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Nonsteroidal Anti-Inflammatory Drug Poisoning

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Ovid: 5-Minute Sports Medicine Consult, The


Nonsteroidal Anti-Inflammatory Drug Poisoning
Kenneth Barnes
Shane Hudnall
Basics
  • Primary effect is competitive inhibition of cyclooxygenase (COX) enzyme, thus inhibiting production of prostaglandins, thromboxanes, and prostacyclin from arachidonic acid
  • There are 2 COX isoforms, COX-1 and COX-2.
  • COX-1 is expressed in most tissues.
  • COX-2 is induced more in inflammation and pain.
  • Most adverse effects are attributed to COX-1 inhibition.
  • Class of drugs works as antipyretics, analgesics, and anti-inflammatory agents.
  • Reduction of circulating prostacyclin and thromboxane results in platelet aggregation and vasodilation, respectively.
  • OTC NSAIDs include ibuprofen, naproxen, and aspirin.
  • Classification:
    • Carboxylic acids:
      • Salicylates: Aspirin, diflunisal
      • Propionic acids: Ibuprofen, naproxen, ketoprofen
      • Acetic acids: Indomethacin, etodolac, ketorolac, sulindac, diclofenac
      • Fenamates: Meclofenamate, mefenamic acid
    • Enolic acids:
      • Oxicams: Piroxicam, meloxicam
      • Pyrazolones: Phenylbutazone
    • COX-2 inhibitors: Celecoxib
  • Meloxicam and etodolac have slightly greater inhibition of COX-2 than COX-1 at low doses (1).
Epidemiology
Incidence
  • Up to 20 million Americans take NSAIDs on a regular basis.
  • It is estimated that >30 billion OTC NSAID tablets are sold annually in the U.S.
  • ∼70 million NSAID prescriptions are written each year in the U.S.
  • NSAID poisoning is rare despite their extensive use.
  • Aspirin caused 63 fatalities and other NSAIDs 44 fatalities in 2007 in the U.S.
  • Most poisonings are attributable to ibuprofen (nearly 80,000 total) (2).
Risk Factors
  • Suicidal ideation
  • Untreated pain
  • Patients unclear of maximum allowed dosage of NSAIDs
Etiology
  • Toxicity (3,4,5):
    • Only a small percentage of overdoses (<1%) lead to serious harm (ie, GI bleeding, renal failure).
    • Most are asymptomatic or have nonspecific symptoms (eg, nausea, vomiting, dizziness, somnolence).
    • Generally doses >400 mg/kg of an NSAID are needed to cause severe toxicity.
    • COX-2 inhibitors have been shown to decrease HTN, edema, and hepatotoxicity in addition to the other benefits listed below.
  • GI:
    • Most common adverse effects are GI related (ie, vomiting, abdominal pain, dyspepsia, diarrhea, constipation).
    • Gastric, duodenal, and large intestinal ulceration may occur (1–4% of users annually).
    • 3–10× more likely to have serious hemorrhage with NSAIDs
    • COX-2 inhibitors have been shown to delay ulcer healing in animal studies, but this has not been elucidated in humans (6).
    • Celecoxib may be associated with decreased colon adenomas and cancer from inhibiting COX-2 and tumor growth. More studies are being done on this to assess the validity of this finding (7).
  • Renal:
    • 2nd most common adverse effects
    • Inhibition of prostaglandins interferes with renal blood flow and glomerular filtration rate.
    • Leads to vasoconstriction (from blocking prostaglandin synthesis) and possibly acute renal failure or acute interstitial nephritis
    • Retention of sodium, potassium, and water may lead to CHF exacerbation.
    • COX-2 inhibitors: Little toxicity demonstrated at renal level, but use caution in patients who are dehydrated, have renal insufficiency, heart failure, or cirrhosis (8).
  • CNS:
    • Elderly particularly at risk
    • Can cause headache, confusion, delirium, psychosis, hallucinations, nightmares, tremor, seizures, tinnitus, transient hearing loss, and aseptic meningitis
  • Cardiovascular:
    • Can raise BP and worsen control of HTN
    • Controversy exists regarding whether or not NSAIDs in combination with aspirin leads to increased mortality and cardiovascular events (9,10).
