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How can you classify non-steroidal anti-inflammatory drugs (NSAIDs)?

Specific COX-2 Inhibitors
  • Aspirin
Specific COX-2 Inhibitors
Acetic acid derivatives
  • Diclofenac
  • Ketorolac
  • Indomethacin
Specific COX-2 Inhibitors
Anthralinic acids
  • Mefanamic acid
Specific COX-2 Inhibitors
Propionic acids
  • Ibuprofen
  • Naproxen
Specific COX-2 Inhibitors
  • Paracetamol
Preferential COX-2 Inhibitors
  • Tenoxicam
  • Piroxicam
Specific COX-2 Inhibitors
  • Parecoxib
  • Celecoxib
Specific COX-2 Inhibitors
  • Etoricoxib


What are the classical pharmacokinetics of NSAIDs?

  • Most are well absorbed through the small bowel and have high bioavailability
  • Antacids may delay absorption
  • Diclofenac undergoes first pass metabolism reducing bioavailability and is often given rectally or intravenously
  • Highly protein bound (mostly to albumin) - around 99% in most cases
  • Have a low apparent volume of distribution (<0.2 L/kg)
  • Competition for protein binding sites can lead to enhanced action of other drugs as they are displaced (oral anticoagulants and hypoglycaemics)
  • High protein binding means NSAIDs are not dialysable
  • Primarily eliminated by metabolism in the liver
  • Liver disease can significantly alter behaviour
  • Excreted in an inactive form in urine and bile

Mechanism of Action

What are prostaglandins?

  • Biologically active lipid compounds derived from arachidonic acid
  • Like hormones act as chemical messengers but act on the cell they are synthesized in rather than moving to other sites
  • Variety of prostaglandins exist with different physiological effects:
  • Vasoconstriction
  • Vasodilation (particularly renal afferent vessels)
  • Increase in gastric mucous and bicarbonate production
  • Suppression of lymphocytes
  • Sensitization of peripheral nerve ending to pain
  • Involved in fever generation
  • Mixed vascular effects
  • Uterine contraction and cervical ripening
  • Vasodilation (particularly renal afferent vessels)
  • Inhibition of platelet aggregation
  • Bronchodilatation
  • Sensitization of peripheral nerve ending to pain
  • Vasoconstriction
  • Induction of platelet aggregation
  • Bronchoconstriction
  • Uterine contraction

What is cyclooxygenase? What are the different forms and where are they found?

  • Group of enzymes responsible for the production of prostanoids from arachidonic acid
  • Prostanoids are biologically active molecules including prostaglandins and thromboxane
  • Two primary isoforms of cyclooxygenase (COX) are described:
(Constitutive Form)
  • Located throughout most tissues in the body
  • Plays a house keeping role in most tissues
  • Activity most strongly associated with:
    • Prostaglandin production in gastric mucosa - stimulate bicarbonate and protective mucus secretion
    • Prostaglandin production in renal vasculature - promote vasodilatation of glomerular afferent vessels
    • Thromboxane production in platelets - mediates platelet aggregation and adhesiveness
(Inducible Form)
  • Usually absent in most tissues except brain, uterus and kidneys
  • Up-regulated in other tissues in response to damage and inflammatory cytokines:
    • Facilitates the inflammatory response at site of injury
    • Mediates production of prostacyclin (PGI2) in vascular endothelium
  • Third type called COX-3 has been described
    • Splice variant of COX-1 enzyme
    • Exists in central nervous system
  • COX-3 inihibition is a proposed mechanism of paracetamol activity

What is the mechanism of action of NSAIDs?

  • Inhibit the enzyme cyclo-oxygenase.
  • Prevents the production of:
    • Prostaglandins (including prostacyclins)
    • Thromboxane

Which COX enzymes are inhibited by specific NSAIDs?

Side Effects & Contraindications

What are the clinically significant side effects of NSAIDs?

Gastrointestinal System
  • Dyspepsia
  • Gastroduodenal ulcers
  • GI bleeding and perforation
  • Hepatotoxicity (transaminitis seen in up to 15% after prolonged use)
Cardiovascular System
  • Coronary thrombosis and myocardial infarction
  • Hypertension
Renal System
  • Reduce glomerular filtration rate (leading to AKI or CKD)
  • Sodium retention
  • Acute interstitial nephritis
Respiratory System
  • Precipitation of bronchospasm in asthmatics
Haematological System
  • Impaired platelet function
  • Increased risk of bleeding
  • Interference with ovulation and implantation
  • Premature closure of the patent ductus arteriosus
  • Prolonged gestation and labour

What are the GI side effects of NSAIDs and why do they occur?

