Link to [[:wikitox:2.1.1.2_nonsteroidal_anti_inflammatory_drugs_teaching_resources|2.1.1.2 Nonsteroidal Anti-inflammatory Drugs Teaching Resources]]\\ Link to [[:wikitox:problems_for_discussion_2_analgesics_and_anti_inflammatory_nsaid_poisoning|Problems for Discussion]] \\ \\ \\ Non-Steroidal Anti-Inflammatory Drugs (NSAIDS) ---- ===== Overview ===== \\ Common agents: Ibuprofen, naproxen, diclofenac, indomethacin and mefenamic acid.\\ \\ Due to their widespread availability, NSAID overdose is common. Fortunately, ingestions are generally associated with minimal to mild toxicity.\\ \\ Treatment is entirely supportive in nature, including fluid replacement and in some cases provision of activated charcoal. ---- ===== Mechanism of Toxic Effects ===== \\ In therapeutic concentrations, NSAIDs act by competitively inhibiting the enzyme cyclo-oxygenase and preventing the production of prostaglandins from arachidonic acid.\\ \\ However, cyclo-oxygenase is generally maximally inhibited with therapeutic doses and few of the acute toxic effects are attributable to this action. Thus, toxicity is not necessarily similar between different NSAIDs.\\ \\ This is evident for mefenamic acid, which causes seizures much more commonly than other NSAIDs. The mechanism for these non-class related effects are obscure. ---- ===== Risk Assessment ===== \\ Ibuprofen ingestions of less than 400mg/kg are unlikely to cause major effects. Coma has been reported with ingestions >1g/kg. Seizures can occur with mefenamic acid ingestion >25mg/kg. ---- ===== Kinetics in Overdose ===== ==== Absorption ==== \\ NSAIDs are rapidly absorbed following oral ingestion with peak concentrations at 2 hours and 2-5 hours for immediate and sustained release preparations respectively. There is minimal first-pass metabolism for most of these drugs (except for diclofenac) and so bioavailability is usually greater than 90%. ==== Distribution ==== \\ NSAIDs are weakly acidic, with a low volume of distribution (0.1-0.2 L/kg) and are highly bound to protein. ==== Metabolism-Elimination ==== \\ Metabolism is mostly hepatic with renal elimination. The half-life is variable; 2 hours for ibuprofen, diclofenac and mefenamic acid, 4 hours for indomethacin and up to 15 hours for naproxen.\\ [[:wikitox:nsaids_table_2.png?id=wiki:2.1.1.2_nonsteroidal_anti_inflammatory_drugs&media=wikitox:nsaids_table_2.png|{{:wikitox:nsaids_table_2.png?nolink&400}}]] ---- ===== Clinical Effects ===== \\ **The vast majority of NSAID poisoning and benign and asymptomatic.** \\ \\ Toxic effects of NSAID poisoning can include: * **Gastrointestinal:** Nausea, vomiting, mild upper GI irritation. GI haemorrhage is rare unless NSAIDs are being abused chronically. Mild LFT raises have been reported. * **Metabolic effects:** metabolic acidosis in large ingestion (>400mg/kg ibuprofen) * **Renal:** More common when dehydration is present, generally mild and reservable with rehydration. * **Neurotoxicity:** Drowsiness, confusion, coma and seizures are uncommon but possible with large ingestions. Seizures are predominantly seen in mefenamic acid overdose. * **Haematological:** The bleeding time is prolonged due to a reversible inhibition of thromboxane production leading to reduced platelet aggregation. NSAIDs differ in duration of effect from less than 1 day for those with short half-lives to 2 weeks or more for those with long half-lives. . ---- ===== Investigations ===== \\ **Key investigations:** * Serum electrolyte, urea and creatinine – looking for evidence of renal injury. * Bloods gas – looking for metabolic acidosis (in large ingestions). * Serum paracetamol level – in cases where patient has taken an ibuprofen-paracetamol combination agent. \\ //Note:// \\ \\ //Bilirubin levels can be falsely elevated following a naproxen overdose. This is due to interference in the bilirubin assess by a metabolite and does not represent a true elevation. The bilirubin level will normalise as the metabolite is cleared. NSAID plasma concentrations are not widely available and have not been shown to be useful for the evaluation and management of overdose. // ---- ===== Treatment ===== ==== Supportive ==== Most NSAID ingestion do not need any specific management, treatment is entirely supportive. Treatment of gastritis post NSAID ingestion has not been studied, treatment along standard lines with antacids or proton pump inhibitors can be considered and is likely to be safe. Renal impairment, if present, usually responds to rehydration. Treat seizures if they occur along standard lines with titrated benzodiazepines. Metabolic acidosis and multi-organ failure is rare and only associated with massive ingestions. ICU input for consideration of dialysis may be required. ==== Decontamination ==== Given the benign nature of most ingestion, decontamination is rarely indicated. Consider activated charcoal, in a co-operative patient, up to 2 hours post an ingestion of >400mg/kg of ibuprofen or 25 mg/kg of mefenamic acid. ==== Enhanced Elimination ==== Enhanced elimination is not indicated following NSAID ingestion. ==== Antidotes ==== There are no specific antidotes for the treatment of NSAID ingestion. ---- ===== Observation and Disposition ===== \\ Observe asymptomatic patients for 4 hours post ingestion. \\ \\ In cases with larger ingested doses a longer period of observation is required: * >400mg/kg of ibuprofen – check renal function at 8 hours and discharge if normal and patient remains well. * >25mg/kg of mefenamic acid – observe for 12 hours given risk of seizures. \\ Patients who develop renal injury should be treated supportively and discharged when renal function as improved. ---- ===== Further Reading ===== - Hunter L, Wood D and Dargan P. “The patterns of toxicity and management of acute nonsteroidal anti-inflammatory drug (NSAID) overdose.” Open Access Emergency Medicine 2011:3; 39-48. {{:wikitox:hunter_-_the_patterns_of_toxicity_and_management_of_acute_nonsteroidal_anti-inflammatory_drug_nsaid_overdose.pdf|PDF}} - Hall A et al. “Ibuprofen Overdose: 126 cases.” Ann Emerg Med 1986; 15: 1308-13 {{:wikitox:hall_-_ibuprofen_overdose_126_cases.pdf|PDF}} - Levine M, Khurana A, Ruha AM. Polyuria, acidosis, and coma following massive ibuprofen ingestion. J Med Toxicol 2010;6(3):315–7. {{:wikitox:levine_-_polyuria_acidosism_and_coma_following_massive_ibuprofen_ingestion.pdf|PDF}} - Heutlinger O, Mathew T, Fujimoto D, Bharani V, Yamarik R, Baz S. Bilirubin Elevation Caused by Naproxen Overdose: A Case Report Highlighting Laboratory Interference. Am J Case Rep. 2023 Oct 16;24:e941267. doi: 10.12659/AJCR.941267. PMID: 37845784; PMCID: PMC10588760. {{:wikitox:heutlinger_-_bilirubin_elevation_caused_by_naproen_overdose.pdf|PDF}} - Hall AH, Smolinske SC, Stover B, Conrad FL, Rumack BH. Ibuprofen overdose in adults. //J Toxicol Clin Toxicol// 1992;30(1):23-37 {{:wiki:ibuprofen_overdose_in_adults.pdf|PDF}} - Wood DM, Monaghan J, Streete P, Jones AL, Dargan PI. Fatality after deliberate ingestion of sustained-release ibuprofen: a case report. //Crit Care//. 2006;10(2):R44 [[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1550881/pdf/cc4850.pdf|PDF (113K)]]