    • COX-2 inhibitors may increase cardiovascular risk, although celecoxib has not yet been shown at recommended doses to confer this risk. Rofecoxib and valdecoxib were withdrawn from the market (September 2004).
    • All are associated with increased risk of CHF exacerbation in those with a history of CHF.
  • Pulmonary:
    • Respiratory arrest is rare.
    • Asthmatics are at increased risk for bronchospasm owing to increased production of leukotrienes.
    • COX-2 inhibitors are much less likely to trigger bronchospasm.
    • Pulmonary infiltrates with eosinophilia are also possible.
    • Patients with clinical triad of asthma, nasal polyps, and allergic rhinitis are at increased risk of anaphylaxis to both salicylates and NSAIDs.
  • Hepatic:
    • Possibility (though rare) of fulminant hepatic failure, hepatitis, elevated transaminases
    • Generally this is reversible and only rarely fatal.
  • Hematologic:
    • Aplastic anemia (now rare with decreased use of phenylbutazone and indomethacin), agranulocytosis, neutropenia, hemolytic anemia, thrombocytopenia possible
    • Decreased platelet aggregation may lead to increased GI bleeding.
    • COX-2 inhibitors have not been shown to decrease platelet function and are associated with a decreased risk of bleeding compared with nonselective NSAIDs.
  • Skin: Toxic epidermal necrolysis and Stevens-Johnson syndrome are uncommon, but relative risk is increased slightly with NSAID use compared with placebo.
  • Metabolic: May lead to anion-gap metabolic acidosis
  • Drug interactions:
    • Increased risk of GI bleeding when used with anticoagulants
    • Digoxin, lithium, sulfonylurea, and aminoglycoside levels are all increased with use of NSAIDs.
    • NSAIDs reduce antihypertensive effects of diuretics, beta blockers, and ACE inhibitors.
    • Celecoxib contains a sulfa moiety and thus is contraindicated in patients allergic to sulfa-containing agents.

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Diagnosis
History
  • There is a poor correlation between the amount ingested and toxic poisoning, although significant symptoms may occur after 5–10× the maximum dose has been ingested.
  • Timing of ingestion
  • Past medical history (ie, peptic ulcer disease, chronic renal insufficiency)
Physical Exam
  • ABCs
  • Vital signs: Monitor BP, respiratory rate, and oxygen saturation.
  • Thorough neurologic examination (especially monitoring mental status)
  • Rectal examination for gross or occult blood
Diagnostic Tests & Interpretation
Lab
  • CBC, comprehensive metabolic panel (attention to transaminases), prothrombin time/partial thromboplastin time (PT/PTT; coagulation studies), arterial blood gases (if patient has anion gap on CMP or altered mental status), fingerstick glucose (rule out hypoglycemia), pregnancy test (if child-bearing female)
  • Consider salicylate and acetaminophen levels, but do not check serum or urine levels of other NSAIDs. Just treat presumptively.
  • ECG to look for prolongation of QRS or QTc
Imaging
Generally not necessary unless concern for perforated ulcer is present
Treatment
  • Acute treatment:
    • Supportive measures:
      • Call poison control.
      • Secure the ABCs.
      • There is no antidote for NSAID poisoning.
      • Close monitoring is warranted for almost all patients, and usually this is the only treatment necessary.
      • Consider giving IV fluids if there is any volume deficit clinically.
      • Benzodiazepines IV if patient has seizures
    • Decontamination:
      • Gastric lavage if patient presents within 1 hr of ingestion or patient has massive overdose
      • Activated charcoal (1 g/kg adults, 0.5–1 g/kg in children) should be given to all patients with acute NSAID ingestion unless contraindicated (eg, bowel perforation) (11).
      • Dialysis is unnecessary and ineffective.
  • Long-term treatment: Disposition:
    • Admit patient for any signs of toxicity (eg, renal failure, vital sign changes, somnolence, electrolyte abnormalities).
    • Asymptomatic patients should be monitored for 4–6 hr to ensure that they do not have any signs of toxicity before discharging home (possibly longer for drugs such as naproxen that have longer half-lives).
    • Obtain psychiatric consultation for suicide attempts once medically stable.
References
1. Glaser K, Sung ML, O'Neill K, et al. Etodolac selectively inhibits human prostaglandin G/H synthase 2 (PGHS-2) versus human PGHS-1. Eur J Pharmacol. 1995;281:107–111.
