NSAIDs Flashcards
What are autocoids
Autocoids are local inflammatory mediators in acute inflammation (acute response to noxious stimuli)
bradykinin, histamine, leukotriene, prostaglandins
They act locally with short T1/2 - can be finely controlled
Their signalling pathways overlap - robust inflammatory response
What are prostaglandins
Type of autocoids synthesised from Arachidonic acid
How are prostaglandins synthesised
From arachidonic acids by COX enzymes:
Cell membrane Phospholipid to Arachidonic acid by phospholipase A
Arachidonic acid to PG H by COX 1 or COX2
PG H to PG E/F/I/D by specific PG enzymes
PG E most important in Inflammation
What are COX enzymes
Enzymes involved in synthesis of prostaglandins from arachidonic acid
What are the differences in COX1 and COX2 enzymes
COX1: constitutively expressed
COX2: only active in inflammation, expression is induced by inflammatory mediators
Different binding site for NSAIDs
What is the role of COX1
Produce PGs constantly in normal state to allow vasodilation and perfusion of tissues in: GI mucosa, renal parenchyma, myocardium
What is the effect of COX1 inhibition
Side effects of NSAIDs
Prostaglandins are required in normal state but have short half life so need to be constantly produced by COX1
What is the role of COX2
Produce PGE in inflammation
What is the effect of COX2 inhibition
Therapeutic effect of NSAIDS
Anti inflammatory, antipyrexial, analgesia
What is the mechanism of action of PGs in inflammation
Pyrexia, inflammation and pain sensitisation by acting on GPCRs
What is the process of peripheral nociceptor sensitisation
PGE bind to EP1 GPCR receptor on C fibre neurones
Increase neuronal sensitivity to bradykinin
Activate Na channels, inhibit K channels
Increase excitability of C fibres
Cause hyperalgesia: increased sensitivity to pain
What is the process of central nociceptor sensitisation
Sustained peripheral pain signalling cause cytokine release in dorsal horn cell body
Cytokines increase COX2 activity and PGE
PGE bind to EP2 GPCR
Remove glycinergic inhibition by inhibitory interneurones
Increase sensitivity of secondary pain fibres
Allodynia: perceive pain to stimuli that normally doesn’t cause pain
What is the process of pyrexia
Macrophages release IL-1 in inflammation
IL-1 act on hypothalamus to produce PGE
PGE act on EP3 GPCR in hypothalamus
Increase heat production and decrease heat loss
What is mechanism of action of NSAIDs
Competitive inhibition of COX1/2 enzymes
What are PK properties of NSAIDs
Administration: oral, topical
T1/2: <6 hours or >10hours
Linear PK
Heavily bound to plasma proteins
What are the main effects of NSAIDs
Anti inflammatory
Analgesia
Antipyrexial
What are indications of NSAIDs
Inflammatory joint disease
Mild to moderate pain - isolation
Severe pain with opioids - acts as Opioid-sparing agent (better adr profile, extended therapeutic range than in isolation)
What are the main side effects of NSAIDs
GI Nephrotoxicity Vascular Hypersensitivity Reye’s syndrome
What are the GI side effects of NSAIDs
Peptic ulcer disease, UGI Bleeding, gastritis, nausea, heartburn, abdominal pain
How can you offset GI side effects
PPI
Misoprostol (PGE derivative - when Hx of PUD but NSAID cannot be stopped)
Why do GI side effects occur
Non-selective inhibition of COX1
Inhibit constitutive synthesis of PGE in GI mucosa
Loss of cytoprotective effects: bicarbonate and mucus production, vasodilation
What are renal side effects
Na retention
Renal failure
Why do renal side effects occur
Non-selective inhibition of COX1 enzymes
Inhibit constitutive production of PG in medulla + glomeruli
PG normally cause Na excretion, AA vasodilation
Which patients are more at risk of nephrotoxicity from NSAIDs
Hepatic cirrhosis (hepatorenal Syndrome) Renal disease (preexisting poor renal function) Heart failure (poor renal perfusion)
What are the vascular side effects
Increased bleeding time, bruising, haemorrhage
What causes vascular side effects
Aspirin inhibits thromboxane A2 synthesis thus inhibits platelet aggregation
What are the hypersensitivity side effects
Skin rash
Bronchial asthma - caution in asthmatics
What is Reye’s syndrome
Encephalopathy associated with aspirin use after a viral infection in children, involving serious liver and brain injury
What drug interactions can occur with NSAIDs
Heavily protein-bound Drugs: Wafarin - bleeding Sulphonylurea - hypoglycaemia Methotrexate - serious SEs Other NSAIDs - e.g. reduced antiplatelet action of aspirin
What is aspirin
Type of NSAID, salicylic acid derivative
What is the mechanism of action of aspirin
Irreversibly bind to COX enzymes
(the only NSAID to irreversibly bind)
Inhibit thromboxane A2 synthesis
Inhibit platelet aggregation
What are the indications for aspirin
Athero-thrombotic disease: MI, Stroke
Pain
GI/Breast cancer prophylaxis (on trial, cancer cells produce PGE for growth)
What type of drug is paracetamol
Non-NSAID non-opioid analgesic
What are the therapeutic effects of paracetamol
Analgesia
Antipyretic
NOT anti inflammatory
What are indications for paracetamol
Agent of choice for mild-moderate pain and fever:
Effective
Better ADR profile than NSAIDs
What are the PK properties of paracetamol
1st order kinetics at therapeutic dose
0 order kinetics at higher dose
Unknown mechanism of action
What is the normal metabolism of paracetamol
90% metabolised by Phase II Conjugation with glucoronide or sulphate
10% metabolised by Phase I Oxidation to NAPQI and Phase II conjugation with glutathione
What occurs in paracetamol overdose
First step Phase II metabolism saturated
Increased production of NAPQI - directly hepatotoxic
Second step Phase II metabolism saturated W Glutathione depletion
Build-up of NAPQI
Liver damage, liver necrosis
How do you treat paracetamol overdose
0-4 hours since ingestion: Oral activated charcoal to reduce GI uptake
<36 hours since ingestion: IV acetylcysteine (replaces glutathione)
At stare of encephalopathy: liver transplantation (irreversible liver damage has occurred)
