Anti-inflammatories Flashcards
What does COX do?
Acts on Arachidonic acid and creates an intermediate which is further acted on by different prostaglandins
What does prostaglandin B2 do?
Platelet aggregation
How does blood temperature increase?
IL-1 which induces COX enzyme in hypothalamus to produce prostaglandin which raised blood temperature
What does TxA2 do?
Endothelium vasoconstriction
What does PGE2 do?
Inflammation, bronchoconstriction, vasodilation
What are the 2 sites on COX?
Cycloxygenate site and then peroxidase
Where is COX docked?
The ER
Where do drugs bind to COX?
To the active site
Where does aspirin bind to COX?
Serine residue
What is aspirins duration?
10-20 minutes to be absorbed, 4 hours to go
What do amino acid to NSAIDs interact with on COX1 and COX2?
COX1-iosleucine, COX2-Valine
What does Dicholenic show some selectivity towards?
COX2- for musculoskeletal pain
What does ibuprofen show some selectivity towards?
COX1
What are side effects of NSAIDs?
Renal function, gut problems, bronchospasm, liver damage, skin rashes
Why do NSAIDs cause kidney function problems?
Prostaglandins normally maintain renal blood flow
Why do NSAIDs cause liver damage?
Toxic intermediates
What are the advantages and disadvantages for NSAIDs selective for COX1?
Advantages- reduce strokes due to involvement in platelet aggregation
Disadvantages- bad for gut
What are the advantages and disadvantages for NSAIDs selective for COX2?
Advantages- anti inflammatory and analgesics
Disadvantages- kidney - salt retention so raised bp
What are novel therapeutic uses for NSAIDs?
Parkinsons, HIV, Alzheimers
What is the occurrence of Rheumatoid arthritis?
Half a million in UK, 3x more common in females than males
What is the cause of arthritis?
Tk1 cells autoimmune disease
What is the pathway leading to joint damage in arthritis?
TCD4-TH0-activated Th1 - osteoclast, fibroblast= joint damage, Th1- macrophages which activates Il-1/TNFa (cytokines) - increase osteoclast and fibroblast and also the influx of other inflammatory cells leading to joint damage
What is methotrexate?
Immunosuppressant, folic acid antagonist which slows down the conversion of TH0 to Th1 so limits cytokines
What is the key treatment for arthiritus?
Disease Modifying Anti Rheumatic Drugs DMARDs
What is Sulfasalazine?
A DMARD, also used to treat chronic inflammatory bowel disease
Give example of DMARDs.
Sulfasalzine, Pencilllaminine
What do anti-TNF agents act through?
IL-1, TNF
How does cyclosporine work?
In activation stage of T cells- rise in calcium - activation of Caloneurin phosphatase- target TF NFkappa- IL-1 and others. Cyclosporine inhibits Coloneurin
What do humanised monoclonal antibodies do?
Mimic soluble receptors of TNF - highly specific and effective, recognise TNFa/ its receptor, so neutralises action of soluble or membrane bound pro inflammatory cytokines
What are all the possible treatments for arthritis?
Methotrexate, DMARDs, Cyclosporine, antiTNF, monoclonal antibodies
What is an allergy?
Disease following an immune response to innocuous antigen, mostly IgE mediated
What are hypersensitivity reactions?
Inappropriate or exaggerated immune responses that cause inflammation
What is the response for Wheal and Flare syndrome?
Local increase in blood flow, vascular permeability
What is the response to hay fever?
Irritation of nasal mucosa, oedema of nasal mucosa
What is the response to a food allergy?
vomititing, diarrhoea, pruitis, anaphylaxis, urticarial
What happens to the skin on allergy/
Angiodema, hibes
What are activated in chronic allergy reactions?
Eosinophils
What causes hay fever (allergic Rhinitis)?
Allergen activates mast cells in nasal mucosa
What is allergic asthma caused by?
Allergen activates mast cells in lower respiratory tract
What is early phase allergic asthma?
Reversible obstruction of airway, inflammation- many mast cells in bronchi
What is late phase allergic asthma?
Activation of transcription factor such as NFkappaB leading to producing of cytokines which cause leukocyte infiltration
What is allergic asthma associated with?
Overactivity of Th2, produce IL-4, produces IgE antibodies
What environmental factors increase susceptibility to allergen?
Level of allergen, nutrition, pollutants, family size
What do inflammatory mediators do?
Smooth muscle contraction, increased vascular permeability, mucous secretion, platelet activation, stimulation of nerve endings, recruitment and activation of eosinophils
What are new therapies for treating asthma?
Humanised antibodies and soluble receptors to IgE, PGD-12 antagonists- inhibits immune cell and mast cell signalling
