Acetaminphen (APAP) Toxicity Flashcards
When talking about acetaminophen (APAP), what is its absorption like?
Well absorbed
- Rapid and nearly complete
How does APAP distribute in the body?
- 1/4 is protein bound in plasma
- Uniformly distributed in body
What is the major metabolite of APAP that you need to know?
NAPQI
Why do we care about NAPQI? (2)
- Free NAPQI is highly toxic due to its high reactivity with –SH group present in DNA, RNA and Proteins.
- NAPQI reacts with glutathione in liver and gets neutralised to a non-toxic metabolite.
What is the mechanism of hepatocyte death via active metabolite (NAPQI)? (5)
- Forms covalent bonds with vital proteins and lipid bilayers, killing the cells.
- Creates reactive O2 species (ROS)
- Decreases glutathione and cytosolic thiols
- Loss of mitochondrial membrane potential
- Inability of mitochondria to produce ATP - It causes necrosis in the liver cells and kidney tubules.
What are the symptoms of NAPQI toxicity? (3)
- Pain in upper right abdomen
- Vomiting
- Decrease in clotting factors
66% of APAP overdoses are ______-___________
single-ingredient
What is the Vd of APAP?
0.7-1.2 L/kg
- Widely distributed to most body fluids and tissues
Obviously APAP is metabolized in the liver. What are the key enzymes? (3)
- CYP2E1
- CYP3A4
- CYP1A2
True or False? NAPQI + Glutathione conjugate is toxic
False - not toxic
What are 2 circumstances mostly commonly associated with APAP poisoning?
- Overdose
- Liver not working properly - decreased glutathione = decrease in NAPQI neutralization
Why are chronic alcoholics more prone to APAP poisoning? (2)
- Alcohol causes liver disease –> glutathione levels decrease
- Alcohol stimulates CYP –> increased NAPQI levels
Younger children have an increased tolerance to higher doses of APAP on a mg/kg basis in single-dose toxicity. What are some possible explanations as to why? (4)
- Increased capacity of sulfation pathways
- Increased glutathione stores
- Propensity to vomit post-ingestion
- Immature CYP2E1 (infants) - meaning less NAPQI in general
What is the toxic single dose of APAP for an adult (in grams and in mg/kg)
> 12g OR 150mg/kg
What is the toxic single dose of APAP for pediatrics (in mg/kg)
> 150mg/kg (200mg/kg in healthy children aged 1-6 years)
Acetaminophen can cause dangerous skin reactions, such as? (3)
- Stevens-Johnson syndrome (SJS)
- Toxic epidermal necrolysis (TEN)
- Acute generalized exanthematous pustulosis (AGEP)
What are the APAP toxicity at-risk populations? (3)
- Those with ↓ glutathione stores:
- Chronic alcohol consumption
- Fasting and malnutrition: depletes glycogen stores
– Glucose is required for the uridine diphosphate (UDP)-glucuronic acid form of APAP.
– Also decreases glutathione stores. - Concomitant enzyme-inducing drugs
- Chronic alcohol, isoniazid, phenobarbital,primidone, possibly St. John’s wort - Chronic liver disease, Non-alcoholic fatty liver disease, hepatitis
APAP can cause toxicity outside of the liver as well. Such as? (2)
- Renal failure
- Myocardial necrosis
What is the timeframe for Phase I acute APAP toxicity?
0-24h
What are the symptoms of acute Phase I APAP toxicity? (4)
- Vomiting
- Anorexia
- Nausea
- Diaphoresis
What is the timeframe for Phase II acute APAP toxcity?
18-72h
What are the symptoms of acute Phase II APAP toxicity? (4)
- Reduction of symptoms from Phase 1
- ↑ liver enzymes (ALT, AST)
- Hepatic failure (death of hepatocytes)
- RUQ pain (near end of phase)
What is the timeframe for Phase III acute APAP toxicity?
72-96h
What are the symptoms of acute Phase III APAP toxicity? (4)
- Hepatitis is acute in onset, progresses rapidly
- Elevation of plasma aminotransferases
- Rising prothrombin time/INR
- Several days following APAP ingestion:
- Nausea, vomiting
- Jaundice, liver
- Hepatic encephalopathy
- Death at 3-5 days post-ingestion
What is the timeframe for Phase IV acute APAP toxicity?
4 days to 3 weeks
What are the symptoms of acute Phase IV APAP toxicity? (3)
Assuming they are coming around
1. Complete resolution of symptoms
2. Return to baseline liver enzyme levels
3. No chronic hepatic dysfunction
What is the clinical presentation of each phase of APAP toxicity?
