4. Non-steroidal anti-inflammatory drugs (NSAIDs)

Question 1

Types of NSAIDs

Answer 1

1. Non-selective COX inhibitor: aspirin, naproxen, indomethacin, diclofenac
2. COX2 selective NSAIDs: celecoxib, etoricocib
3. CNS-selective COX inhibitor: paracetamol

Question 2

MOA of aspirin

Answer 2

1. Irreversible COX-1 inhibition → inhibition of thromboxane (TXA2) synthesis in platelets → inhibition of platelet aggregation (antithrombotic effect)
   - Onset of antiplatelet action: within minutes
   - Duration of antiplatelet action: 7–10 days
2. Irreversible COX-1 and COX-2 inhibition → inhibition of prostacyclin and prostaglandin synthesis → antipyretic, anti-inflammatory, and analgesic effect

Question 3

Aspirin has been linked to which medical condition?

Answer 3

Reye’s syndrome:

1. very rare but life-threatening condition
2. swelling of the brain (encephalitis) and liver
3. symptoms include: vomiting, personality changes, listlessness, delirium, convulsions, loss of consciousness

Increased risk if aspirin is taken by children with viral infections

Question 4

Aspirin is indicated in which medical condition?

Answer 4

Kawasaki syndrome

Question 5

Adverse effects of typical NSAIDs

Answer 5

1. Gastrointestinal: dyspepsia, nausea, vomiting, ulcer formation and potential haemorrhage risk in chronic users
   * PGs reduce gastric acid secretions, increase mucosal blood flow, secretion of mucus and of bicarbonates*
2. Renal: inhibition of PGE2 and PGI2 production alters renal blood flow dynamics
   a. Inhibition of PGE2: sodium retention, water retention, peripheral oedema, hypertension
   b. Inhibition of PGI2: suppression of renin and aldosterone secretion, hyperkalemia, acute renal failure
3. “Pseudo-allergic reaction”: skin rashes, swelling, itching, nasal congestion, anaphylactic shock
4. Asthma: can trigger bronchospasm in susceptible asthmatics
   * Inhibition of COX → accumulation of AA → shunting of AA to 5-Lipoxygenase pathway → excess leukotrienes → bronchospasm in asthmatics (LTD4) and allergic reaction-like symptoms
5. Bleeding: failure of hemostasis, bruising
   Note that effects may be stronger for aspirin as it is an irreversible COX inhibitor

Question 6

Which NSAID is often used for dysmenorrhoea?

Answer 6

naproxen

• more effective in women
• half-life 12 to 14h

Question 7

Which NSAID is strongly anti-inflammatory

Answer 7

indomethacin

• due to additional steroid-like phospholipase A inhibitor
• CNS adverse effects: confusion / depression, psychosis & hallucinations also occur

Question 8

Which NSAID is useful in inflammatory joint disease

Answer 8

Diclofenac

• short plasma half-life (<2h) → low GI risk
• longer half-life in synovial fluid

Question 9

Constitutive COX-2 in?

Answer 9

1. CNS
2. Kidneys
3. Female reproductive tract
4. Synovium

Question 10

Unwanted effects / adverse effects of COX2 inhibition

Answer 10

1. Renal toxicity
2. Effects on ovulation, including delayed follicular rupture
3. Premature closure of ductus arteriosus in late pregnancy → contraindicated in third trimester of pregnancy
4. Impairment of wound healing → exacerbation of ulcers
5. Increased risk of thrombosis: inhibition of COX2 → accumulation of AA → shunting via COX1 pathway → increase TXA2 → increase risk of thrombosis

Note that all NSAIDs are COX2 inhibitors!

Question 11

MOA of paracetamol

Answer 11

CNS-selective COX inhibition

Question 12

Advantages of paracetamol

Answer 12

1. good analgesic
2. potent antipyretic
3. spares GI tract
4. side-effects few and uncommon
5. few drug-drug interactions
6. relatively safe for paediatric use

Question 13

Disadvantages of paracetamol

Answer 13

1. Weak anti-inflammatory
2. Toxic doses causes nausea, vomiting and liver damage
3. Allergic skin reactions sometimes occur

Hepatotoxicity should not occur at therapeutic dosage in otherwise healthy individuals, but may be exacerbated by overdose or chronic alcohol use/abuse