Inflammatory response Flashcards
Definition of inflammatory response
A local response to injurious stimuli which signals pain to reduce further damage
What are eicosanoids
C20 signalling molecules derived from arachidonic acid (from membrane phospholipid)
Includes prostanoids - prostaglandins, prostacyclins, thromboxanes
Describe enzymatic reactions involved in producing prostaglandins
Membrane phospholipids converted to arachidonic acid by phospholipase A2
Arachidonic acid converted to PG-G by COX 1/2
PG-G converted to PG-H by COX 1/2
PG-H converted to PG-D/E/F/I by specific enzymes
Properties of prostaglandin E
Released from BVs and local tissue
Causes vasodilation, hyperalgesia, fever and immunomodulation
Describe COX1 enzyme
Constantly synthesised
Expressed in range of tissues (gastric mucosa, renal parenchyma, myocardium)
Narrow mouthed
Describe COX2 enzyme
Unregulated in response to inflammatory mediators such as bradykinin
Wide mouthed
What’s responsible for NSAIDs therapeutic and adverse effects
Why is this the case
Adverse reaction - COX1 inhibition (lost protective role in maintaining optimal perfusion in tissues - renal and gastric)
Therapeutic action - COX2 inhibition
MoA of prostaglandins in causing pain via peripheral nervous system
Injury
Surrounding neurones synthesise PG-E2 which binds to EP1 receptors on C fibres (Gq) causing increased neurotransmitter release
This increases C fibre activity by:
Increasing neuronal sensitivity to bradykinin
Inhibiting K channels and activating Na channels
MoA of prostaglandins in causing pain via central nervous system
Sustained peripheral nociception (2 weeks)
Increased cytokines production in dorsal horn cell body increases COX2 synthesis
Increased PG-E2 which binds to EP2 receptors (Gs)
Decreased glycine receptor affinity so increased pain perception
MoA of prostaglandins in causing pyrexia
Endotoxins stimulate macrophages to release IL1 which stimulates PG-E2 synthesis in hypothalamus (via COX2 expression)
PG-E2 binds to EP3 receptors (Gi) which increases heat production and decreases heat loss
What order kinetics do NSAIDs show
First order in therapeutic range
4 main categories of adverse effects of NSAIDs
GI
Renal
Vascular
Hypersensitivity
Mechanism of GI side effects with NSAIDs
COX1 inhibition reduces PG-E2 so there is reduced mucosal perfusion, less mucus secretion and more acid production
Leading to ulceration, bleeding, nausea and abdo pain
Mechanism of renal side effects with NSAIDs
COX1 inhibition reduces PG-E2 and PG-I2 in renal parenchyma so there is reduced renal perfusion and decreased GFR
Leading to hyperkalaemia and fluid retention
Mechanism of vascular side effects with NSAIDs
Inhibition of thromboxane A2 leads to increased bleeding time
Bruising and haemorrhage risk
Describe hypersensitivity reactions with NSAIDs
Skin rashes
Asthmatic bronchospasm
Steven Johnson syndrome (immune complex mediated)
Describe NSAIDs interaction with other NSAIDs, opiates and low dose aspirin
With other NSAIDs - affect each others protein binding so increased adverse drug reactions
With low dose opiates - treat pain better and less opiate mediated side effects
With low dose aspirin - compete for COX1 inhibition so aspirin loses its cardioprotective function
What protein bound drugs can be displaced by NSAIDs and what will be the consequence
Sulphonylureas - hypoglycaemia
Warfarin - haemorrhage
Methotrexate - range of serious adverse drug reactions
How does aspirin inhibit COX enzymes
Irreversible inhibition via acetylation
Metabolism of aspirin
Short half life
Metabolised to salicylate
What order kinetics does aspirin show
First order at low dose
Zero order at high dose
Secondary benefits of aspirin
Inhibits thromboxane A2 so prevents atherothrombotic disease
Prophylactic for GI cancer
Usual dose for paracetamol and when it needs altering
8x 500mg per day
Lower in liver patients/alcoholics
Potential MoA of paracetamol for analgesia
COX inhibition in CNS
