Mostly metabolized by conjugation/glucuronidation in liver. 5% excreted renally.
5-15% normally done by p450 to NAPQI which is then reduced to non-toxic form by glutathione which gets depleted in overdose. Mucomyst is metabolized to glutathione
If you see an ALT>3000, think APAP
Stage I-7-14 hrs, increase in liver enzymes, N/V, diaphoresis, possibly drowsiness
Stage II-1-2 days, Increase in liver enzymes and size. RUQ pn possible. Potential renal failure
Stage III-3-4 days, liver failure, death
Stage IV-5 days, recovery
Get levels 4 or more hours after overdose then use Rumack-Matthew Nomogram. The nomogram has not been verified beyond 15 hours. Reports of cancer pts not peaking until eight hours or 2 peaks.
150 mg/kg is toxic dose
Cathartic if within one hour
Charcoal
- Oral: Give odansetron .15 mg/kg IV or Reglan 20-40 mg. Hydrate, then } NAC 140 mg/kg then 70 mg/kg Q4 x 3 days (17 doses) Dilute to 5% solution with lemonade or fruit juice
- IV: 140 mg/kg in D5W over 60 minutes. Then 70 mg/kg in 500 cc D5W over 1 hour Q 4 hours. (Annals EM 42:1, 2003) shows inhalant NAC used in IV form is stable and sterile. Inject 150 cc of 20% solution through 22 um filter into 1 L of 5% dextrose.
Protocol for Intravenous Administration of Oral N-acetylcysteine for Acetaminophen Overdose Obtain informed Consent Dilute 20% NAC solution to 3% solution with 5% dextrose in water Administer loading dose of NAC: 140 mg/kg infused through a peripheral intravenous catheter over 1 hour using an in-line 0.2µ millipore filter Administer maintenance doses of NAC (first maintenance dose 4 hours after initiating the loading dose): 70 mg/kg/dose; doses administered every 4 hours after initiation of preceding dose, to a total of 12 maintenance doses, each infused over 1 hours through an in-line 0.2µ millipore filter Adapted from: Yip L, et. al. Intravenous Administration of oral N-acetylcysteine Crit Care Med 1998; 26: 40-42
Smilkstein MJ, et. al. Acetaminophen Overdose: A 48 hours Intravenous N-acetylcysteine Treatment Protocol Ann Emerg Med 1991; 20: 1058-1063
Discussion of safety of using Oral as IV (Annals EM Dec 2003 42:6)
Acetadote
comes in a solution containing 200 mg/mL, or 6 grams per 30 mL vial. It offers several advantages over standard oral therapy, but especially the dosing schedule. Rather than 18 doses over 72 hours, the intravenous therapy achieves the same results with a loading dose of 150 mg/kg infused over 15 minutes (may have less side effects if given over 60 minutes), followed by an infused maintenance dose over the next 20 hours; thus, the 72 hour oral protocol is reduced to 20¼ hours
At end of protocol, recheck APAP and LFT levels. If lfts still abnormal or any APAP, continue infusion.
Monitor LFTs and PT in any late presenters. AST and ALT will rise early. If a patient has an ALT>1000 they will develop hepatotoxicity. If it is normal at presentation and treated, those patients will do great.
Never stop therapy until LFTs are normalizing, even if beyond the 48-72 hour treatment course. A pH less than 7.3 caused solely by APAP indicates that the pt will die without a liver transplant. Other predictors:
- PT>60
- Creatinine>3.2 mg/dL
- Grade 3 or 4 encephalopathy
- Phosphate <1.2 on day 2 or 3 sens/spec for need for transplant
Rx all chronic ingestions
prospective study of NAC in hepatic fx (bmj 1991;303:1026)
New nomogram to assess low risk for early discharge
Risk of hepatotoxicity after acute acetaminophen [APAP] ingestion treated with N-acetylcysteine (N-AC). The graph illustrates the discrete probability of developing peak aminotransferase ≥1,000 IU/L after acute acetaminophen overdose (curved blue lines), conditioned on the absence of ethanol. For reference, the lower treatment line of the Rumack-Matthew nomogram is included (straight red line). To use the graph, plot the earliest measured postpeak [APAP] obtained at least 4 hours postingestion against the time of phlebotomy. Then draw a line parallel to the red Rumack-Matthew nomogram line until the time of N-AC initiation is reached. The risk of hepatotoxicity is then estimated using the blue lines. For patients not given N-AC, extend the line toward the right into the area of approximately parallel isoprobability lines to estimate the risk of hepatotoxicity. To illustrate, a patient with a serum [APAP] of 380 μg/mL measured 5 hours after ingestion is treated with N-AC beginning 9 hours after ingestion. The measured unadjusted [APAP] is plotted (red square) and then extended to 9 hours (blue square). Assuming the patient did not coingest ethanol and is not an alcoholic, the estimated probability of hepatotoxicity is approximately 15%. Had N-AC been initiated within 6 hours of ingestion, this risk would be less than 1%. Note that the Rumack-Matthew nomogram should continue to govern the decision to initiate treatment with N-AC and that there is no requirement to remeasure serum [APAP] at N-AC initiation. Downloading for patient use is permissable by the authors. (Annal Emerg Med 2005;46(3):272)
see liver section
Metabolism and toxicity:
primary pathways include glucuronidation (primary pathway in adults) and sulfation (primary
pathway in children <8 yr of age); 5% to 10% of therapeutic dose metabolized through cytochrome P
