Use of N-Acetylcysteine in Clinical Toxicology ROBERTJ.

FLANAGAN, Ph.D.,

T. J.

MEREDITH, M.D., London, LLK.

The major use of N-acetylcysteine in clinical

toxicology is in the treatment of acetaminophen (paracetamol) overdosage. The hepatorenal toxicity of acetaminophen is mediated by a reactive metabolite normally detoxified by reduced glutathione. If glutathione is depleted, covalent binding to macromolecules and/or oxidation of thiol enzymes can lead to cell death. Oral or intravenous N-acety!cysteine or oral D,L-methionine mitigates acetaminopheninduced hepatorenal damage if given within 10 hours, but becomes less effective thereafter. In vivo, N-acetylcysteine forms L-cysteine, cystine, L-methionine, glutathione, and mixed disulfides; L-methionine also forms cysteine, thus giving rise to glutathione and other products. Oral therapy with N-acetylcysteine or methionine for acetaminophen poisoning is contraindicated in the presence of coma or vomiting, or if activated charcoal has been given by mouth. Nausea, vomiting, and diarrhea may also occur as a result of oral N-acetylcysteine administration. Anaphylactoid reactions including angioedema, bronchospasm, flushing, hypotension, nausea/vomiting, rash, tachycardia, and respiratory distress may occur 15-60 minutes into N-acetylcysteine infusion (20 hour intravenous regimen) in up to 10% of patients. Following accidental intravenous overdosage, the adverse reactions of N-acetylcysteine are similar but more severe; fatalities have occurred. A reduction in the loading dose of N-acetylcysteine may reduce the risk of adverse reactions while maintaining efficacy. Administration of N-acetylcysteine for a longer period might provide enhanced protection for patients in whom acetaminophen absorption or elimination is delayed. N-acetylcysteine may also have a role in the treatment of toxicity from carbon tetrachlo-

From the Poisons Unit, Guy's Hospital and Division of Toxicology and Environmental Health, Department of Health, London, U.K. The contents of this article represent the authors' views alone and in no way commit the Department of Health. Requests for reprints should be addressed to Robert J. Flanagan, Ph.D., Poisons Unit, Guy's Hospital, St Thomas' Street, London SE1 9RT, U.K.

ride, chloroform, 1,2-dichloropropane, and other compounds. The possible use of N-acetylcysteine and other agents in the prevention of the neuropsychiatric sequelae of acute carbon monoxide poisoning is an important area for future research. -Acetylcysteine (NAC) was introduced as a mucolytic agent in the 1960s and has since N found wide application as a cytoprotective agent in acute acetaminophen (paracetamol) poisoning [1]. As such, it can be regarded as an essential antidote [2]. Other applications in clinical toxicology, including treatment of heavy metal poisoning, have been investigated. This article reviews the pharmacokinetics, metabolism, possible mode(s) of action, and toxicity of NAC with special reference to the treatment of acetaminophen poisoning.

ACUTE ACETAMINOPHENPOISONING Acetaminophen is an effective analgesic and side effects are few at therapeutic doses. Most patients who ingest overdoses show only mild toxicity (nausea, vomiting, and abdominal tenderness) in the first 24 hours, although the plasma half-life is prolonged (>5 hours). Ingestion by an adult of 10-15 g of acetaminophen in a single dose may result in hepatic damage 2-5 days later and death from fulminant hepatic failure [3]. Renal damage, which may lead to acute renal failure, occurs in 1-5% of patients up to 14 days postingestion, sometimes without evidence of hepatic damage [4]. Coma and severe metabolic acidosis rarely occur in the absence of other drugs or signs of hepatorenal damage in patients with plasma acetaminophen concentrations >800 mg/L at 4-20 hours postingestion [5]. MECHANISMS OF ACETAMINOPHEN CYTOTOXICITY The cytotoxicity of acetaminophen is mediated by a reactive metabolite, probably N-acetyl-p-benzoquinoneimine (NAPQI), formed in the liver by a cytochrome P450-dependent mixed-function oxidase [6] and in the kidney by a prostaglandin synthetase system [7,8]. NAPQI, a strong electrophile and oxidizing agent, is detoxified by reduced glutathione (GSH) (Figure 1). If mitochondrial and cytosolic GSH become depleted (to 20-30% of normal), covalent binding to nucleophilic cell macromole-

September 30, 1991 The American Journal of Medicine Volume 91 (suppl 3C)

3C-131S

SYMPOSIUM ON OXIDANTSAND ANTIOXIDANTS/FLANAGANand MEREDITH

HN" C(~H3

HNi COCH3

Glu u r ° n i d e ~ ¢raseHNi C O C H 3 / Sulp I hate ~ / Aryisulphotransferase

TOH

HO.. N" COCH3 ~

HN~"COCH3 -

N / COCH3"

+

. .....V @ C e l l Ott

constituents

o

NAPQI ,..COCH3/ HN / G S H

.. COCH3

.......lb.Glutathionases COOH

HN " COCH3 Acetaminophen-3-mercapturicacid Ott

cules and other reactions may lead to cell death. 3-(Cystein-S-yl)acetaminophen-protein adducts have been found in liver and in serum after administration of acetaminophen to mice [9], and in plasma after acetaminophen overdosage in humans [10]. Disturbed calcium homeostasis, due to oxidation of intracellular thiol enzymes, in particular Ca 2+ translocases, may also be important [11,12]. GSH may thus exert a general protective effect by reducing oxidized thiols [13]. The role of GSH in protecting the cell against toxic insults, such as encountered after acetaminophen overdosage, has been reviewed [14,15].

