Keeping cats safe

Nicola Bates has worked in human andveterinary toxicology for 25 years and hasbeen with the Veterinary Poisons InformationService (VPIS) since it started. As well asproviding emergency advice via thetelephone she has written extensively onveterinary toxicology. In addition to serviceprovision, she is involved in training of VPISstaff and veterinary professionals. She iscurrently the congress abstract editor for theEuropean Association of Poisons Centres andClinical Toxicologists (EAPCCT).

Nicola Bates BSc (Brunel) BSc (Open) MSc MA

Paracetamol poisoning in cats

Cats are particularly sensitive to paracetamol(acetaminophen) toxicity because of their limited abilityto metabolise the drug to non-toxic metabolites.Alternative metabolite pathways lead to the productionof toxic metabolites which causemethaemoglobinaemia, cyanosis, anaemia andjaundice. Even a single paracetamol tablet can causesevere toxicity in a cat. Treatment is therefore aimed atensuring adequate oxygenation, preventing furthermetabolism of paracetamol to toxic metabolites withthe use of antidotes, particularly acetylcysteine, toprevent damage to the liver and red blood cells.

Paracetamol (also known asacetaminophen or APAP in somecountries) is a very widely and readily

available non-narcotic analgesic. It is not usedtherapeutically in cats.

Paracetamol is sold under many brand namesand is available in many formulationsincluding tablets, capsules, liquid suspensionsand powder preparations (usually for mixingwith water). Tablets are typically 500 mg (or250 mg for children over 6 years of age) andsuspensions 120 mg/5 ml or 250 mg/5 ml.Paracetamol is also commonly available incompound products with other drugsincluding codeine, caffeine, aspirin, ibuprofenand decongestants.

ExposureCats may be exposed after eating aparacetamol-containing product butpoisoning can also occur when an owner,believing their cat to be unwell, misguidedlygives them part or a whole tablet or dosesthem with a few millilitres of a paediatricparacetamol suspension.

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The Veterinary Poisons InformationService (VPIS) is a 24-h telephoneemergency service providinginformation on the management ofactual and suspected poisoning inanimals. It provides direct support toveterinary professionals worldwide.

See http://vpisglobal.com/ for moreinformation and how to sign yourpractice up to receive this vitalservice.

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Keeping cats safe

Mechanisms of toxicityCats are differentCats are very sensitive toparacetamol. In particular they maydevelop methaemoglobinaemia(high blood levels ofmethaemoglobin; an oxidised formof haemoglobin which cannot bindoxygen), haemolytic anaemia, Heinzbody formation and hepaticnecrosis.

In all species paracetamol ismetabolised in the liver byglucuronidation, sulphation andoxidation (Figure 1). The glucuronideand sulphate conjugates are non-toxic and are excreted in bile andurine. In most species the oxidationpathway is minor whilstglucuronidation is the majorpathway of paracetamolmetabolism. Cats, however, have arestricted ability to conjugate withglucuronic acid as they have lowlevels of glucuronyl transferase, theenzyme that catalyses the final stepof the glucuronidation pathway.They, therefore, have a limited abilityto metabolise paracetamol to non-toxic metabolites.

The toxic metaboliteThe oxidation pathway produces ahighly reactive compound called N-acetyl-p-benzoquinoneimine(NAPQI). Normally this compound isconjugated with glutathione, thenfurther metabolised to non-toxicmetabolites. At low dosing this is an

effective and efficientdetoxification pathway despite thefact that cats have low glutathioneconcentrations. At higherparacetamol doses, theglucuronidation and sulphationroutes are saturated and theoxidation pathway increases inactivity. This results in increasedproduction of NAPQI, causingglutathione depletion in the liver.NAPQI then binds with cellularmolecules and proteins causingcell death in the liver.

Oxidising metabolitesAlternative metabolic pathwaysalso allow accumulation ofoxidising metabolites that may

Key point

Cats have a limitedability to metaboliseparacetamol to non-toxicmetabolites due totheir reduced capacity forglucuronidation in the liver.

