week 21p1 Flashcards
How can Drugs of all kinds influence the immune system
- Some target B-cell lymphomas (Rituximab), whereas some have a broad effect causing immunosuppression or anti-inflammatory effects.
- Thalidomide (inhibit the production of interleukin 6)
- leflunomide (antirheumatic drug)
- Rapamycin (inhibits T-lymphocyte activation and proliferation)
What is anti-inflammatories drugs
- NSAIDS
* Steroids
What is Inflammation
- Inflammation is a response to infection
- C-reactive protein used as a general biomarker for inflammation and infection
- Anti-inflammatories increase risk of infection
What is the structure of NSAID
- mostly weak organic acids
- 90% of the NSAIDS are highly bound to plasma proteins.
- CYP2C9 is the most important oxidase primarily responsible for metabolism of a wide range of NSAIDs including celecoxib,
How can NSAID be beneficials
• Occurs when there is a PG deletion and reduced platelet regression
• Causes Antiart tic , antipyretic effects
PG - prostaglandin
How can NSAID cause side effect
• Occurs by mitochondria toxicity and PG deffinvy
Causes renal injury, cardiovascular issue and respiratory tract issues
How can NSAID cause action in Cyclooxygenase inhibitor
• general mode of action of NSAIDs involves the inhibition of cyclooxygenase(blocks cox enzyme)
• involved in the biosynthesis of prostaglandin (PG) which is strongly implicated in inflammation
• Interference with normal arachidonic acid metabolism.
• Reduced prostaglandin (PG) synthesis.
• Downstream PGs affected
Bindu, S., Mazumder, S., & Bandyopadhyay, U. (2020). Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective. Biochemical pharmacology, 180, 114147. https://doi.org/10.1016/j.bcp.2020.114147
NSAID and Immunity
• PGE2 influences adaptive immunity
Cross talk between PGE2 and TLR
How can NSAIDS cause immunity
• PGE2 required in response to bacterial infection
• In tuberculosis PGE2 activated macrophages through TLR2/p38 MAPK and nuclear receptor PPARγ
• PGE2R KO in mice are more susceptible to infection.
Stage of infection important
How does ‘PGE2-mediated suppression of type-1 immunity function
y PGE2 shifts the pattern of immune reactivity toward less
• aggressive form of immunity mediated by Th2 and Th17 cell as well as B cells, and enhancement of the Treg- and MDSC-mediated suppressive events.’
Kalinski P. (2012). Regulation of immune responses by prostaglandin E2.
What are the Withdrawn NSAIDs
- Name: Rofecoxib (Vioxx)
- Mechanism: selective cyclooxygenase-2 (Cox-2) inhibitor • Withdrawn: 2004
- Reason: Association with CVD in long term use
Examples of Steroids glucocorticoids
- Dexamethasone • Prednisolone
* Beclomethasone
What is short term, and long term use of Dexamethasone
• St: prolong viremia, bacterial super infection, autoimmune and cardiovascular events
Lt: cataracts, hypertension, physiological mood swings, menstrual disorder
What is the steroid mechanism?
- Intracellular glucocorticoid receptor binding, translocation to the nucleus and inhibition of gene expression.
- Decreases WBC proliferation (neutrophils)
- Inhibition of cytokines (IL-1, IL-12, IL-18, TNF-a, IF-y, GMCSF)
How can Steroids work in COVID-19 Treatment
• Cytokine storm is a positive feedback loop
• that leads to ARDs and organ damage from infiltrative neutrophils.
• In ARDS, alveolar-capillary membranes are injured due to inflammation, leading to more lung permeability and exudation of high protein edematous fluid into air sacs
Give steroids late, not early for better prognosis.