USE OF PROTECTIVEAGENTS In animals, prior administration of high doses of inhibitors of oxidative metabolism, such as cimeti3C-132S

Figure 1. Summary of acetaminophen (paracetamol) metabolism.

dine, reduces NAPQI formation and thus the frequency and severity of hepatotoxicity. This approach is not appropriate for the treatment of poisoning in humans, for an inhibitor would have to be given before acetaminophen overdose. Use of other sulfur compounds to maintain NAPQI detoxification and/or to mitigate hepatorenal damage has been investigated. Many of these are unsuitable: (a) cysteine is unstable in solution; (b) GSH for drug use is not widely available and penetrates cell membranes poorly; (c) dimercaprol and D-penicillamine provide little or no protection against acetaminophen-induced hepatorenal toxicity in humans [3]; and (d) cysteamine (mercaptamine, 2mercaptoethanolamine), an effective protective agent when used in acetaminophen poisoning up to 10 hours postingestion, had unacceptable side ef-

September30, 1991 The American Journal of Medicine Volume 91 (suppl 3C)

SYMPOSIUMON OXIDANTSAND ANTIOXIDANTS/FLANAGANand MEREDITH

fects, including nausea, vomiting, drowsiness, and cardiotoxicity at the doses used [3]. On the other hand, D,L-methionine and NAC have been found to be effective in the treatment of acetaminophen poisoning in humans. Methionine is safe, and oral therapy (4 × 2.5 g over 12 hours) has been widely used [16]. The efficacy of oral therapy is reduced if the patient vomits or is given activated charcoal by mouth. Intravenous NAC (a total of 300 mg/kg over 20 hours) also mitigates hepatic [1] and renal [4] damage if given within 10 hours of ingestion. Oral NAC (140 mg/kg and then 17 x 70 mg/kg every 4 hours) is also effective in the treatment of acetaminophen poisoning if commenced within 10 hours [17] and it has been extensively given by this route in the United States. NAC can act as a precursor of inorganic sulfate [18], but although sulfate replenishment may be important in the detoxification of acrylonitrile [19], this is not thought to be so for acetaminophen. In this latter case, NAC and C-methionine probably act by restoring intracellular GSH [20]. Both compounds require prior conversion to cysteine. NAC is deacetylated and L-methionine undergoes sequential metabolism by five enzymes. Both could also exert a cytoprotective effect by other mechanisms including reduction of NAPQI, oxidised thiol enzymes, and other cell constituents. NAC may even be directly conjugated with NAPQI. Other possible protective mechanisms include inhibition of neutrophil accumulation [21] and restoration of the ability of proteolytic enzymes to dispose of arylated protein [22].

INITIATION OF PROTECTIVE THERAPY Although a history of acetaminophen poisoning is usually forthcoming, the diagnosis should also be considered in comatose patients who may have taken opiates such as dextropropoxyphene, and in patients with nonspecific clinical features such as nausea, vomiting, or abdominal pain. Early diagnosis is important because NAC and methionine are less effective if given more than 10 hours after ingestion [1,16,17].

Role of Plasma Acetaminophen Measurements NAC or methionine should be given if the plasma acetaminophen concentration is above a line joining 200 mg/L (1.32 retool/L) at 4 hours postingestion and 30 mg/L (0.20 mmol/L) at 15 hours on a semilogarithmic plot (Figure 2). A plasma aeetaminophen measurement before 4 hours can be misleading due to incomplete absorption. Treatment should not await an aeetaminophen measurement if a single dose of more than 7.5 g has been taken by an adult, or if the patient presents more than 8 hours afterward. The time postingestion, the occurrence of coma or vomiting, the cost of a course of treatment (in the United Kingdom, the cost of a course of methionine is about one-sixteenth that of intravenous NAC), and the risk of adverse reactions to intravenous NAC (vide infl'a) should be e0nsidered before giving a protective agent. Twenty percent or so of patients with acetaminophen concentrations above the "treatment line" (Figure 2) will escape hepatorenal damage even if

[Acetaminophen] (mg/L)

500 :

Hepatic Damage Likely -

2001

Give

Protective Agent Treatment

Absorption 50 Phase

Controversial

Hepatic Damage Unlikely

5

Figure 2. Nomogram relating plasma acetaminophen (paracetamol)concentrations and risk of hepatic damage [3].

0

i

i

1

i

i

8

12

16

20

24

Time Post-Ingestion (h) September 30, 1991 The American Journal of Medicine Volume91 (suppl 3C)

3C-133S

SYMPOSIUMON OXIDANTSAND ANTIOXIDANTS/FLANAGANand MEREDITH

untreated. There are several groups such as chronic alcohol abusers who may be at risk of hepatic toxicity from high therapeutic acetaminophen dosage since hepatic GSH may be low initially [23,24]. Likewise, HIV-positive individuals may be especially susceptible to acetaminophen-induced hepatotoxicity [25]. Other patients, for example those taking anticonvulsants or other enzyme inducers, may form NAPQI readily and may deplete endogenous GSH more quickly [26], and this may place them at greater risk. Note that interpretation Of plasma acetaminophen concentrations fi'om the time of i~gestion may be difficult to determine precisely. ~Sbme patients even ingest several overdoses in succession before being admitted to the hospital [2~]; Concealment of the true time of ingestion may lead :to fatalities because treatment is withheld When the~plasma acetaminophen concentration is th0ught to be "nontoxic" [28].

