TECHNICAL DETAILS:

Acetaminophen is the most widely used pharmaceutical analgesic and antipyretic agent in the United States and the world; it is contained in more than 100 products. As such, acetaminophen is one of the most common pharmaceuticals associated with both intentional and accidental poisoning. Acetaminophen is one of the most common agents in overdose reported to the American Association of Poison Control Centers. Acetaminophen(APAP) toxicity is the most common cause of hepatic failure requiring liver transplantation in the United States and Great Britain. Paracetamol is derived from coal tar, and is part of the class of drugs known as "analine analgesics”; it is the only such drug still in use today. It is the active metabolite of phenacetin once popular as an analgesic and antipyretic in its own right, but unlike phenacetin and its combinations, paracetamol is not considered to be carcinogenic at therapeutic doses. The words acetaminophen (used in the United States, Canada, Hong Kong, Iran, Colombia and other Latin American countries) and paracetamol (used elsewhere) both come from chemical names for the compound: para-acetylaminophenol and para-acetylaminophenol. In some contexts, it is simply abbreviated as APAP, for N-acetyl-para-aminophenol.

The maximum daily dose of APAP is 4 g in adults and 90 mg/kg in children. The toxic dose of APAP after a single acute ingestion is 150 mg/kg or approximately 7 g in adults, although the at-risk dose may be lower in persons with alcoholism and other susceptible individuals.

Acetaminophen toxicity is the most common cause of hepatic failure requiring liver transplantation in the United States and Great Britain.

Acetaminophen is NOT anti-inflamitory:   "Many individuals, physicians included, seem unaware of the poor anti-inflammatory activity of acetaminophen"  (Goodman & Gilman, 7th Ed. p. 692).  Uninformed users presume it is as safe as aspirin, and will up the dosage when pain persists.  Often they are also taking it in a cocktail with other drugs, thus increasing their risk of overdose.
 
Acetaminophen-induced hepatotoxicity is well recognized. Acetaminophen also is known as paracetamol and N-acetyl-p-aminophenol (APAP). It is found in the United States as 325-mg and 500-mg immediate-release tablets and as a 650-mg extended-release preparation. Various children's chewable, suspension, and elixir formulations of acetaminophen also are available. Furthermore, acetaminophen is found as a component of combination drugs such as propoxyphene-acetaminophen (eg, Darvocet) and oxycodone-acetaminophen (eg, Percocet).

Acetaminophen is rapidly absorbed from the stomach and small intestine and metabolized by conjugation in the liver to nontoxic agents, which then are eliminated in the urine. In acute overdose or when maximum daily dose is exceeded over a prolonged period, the normal pathways of metabolism become saturated. Excess APAP is then metabolized in the liver via the mixed function oxidase P450 system to a toxic metabolite, N-acetyl-p-benzoquinone-imine (NAPQI). NAPQI has an extremely short half-life and is rapidly conjugated with glutathione, a sulfhydryl donor, and removed from the system. Under conditions of excessive NAPQI formation or reduced glutathione stores, NAPQI is free to covalently bind to vital proteins and the lipid bilayer of hepatocytes; this results in hepatocellular death and subsequent centrilobular liver necrosis.

The antidote for APAP poisoning is N-acetylcysteine (NAC). NAC is theorized to work by a number of protective mechanisms. Early after overdose, NAC prevents the formation and accumulation of NAPQI. NAC increases glutathione stores, combines directly with NAPQI as a glutathione substitute, and enhances sulfate conjugation. NAC also functions as an anti-inflammatory and antioxidant and has positive inotropic and vasodilating effects, which improve microcirculatory blood flow and oxygen delivery to tissues. Vasodilating effects decrease morbidity and mortality once hepatotoxicity is well established.

NAC is most effective when administered within 8 hours of ingestion. When indicated, however, NAC should be administered regardless of time since the overdose. Therapy with NAC has been shown to decrease mortality rates in late-presenting patients with fulminant hepatic failure (in the absence of acetaminophen in the serum).

