NSAIDs

Question 1

NSAID common MoA

Answer 1

inhibition of COX which ↓prostaglandin, prostacyclin and thromboxane synthesis (compete with arachidonic acid for hydrophobic site of COX enzymes); however they’re chemically dissimilar so have different antipyretic, analgesic and anti-inflammatory properties

Question 2

NSAID analgesic MoA

Answer 2

local peripheral action at site of pain (greater efficacy if inflamed), inhibition reduces peripheral pain fibre sensitivity by ↓PGE2 synthesis in dorsal horn - ↓neurotransmitter release → ↓excitability of neurons in pain relay pathway; efficacious after first dose but full analgesia after several days dosing

Question 3

NSAID anti-inflammatory MoA

Answer 3

prostaglandins cause vasodilation and oedema, NSAIDs inhibit it so reduce the inflammation symptoms BUT underlying cause doesn’t get treated

Question 4

NSAID anti-pyretic MoA

Answer 4

PGE2 is a critical component of preoptic area of hypothalamus which controls thermoregulation, so inhibition of hypothalamic COX-2 where cytokine induced prostaglandin synthesis is elevated results in a reduction in temperature

Question 5

Name 6 NSAIDs (in order of COX1 to COX2 selectivity)

Answer 5

Aspirin (low dose)
ibuprofen
naproxen
diclofenac
celecoxib
etoricoxib

Question 6

indications for NSAIDs

Answer 6

• Inflammatory conditions – joint and soft tissue
• Osteoarthritis – topical NSAID and paracetamol should be tried first
• Postoperative pain
• Topical use on cornea
• Menorrhagia (moderate reduction in blood loss)
• Low dose aspirin for platelet aggregation inhibition
• Opioid sparing when used in combination

Question 7

NSAID GI general effects

Answer 7

Probably the most common ADRs, relative risk of GI bleed ~1-10X depending on NSAID

↓mucus and bicarbonate secretion, ↑acid secretion; ↓mucosal blood flow → enhanced cytotoxicity and hypoxia

Question 8

NSAID GI adverse effects

Answer 8

• Dyspepsia, nausea, peptic ulceration, bleeding and perforation
• Exacerbation of inflammatory bowel disease

Question 9

NSAID GI contraindications

Answer 9

• Elderly, prolonged use
• smoking, alcohol
• History of peptic ulceration, helicobacter pylori

Question 10

NSAID GI drug interactions

Answer 10

aspirin, glucocorticoid steroids, anticoagulants (PPI should be considered)

Question 11

NSAID renal adverse effects

Answer 11

• NSAIDs produce reversible ↓GFR ↓renal blood flow (less issues at therapeutic dose in a healthy person)
• Prostaglandins inhibit sodium absorption in the collecting duct (natriuresis); NSAIDs inhibit this action therefore ↑Na, ↑H2O, ↑BP ~5mmHg

Question 12

NSAID renal contraindications

Answer 12

Patients with underlying CKD or heart failure (greater reliance on prostaglandins for vasodilatation and renal perfusion)

Question 13

NSAID renal drug interaction

Answer 13

ACEi, ARBs, diuretic

Question 14

Features of paracetamol

Answer 14

A unique case – non-NSAID, non-opiate analgesic with antipyretic action, used for moderate to analgesia and fever

At therapeutic doses generally well tolerated with fewer common ADRs with no effect on platelets and limited effect on GI

Gets inactivated in the liver into NAPQI, which at therapuetic doses conjugates with hepatic glutathione so is harmless. NAPQI is highly nucleophilic, oxidising metabolic enzymes ultimately causing cell necrosis and apoptosis

N-acetylcysteine used to treat paracetamol overdose