Units'of Measurement and Analytical Methods It is !mportant to know the units used to report quantitative acetaminophen results r (to convert mmol/L to rag/L, multiply by 151; to convert mg/L to mmol/L, multiply by 0.00661). Fatalities have occurred with treatment being withheld due to confusion abbut the units employed. Colorimetric acetaminophen assays have a limit of sensitivity of about 50 mg/L (100 mg/L or more with uremic sera) and salicylates may interfere; hence, results obtained using these methods in suspected "late" cases are of doubtful value. An enzyme-based, chromat/ographic, or other selective assay should be used together with a qualitative urine test.

Treatment of Children and in Pregnancy

"Young

children seem to be tess susceptible than adults to the hepatorenal toxicity of acetaminophSn, for the amount ingested is usually small, and hepatic sulfation capacity and hepatic GSH stores are ~increased [29,30]. Older children and adolescents do sometimes ingest potentially serious acetaminophen overdoses, and those at risk of hgpatorenal damage according to a plasma acetami' nophen measurement should be treated in the same way as adults. N o adverse sequelae were reported when courses of oral and intravenous NAC were given to two pregnant patients with acetaminophen overd0s~ at 36 and 32 weeks of gestation, respectively [31,32]. In a study of 60 pregnant patients having ingested an overdose of acetaminophen, 24 were at risk of developing hepatorenal damage due to high plasma acetaminophen concentrations and were given oral NAC [33]. There was a significant corre~ !afibn between time to loading NAC dose and out3C-134S

come, with an increase in spontaneous abortion or fetal death when treatment was delayed, suggesting that treatment should commence as soon as possible after the overdose. Intravenous NAC administration would appear to be preferable. There is no information on the excretion of NAC into breast milk, but breast feeding should not be a contraindication to the use of NAC in a nursing mother when there is a risk of acetaminopheninduced hepatorenal toxicity.

DOSE, ROUTE, AND DURATION OF N-ACETYLCYSTEINE THERAPY NAC can be administered orally and intravenously in the treatment of acetaminophen poisoning, but methionine is normally given only by the oral route. The dosage regimens used were empirically derived and it is difficult to compare the relative efficacy of treatments, particularly as patients show great variation in the severity of hepatorenal damage after overdosage even if similar amounts have been ingested. Reports suggest some benefit from intravenous NAC (20-hour regimen) when commenced up to 24 hours [34], and possibly even up to 36 hours [35], after the overdose, while some protection up to 24 hours seems apparent with the 72-hour oral NAC regimen [17].

Intravenous N-Acetylcysteine NAC BP (20% weight/volume), adjusted to pH 7.0, is available in the United Kingdom for intravenous use. It is supplied in 10 mL ampules (each ampule contains 2 g of NAC). The risk of accidental overdosage has been reduced following changes in the labeling of the ampule [36]. In the treatment of acetaminophen poisoning, an initial dose of 150 mg/kg of body weight of NAC is infused intravenously in 200 mL of 5% dextrose over 15 minutes, followed by 50 mg/kg in 500 mL of 5% dextrose over 4 hours and 100 mg/kg in 1 L of 5% dextrose over the next 16 hours (300 mg/kg of NAC Over 20 hours) [3]. The quantity of intravenous fluid used in children should take into account age and weight, for fluid overload is a potential risk in young children. Bronstein et al [37] reported in 24 patients that intravenous NAC dosage over 48 hours (initial dose of 140 mg/kg followed by 12 × 70 mg/kg doses every 4 hours) was more effective than the 20-hour protocol. Nevertheless, initial use of less NAC should reduce the risk of adverse reactions while still providing adequate cytopr0tection [38].

Oral N-Acetylcysteine NAC is available in the U.S. as 10% and 20% (weight/volume) solutions and is given orally as a 5% (weight/volume) solution in a soft drink or, if

September30, 1991 The American Journal of Medicine Volume 91 (suppl 3C)

SYMPOSIUM ON OXIDANTSAND ANTIOXIDANTS/FLANAGANand MEREDITH

given intragastrically, in water. NAC preparations suitable for oral use are available in many other countries. The initial dose of 140 mg/kg is followed by 17 maintenance doses (70 mg/kg every 4 hours for 68 hours) [17]. If the patient vomits within 1 hour of a dose, the dose should be repeated. Oral NAC is extensively used, but intravenous NAC is only available on an investigational basis in the U.S. [37]. As with methionine, the efficacy of oral NAC may be reduced if an adsorbent such as activated charcoal is also given orally. In six volunteers, activated charcoal had no significant effect on NAC absorption [39], but was associated with a mean reduction in NAC bioavailability of 40% in a second study in 19 subjects [40]. Vomiting is a contraindication to oral therapy, although it may itself be associated with the use of oral NAC (vide infra).

(N, N'-diacetylcysteine, N-acetylcysteine-cysteine, etc.), and metabolism gives rise to a number of products (cysteine, cystine, methionine, GSH, and other products; mixed disulfides; etc.). In plasma, most of a NAC dose is present as disulfides. In one study, oral NAC increased free cysteine in plasma although total cysteine and free and total GSH concentrations remained unchanged [43]. Plasma total NAC concentrations soon after the start of an infusion (20-hour intravenous regimen) range from 300 to 900 rag/L, and concentrations of only 11-90 mg/L are found at the end [38], these latter concentrations (11-90 mg/L) being similar to those found following oral NAC administration [43].

