Aspirin
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Mechanism of action
Aspirin (also known as acetylsalicylic acid) works by blocking the action of both cyclooxygenase-1 (COX1) and cyclooxygenase-2 (COX2) enzymes. Aspirin binds to cyclooxygenase enzymes leading to irreversible inhibition.Aspirin is a non-selective inhibitor COX1 and COX2
Cyclooxygenase is responsible for prostaglandin, prostacyclin and thromboxane synthesis. The blocking of thromboxane A2 formation in platelets reduces the ability of platelets to aggregate which has lead to the widespread use of low-dose aspirin in cardiovascular disease.
Anti-platelet effect
COX1 converts free arachidonic acid into prostaglandin H2. Thromboxane A2 (TXA2) is generated from prostaglandin H2 by thromboxane-A synthase. Thromboxane A2 stimulates activation of new platelets and increases platelet aggregation.Inhibition of COX-1 therefore results in the inhibition of platelet aggregation for about 7-10 days (average platelet lifespan).
Metabolism
Aspirin is hydrolysed in the plasma to salicylic acid. The half-life of aspirin in the circulation is approximately 15 minutes with blood concentration dropping rapidly after complete absorption. The half-life of the salicylate metabolites is approximately 4 hours. Excretion is primarily via the renal route.Indications
- Cardiovascular disease (secondary prevention)
- Secondary prevention of DVT and PE (in patients who decline continued anticoagulation treatment)
- Acute coronary syndrome (STEMI, NSTEMI and unstable angina)
- Suspected TIA, TIA and ischaemic stroke
- Secondary prevention of ischaemic stroke and TIA
- Pain and/or pyrexia (analgesia and antipyretic)
- Migraine
- Prevention of pre-eclampsia in women at moderate or high risk
Note that in the past aspirin was widely used for primary prevention of cardiovascular disease. In 2010 the results of 2 large trials prompted the MHRA to issue a warning that aspirin should not be used for primary prevention.
Contra-indications
- Active peptic ulceration & previous peptic ulceration
- Bleeding disorders including haemophilia
- Children under 16 years (risk of Reye’s syndrome)
- Severe cardiac failure (analgesic dose)
- Breast feeding (risk of Reye’s syndrome)
- Severe hepatic impairment
- Severe renal impairment
- history of hypersensitivity to aspirin or any other NSAID
Peptic ulceration and aspirin
Aspirin inhibits prostaglandin synthesis via its inhibitory effect on COX1 and COX2.
Prostaglandin E2 (PGE2) inhibits gastric acid secretion and promotes the secretion of protective gastric mucus. Its inhibition is thought to increase the risk of peptic erosion and ulceration.
Prostacyclin, also known as prostaglandin I-2 (PGI-2) promotes vasodilation in the gastric mucosa. Its inhibition is thought to be a cause of focal areas of erosion and ulceration.
Aspirin inhibits prostaglandin synthesis via its inhibitory effect on COX1 and COX2.
Prostaglandin E2 (PGE2) inhibits gastric acid secretion and promotes the secretion of protective gastric mucus. Its inhibition is thought to increase the risk of peptic erosion and ulceration.
Prostacyclin, also known as prostaglandin I-2 (PGI-2) promotes vasodilation in the gastric mucosa. Its inhibition is thought to be a cause of focal areas of erosion and ulceration.
Cautions
- Pregnancy (see box below)
- Mild to moderate renal impairment (risk of fluid retention, further renal impairment, and gastro-intestinal bleeding)
- Mild to moderate hepatic impairment
- Asthma or allergic disease (risk of bronchospasm)
- Anaemia
- Dehydration
- Elderly
- G6PD deficiency
- History of gout
- Hypertension
- Thyrotoxicosis
Aspirin and pregnancy
There are a number of potential issues with aspirin in pregnancy, particularly at higher doses, these are summarised below:
There are a number of potential issues with aspirin in pregnancy, particularly at higher doses, these are summarised below:
- Use antiplatelet doses (300mg once daily in adults) with caution during third trimester
- Impaired platelet function and risk of haemorrhage
- Delayed onset and increased duration of labour with increased blood loss
- Avoid analgesic doses (300–900 mg every 4–6 hours in adults) if possible in last few weeks of pregnancy. Low doses probably not harmful.
- High doses may be related to intrauterine growth restriction, teratogenic effects, closure of fetal ductus arteriosus in utero and possibly persistent pulmonary hypertension of newborn
- Kernicterus may occur in jaundiced neonates.
Important drug interactions
It goes without saying that if combined with other antiplatelets, NSAID's or anticoagulant drugs there is an increased risk of bleeding. SSRI's and steroids also increase bleeding risk.
Drugs that reduce renal function should also be used cautiously in conjunction with aspirin as there is an increased risk of nephrotoxicity.
Side effects
| Common or very common | Uncommon | Rare or very rare |
|---|---|---|
| Dyspepsia haemorrhage | Dyspnoea Rhinitis Severe cutaneous adverse reactions (SCARs) Skin reactions | Aplastic anaemia Erythema nodosum GI haemorrhage Granulocytosis Haemorrhagic vasculitis Intracranial haemorrhage Menorrhagia Nausea Thrombocytopenia Vomiting |
Aspirin overdose
The main features of salicylate poisoning are hyperventilation, tinnitus, deafness, vasodilatation, and sweating. Coma is uncommon but indicates very severe poisoning.Aspirin key points
- Aspirin can be given orally or rectally. It has anti-pyretic, anti-platelet and analgesic properties.
- Aspirin can cause sodium and water retention, so caution should be exercised in renal and cardiac failure.
- It is contra-indicated in under 16 year olds due to the risk of Reye's syndrome. It is also best to avoid in breastfeeding women primarily for this reason.
- It should be avoided in pregnancy due to intrauterine growth restriction and teratogenic effects. If given in late pregnancy it may cause premature closure of fetal ductus arteriosus.