a3: antidotes in depth
TRANSCRIPT
A3: Antidotes in Depth
Robert G. Hendrickson; Mary Ann Howland
INTRODUCTION
N-acetylcysteine (NAC) is the cornerstone of therapy for patients with potentially lethal acetaminophen (APAP)
overdoses. If administered early, NAC can then prevent APAP induced hepatotoxicity. If administered after the
onset of hepatotoxicity, NAC improves outcomes and decreases mortality. NAC may also limit hepatotoxicity
from other xenobiotics that result in glutathione depletion and free radical formation, such as cyclopeptide-
containing mushrooms, carbon tetrachloride, chloroform, pennyroyal oil, clove oil, and possibly liver failure from
chronic valproic acid use.31 Finally, NAC may be useful in the management of adults with fulminant hepatic
failure caused by nontoxicologic etiologies.20,75,81,84,149
HISTORY
Shortly after the first case of APAP hepatotoxicity was reported, Mitchell described the protective effect of
glutathione.97,127 Prescott113 first suggested NAC for APAP poisoning in 1974. Early experiments demonstrated
that NAC could prevent APAP-induced hepatotoxicity in mice and that the oral (PO) and intravenous (IV) routes
were equally efficacious when treatment was initiated early after ingestion.106 Several groups96,112,113,126 performed
human research with oral and IV NAC in the 1970s. The US Food and Drug Administration (FDA) approved
NAC for oral use in 1985 and for IV use in 2004.
PHARMACOLOGY
Chemistry
NAC is a thiol containing (R-SH) compound that is deacetylated to cysteine, an amino acid used intracellularly.
The amino acids cysteine glycine and glutamate are used to synthesize glutathione.123
Related Xenobiotics
Cysteamine, methionine, and NAC, which are all glutathione precursors or substitutes, have been used
successfully to prevent hepatotoxicity, but cysteamine and methionine both produce more adverse effects than
NAC, and methionine is less effective than NAC. Therefore, NAC has emerged as the preferred
treatment.110,137,160,162
Mechanism of Action
NAC has several distinct roles in the treatment of APAP poisoning. Early after ingestion when APAP is being
metabolized to N-acetyl benzoquinoneimine (NAPQI), NAC prevents toxicity by rapidly detoxifying NAPQI. After
hepatotoxicity is evident, NAC decreases toxicity through several nonspecific mechanisms, including free
radical scavenging, increasing oxygen delivery, increased mitochondrial adenosine triphosphate (ATP)
production, antioxidant effects, and alteration of microvascular tone.
NAC effectively prevents APAP induced hepatotoxicity if it is administered before glutathione stores are
depleted to 30% of normal. This level of depletion occurs approximately 6 to 8 hours following toxic APAP
ingestion.112,120 In this preventive role, NAC acts primarily as a precursor for the synthesis of glutathione.77 The
availability ofcysteine is the rate-limiting step in the synthesis of glutathione, and NAC is effective in
replenishing diminished supplies of both cysteine and glutathione. Additional minor mechanisms of NAC in
preventing hepatotoxicity include acting as a substrate for sulfation,139 as an intracellular glutathione substitute
by directly binding to NAPQI,29 and by enhancing the reduction of NAPQI to APAP.78,135
After NAPQI covalently binds to hepatocytes and other tissues,120 NAC modulates the subsequent cascade of
inflammatory events in a variety of ways.55 NAC may act directly as an antioxidant or as a precursor to
glutathione. Glutathione protects cells against electrophilic compounds by acting as both a reducing agent and
an antioxidant.124 NAC improves oxygen delivery38,55,146,163,164 and utilization in extrahepatic organs such as the
brain, heart, and kidney, probably by improving blood flow in the microvasculature, although the exact
mechanism is unclear.83,133 In addition, NAC increases hepatic mitochondrial ATP production in mice129 and
demonstrates a suppressive action on macrophages, neutrophils, leukocyte endothelial cell adhesion, and
cytokines.75
Pharmacokinetics/Pharmacodynamics
Administered NAC is present in plasma in the reduced or oxidized state and is either free or bound to plasma
proteins or with other thiols and SH groups to form mixed disulfides such as NAC–cysteine.111 NAC has a
relatively small volume of distribution (0.5 L/kg), and protein binding is 83%. NAC is metabolized to many sulfur
containing compounds such ascysteine, glutathione, methionine, cystine, and disulfides, as well as conjugates
of electrophilic compounds, that are not routinely measured.47,105,111 Thus, the pharmacodynamic study of NAC is
complex. In addition, the pharmacokinetics of NAC are complicated based on whether total or free NAC is
being measured.111
Pharmacokinetics of Oral N-Acetylcysteine.
