Management of Acetaminophen Toxicity

HistorySynthesized in 1877 in U.S.Extensive use began around 1947Initially prescription only in the U.S.Otc status gained in 1960

toxic effects first noted in U.S. in 1971

Its everywhere!APAP is found in over 200 products

TylenolAnacin 3TempraTylenol coldGoodysComtrex multi sxContac Severe ColdJunior Strength TylenolVicks NyquilSinutab SinusTherafluSine-offSinarestRobitussin ColdPanadolMidol PMSSudafed SinusVanquishVicks 44MUnisomSingletPyrroxateMidol teenCoricidinDimetapp allergyDrixoral ColdAlka Seltzer PlusActifed SinusBenadryl allergyPanex

Actions

AnalgesiaRelieves mild to moderate painEfficacy equivalent to salicylatesInhibits brain prostaglandin synthetaseBlocks pain impulses peripherally

AntipyresisEfficacy similar to salicylatesInhibits prostaglandin synthetase in the hypothalamus

In overdose situations, liver enzymes become saturated, glutathione is depleted, NAPQI(N-acetyl-p-benzoquinoneimine) accumulates, and hepatic necrosis occurs

PharmacokineticsAbsorption

Rapidly absorbed from the GI tractPeak concentration usually occurs between 60 and 120 minutesPeak plasma levels almost always occur within 4 hours

Distribution

Vd 1.0 - 2.0 L/KgApproximately 20% plasma protein boundmay increase to 50% in overdoseHas been reported to cross the placenta

MetabolismOccurs via several pathways in the liver52% by sulfation42% by glucuronidation2% excreted unchanged in the urine4% biotransformed by C-P450 MFO system

Excretion

APAPs metabolic products are excreted by the kidneys

Minimal excretion into breast milk

Half life

Average 2 hoursrange 0.9 to 3.25 hoursNo age related differencesNo change in patients with renal diseaseWith liver dysfunction, may increase to 17 hours

Extracorporeal elimination

HemodialysisNot proven effective in reducing or preventing liver damage in overdose

Peritoneal dialysisNot effective

ToxicityFactors involved in predicting hepatotoxicitytotal quantity ingestedtime from ingestion to treatmentage of the patientalcoholismenzyme inducing medications

serum concentration in relation to Rumack nomogram

Toxic dose

In adults, threshold for liver damage is 150 to 250 mg/kg

Children under 10 appear to be more resistant

Potential liver damage

Adults: > 150 mg/kg in acute dose

Adults: > 7.5 Grams in 24 hours (chronic)

Children ( 200 mg/kg

4 Stages of Acetaminophen PoisoningPhase I (30 minutes to 4 hours)

Within a few hours after ingestion, patients experience anorexia, nausea, pallor, vomiting, and diaphoresis. Malaise may be present.

Patient may appear normal

Phase II (24 to 48 hours)

Symptoms of Phase I are less severe. May seem like a period of recovery. Right upper quadrant pain may be present due to hepatic damage. Blood chemistry becomes abnormal with elevations of liver enzymes. Prothrombin times may be prolonged. Renal function may begin to deteriorate.

Phase III (3 to 5 days)

Characterized by symptoms of hepatic necrosis. Coagulation defects, jaundice, and renal failure have all been noted. Hepatic encephalopathy has been noted. Hepatic biopsy at this time would indicate centrilobular necrosis. Nausea and vomiting may reappear. Death is due to hepatic failure

Phase IV (4 days to 2 weeks)

Complete resolution or death

TreatmentGI decontaminationSyrup of Ipecacreturn usually 30-40% at bestbest if used early (first 1-2 hours)

Gastric lavageeffectiveness diminishes with time

Activated charcoalShould not be withelddose 50-100 Grams

Catharticutilized to speed transit time

HemodialysisLimited benefitDamage occurs quickly

HemoperfusionNo benefit

Peritoneal dialysisNo benefit

Blood Sample

4 hour post ingestion APAP levellevels drawn earlier may be erroneouslevels may be accurate out to 18 hours

Plot level on Rumack-Matthews nomogram

150 mg/dl at 4 hours is possibly toxic

Do not use therapeutic normal values to determine potential toxicity!