Case series report that almost 4% of patients who suffer severe hepatotoxicity develop hepatic failure; fatalities or liver transplantation occur in almost of these patients.

Patients with malnutrition, AIDS, chronic ethanol abuse, or anorexia nervosa may be at increased risk for morbidity because of deficient glutathione stores and inadequate detoxification of NAPQI. Patients with enhanced ability to make NAPQI because of induction of the P450 system, specifically cyp2E1, may be at increased risk of morbidity; these patients include those taking agents known to induce this enzyme activity, such as rifampin, phenobarbital, isoniazid, phenytoin, carbamazepine, or patients with chronic ethanol abuse.

Pediatric patients younger than 5 years appear to fare better than adults after APAP poisoning, perhaps owing to a greater capacity to conjugate acetaminophen, enhanced detoxification of NAPQI, or greater glutathione stores. However, since no controlled studies have supported any alternative pediatric therapy, treatment in children should not be different than in adults.

The course of acetaminophen toxicity generally is divided into 4 phases. Evidence of end-organ (hepatic, renal) toxicity often occurs within 24-48 hours after ingestion.

Because antidotal therapy is most efficacious when initiated within 8 hours postingestion, the clinician must attempt to obtain an accurate history of the time(s) of ingestion, the quantity and formulation of acetaminophen ingested, and any co-ingestants (eg, diphenhydramine, other anticholinergic drugs, opioids), which may delay absorption.

However, as a patient's history often is inaccurate, the serum acetaminophen concentration is important for diagnosis and treatment, even in the absence of symptoms.

Phase 1 (0-24 h)
Asymptomatic
Anorexia
Nausea and vomiting
Diaphoresis
Malaise
Pallor

Phase 2 (18-72 h)
Right upper quadrant abdominal pain and rising liver enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST])

Tachycardia
Hypotension possibly due to volume loss

Phase 3 (72-96 h)
Centrilobular hepatic necrosis with accompanying abdominal pain
Jaundice
Coagulopathy
Hepatic encephalopathy
Recurrence of nausea and vomiting
Renal failure

Phase 4: Death

Production of acetaminophen's toxic metabolite, NAPQI, in excess of an adequate store of glutathione necessary to conjugate it, leads to NAPQI-induced hepatocellular necrosis and hepatic failure.

Acetaminophen serum concentration
A serum acetaminophen concentration drawn 4 or more hours after a single ingestion may be plotted on the Rumack-Matthew nomogram as a guide to recommended NAC therapy. Do not rely upon this nomogram following multiple acetaminophen ingestions, multiple ingestions such as those involving anticholinergics or opioids, extended release formulations, or chronic ingestions. Note that the Rumack-Matthew nomogram is a treatment nomogram and distinct from the Done nomogram, which serves to predict the severity of toxicity in salicylate poisoning.

Determine serum acetaminophen concentration in any intentional overdose because the history of acetaminophen ingestion may not be elicited, and manifestations of toxicity may not become evident until after treatment should have been initiated. (See Special Concerns for information regarding extended-relief acetaminophen.)

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) begin to rise within 24 hours postingestion and peak at 48-72 hours. Severe toxicity can be defined as AST or ALT greater than 1000 IU/L.

Serum glucose
Prothrombin time (PT) and bilirubin
Electrolytes and creatinine
Look for anion gap acidosis to help rule out co-ingestion, metabolic disorder from vomiting, or liver failure (if subacute ingestion).
Renal failure has been shown to coexist with or, rarely, be independent of liver toxicity in overdose. One study indicated that this is more likely to occur in alcoholic persons. Renal failure usually is not observed acutely but rather within 2-3 days of overdose.

Human chorionic gonadotropin (HCG) in females of childbearing age
Acetaminophen crosses the placenta, and the fetal liver is able to elaborate NAPQI by 14 weeks of gestation.
Delay in treating pregnant patients with antidotal therapy is associated with fetal demise.
A type and crossmatch should be drawn for the treatment of active bleeding in the face of coagulopathy.
Urinalysis: Proteinuria and hematuria may be seen with acute tubular necrosis (ATN), usually in conjunction with hepatic failure.
Arterial blood gas
Poor prognosis is associated with an arterial pH less than 7.30 (which fails to correct with fluid administration) and serum creatinine greater than 3.4 mg/dL.
An arterial blood gas (ABG) should be drawn in patients with clinical or laboratory evidences of toxic overdose or altered mental status.

