Cystic fibrosis and cough Flashcards
What is cystic fibrosis and aims of treatment
An inherited disorder of ion transport in epithelial cells. leads to respiratory, hepajobiliary, GI, reproductive tracts and pancreas effects.
Defects in the CFTR chloride transporter - reduces Na+ and H2O transport. Leads to thicker mucous secretions that obstruct and destroy exocrine glandular ducts - leads to recurrent infections. it is marked by pancreatic exocrine insufficiency - reduced or absent secretion of pancreatin.
Patients with longer life span develop other complications such as diabetes, liver disease, and osteoporosis.
Aims of treatment in the airways are to clear viscous mucous, treat infection, and improve function
CFTR modulators
Ivacaftor is a CFTR potentiator. binds to CFTR and keeps channel open longer enabling more chloride transport.
Tezacaftor improves the folding of CFTR (a CFTR Corrector). It increases the amount of glycosylated CFTR present at the membrane. It binds to the transmembrane domain 1, which sees mutations that lead to reduced amounts of glycosylated CFTR. MoA not fully clear, but probably stabilises the folded protein.
Lumacaftor acts as a chaperone during folding. increases the number of CFTR that are trafficked to membrane. also binds to TM domain 1 - different region than tezacaftor. It is thought to stabilise the TMD1 during folding to prevent the defective folding that leads to degradation of CFTR in cystic fibrosis.
When multiple of these drugs are combined (e.g., lumacaftor and ivacaftor), there is more efficacy of treatment. leads to more protein at the cell surface.
Elexacaftor isa drug that is probably a CFTR corrector and a CFTR potentiator.
What is cough and what drives it
a protective mechanism triggered by irritants and mediated by sensory nerves. caused by contraction of abdominals, diaphragm, and intercostal muscles.
Sensory nerves may be unregulated by inflammation and may have potential roles in asthma induced cough, exercise-induced asthma, and cold-induced asthma.
Capsaicin induces cough through stimulation of TRPV1 on sensory nerves.
Studies found asthmatics and COPD patients were more sensitive to capsaicin induced-cough at the same dose.
Exercise can cause water loss from the airways, which is thought to stimulate the release of mediators that activate sensory nerves
TRPM8 receptors detect change in temperature - may be involved in cold-induced asthma. activate mast cells and production of mucous.
Antitussive agents
Codeine and dextromethorphan.
Codeine acts on the mu-opioid receptor in the cough centre. only marginally better than placebo.
Levodropropizine inhibits the release of sensory neuropeptides in vitro
Targeting of sensory nerves for the treatment of cough
Gefapixant is a P2X3 antagonist. an ion channel on sensory nerves that is stimulated by ATP.
QX-314 is a charged Na+ channel blocker. Enters the cell through TRP channels and then blocks Na+ channels from the inside of pore. functions like an anaesthetic. non-selective so affects all sensory nerves. was found to reduce allergic airway inflammation, and may have a potential role in reducing hyperresponsiveness in asthma.
BW-031 is more potent then QX-314 - same mechanism. Effective in inhibiting sensory nerves even without prior exogenous TRP channel activation (needed so it can enter cytoplasm), as the TRP channels are already activated in inflammation. this means that it would be able to selectively target nerves that are being affected by inflammation