Baseline CBCcreatinine, BUN, blood sugar, electrolytesprothrombin timesAST, ALTrepeat q 24 hourselevations typically seen 24-36 hours post ingestion

mcg/ml 4 8 12 16 20 24Hours After Acetaminophen Ingestion

150

510 50500Rumack and Matthew Nomogram100LateNot valid after 24 hours

If APAP level plots above the possible risk line administer N-acetylcysteine (NAC).

If NAC is indicated, full regimen should be followed. Do not stop NAC early if nomogram indicates toxic possibility

N-acetylcysteine (NAC)Mechanism of actionglutathione substitutemay supply inorganic sulfur, altering metabolism

Route of administrationOrally or IVIV not approved in the U.S.

NAC dosing

Oral 72 hour protocolLoading dose is 140 mg/kg

Maintenance doses: 70 mg/kgGiven every 4 hours x 17 doses starting 4 hours after loading dose

NAC supplied as 10 or 20% oral solutiondilute to 5% final concentration with juice or soft drink

May be administered via NG tube

If emesis occurs within 1 hour of administration, repeat the dose

If emesis persists, antiemetics may be used

Reglan (metoclopramide)0.1 to 1.0 mg/kg iv is often effective

If emesis is refractory, may considerZofran (ondansetron) or Kytril (granisetron)Expensive, but very effective

Pediatric overdosesMore resistant to toxicity vs. adultsif a child plots in the possible risk category on the Rumack nomogram, do not resist using NAC because of this greater tolerance to APAP

Administer full course of NAC if nomogram indicates that it is needed

Special considerations with NACNAC administered on basis of nomogram plotif initial level indicates need for NAC do not discontinuesubsequent APAP levels of interest onlyIf NAC begun before APAP level obtained, may DC NAC if level plots subtoxic on nomogram

NAC side effectsRelatively free of side effects when given orally

Emesis may occurextremely offensive sulfur odor

ED Admission

Estimate time of ingestionLess than 4 hours since overdose 4 or more hours since overdoseLess than 2 hours More than 2 hours since overdose since overdoseGastric emptying Activated charcoalActivated charcoalDraw blood plasma 4 hours after overdose forplasma acetaminophen assayDraw blood ASAP for plasma acetaminophen assayAcetaminophen concentration available Acetaminophen concentration not within 8 hours of overdose available within 8 hours of overdose Wait for acetaminophen assay result Start NAC pending assay result Loading does: 140 mg/kgAPAP level below risk line on nomogram APAP level on or above risk lineDC NAC if started Treat with full course of NACNo further medical management needed Daily LFTs, prothrombin times Treat other med or psychiatric problems Provide supportive care

SummaryIn overdose, APAP may overwhelm the liver stores of glutathione. A rise in liver enzymes may occur, which reflects the hepatic toxicity which may ensue. Timely administration of NAC may protect the patient from hepatic damage. Therapy should be initiated as soon as possible, but NAC is beneficial at any time. If APAP levels can not be obtained, assume a toxic dose has been ingested, initiate NAC, and continue until regimen complete.

Case StudiesCase 1A 32 year old female presents to the ED 30 minutes after taking 31 Tylenol Extra Strength caplets in an apparent suicide attempt. She weighs 134 pounds, ambulated into the ED, is in no obvious distress, has had no symptoms prior to arrival.

Signs/symptomsPatient is awake and alertHEENT: normalNo GI distressPERRLATemp 98.7FHR 84, BP 128/76, R 19

Lab resultsAPAP pendingSalicylate pendingTox screen Negative

CalculationsPatient weighs 60.9 kilograms

15,500 mg of APAP ingested

mg/kg = 254a potentially toxic acute dose

TreatmentLavage Activated charcoalCatharticHold NAC until APAP level results obtainedcan get APAP level back within 2 hours

OutcomeAPAP level 56 mg/dl drawn 4 hours post ingestionASA level 0patient discharged asx to mental health unit7 hours after arrival

Case 2A 25 year old male is brought to the ED by his girlfriend. She states that he has taken 24 Tylenol tablets. She brought the bottle with her and in fact the product is Tylenol ER. He ingested the caplets approximately 5 hours ago.

