Acetaminophen Toxicity: Michira I Getange Umb/15-A/054

Acetaminophen toxicity
Michira I getange
Umb/15-a/054
Outline.
• Definittion.
• Pathophysiology.
• Clinical presentation.
• Differential diagnosis.
• Treatment and management.
• Complications.
Introductions.
• Acetaminophen is the most commonly used oral analgesics and
antipyretics.
• But when overdosed or misused hepatoxicity can occur .
• Acetaminophen toxicity has replaced viral hepatitis as the most
common cause of acute liver failure.
• Acetaminophen metabolism occurs primarily in the liver.
Signs and symptoms.
• Initial can be asymptomatic as clinical symptoms of end organ toxicity
do not manifest until 24-48 hrs after an acute ingestion.
• Therfore to determine the time of ingestion ,the quantity and the
formulation of acetaminophen ingested,this is to identify the pts who
is at the risk of hepatoxicity.
• Minimum toxic doses of acetaminophen for a single ingestion,posing
significant risk of severe hepatoxicity include;
Cont’d
• Adults;7.5-10g
• Children;150mg/kg;200mg/kg in healthy children aged in 1-6yrs.
• The clinical phases of acetaminophen toxicity are in 4.
• Physical findings may vary depending on the degree of hepatoxicty.
Phase 1
• 0.5-24 hrs after ingestion.
• Pts may asymptomatics or report anorexia ,nausea or vomiting and
malaise.
• Physical examination may reveal pallor,diaphoresis,malaise,and
fatigue.
Phase 2
• 18 -72 hrs after ingestion.
• Pts develop right upper quadrant abdominal pain,anorexia,nausea
and vomiting .
• Tachycardia and hypotension may indicate volume losses.
• Some patients may report oliguria.
Phase 3 ;Hepatic phase.
• 72-96hrs after ingestion.
• Pts have cont’d nausea and vomiting ,abdominal pain,and a tender
hepatic edge.
• Hepatic necrosis and dysfunction may manifest as jaundice
,coagulopathy,hypoglycaemia,and hepatic encelophalopathy.
• Acute renal failre develops in some criticaly ill pts .
• Death from end organ damage .
Phase 4;Recovery phase.
• 4 days to 3 weeks after ingestion.
• Pts who survive this in phase 3 have complete resolution of
symptoms and complete resolution of organ failure
Diagnosis.
• The serum concetration of acetaminophen is the basis for diagnosis
and treatment.
• The Rumack –Matthew nomogram interprets the acetaminophen
concetration,and is predictive of possible hepatoxicity after single
acute ingestions of acetaminophen.
Cont’d
• Also liver function test(ALT,AST,alkaline phosphatase,bilirubin (total
and fractioned)).
• Prothrombin time with international normalized ratio.
• Glucose.
• Renal fxn studies(electrolytes,BUN,creatinine)
• Lipase and amylase .with abdominal pain.
• Serum hCG those in child bearing age.
• Arterial blood gas and ammonia.
Cont’d
• Urinalysis (to check hematuria and proteinuria)
• ECG
• In pts with mental status changes ,consider serum ammonia levels
and ct scanning of the brain
Management.
• GIT decontamination agents can be used in emergency settings
,administer activated charcoal if pts is alert.
• Pts with conc above “possible” line admit for rx with N-acetylcysteine.
• NAC is nearly 100%hepatoprotective within 8 hrs after acute ingestion
of acetaminophen.
• NAC is approved for both oral and iv admin
• Loading dose of 140 mg/kg,17 doses of 70 mg/kg given every
4hrs,total rx duration of 72 hrs.
Cont’d
• Iv formulation of NAC(acetadote),is used,but is used in following
situations ;
• Altered mental status.
• GI bleeding and or obstruction.
• A hx of caustic ingestion
• Pontetial toxicity in a pregnant woman.
• Inabilty to tolerate oral NAC bcoz of emesis reflactory to proper use of
antiemetics.
Cont’d
• Surgical evaluations for possible liver transplantation is indicated for
pts who have severe hepatoxicity and potential to progress to hepatic
failure.
• Criteria for liver transplantation include the following;
• Metabolic acidosis,persistent after fluid resuscitation.
• Renal failure
• Coagulopathy
• encephalopathy
Pathophysiology.
• Acetaminophen is rapidly absorbed from stomach and small intestine.
• Acetaminophen is primarily metabolized by conjugation in the liver to
nontoxic ,water soluble compounds that are eliminated in the urine.
• When dose is exceded over prolonged time ,metabolism by
conjugation becomes saturated and excess APAP is oxidatively
metabolized by the cyp enzymes to N-acetyl-p-benzoquinoneimine.
• The NAPQI causes inflammatory response which propagates
hepatocellular injury and death.
Etiology.
• Susceptibility is enhanced by conditions that reduce gluthathione
stores in the body ,which include the following;
• Older age
• Restricted diet
• Underlying hepatic or renal diseases
• Compromised nutriotional status
• Agents and medications that induce CYP enzyme activity are
numerous,and include some of the following;
• Ethanol ingestion,tobacco
smoking,isoniazid,rifampin,phenytoin,phenobarbital,zidovudine e.t.c.
Risk factors.
• Repeated administration of high doses and proper dose at shortened
time intervals.
• Fever
• Poor oral intake
• Young age.
SALICYLATE POISOINING.
• Ubiquitious agents found in hundreds OTC medication and in
numerous prescription drugs,thus can cause significant morbidity and
mortality.
• Are analgesic agents,aspirin is an antipyretic and an anti-
inflammatory agents for the soft tissues and joint inflammation and
vasculitides,acute coronary syndrome,low dose helps prevent
thrombosis.
• Available fo ingestion as tablets ,capsules and liquids.also as topical
agents .
• Common cause of poisoining in children and adolscents.
• Common sources of unintetionaland suicidal ingestion.
• But the incidence has declined due to use of other analgesic
agents,use of child resistant containers.
Phases and symptoms
• Ther is fluid, electrolyte,acid –base abnormalities.
• PHASE ONE.
• Hyperventilation leading to respiratory alkalosis and compensatory

