Pharmacotherapy Of Cystic Fibrosis Flashcards
What is the aim of the therapy of CF?
Improve CFTR function and expression at the cell surface, help keep a balance of salt and water in certain organs like the lungs
What are the examples of potentiators?
Ivacaftor and Elexacaftor
Which classes do the potentiators target?
Gating mutation (Class 3)
Conduction mutations (Class 4)
Insufficient protein mutations (Class 5)
What is gating mutation (class 3)?
CFTR forms a channel that does not open properly
What is a conduction mutation (class 4) ?
Malformed channel is produced, which limits the rate of chloride and bicarbonate movement
What is an insufficient protein mutation (class 5)?
The amount of CFTR protein present at cell surface is not sufficient. This can be caused due to too little production or increased rate of channel removal
Mechanism of action of potentiators?
Help open the CFTR channel and increase the flux of chloride and bicarbonate across the cell surface
What are the examples of correctors?
Elexacaftor, Lumacaftor, Tezacaftor
Which classes do correctors target?
Processing mutation (Class 2)
What is a processing mutation?
CFTR protein is created but misfiles, preventing it from reaching the cell surface
What is the mechanism of action of correctors?
Help normalise the folding of defective CFTR protein and its movement to the cell surface
Which classes do amplifiers target?
Process, gating, condition and insufficient protein mutation (Classes 2 to 5) –> A channel is created with limited activity
What is the mechanism of action of amplifiers?
Increase production of the CFTR protein
Which classes do stabilisers target?
Process, gating, condition and insufficient protein mutation (Classes 2 to 5) –> A channel is created with limited activity
What is the mechanism of action of stabilisers?
Limit removal and degradation of CFTR protein from the cell surface
Which kinds of modulators are not approved for clinical use yet?
Amplifiers and stabilisers
What is an example of production-correctors?
Ataluren
Which classes do production-correctors target?
Class 1 CFTR mutation (protein synthesis defect)
Mechanism of action of production-correctors?
Promote the read-through of premature termination codons in mRNA, generating more production of CFTR protein.
What happened to Ataluren?
Production was terminated due to lack of efficacy in phase 3 trials
What is the recommended treatment for CF patients who are ≥2 years old?
Elexacaftor-Tezacaftor-Ivacaftor (ETI)
(corrector/potentiator - corrector - potentiator)
When is ivacaftor mono therapy suggested?
Patients as young as one month with responsive mutations
When is lumacaftor - ivacaftor treatment given?
For patients 1 to 2 years of age
What is the suggested sequence of treatment for a patient who is eligible for multiple kinds of therapies due to their mutations?
ETI > dual therapy > mono therapy
When is tezacaftor-ivacaftor treatment recommended?
Patients ≥ 6 years of age when ETI is not available or with approved mutations
Which kind of mutation was Ivacaftor designed to treat?
G551D mutation (gating mutation) in at least one of GFTR genes
Mechanism of action of Ivacaftor?
Binds to defective CFTR protein and increases the probability of the open conformation of the mutant chloride channel.
Increased chloride and bicarbonate ion transport
What are the side effects of Ivacaftor?
Headache, nasopharyngeal pain & URTI
In dual combination therapy, which two kinds of drugs are mixed?
The potentiator is mixed with a corrector to improve CFTR function
What are the side effects of dual therapy?
Overall well tolerated –> good safety profile.
HOWEVER, chest discomfort and dyspnea might appear due to lumacaftor
Pharmacokinetics of all CFTR modulator treatments?
Oral
Dosing depends on age and weight
Should be taking with fat-containing foods
Hepatic impairment –> dose reduction
Drugs that inhibit CYP3A4 –> dose reduction
Which foods should be avoided with the CFTR modulators therapy?
Foods that contain grapefruit
What are the side effects of triple therapy?
Well tolerated
Abdominal pain, diarrhoea and rash
What kind of tests need to be done to the patients prior to CFTR modulator treatment is initiated?
Measurement of liver transaminases (ALT & AST) and serum bilirubin, with ongoing monitoring every three months for the first year and then annually.
When should ETI be interrupted?
If ALT or AST are more than x5 normal
OR
ALT or AST are x3 normal AND bilirubin x2 the upper limit
Why does a reduction in CFTR function/expression cause multi-system disease?
CFTR proteins are expressed in the epithelial cells of many different organs
IN the CF lung what does a shift in electrolytes cause?
Increase in water absorption –> thickened/viscous mucus
Accumulation of mucous –> recurrent infections and inflammation
What are the most common causes of morbidity and mortality for CF patients?
Decline in pulmonary function and pulmonary failure
What are the therapeutic objectives of CF therapy?
Correction of the Main Defect
Reduction in Mucus Burden
Control of Infection
Control of Inflammation
Who is eligible for targeted therapy?
Patients < 12
Patients ≥ 12 who are on ETI and have moderate to severe lung disease
Patients ≥ 12 who are not on ETI
What are the airway clearance therapies?
