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N-acetyl-para-benzoquinone-imine(NAPQI).1 This reactive metaboliteis inactivated by conjugation withglutathione.4,5 In acetaminophenoverdose, NAPQI is formed inamounts sufficient to deplete hepaticand erythrocyte glutathionereserves.3–5 NAPQI also binds cova-lently to cellular macromolecules,mediates the conversion of hemoglo-bin to methemoglobin, and inducesHeinz body formation.5 The pres-ence of Heinz bodies increases theosmotic fragility of erythrocytes,leading to hemolysis and anemia.4,5

Furthermore, large doses of aceta-minophen produce activated oxygenfree radicals that cause an inflamma-tory process.7

PHARMACOKINETICS ANDPHARMACOLOGY

In humans, NAC is rapidly andcompletely absorbed in the gastroin-testinal tract after oral administra-tion.8 Peak plasma concentration isreached less than an hour after in-gestion.9 NAC diffuses into mostbody tissues, including the lungs,liver, and kidneys.8 Extensive first-pass metabolism by the small intes-tine and liver results in the forma-tion of cysteine and inorganicsulfite.10 The plasma half-life ofNAC is 2.15 hours.11

NAC acts by several mechanisms.Its main action is replenishment of

intracellular glutathione stores.1 Glu-tathione, one of the most importantantioxidants and detoxifiers in thebody, is a tripeptide consisting ofglutamic acid, cysteine, and glycine.12

As food and several metabolic path-ways supply glutamic acid andglycine, attention is focused on pro-viding cysteine to the patient. Invivo, NAC is rapidly metabolized tocysteine, which is an essential aminoacid required for the synthesis of glu-tathione.12 The second action ofNAC is detoxification of the reactivemetabolite. The sulfhydryl group ofNAC may bind the reactive metabo-lite NAPQI, which is inactivated andexcreted.1 Third, NAC treatment in-creases the fraction of acetaminophenexcreted as the sulfate conjugate.13 Incats treated with acetaminophen andNAC, the plasma half-life of aceta-minophen is approximately half (2.3hours) of that in cats treated withacetaminophen alone.14

INDICATIONSNAC is very effective in the treat-

ment of acetaminophen poisoning.1

Although it is most effective if lessthan 12 hours has elapsed since ingestion of high doses of acetamino-phen, NAC is still recommended upto 36 to 80 hours after acetaminopheningestion.4,15

NAC can reduce the extent of liverinjury. In humans, NAC infusion is

Lotfi El Bahri, DVM, MSc, PhDEcole Nationale de Medecine

Veterinaire Sidi Sidi-Thabet, Tunisia

Normand Lariviere, DVM, MSc, PhDFaculte de Medecine Veterinaire

Saint Hyacinthe, Canada

P H A R M P R O F I L E

N-ACETYLCYSTEINE

276 Small Animal/Exotics Compendium April 2003

• Used to treat acetaminophen poisoning

N -Acetylcysteine (NAC) isthe antidote of choice forthe treatment of acetami-

nophen poisoning, one of the mostcommon types of intoxication indogs and cats.1,2 Cats are extremelysensitive to this analgesic, antipyreticdrug, which is marketed only for hu-man use (Tylenol, McNeil). Inges-tion of one 325-mg tablet by a catresults in severe toxicosis; two tabletsingested within 24 hours is fatal.3

The toxic dose of acetaminophen incats is 10 mg/kg and in dogs 150 to200 mg/kg.4

In animals, acetaminophen is me-tabolized as glucuronide and sulfateconjugates.5 However, cats have lowlevels of glucuronyl transferase andlimited sulfate-conjugating activity.6

After ingestion of toxic doses, theseconjugation reactions are saturatedand the excess acetaminophen is oxi-dized via cytochrome P450 microso-mal enzyme resulting in the forma-tion of a highly toxic metabolite,

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used selectively to treat some forms ofacute liver failure.16 NAC may alsoimprove hepatic microcirculation.1 Itenhances endogenous production ofnitric oxide, which dilates hepaticvessels and improves hepatic bloodflow.17 NAC also acts as a scavenger ofoxygen free radicals and can reducethe extent of methemoglobinemia.18