alkauria
• Potassium and sodium bicarbonate are excreted in the urine
• May last for 12 hrs.
Phase 2
• Paradoxical aciduria,due sufficient loss of potassium from kidneys and
ther is also respiratory alkalosis.
• May last 12-24 hrs
Phase 3
• Dehydration,hypokalemia,progressive metabolic acidosis.
• 4-6 hrs after ingestion in peds pts,24 hrs for aduts and adolscents .
• Nausea and vomiting ,diaphoresis and tinnitus are the earliest signs
and symptoms.
• Vertigo,hyperventilation,tachycardia and hyperactivity.
• As it progresses delirium hallucination convulsions,lethargy and
stupor may occur.
• Hyperthermia in young children.
Treatment
• Stabilizing ABCs limiting absorption,enhancing elimination ,correcting
metabolic abnormalities and providing supportive care.
• No known antidote .
Etiology and pathophysiology
• Ingestion of acetysalicyclic acid- converted to salicyclic acid absorbed
in the stomach and small bowel.
• Metabolized in the liver and eliminated in 2-3 hrs.
• Its toxicity uncouples oxidative phosphorylation,inhibits krebs cycle
enzymes,and inhibits amino acid synthesis.
Acid –Base status
• Inhibition of citric acid cycle and uncupling of oxidative
phosphorylation and may produce renal insufficiency that causes
accumulation of phosphoric and sulphuric acids
• Fatty acids metabolism increased thus formation of ketone bodies.
• Thus devt of elevated anion gap metabolic acidosis.
• Inhibiton of ATP dependent rxns will result to;respiratory alkalosis.
Respiratory system effects
• 35mg/Dl or higher may cause tachypnea and hyperpnea.
• May also cause nan cardiogenic pulmonary edema and acute lung
injury.
Glucose metabolism
• Intracellular metabolic activity is increased thus decrease of
glucose,may altermental status if it affects cns.
• Hypoprothrombinemia and platelet dysfunction will cause bleeding
by inhibition of vit k dependent enzymes.
• Musculoskeletal effects ;rhabdomyolysis bco of dissipationof heat and
energy due to uncoupling of oxidative phosphorylation
Categories of toxicity
• <150 mg/kg ingested;no to mild toxicity
• 150- 300mg/kg mild to moderate toxicity
• 301-500mg/kg serious toxicity
• >500mg/kg potentially lethal toxicity.

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Acetaminophen toxicity

• Hyperventilation leading to respiratory alkalosis and compensatory

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