CT scan of the head may reveal cerebral edema in patients with late presentation and encephalopathy.
Consider in patients with altered mental status.

Ultrasound may reveal mild hepatic enlargement in late presentation.
If clinically indicated, this is usually an inpatient procedure.

Gastric lavage is controversial and has no proven efficacy in isolated acetaminophen overdose.
Consider in early presentation (<1 h) following a multidrug ingestion with altered mental status or hemodynamic compromise.
Prehospital Care: Stabilize immediate life-threatening conditions and initiate supportive care.

Emergency Department Care:

Supportive therapy, including IV fluids, oxygen, and cardiac monitor
Gastric decontamination
Oral activated charcoal avidly adsorbs acetaminophen and should be administered if the patient presents within 1-2 hours of ingestion or later, especially if a GI motility-inhibiting co-ingestant may have been involved.
Administer oral activated charcoal if the time of ingestion is unknown, the patient ingested extended-relief acetaminophen, or possibility of a drug co-ingestion exists.
Administer N-acetylcysteine, if indicated.
Assess for evidence of other life-threatening co-ingestions.

Medical toxicologist, available through consultation with a regional poison control center
This consultation is recommended if using IV NAC.
Consultation with a medical toxicologist also is recommended for patients who have a complicated or late presentation, hepatic or renal dysfunction, or a history of potentially toxic co-ingestants.

If fulminant hepatic failure is present, consult a hepatologist and transplant surgeon.
Agents used in the treatment of acetaminophen poisoning include activated charcoal, N-acetylcysteine, and antiemetics.

Drug Category: GI decontaminants -- Emergency treatment in poisoning caused by drugs and chemicals. Network of pores present in activated charcoal adsorbs 100-1000 mg of drug per gram of charcoal. Does not dissolve in water.

Activated charcoal (Liqui-Char) -- DOC for patients presenting within 1-2 h postingestion or in cases where co-ingestants may delay gastric emptying or gut motility. Expect minimal benefit if administered >4 h postingestion.

Adult Dose

1 g/kg PO or 10 times the amount of drug ingested

Pediatric Dose

Administer as in adults

Contraindications

Documented hypersensitivity; poisoning or overdosage of mineral acids and alkalies; unprotected airway with absent gag reflex

Interactions

May inactivate ipecac syrup if used concomitantly; effectiveness of other medications decreases with coadministration; do not mix with sherbet, milk, or ice cream (decreases adsorptive properties)

Pregnancy

C - Safety for use during pregnancy has not been established.

Precautions

Not very effective in poisonings of ethanol, methanol, and iron salts; induce emesis before administering activated charcoal; after emesis with ipecac, patient may not tolerate activated charcoal for 1-2 h; can administer in early stages of gastric lavage; without sorbitol, gastric lavage returns are black; adverse effects include nausea, vomiting, and aspiration if the airway is not secure; monitor for bowel sounds to minimize risk of charcoal ileus

Drug Category: Antidote -- May provide substrate for conjugation with the toxic metabolite of acetaminophen. Administer all doses, even if acetaminophen level has dropped below toxic range.

Drug Name

N-acetylcysteine (Mucomyst) -- DOC for prevention and treatment of acetaminophen-induced hepatotoxicity. Approved by the FDA for PO administration but is also administered IV, especially when PO NAC is not tolerated due to refractory vomiting. For maximum hepatoprotective effect, administer within 8-24 h of acetaminophen ingestion. When given PO, dilute in chilled juice or cola to a 5% solution. May be dripped slowly via nasogastric tube if severe nausea threatens administration. Repeat dose if vomiting occurs within 1 h of NAC administration. When administered IV, infuse over 1 h through a 0.2 micron Millipore pyrogen filter.

