Fever

Question 1

Aspirin

Common indications

Answer 1

1. For treatment of acute coronary syndrome and acute ischaemic stroke, where rapid inhibition of platelet aggregation can prevent or limit arterial thrombosis and reduce subsequent mortality.
2. For long-term secondary prevention of thrombotic arterial events in patients with cardiovascular, cerebrovascular and peripheral arterial disease.
3. To reduce the risk of intracardiac thrombus and embolic stroke in atrial fibrillation where warfarin and novel oral anticoagulants are contraindicated.
4. To control mild-to-moderate pain and fever (see Non-steroidal anti-inflammatory drugs, although other drugs are usually preferred, particularly in patients with inflammatory conditions).

Question 2

Aspirin

MOA

Answer 2

• Thrombotic events occur when platelet-rich thrombus forms in atheromatous arteries and occludes the circulation.
• Aspirin irreversibly inhibits cyclooxygenase (COX) to reduce production of the pro-aggregatory factor thromboxane from arachidonic acid, reducing platelet aggregation and the risk of arterial occlusion.
• The antiplatelet effect of aspirin occurs at low doses and lasts for the lifetime of a platelet (which does not have a nucleus to allow synthesis of new COX) and thus only wears off as new platelets are made.

Question 3

Aspirin

Important adverse effects

Answer 3

• The most common adverse effect of aspirin is gastrointestinal irritation.
• More serious effects include gastrointestinal ulceration and haemorrhage and hypersensitivity reactions including bronchospasm.
• In regular high-dose therapy aspirin causes tinnitus.
• Aspirin is life-threatening in overdose. Features include hyperventilation, hearing changes, metabolic acidosis and confusion, followed by convulsions, cardiovascular collapse and respiratory arrest.

Question 4

Aspirin

Warnings

Answer 4

• Aspirin should not be given to children aged under 16 years due to the risk of Reye’s syndrome, a rare but life-threatening illness that principally affects the liver and brain.
• It should not be taken by people with aspirin hypersensitivity, i.e. who have had bronchospasm or other allergic symptoms triggered by exposure to aspirin or another NSAID.
• However, aspirin is not routinely contraindicated in asthma. Aspirin should be avoided
• In the third trimester of pregnancy when prostaglandin inhibition may lead to premature closure of the ductus arteriosus.
• Aspirin should be used with caution in people with peptic ulceration (e.g. prescribe gastroprotection) or gout, as it may trigger an acute attack.

Question 5

Aspirin

Interactions

Answer 5

• Aspirin acts synergistically with other antiplatelet agents, which although therapeutically beneficial can lead to increased risk of bleeding.
• Thus, although it may be given with antiplatelet drugs (e.g. clopidogrel, dipyridamole) and anticoagulants (e.g. heparin, warfarin) in some situations (e.g. acute coronary syndrome), caution is required.

Question 6

Aspirin

prescription

Answer 6

• ACS: Initially 300mg, followed by 75mg OD
• Ischaemic stroke: 300mg OD for 2 weeks then 75mg OD thereafter
• Long-term prevention of thrombosis in patients with AF: 75mg OD
• Pain: 4g in divided doses
• NB- aspiri shoudl come with GI protection (PPI) in people who have risk factors
  
  • >65, Peptic ulcer disease, Co-morbidities (CVD, diabetes etc), concurrent therapy with other drugs with GI effects: NSAIDs, pred

Question 7

Paracetamol

Common indications

Answer 7

1. Acute and chronic pain
2. Fever

Question 8

Paracetamol

MOA

Answer 8

• The mechanisms of action of paracetamol are poorly understood. Paracetamol is a weak inhibitor of cyclooxygenase (COX), the enzyme involved in prostaglandin metabolism.
• In the central nervous system, COX inhibition appears to increase the pain threshold and reduce prostaglandin (PGE2) concentrations in the thermoregulatory region of the hypothalamus, controlling fever.
• Paracetamol has specificity for COX-2 (the isoform induced in inflammation) rather than COX-1 (the isoform involved in protecting the gastric mucosa and regulating renal
• blood flow and clotting).
• However, despite its COX-2 selectivity, paracetamol is a weak anti-inflammatory, as its actions are inhibited in inflammatory lesions by the presence of peroxides.

Question 9

Important adverse effects

Paracetamol

Answer 9

• At treatment doses, paracetamol is very safe with few side effects. Lack of COX-1 inhibition means that it does not cause peptic ulceration or renal impairment or precipitate cardiovascular events (unlike NSAIDs).
• Its safety makes it a popular choice as a first-line analgesic. In overdose, paracetamol causes liver failure.
• Paracetamol is metabolised by cytochrome P450 enzymes to a toxic metabolite (N-acetyl-p-benzoquinone imine [NAPQI]), which is conjugated with glutathione before elimination.
• After overdose, this elimination pathway is saturated, and NAPQI accumulation causes hepatocellular necrosis.
• Hepatotoxicity can be prevented by treatment with the glutathione

Question 10

Warnings

Paracetamol

Answer 10

• Paracetamol dose should be reduced in people at increased risk of
  liver toxicity, either because of increased NAPQI production (e.g. in
  chronic excessive alcohol use, inducing metabolising enzymes)
  or reduced glutathione stores (e.g. in malnutrition, low body
  weight (<50 kg) and severe hepatic impairment).
• This is particularly important where paracetamol is given by IV infusion.