Oral NAC is rapidly absorbed, but its bioavailability is low (10%–30%) because of significant first-pass
metabolism.47,105,111 The mean time to peak serum concentration is 1.4 ± 0.7 hours. The mean elimination half-life
is 2.5 ± 0.6 hours and is linear with increasing dose up to 3200 mg/m2/day given as a single daily dose. Inter-
subject serum NAC concentrations vary tenfold.105 Chronic administration leads to a decrease in plasma
concentrations from a Cmax of 8.9 mg/L (55 µmol/L) at the end of 1 month to 5.1 mg/L (31 µmol/L) at the end of 6
months.105
Conflicting in vitro30,73,127 and in vivo28,45,101,117 data regarding the concomitant use of PO NAC and activated
charcoal suggest that the resultant bioavailability of NAC is either decreased or unchanged. This interaction is
likely of limited clinical importance, and PO or IV NAC can be initiated without concern for activated charcoal
interaction (Chap. 35).
Pharmacokinetics of IV N-Acetylcysteine.
When only free NAC was analyzed, healthy volunteers given 600 mg IV NAC achieved peak serum NAC
concentration of 49 mg/L (300 µmol/L) with a half-life of 2.27 hours compared with a peak serum concentration
of 2.6 mg/L (16 µmol/L) after 600 mg PO.24Serum concentrations after IV administration of an initial loading
dose of 150 mg/kg over 15 minutes reach approximately 500 mg/L (3075 µmol/L).111 A steady-state serum
concentration of 35 mg/L (10–90 mg/L) is reached in approximately 12 hours with the standard IV
protocol.111 Approximately 30% is eliminated renally.
Once in the blood, IV and PO NAC have a similar half-life (2–2.5 hours). This half-life is increased in the setting
of severe liver failure or end-stage kidney disease because of a reduction in clearance.67,100
Intravenous vs. Oral Administration.
As in the case of many issues related to APAP toxicity, the choice of PO versus IV NAC is complex. The
available information suggests that each has advantages and disadvantages, and each may be more
appropriate than the other in certain settings. Because no controlled studies have compared IV with PO NAC,
conclusions about the relative benefit of each are largely speculative.
With the exception of fulminant hepatic failure, for which only the IV route has been investigated, IV and PO
NAC administration are equally efficacious in treating patients with APAP toxicity.114 Some data suggest that IV
NAC may be slightly more efficacious when given less than 12 hours after an overdose and that PO NAC is
significantly more efficacious when given after 16 hours after overdose; however, this study compared patient
groups that differed by decade of treatment and by country. It remains unclear if these differences are true or
clinically relevant.114,172,173 In addition, any difference in outcome for patients who are treated after 16 hours
almost certainly is related to theduration and total dose of NAC therapy rather than the route itself. The decision
of which route to use should depend on the rate of adverse events, safety, availability, and ease of use.
Efficacy should not be a consideration.