Adverse Reactions to N-acetylcysteine Oral NAC treatment of acetaminophen poisoning is rarely accompanied by serious adverse reactions. Duration of Therapy Cytoprotective therapy commenced before the After repeated high doses, nausea/vomiting and result of a plasma acetaminophen measurement diarrhea have been reported in up to 50% and 35% becomes available should be stopped in patients of patients, respectively; headache, rash, hypotenthought not to be at risk. Treatment should also be sion, and respiratory distress rarely occur [45]. withdrawn in patients who exhibit serious adverse Urticaria has also been reported [46]. Hepatotoxicreactions. It has been suggested that NAC or me- ity following oral and rectal administration of NAC thionine should not be given to patients showing in high doses (106 g over 3 days) to treat meconium signs of developing liver failure because of the risk ileus equivalent in a 3-year-old boy with cystic fiof precipitating hepatic encephalopathy [41]. There brosis has been observed [47]. High-dose NAC intravenous administration may are no reports, however, of acetaminophen overdosage in which NAC or methionine administration be accompanied by adverse effects, including anaphylactoid reactions such as flushing, rash/prurihas precipitated coma. NAC treatment may need to be prolonged in pa- tus, angioedema, bronchospasm, nausea/vomiting, tients with high initial plasma acetaminophen con- hypotension, tachycardia, and respiratory distress, centrations (>800 mg/L at 4-12 hours postinges- occurring 15-60 minutes into the infusion in up to tion), delayed acetaminophen absorption due to 10% of patients [36,48-50]. Asthmatics are at speconcomitant ingestion of an opiate or anticholiner- cial risk. These toxic reactions appear to be due to gic drug [42], or other factors complicating inter- NAC rather than any other component of the infupretation of plasma acetaminophen concentrations. sion [48]. Following accidental NAC overdosage, Use of the 40-hour intravenous NAC protocol [37] adverse effects observed are similar but of greater seems appropriate in such patients until more data severity, and this, together with the observation become available. Serial plasma acetaminophen that the reactions occur in pharmacologically naive measurements with consequent adjustment of the subjects and usually respond quickly to withdrawal duration of NAC treatment is an alternative ap- of the infusion, suggests a dose-dependent (nonallergic) mechanism. proach. Treatment of NAC toxicity is directed at the reCLINICAL PHARMACOLOGY OF versal of anaphylactoid features and/or controlling N-ACETYLCYSTEINE nausea and vomiting. Airway support, reversal of Absorption of NAC occurs rapidly after oral bronchospasm, and management of vital functions administration of doses of 100-600 rag, although may also be required. If a patient shows a severe bioavailability is less than 10% [43]. After intrave- anaphylactoid reaction but still needs treatment on nous administration, elimination half-lives of 2-6 the basis of plasma acetaminophen measurements, hours have been reported, and 20-30% of the dose either an antihistamine may be given or infusion is excreted unchanged in urine [38,44]. The phar- recommenced at a lower rate. Alternatively, oral macokinetics of NAC are complicated because of NAC/methionine may be administered provided the variety of forms in which NAC can be present there is no contraindication. September 30, 1991 The American Journal of Medicine Volume91 (suppl 3C)

3C-135S

SYMPOSIUM ON OXIDANTSAND ANTIOXIDANTS/FLANAGANand MEREDITH

TABLE I Hepatorenal Damage in 27 Cases of Acute Carbon Tetrachloride Poisoning:Guy's Poisons Unit 1981-1988" Therapy

Numberof Patients

Hepatic Damager(%)

Renal Damage(%)

Deaths

NACSsupportive Supportive alone

17 10

6 (35) 8 (80)

1 (6) 4 (40)

1 1

*Includes data from [58]. 1Serum aminotransferaseactivities at least five times normal, $20 hours' intravenous regimen [3].

NAC administration, usually in excess of the recommended dose, has been associated with some deaths [36,51,52]. OTHER APPLICATIONS OF N-ACETYLCYSTEINE IN CLINICAL TOXICOLOGY Chloroform, 1,2-Dichloropropane, and Carbon Tetrachloride Chloroform (CHCI3) and carbon tetrachloride (CC14) are potent hepatorenal toxins. The fatal dose of either compound in an adult may be as little as 5-10 mL by ingestion or inhalation [53]. 1,2-Dichloropropane (DCP) is also a potent hepatorenal toxin in humans [54]. There is a clear theoretical role for the use of NAC in the treatment of CHC13 poisoning because phosgene (COC12) is an important metabolite. Phosgene depletes GSH to form diglutathionyldithiocarbonate (GS-CO-SG) [55], but also binds to cell macromolecules and causes tissue necrosis. Administration of DCP to rats is again associated with GSH depletion, possibly via the production of l-chloro-2-hydroxypropane [54]. NAC could be used to replete intracellular GSH and thereby mitigate the toxicity of the parent compounds as in the case of acetaminophen. With CC14, the mechanism of toxicity, and possible role of NAC in its treatment, is more complex. The trichloromethyl free radical (. CC13) initially formed may bind covalently to macromolecules or react further. CHC13 is a minor metabolite and may be metabolized to phosgene, but this is unclear. CC14 does not deplete hepatic GSH to the same extent as CHCI~ in animals [52]. A number of antioxidants/free radical scavengers, including vitamin E [56] and sulfydryl compounds [55], have been used as cytoprotective agents in CCI 4 poisoning. Hyperbaric oxygen has been also used to treat one patient [57]. There is no information on blood CC]4 concentrations in relation to the time of exposure and the incidence of hepatorenal damage comparable to that available for acetaminophen (Figure 2). In a series of 17 patients in whom the diagnosis of CC14 poisoning had been analytically confirmed and in3C-136S

