- Asprin absorbed and hydrolysed to acetic acid and then salicylate in tissue and blood esterases.
- Asprin has pKA of 3.5 and salicylic acid is an Organic acid with PkA 3
- Rapidly absorbed from stomach and upper GI, reaching peak concetration in 1-2hrs
- Salicylate is non linearly bound to albumin
- Alkalinization of urine increases rate of excretion.
- Gastric trapping – asprin is a weak acid so in an acidic environment like the stomach it stays unionized. Unionized substances are more lipophilic so they are easy absorbed into the cells and into the blood stream. The blood has a pH of 7.4 so asprin ionizes which prevents it from diffusing back into the stomach.
- Variable-order kinetics.
- Elimination half life varies because glycine conjugation (salicylate to salicyluric acid) may become saturated in overdose resulting in zero-order kinetics
- Irreversible acetylates and blocks platelet cyclo-oxygenase
- Used for its anti platelet aggregation rather than analgesia.
- Effect lasts for 8-10d
- Salicylate is the major active metabolite of asprin, it has T1/2 of 2-19hrs and 2-30% of it is renally excreted
- Uses – decreases incidence of MI, unstable angina, TIA, throbosis after CABG and decrease rate of colon ca.
- Aspirin overdose.
- Common features – sweaty, tinnitus, blurred vision, tachycardia, pyrexia, hyperventilation, resp alkalosis
- Rare/high dose – unconscious, nausea, vomiting, coagulopathy, GI bleed, pulm oedema, hypoK
- Reye syndrome – rare, mainly affects children – causes widespread mitochondrial damage–> hepatic failure, cerebral oedema, 40% mortality
- Treatment – activated charcoal, forced alkaline diuresis, haemodialysis
- Seen in synovial fluid after repeat dosing
- Renally excreted mostly, some biliary excretion
- Metabolised by P450 system in liver
- Well absorbed, 98% protein bound
- All are weak organic acids except nabumetone.
- Anti inflammatory, antipyretic, analgesic. Inihibit platelet aggreggation(except COX2 inhibitors)
- Inhibition of synthesis of prostaglandins
- COX 1 – homeostatic, Cox 2 – inflammation – selectivity varies
- Decrease sensitivity of vessels to histamine and bradykinin, reverse vasodilation of inflammation in affect lymphokine production of T-cells
- Gastric irritants, can lead to GI ulcers and bleeds, abdo pain
- CNS – headache, tinnitus, dizziness
- CVS – fluid retention, HTN
- Rash, allergy
Know that there are 4 classes
- Nonacetylated salicylates – anti inflamm, less COX inhibition and analgesia than asprin
- COX 2 selective inhibitors
- Celecoxib, meloxicam\
- Half the GI side effects, same anti inflammatory and analgesic effects.
- COX 2 inhibitors don’t affect platelet function at normal doses. They can increase incidence of oedema and hypertension. They are associated with increased thrombotic cardiovascular events.
- Non selective COX inhibitors
- Diclofenac – used in eye drops for post surgical eye inflammation
- Ibuprofen – closes patent ductus arteriosus in preterm babies, topical and oral use, causes less fluid retention and decrease in urine output compared to indomethacin. Concurrent use with asprin can lower its cardioprotective role.
- Indomethacin – reduce neutrophil migration, lower T cell and B cell proliferation, inhibit phospholipase A and C. Uses – closes PDA, gout, ank spon. Probenecid prolongs indomethacin’s half life. Other SE – pancreatitis, headache, confusion, depression, thrombocytopenia, aplastic anaemia.
We wouldn’t advocate strongly about learning other anti-rheumatic drugs (e.g. Gold, Penicillamine, Methotrexate, etc.)
Steroids will be covered later in Week 20
- Analgesic and antipyretic
- No significant anti-inflammatory properties
- Weak Cox 1 and 2 inhibitor
- Oral administrataion
- Absorption related to rate of gastric emptying
- Peak blood concentration in 30-60mins
- Slightly bound to plasma proteins
- Hepatic metabolism to inactive metabolites – sulfate and glucuronide
- Less than 5% excreted unchanged
- T 1/2 2-3 hrs (can double in toxicity or liver impairment)
- SE – mild rise in transminases,
- NAPQ is a minor but active metabolite which is toxic at high levels to liver and kidney
- Paracetamol overdose.
- 15g (159mg/kg) is fatal, over 4g/d is toxic.
- Severe hepatotoxicity – centrilobular necrosis
- Sometime renal tubular necrosis
- Sx – nausea, vomiting, diarrhoea, abdo pain, usually conscious
- Normal hepatic conjugation pathways become saturated so accumulation of NAPQ results in hepatotoxicity
- Rx – supportive treatment, check paracetamol levels 4hrs apart if above toxic levels give N-acetylcysteine which replenishes hepatic glutathione so acetaminophen can continue to be metabolised to its inactive metabolite.
- Readily absorbed after oral admin, peak plasma level in 2hrs, T1/2 9hrs, metabolised and excreted in intestinal tract and urine
- No change in urates
- Binds intracellular protein tubulin–> prevents polymerization into microtubules–> inhibition of leukocyte migration and phagocytosis. Inhibits Leukotriene B4 formation too.
- Relieves pain and inflammation of gout in 12-24hrs
- NSAIDS have largely replaced cholchicine in acute gout, it is instead used in prophylaxis of recurrent gout
- SE – diarrhoea, nausea, vomiting, abdo pain, hepatic necrosis, acute renal failure, DIC, seizures.
- OD – burning throat pain, bloody diarrhoea, shock, haematuria, oliguria. Fatal ascending CNS depression. Supportive treatment.
- Used for gout prophylaxis
- Reduces total uric acid body burden by inhibiting Xanthine oxidase(allopurinol metabolised by XO but the metabolite alloxanthine inhibits XO)
- Can precipitate gout so needs cholchicine or NSAID cover when starting it
- 80% absorbed after oral admin
- T 1/2 1-2hrs
- Given once a day
- SE – GI upset, nausea, vomiting, diarrhoea, 3% get allergic maculopapular rash, necrotising vasculitis, aplastic anaemia all rare.
- Need to dose reduce chemotherapeutics when given concurrently
- Target uric acid level below 6mg/dL.
- Tell me about Aspirin .
- Tell me about Aspirin overdose.
- Tell me about the NSAIDs.
- Tell me about Paracetamol.
- Tell me about Paracetamol toxicity.
- Tell me about Colchicine overdose.
- What drugs can be used for gout ?