Adult Dose

140 mg/kg PO loading dose, followed by 70 mg/kg q4h for 17 additional doses (total 1330 mg/kg over 72 h)
140 mg/kg IV loading dose, followed by 70 mg/kg q4h for 12 doses (total 980 mg/kg over 48 h); infuse over 1 h through a micropore filter (consult with a regional poison center and/or medical toxicologist)
Some centers use a 20-h treatment protocol (consult regional poison center and/or medical toxicologist)

Pediatric Dose

Administer as in adults

Contraindications

Documented hypersensitivity

Interactions

None reported

Pregnancy

A - Safe in pregnancy

Precautions

Adverse effects associated with PO NAC include nausea and vomiting, probably induced by its foul "rotten egg" odor and, rarely, clinically insignificant sulfhemoglobinemia; only 1 case of an anaphylactoid reaction following PO NAC has been reported; IV NAC may cause various degrees of infusion rate-dependent erythema at infusion site, urticaria, fever, and bronchospasm (anaphylactoid reaction); respond to antihistamines and epinephrine; may be limited by slowing the infusion rate

Drug Category: Antiemetics -- Emesis frequently is associated with acetaminophen toxicity and is a common consequence of activated charcoal and NAC administration. For these reasons, antiemetic therapy often is necessary to allow successful administration of NAC.

Antiemetics that do not decrease gastric motility or significantly alter mental status are the DOC; anticholinergic drugs, such as prochlorperazine (Compazine) are not considered beneficial, in part because of their propensity to cause both of these effects. Phenothiazines also may add to the toxicity associated with other anticholinergic drugs, which are often in APAP-containing formulations.

Drug Name

Metoclopramide (Reglan) -- Functions as antiemetic by blocking dopamine receptors in the chemoreceptor trigger zone of CNS. Is generally DOC due to lower cost than ondansetron (Zofran).

Adult Dose

10-20 mg IV, not to exceed 1 mg/kg; not to exceed 3 mg/kg/d divided prn

Pediatric Dose

1-2 mg/kg total dose

Contraindications

Documented hypersensitivity

Interactions

May antagonize effects of metoclopramide; opiate analgesics may increase metoclopramide toxicity in CNS

Pregnancy

B - Usually safe but benefits must outweigh the risks.

Precautions

Caution in history of mental illness and Parkinson disease; adverse effects include drowsiness, hypotension, and acute dystonia, especially at high doses; may increase frequency of seizure in individuals with epilepsy

Drug Name

Ondansetron (Zofran) -- Selective 5-HT3receptor antagonist that blocks serotonin both peripherally and centrally. Considered potentially more effective than metoclopramide; in addition, adverse effects are less common.

Adult Dose

0.15 mg/kg or 8 mg IV q8h, not to exceed 3 doses

Pediatric Dose

0.15 mg/kg IV q 8h, not to exceed 3 doses

Contraindications

Documented hypersensitivity

Interactions

Although cytochrome P-450 inducers (barbiturates, rifampin, carbamazepine, and phenytoin) may potentially change half-life and clearance of ondansetron, dosage adjustment is not usually required

Pregnancy

B - Usually safe but benefits must outweigh the risks.

Precautions

Medication is to be administered for prevention of nausea and vomiting, not for rescue of nausea and vomiting

Further Inpatient Care:

Admit patients for NAC therapy if they have an acetaminophen level associated with potential toxicity, as suggested by the Rumack-Matthew treatment nomogram.
Unless coexisting toxicologic, medical, or psychiatric issues are present, patients with acetaminophen toxicity may be admitted and treated on a general medical floor.
Admit patients to an ICU setting if they show signs of significant hepatotoxicity; hepatic failure; or other potentially life-threatening, coexisting, toxicologic, or medical issues.