Tylenol ER is a relatively new product which throws a curve into the traditional management of APAP overdoses. This product releases 325 mg of APAP immediately and 325 mg over the next 8 hours.

Tylenol ER is referred to by poison center staff as

Tylenol Emergency Room

Unsure if nomogram is useful with this product

1 case demonstrated to have biphasic peaks

Signs/symptomsPatient has vomited x 6 prior to arrivalComplaining of GI discomfortHEENT: normalPEERLATemp 98.9FHR 80, BP 130/78, R 20

LabsAPAP level 110 mcg/ml at 5.0 hours post ingestion

ASA level 0Tox screen negative for other substances

CalculationsPatient weighs 85 kilograms

11,050 mg APAP was ingested

183 mg/kg APAP ingestedPotentially toxic amount in acute od

TreatmentActivated charcoal with sorbitol givenRepeat APAP level 4 hours past the 1st levelStrongly consider NAC with this levelInitial 4 hour level > 100 start NAC

OutcomePatient was treated with full course NACLiver enzymes were AST 220 U/L, and ALT 388 U/L at 27 hours post ingestion.Liver enzymes returned to normal ranges within 72 hours. Patient recovered uneventfully

Points to rememberAPAP is present in many poly drug overdoses No symptoms may be presentscreen150 mcg/ml at 4 hours is a treat levelNAC loading dose is 140 mg/kgNAC maintenance doses are 70 mg/kgOnce NAC is started, DO NOT DCMetoclopramide 0.1-1.0 mg/kg is very effective in controlling nausea/vomiting associated with APAP toxicity

The End

*APAP (N-acetyl-p-aminophenol_Paracetamol in the UK, Mexico, many other countries

Now surpasses ASA as a major cause of poisoning in USUse incr. Dramatically as Reyes syndrome was linked to salicylate use.Now considered safed than aspirin

One of the most commonly used analgesic/antipyretic agents in the US

Has none of ASAsunderirable side effects when used in therapeutic doseDue to this increased availability and use, toxic exposures have also increased.

Toxic effects seen in great Britain in late 1960s.In each of the last few years, over 60,ooo queries related to APAP thru TESS each year*In over 50 Trade name products

Some are APAP alone, many others in combo with other agents.Most pain meds today contain APAP Codeine/APAP, Hcodone/APAP,Oxycodone/APAPSuppositories, elixirs, tablets, caplets, geltabs, capsules, powdered (Tylenol Cold?Flu)some up to 1000 mg/dose*Peripheral action is blockade of Pain Impulse generation

Less effect on peripheral enzyme

Studies have shown that both apap and asa have equal effects on pain when given in equiv. Doses when the pain in non inflammatory in origin

For inflammatory pain, salicylates are superior.They also inhibit prostaglandin synthetase peripherally, resulting in anti inflammatory activity.*Inhib. Prost. Snythetase in the hypothalamus, altering response of the heat regulating center.

Studies comparing APAP and ASA have shown no significant difference in temperature response, time of onset, time of peak activity, or duration of antipyretic activity**Peak concentration occur even more quickly with liquid formulations

Bezoar formation has not been seen with APAP like it has with ASA**The 4% metab by the P450 system is an active intermediate (NAPQI)Normally, this minor metabolite of hydroxylation is detoxified by conjugation with hepatic glutathione, with the conjugated products mercapturic acid and cysteine excreted in the urine

When large doses of APAP are ingested, both the glucoronidation and sulfation pathways become saturated, shunting more APAP toward the P-450 system and increasing NAPQI formation.

When glutathione depletes to 30% of normal, NAPQI accumulates. The NAPQI arylates to protein in the cytosol and endoplasmic reticulum in the centrilobular zone of the liver, producing cell necrosis and death.NAPQI is neutralized by glutathioneNAPQI contains a sulfhydryl group. If all glutathione is used up, other sulfhydryl groups in the liver are attacked and cells are damaged or destroyed***Haemodialysis readily removes APAP, but the toxic metabolite is formed rapidly

Peritoneal dialysis- Protein binding may increase up to 50% in overdose

Forced diuresis- Not effective because of small amount excreted unchanged in the urine.**************************************