travenous NAC (20-hour regimen) [3] given within about 10 hours of exposure, only six developed hepatic damage and one suffered acute renal failure (Table I). In contrast, of 10 further patients who were not treated with NAC, eight had hepatic damage and four suffered renal failure. One patient from each group died, but in each case this was unrelated to the CC14 toxicity. The results in patients not treated with NAC are in agreement with observations reported in the literature [59] for 109 patients (1965-1987) poisoned with CC14 and not given protective agents: 84 (77%) and 64 (59%) developed hepatic and renal damage, respectively, and 48 underwent hemodialysis. There was a higher incidence of damage compared with that observed with acetaminophen, even though NAC had been administered within about 10 hours of exposure (Table I). CC14 has a longer terminal half-life (37 hours in one patient) [60] compared with acetaminophen and thus cytoprotective therapy should probably have been continued for longer than 20 hours. Blood CC14 concentrations should be measured to guide therapy. More studies are necessary. Carbon Monoxide Carbon monoxide (CO) remains the single most common cause of fatal poisoning in both the U.K. and U.S. Oxygen is effective as treatment, and few acutely poisoned patients who survive to reach the hospital die (10 deaths out of 475 admissions in England and Wales in 1985) [61]. Neuropsychiatric disturbances (intellectual deterioration; memory irapairment; cerebral, cerebellar, and midbrain damage such as Parkinsonism and akinetic mutism; and personality changes such as irritability, violence, verbal aggressiveness, impulsiveness, and moodihess) may develop some weeks after apparent full recovery [61]. At present, there are no prognostic indicators. Hyperbaric oxygen may reduce the incidence of neuropsychiatric sequelae from about 40% to less than 5% [62-64], although this is controversial [61]. It has been suggested that delayed neuropsychiatric sequelae after CO could be due to oxidative damage as the oxygen tension rises in a reducing environment (hypoxic/reperfusion injury) [65]. Howard et al [66] reported a 26-year-old man who had been comatose for 35 hours following CO poisoning (carboxyhemoglobin of 25% at 40 hours); the patient's cardiorespiratory status was satisfactory and he was not given supplemental oxygen. The patient remained unrousable for 4 days, but on day 5 he was given intravenous NAC (300 mg/kg over 20 hours) [3] together with a xanthine oxidase inhibitor, allopurinol (100 mg/day, 14 days), via naso-

September 30, 1991 The American Journal of Medicine Volume 91 (suppl 3C)

SYMPOSIUMON OXIDANTSAND ANTIOXIDANTS/FLANAGANand MEREDITH TABLE II Possible Additional Applications of N-Acetylcysteinein Clinical Toxicology (cf. [52]) Compound Drugs Chtoramphenicol Cyclophosphamide Doxorubicin Iphosphamide Other poisons Acrytonitrile Bromobenzene Dichtorodiethylsulfide (mustardgas) Naphthalene

Feature(s)ofToxicity

MechanismofToxicity

References

Bone-marrowtoxicity Hemorrhagiccystitis Cardiomyepathy Hemorrhagiccystitis

Reactivemetabolite Reactivemetabolite Freeradicaldamage Reactivemetabolite

[67] [68] [69, 70] [71]

Coma,fits, cardiorespiratory arrest Livernecrosis Multiplelesions

Reactivemoleculeand/or metabolite Reactivemetabolite Reactivemolecule

[19]

Methemoglobinemia,cataract formation, hemolysis

Reactivemetabolites

[73]

gastric tube. Signs of recovery were apparent 8 hours after the end of the infusion and full recovery was made over the next 3 weeks. There was no evidence of neurologic or mental impairment on examination 6 weeks later. This report raises many questions. If neuropsychiatric sequelae from acute CO poisoning are due to hypoxic/reperfusion injury, than it could be argued that all survivors, even those given hyperbaric oxygen, should also receive cytoprotective therapy before, or very soon after, oxygen administration. The role of NAC, allopurinol, and other antioxidants, such as vitamin E, in the treatment of CO poisoning warrants further investigations. Other Chemoprotective Applications

Some other areas of clinical toxicology where use of NAC has been suggested are listed in Table II. However, NAC treatment has not found wide application in mitigating the toxicity of chemotherapeutic agents. Acute poisoning with some of the other agents listed is very rare and there are no reports showing the efficacy of NAC therapy. NAC is contraindicated in acute paraquat poisoning [52]. Treatment of Heavy Metal Poisoning

NAC shares with other sulfydryl compounds the ability to chelate heavy metal ions. Potential advantages over other chelating agents are that NAC is safe and high tissue concentrations are achieved. Only a few studies [52] have been undertaken to evaluate the efficacy of NAC as a chelating agent for heavy metals, and other, more effective, agents are now available [74]. COMMENTS

Intravenous and oral NAC and oral D,Lmethionine mitigate hepatorenal damage following acetaminophen overdosage if given within 10 hours of ingestion. NAC may even provide some protec-