Safety is the best understood of these issues. Nausea and vomiting may occur in up to 20% of patients treated
with PO NAC compared to 7% with IV NAC.57 Diarrhea and headache are prevalent, but there is no credible
evidence of more serious complications resulting from PO NAC. Reports of skin rash and unusual
complications are rare.97 In contrast, IV NAC is associated with a 14% to 18%72 rate of anaphylactoid reactions,
although rates of 2% to 6% are reported in retrospective trials.63,68,168,175 Most of these reactions are mild and
include rash, flushing, nausea, and vomiting.10,72,130,140,177Anaphylactoid reactions may be severe in approximately
1% of cases72,94,176 and in rare instances may lead to hypotension and death.7,17,35,68,89,93,106,140,173,174 Anaphylactoid
reactions are attributed to both the dose and concentration of NAC and are caused by a non IgE mediated
release of histamine from mast cells and mononucleocytes.32 APAP inhibits mast cell histamine release;
therefore, a higher APAP concentration at the time of NAC delivery decreases the risk of anaphylactoid
reactions.32,166 The anaphylactoid reaction rate is decreased by using a more dilute NAC solution68,72,175 and by
slowing NAC infusions in some studies.28 In one prospective study, prolongation of the loading infusion from 15
to 60 minutes did not decrease the anaphylactoid rate significantly (from 18% to 14%).48,63,72,88
Minor reactions, such as rash, generally do not require treatment, rarely recur, and do not preclude
administration of subsequent NAC doses.11,140,175,178 Even when urticaria, angioedema, and respiratory symptoms
develop, they usually are easily treated, and NAC can be subsequently restarted with a very low incidence of
recurrence.11,108,130,178Although proper dosing of IV NAC is very safe, it nevertheless must be considered less safe
than PO NAC because of the possibility of severe anaphylactoid reactions, the risk of dosing errors,56,58,98 and
the possibility of incomplete or delayed treatment because of anaphylactoid reactions.63,108
IV NAC is dosed using a complex three-bag preparation system (see Dosing and Administration below) that
has led to an up to 33% error rate including 19% of patients having a greater than 1 hour interruption of
NAC.56 Attempts at simplifying this system are described but have not been adequately studied for general
use67,136 (Table A3–1).
TABLE A3–1. Three-Bag Method Dosage Guide1 for Patients Weighing ≥ 40 kga
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Additional safety concerns have involved dosing for both small children and obese adults. The IV NAC dosing
regimen includes a milligrams per kilogram dose in a fixed water volume, leading to variability of IV NAC
concentration.27,63 This leads to a large solute-free water administration in children, with the potential for
hyponatremic seizures.149 The NAC high concentration in obese adults potentially risks an increased rate of
anaphylactoid reactions. Thus, alternative dosing strategies have been developed for children (constant 3%
concentration)27 and obese adults (ceiling weight of 100 kg; seeDosing).42
The main disadvantage of the NAC PO formulation is the high rate of vomiting and the concern that vomiting
may delay therapy.114 Delays in administration of NAC are correlated with an increased risk of
hepatotoxicity.141 The IV route avoids an increased rate of vomiting in patients who typically are already
nauseated and avoids the use of high-dose antiemetics that may alter mental status.94 A potential disadvantage
of PO NAC is that its absorption may be delayed up to one hour compared with IV NAC.61 Finally, PO NAC
doses may be difficult to administer to patients with altered mental status because of aspiration risks; IV NAC
offers a distinct advantage in these instances.
One theoretical, albeit unproven, advantage of PO NAC early in the course of toxicity is that direct delivery via
the portal circulation yields a higher concentration of NAC in the target compartment of toxicity, the liver.
Because of this first-pass clearance, PO NAC results in circulating NAC 20 to 30 fold lower than after IV
dosing, suggesting that most PO NAC is taken up by the liver.24,61 However, an elevated serum NAC
concentration may be an advantage of IV NAC administration when the liver is not the only target organ of
NAC, such as liver failure accompanied by cerebral edema or in pregnancy.
Several economic analyses have concluded that IV NAC is less expensive than PO NAC,92,93 whereas others
have concluded the opposite.79 However, the majority of cost is associated with length of hospital stay and
since none of these studies have taken into account that many patients treated with PO NAC now receive
shorter courses than 72 hours,19,34 the studies do not represent current use.
Prior to the availability of the current IV formulation in the United States, the PO formulation was used
intravenously with an excellent safety profile41,68,175 and without published evidence of infectious or febrile
consequences.41,68 The IV use for this purpose is not generally recommended, but was historically effective and
necessary in cases in which only the PO formulation was available and the patient had intractable vomiting or
APAP induced fulminant hepatic failure.79
Specific Indications for IV NAC.
In addition to decisions based on cost, duration, safety, and ease of use, three situations exist for which the
available information suggests IV NAC is preferable to PO NAC: (1) fulminant hepatic failure, (2) inability to
tolerate PO NAC, and (3) APAP poisoning in pregnancy. Each of these requires further study for validation, but
all three seem well supported by current information.
