400-800 IU daily
  • Vit E 100-400 IU daily
  • Vit K 0.3-0.5 mg daily
  • > 8 yrs: ADEK 1 vitamin BID
  • Monitor Vit A,D,E levels yearly

Beta-Carotene

 

Calcium

 

Iron

 

Zinc

 

Sodium


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Antacids, H2 Receptor Antagonists, and PPI: Place in GI therapy
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Antacids, H2 Receptor Antagonists, and PPI

 

Decreases HCO3- secretion, gastric acid causes decreased absorption of pancreatic enyzmes

 

Metoclopramide + the agents above for gastroesophageal reflux

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Ursodiol: Place in Hepatobiliary Disease
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Improves bile flow, displaces toxic bile acids that accumulates in liver disease

 

 

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Propranolol: Place in Hepatobiliary Disease
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  • Treatment of Portal Hypertension
  • Prophylaxis for variceal bleeding

 

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Cystic Fibrosis Related Diabetes: Causes, Age of onset, Treatment, Monitoring
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Causes

Insulin deficiency

 

Age of Onset

18-21 yrs

 

Individualized Insulin Regimen

  • Split dose NPH/regular insulin
  • Lispro before meals/Lantus HS
  • Insulin pump therapy

Monitoring

  • > 10 yr should be tested every year for CFRD
  • Diagnosing and treating CFRD earlier results in better outcomes


 

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Cystic Fibrosis Bone Disease: Non-Pharm Treatment, Pharm Treatment
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Non-Pharmacological Treatment

  • Weight bearing exercise
  • Avoid tobacco, alcohol, caffeinated/carbonated beverages

Calcium

9 yrs: 1300-1500 mg daily

 

Vitamin D

  • 0-1 yr: 400 IU daily
  • > 1 yr: 800 IU daily
  • Monitor 25(OH)D levels yearly (nl 30-60 ng/ml)

Vitamin K

 

Magnesium

 

Zinc

 

Copper

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Monitoring CF
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Regular visits usually quarterly

 

Annual Visits

  • Multidisciplinary approach
  • History and physical
  • Lab measurements
  • Sputum/throat swab culture
  • Spirometry
  • Oral glucose tolerance test (> 10 yrs)
  • DEXA (> 18 yrs or > 8 yrs with RF)
  • Education

 

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Progression of CF Lung Disease
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  • Increased pulmonary vascular resistance
  • Fixed pulmonary vascular obstruction
  • Cor pulmonale and CHF
  • Patients with FEV1 < 30%, PaO2 < 50 mmHg, or PCO2 > 50 mmHg have about a 50% chance of surviving 2 yrs
  • Lung transplant is very risky and the supply of good lungs for transplant is limited
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