NSAIDs

Question 1

What are autocoids

Answer 1

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

Question 2

What are prostaglandins

Answer 2

Type of autocoids synthesised from Arachidonic acid

Question 3

How are prostaglandins synthesised

Answer 3

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

Question 4

What are COX enzymes

Answer 4

Enzymes involved in synthesis of prostaglandins from arachidonic acid

Question 5

What are the differences in COX1 and COX2 enzymes

Answer 5

COX1: constitutively expressed
COX2: only active in inflammation, expression is induced by inflammatory mediators

Different binding site for NSAIDs

Question 6

What is the role of COX1

Answer 6

Produce PGs constantly in normal state to allow vasodilation and perfusion of tissues in: GI mucosa, renal parenchyma, myocardium

Question 7

What is the effect of COX1 inhibition

Answer 7

Side effects of NSAIDs

Prostaglandins are required in normal state but have short half life so need to be constantly produced by COX1

Question 8

What is the role of COX2

Answer 8

Produce PGE in inflammation

Question 9

What is the effect of COX2 inhibition

Answer 9

Therapeutic effect of NSAIDS

Anti inflammatory, antipyrexial, analgesia

Question 10

What is the mechanism of action of PGs in inflammation

Answer 10

Pyrexia, inflammation and pain sensitisation by acting on GPCRs

Question 11

What is the process of peripheral nociceptor sensitisation

Answer 11

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

Question 12

What is the process of central nociceptor sensitisation

Answer 12

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

Question 13

What is the process of pyrexia

Answer 13

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

Question 14

What is mechanism of action of NSAIDs

Answer 14

Competitive inhibition of COX1/2 enzymes

Question 15

What are PK properties of NSAIDs

Answer 15

Administration: oral, topical
T1/2: <6 hours or >10hours
Linear PK
Heavily bound to plasma proteins

Question 16

What are the main effects of NSAIDs

Answer 16

Anti inflammatory
Analgesia
Antipyrexial

Question 17

What are indications of NSAIDs

Answer 17

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)

Question 18

What are the main side effects of NSAIDs

Answer 18

GI
Nephrotoxicity 
Vascular 
Hypersensitivity 
Reye’s syndrome

Question 19

What are the GI side effects of NSAIDs

Answer 19

Peptic ulcer disease, UGI Bleeding, gastritis, nausea, heartburn, abdominal pain

Question 20

How can you offset GI side effects

Answer 20

PPI

Misoprostol (PGE derivative - when Hx of PUD but NSAID cannot be stopped)

Question 21

Why do GI side effects occur

Answer 21

Non-selective inhibition of COX1
Inhibit constitutive synthesis of PGE in GI mucosa
Loss of cytoprotective effects: bicarbonate and mucus production, vasodilation

Question 22

What are renal side effects

Answer 22

Na retention

Renal failure

Question 23

Why do renal side effects occur

Answer 23

Non-selective inhibition of COX1 enzymes
Inhibit constitutive production of PG in medulla + glomeruli
PG normally cause Na excretion, AA vasodilation

Question 24

Which patients are more at risk of nephrotoxicity from NSAIDs

Answer 24

Hepatic cirrhosis (hepatorenal Syndrome)
Renal disease (preexisting poor renal function) 
Heart failure (poor renal perfusion)

Question 25

What are the vascular side effects

Answer 25

Increased bleeding time, bruising, haemorrhage

Question 26

What causes vascular side effects

Answer 26

Aspirin inhibits thromboxane A2 synthesis thus inhibits platelet aggregation

Question 27

What are the hypersensitivity side effects

Answer 27

Skin rash

Bronchial asthma - caution in asthmatics

Question 28

What is Reye’s syndrome

Answer 28

Encephalopathy associated with aspirin use after a viral infection in children, involving serious liver and brain injury

Question 29

What drug interactions can occur with NSAIDs

Answer 29

Heavily protein-bound Drugs: 
Wafarin - bleeding
Sulphonylurea - hypoglycaemia 
Methotrexate - serious SEs
Other NSAIDs - e.g. reduced antiplatelet action of aspirin

Question 30

What is aspirin

Answer 30

Type of NSAID, salicylic acid derivative

Question 31

What is the mechanism of action of aspirin

Answer 31

Irreversibly bind to COX enzymes
(the only NSAID to irreversibly bind)
Inhibit thromboxane A2 synthesis
Inhibit platelet aggregation

Question 32

What are the indications for aspirin

Answer 32

Athero-thrombotic disease: MI, Stroke
Pain
GI/Breast cancer prophylaxis (on trial, cancer cells produce PGE for growth)

Question 33

What type of drug is paracetamol

Answer 33

Non-NSAID non-opioid analgesic

Question 34

What are the therapeutic effects of paracetamol

Answer 34

Analgesia
Antipyretic
NOT anti inflammatory

Question 35

What are indications for paracetamol

Answer 35

Agent of choice for mild-moderate pain and fever:
Effective
Better ADR profile than NSAIDs

Question 36

What are the PK properties of paracetamol

Answer 36

1st order kinetics at therapeutic dose
0 order kinetics at higher dose
Unknown mechanism of action

Question 37

What is the normal metabolism of paracetamol

Answer 37

90% metabolised by Phase II Conjugation with glucoronide or sulphate
10% metabolised by Phase I Oxidation to NAPQI and Phase II conjugation with glutathione

Question 38

What occurs in paracetamol overdose

Answer 38

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

Question 39

How do you treat paracetamol overdose

Answer 39

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)