Further Outpatient Care:

Patients who do not have a suggestive history or acetaminophen level associated with potential toxicity, as determined by the Rumack-Matthew nomogram, may be discharged or transferred for psychiatric evaluation if indicated.
Transfer:

Transfer patients with fulminant hepatic failure to a facility capable of intensive care monitoring and evaluation for potential transplantation.
Patient Education:

Advise patients of the potential risk associated with the inappropriate use of acetaminophen, which commonly is considered an innocuous over-the-counter drug.
Educate parents of the proper acetaminophen dosing for children and the danger associated with misusing various acetaminophen preparations (eg, infant suspension vs pediatric elixir, pediatric vs adult suppositories). Because infant suspension (drops) is a more concentrated formulation than the elixir (100 mg/mL vs 32 mg/mL), this can be a potential source of therapeutic error. Parents always should be given clear dose and formulation instructions.
Educate patients of the increased potential for renal toxicity associated with concurrent acetaminophen and NSAID analgesic use or chronic alcoholism.

Medical/Legal Pitfalls:

NAC-activated charcoal interaction
In vitro studies have shown that NAC is adsorbed to activated charcoal and the administration of activated charcoal reduced total NAC absorption by 39% in human volunteers, as measured by serum NAC levels. Prospective evaluation of patients treated with activated charcoal and NAC, however, indicated no adverse outcome associated with this treatment.

Despite binding to NAC, activated charcoal adsorbs acetaminophen more avidly. Therefore, although charcoal may decrease the bioavailability of NAC, this decrease is clinically inconsequential.

Finally, activated charcoal administration may prevent significant acetaminophen absorption and obviate the need for NAC.
Super-loading doses of NAC have shown to be of no greater clinical benefit than the current recommended loading dose.
Administer activated charcoal and draw a 4-hour serum acetaminophen concentration if the patient presents within 1-2 hours of ingestion, presents later after co-ingestion with a substance that could delay systemic absorption, or the history is unclear.
Draw an acetaminophen level if the patient presents later than 4 hours after ingestion. Administer NAC if presentation is close to 8 hours postingestion or if the acetaminophen level will not be available within 8 hours postingestion.
NAC may be staggered with activated charcoal if multiple doses of activated charcoal are necessary for treatment of a co-ingestant.

For greatest efficacy, administer NAC within 8 hours of ingestion; however, a later presentation should not preclude its administration if the history or presentation suggests potential toxicity. Failure to administer NAC because of late presentation could be considered medically and legally risky.

Failure to consider and evaluate for possible co-ingestants or to consider the effects of decreased GI motility on absorption of APAP; the treatment nomogram does not pertain to these situations. Therefore, in the absence of good data on multidrug or co-ingestions involving APAP, administer NAC as early as possible and consult the regional poison control center for guidance on a treatment regimen.
Special Concerns:

Chronic ingestion
If a patient presents with ingestion of supratherapeutic doses of acetaminophen over hours or days, evaluate for presence of hepatotoxicity and unmetabolized acetaminophen.
Begin NAC therapy if the patient has elevated AST and ALT and a measurable acetaminophen concentration.
Consult the regional poison control center for guidance on a treatment regimen.

Late presentation
If a patient presents 8-24 hours or longer postingestion, evaluate for ongoing hepatotoxicity and initiate NAC therapy if indicated.
NAC administration in cases of hepatic failure has been associated with decreased incidence of cerebral edema and improved survival.
Extended-relief acetaminophen (Tylenol ER)
The Tylenol ER preparation became available in 1995. The tablet is composed of acetaminophen 325 mg in immediate release form with a matrix of acetaminophen 325 mg formulated for slow release. Some alteration of the elimination kinetics of this preparation may affect the ability of the Rumack-Matthew nomogram to guide treatment. Several studies show that eliminations of extended and immediate-release acetaminophen are nearly identical after 4 hours. However, some case reports have documented acetaminophen levels falling above the treatment nomogram line as late as 11-14 hours postingestion of the extended-release preparation.
Check 4-, 6-, and 8-hour acetaminophen concentration levels. Begin NAC therapy if any level crosses above the nomogram treatment line. If the 6-hour level is greater than the 4-hour level, begin NAC therapy. More prolonged monitoring of levels may be necessary if the patient has food in the stomach or co-ingestants that delay gastric emptying. Consult the regional poison control center for guidance in evaluation and treatment regimen.

