S8 NSAIDS Flashcards
The inflammatory response
A protective response to injurious stimuli to reduce risk of further damage to organism. Local injury results in an inflammatory signalling response provided by autacoids (e.g bradykinins, histamines, cytokines. Prostaglandins are eicosanoids), it is rapid, localised and has short half-lives.
Prostaglandins
• Synthesised from arachidonic acid, which itself is produced from cell memb phospholipids via phospholipaseA2. The pathway involves metabolism by COX enzymes;
o Phospholipidsarachidonic acid, which is metabolised by COX 1 to PG G, which is metabolised by COX 2 to PG H
o From PG H we can produce specific PGs, PG E most important in mediating inflammatory response.
• Prostaglandins bind to GPCRs, the action usually involves synergising effects of other autacoids
• Autacoid release following injury induces the expression of COX-2 and prostaglandins themselves synergise the action of other autacoids, which means there is a positive feedback loop mechanism
• PGs act as potent vasodilators. They induce pain, pyrexia and inflammation, which NSAIDs can prevent by inhibiting prostaglandins
Effects of NSAIDs
Anti-inflammatory
• Following injury, there’s increased release of PGE2 which results in swelling. NSAIDs inhibit COX leading to reduced PGE2 synthesis. This reduces inflammation but has little effect on the underlying condition
Analgesic
• Decreased synthesis of PGE2 in the dorsal horn leads to reduced neurotransmitter release, and therefore reduced excitability of pain relay neurones
Anti-pyretic
• Cytokines act on the hypothalamus to stimulate PGE2 release, this causes increased [Ca2+] and increased temp. NSAIDs inhibit hypothalamic COX2 enzymes, reducing PGE2 and therefore temp
Cox enzymes
Both convert arachidonic acid to PGH
COX 1
COX-1 is expressed in a wide range of tissues, PG synthesis by COX-1 has a major cytoprotective role (in gastric mucosa, renal blood flow, platelet aggregation). Due to PG t1/2 of 10 minutes, need constant synthesis of it. However, due to its constitutive expression, most of the ADRs of NSAIDs are caused by COX-1 inhibition
cox 2
COX-2 expression induced by inflammatory mediators (e.g bradykinin) and so is only expressed during injurious stimuli. Involved in renal homeostasis and tissue repair. The main therapeutic effects of NSAIDs come via COX-2 inhibition.
COX-1 and COX-2 do not work independently and PG synthesis from both enzymes is dependent on tissue and organ type.
NSAIDs
Main therapeutic effect of NSAIDs achieved via COX-2 inhibition (celecoxib), but most NSAIDS will competitively inhibit the COX-1 and COX-2, by occupying arachidonic acid binding sites. NSAIDs vary in affinity and efficacy to the COX-enzymes. However, all NSAIDs act as analgesics, anti-inflammatories, and antipyretics.
Pharmacokinetics
- Given orally
- Show linear pharmacokinetics (first-order elimination) within therapeutic dose range
- Two groups; those with short half-lives <6hrs, and long >10hrs
- Are heavily bound to plasma proteins
Uses
Anti-Inflammatories in MSK disorders. Analgesia (pain relief).
ADRs
Inhibition of COX-1 constitutive PG synthesis leads to many side effects;
• GI: COX-1 PGE2 usually stimulates protective mucus production and inhibits acid secretion, thus inhibition to PGE2 production will result in damage to the stomach. Can lead to ulceration, gastric bleeding.
• Renal: occurs in young/old, PGE2 maintains renal blood flow, if PGE2 reduced by NSAIDs then GFR shall drop, hypertension can also occur
• Vascular: NSAIDs cause increased risk of prolonged bleeding time, haemorrhage, and increased bruising
• Hypersensitivity: skin rashes (mild or severe e.g Stevens Johnson syndrome)
• Reyes syndrome: brain/liver injury
Drug interactions
NSAIDs can be used in combination with low-dose opiates, extending the range for treating pain and will also reduce the ADRs seen with opiates alone.
However, use of combination of NSAIDs can increase risk of ADRs, as they affect each other’s binding of plasma protein; this is important with NSAIDs and low-dose aspirin administration, as they compete for the COX-1 binding sites and interfere with the cardioprotective mechanism of aspirin.
Furthermore, the protein binding of NSAIDS can mean certain drugs are displaced by NSAIDs and may require dose adjustment if they want to prevent:
• ↑ Sulphonylurea – hypoglycaemia
• ↑ Warfarin – increased bleeding
• ↑ Methotrexate – hepatotoxicity
Aspirin
- Only NSAID which irreversibly inhibits COX enzymes via acetylation (not by competitive blocking).
- Gets converted to salicylate
- Also acts as an as an anti-platelet as it prevents thromboxane A2 production
Paracetamol
Not an NSAID. Effective for mild analgesia and fever. Less ADRs than NSAIDs. Its therapeutic dose is 8x500mg a day, yet should be lowered for those with compromised hepatic function. Unknown action but appears to selectively inhibit COX 1&2 activity in CNS. First order PKs, half-life 2-4hrs.