Fulminant hepatic failure is an important indication for IV NAC. IV is the only route that has been studied in liver
failure.71 Although PO NAC may be effective, it has not been formally studied. Second, evidence that (some or
all of) the benefit of NAC in liver failure is extrahepatic suggests that IV NAC is preferable.56 IV NAC results in
higher serum NAC concentrations, which presumably leads to more NAC delivery to critical organs. Finally,
concomitant gastrointestinal bleeding, use of lactulose, and other factors make IV NAC more practical.
Common indications for IV NAC are for patients with very high APAP concentrations who are approaching or
are more than 6 to 8 hours from the time of ingestion as well as those who are unable to tolerate PO NAC
following a brief aggressive trial of antiemetic therapy. Use of IV NAC is logical to prevent further delays and
resultant loss of NAC efficacy, even without proof that continued vomiting significantly limits NAC absorption.
The most controversial indication for IV NAC use is during pregnancy. Administration of IV NAC to the mother
has the theoretical advantage of increased delivery to the fetus over PO NAC use. IV administration
circumvents first-pass metabolism, presumably exposing the fetal circulation to higher maternal serum
concentrations. Some studies have suggested that placental transfer of NAC to the fetus is
limited.66,133 However, one case series found that the NAC concentration in cord or neonatal blood after PO
maternal NAC administration equaled the NAC concentration that is achieved in patients treated with PO
NAC.64 Of course, an equivalent serum NAC concentration does not prove adequacy of therapy. Unlike the
neonates studied, patients treated with PO NAC have extensive first-pass hepatic uptake before NAC entry into
the serum, where NAC concentration was measured.24,61 Whether serum NAC concentration in the neonates
studied reflects any significant hepatic NAC delivery is uncertain.
ROLE IN ACETAMINOPHEN TOXICITY
In acute overdose, treatment with NAC should be initiated if the serum APAP concentration is plotted on or
above the treatment line on the Rumack-Matthew nomogram or the patient’s history suggests an acute APAP
ingestion of 150 mg/kg or greater and the results of blood tests will not be available within 8 hours of ingestion.
In patients with chronic APAP ingestions, treatment with NAC should be initiated if either aspartate
aminotransferase (AST) is above normal or the APAP concentration is above 10 µg/mL (Chap. 35).
IV NAC is approved by the FDA for treatment of potentially hepatotoxic quantity of APAP within 8 to 10 hours
following ingestion. The oral formulation is approved for use in a 72 hour protocol for APAP toxicity.
ROLE IN NONACETAMINOPHEN POISONING
Diverse investigations of NAC as a treatment for a number of xenobiotics associated with free radical or
reactive metabolite toxicity are reported. Some of these xenobiotics include acrylonitrile, amatoxins, cadmium,
chloroform, carbon tetrachloride, cyclophosphamide, 1,2-dichloropropane, doxorubicin, eugenol, pulegone,
ricin, and zidovudine.31,44,47,154,155,157,162 NAC has not been studied well enough for any of these xenobiotics in
humans to definitively recommend it as a therapeutic intervention. However, the best evidence supports the
use of NAC in cases of acute exposures to cyclopeptide-containing mushrooms and carbon
tetrachloride.31,47,162 NAC has also decreased cisplatin-induced nephrotoxicity in both rats and human cell
cultures, although in vivo human data are sparse.7,122 NAC may be considered in cases of acute pennyroyal oil
(ie, pulegone) or clove oil (eg, eugenol) ingestions based on their similarities to APAP-induced hepatoxicity.
Both pulegone and eugenol are converted to reactive metabolites that deplete glutathione, leading to
centrilobular hepatic necrosis.153, 154, 155, and 156 NAC may be effective in treating patients with hepatotoxicity from
chronic valproate use, given the evidence that the 2,4-diene valproic acid metabolite acts as an electrophile
and reduces hepatic glutathione. However, there is no evidence that NAC is effective in treating patients with
acute valproate toxicity and no evidence or theoretical efficacy in treating valproate-induced hyperammonemia.
In animal studies NAC increases the excretion of several metals and other elements, including boron,
cadmium, chromium, cobalt, gold, and methylmercury.13,15,31,59 The clinical usefulness of this effect remains
unclear.
