NSAIDs Flashcards
What is the role of arachidonic acid is prostaglandin synthesis.
The cyclo-oxygenase enzymes (COX-1 and COX-2) synthesise prostanoids, (which include prostaglandins, prostacyclins and thromboxanes) from arachidonic acid (which is derived from membrane phospholipids)
How do NSAIDs work?
NSAIDs inhibit the cyclo-oxygenase enzymes (COX1 and COX2), which are responsible from cleaving arachidonic acid to prostanoids:
- Prostaglandins which causes dilation of smooth muscle (increases vascular permeability too but indirectly by increasing bradykinin)
- Prostacyclins vasodilates
- Thromboxanes cause platelet synthesis
What are the different prostaglandin receptors? What does their activation result in?
• EP1 receptor expressed on C fibres (nociceptors) – involved in pain. They are Gq receptors – increases intracellular calcium. Activation results in:
o Increased sensitivity of the neuron to bradykinin
o Inhibition of potassium channels
o Increased sensitivity of sodium channels -hyperexcitable causing hyperalgesia and allodynia (a normally non-painful stimulus causes pain because threshold reached more easily)
o All of which act to increase the activity of the C fibre
• EP2 receptors (which are Gs) are expressed in the dorsal horn, prostaglandins enhance pain transmission by removing glycinergic inhibition, enhancing sensitivity of secondary interneurons. leads to central sensitisation
• EP3 – responsible for pyrexia. It is Gi.
Heat production and less heat loss (this is beneficial when infected as better at killing micro-organisms and protecting the brain)
What are the therapeutics/ADRs of NSAID action on COX1 and COX2 receptors?
Inhibition of COX-1 results in most NSAID ADRs – it is widely expressed and its PG synthesis protects the gastric mucsa, the myocardium, the renal parenchyma by ensuring optimal local perfusion. The enzyme has a short half life and needs constant synthesis.
Inhibition of COX-2 provides the therapeutic benefit – COX-2 is induced in inflammatory cells (by mediators like bradykinin) that have been activated by cytokines, and the prostanoids mediate the inflammatory response. Blocking this pathway provides anti-inflammatory action, and also analgesia (since prostanoids stimulate nociceptors). COX-2 is constitutively expressed in the kidneys and brain.
What are the uses of NSAIDs?
Analgesia: reduces synthesis of prostaglandins which sensitise nociceptors to inflammatory mediators, reduces headache pain by preventing cerebral vasodilation mediated by prostaglandins. Secondary effect on facilitation of transmission of pain in the dorsal horn.
Anti-inflammatory: prostaglandins are involved in the orchestration of the inflammatory response – so antagonising them can help to reduce erythema, swelling, and the pain associated with swelling.
Antipyresis: bacterial endotoxins trigger macrophages to release endogenous pyrogen, which triggers the hypothalamus to produce prostaglandin E – this elevates the set point of the central thermostat. Reduction of prostaglandin synthesis prevents this elevation of temperature.
So:
MSK disorders - OA/RA
Mild/moderate pain
How do NSAIDs result in analgesia?
reduces synthesis of prostaglandins which sensitise nociceptors to inflammatory mediators, reduces headache pain by preventing cerebral vasodilation mediated by prostaglandins. Secondary effect on facilitation of transmission of pain in the dorsal horn.
How do NSAIDs result in anti-inflammation?
Prostaglandins are involved in the orchestration of the inflammatory response – so antagonising them can help to reduce erythema, swelling, and the pain associated with swelling.
How do NSAIDs result in antipyresis?
Bacterial endotoxins trigger macrophages to release endogenous pyrogen, which triggers the hypothalamus to produce prostaglandin E – this elevates the set point of the central thermostat. Reduction of prostaglandin synthesis prevents this elevation of temperature.
What kinetics do NSAIDs show? What are the half-lives of different NSAIDs?
First order kinetics
• Ibuprofen/Diclofenac – 2 hours
• Naproxen – 14 hours
Aspirin has dose-dependent pharmacokinetics – first order at low doses, higher doses exhibit zero-order kinetics. It has a very short half-life as it is hydrolysed in plasma to salicylate
What are ADRs of NSAIDs? What does this occur?
ADRs (due to COX-1 inhibition)
• Prostaglandins usually protect the gastric mucosa by inhibiting acid secretion and stimulating mucus production. Inhibiting prostaglandin synthesis increases mucosal permeability and decreases blood flow. All this can lead to (particularly with chronic use in the elderly):
o Ulceration
o Haemorrhage
o Perforation
• Renal ADRs – reduction in renal blood flow and GFR
• Skin reactions
• Asthmatic bronchospasm
• Allergy
• Prolonged bleeding time
• Aspirin can lead to post-viral Reye’s Syndrome in children (brain and liver injury)
What are DDIs of NSAIDs?
- Aspirin and warfarin – displaces warfarin from plasma proteins increasing free concentration & both affect platelet aggregation
- NSAIDs and ACEIs – attenuate the action of ACEIs (since prostaglandins vasodilate and their production is being stopped)
- NSAIDs are highly protein bound – affects sulphonylureas (hypoglycaemia), warfarin (bleeding) and methotrexate – need to adjust dosage
How do NSAIDs affects platelet function?
Aspirin is the best example of the effect of NSAIDs on platelets as it irreversibly inactivates COX-1. COX-1 produces thromboxanes which are important in platelet aggregation, so aspirin (given low dose and long term) can reduce the likelihood of thrombus formation.
How does paracetamol work?
What are the pharmacokinetics of paracetamol?
Paracetamol is similar to the NSAIDS in structure but lacks the anti-inflammatory properties. It is still the first choice agent for mild pain and fever. It seems to selectively inhibit COX enzymes in the CNS, metabolites in the CNS can combine with arachidonic acid – this substrate inhibits COX-1 and COX-2 in the CNS.
At therapeutic dose ADRs are uncommon – can include minor hepatic insult with chronic use.
Pharmacokinetics – peaks within 30 minutes to an hour when given orally, the half life is 2-4 hours, half life increases at toxic doses due to hepatotoxicity.
First order kinetics.
Phase II conjugation to glucoronide or sulphate - 10% phase I to NAPQI which is detoxified by glutathione in phase II.
Paracetamol is given with weak opiates to enhance its analgesic effect.
No need to monitor hepatic and renal function unless given in the long term.
What happens in paracetamol overdose? How to treat?
Due to saturation of phase 2 metabolism of paracetamol, means it is then metabolised by CYP450 enzymes to NAPQI then conjugated with glutathione. NAPQI is toxic to the liver once glutathione has been depleted – it binds to macromolecules leading to necrotic cell death. It also exerts a systemic burden as the liver cant deal with free radicals - The lack of glutathione also makes the body vulnerable to reactive oxygen species as it then has no anti-oxidant defenceproduced elsewhere.
How to treat paracetamol overdose?
You should treat within 8 hours if possible. If you see the patient within an hour give activated charcoal by mouth. After that give IV n-acetylcysteine (or oral methionine) to replace the depleted glutathione. If treatment isnt given within 24-48 hours the patient is likely to die of liver failure.
They will be asymptomatic at first, then develop liver failure, also possibly renal tubular necrosis and hypoglycaemic coma.
