28. Non-steroidal antiinflammatory drugs. Aspirin, paracetamol

Last updated on June 21, 2019 at 10:55

Introduction to non-steroidal anti-inflammatory drugs

Non-steroidal anti-inflammatory drugs (NSAIDs) all have a similar mechanism of action; they inhibit cyclooxygenase (COX). This reduces the synthesis of prostaglandins and thromboxanes. This has three main effects:

  • Antipyretic effect
  • Anti-inflammatory effect
  • Analgesic effect

Antipyretic effect: Prostaglandins in the hypothalamus increase the set-point temperature during fever.

Anti-inflammatory effect: Prostaglandins induce hyperaemia and oedema during inflammation. By inhibiting these mechanisms, the inflammatory response is decreased.

Analgesic effect: Prostaglandins in the periphery and the CNS increase the sensitivity of nociceptive fibres. By inhibiting COX this sensitization is reduced.

NSAIDs are effective at treating pain associated with inflammation and tissue damage, but not effective in treating visceral pain (like appendicitis, pain associated with gallstones). They’re also not effective at treating neuropathic pain.

Other medical uses of NSAIDs:

  • Induce closure of persistent ductus arteriosus – prostaglandins keep this duct open
  • Inhibit platelet aggregation
    • Via COX1 inhibition
  • Prevention of colorectal cancer
  • Dysmenorrhoea


Two isoforms of COX exist: COX1 and COX2.

COX1 is constitutively expressed in all cells. It produces prostaglandins and thromboxanes involved in maintaining haemostasis. These prostaglandins and thromboxanes are important for platelet aggregation and for protection of the gastric mucosa.

COX2 is found in endothelium and smooth muscle in vessels and is only activated during inflammation. It produces prostaglandins that increase vascular permeability, thereby causing hyperaemia and oedema. These prostaglandins also increase pain sensitivity and produce fever. COX2 also produces prostaglandins that prevent platelet aggregation.

Both COX1 and COX2 produces prostaglandins that dilate the afferent arteriole in the kidney.

The following table sums up the side-effects of inhibiting each COX isoenzyme.

Inhibition of COX1Inhibition of COX2
Decreased vasodilation of afferent arteriole Decreased vasodilation of afferent arteriole
Gastric mucosa toxicity Antipyretic effect
Prolonged bleeding timeAnalgesic effect
Anti-inflammatory effect
Increased risk of arterial thrombosis (AMI, stroke)

Important NSAIDs:

According to the table above it seems like we can avoid many side effects by making COX2-selective NSAIDs. Indeed, NSAIDs are categorized according to whether they’re selective for COX2 or nonselective:

  • COX-nonselective NSAIDs (“traditional NSAIDs”) – these NSAIDs inhibit both isoforms
    • Aspirin
    • Naproxen
    • Indomethacin
    • Diclofenac
    • Ibuprofen
  • COX2-preferential NSAIDs – these NSAIDs inhibit COX2 more than COX1
    • Paracetamol
    • Celecoxib
    • Meloxicam
  • COX2-selective NSAIDs (“coxibs”) – these NSAIDs inhibit COX2 only
    • Parecoxib
    • Etoricoxib

Side effects of NSAIDs:

  • Gastritis, erosion, peptic ulcers
    • Due to loss of mucosa-protective prostaglandins by inhibition of COX1
  • Reduced GFR
    • Due to loss of prostaglandins that dilate afferent arteriole
    • Acute interstitial nephritis
    • Analgesic nephropathy
  • Prolonged bleeding time
    • Due to loss of platelet-aggregating prostaglandins produced by COX1
  • In utero closure of ductus arteriosus -> abortion
    • NSAIDs should be used with care in pregnant women
  • Hypersensitivity reactions
    • Urticaria
    • “Aspirin asthma”
  • Increased risk of thrombosis
    • Due to loss of prostaglandins produced by COX2 that prevent platelet aggregation


  • Peptic ulcer
  • Renal damage or other impairment of renal circulation, like heart failure and cirrhosis
  • Before surgery
  • Pregnancy
    • Except short-term treatment with aspirin or paracetamol

Common pharmacokinetics:

  • Most are weak acids
  • Strong plasma protein binding
  • Actively secreted into tubules

Drug interactions:

  • Glucocorticoids
    • Both damage the gastric mucosa
  • Drugs inhibiting RAAS
    • Would cause hyperkalaemia

Aspirin, also called acetylsalicylic acid or ASA is the only NSAID not primarily used as an analgesic or anti-inflammatory.


Given in low doses to prevent coronary artery disease like AMI or cerebrovascular disease like ischaemic stroke. Used after stent placement to prevent platelets from aggregating on the stents.

Mechanism of action:

Aspirin is the only irreversible COX inhibitor. In low doses it mostly inhibits COX1, which decreases the level of the thromboxane A2, a potent platelet aggregator and vasoconstrictor.

Platelets don’t have nuclei, so they can’t synthetize new COX enzymes after they have been irreversibly inhibited. For this reason, the effect of aspirin lasts for the total lifetime of platelets, 7 – 10 days.


Orally, in low dose (20% of the dose which would give analgesic and antipyretic effects).


See above.


See above.

Side effects:

See above.

The use of aspirin in children under 16, especially those with a preceding viral infection, can cause Reye syndrome. This is characterised by liver failure and encephalopathy.


Intoxication causes tinnitus, hyperpnoea and acid-base disorders.

Treatment involves gastric lavage with activated charcoal, sodium bicarbonate, cooling and dialysis.


Paracetamol (also known as acetaminophen) is the weirdest of all NSAIDs. It only has weak COX-inhibiting effect (so some don’t even consider it an NSAID), yet still causes analgesia and antipyretic effects. It does not inhibit inflammation.

Because of its weak NSAID effects it doesn’t have the classic NSAID side effects either. Because of this it’s the preferred drug for treating pain or fever when no anti-inflammatory effect is needed. It can also be safely used during pregnancy.


Pain or fever, when no anti-inflammatory effect is necessary.

Mechanism of action:

Incompletely understood. Paracetamol weakly inhibits COX in the CNS but does not influence COX in the periphery, hence no anti-inflammatory effect. It might stimulate descending pain inhibitory pathways.


Oral, rectal or IV.


Liver failure.


Metabolized into a toxic metabolite (NAPQI) by the liver. This toxic metabolite can be neutralized by glutathione as long as non-toxic doses are used.


In toxic doses glutathione stores are depleted, so the toxic metabolite accumulates, causing liver necrosis and renal necrosis.

Treatment involves activated charcoal and N-acetylcysteine. This compound promotes glutathione synthesis.

Side effects:

Produces few significant side effects.

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27. Opioid analgesic drugs. Semisynthetic, synthetic opioids, opioid antagonists

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29. Non-steroidal antiinflammatory drugs. Drugs other than aspirin or paracetamol

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