[72] [52]

tion up to 24 hours, and possibly up to 36 hours, postingestion. Intravenous NAC (300 mg/kg over 20 hours) is preferred if the patient is in a coma or vomiting, if activated charcoal has been given by mouth, or if the patient is treated more than 10 hours after ingestion of the overdose. Anaphylactold reactions including angioedema, bronchospasm, hypotension, nausea/vomiting, tachycardia, and respiratory distress may occur 15-60 minutes into a NAC infusion. A lower initial rate of infusion should reduce the risk of adverse reactions, while administration for a longer period would provide protection in patients in whom acetaminophen absorption or elimination is delayed. NAC may also have a role in the treatment of poisoning due to CHCI~, DCP, CCI4, and possibly other compounds if (a) toxicity is predictable and (b) if reactive metabolites play a part in the development of toxicity and/or GSH is involved in detoxification. The prevention of neuropsychiatric sequelae after acute CO poisoning is an important area for future research. REFERENCES 1, Prescott LF, Illingworth RN, Critchley JAJH, Stewart MJ, Adam RD, Proudfoot AT. Intravenous N-acetylcysteine: treatment of choice for paracetamol poisoning. Br Med J 1979; 2: 1097-100. 2. Meredith T, Caisley J, Volans G. Emergency drugs: agents used in the treatment of poisoning. Br Med J 1984; 289: 742-8. 3. Prescott LE Paracetamol overdose: pharmacological considerations and clinical management. Drugs 1983; 25: 290-314. 4. Prescott LF, Proudfoot AT. Cregeen RJ. Paracetamol-induced acute renal failure in the absence of fulminant liver damage. Br Med J 1982; 284: 421-2. 5. Ftanagan RJ, Mant TGK. Coma and metabolic acidosis early in severe acute paracetamol poisoning. Hum Toxicot 1986; 5: 179-82. 6. Mitchell JR, Thorgeirsson SS, Potter WZ, Jollow DJ, Keiser H. Acetaminopheninduced hepatic injury: protective role of glutathione in man and rationale for therapy. Clin Pharmacol Ther 1974; 16: 676-84. 7. Boyd JA, Eling TE. Prostaglandin endoperoxidase synthetase-dependent cooxidation of acetaminophen to intermediates which covalently bind in vitro to rabbit renal medullary microsomes. J Pharmacol Exp Ther 1981; 219: 659-64. 8. Moldeus P, Rahimtula A, Andersson B, Berggren M. Prostaglandin synthetase catalyzed activation of paracetamoL In: Snyder R, Jollow DJ, Parke DV, Gibson CG, Kocis JJ, Witmer CM, eds. Biological reactive intermediates--II. Chemical mecha-

September 30, 1991 The American Journal of Medicine Volume 91 (suppl 3C)