NAC is also used as a mucolyticagent in the adjunctive treatment ofbronchopulmonary disorders.19 Thesulfhydryl group in the molecule actsdirectly to split disulfide linkages be-tween mucoprotein molecular com-plexes, resulting in depolymerizationand decreased mucus viscosity. NAC isalso used to treat ulcerative keratitis20

and appears to have some clinicalusefulness as a chelating agent in thetreatment of acute heavy metal poi-soning (mercury, arsenic, copper).21,22

CAUTIONSNAC can cause phlebitis when ad-

ministered perivascularly; and rapidintravenous administration can causehypotension, bronchospasm, andflushing.1 Reactions can be mini-mized by giving each dose very slow-ly. When given orally, NAC typicallycauses nausea and vomiting.1

No teratogenic or embryotoxic ef-fects have been observed in repro-duction studies in rabbits and rats.19

ACUTE TOXICITYThe LD50 of intravenous NAC in

dogs is 700 mg/kg.19

DRUG INTERACTIONSBecause activated charcoal may ad-

sorb NAC, thereby reducing its ef-fectiveness, NAC should not be giv-

en within 2 hours of administeringactivated charcoal.1 Administrationof activated charcoal may exacerbatevomiting and lead to aspiration.5 Astrong antiemetic agent (metoclo-pramide, 0.4 mg/kg IV) may be nec-essary to prevent emesis.23

DOSAGE AND ADMINISTRATIONIn dogs and cats, NAC should be

given intravenously or orally but hasa pungent aroma.5 In swine, rectaladministration results in effective ab-sorption into the systemic circula-tion. This represents a potential al-ternative route for the administrationof NAC to dogs.24

Some veterinarians prefer slow bo-lus intravenous injection because ofthe vomiting associated with aceta-minophen poisoning. NAC shouldbe given intravenously at an initialdose of 140 mg/kg (280 mg/kg in se-vere toxicosis) and then at a mainte-nance rate of 70 mg/kg every 6 hoursfor seven treatments.4 The 10% or20% NAC solution should be dilut-ed to a 5% concentration with 5%dextrose.1 Each dose is infused over30 to 60 minutes through a periph-eral intravenous catheter using an in-line 0.2-µm millipore filter.1,4 Benefi-cial effects are expected within 48hours after initial therapy.2 Cimeti-dine can have an additive effect andis administered at a loading dose of10 mg/kg followed by 5 mg/kg every6 hours for 48 hours.4 To reducemethemoglobin to hemoglobin,ascorbic acid can be administered ata dose of 30 mg/kg IV every 6 hoursuntil the cyanosis is no longer appar-ent.4 Fluid therapy with added sodi-um bicarbonate may be needed in

severe cases to reverse metabolic aci-dosis.25 Corticoids and antihista-mines are contraindicated.5

Plasma or urine concentrations ofacetaminophen are of predictive val-ue. Acetaminophen toxicity is dosedependent. Hemogram with methe-moglobin value (particularly in cats),detection of Heinz bodies in the eryth-rocytes, and acid–base status shouldbe determined. Hepatocellular damagemay be monitored by assays of aspartate aminotransferase, alanineaminotransferase, γ-glutamyl trans-ferase, and prothrombin time, partic-ularly in dogs.19

PREPARATIONSNAC is currently not approved by

the FDA for use in dogs and cats, al-though it is available in human phar-maceutical preparations (Mucomyst,Bristol-Myers Squibb; Mucosol, DeyLabs).19 It is sold both as a 10% or20% solution for inhalation and invials containing 4, 10, or 30 ml fororal administration.1 No intravenousNAC preparation is available in theUnited States. Because the commer-cially available NAC solution is ster-ile (oral treatment), patients may besafely treated with the oral NAC for-mulation administered via the intra-venous route.1

STORAGE AND HANDLINGUnopened vials of NAC should be

stored below 25°C and protectedfrom light.19 Open vials should bekept refrigerated and used within 96hours for oral treatment.19 The solutioncolor may change in the opened bottle,but this does not significantly impairthe drug’s safety or efficacy.19

REFERENCES1. Dart RC: The 5 Minute Toxicology

Consult. Philadelphia, LippincottWilliams & Wilkins, 2000.

2. Jones RD, Baynes RE, Nimitz CT: Non-steroidal anti-inflammatory drug toxico-sis in dogs and cats: 240 cases (1989-1990). JAVMA 201(3):475–477, 1992.