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Figure 1: Paracetamol in cats — proposed metabolism andmechanism of toxicity. *N-acetylation of compoundsinvolves two enzymes, N-acetyltransferase 1 and N-acetyltransferase 2 (NAT1 and NAT2). Cats have only NAT1and dogs have no NAT enzymes

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induce methaemoglobin formation,Heinz body formation anddenaturation of erythrocytemembranes. In the presence ofglutathione, methaemoglobin will bereduced to haemoglobin. However,as glutathione becomes depletedinsufficient quantities will beavailable for this reduction reaction.Methaemoglobin concentrations inblood rise (it is typically measuredas a percentage of haemoglobin)and tissue hypoxia occurs. Heinzbodies are denatured chains ofhaemoglobin with oxidisedsulphydryl groups. They precipitateand migrate towards cellmembranes where they render cellsfragile. Haemolysis and restrictedpassage of erythrocytes through themicrocirculation and spleen mayresult in anaemia.

It has been suggested that themetabolite para-aminophenol, andnot NAPQI, is responsible for themethaemoglobinaemia seen in catsand dogs with paracetamolpoisoning.1 This is a minormetabolite of paracetamol that isremoved as N-acetyl conjugates.Cats have only one of the enzymesresponsible for this reaction anddogs have none. This means thatboth species are less efficient atremoving this toxic metabolitewhich is known to undergo reactionswith oxyhaemoglobin. Humans, whofrequently overdose withparacetamol and possess bothenzymes, do not developmethaemoglobinaemia due toparacetamol toxicity.

How the antidotes workAcetylcysteine (previously N-acetylcysteine, NAC)The most widely used antidote inparacetamol poisoning isacetylcysteine because it can reducethe toxicity of the drug by threemain mechanisms:

• Acetylcysteine is a precursor ofglutathione and is metabolised toform a substrate for glutathionesynthesis in red blood cells andthe liver.

• Acetylcysteine acts directly onthe reactive metabolite NAPQI toform an acetylcysteine conjugatewhich can be excreted (althoughthis reaction is slow).

• Acetylcysteine is oxidised in theliver to form sulphate therebyincreasing the capacity of thesulphation pathway.

Administration of acetylcysteine hasbeen shown to reduce the half-life ofparacetamol by half in cats.2

S-adenosyl-methionine (SAMe)S-adenosyl-methionine (SAMe) isalso a precursor of glutathione,reducing methaemoglobin tohaemoglobin. In mice, SAMesignificantly reduced paracetamoltoxicity and was more potent thanacetylcysteine in reducing livertoxicity.3 Administration 1 h afterparacetamol ingestion providesprotection by reducing oxidationand Heinz body formation, buttreatment after 4 h in cats may be oflimited benefit.4

Ascorbic acidAscorbic acid can be given toreduce methaemoglobin tohaemoglobin, although the reactionoccurs slowly.5 There is someevidence to suggest it may also

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Keeping cats safe

TipCats with suspected orconfirmed paracetamoltoxicity should betreated promptly and theantidote acetylcysteine canbe obtained from localhospitals.

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Keeping cats safe

scavenge NAPQI before it binds toproteins, possibly reducing it back toparacetamol. Ascorbic acid isnormally given in combination withthe other antidotes.6

MethionineMethionine is another glutathioneprecursor and has some use inparacetamol poisoning — it waswidely used in cases of humanpoisoning. It may be given whereacetylcysteine is unavailable or usedin conjunction with acetylcysteinetherapy, but is not widely availableand only as an oral preparation.

Methylene blue(methylthioninium chloride)In cases of severemethaemoglobinaemia, methyleneblue has been used in cats. This drugincreases reduction ofmethaemoglobin back tohaemoglobin. Although methyleneblue can itself causemethaemoglobinaemia andhaemolytic anaemia, particularly incats, it is safe to use at correctdoses.7

CimetidineCimetidine is a potent inhibitor ofcytochrome P450 metabolism in theliver and theoretically administrationcould result in inhibition of theoxidation pathway,8 but its efficacyhas not been evaluated forparacetamol poisoning cases in cats.

Toxic doseThe toxic dose of paracetamol incats is 50–00 mg/kg.9 In anexperimental study cats given 90mg/kg showed a rapid increase inmethaemoglobin formation within 4 h of ingestion. One cat died at 24h without treatment. A second catthat had been treated with SAMe 1 hafter dosing was found in distress at36 h, failed to respond to supportivecare and was euthanased.4 In

another study a dose of 60 mg/kg incats produced amethaemoglobinaemia of 22% in 4 hwhereas a dose of 120 mg/kgproduced a concentration of 45%.10

In essence, one tablet ofparacetamol is likely to cause severetoxicity in a cat (Figure 2).

