• most frequently prescribed analgesia after paracetamol

• associated with serious ADR

• Prescribe all NSAIDs with caution

• lowest effective dose for shortest time

• older patients (T2DM, Renal, increase CVRA) increased risk of NSAID related comlications

• Naproxen (up to 1g/day) or ibuprofen (1200mg/day) first line

• bsed on current knowledge of NSAID and CV risk

• ibuprofen most appropirate NSAID for children

• Avoid LA NSAID

• increased risk of GI adverse effects

Mechanism of action

• COX1/2 produce prostaglandins following metabolism of omega-6-polyunsaturated fatty acid(arachidonic acid)

• Prostaglandins: mediate inflammation, fever, sensation of pain

• anaglesa/anti inflam produced thorugh prevention of prostaglanding production by inhibition of COX

COX 1

• concentrated stomahc, kidney, endothelium, platelets

• control renal perfusion

• promote platelet aggregation

• provide gastroprotection by regulating mucous secretion

COX2

• induced by inflammation

• macrophages, leukocytes, fibroblasts, synovial cells

• mediate pain, inflammation, fever, inhibit platelet aggregation

NSAIDs and COX

• diclofenac inhibits COX-2 relatively more than COX 1

• meloxicam currently only subsidised COX2

  • but as dose increases COX1 increasingly inhibited

COX selectivity and CV risk

• initially developed on rationale that selective inhibition gain benefit wile reducing GI Adverse effects

• COX 2 promote thombosis and MI

• Naproxen not associated with increased vasuclar risk

• COX 1 inhibition sufficieintly prolonged and intense

  • effectively block platelet activation anc counter balance prothrombotic effect of cocx2

Combination

• Paracetamol + ibuprofen;

  • post operative pain, osteoarthtisis:

    • better than either medicine alone

  • but no strong synergistic analgesic effect

Adverse effects

Cardiovascular

• double risk of admission due to heart failure

• increase systolic bp by 2-3mmHg

• increase cardiovascular risk (coronary events) by \~33% using high dose diclofenac, cox2 and high dose ibuprofen

• naproxen not associated with increased risk

Gastrointestinal

• increased 2-4 fold

• increase dose dependent

• include:

  • dyspepsia

  • GI bleeding

  • Peptic ulcers

  • perforations of upper GI tract

• increased in concurrent aspirin use

• Risk factors:

  • Age > 65

  • previous adverse reaction

  • use of other mediicnes

    • anticoagulants

    • SSRI

    • corticosteroids

  • liver disease

  • CKD

  • smoking

  • excesive etoh consumptoms

Reducing GI adverse effects

• full tummy

• co-prescribing PPI prophylactically in >45yo

  • daily ccompared to as needed

  • require 3d to achieve steady state inhibition of acid secretion

• NSAID induced ulcer: omeprazole 20mg od for 4 weeks and another 4 weeks if not resolved

  • also ranitidine 150mg bd up to 8wks

• @ high risk of devleoping GI complication

  • prescribe PPI

  • monitor Hb levels for first month of treatment

  • if GI effects

    • consider switching NSAID

Renal function

• All medicines that block COX2: nephrotoxic

  • prevent prostaglandin-mediated vasodilation

  • especially dehydration

• also cause immune mediated AKI

• all people with CKD should avoid NSAIDS where possible

• T2DM should avoid

  • reduced renal functiona nd albuminuria risk factors for micro and macrovasuclar complicatoins

  • preservation of renal function essential managmenet T2 DM

Hypersensitivity

• anaphylaxis and bronchospasm to delayed skin and systemic reactions

• reaction due to COX1 inhibition and not mediated by IgE - not true allergy

• 0.5-1.9% of population

• can be routinely prescribed to patients with ashtam who have no pevious history of NSAID associated symptoms

  • dsicuss with patient first

Pregnancy

• not recommended

• first timester doubles risk of spont. abortion

• later - premature closure of ducuts arteriosus

• BF safe

  • low concentrations in breast milk