Pharmacology of Cystic Fibrosis

cystic fibrosis

life-shortening recessively inherited disorder that alters the function of the cystic fibrosis transmembrane conductance regulator (CFTR)

chloride

The CFTR gene codes for an ion channel that transports __________ across the apical membrane of epithelial cells. It modulates activity of other ion channels, regulating fluid and electrolyte balance in mucosal membranes. It also secretes bicarbonate (crucial for pH regulation, host defense, and protection against noxious stimuli).

missense

What type of mutations in the CFTR gene causes CF?

1700

How many mutations are related to CF?

Delta F508 mutation

most common gene mutation causing CF (60%)

Delta F508

-abnormal protein folding

-abnormal trafficking of the CFTR protein

-degraded by the ubiquitin-proteasome pathway

-no functional protein on apical membrane

correct protein folding

What are the required approaches for Delta F508?

no protein

wt-CFTR type 1

no traffic

wt-CFTR type 2

no function

wt-CFTR type 3

less function

wt-CFTR type 4

less protein

wt-CFTR type 5

less stable

wt-CFTR type 6

rescue protein synthesis

What is the required approach for wt-CFTR 1 (No protein)?

correct protein folding

What is the required approach for wt-CFTR 2 (No traffic)?

restore channel conductance.

What is the required approach for wt-CFTR 3 (No function)?

restore channel conductance

What is the required approach for wt-CFTR 4 (less function)?

maturation/correct misplicing

What is the required approach for wt-CFTR 5 (less protein)?

promote protein stability

What is the required approach for wt-CFTR 6 (less stable)?

thickened secretions

What does defective Cl transport lead to?

duct/lumen obstruction

What do thickened secretions lead to?

epithelial cell injury

What does duct/lumen obstruction lead to?

organ injury/failure

What does epithelial cell injury lead to?

pancreatic duct

-duct obstruction

-enzyme deficiency, maldigestion

biliary duct

-duct obstruction

-cirrhosis, portal HTN, esophageal varices

intestines

-viscous secretions

-distal intestinal obstructive syndrome (DIOS)

pulmonary

-viscous secretions

-obstruction, infection

sweat glands

-fail to absorb Na (salty taste of skin)

-hyponatremia

reproductive

-obstruction epididymis, vas deferens, seminal vesicles

-aspermia

-obstructive cervix

-decreased fertility

bone, joint

-unknown

-arthritis, osetopenia

lung injuries

are the most common clinical characteristic due to mucociliary clearance impairment in the airways

lung injuries

major cause of morbidity and mortality

epithelial damage, tissue remodeling and end stage lung disease

Vicious cycle of obstruction of the airways, inflammation and infection that leads to:

excessive sodium transport

A faulty conductance of other ions like the epithelial Na channel does within the cascade of respiratory disorder in CF?

depletes water content

The imbalance of ion regulation ____________ and/or decreases pH in the airway surface liquid.

amount and viscosity of mucus

Dehydration and/or acidification of epithelial lining, as well as increased mucin polymer cross-links, raise the ________________, making the mucus tenacious and difficult to remove by ciliary beating.

obstruction; inflammation

Accumulation of mucus leads to ___________ of the airways, ____________ and bronchiectasis.

pathogens

colonize the airways and increase the recruitment of inflammatory cells. Furthermore, oxygen depletion below the sputum-air interface favors biofilm formation

tissue remodeling, reduction of gas exchange area and impairment of lung function

What does the destruction of airway and lung parenchyma epithelial cells cause?

respiratory failure

as CF progresses, the pt succumbs to death due to:

-treat GI/hepatic disease

-treat respiratory disease

TX of CF:

GI and Hepatic Care

-Pancreatic enzyme replacement therapy

-vitamin, mineral, and electrolyte replacement therapy

-choleretic therapy

pancreatic enzyme replacement therapy

-Digest carbohydrates, proteins and fats (amylase, lipase, protease)

-Gain and maintain a healthy weight

-Absorb essential nutrients such as vitamins and minerals

vitamin, mineral and electrolyte replacement therapy

fat soluble vitamins are required for pts who are pancreatic insufficient

choleretic therapy

given prophylactically to increase bile secretion from liver to prevent end stage liver failure

-anti obstruction

-anti inflammation

-anti infective therapy

What is traditional tx of CF (pulmonary disease) focused on?