NAC has been studied as an oncological chemopreventive and antineoplastic3,36,84,123 as well as for lung
injury,36,37 cardiac injury,143,144 multiorgan failure from trauma and sepsis,52,115,131,145 traumatic brain
injury,14,153,174 chronic obstructive pulmonary disease,148 ifosfamide-induced nephrotoxicity,53 postcardiac
surgery,87 hepatorenal syndrome,62H. pylori infections,88 necrotizing enterocolitis,151 sickle cell disease,102 and
bipolar disorder.18 NAC has extracellular antimutagenic effects, enhances repair of nuclear DNA damaged by
carcinogens, and inhibits malignant cell invasion and metastases.36,104,116 Rescue NAC therapy has been studied
with high-dose APAP (> 20 g/m2) used as chemotherapy in patients with select advanced malignancies.74,169
NAC has been extensively studied to determine its effects on IV contrast-induced nephropathy. Pretreatment
with either PO5,21,25,39,50,70,138,152 or IV12,43,91 formulations has been studied before angiography with mixed results.
Absolute creatinine change in the positive studies remains quite small and is typically below 0.2
mg/dL.51,76 Recent large randomized trials found no reduction in the risk of nephrotoxicity after intravascular
angiographic procedures2 or in emergency department computed tomography,159 and current knowledge
suggests that NAC is ineffective for these indications.51,58,76,103,128
NAC has been studied in the treatment of patients with non APAP-related acute liver failure with mixed results.
In a randomized trial in adults, NAC improved transplant-free survival in early non–APAP-related acute liver
failure (eg, mild encephalopathy), but had no effect in those with severe encephalopathy.81 However, although a
study using historic controls suggests that NAC improves survival in children with non–APAP-related acute liver
failure,75 a randomized study showed no difference in 1 year survival rates and a lower 1 year transplant-free
survival rate, particularly in children younger than 2 years of age.147
NAC has been used for decades in cases of cyclopeptide-containing mushroom poisoning, particularly
poisoning with Amanita phalloides. NAC therapy for amatoxin poisoning is largely based on the similarity of
toxicity of amatoxin to APAP, specifically delayed onset of centrilobular hepatic necrosis. Decreases in
intracellular glutathione stores were identified in isolated rat hepatocytes that were exposed by amanita
extracts,69leading to the reasonable conclusion that supplying the tissue with thiols may decrease toxicity. In
retrospective studies, patients treated with NAC had lower mortality rates than those treated with supportive
care;46 however, in animal studies, NAC has little effect on hepatotoxicity.158
ADVERSE EVENTS AND SAFETY ISSUES
Oral NAC may cause nausea, vomiting, flatus, diarrhea, gastroesophageal reflux, and dysgeusia; generalized
urticaria occurs rarely. Generalized anaphylactoid reactions described following IV NAC
dosing6,17,23,35,49,60,86,90,111,118,161,165 are not noted after PO therapy and may be related to rate, concentration, or high
serum NAC concentrations.16,111
While the IV route ensures delivery, rate-related anaphylactoid reactions occur in up to 18% of patients.72 Most
reactions are mild (6%) or moderate (10%) such as cutaneous reactions, nausea, and vomiting; severe
reactions such as bronchospasm, hypotension, and angioedema are rare (1%).1 Anaphylactoid reactions are
more common in patients with lower [APAP] (25% if APAP < 150 µg/mL) than in those with high [APAP] (3% if
APAP > 300 µg/mL),166 because APAP decreases histamine release from mononucleocytes and mast cells in a
dose-dependent manner.32
If hypotension, dyspnea, wheezing, flushing, or erythema occurs, then NAC should be stopped and standard
symptomatic therapy instituted. After the reaction resolves, NAC can be carefully restarted at a slower rate after
one hour, assuming NAC is still indicated. If the reaction persists or worsens, IV NAC should be discontinued
and a switch to PO NAC should be considered. Adverse reactions, confined to flushing and erythema, are
usually transient, and NAC can be continued with meticulous monitoring for systemic symptoms that indicate
the need to stop the NAC. Urticaria can be managed withdiphenhydramine with the same
precautions.11 Iatrogenic overdoses with IV NAC have resulted in severe reactions, hypotension, cerebral
edema, seizures, and death.1,11,58,90
IV NAC decreases clotting factors and increases the prothrombin time in healthy volunteers and overdose
patients without evidence of hepatic damage.65,85,99,107,167 This effect occurs within the first hour, stabilizes after 16
hours of continuous IV NAC, and rapidly returns to normal when the infusion is stopped.65 International
normalized ratio (INR) elevations are mild and are typically below 1.5 to 2.0. Because the INR is used as a
marker of the severity of toxicity and is one of the criteria for transplantation, this adverse effect of NAC should
always be considered when evaluating the patient’s condition. An elevated INR that remains below 2 without
other indicators of hepatic damage is probably related to the NAC.