Coughing and huffing / chest physical therapy –> techniques that loosen sticky mucus so it can be cleared
Which other therapies can be use for reduction of mucus burden?
Bronchodilators
Mucolytics
Inhaled / oral antibiotics
Which kind of bronchodilator should be used in the treatment of CF?
β2 agonists
When should the bronchodilators be given?
Before starting airway clearance treatment
What is the function of the bronchodilators?
Help to widen the airways by relaxing the muscles lining the airway wall
Examples of bronchodilators (β2 agonists)?
Salbutamol, Albuterol
When are mucolytics taken? How?
Can be taken during airway clearance therapy; nebulised
What is the function of mucolytics?
Help to thin and then move the mucus out of the airways so it can be coughed out.
What are the different kinds of mucolytics?
Inhaled Dornase alfa (Dnase)
Inhaled hypertonic Saline
Inhaled mannitol
What is Inhaled Dornase alfa?
It is an endonuclease that cleaves and depolymerizes extracellular long-chain DNA in the sputum –> reducing mucous viscosity and preventing airway infection
What is the pharmacokinetics of Inhaled Dornase alfa?
Once daily via inhalation
What is the mechanism of action of inhaled hypertonic saline?
The high osmolarity of the solution induces an osmotic flow of water into the mucus layer –> rehydration of airway surface liquid and improving mucociliary clearance
How would you improve efficacy of mucolytics?
Combination of hypertonic saline with Dnase
Pharmacokinetics of Inhaled hypertonic saline?
Given twice daily
What is inhaled mannitol?
A sugar alcohol that is used as an osmotic agent.
What happens when inhaled mannitol is inhaled?
It creates an osmotic gradient that facilitates water flow into lumen of airway –> increasing the volume of airway surface liquid and improving clearance of mucus
When is inhaled mannitol used?
Second-line option to replace Dnase/hypertonic saline combination
What is a contraindication when it comes to inhaled mucolytics?
Inhaled medications should not be mixed together in the same nebulizer
Why are inhaled antibiotics given to CF patients?
They develop chronic bacterial infection within the airway
When should the antibiotics be taken?
After the airway clearance therapies as the lungs are clear of mucus allowing the medication to reach deeply into smaller areas to attack bacteria
Which medication should be given if P. aerugonisa is detected?
Inhaled tobramycin should be given for 28 days
What are the other alternatives to inhaled tobramycin?
Inhaled aztreonam
Inhaled colistin
When is tobramycin prescribed and why?
Prescribed for treatment of both superficial and deep infections because of the broad spectrum
What is the mechanism of action of tobramycin?
Inhibits protein synthesis: Aminoglycosides bind to 30s subunits and interfere with three different ways
- Block formation of the initiation complex
- Cause misreading of the code on mRNA template
- Inhibit translocation
What are the pharmacokinetics of tobramycin\?
Half-life of about 2 hours
Metabolised in the liver (minimally)
Excreted via the kidneys
Low therapeutic index
What are the side effects of tobramycin?
GI disturbances, headache, skin rash.
Can induce ototoxicity, neuropathy and nephrotoxicity
What is an example of a β - lactic antibiotic?
Aztreonam
When is aztreonam used?
To treat infections caused by gram-negative bacteria
What is the mechanism of action of aztreonam?
Inhibits synthesis of the bacterial wall by blocking peptidoglycan crosslinking –> bacterial death
What are the side effects of aztreonam?
Wheezing, coughing and vomiting
What is aztreonam often used as alternative to and why?
Alternative to aminoglycosides because it is not ototoxic or nephrotoxic
What is an example of a polymyxin antibiotic?
Colistin
How does colistin work?
It binds to lipopolysaccharides and phospholipids in the outer cell membrane of Gram-negative bacteria.
Mechanism of action of colistn?
Displaces divalent cations from the phosphate groups of membrane lipids, which leads to disruption of the outer cell membrane –> leakage of intracellular contents –> bacterial death
Pharmacokinetics of colistin?
There is no GI absorption
It can be given inhaled or parentrally
What are the side effects of colistin?
Nephrotoxicity and neurotoxicity
What is an example of oral antibiotic?
Azithromycin
What is azithromycin?
It is a macrolide antibitic that has been shown to benefit those with chronic P. aeruginosa infection
Why is azithromycin given to patients even though they are usually resistant?
The benefits are due to its anti-inflammatory effect
What is a dominant pathologic feature of the airways of CF patients?
Neutrophilic inflammation
What is an example of NSAIDs that is used in CF patients?
Ibuprofen
Who is Ibuprofen usually given to ?
High-dose oral ibuprofen is usually given to children and young adolescents with good lung function
What is the main role of Ibuprofen?
Agent to reduce airway inflammation
When are ICS given in patients with CF?
When they have symptoms of asthma
When is lung transplantation an option?
When all other medical treatments have failed
What is a major Gi contributor to malnutrition of CF patients?
Pancreatic dysfunction
What are the pharmacologic options to be given to Cf patients struggling with malnutrition?
Growth hormone
Appetite stimulants
Insulin