2. American Association of Poison Control Centers 2008 Annual Report. http://www.aapcc.org/DNN/Portals/0/NPDS%20reports/2008%20AAPCC%20Annual%20Report.pdf
3. Carson JL, Willett LR. Toxicity of nonsteroidal anti-inflammatory drugs. An overview of the epidemiological evidence. Drugs. 1993;46 (Suppl 1):243–248.
4. Hall AH, Smolinske SC, Stover B, et al. Ibuprofen overdose in adults. J Clin Toxicol. 1992;30:23–37.
5. Keller KH. In: Olson KR, ed. Poisoning and drug overdose. Stamford: Appleton & Lange, 1999.
6. Mizuno H, Sakamoto C, Matsuda K, et al. Induction of cyclooxygenase 2 in gastric mucosal lesions and its inhibition by the specific antagonist delays healing in mice. Gastroenterology. 1997;112:387–397.
7. Sheehan KM, Sheahan K, O'Donoghue DP, et al. The relationship between cyclooxygenase-2 expression and colorectal cancer. JAMA. 1999;282:1254–1257.
8. Perazella MA, Eras J. Are selective COX-2 inhibitors nephrotoxic? Am J Kidney Dis. 2000;35:937–940.
9. García Rodríguez LA, Varas-Lorenzo C, Maguire A, et al. Nonsteroidal antiinflammatory drugs and the risk of myocardial infarction in the general population. Circulation. 2004;109:3000–3006.
10. Kurth T, Glynn RJ, Walker AM, et al. Inhibition of clinical benefits of aspirin on first myocardial infarction by nonsteroidal antiinflammatory drugs. Circulation. 2003;108:1191–1195.
11. Donovan JW. In: Haddad LM, ed. Clinical management of poisoning and drug overdose. Philadelphia: WB Saunders, 1998.
Additional Reading
Andreoli TE, Carpenter CCJ, Griggs RC, et al. Cecil Essentials of Medicine. 6th Ed. 2004.
Braunwald E, Fauci AS, Kasper DL, et al. Harrison's Principles of Internal Medicine, 15th Ed. 2001.
Bruno GR, Carter WA. In: Tintinalli JE, ed. Emergency medicine: a comprehensive study guide. New York: McGraw-Hill, 2000.
Hall AH, Smolinske SC, Conrad FL, et al. Ibuprofen overdose: 126 cases. Ann Emerg Med. 1986;15:1308–1313.
Halpern SM, Fitzpatrick R, Volans GN. Ibuprofen toxicity: A review of adverse reactions and overdose. Adverse Drug Reac Toxicol Revi. 1993;12:107–128.
Palmer ME, Howland MA. In: Goldfrank LR, ed. Gotdfrank's toxicologic emergencies. Stamford: Appleton & Lange, 1998.
Patrignani P, Panara MR, Greco A, et al. Biochemical and pharmacological characterization of the cyclooxygenase activity of human blood prostaglandin endoperoxide synthases. J Pharmacol Exp Ther. 1994;271:1705–1712.
Polisson R. Nonsteroidal anti-inflammatory drugs: practical and theoretical considerations in their selection. Am J Med. 1996;100:31S–36S.
20. Seger DL, Murray L. In: Rosen P, ed. Emergency medicine: concepts and clinical practice. St. Louis: Mosby, 1998.
21. Silverstein FE, Faich G, Goldstein JL, et al. Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA. 2000;284:1247–1255.
22. Simon LS, Weaver AL, Graham DY, et al. Anti-inflammatory and upper gastrointestinal effects of celecoxib in rheumatoid arthritis: a randomized controlled trial. JAMA. 1999;282:1921–1928.
Codes
ICD9
  • 965.7 Poisoning by other non-narcotic analgesics
  • 965.9 Poisoning by unspecified analgesic and antipyretic
  • 965.61 Poisoning by propionic acid derivatives
  • 965.69 Poisoning by other antirheumatics
Clinical Pearls
  • Studies have shown that there is no additional benefit to giving >1 dose of activated charcoal.
  • Ipecac generally has fallen out of favor for most if not all acute ingestions. It is no longer recommended for NSAID toxicity.


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