  • When gastric mucosa damaged prostaglandins released:
    • Stimulate secretion of protective mucous layer
    • Stimulates bicarbonate ions to neutralise acid
  • COX-1 inhibition reduces synthesises of prostaglandins:
    • Prevents production of gastric protective elements
    • Leads to gastric and intestinal erosions and ulcers
  • Potential for GI bleeding increased due to effect on platelet function

What are the renal complications of NSAIDs and why do they occur?

  • Renally produced prostaglandins essential for maintenance of adequate perfusion pressure:
    • Cause vasodilatation of afferent vessels
  • COX-1 expressed in renal vasculature and glomerular cells:
    • Inhibition reduces synthesis of prostaglandins
    • Prevents normal haemostatic mechanisms to maintain afferent flow, glomerular perfusion and filtration rate
  • Precipitate sodium and fluid retention:
    • Can exacerbate hypertension
    • Average increase in MAP of 5-10mmHg with NSAIDs
  • Long term NSAID use has been associated with interstitial nephritis

What are the cardiovascular complications associated with COX-2 inhibitors? What are the underlying mechanisms for this?

  • Increased risk of coronary vascular events
    • 3 extra coronary events per 1,000 patients per year
    • Trend towards increased risk of stroke but not reached significance
  • Has resulted in a number of high profile drug withdrawals including rofecoxib, lumiracoxib and etoricoxib
    • European review concluded diclofenac has a similar thrombotic risk profile
  • COX-2 inhibitors alter the delicate thromboxane/prostacyclin balance in favour of platelet aggregation, vasoconstriction and thromboembolism:
    • Inhibit prostacyclin production mediated via COX-2
    • Thromboxane production unaffected as mediated by COX-1

What are the haematological effects of NSAIDs and why do they occur?

  • Thromboxane A2 plays a key role in platelet aggregation and activation
  • COX-1 inhibition reduces synthesises of thromboxane A2 inhibiting the haemostatic process
  • May increase blood loss in the perioperative period
  • Effect is used therapeutically for prevention of thrombotic disease (aspirin)

What are the effects of NSAIDs on bone and why do these occur?

  • COX-2 plays important role in bone healing with prostaglandins increasing cortical mass and trabeculation in animal models
  • Evidence is equivocal as to whether NSAIDs prevent bone healing in humans:
    • No strong evidence to preclude their use in fractures or orthopaedic surgery

Why are asthmatics often sensitive to NSAIDs?

  • COX-2 inhibition increases the amount of arachidonic acid metabolised by lipooxygenase to leukotrienes
  • Leukotrienes known to cause bronchospasm
  • Middle aged asthmatics usually more affected than children


What are the clinical properties of diclofenac?

  • Oral: 25/50/100 mg tablets
  •  Rectal: 12.5/25/50/100 mg suppositories
  • IV / IM: clear colourless solution in ampules containing 25 mg/ml or 75 mg/3ml


  • Oral: 75-150mg daily in 2-3 divided doses
  • Rectal: 75-150mg daily in 2-3 divided doses
  • IV / IM: 75mg, OD or BD for a maximum 2 days

Before administration of any drug confirm dosage in the BNF

  • As per other NSAIDs
  • IV and PR preparations lend itself to use as intraoperative analgesia


  • As per other NSAIDs
Chemical Structure
  • Acetic acid derivative


  • The drug is well absorbed when administered by all routes
  • Oral bioavailability is 60% due to significant first-pass metabolism


  • 99.5% protein-bound in the plasma, predominantly to albumin
  • The VD is 0.12–0.17 l/kg


  • Principally metabolised in the liver
  • Undergoes hydroxylation and methoxylation to phenolic metabolites
  • Subsequent conjugation to inactive glucuronide and sulphate metabolites


  • Approximately 65% of the dose is excreted in the urine and 35% in the bile
  • Less than 1% is excreted unchanged
Mechanism of Action
  • As per other NSAIDS acts as a COX inhibitor
  • In vitro selectivity for COX-2 inhibition:
    • Lower than that of celecoxib,
    • Higher than ibuprofen, and naproxen


    What are the clinical properties of ibuprofen?

    • Oral: 50/100/200/400 mg tablets



    Before administration of any drug confirm dosage in the BNF

    • Oral: 300-400mg 3-4 time daily
    • Max 600mg 4 times daily


    • As per other NSAIDs


    • As per other NSAIDs
    Chemical Structure
    • Propionic acid derivative


    • The drug is well absorbed
    • Oral bioavailability is 80%


    • 90-99% protein-bound in the plasma, predominantly to albumin
    • The VD is 0.14 l/kg


    • Principally metabolised in the liver
    • Undergoes oxidation to two inactive metabolites


    • Excreted in the urine
    Mechanism of Action
    • As per other NSAIDS acts as a COX inhibitor:
    • Non-selective inhibitor (1:1 ratio for COX-1 and COX-2)


    The Guidewire
    Trainee in ICM & Anaesthesia


    The Guidewire
    Trainee in ICM & Anaesthesia