NSAIDs Flashcards
What are eicasanoids?
Phospholipid derivatives used as signalling molecules eg. Prostaglandins
They’re all derived from arachinoid acid
What enzymes are used to synthesise prostaglandins?
Cycloxygenase enzymes
How do COX enzymes synthesise prostaglandins?
Phospholipase A2 from cell membrane phospholipids makes arachindonic acid
COX 1 and 2 synthesise prostaglandins from this
Which prostaglandin is most important in mediating an inflammatory response?
E
Does vasodilation, hyperalgesia, fever, immunomodulation
What are some of the other roles of prostaglandins produced by COX-1?
Protection of
- gastric mucosa
- myocardium
- renal parenchyma
What is COX-2 expression induced by?
Inflammatory mediators like bradykinin
What COX in particular do NSAIDs work on?
2
Discuss the structures of COX 1 and 2?
1 is very narrow mouthed so it fits small, sharp drugs like aspirin
2 is big and blunt
Aspirin fits in both
When are autacoids and prostaglandins released?
Released from local tissues and blood vessels post-injury
Prostaglandins act as potent vasodilators
What receptors of prostaglandins do what?
EP1 receptors (Gq) increase peripheral nociception EP2 receptors (Gs) increases vasodilation
How does EP1 work?
Painful stimuli is carried by afferent C fibres
Following trauma, surrounding tissue and neurones synthesise PG
PG binds with GPCR on EP1 and activates it
GPCR activation leads to
- increased neuronal sensitivity
- decreased potassium channels
- increased sodium channel sensitivity
All of this increase C fibre activity by increasing intracellular ca2+
How does EP2 work?
Increased sustained nociceptive signalling peripherally result in increased cytokines levels in the dorsal horn cell body
Causes increased COX2 and prostaglandin synthesis
Acts on the GPCR on EP2: increasing cAMP and pKa
This decreases glycine receptor binding affinity
Which increases pain perception
What does EP3 bring about?
Pyrexia
How does EP3 work?
In infected sites, bacterial endotoxins stimulate macrophage release of IL-1
IL-1 within the hypothalamus stimulates PG synthesis
When this activates the GPCR on EP3
Results in increased heat production and decreased heat loss
How do NSAIDs work?
COX-2 inhibition is the main thing
Work on COX 1 too
Nearly all have therapeutic efficacy as analgesics, anti-inflammatories and anti-pyretics
How are NSAIDs given?
Orally
Can be given topically for soft tissue injury
What is the anti-inflammatory effect of NSAIDs?
MSK Disorders: rheumatoid and osteoarthritis
What are the analgesic effects of NSAIDs?
Work on mild to moderate pain
What are the ADRs of NSAIDs?
Peptic ulcers Renal failure - prostaglandins important for maintaining renal blood flow - NSAIDs can reduce GFR therefore Increased risk of bleeding, bruising and haemorrhage Hypersensitivity - skin rashes - bronchial asthma Steven Johnson's Syndrome
Discuss the drug interactions of NSAIDs
Extends therapeutic range with low dose opiates
In combination with other NSAIDs, increase risk of ADRs
Affects other drugs that are highly protein bound like
- sulphonylureas
- warfarin
- methotrexate
What are autacoids?
A range of molecular mediators and signalling agents such as
Bradykinin, histamine, cytokines, leukotrienes, nitric oxides
What is the mechanism of action of Paracetamol?
Mainly use phase 2 but some uses phase 1 - producing a little NAPQI
NAPQI is usually detoxified by phase 2 using glutathione
What happens when you overdose on paracetamol?
Phase 2 becomes saturated So glutathione is rapidly depleted So there is an increase in NAPQI Unconjugated NAPQI binds with mitochondria and causes - necrotic hepatic cell death - renal failure
How do you treat paracetamol overdose?
0-4 hours: oral activated charcoal
0-36 hours: N-acetyl cysteine