Time courseParacetamol is rapidly absorbedfrom the gastrointestinal tract undernormal conditions and clinicalmanifestations of paracetamolingestion may occur within 4 h incats,11 but definitely within 6–24 h.12

Recovery in treated cats usuallyoccurs within 2 days, depending onthe severity of signs, butbiochemical abnormalities may take

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Key pointIt is important thatowners are informedthat any amount ofparacetamol may betoxic. One tablet ofparacetamol is enough to causesevere toxicity and death in a cat.

Figure 2: One tablet or a few millilitres of paediatricsuspension of paracetamol is enough to cause deathin a cat (picture courtesy of Mark Jackson)

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several weeks to return to normalconcentrations.13

Clinical signsEarly effects (typically 1–4 h)Progressive cyanosis is the moststriking sign in cats withparacetamol toxicity and isassociated with tachycardia,tachypnoea and dyspnoea. Mucousmembranes appear brown in colour,and weakness and lethargy may beobserved.

At 4–24 hFacial and paw oedema may beobserved in some cases. Depression,vomiting, anorexia and vocalisationmay occur and dark brown bloodmay be noted indicating thepresence of methaemoglobinemia.9

Haematuria, anaemia, and evidenceof haemolysis may be present. Lesscommon effects include hyper- orhypothermia, ataxia and lethargy.

Later effects (day 2-7)Although raised liver enzymes andbilirubin have been reported incats,12 hepatic necrosis is not theprincipal cause of fatality in cats asthey usually die as a result of severemethaemoglobinaemia.Haemoglobinuria, intravascularhaemolysis, jaundice and otherevidence of liver damage may beseen in animals that survive the

initial stages of paracetamolpoisoning. Coma, convulsions andpulmonary oedema are occasionallyreported. Oliguria and renal damagecan occur after high doses, althoughthe exact dose is unknown in cats.14

Prognosis The prognosis of cats withparacetamol toxicity is good withprompt treatment but depends onthe severity ofmethaemoglobinaemia.9,13 It alsoappears that time between ingestionand treatment may be as important,or even more important, than thedose ingested.13 Coma, convulsionsand pulmonary oedema are poorprognostic signs.

DiagnosisDiagnosis of paracetamol is basedon clinical signs and history. It isimportant to ask the owners if theyhave given their cat any medication.Laboratory changes may also aiddiagnosis with changes inhaematology, methaemoglobinconcentration, liver enzymes andurinalysis (Box 1).

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TipClinical signs ofparacetamol toxicityinclude cyanosis withtachypnoea anddyspnoea, facial andpaw oedema,depression, vomiting and haematuria. Ifa cat presents with consistent clinicalsigns the owner should be questionedabout exposure to paracetamol.

Keeping cats safe

Box 1: Diagnosis of paracetamol toxicity

A diagnosis of paracetamol toxicity ismade by:• clinical signs; • history — have the owners treated theircat with any medication?;

• laboratory changes, including: — Heinz body anaemia, decreasedpacked cell volume;— methaemoglobin >15% (a drop ofblood on paper towel will appearbrown), usually begins within 4 h;7,10

— serum chemistry profile — increasedliver enzyme activity from 24–36 h;14

— urinalysis (haemoglobinuria,proteinuria and bilirubinuria).

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TreatmentDecontamination The aim of treatment for a cat withparacetamol toxicity is to ensureadequate oxygenation and preventfurther metabolism of paracetamolto toxic metabolites with the use ofantidotes and to prevent damage tothe liver and red blood cells. Any catwith signs consistent withparacetamol toxicity should betreated irrespective of the time sinceingestion or the dose ingested. Ifingestion was recent an emetic andactivated charcoal can beconsidered, depending on theclinical condition of the cat.

Antidotal therapy Antidotal therapy should be startedin any cat with signs of toxicity orthat has ingested a potentially toxicdose (Table 1). Acetylcysteine is theantidote of choice and if notavailable in the practice can usuallybe obtained from your local hospitalemergency department (since it isused for humans with paracetamolpoisoning). It can be given byintravenous infusion or orally;however, it has a sulphurous smelland taste which can causesignificant hypersalivation so itneeds to be diluted to improvepalatability or given by naso-oesophageal tube if clinically

indicated. SAMe and ascorbic acidcan also be given in combinationwith acetylcysteine.

