Ibuprofen. Ibuprofen and Paracetamol: prescribing overview. Ibuprofen indications CYCLO-OXYGENASE (COX I) CYCLO-OXEGENASE (COX II) INFLAMMATORY PAIN

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1 Ibuprofen Ibuprofen and Paracetamol: prescribing overview Sarah Holloway Macmillan CNS in palliative care NSAID Non-selective COX inhibitor Oral bioavailability: 90% Onset of action: mins (can take weeks for full anti-inflammatory effect) PHL: 2-3h Duration of action: 4-6 h Metabolized in liver by p450 enzymes Palliative & End of Life Care Services N E Lincs 1 Palliative & End of Life Care Services N E Lincs 2 Ibuprofen indications Pain: arthritis, musculoskeletal disorders, postop, dental, dysmenorrhoea, headache, cancer pain Fever CYCLO-OXYGENASE (COX I) PHOSPHOLIPID ARACHIDONIC ACID PROSTAGLANDINS AND THROMBOXANES Palliative & End of Life Care Services N E Lincs 3 Palliative & End of Life Care Services N E Lincs 4 CYCLO-OXEGENASE (COX II) PHOSPHOLIPID ARACHIDONIC ACID INFLAMMATORY PAIN PGE 2 + histamine + bradykinin = vasodilation Vasodilation = increased vascular permeability, increased sensitivity of pain receptors PGE2 synthesis is increased when COX 2 is upregulated PROSTAGLANDIN E2 Palliative & End of Life Care Services N E Lincs 5 Palliative & End of Life Care Services N E Lincs 6 1

2 COX SELECTIVITY NSAIDs ostensibly targets COX 2 but also binds to and suppress COX 1 Side effects do not always reflect selectivity Specific COX 2 inhibitors exist, e.g. celecoxib, but note side effects and chequered history GASTRIC DISCOMFORT - PGE 2 has role in protecting gastric mucosa RISK FACTORS FOR COMPLICATIONS - Age>65 - Peptic ulceration in last 12 months - Long term use NSAID - Serious co-morbidity - Concurrent use of other GI irritant/anticoagulant/antiplatelet Palliative & End of Life Care Services N E Lincs 7 Palliative & End of Life Care Services N E Lincs 8 CVS RISK - COX II produces endothelial prostacyclin (PG1(2) an endogenous anticoagulant - All NSAIDS tend to raise BP (due to action on ADH) RENAL FUNCTION - Increases Cl- resorption from proximal tubules - This increases ADH so sodium and water retention - Antagonistic effect on diuretics RISK FACTOR FOR COMPLICATIONS - Previous MI or cardiac history Palliative & End of Life Care Services N E Lincs 9 Palliative & End of Life Care Services N E Lincs 10 RISK FACTORS FOR RENAL COMPLICATIONS Age >60 with co-morbidities CHF Dehydration (vasoconstriction BUT renal PG production to maintain perfusion prevented) MM (Bence Jones) Chronic NSAID use Cirrhosis, ascites Nephrotic syndrome INTERACTIONS Lots!! Generally can significantly affect plasma concentrations of renally excreted drugs Notable: - Digoxin: decreased excretion so increased plasma concentration Phenytoin: may displace this from plasma proteins and inhibit liver enzymes that metabolise ph. Palliative & End of Life Care Services N E Lincs 11 Palliative & End of Life Care Services N E Lincs 12 2

