Respiratory Pharmacology: Treatment of Cystic Fibrosis

Transcription

1 Respiratory Pharmacology: Treatment of Cystic Fibrosis Dr. Tillie-Louise Hackett Department of Anesthesiology, Pharmacology and Therapeutics University of British Columbia Associate Head, Centre of Heart Lung Innovation, St Paul s Hospital Tillie.hackett@hli.ubc.ca

2 Aims of Lecture Define the disease pathology of Cystic Fibrosis, specifically the role of CFTR in normal lung function and disease. Explain the different classes of CFTR mutations. Describe the maintenance therapies used in CF compared to treatment for specific mutations.

3 Cystic Fibrosis: Epidemiology Hereditary, chronic disorder affecting the exocrine glands that causes severe damage to the lungs and digestive system Name refers to scarring (fibrosis) and cyst formation in pancreas -1930s It is the most common life-threatening disease inherited in the Caucasian population Autosomal recessive (must have mutations in both alleles 4% of people of European descent are carries for one allele for CF Incidence: 1 in Asia and Africa: 1 in 90,000

4 CFTR Defect in a gene, called the cystic fibrosis transmembrane conductance regulator (CFTR) CFTR is the main chloride channel in epithelia of various tissues -ENaC - epithelial sodium channel -CFTR chloride Channel -AQP - aquaporin (water channel) Water follows the salt (NaCL) gradient by osmosis

5 CF pathophysiology Fluid / volume secretion problem In CF, the defect in CFTR causes decreased Cl- ions to apical surface Inhibits H 2 0 transcellular flow, water influx and dehydration of mucus Low fluid volume

6 CFTR is the main chloride channel in epithelia of various tissues Epithelial perform diverse functions: 1) water or volume-absorbing (airways and intestinal tract) 2) Salt-absorbing (sweat ducts, lung) 3) water or volume-secreting (pancreas, lung) all processes involve chloride ion transport; disruption of this transport in cystic fibrosis leads to multiple effects

7 Cystic Fibrosis: Clinical Features Affects epithelial in multiple organs Chronic lung infections and inflammatory destruction of the lungs Nutritional abnormalities due to gastrointestinal obstruction and lack of fluid secretion by intestinal cells Pancreatic insuffciency Thick viscous mucus Fertility Males: Can affect development of vas deferens, or blockage by thick mucus Females: Thick mucus may affect fertilization of the egg Excessive salt loss from the sweat glands leading to heat exhaustion and dehydration in hot weather and fever

8 Lung Defenses Human airway contains two distinct aqueous layers 1) Mucus layer traps inhaled bacteria and foreign particles Problem: Thick mucus inactivates mucociliary clearance 2) Airway surface liquid (ASL) provides microenvironment for beating cilia to clear mucus layer with assistance of coughing ASL is also rich in proteases, antibiotics & oxidants Defensins: small peptide molecules (12-50 aa) containing positively charged and hydrophobic residues. Kill microbes via membrane disruption Their non-specific action makes it difficult for bacteria to acquire resistance Problem: High salt inactivates defensins

9 Biofilms: Sticky mucus traps bacteria, difficult to remove by cilia of the lung epithelium

10 CF Progressive lung Disease Lungs are plagued by persistent bacterial infections Biodiversity of bacteria decreases Main culprits: Pseudomonas aeruginosa, B. cepacia, S. aureus Once Colonization occurs impossible to eradicate (prevention measures) Lung tissue eventually destroyed by onslaught of immunes cells (Neutrophils) that respond to the infections Respiratory failure due to obstructive lung disease

11 CFTR Gene 250 kb, 27 exons, located on chromosome 7 Over 2000 different mutations identified in the CFTR gene 2 membrane spanning domains (MSD): anchor protein to the plasma membrane and form the ion channel 2 nucleotide-binding domains (NBD-1, NBD-2): hydrolyze ATP and control ion channel gating (opening and closing) Positive charge of Arg = electrostatic barrier 1 Regulatory domain: controls activation of CFTR Cl- to Na+ permeability ratio = 150 (without Arg352 = 15)

12 Classes of CFTR mutations Class I: Defective protein production (premature stop condon). No or little CFTR protein is produced. Class II: Defective trafficking (DF508) results in misfolding of protein and degradation in endoplasmic reticulum. Affects 75% of CF patients. Class III: Mutation (G551D) in regulatory regions, protein reaches surface but remains closed. Affects 4-5% of CF patients. Class IV: Mutation (Arg 352) in the membrane-spanning regions, unable to move CL- ions efficiently Class V: Reduced synthesis of functional CFTR, unstable mrna Class VI: Accelerated turnover of membrane bound protein

13 Cystic Fibrosis Treatment Airway Clearance Technique Bronchodilators Mucous thinners mucolytics Pulmozyme (Dnase) removes DNA from white blood cells Airway clearance percussion, coughing & huffing Antibiotics inhaled via nebulizer (Tobramycin) Hypertonic saline Salt-water inhaled twice per day. Helps draw water into the mucus. Side effects Airway irritation cough, chest tightness

14 Cystic Fibrosis Treatment: Pancreas One of the main functions of the pancreas is the secretion of digestive enzymes Low fluid secretion leads to thick mucus which prevents enzymes from reaching the intestines: Enzymes are retained in the pancreas and eventually destroy all pancreatic tissue Lack of digestive enzymes lead to poor nutrient absorption, weight loss etc Treatments Pancreatic enzyme replacement Pancrelipase replaces natural enzymes (Amylase, Lipase, proteases) so that fat and proteins can be absorbed properly Adequate nutrients to maintain BMI

15 Cystic Fibrosis: Targeted Treatment I Ivacaftor First FDA approved drug for CF G551D mutation (class IV) Mutation causes glycine to aspartic acid switch Present in cell membrane but defective in CL - transport Affects 4-5% of patients Mechanisms of action Oral bio-available CFTR potentiator Binds to the channel inducing a non-conventional mode of gating, increasing the probability that the channel remains open Treatment 150 mg dose (half life 12 hours) given twice a day to children >2 years and adults $300,000 per year

16 Cystic Fibrosis: Targeted Treatment II Lumacaftor/Ivacaftor FDA approved drug for CF July 2015 df508 mutation (class II) deletion causes loss of the amino acid phenylalanine 508 defective trafficking of CFTR to cell membrane Affects 75% of patients 47% df508 homozygous severe phenotype 40% df508 heterozygous not treated Mechanisms of action Oral bio-available CFTR corrector Promotes correct folding of CFTR in endoplasmic reticulum and trafficking to plasma membrane Treatment Lumacaftor 200 mg/ Ivacaftor 125 mg every 12 hours in adults and children >12 years $259,000 per year Side effects Shortness of breath, diarrhea, respiratory infections, rash

17 Questions