Monitoring and supportive careOther treatment is essentiallysupportive with monitoring for signsof hypoxia, methaemoglobinaemia,liver damage, anaemia, haemolysisand renal impairment. Oxygen willbe required in cats with cyanosisand in cats with severe respiratorysigns oxyglobin (haemoglobinglutamer) can be given.14 Wholeblood transfusions may be requiredin cats with evidence of severehaemolysis, significant decrease inpacked cell volume (PCV) or severeanaemia.

ConclusionsIncreased metabolism ofparacetamol via the oxidativepathway with unopposedproduction of toxic metabolitescauses toxicity in cats followingparacetamol administration. Thecharacteristic picture is one ofmethaemoglobinaemia, cyanosis,anaemia and jaundice. Death usuallyoccurs from progressivemethaemoglobinaemia or, morerarely, from severe hepatic necrosis.The aim of treatment for the catwith paracetamol toxicity is toensure adequate oxygenation and

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Keeping cats safe

Drug Dosage

Acetylcysteine • IV or oral: 140 or 280 mg mg/kg diluted in 12–25 ml/kg of fluid IVover 6 h, followed immediately by 70 mg/kg IV (over 15–20 minutes)every 6 h for 36 h or more dependent on the clinical condition of theanimal

• Continue treatment until cat is clinically well• Can be diluted in dextrose or saline

SAMe • Oral: 90 mg twice daily for 3 days, then 90 mg daily for 14 days

Ascorbic acid • SC: 30–40 mg/kg every 6 h for at least 36 h

Table 1: Dosages of antidotes for the management of paracetamol poisoning

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in dogs and cats. J Vet Emerg Crit Care2000; 10: 285–291.

15 St Omer VV and McKnight ED 3rd.Acetylcysteine for treatment ofacetaminophen toxicosis in the cat. J AmVet Med Assoc 1980; 176: 911–913.

prevent further metabolism ofparacetamol to toxic metaboliteswith the use of antidotes,particularly acetylcysteine, and toprevent damage to the liver and redblood cells.

References1 McConkey SE, Grant DM and Cribb AE.

The role of para-aminophenol inacetaminophen-inducedmethemoglobinemia in dogs and cats.J Vet Pharmacol Ther 2009; 32: 585–595.

2 Rumbeiha WK, Lin YS and Oehme FW.Comparison of N-acetylcysteine andmethylene blue, alone or in combination,for treatment of acetaminophen toxicosisin cats. Am J Vet Res 1995; 56: 1529–1533.

3 Terneus MV, Brown JM, Carpenter AB, etal. Comparison of S-adenosyl-L-methionine (SAMe) and N-acetylcysteine(NAC) protective effects on hepaticdamage when administered afteracetaminophen overdose. Toxicology2008; 244: 25–34.

4 Webb CB, Twedt DC, Fettman MJ, et al.S-adenosylmethionine (SAMe) in felineacetaminophen model of oxidative injury.J Feline Med Surg 2003; 5: 69–75.

5 Hjelle JJ and Grauer GF. Acetaminophen-induced toxicosis in dogs and cats. J AmVet Med Assoc 1986; 188: 742–746.

6 Steenbergen V. Acetaminophen and cats.Vet Tech 2003; 24: 43–45.

7 Rumbeiha WK and Oehme FW.Methylene blue can be used to treatmethemoglobinemia in cats withoutinducing Heinz body hemolytic anemia.Vet Hum Toxicol 1992; 34: 120–122.

8 Ilkiw JE and Ratcliffe RC. Paracetamoltoxicity in a cat. Aust Vet J 1987; 64:245–247.

9 Osweiler GD. Over-the-counter drugs andillicit drugs of abuse. National VeterinaryMedical Series. Philadelphia, Williams &Wilkins, 1996, p303.

10 Savides MC, Oehme FW, Nash SL andLeipold HW. The toxicity andbiotransformation of single doses ofacetaminophen in dogs and cats. ToxicolAppl Pharmacol 1984; 74: 26–34.

11 Marcella KL. Acetaminophen poisoning incats and man. J Am Vet Med Assoc 1983;183: 836.

12 Kolf-Clauw M, Keck G. Paracetamolpoisoning in dogs and cats. Eur JCompan Anim Pract 1994; 4: 85–92.

13 Aronson LR and Drobatz K.Acetaminophen toxicosis in 17 cats.J Vet Emerg Crit Care 1996; 6: 65–69.

14 Richardson JA. Management ofacetaminophen and ibuprofen toxicosis

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Reference 15 is notcited

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