anti-obstruction

-eliminate retained mucus or prevent its accumulation

-Non-pharmacological (percussion and postural drainage, e.g. percussion vest)

-Bronchodilators

-Mucolytics

anti inflammatory

ibuprogen (long term dangers of corticosteroids or other NSAIDs)

anti infective therapy

antibiotics

CFTR modulator therapy

What is the newest tx in CF (pulmonary disease)?

oxygen

as the disease progresses pts require continuous therapy with ___________

lung transplantation (high risk of rejection)

What is the only option for end stage lung disease with CF?

beta 2 agonist

-Albuterol

-Levalbuterol

beta 2 agonist MOA

-open up airways

-prevents bronchospasm

Albuterol

2 puffs prior to therapy 2-4 times a day

HyperSal (hypertonic saline)

4ml delivered via neb 2-4 times daily

Pulmozyme (dornase alfa)

2.5 mg delivered via a neb 1-2 times a day

Nebulized mucolytics

-hypertonic saline

-recombinant dornase alpha

hypertonic saline

(7% sterile solution): hydrates the airway's mucus secretions and facilitates mucociliary function

recombinant dornase alpha (Pulmozyme)

(inhaled): Enzyme (DNase) that cleaves extracellular DNA released by neutrophils (NETs) → decreased viscosity of mucus

neutrophil extracellular traps

are web-like structures that neutrophils use to catch and kill bacteria. NETs are shown as DNA (blue) forming a complex with the neutrophil elastase (red)

antibiotic therapy

-recurrent & persistent infections• Acute pulmonary exacerbations are primarily caused by: Staphylococcus aureus, H. influenzae, Pseudomonas aeruginosa

P. aeruginosa

What is the primary infection in CF?

P aeruginosa

produces biofilm that protects it from local host defense and most antibiotics

azithromycin

doesnt have pseudomonas activity but can break the biofilm

CFTR potentiator

-Ivacaftor

-Deutivacaftor

CFTR corrector

-Lumacaftor

-Tezacaftor

-Elexacaftor

-Vanzacaftor

corrector therapy

restores normal trafficking of CFTR to the membrane by improving the conformational stability of the protein (pharmacological chaperones or proteostasis regulators) →increased number of CFTR proteins that make it to the cell surface

potentiator therapy

increases channel opening probability and duration → increases chloride transport through the channel

combos CFTR modulator therapy

CFTR potentiator + CFTR corrector = improves trafficking to the membrane, and its function once it gets there

Kalydeco

Ivacaftor

Orkambi

lumacaftor/ivacaftor

potentiator

Ivacaftor (Kalydeco®)

corrector (1st gen; more AE, less effective) + potentiator

Lumacaftor/Ivacaftor (Orkambi®)

Symdeko

Tezacaftor/Ivacaftor

corrector (2nd gen; less AE, better PK) + potentiator

Tezacaftor/Ivacaftor (Symdeko ®)

Trikafta

Tezacaftor/Elexacaftor/Ivacaftor

2 correctors (bind to different sites in the CFTR → additive effect) + Potentiator

Tezacaftor/Elexacaftor/Ivacaftor (Trikafta®)

Alyftrek

Vanzacaftor/Tezacaftor/Deutivacaftor

Vanzacaftor/Tezacaftor/Deutivacaftor (Alyftrek®)

2 correctors (bind to different sites in the CFTR → additive effect) +New Potentiator (longer half-life → 1/day)

pts mutations to improve lung function

What is CFTR modulator therapy indicated based on?

2 correctors + potentiator.

wt-CFTR 2 (no traffic)

2 correctors + potentiation

wt-CFTR 3 (no function)

Potentiator

wt-CFTR 4 (less function)

2 correctors + potentiator.

wt-CFTR 5 (less protein)

2 correctors + potentiator.

wt-CFTR 6 (less stable)

thick secretion that obstruct systems, block exocrine gland ducts, and constantly produce infections with inflammation

What does the pathology of CF result in?

obstruction

-albuterol

-dornase alpha

-hypertonic saline

inflammation

corticosteroids, ibuprofen

infection

-IV antibiotic for exacerbations and prophylactic antibiotics to reduce progression of the disease

-antibiotic therapy aimed at P aeruginosa the most common pathogen in the CF lung

1) Albuterol

2) Hypertonic Saline

3) Dornase Alpha

What is the order in which you use the drugs for obstruction in CF?