450 mixed-function
oxidase system in liver;
N-acetylbenzoquinoneimine (NAPQI)metabolite of P450 system; kills hepatocytes; damage
occurs when glutathione stores (required for detoxification of NAPQI) depleted; treatment involves reduction of NAPQI;
liver damage
highest concentration of NAPQI occurs around central vein, resulting in centrilobular hepatic necrosis and
distinguishing acetaminophen-induced necrosis from other forms,
eg, iron-induced (toxicity highest around portal triad)
Progression of toxicity:
phase 1patients asymptomatic or have mild GI symptoms (nausea, vomiting, pain in right
upper quadrant); slight elevation in liver enzymes may occur;
phase 224 to 72 hr after ingestion, patient has
increasing gastroenteritis and pain and may develop jaundice; liver enzymes increase dramatically;
noteto ensure
successful treatment with N-acetylcysteine (NAC; Mucomyst), initiate therapy before patient enters phase 2;
phase
3
most deaths from overdose occur 72 to 96 hr after ingestion; almost all patients who survive phase 3 recover completely
Toxic dose: ingestions <200 mg/kg do not require decontamination or treatment with NAC; if amount of ingestion is
unknown, plot 4-hr level on Rumack-Matthew nomogram; extrapolated level of acetaminophen of ≥200 μg/mL (in
California) or ≥150 μg/mL (in some other states) warrants treatment with NAC (initial laboratory studies used cutoff
of 500 μg/mL); ongoing study by California poison control system suggests 200 μg/mL cutoff safe Increased risk:
theoretic risk occurs with relative starvation, alcoholism, and agents that induce P450 activity; review of
literature yields conflicting data; some evidence that intoxication with alcohol protects against acetaminophen toxicity by
competing for P
450 enzymes
Evidence for increased risk: registry (developed by HJ Zimmerman and WC Maddrey) collects cases involving
interaction of alcohol and acetaminophen; widely publicized article (Whitcomb and Block, 1994) reported association
between acetaminophen toxicity and fasting or ingestion of ethanol; studies with mice showed LD
50 (dose at which
50% of mice die) for acetaminophen decreased by 50% in animals given ethanol
Evidence against increased risk: therapeutic levels of acetaminophen, when taken with alcohol, did not produce
deleterious effects in baboons; 2 studies interviewing alcoholic patients found no case of toxicity with use of
acetaminophen at therapeutic doses; study conducted by Rocky Mountain Poison Center found no differences in liver
function tests (LFTs) between alcoholic patients and controls taking 4 g of acetaminophen for 2 days; even Whitcomb
study found no cases of hepatotoxicity with therapeutic doses; no epidemic documented in 40 yr of use;
conclusions
daily doses of 10 g unlikely to cause problems in healthy adults; daily doses of <7.5 g unlikely to cause problems in
alcoholic patients;
noteZimmerman registry receives support from Whitehall Laboratories (makers of Advil)
P
450 -inducing agents: study (Prescott) found no difference in levels of NAPQI between patients taking P450 -inducing
agents (
eg, carbamazepine) and controls
Other concerns: study found no problems in patients with stable chronic liver disease,
eg, hepatitis C, taking
therapeutic doses of acetaminophen; fasting or starvation state may lower glutathione stores and increase risk for
toxicity
if acetaminophen level zero (NAPQI presumed
gone, since its half-life <30 min)
(Audiodigest EM 22(22)
Repeat APAP Levels
From Emedhome
Repeating a Normal APAP Level?
The standard of care for acute acetaminophen overdoses has been to
obtain a single plasma APAP concentration between 4 and 24 h after an
overdose and to determine the need for antidotal therapy based on that
one PAC.
There are case reports of delayed toxic PACs after overdoses of non-extended release products when acetaminophen-diphenhydramine was ingested and the initial PAC was non-toxic on the nomogram (1-4).
A recent case review found a subset of patients with acute APAP
overdose in whom the nomogram failed to predict toxicity based on a
single PAC (1). The majority of such patients ingested combination
products containing APAP with other medications (diphenhydramine,
opioids) that slow GI motility; features of the opioid or
anticholinergic toxidromes were evident and may have driven the
decision to obtain a second PAC.
Thus, Emergency Physicians should be aware that patients who
intentionally overdose on APAP combination products who have initial
plottable, supratherapeutic, non-toxic plasma acetaminophen
concentrations, and are symptomatic from the opioid or diphenhydramine
ingredients may require that a subsequent acetaminophen concentration
be determined to accurately assess their risk of developing
hepatotoxicity.
References:
(1) Dougherty PP, Klein-Schwartz W. J Emerg Med 2011 Jun 28. [Epub ahead of print].
(2) Tighe TV, Walter FG. Clin Toxicol 1994;32:431-434.
(3) Ho S, et al. Am J Emerg Med 1999;17:315-317.
(4) Schwartz EA, et al. Ann Emerg Med 2009;54:421-423
Patients on CRRT
Antidote removal during haemodialysis for massive acetaminophen overdose (Clin Toxicol (Phila). 2013 Nov;51(9):855-63. doi: 10.3109/15563650.2013.844824.)