NSAIDS

Question 1

What are the main effects of NSAIDs?

Answer 1

• analgesia
• anti-Pyretic
• anti-inflammatory

Question 2

Selective COX-2 inhibitors (celecoxib and etoricoxib)

Answer 2

• intention: to avoid inhibition of homeostatic actions mediated by COX-1
• less inhibitory on COX-1 but selectivity for COX-2 varies among drugs
• less GI ADRs
• renal ADRs similar to non-selective
• no antiplatelet action but impairs PGI2 which can potentially lead to unopposed aggregators effects
• some evidence of less analgesic effect
• can be useful when monitored in severe osteo and rheumatoid arthritis

Question 3

What are the considerations and indications for NSAID use?

Answer 3

Considerations

• CVS disease risk
• Renal function (age)
• GI disease (previous use of NSAIDs)
• DDIs (ACEi and ARBs, diuretics, SU, methotrexate, warfarin)
• level of pain, pyrexia, level of inflammtion

Indications

• inflammatory conditions: joint and soft tissue
• OA: 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
• cancer reduction by up to 30-50% nuclear transcriiption factors, reduced cell proliferation, inflammation

Question 4

Paracetamol

Answer 4

• non-NSAID, non-opioid analgesic with antipyretic action
• from mild to moderate analgesia and fever
• generally well tolerated at therapeutic doses with fewer common ADRs, no effect on platelets and limited effect on GU
• mechanism still not COMPLETELY known
• COX-2 selective inhibition in CNS (decreases pain signals in higher centres)
• peroxidases in peripheral inflammation inhibit the paracetamol so little anti-inflammatory action
• well absorbed from GI
• but predominantly inactivated by conjugation in the liver

Question 5

NAPQI

Answer 5

• highly reactive metabolite with some analgesic effect
• at normal therapeutic doses, conjugation with glutathione makes it harmless
• hepatic glutathione is limited
• NAPQI is highly nucleophilic and can ultimately cause cell death
• 150mg/kg sufficient to cause irreversible damage

Question 6

What to do in a paracetamol overdose?

Answer 6

• N-acetylcysteine
• can be asymptomatic for many hours
• nausea, vomiting, abd pain in the first 24hours
• maximal liver damage in 3 to 4 days
• give glutathione theology replacement: IV acetylcysteine which will reduce the amount of toxic NAPQI
• do not give glutathione directly because it doesnt absorb into the hepatocytes
• need to give N-acetylcysteine to act on phase 2 metabolism