3C-137S

SYMPOSIUM ON OXIDANTSAND ANTIOXIDANTS/FLANAGANand MEREDITH nisms and biological effects, part B. New York: Plenum, 1982: 1099-107. 9. Pumford NR, Hinson JA, Potter DW, Rowland KL, Benson RW, Roberts DW. Immunochemical quantitation of 3-(cystein-S-yl)acetaminophen adducts in serum and liver proteins of acetaminophen treated mice. J Pharmacol Exp Ther 1989; 248: 190-6. 10, Hinson JA, Roberts DW, Benson RW, eta/. Mechanism of paracetamol toxicity. Lancet 1990; 335: 732. 11, Moore M, Thor H, Moore G, Nelson S, Moldeus P, Orrenius S. The toxicity of acetaminophen and N-acetyl-p-benzoquinoneimine (NAPQI) in isolated hepatocytes is associated with thiol depletion and increased cytosolic Ca2+. J Biol Chem 1985; 260: 13035-40. 12. Corcoran GB, Wong BK, Neese BL. Early sustained rise in total liver calcium during acetaminophen hepatotoxicity in mice. Res Commun Chem Pathol Pharmacol 1987; 58: 291-305. 13. Tee LBG, Boobis AR, Huggett AC, Davies DS. Reversal of acetaminophen toxicity in isolated hamster hepatocytes by dithiothreitol. Toxicol Appl Pharmacol 1986; 83: 294-314. 14. Kretzschmar M, Klinger W. The hepatic glutathione system--influences of xenobiotics. Exp Pathol 1990; 38: 145-64. 15. Reed DJ. Glutathione: toxicological implications. Annu Rev Pharmacol Toxicol 1990; 30: 603-31. 16. Vale JA, Meredith TJ, Goulding R. Treatment of acetaminophen poisoning: the use of oral methionine. Arch Intern Med 1981; 141: 394-6. 17. Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH. Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985). N Engl J Med 1988; 319: 1557-62. 18. Lin JH, Levy G. Sulfate depletion after acetaminophen administration and replenishment by infusion of sodium sulfate or N-acetylcysteine in rats. Biochem Pharmacol 1981; 30: 2723-5. 19. Benz FW, Nedand DE, Pierce WM, Babiuk C. Acute acrylonitrile toxicity: studies on the mechanism of the antidotal effect of D- and L-cysteine and their N-acetyl derivatives in the rat. Toxicol Appl Pharmacol 1990; 102: 142-50. 20. Miners JO, Drew R, Birkett OJ. Mechanism of action of paracetamol protective agents in mice in rive. Biochem Pharmacoi 1984; 33: 2995-3000. 21. Mitchell JR. Acetaminophen toxicity. N Engl J Med 1988; 319: 1601-2. 22. Bruno MK, Cohen SD, Khairallah EA. Antidotal effectiveness of N-acetylcysteine in reversing acetaminophen-induced hepatotoxicity. Enhancement of the proteolysis of arylated proteins. Biochem Pharmacol 1988; 37: 4319-25. 23. Seeff LB, Cuccherini BA, Zimmerman HJ, Adler E, Benjamin SB. Acetaminophen hepatotoxicity in alcoholics. A therapeutic misadventure. Ann Intern Med 1986; 104: 399-404. 24. Lauterberg BH, Velez ME. Glutathione deficiency in alcoholics: risk factor for paracetamol hepatotoxicity. Gut 1988; 29: 1153-7. 25. Henry JA. Glutathione and HIV infection. Lancet 1990; 335: 235-6. 26. Pirotte JM. Apparent potentiation by phenobarbital of hepatotoxicity from small doses of acetaminophen. Ann Intern Med 1984; 101: 403. 27. Mathis RD, Walker JS, Kuhns DW. Subacute acetaminophen overdose after incremental dosing. J Emerg Med 1988; 6: 37-40. 28. Read RB, Tredger JM, Williams R. Analysis of factors responsible for continuing mortality after paracetamd overdose. Hum Toxicot 1986; 5: 201-6. 29. Peterson RG, Rumack BH. Age as a variable in acetaminophen overdose. Arch Intern Med 1981; 141: 390-3. 30. Leih-Lai MW, Sarnaik AP, Newton JF, et al. Metabolism and pharmacokinetics of acetaminophen in a severely poisoned young child. J Pediatr 1984; 105: 125-8. 31, Byer/M, Traylor TR, Semmer JR. Acetaminophen overdose in the third trimester of pregnancy. JAMA 1982; 247: 3114-5. 32. Rosevear SK, Hope PL. Favourable neonatal outcome following maternal paracetamol overdose and severe fetal distress. Br J Obstet Gynaecol 1989; 96: 491-3. 33. Riggs BS, Bronstein AC, Kulig K, Archer PG, Rumack BH. Acute acetaminophen overdose during pregnancy. Obstet Gynecol 1989; 74: 247-53. 34. Parker D, White JP, Paten D, Routledge PA. Safety of late acetylcysteine treatment of paracetamol poisoning. Hum Exp Toxicol 1990; 9: 25-7. 35. Harrison PM, Keays R, Bray GP, Alexander GJM, Williams R. Improved outcome of paracetamol-induced fulminant hepatic failure by late administration of acetylcysteine. Lancet 1990; 335: 1572-3. 36. Mant TGK, Tempowski JH, Volans GN, Talbot JCC. Adverse reactions to acetylcysteine and effects of overdose. Br Med J 1984; 289: 217-9. 37, Bronstein AC, Linden CH, Hall AH, et al. Intravenous N-acetylcysteine for acute acetaminophen poisoning. Vet Hum Toxicol 1985; 27: 316. 38. Prescott LF, Donovan JW, Jarvie DR, Proudfoot AT. The disposition and kinetics

