Block D Lecture 3 - Emerging Therapies for COPD Flashcards
How does raising cAMP levels in airways cells produce an anti-inflammatory effect?
- cAMP activates protein kinase A (PKA)
2a. PKA phosphorylates and inhibits NF-κB transcription factors, reducing the amount of transcription of pro-inflammatory cytokines
2b. PKA phosphorylates and activates CREB transcription factors, increasing the amount of transcription of anti-inflammatory cytokines
(Slide 4)
What is the role of phosphodiesterases (PDEs) in regulating signalling by cyclic nuceltoides?
They are responsible for breaking down cAMP and cGMP into 5-AMP and 5-GMP respectively, preventing them from activating their pathways
(Slide 6)
What is the mechanism of action of Roflumilast in treating COPD?
It inhibits PDE4, which prevents the breakdown of cAMP, increasing cAMP levels and therefore the frequency of PKA activation
PKA then reduces the production of inflammatory cytokines and immune cell activation, resulting in decreased lung inflammation, inhibition of fibrosis, and relaxation of smooth muscle
(Slide 7)
What are 4 cells where are PDE4 isoforms found?
Answers Include:
Inflammatory cells
Fibroblasts
Pulmonary arterial smooth muscle cells
Airway smooth muscle cells
Epithelial cells
Endothelial cells
(Slide 9)
Why is Roflumilast increasing cAMP levels in response to β2-adrenoceptor agonists (such as formoterol) important?
As β2-adrenoceptor agonists also increase cAMP levels through a different pathway, meaning they have good synergy and can be used in combination therapy
(Slide 11)
What are the in vitro (in glass) effects of Roflumilast?
Decreased release of inflammatory cytokines, mediators and chemotactic factors from cells and reduced neutrophil migration
Increases frequency of apoptosis in pro-inflammatory cells and increased expression of anti-inflammatory cytokines
(Slide 14)
What are the in vivo (in living organisms) effects of Roflumilast?
Reduces accumulation of neutrophils in bronchoalveolar lavage fluid in LPS treated mice.
Prevents bleomycin-induced lung infiltration of neutrophils
Improves lung function in animal COPD models
Note: all of these are animal studies
(Slide 14)
What is bleomycin?
A chemotherapy drug used to treat cancer, which inserts itself between DNA base pairs, increased free radical formation and inhibits DNA repair
Note: The above effects cause inflammation, which is why it cases the lung infiltration of neutrophils which Roflumilast prevents
(Slide 14)
What are 3 properties of the pharmacokinetics of Roflumilast?
Answers Include:
Metabolised by cytochrome P450 (CYP450) enzymes (specifically 3A4 and 1A2) into the active metabolite roflumilast N-oxide
It is rapidly and almost completely absorbed after oral administration, which max concentrations occurring within about an hour
Absolute bioavailability is 80% as an immediate-release tablet (only 20% of dose is lost)
Therapeutic dose is 500 μg, taken once a day
Plasma protein binding of RF N-oxide is approximately 97% (plasma bound drug is inactive but can mean the drug can stay active for longer)
Drug interaction studies show dose of Roflumilast doesn’t have to be adjusted when co-administrated with various drugs (erythromycin, ketoconazole, midazolam, digoxin and maalox)
(Slide 20)
Why does Roflumilast cause weight loss?
As PDE4, which it inhibits, is involved in lipolysis, via controlling activation of PKA through regulating cAMP levels.
(Slide 25)
What is lipolysis?
The metabolic process where triglycerides (fats) are broken down into glycerol and free fatty acids, which are then used for energy or stored.
Note: Affecting this can influence weight
(Slide 25)
What affect does Roflumilast (and Rolipram, a fellow PDE4 inhibitor) have on plasma glucagon-like peptide-1 (GLP-1) levels and what can this affect?
It increases GLP-1 concentration by amplifying its secretion through increasing cAMP levels.
GLP-1 enhances insulin secretion in response so this can therefore help lower blood pressure levels. GLP-1 also reduces appetite by acting on the hypothalamus so Roflumilast increasing its concentration can enhance this effect.
(Slide 25)
Other than weight loss, what is 1 other side effect which PDE4 inhibitors can cause and how and why does this vary between drugs?
Can cause gastrointestinal disturbances, such as emesis (vomiting). This is mainly associated with inhibiting the PDE4D isoform of PDE4.
Though Roflumilast has a similar specificity for PDE4D as other subtypes, its gastrointestinal adverse effects are less severe than other PDE4 inhibitors.
Cilomilast is 10x more selective for PDE4D than other subtypes. This is expressed in PDE4D-type nausea-inducing neurons, and inhibiting PDE4D in these results in a build up of cAMP which initiates the vomiting reflex, which could explain the lower tolerability compared to other PDE4 inhibitors
(Slide 26)
Other than Roflumilast, name 1 other PDE4 inhibitor and its effects / use.
Answers Include:
Cilomilast: Improves lung function and reduces exacerbation rates in patients with COPD. Associated with gastrointestinal disturbances such as emesis and nausea
Oglemilast: Inhibits pulmonary cell infiltration. Used to treat eosinophilia and neutrophilia
Tetomilast: Oral inhibitor in development for treatment in COPD and ulcerative colitis
(Slide 27)
What are eosinophilia and neutrophilia?
When the body has too many eosinophil and neutrophil white blood cells in the blood respectively
(Slide 27)
What is ulcerative colitis?
A chronic inflammatory bowel disease (IBD) that causes inflammation and ulcers in the lining of the large intestine (colon) and rectum, leading to symptoms like bloody diarrhea and abdominal pain
(Slide 27)