Anker AL, Smilkstein MJ: Acetaminophen. Concepts and controversies. Emerg Med Clin North Am 1994 May; 12(2): 335-49[Medline].

Bailey B, McGuigan MA: Management of an aphylactoid reactions to intravenous N-acetylcysteine. Ann Emerg Med 1998 Jun; 31(6): 710-5[Medline].

Bizovi KE, Aks SE, Paloucek F, et al: Late increase in acetaminophen concentration after overdose of Tylenol Extended Relief. Ann Emerg Med 1996 Nov; 28(5): 549-51[Medline].

Brent J: Are activated charcoal-N-acetylcysteine interactions of clinical significance? Ann Emerg Med 1993 Dec; 22(12): 1860-2[Medline].

Burkhart KK: The acetaminophen nomogram: will it withstand the test of the extended relief formulation? Acad Emerg Med 1996 Aug; 3(8): 738-9[Medline].

Chamberlain JM, Gorman RL, Oderda GM, et al: Use of activated charcoal in a simulated poisoning with acetaminophen: a new loading dose for N-acetylcysteine? Ann Emerg Med 1993 Sep; 22(9): 1398-402[Medline].

Douglas DR, Sholar JB, Smilkstein MJ: A pharmacokinetic comparison of acetaminophen products (Tylenol Extended Relief vs regular Tylenol). Acad Emerg Med 1996 Aug; 3(8): 740-4[Medline].

Ekins BR, Ford DC, Thompson MI, et al: The effect of activated charcoal on N-acetylcysteine absorption in normal subjects. Am J Emerg Med 1987 Nov; 5(6): 483-7[Medline].

Gardner CR, Heck DE, Yang CS, et al: Role of nitric oxide in acetaminophen-induced hepatotoxicity in the rat. Hepatology 1998 Mar; 27(3): 748-54[Medline].

Perry H, Shannon MW: Acetaminophen. In: Haddad LM, Shannon MW, Winchester J, Fletcher J, eds. Clinical Management of Poisoning and Drug Overdose. 3rd ed. WB Saunders Co; 1998:664-74.

Smilkstein MJ: A new loading dose for N-acetylcysteine? The answer is no. Ann Emerg Med 1994 Sep; 24(3): 538-9[Medline].

Spiller HA, Krenzelok EP, Grande GA, et al: A prospective evaluation of the effect of activated charcoal before oral N-acetylcysteine in acetaminophen overdose. Ann Emerg Med 1994 Mar; 23(3): 519-23[Medline].

Vassallo S, Khan AN, Howland MA: Use of the Rumack-Matthew nomogram in cases of extended-release acetaminophen toxicity. Ann Intern Med 1996 Dec 1; 125(11): 940[Medline].

Toxicity, Acetaminophen excerpt

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Excerpt from Toxicity, Acetaminophen

Author: Susan E Farrell, MD, Program Director, Instructor, Department of Emergency Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center

Editor(s): Miguel C Fernandez, MD, Medical Director of South Texas Poison Center, Associate Clinical Professor, Departments of Emergency Medicine and Toxicology, University of Texas Health Science Center at San Antonio; John T VanDeVoort, PharmD, DABAT, Manager, Clinical Assistant Professor, Pharmacy Department, Regions Hospital; Michael J Burns, MD, Instructor, Department of Emergency Medicine, Harvard University Medical School, Beth Israel Deaconess Medical Center; John Halamka, MD, Chief Information Officer, CareGroup Healthcare System, Assistant Professor of Medicine, Department of Emergency Medicine, Beth Israel Deaconess Medical Center; Assistant Professor of Medicine, Harvard Medical School; and Raymond J Roberge, MD, MPH, FAAEM, FACMT, Clinical Associate Professor of Emergency Medicine, University of Pittsburgh School of Medicine; Attending Staff, Department of Emergency Medicine, Magee-Women's Hospital of the University of Pittsburgh Medical Center.