Acetaminophen Flashcards
Therapeutic dose of Acetaminophen
325-1000 mg (10-15 mg/kg/dose for children) Q4H
Max: 4 g (75 mg/kg/day in children)
Adult Acute Toxic Dose
> /= 10 grams or 200 mg/kg, which ever is less
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
Children Acute Toxic Dose
> 200 mg/kg
**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
Acetaminophen Metabolism
Sulfation (30%)
Glucoronidation (60%)
2E1 (10%)
2E1 Pathways
Acetaminophen –> NAPQI (toxic metabolite)
Then broken down by glutathione to cysteine and mercapturic acid which can be excreted renally
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
Consequences of Acetaminophen Toxicity
Liver damage and possible kidney damage through necorsis (centrilobular hepatic and proximal convoluted tubule)
Centrilobular Necrosis Mechanism
NAPQI freely binds to cysteine which causes oxidation damage and necrossi of the central region of the liver
APAP Peak Effects
Oral: 30 minutes
IV: 15 minutes
Toxic Doses: 4 hours!!!!
APAP Absorption
Small intestine
Complete within 1.5-2.5 hours
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
***Acetaminophen Toxidrome Phase 1
0-24 hours
Asymptomatic
N/V and anorexia
+/- malaise, diaphoresis
***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
***Acetaminophen Toxidrome Phase 3
72-96 Hours
Hepatic necrosis, jaundice, increase PT/INR, encephalopathy, renal failure
Death due to multi-organ failure
***Acetaminophen Toxidrome Phase 4
4-14 days
AKA recovery phase
Complete resolution of hepatic dysfunction without fibrosis
Excessive CYP activity can be caused by?
Fasting Drugs Chronic alcohol ingestion Genetics All lead to increased NAPQI metabolites
Define Gilbert’s disease
Decreased compatibility for glucuronidation and sulfation
GSH-dependent pathways?
Chronic liver disease
Chronic alcohol ingestion
Malnutrition
All lead to GSH depletion
Acute Alcohol + APAP
Alcohol competes wtih APAP for 2E1 binding site and decrease APAP conversion to NAPQI
- ACUTE = PROTECTIVE
Effects of Chronic Alcohol Co-Ingestion
Acetaldehyde accumulation inhibiting glutathione synthetase
Induced GGT –> increased glutathione degradation
Poor dietary intake of glutathione
Induced 2E1
Systematic Management of APAP Toxicity
Emergency Stabilization Patient Evaluation Treatment to reduce absorption Measures to improve elimination Antidote Continuing care and disposition
ABCDEF
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:
NO
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