3 NSAID INDUCED ASTHMA NSAIDS AND PYREXIA PHOSPHOLIPID ARACHIDONIC ACID PGE 2 5HPTE LEUKOTRIENE C4 MAST CELLS Anti-inflammatory pathway all NSAIDS Long term pyrexia, e.g. paraneoplastic respond to all NSAIDS May need rotation after several months Second line often shorter duration effect Consider antimuscarinic, H2 antagonist, gabapentin, thalidomide? Palliative & End of Life Care Services N E Lincs 13 Palliative & End of Life Care Services N E Lincs 14 - Non anti-inflammatory analgesic, indicated in acute musculoskeletal pain and headache - Antipyretic (via prostaglandin antagonism) - Primary action is modulation of CNS cannabinoid pain receptors by paracetamol metabolite - Also strong selectivity for COX 2 (stronger in CNS cells) - And activates descending serotinergic inhibitory pain pathways Bioavailability: 60% after 500g po, 90% after 1g PR is about 2/3 po but greater with 2x500mg supps than 1g Onset of action: mins po, 5-10 mins IV (pain), 30 mins IV (pyrexia) TTPPC: very variable, 20mins 2 hrs po depending on gastric emptying, 15 mins IV PHL: 1-4 hrs po; 2-3 hrs IV Duration of action: 4-6 hrs NOTE very narrow therapeutic index Palliative & End of Life Care Services N E Lincs 15 Palliative & End of Life Care Services N E Lincs 16 METABOLISM About 10% excreted unchanged in urine Mostly metabolised in liver Most converted into metabolites that are excreted in bile Most of these metabolites are inactive BUT 5-15% converted to hepatotoxic metabolite NAPQI (N-acetyl-p-benzoquinoneimine Narrow therapeutic window Metabolism CONJUGATION OXIDATION P. gluconaride NAPQI P. sulfate Hepatotoxicity (via glutathione) Conjugation Inactive derivatives Palliative & End of Life Care Services N E Lincs 17 Palliative & End of Life Care Services N E Lincs 18 3

4 NAPQI Binds to proteins within hepatocyte cell membranes and causes necrosis Small amounts can be conjugated but overdose overwhelms the metabolism and body s stores of glutathione are rapidly diminished Risk factors for hepatotoxicity Old age Poor nutritional status Fasting/anorexia Weight < 50kg Chronic alcohol use Genetics: rapid metabolisers greater production of NAPQI Lower glutathione stores Palliative & End of Life Care Services N E Lincs 19 Palliative & End of Life Care Services N E Lincs 20 HEPATOTOXICTY CASE STUDIES Male Age 43 Crohn s 30kg Paracetamol 4g/24 hours for 4 days Died of hepatic failure Elderly pts, no other risk factors, 4g/24 hours for 4 weeks death from hepatic failure Chronic use 5-7.5g/24 hours Staggered overdose more likely to cause organ failure and less likely to survive (likely analgesic use rather than suicide attempt) Alcohol and paracetamol competitively bind to liver enzymes so alcohol at time of overdose is protective BUT alcohol use induces production of these enzymes so if chronic alcohol use stops suddenly paracetamol will be metabolised more rapidly and raise risk of hepatotoxicity TREATMENT OF OVERDOSE Use glutathione precursor e.g. IV acetylcysteine Give as soon as possible Prevents NAPQI from reacting with cell proteins Replenishes glutathione stores Protects against apoptosis Palliative & End of Life Care Services N E Lincs 21 Palliative & End of Life Care Services N E Lincs 22 CAUTIONS Severe hepatic impairment Renal failure use lower doses Dispersible formulations have large amount of Na so avoid in renal failure and hypertension Give test dose to pts with history of NSAID induced asthma (about 2/3 can take without problems) Use in pregnancy and early childhood increases risk of childhood asthma INTERACTIONS Warfarin concurrent paracetamol causes significant dose dependent increase in INR, possibly because paracetamol interferes with hepatic synthesis of clotting factors Anticonvulsants may increase rate of metabolism of paracetamol Some cytotoxics: paracetamol may inhibit metabolism of these Metoclopramide may increase rate of paracetamol metabolism Palliative & End of Life Care Services N E Lincs 23 Palliative & End of Life Care Services N E Lincs 24 4

5 COMBINING WITH OPIODS Opioid sparing effect in post-op pain But trial evidence for this in cancer pain is not convincing Tablet burden: if not helping within 48 hrs stop it If using paracetamol then pain increases and add opioid, once pain stable stop paracetamol and if no worsening of symptoms don t restart Palliative & End of Life Care Services N E Lincs 25 5