Acetaminophen Flashcards by Beth Cocker

Therapeutic dose of Acetaminophen

325-1000 mg (10-15 mg/kg/dose for children) Q4H

Max: 4 g (75 mg/kg/day in children)

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Adult Acute Toxic Dose

> /= 10 grams or 200 mg/kg, which ever is less

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Adult Chronic Toxic Dose

For >48 hours: >6 g/day or 150 mg/kg/day

If risk factors: >4 g/day or 100 mg/kg/day

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Children Acute Toxic Dose

> 200 mg/kg

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**Risk Factors influencing hepatotoxicity

Chronic alcohol ingestion
Meds/herbs that induce 2E1 (rifampicin, phenobarbital, St. John's wort)
Meds that compete with hepatic glucorunidation (bactrim and zidovudine)
Gilbert's syndrome
Malnutrition
Fasting state
Chronic liver disease
Advanced age
Pregnancy

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Acetaminophen Metabolism

Sulfation (30%)
Glucoronidation (60%)
2E1 (10%)

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2E1 Pathways

Acetaminophen –> NAPQI (toxic metabolite)

Then broken down by glutathione to cysteine and mercapturic acid which can be excreted renally

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Glutathione Levels and Timing

As long as our body have at least >30% glutathione, there shouldn’t be toxicity
BUT glutathione is completely depleted in 6-8 hours

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Consequences of Acetaminophen Toxicity

Liver damage and possible kidney damage through necorsis (centrilobular hepatic and proximal convoluted tubule)

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Centrilobular Necrosis Mechanism

NAPQI freely binds to cysteine which causes oxidation damage and necrossi of the central region of the liver

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APAP Peak Effects

Oral: 30 minutes
IV: 15 minutes
Toxic Doses: 4 hours!!!!

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APAP Absorption

Small intestine

Complete within 1.5-2.5 hours

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APAP Protein binding and Elimination

10-25% PB

2% excreted unchanged and its half-life is 2-3 hours but at toxic doses the half life is 4-12 hours

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***Acetaminophen Toxidrome Phase 1

0-24 hours
Asymptomatic
N/V and anorexia
+/- malaise, diaphoresis

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***Acetaminophen Toxidrome Phase 2

24-72 hours
Decreased N/V and anorexia
Increased AST (liver damage)
+/- Right upper quadrant pain (inflammed liver), increased bulirubin, prolong PT, decreased renal function

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***Acetaminophen Toxidrome Phase 3

72-96 Hours
Hepatic necrosis, jaundice, increase PT/INR, encephalopathy, renal failure
Death due to multi-organ failure

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***Acetaminophen Toxidrome Phase 4

4-14 days
AKA recovery phase
Complete resolution of hepatic dysfunction without fibrosis

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Excessive CYP activity can be caused by?

Fasting
Drugs
Chronic alcohol ingestion 
Genetics
All lead to increased NAPQI metabolites

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Define Gilbert’s disease

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Decreased compatibility for glucuronidation and sulfation

GSH-dependent pathways?

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Chronic liver disease
Chronic alcohol ingestion
Malnutrition
All lead to GSH depletion

Acute Alcohol + APAP

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Alcohol competes wtih APAP for 2E1 binding site and decrease APAP conversion to NAPQI
- ACUTE = PROTECTIVE

Effects of Chronic Alcohol Co-Ingestion

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Acetaldehyde accumulation inhibiting glutathione synthetase
Induced GGT –> increased glutathione degradation
Poor dietary intake of glutathione
Induced 2E1

Systematic Management of APAP Toxicity

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Emergency Stabilization
Patient Evaluation
Treatment to reduce absorption
Measures to improve elimination
Antidote
Continuing care and disposition

ABCDEF

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Airway
Breathing
Circulation BP, Pulse
DONT (dextrose, oxygen)
Exposure
Fever

Diagnostic Testing for APA

Taken 4 hours after ingestion!!!! AST/ALT elevated --> treat regardless AST/ALT WNL + APAP below treatment line --> observe - Bili and SCr - PT/INR to assess degree of liver injury

Rumack-Matthew Nonogram

NEEDS TO BE IN mcg/mL Start more than 4 hours since ingestion and repeat 4 hours later Above the line = AST/ALT > 100 --> increased risk of hepatotoxicity --> TREAT

Treatment to reduce absorption

Gastric emptying: NO | Activated Charcoal: YES

Measures to improve elimination:

Specific Antidote for APAP

N-Acetylcystein (NAC)

NAC =

GLutathione precursor and substitute Provides sulfhydryl group for sulfate conjugation Antioxidant

NAC Indication

- APAP in the potentially toxic range on the RM nonogram - History suggests an acute ingestion of 150 mg/kg and/or results could not be obtained within 8 hours - Measurable APAP 24 hours after ingestion - Evidence of hepatic injury - Chronic APAP abuser with elevated AST or APAP > 10 mcg/mL

***When do you start NAC

START WITHIN 6-8 HOURS OF INGESTION - delay decreases effectiveness*****

NAC MOA

Increases sulfation and blocks 2E1 before complete depletion of glutathione (within 6-8 hours)

NAC + Pregnacy

Category B Crosses placenta Gives the baby some protection too so get on board ASAP

IV NAC Name, AE, Indication, Dose

Acetaladote Anaphylatic reaction, bronchospams I: pregnant, fulminant hepatic failure, intractable vomiting, altered mental status D: 300 mg/kg over 20 hours

Oral NAC Name, AE, Indication, Dose

Mucomyst Bad smell and taste --> N/V Asthma and no indication for IV D: 1330 mg/kg NAC over 72 hours

NAC Note

Repeat dose if emesis occurs within 1 hours of administration Solution should be DILUTED to 5% and can be mixed with soft drink to lessen the bad taste

When to d/c oral dose?

71 hours, d/c when: LFTs are trending towards normal, coagulation studies/pH/bilirubin are WNL, APAP no longer present, continuing would be harmful

When to d/c IV dose

21 hours, d/c when: LFT and coagulation studies are normal, APA undetectable in serum If neither of these, continue for at least 24 hours and repeat labs Q24H

Continuing Care

Psych eval Monitoring effifacy (daily assessment of APAP, AST/ALT, total bilirubin and INR Monitoring toxicity Last: liver transplant

AST/ALT + Treatment

May peak at several thousand units even with NAC therapy

Monitoring with Oral NAC

Must be retained for 1 hour after dose | Protracted vomiting - treat with antiemetic like ondansetron, feeding tube or switch to IV

Monitoring with IV NAC

Allergy or anaphylactic reaction | Administer slowly over 1 hour

Pharmacist Role

``` Do not use APAP or ACET on label Use warning lables Check for multiple sources of APAP Look for drug interaction Watch opioid tolerance increased usage of Rx Warn the patient In-store flyers/signs Education ```

Education to Patients

``` Read labels Avoid OTC APAP Don't go over max dose Never take more than 1 OTC APAP product Store away from children Measure liquids accurately Use child's weight then age ```

Acetaminophen Flashcards

(45 cards)