SAFETY IN PREGNANCY AND NEONATES
Untreated APAP toxicity is a far greater threat to fetuses than is NAC treatment.33,119 NAC traverses the human
placenta and produces cord blood concentrations comparable to maternal blood concentrations.64 For treatment
of the pregnant patient with APAP toxicity, IV NAC (not PO NAC) has the advantage of assuring fetal delivery
of NAC due to reduction of the first pass metabolism. NAC is FDA Pregnancy Category B.
Limited data exist with regard to the management of neonatal APAP toxicity,9,80,121,134although IV and PO NAC
have been used safely.1,9 No adverse events were observed when preterm newborns were treated with IV
NAC1,4,109 (Chaps. 31 and 35). The elimination half-life of NAC in preterm neonates was 11 hours compared with
5.6 hours in adults.4 When treating neonates, IV administration has the advantage of assuring adequate
antidotal delivery and has been administered without adverse effects.4,109
DOSING AND ADMINISTRATION
The standard IV NAC protocol is a loading dose of 150 mg/kg up to a maximum of 15 g in 200 mL of 5%
dextrose in water (D5W) (for adults) infused over 60 minutes followed by a first maintenance dose of 50 mg/kg
up to a maximum of 5 g in 500 mL D5W (for adults) infused over 4 hours followed by a second maintenance
dose of 100 mg/kg up to a maximum of 10 g in 1000 mL D5W (for adults) infused over 16 hours (6.25 mg/kg/h).
When NAC is administered orally, the patient should receive a 140-mg/kg loading dose either orally or by
enteral tube. Starting 4 hours after the loading dose, 70 mg/kg should be given every 4 hours, for an additional
17 doses, for a total dose of 1330 mg/kg. The solution should be diluted to 5% and can be mixed with a soft
drink to enhance palatability. If any dose is vomited within one hour of administration, then the dose should be
repeated83 or IV delivery used. Antiemetics (eg, metoclopramide, or ondansetron) should be used to ensure
absorption.
Several other regimens, including 48 hours IV, 36 hours IV, 36 hours PO, and 20 hours PO protocols, are
described; however, none of these has been adequately studied for general use34,140,170,176 (Chap. 35).
Conceptually, NAC therapy should be started if the patient is at risk of toxicity, continued as long as is
necessary, and it should be stopped when the patient is no longer at risk of toxicity.171 For a detailed description
of the indications for treating APAP toxicity with NAC, see Chap. 35. Briefly, in acute overdoses (from 4–24
hours after ingestion), NAC therapy should be initiated if the initial APAP concentration falls above the
treatment line of the Rumack-Matthew nomogram. In acute overdoses where the patient arrives more than 24
hours following ingestion, then NAC should be started if the APAP concentration is detectable or if the AST is
elevated. In repeated supratherapeutic ingestions, NAC therapy should be initiated if either the APAP
concentration is detectable or the AST is elevated. For other scenarios, see Chap. 35.
Once the protocol is initiated, an APAP concentration and AST are evaluated prior to the end of the NAC
infusion (20 hours for IV NAC) or at 24 hours (for oral NAC). If the APAP concentration is undetectable and the
AST is normal, then NAC can safely be discontinued. NAC should be continued beyond the “protocol length” if
the APAP concentration remains detectable or the AST is significantly elevated. There are no data to support
what degree of AST elevation should be used as a cutoff for treatment. The NAC protocol should be continued
until the APAP concentration is undetectable, there is no evidence of hepatic failure, and the AST, if it were
elevated, is decreasing. If hepatic failure intervenes, then IV NAC should be administered at the dose of the
“third bag” (16 hour infusion of 6.25 mg/kg/h) and continued until the patient has a normal mental status (or
recovery from hepatic encephalopathy)55 and the patient’s INR decreases below 2.0119 or until the patient
receives a liver transplant.26,54,71
For the rare patient who ingests exceptionally large doses of APAP, or who has prolonged and significantly
elevated APAP concentrations, consideration should be given to treating with greater amounts of NAC once
prolonged, massive APAP concentrations are evident.40,133,143 The rationale for increasing NAC dosing include
that the IV infusion rate (6.25 mg/kg/h) was derived to treat a 16 g ingestion of APAP.124 While it is effective for
most patients who ingest APAP, an ingestion that is several times larger than 16 g may require additional NAC.