3C-138S

of intravenous N-acetylcysteine in patients with paracetamol overdosage. Eur J Clin Pharmacol 1989; 37: 501-6. 39. Renzi FP, Donovan JW, Martin TG, Morgan L, Harrison EE Concomitant use of activated charcoal and N-acetylcysteine. Ann Emerg Med 1985; 14: 568-72. 40, Ekins BR, Ford DC, Thompson MIB, Bridges RR, Rollins DE, Jenkins RD. The effect of activated charcoal on N-acetylcysteine absorption in normal subjects. Am J Emerg Med 1987; 5: 483-7. 41. Holloway CJ, Brunner C, Schmidt E, Schmidt FW. Thiols and hepatic coma. Artif Organs 1979; 3: 15-9. 42, Bartle WR, Paradise FL, Derry JE, Livingstone DJ. Belayed acetaminophen toxicity despite acetylcysteine use. Drug Intell Clin Pharmacol 1989; 23: 509. 43. Burgunder JM, Varriale A, Lauterberg BH. Effect of N-acetylcysteine on plasma cysteine and gtutathione following paracetamol administration. Eur J Clin Pharmacol 1989; 36: 127-31. 44. Borgstrom L, Kagedal B, Paulsen O. Pharmacokinetics of N-acetylcysteine in man. Eur J Clin Pharmacol 1986; 31: 217-22. 45. Miller LF, Rumack BH. Clinical safety of high oral doses of acetylcysteine. Semin Oncol 1983; 10 (suppl 1): 76-85. 46. Charley G, Dean BS, Krenzelok EE Oral N-acetylcysteine-induced urticaria: a case report. Vet Hum Toxicol 1987; 29: 477. 47. Bailey DJ, Andres JM. Liver injury after oral and rectal administration of Nacetylcysteine for meconium ileus equivalent in a patient with cystic fibrosis. Pediatrics 1987; 79: 281-2. 48. Bateman DN, Woodhouse KW, Rawlins MD. Adverse reactions to N-acetylcysteine. Hum Toxicol 1984; 3: 393-8. 49. Tenenbein M. Hypersensitivity-like reactions to N-acetylcysteine. Vet Hum Toxicol 1984; 26: 3-5. 50. Dawson AH, Henry DA, McEwen J. Adverse reactions to N-acetylcysteine during treatment for paracetamol poisoning. Med J Aust 1989; 150: 329-31. 51. Donovan JW, Proudfoot AT, Prescott LF. Adverse effects of intravenous N-acetylcysteine, Vet Hum Toxicol 1986; 28: 487. 52. Flanagan RJ. The role of acetylcysteine in clinical toxicology. Med Toxicol 1987; 2: 93-104. 53. Dreisbach RH, Robertson C. Handbook of poisoning: prevention, diagnosis and treatment, 12th edition. Norwalk, CT: Appleton & Lange, I987: 148-50,314. 54. Imberti R, Mapelli A, Colombo P, Richelmi P, Bert~ F, Bellomo G. 1,2-Dichloropropane (DCP) toxicity is correlated with DCP-induced glutathione (GSH) depletion and is modulated by factors affecting intracellular GSH. Arch Toxicol 1990; 64: 459-65. 55. Pohl LR, Branchflower RV, Highet RJ, et al. The formation of diglutathionyl dithiocarbonate as a metabolite of chloroform, bromotrichloromethane, and carbon tetrachloride. Drug Metab Dispos 1981; 9: 334-9. 56. Yurdakok M, Yurdakok K, Caglar M. Carbon tetrachloride poisoning. Lancet 1985; 1: 1336. 57. Truss CD, Killenberg PG. Treatment of carbon tetrachloride poisoning with hyperbaric oxygen. Gastroenterology 1982; 82: 767-9. 58. Ruprah M, Mant TGK, Flanagan RJ. Acute carbon tetrachloride poisoning in 19 patients: implications for diagnosis and treatment. Lancet 1985; i: 1027-9. 59. Ruprah M. Development and application of simple analytical procedures to aid the diagnosis and management of poisoning with volatile substances. Ph.D. Thesis, University of London, 1988. 60. Mathieson PW, Williams G, MacSweeney JE. Survival after massive ingestion of carbon tetrachloride treated by intravenous infusion of acetylcysteine. Hum Toxicol 1985; 4: 627-31. 61. Meredith T, Vale A. Carbon monoxide poisoning. Br Med J 1988; 296: 77-9. 62. Mathieu D, Nolf M, Durocher A, eta/. Acute carbon monoxide poisoning. Risk of late sequelae and treatment by hyperbaric oxygen. J Toxicol Clin Toxicol 1985; 23: 315-24. 63. Myers RAM, Snyder SK, Emhoff TA. Subacute sequelae of carbon monoxide poisoning. Ann Emerg Meal 1985; 14: 1163-7. 64. Norkool DM, Kirkpatrick JN. Treatment of acute carbon monoxide poisoning with hyperbaric oxygen: a review of 115 cases. Ann Emerg Med 1985; 14: 1168-71. 65. Werner B, Persson H, Kulling P (eds.). Symposium. Carbon monoxide poisoning: mechanism of damage, late sequelae and therapy. J Toxicol Clin Toxicol 1985; 23: 247-326. 66. Howard RJMW, Blake DR, Pall H, Williams A, Green ID. AIIopurinol/N-acetylcysteine for carbon monoxide poisoning. Lancet 1987; ii: 628-9. 67. Yunis AA, Lira LO, Arimura GK. DNA damage induced by chloramphenicol and nitrosochloramphenicol:, protection by N-acetylcysteine. Respiration 1986; 50 (suppl 1): 50-5.

September 30, 1991 The American Journal of Medicine Volume 91 (suppl 3C)

SYMPOSIUM ON OXIDANTSAND ANTIOXIDANTS/FLANAGANand MEREDITH 68. Gurtoo HL, Marinello AJ, Bemgan MJ, eta/. Effect of thiols on toxicity and carcinostatic activity of cyclophosphamide. Semin Oneo11983; I0 (suppl 1): 35-45. 69. Freeman RW, MacDonald JS, Olson RD, Boerth RC, Oates JA, Harbison RD. Effect of sulphydryFcontaining compounds on the antitumor effects of Addamycin. Toxicol Appl Pharmacol ]980; 54: 168-75. 70. Unverferth DV, Mehegan JP, Nelson RW, Scott CC, Leier CV, Harnlin RL The efficacy of N-acetylcysteine in preventing doxorubicin-induced cardiomyopathy in dogs. Semin Oncot 1983; 10 (suppl 1): 2-6. 71. Slavik M, Saiers JH. Phase I clinical study of acetylcysteine's preventing ifos-

famide induced hematuria. Semin Oncol 1983; 10 (suppl ]): 62-5. 72. Corcoran CB, Racz WJ, Smith CV, Mitchell JR. Effects of N-acetylcysteine on acetarnJnophen covalent binding and hepatic necrosis in mice. J Pharmacol Exp Ther 1985; 232: 864-72. 73. Buckpitt AR, Warren DL Evidence for hepatic formation, export and covalent binding of reactive naphthalene metabolites in extrahepatic tissues in vivo. J Pharrnacol Exp Ther 1983; 225: 8-16. 74. Aposhian HV. DMSA and DMPS: Water soluble antidotes for heavy metal poisoning. Ann Rev Pharmacol Toxicol 1983; 23: I93-215.

September 30, 1991

The American Journal of Medicine

Volume 91 (suppl 3C)

3C-139S

Use of N-acetylcysteine in clinical toxicology.

The major use of N-acetylcysteine in clinical toxicology is in the treatment of acetaminophen (paracetamol) overdosage. The hepatorenal toxicity of ac...
920KB Sizes 0 Downloads 0 Views