NSAIDs

Question 1

Talk about COX-1?

Answer 1

Expressed in wide range of tissues
Ensures optimised local perfusion
Narrow mouthed

Question 2

Talk about COX-2?

Answer 2

Expression induced by inflammatory mediators (bradykinin)
Always expressed in parts of brain and kidney
Wide mouthed

Question 3

What prostaglandins are released in injury?

Answer 3

PGE2 and PGD2

Question 4

What is the action of prostaglandins?

Answer 4

Released from local tissues and blood vessels to act as potent vasodilators
(Don’t increase capillary permeability directly -> synergise bradykinin and histamine)

Question 5

What is sensitising afferent nociception?

Answer 5

Painful stimuli carried by afferent C fibres
Following trauma, neurones synthesise PGE2
PGE2 binds with c fibre neuronal EPI GPCR receptor

Question 6

What is sensitising peripheral nociception?

Answer 6

GPCR activation results in: increased neuronal sensitivity to bradykinin, inhibition of K+ channels (can’t hyperpolarise -> closer to AP), increase Na+ channel sensitivity (increase AP chance)
Increased C fibre activity
Increased intracellular Ca2+ -> increased neurotransmitter release

Question 7

What is sensitising central nociception?

Answer 7

Increased sustained nociception signalling peripherally leads to increased cytokines levels in the dorsal horn -> increased COX-2 and PGE synthesis -> PGE2 acts via local GPCR EP2 receptor -> increase sensitivity of secondary interneurones -> removal of glycinergic inhibition

Question 8

What is the mechanism of pyrexia?

Answer 8

Bacterial endotoxins stimulate macrophage release of IL-1 -> PGE synthesis -> EP3 receptor -> Increased heat production and decrease heat loss

Question 9

MoA of NSAIDs?

Answer 9

Competitive inhibition of COX-2

Question 10

ADRs of NSAIDs?

Answer 10

Long term use in elderly -> increased morbidity and mortality
GI - pain, nausea, heart burn, gastric bleeding, ulceration (offset with PPIs)
Renal - long term decreased GFR, hypertension (due to reduced renal function)
Vascular - increase bleeding time
Skin rashes
Bronchial asthma
Reye’s syndrome - rare brain/liver injury usually in viral infections treated with aspirin

Question 11

Name some specific COX-2 inhibitors?

Answer 11

Rofecoxib

Celecoxib

Question 12

Drug interactions of NSAIDs?

Answer 12

Opiates
Heavily plasma bound:
Sulphonlurea -> hypoglycaemia
Warfarin -> increased bleeding
Methotrexate

Question 13

MoA of aspirin?

Answer 13

Irreversibly inhibits COX enzymes by acetylation

Question 14

ADRs of paracetamol?

Answer 14

Caution if decreased hepatic function/alcoholics

OD leads to increase in NAPQI (toxic)

Question 15

Treatment of paracetamol overdose?

Answer 15

Activated charcoal orally if 0-4hrs

N-acetylcysteine IV if 0-36hrs