Lecture 12: Emerging Therapies: Roflumilast for COPD Flashcards
What class of drug is Roflumilast?
Phosphodiesterase inhibitor
What is PDE?
Enzyme that breaks down cAMP - a messenger molecule that plays a role in regulating inflammatory responses in the body.
What is the mechanism of action of Roflumilast?
Inhibits PDE4 and increases the levels of cAMP, which in turn reduces the production of pro-inflammatory cytokines such as TNF-alpha, IL-1, and IL-6. This leads to a decrease in the inflammatory response in the lungs, which can help to reduce symptoms of COPD such as shortness of breath and coughing.
How does raising cAMP levels inhibit inflammation?
cAMP can inhibit the production of pro-inflammatory cytokines, such as interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6), by immune cells.
What does roflumilast work synergistically with?
Salbutamol
What are the effects of roflumilast?
- Decrease in inflammatory cell activity
- Inhibition of fibrosis
- Relaxation of smooth muscle
What are the effects of PDE4 inhibition on epithelial cells?
Mucus production
What are the effects of PDE4 inhibition on monocytes?
TNF alpha release
What are the effects of rofluminast in vitro?
- Decreased release of inflammatory cytokines, mediators, chemotactic factors.
- Reduced neutrophil migration
- Increased apoptosis
- Increased expression of anti-inflammatory cytokines
What are the effects of rofluminast in vivo?
- Reduced the accumulation of neutrophils in bronchoalveolar lavage fluid.
- Prevented bleomycin-induced lung infiltration of neutrophils.
What is the active form of roflumilast?
Roflumilast N-oxide
How is roflumilast converted to its active metabolite?
By cytochrome P450 (CYP) 3A4 and 1A2
How is roflumilast absorbed?
Rapidly and almost completely absorbed
What is the bioavailability of roflumilast?
80%
What is the theraputic dose of roflumilast?
500ng taken once daily
What is the plasma protien binding of rofumilast
97%
What is a side effect of roflumilast?
Weight loss, GI disturbances
How does roflumilast lead to weight loss?
PDE3B and PDE4 regulate cAMP pools that affect the activation/
phosphorylation state of AMP-activated protein kinase, thereby influencing lipolysis.
What is the main isoform assosiatied with emisis?
PDE4
Name other PDE4 inhibitors
- Cilomilast
- Oglemilast
- Tetomilast
-ONO-6126
Describe cilomilast
improved lung function and reduced exacerbation rates in COPD. Associated with gastrointestinal disturbances such as emesis and nausea
What is the function of oglemilast?
inhibited pulmonary cell infiltration, including eosinophilia and neutrophilia
What is tetomilast under the development of?
COPD and ulcerative colitis
What other drugs are used in COPD?
- Infliximab
What is the target for infliximab?
TNF alpha antagonist
