Therapeutics Pulmonary Lubsch

Flashcard maker : Henry Lowe
Genetics of Cystic Fibrosis

  • 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


Pathophysiology of Cystic Fibrosis

  • 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

Clinical Presentation of Cystic Fibrosis

  • 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

Cystic Fibrosis Diagnosis

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


  • Genotyping — need two known CFTR mutations to confirm CF

Pathophysilogy of Cystic Fibrosis: Respiratory Tract

  • 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

Common Respiratory Findings in Cystic Fibrosis

  • Cough/sputum production
  • Wheeze/air trapping
  • Radiographic abnormalities
  • Evidence of obstruction on pulmonary function tests
  • Digital clubbing
  • Nasal polyps

Cystic Fibrosis Disease Severity


FEV1 > 70-89% predicted



FEV1 40-69% predicted



FEV1 < 40% predicted

Cystic Fibrosis Infectious Pathogens


  • Staphylococcus aureus
  • Haemophilus influenzae
  • Streptococcus pneumoniae


  • Pseudomonas aeruginosa
  • Burkholderia cepacia
  • Stenotrophomonas maltophilia

Presentation of Acute Pulmonary Exacerbation in Cystic Fibrosis


  • 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


  • Increased respiratory rate
  • Intercostal retractions
  • Decrease in pulmonary function consistent with obstructive airway
  • Fever and leukocytosis
  • Weight loss
  • New infiltrate

Airway Clearance Therapy

  • Exercise
  • Hydration
  • Breathing techniques
  • Conventional Chest Physiotherapy (percussion with cupped hand/vibrator, postural drainage)
  • Oscillating positive expiratory pressure devices
  • High-frequency chest wall oscillation

Antimicrobial Therapy for Initial Infection

  • Oral penicillins, cephalosporins
  • Ex: dicloxacillin, cephalexin

Antimicrobial Therapy Targeted Against Pseudomonas aeruginosa

  • Combo therapy
  • Duration: 14-21 days
  • For synergistic activity and to prevent resistance
  • Ex: ceftazidime + Aminoglycoside, Piperacillin + Aminoglycoside

Common Antipseudomonal Agents in Cystic Fibrosis

  • 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


Common MRSA Agents in Cystic Fibrosis

  • Vancomycin
  • Linezolid
  • Bactrim

Benefits of Aerosolized Antimicrobial Therapy

  • Role — adjunct to antibiotics for treatment, home maintenance therapy
  • Improved drug delivery to site of infection
  • Reduced systemic exposure
  • However, concern of emerging resistance

Aerosolized Antimicrobial Therapy: ADE

  • Bronchospasm — some require SABA prior
  • Increased cough
  • Hoarseness

Criteria for Aerosolized Antimicrobial Therapy

  • > 6 yr
  • + P. aeruginosa

Aerosolized Antimicrobial Therapy: Agents

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


Agents for Mucolytic Therapy

  • Pulmozyme (Dornase Alfa)
  • Mucomyst (N-acetylcysteine)
  • Recombinant Human Deoxyribonuclease I (rhDNAse)
  • Inhaled Mannitol

Pulmozyme (Dornase Alfa): Role, Criteria, Benefits


Mucolytic therapy, reduces sputum viscosity



> 6 yrs



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

Mucomyst (N-acetylcysteine): Role


Mucolytic therapy, thins sputum, induces expectoration


Routine use not recommended

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


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


  • Hoarseness
  • Pharyngitis



Inhaled Mannitol: MOA, Benefits


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


  • FEV1 increased from baseline by 7%

Bronchodilators for Cystic Fibrosis

Short Acting Beta2 Agonists

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


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

Anti-Inflammatory Agents for Cystic Fibrosis


  • 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


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


Hypertonic Saline: Role, Criteria, AE, Benefits


Increases mucociliary clearance



> 6 yr with mild-mod disease



Coughing, sore throat, chest tightness



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


CF Pulmonary Guidelines: Class A

  • Inhaled Tobramycin (mod-severe disease)
  • Dornase alfa (mod-severe disease)

CF Pulmonary Guidelines: Class B

  • Inhaled Tobramycin (Asx – mild disease)
  • Dornase alfa (Asx – mild disease)
  • Hypertonic saline
  • Ibuprofen
  • Macrolides
  • Inhaled Beta-agonists

CF Pulmonary Guidelines: Class D

  • Oral Corticosteroids (age 6-18)
  • Inhaled corticosteroids
  • Anti-staph antibiotics

Pansinusitis: Causes, Treatment


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


Treatment of Nasal Polyps

Topical steroids/antihistamines for allergic symptoms

Some patients require surgical removal

Gastrointestinal/Nutritional Abnormalities

  • 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

Nutritional Management for GI Abnormalities

  • Increased caloric requirements
  • Oral supplements (ensure, scandishakes)
  • Enteral feeding (nocturnal feeding)
  • Pharmacological agents — Anabolic agents, cyproheptadine — not recommended for routine use

Pancreatic Enzyme Replacement Therapy


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


  • Agents vary in amylase:lipase:protease ratios
  • Generic enzymes are NOT bioequivalent/interchangeable

Dosing of Pancreatic Enzyme Replacement Therapy

  • 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

Vitamin/Mineral/Electrolyte Supplementation

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










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

Antacids, H2 Receptor Antagonists, and PPI


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


Metoclopramide + the agents above for gastroesophageal reflux

Ursodiol: Place in Hepatobiliary Disease

Improves bile flow, displaces toxic bile acids that accumulates in liver disease



Propranolol: Place in Hepatobiliary Disease

  • Treatment of Portal Hypertension
  • Prophylaxis for variceal bleeding


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


Insulin deficiency


Age of Onset

18-21 yrs


Individualized Insulin Regimen

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


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


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

Non-Pharmacological Treatment

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


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







Monitoring CF

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


Progression of CF Lung Disease

  • 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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