Anti-Inflammatories Flashcards
How do NSAIDs work?
They decrease prostaglandin and thromboxane production
What are the three properties of NSAIDs?
Anti-Inflammatory - decrease vasodilation and in turn oedema, they’re ineffective against mediators that contribute to tissue damage associated with chronic inflammatory conditions
Analgesic - decrease production of prostaglandins in inflammed tissue which sensitises nociceptiors to inflammatory mediators
Thermostat in hypothalamus activated via IL-1 induced COX production of PDE
What is the structure of COX?
Two identical subunits, each with two catalytic sites
What are the two isoforms of COX and how do they differ?
COX1 - constitutive expression
COX2 - inducible expression
Where is COX1 present?
Platelet, stomach, kidneys, most tissue
Where is COX2 present?
Most cells, especially imflammatory cells after stimulation with cytokines, growth factors or tumour promoters
How do NSAIDs exert their action?
They block COX channels
What are some side effects of NSAIDs?
Diarrhoea, nausea, vomiting (PGs normally inhibit acid secretion and protect muscosa)
Renal failure (PGs maintain renal blood flow)
Liver damage
Bronchospasm asthma attacks
Skin rashes
What are the advantages and disadvantages of COX1 selective NSAIDs?
Advantages:
Antithrombotic
Disadvantages:
Gastrotoxicity
What are the advantages and disadvantages of COX2 selective NSAIDs?
Advantages:
Anti-inflammatory, analgesic
Disadvantages:
Increase BP, salt retention, prothrombotic
How does Aspirin prevent the action of arachnoid acid?
Aspirin binds covalently to a Ser residue in COX preventing arachnoid acid reaching the cyclooxygenase site
Aspirin vs Paracetamol
Aspirin:
Reduced risk of Alzheimer’s, reduced risk of colonic and rectal cancer, anti-platelet action, weak acid, rapid and efficient absorption in the ileum, suicide inhibitor
Paracetamol:
Analgesic-antipyretic, weak anti-inflammatory, well absorbed, metabolised in the liver, N-acetyl-p-quinoneimine is heptotoxic in unconjugated form, competitive inhibitor
Which drugs are used to treat rheumatoid joint damage?
Methotrexate and sulfasalazine
What is methotrexate?
A folic acid antagonist, has cytotoxic and immunosuppressant activity
What is sulfasalazine?
A sulfa drug used for chronic inflammatory bowel disease
What do bacteria in the colon produce that may act as a free radical scavenger?
5-aminosalycylic acid, decreased damage produced by neutrophils
How do immunosuppressant drugs decrease the inflammatory response?
They inhibit the induction phase of the inflammatory response
How do ciclosporin and glucocorticoids reduce the inflammatory response?
They inhibit the transcription of proinflammatory cytokines
What are the advantages of humanised monoclonal antibodies?
They have high affinity and selectivity for the target
They neutralise action of membrane bound or soluble proinflammatory cytokines
They have a long half life
What happens during type-I hypersensitivity?
Mast cells have IgE Fc receptors
IgE antibodies produced against the allergen bind to the Fc receptors
Allergen binds to IgE antibodies and leads to crosslinking which leads to degranulation
Degranulation leads to smooth muscle contraction, increased vascular permeability, mucous secretion, platelet activation, stimulation of nerve endings, recruitment and activation of eosinophils
What causes allergic rhinitis?
The allergen activates mast cells in the nasal mucous and conjuntivae
Hayfever
What is allergic asthma?
Allergen activates mast cells in lower respiratory tract
What happens during early and late phase asthma?
Early - reversible airway obstruction, inflammation. Increased number of mast cells in bronchi mediate these effects
Late - cytokine to leukocyte infiltration
What is asthma associated with?
Over activity of TH2 cells, leads to increased IgE antibodies
Which molecules cause a late phase asthma attack?
Cytokines and chemokines released during the immediate phase
What are some new therapies for treating asthma?
Humanised antibodies and soluble receptors to IgE, cytokines and chemokines
PGD2R antagonists
