Inflammation and anti-inflammatories Flashcards
The local accumulation of fluid containing plasma proteins and white blood cells (WBCs)
Often non-specific (innate response)
Very dynamic (changing and different)
Local physiological response to injury
Responds to infection and cell death
An immediate response aims to…
Restrict damage or infection to a localised area.
Remove the causative agent and damaged tissue.
Promote immune cells (and molecules) access to the site to innate repair of damage tissue.
Innate: Non-specific defence mechanism - First line of defence
Skin
Mucous membrane
Secretions of the skin and mucous membranes
Innate: Non-specific mechanism - Second line of defence
Phagocytic white blood cells.
Antimicrobial proteins.
The inflammatory response.
Adaptive: Specific defence mechanism - Third line if defence
Lymphocytes
Antibodies
Cardinal signs of acute inflammation
Heat (Calor) Erythema (Rubor) Oedema (Tumour) Pain (Dalor) Loss of function
Innate responses that induce actute inflammation
- Bacteria trigger macrophages to release cytokines and chemokines.
- Vasodilation and increased vascular permeability cause redness, heat and swelling.
- Inflammatory calls migrate into tissue, releasing inflammatory mediators that cause pain.
Key cells recruited during acute inflammation
Macrophage
Dendritic cells
Mast cells
Mostly neutrophils
4 stages of inflammation
- Tissue damage
- Vasodilation
- Cell recruitment (phagocyte migration and margination)
- Tissue repair - Clotting, annexin (lipocortin) and fibrin release. Fibrin lays down collagen (scars)
Overview of inflammation
- Damage leads to activation of sentinel cells (via complement or phagocytosis), releasing cytokines (TNF-α, IL-1β), chemokines (IL-8), histamine and prostaglandins.
- Vasodilation and vascular permeability (histamine). Exudate of complement and cells.
- Extravasation and chemotaxis (IL-8), further cell recruitment = swelling
Eicosanoids
Group of physiologically active lipid compounds.
Signalling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid.
20 carbons in length
Prostanoids (prostaglandins and thromboxane)
Leukotrienes
Prostanoids formation
Membrane phospholipids + Phospholipase A2 ->
Arachidonic acid + Cyclo-oxygenase (COX) ->
Intermediate prostaglandin (PGH2) ->
Prostacyclin (PGI2) / Thromboxane (TXA2) / Prostaglandins(PGE2)
Prostacyclin (PGI2) induces…
- Vasodilation
2. Stops platelet activation
Thromboxane (TXA2) induces…
- Vasoconstriction
2. Activates platelets
Prostaglandins (PGE2) induces…
- Fever
- Pain
- Vascular permeability
Leukotrienes formation
Membrane phospholipids + Phospholipase A2 ->
Arachidonic acid + Lipooxygenase (LOX) ->
5-HPETE ->
Leukotrienes
Leukotrienes induce…
- Inflammation
2. Chemotactic effect on neutrophils
Dyspepsia meaning
Indigestion
Eicosanoids formation
1
Membrane phospholipids + Phospholipase A2 ->
Arachidonic acid + cyclo-oxygenase (COX) ->
Intermediate prostaglandin (PGH2) ->
PGI2/PGE2/TXA2
#2
Membrane phospholids + Phospholipae A2 ->
Arachidonic acid + Lipooxygenase (LOX) ->
5-HPETE ->
Leukotrienes
Drugs used to combat pain and inflammation
Antihistamines - Antagonists of the histamine receptors
NSAIDs - Non-steroidal anti-inflammatory drugs
Glucocorticoids - Steroidal anti-inflammatory drugs
Immuno-suppressants - Reduction of immune cell activation or response
NSAIDs and non-opioid analgesics: Paracetamol
Analgesic and antipyretic activity.
No anti-inflammatory action
Liver damage on overdose
NSAIDs and non-opioid analgesics: Ibroprofen
Short term analgesic and anti-inflammatory action.
Gastric irritation, increased rick of ulceration
FDA Cat. D drug
NSAIDs and non-opioid analgesics: Aspirin
Acetylates COX Irreversible inhibitor Anti-platelet activity Increased risk of gastrointestinal bleeding and irritation Bad for asthma patients
NSAIDs and non-opioid analgesics: Celecoxib
Specific COX-2 inhibitor
Fewer side effects
Suggested increased risk of stroke and heart attack following use FDA Cat. D drug
What do NSAIDs block? pg111
Cox-1 and Cox-2
Cox-1
‘Housekeeper’
Performs many roles
Expressed widely
Unwanted responses (side effects) thought to be exerted mainly through Cox-1 isoform inhibition.
Cox-2
Induced upon inflammation cell activation
Also in kidney and CNS
Anti-inflammatory, analgesic and antipyretic activity of NSAIDs thought to be exerted mainly by Cox-2 isoform inhibition.
Glucocorticoid gene targets
Tyrosine aminotransferase immunosupressive.
Lipocortin, inhibition of eicosanoid generation.
NFkB regulated genes (including COX).
AP1 regulated genes - Wound healing, collagenase, vitamin c and d metabolism
Natural glucocorticoids
Adrenocorticotrophic hormone (ACTH) stimulates production of natural glucocorticoid steroid hormones.
Increase in response to stress.
Increased production of cortisol.
Synthetic glucocorticoids
Beclometasone (asthma inhaler)
Hydrocortisone cream
Prednisolone (allergies, skin infections)
Cortisol (hydrocortisone)
Cortisol is a glucocorticoid
Prevents the release of inflammatory mediators
Inhibits TNF-α and Th1 cells
Switches towards Th2 immune response rather than general immunosuppression
Believed to be a protective mechanism which prevents an over-activation of inflammatory response
Adverse effects of glucocorticoids
Cushings syndrome - build up of cortisol.
Latrogenic Cushings syndrome due to long-term high dose corticosteroid use.
Endogenous Cushings syndrome due to ACTH over-production in the body (rare).
Easy bruising, muscle wasting and atherosclerosis, euphoria, depression, psychosis, thinning skin, poor wound healing and hyperglycaemia.
Analgesic meaning
A drug acting to relieve pain
