FRCA Notes

General Pharmacology of Non-Steroidal Anti-Inflammatory Drugs

Resources

  • NSAIDs can be used to treat mild-moderate pain; they reduce opioid consumption in the peri-operative period
  • They are more effective than paracetamol for certain pain aetiologies e.g. pain from bony metastases
  • They can be administered by a wide range of routes, including orally, rectally, intravenously, topically and other e.g. intra-articular
  • Can be classified according to their enzymatic effects and chemical structure:
Group Class Drugs
Non-specific COX inhibitors Salicylates Aspirin
Acetic acid derivatives Diclofenac, ketorolac, indomethacin
Anthralic acids Mefenamic acid
Pyrazolones Phenylbutazone
Propionic acids Ibuprofen, naproxen
Para-amino-phenols Paracetamol
Oxicams Tenoxicam, piroxicam
Preferential COX-2 inhibitors Oxicams Meloxicam
Specific COX-2 inhibitors Pyrazole Parecoxib, celecoxib
Methylsulfone Etoricoxib
Acetic acid derivates Lumiracoxib


  • Mostly cause reversible cyclo-oxygenase inhibition, the exception being aspirin which causes irreversible inhibition
  • There is:
    • Reduced PGE and PGF2ɣ → anti-inflammatory effect
    • Reduced thromboxane A2 → decreased platelet aggregation/adhesiveness
    • Reduced centrally produced prostaglandins → anti-pyretic effect
    • Reduced gastric mucosal cell prostaglandin production → mucosal ulceration

  • Lipoxygenase, which produces leukotrienes from arachidonic acid, is unaffected

Absorption

  • Rapidly absorbed in the small bowel (due to high surface area)

Distribution

  • Highly protein bound in the plasma
  • May potentiate the effects of other highly protein bound drugs (e.g. warfarin) by displacing them
  • The exception is paracetamol (only 10% protein bound)

  • Low volumes of distribution (0.1 - 0.2L/kg)
  • Again, the exception is paracetamol (comparatively high volume of distribution)

Metabolism and excretion

  • Typically metabolised in the liver and excreted as inactive metabolites in the urine and bile

Respiratory

  • Bronchospasm
    • Acute severe asthma may be precipitated in 20% when given NSAIDs due to effect of leukotrienes
    • More common in those whose asthma is associated with chronic rhinitis or nasal polyps
    • Usually affects the middle-aged (children relatively spared)
    • Following COX inhibition, more arachidonic acid is converted to leukotrienes by lipoxygenase, which cause bronchospasm
    • In susceptible patients, aspirin also causes an abnormal platelet reaction leading to the release of cytotoxic mediators

Cardiovascular

  • COX-2 inhibitors, ibuprofen (2.4g/day) and diclofenac (150mg/day) have similar risk profiles with respect to coronary events
  • For 1000 patients taking the NSAID for 1yr, there will be 3 extra coronary events (one of which will be fatal)
  • None of these drugs increase risk of stroke, despite trend towards significance

Renal

  • Renally produced prostaglandins PGE2 and PGI2 help maintain renal perfusion when levels of circulating vasopressors (renin, angiotensin, noradrenaline) are high
  • NSAIDs may alter this balance, potentially leading to:
    • Reduced renal perfusion, increased serum creatinine and AKI in the perioperative period (although evidence for this being a causative relationship is still uncertain)
    • Fluid retention and heart failure

  • Aspirin
    • Low (<2g/day) dose causes inhibition of tubular secretion of urate
    • High (>5g/day) dose becomes uricosuric, as inhibition of urate reabsorption is greater than inhibition of its secretion
    • With prolonged use may cause aspirin nephropathy from papillary necrosis and interstitial fibrosis

Gastrointestinal

  • Gastric irritation
    • Common with prolonged NSAID use
    • Intestinal erosions manifest widely:
      • Mild pain
      • Iron deficiency anaemia
      • Fatal GI haemorrhage
    • Prostaglandins are involved in many elements of intestinal mucosal protection and inhibiting their synthesis reduces this protection

  • Drug-specific effects:
    • Aspirin: acetylsalicylate and salicylate ions are trapped in the alkaline environment of the mucosal cells and demonstrate increased potential for side-effects
    • High risk: ketorolac, piroxicam
    • Intermediate risk: diclofenac, naproxen
    • Low risk: ibuprofen (<1.2g/day) and selective COX-2 inhibitors

Hepatobiliary effects

  • Hepatotoxicity
    • Observed following prolonged or excessive NSAID use
    • 15% may have raised serum transaminase levels, even after short courses

Haematological

  • Altered platelet function (non-specific COX inhibitors)
    • May increase blood loss in the perioperative period
    • Consider holding non-specific COX inhibitors prior to (high risk) surgery
    • Reduced thromboxane A2 production owing to COX inhibition:
      • Prevents platelet aggregation and vasoconstriction
      • Inhibits haemostasis
    • COX-2 inhibition has no effect on platelet function

Drug interaction

  • May displace anticoagulants e.g. warfarin from protein binding sites and increase the free drug concentration
  • May increase bleeding risk if given with anti-coagulants or heparin drugs
  • May increase serum lithium levels by displacement of protein binding