3. Campbell A, Chapman M: Handbook

• NAC is the antidote of choice for the treatment of acetaminophentoxicosis in dogs and cats.

• Oral administration of NAC typically causes nausea and vomiting.

• Adverse reactions to treatment are relatively common but rarely serious.

Client Counseling Information

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of Poisoning in Dogs and Cats. Oxford,Blackwell Science, 2000, pp 31–38.

4. Taylor NS, Dhupa N: Acetaminophentoxicity in cats and dogs. CompendContin Educ Pract Vet 22(2):160–170,2000.

5. Osweiler GD: Over-the-counter drugsand illicit drugs of abuse, in Toxicology.Philadelphia, Lippincott Williams &Wilkins, 1996, pp 303–304.

6. Krotje LJ: Cyanosis: Physiology andpathogenesis. Compend Contin EducPract Vet 9(3):271–279, 1987.

7. Tirmenstein MA, Nelson SD: Aceta-minophen induced oxidation of pro-tein thiols: Contribution of impairedthiol-metabolizing enzymes and thebreakdown of adenine nucleotides. J Biol Chem 265:3059–3065, 1990.

8. De Caro L, Ghizzi A, Costa R, et al:Pharmacokinetics and bioavailability oforal acetylcysteine in healthy volunteers.Arzneim Forsch 39:382–385, 1989.

9. Borgstrom L, Kagedal B, Paulsen O:Pharmacokinetics of N-acetylcysteinein man. Eur J Clin Pharmacol31:217–222, 1986.

10. Cotgreave IA, Berggren M, Jones TW,et al: Gastrointestinal metabolism ofN-acetylcysteine in the rat, including

an assay for sulfite in biological sys-tems. Biopharm Drug Dispos 8:377–386, 1987.

11. Olsson B, Johansson M, Gabrielsson J,et al: Pharmacokinetics and bioavail-ability of reduced and oxidized N-acetylcysteine. Eur J Clin Pharma-col 34:77–82, 1988.

12. Weil JH: Biochimie Generale, ed 7.Paris, Masson, 1995.

13. Savides MC, Oehme F, Leipold HW:Effects of various antidotal treatmentson acetaminophen toxicosis and bio-transformation in cats. Am J Vet Res46(7):1485–1489, 1983.

14. Rumbeiha WK, Lin YS, Oehme FW:Comparison of N-acetylcysteine andmethylene blue, alone or in combina-tion, for treatment of acetaminophentoxicosis in cats. Am J Vet Res 56(11):1529–1533, 1995.

15. Cullison RF: Acetaminophen [parac-etamol] toxicosis in small animals:Clinical signs, mode of action, andtreatment. Compend Contin Educ PractVet 6(4):315–321, 1984.

16. McCarthy M, Wilkinson ML: Recentadvances: Hepatology BMJ 318:1256–1259, 1999.

17. Banner W, Pentel PR: Medical toxicol-

ogy. JAMA 271(21):1681–1682, 1994.

18. Kelly GS: Clinical applications of N-acetylcysteine. Alt Med Rev 3(2):114–127, 1998.

19. Plumb DC: Veterinary Drug Handbook,ed 2. Ames, Iowa State UniversityPress, 1995.

20. Jegou JP: Les urgences ophtalmolo-giques. Rec Med Vet 165(12):1011–1031, 1989.

21. Martin DS, Willis SE, Cline DM: N-acetylcysteine in the treatment of hu-man arsenic poisoning. J Am BoardFam Pract 3:293–296, 1990.

22. Lund ME, Banner W Jr, ClarksonTW, et al: Treatment of acutemethylmercury ingestion by hemodial-ysis with N-acetylcysteine (Mucomyst)infusion and 2,3-dimercaptopropanesulfonate. J Toxicol Clin Toxicol22:31–49, 1984.

23. Kore AM: Over-the-counter analgesicdrug toxicoses in small animals. VetMed 92(2):158–165, 1997.

24. Greenberg MI, Grazioso H, DiSandroD, et al: Rectal administration of N-acetylcysteine in swine: A pilot study. VetHuman Toxicol 39(6):329–331, 1997.

25. Mayer S: Poison paracetamol. In Pract13(1):37, 1991.