In addition, published cases of patients who have developed hepatotoxicity despite early NAC therapy have
ingested more than 16 g of APAP and been treated with the IV (6.25 mg/kg/h) infusion.40,132,142 There are no
reported early NAC failures with the PO protocol.
No data exist to determine which, if any, alternative NAC dosing strategy is effective; however, it seems
reasonable to increase NAC dosing if the hepatic exposure to APAP (and therefore NAPQI) is prolonged and
massive. Several strategies have been theorized, but none have been studied. Potential strategies include:
1. Using the oral protocol for high-risk patients who can tolerate oral NAC
2. Administer both oral NAC and IV NAC simultaneously, an approach that increases initial loading and
total doses
3. Base the IV NAC dosing on the ingestion size or [APAP]:121
a. If the ingestion is between 16 and 32 g, or the initial [APAP] is between the “300 line” and the
“500 line,” then consider using 12.5 mg/kg/h as the 16 hour infusion rate.
b. If the ingestion is between 32 and 48 g, or the initial [APAP] is above the “500 line,” then
consider using 18.75 mg/kg/h as the 16 hour infusion rate.
c. If the ingestion is greater than 48 g, then consider using 25 mg/kg/h as the 16 hour infusion rate.
Your poison control center can help with the most current information (1-800-222-1222).
There are no specific dosing guidelines for patients who are obese. However, it may be reasonable to limit PO
and IV NAC dosing using a maximum weight of 100 kg. This maximum limit is not based on experimental
evidence; however, patients who are larger than 100 kg have an equivalent hepatic volume and similar
ingestion amounts as patients who weight less than 100 kg. Although dosing with a maximum weight is logical,
it has not yet been adequately studied in obese humans.
Previously dosing information for IV NAC was unavailable for patients weighing less than 40 kg, and problems
with osmolarity, sodium concentrations, and fluid requirements became apparent when improper dilutions were
used. The package insert now gives specific information for dosing in these patients (Table A3–2).
TABLE A3–2. Three-Bag Method Dosage Guide by Weight for Patients Weighing < 40 kga
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The IV dosing of NAC is complicated because three different preparations must be prepared with each based
on weight. A retrospective study estimated that there was a 33% medication error rate in the preparation and
delivery of IV NAC.56 To limit these errors, Tables A3–1 and A3–2 from the package insert, which give the
appropriate doses and dilutions for adults and patients weigh less than 40 kg.1 In addition, the following web
site has a dosage calculator: http://acetadote.com/dosecalc.php.
FORMULATION
NAC is available as a 20% concentration in 30 mL single-dose vials designed for dilution before IV
administration. NAC for PO administration is available in 10 mL vials of 10% and 20% for PO administration
and should also be diluted before administration.
SUMMARY
NAC is the primary antidote for APAP toxicity.
Limited evidence also supports NAC use in cyclopeptide containing mushroom toxicity (eg, Amanita
phalloides), carbon tetrachloride, and pulegone toxicity (pennyroyal oil).
NAC should be started if there is significant risk of toxicity and stopped when the risk of toxicity is gone
and any toxicity that had occurred is resolving.
Oral and IV NAC have essentially equivalent efficacy.
IV NAC has approximately an 18% risk of anaphylactoid reactions, most of which are mild, and oral
NAC has a 20% risk of vomiting.
Higher doses of NAC should be considered for cases of massive ingestion or cases in which a
prolonged high concentration of APAP is present.
Acknowledgment
Martin Jay Smilkstein, MD, contributed to this Antidote in Depth in a previous edition.
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