Phase 1 - preclinical toxic effects
Phase 2 - hepatic injury
Phase 3 - hepatic failure
Phase 4 - recovery
What history is needed to help with diagnosis of APAP toxicity? (2)
- Time of ingestion
- Product ingested (dosage form) (release information - determine plasma levels)
Patient has APAP OD, what is the most important thing to do for them?
ABCs and supportive care - including IV fluids and O2
Tmax of APAP is?
4 hours
When using the Rumack-Matthew nomogram at what point would NAC be started?
When concentration of APAP is 150microg/mL or higher
What are the limitations to Rumack-Matthew nomogram? (5)
- Patients presenting late (>24h)
- Chronic/repeated supratherapeutic ingestion
- Modified release products – Absorbed at different rates
- Time of ingestion estimate liable to be inaccurate
- Altered mental status - ‘At-risk’ populations
True or False? Urine pH affects how APAP is excreted
False - neither an acid nor a base
Hemodialysis for APAP OD?
Will remove APAP from plasma but hasn’t been shown to prevent hepatotoxicity
What is the MOA of NAC?
- Numerous proposed theories:
- Maintains glutathione levels
- Promotes formation of sulfate conjugate
- Antioxidant properties
- Improved hepatic blood flow & O2 delivery - NAC - Replenishes glutathione stores in liver
What are the indications for NAC/when to give? (4)
- Plasma [APAP] at, or above “possible hepatotoxicity” on nomogram
- Late presenting patients with symptoms of hepatic damage
- Repeated supratherapeutic with ↑ liver enzymes
- Fulminant (sudden and severe) hepatic failure
What benefit (if any) does NAC have 0-4 since APAP ingestion?
Generally will not administer during this time; waiting for Cmax
What benefit (if any) does NAC have 4-8 since APAP ingestion?
Benefit of NAC equal throughout this period. Though toxicity does not occur until glutathione levels less than or equal to 30% –> takes about 8 hours
What benefit (if any) does NAC have 8-24 since APAP ingestion?
Still effective, though benefit wanes with each passing 4h block
What benefit (if any) does NAC have >24h since APAP ingestion?
Not clear; may reduce mortality rates in late-presenting patients with fulmitant hepatic failure, even if undetectable plasma APAP levels
NAC can be given either __ or ______
IV; orally
When do we stop NAC? (Hint, not just duration) (5)
Stop NAC at end of regimen (ex. 21h IV) or satisfaction of all below
(whichever longer);
1. ALT/AST normal or declining
- 1-2 successive reductions
- 50% reduction from peak
2. Undetectable [APAP] in plasma
3. No coagulopathy (INR ≤ 1.5 and declining)
4. Serum creatinine normal or declining
5. Clinically well (there is no hepatic encephalopathy, no signs of
hepatic failure (RUQ pain, vomiting jaundice)
What are non-immunologic anaphylactic reactions to NAC?
(Incidence, when does it happen, risk factors)
- Incidence = 7-8%
- Concentration/dose-dependent - usually during 1st or 2nd infusion
- Risk factors
- Asthma
- Atopy
- Eczema
- Lower [APAP]
- Increased delay to NAC
How many hours does it typically take to use up 70% of glutathione stores?
a. 2 hours
b. 4 hours
c. 8 hours
d. 16 hours
b
Why are infants/children more tolerant of higher doses of acetaminophen?
a. They have larger glutathione stores
b. They have greater than normal CYP activity
c. They have immature CYP enzymes
d. a and c
D
Which of the following is part of the mechanism by which acetaminophen damages hepatocytes:
A. Creates reactive O2 species (ROS)
B. Breaks covalent bonds in vital proteins
C. Increases mitochondrial ATP output
D. Liberates lipids from cellular membranes
A
A patient with an acetaminophen overdose has their INR measured by the lab. The INR is abnormally elevated. How is this related to the acetaminophen overdose?
A. Heptocyte toxicity resulting in decreased production of clotting factors
B. Not likely related to acetaminophen, but an incidental finding that should be investigated
C. Secondary to renal failure from hepatorenal syndrome
D. Secondary to the elevated liver enzymes in the plasma
A
In acetaminophen overdose, at what point does the patient feel better but liver enzymes are increasing?
A. Phase 2 (18-72 hr)
B. Phase 3 (72-96 hr)
C. Phase 1 (0-24 hr)
D. Phase 4 (4d-3 wks)
A
A patient has been receiving an N-acetylcysteine infusion and suddenly begins feeling hot, flushed and itchy all over their skin. She says it feels like someone is sitting on her chest. A shallow cough is also developing.
How should this patient’s care plan change considering these new symptoms?
A. Give IV antihistamine, administer salbutamol by inhaler and reduce the rate of the N-acetylcysteine infusion.
B. Stop the N-acetylcysteine and administer epinephrine. The patient will require dialysis for removal of acetaminophen.
C. Give oral antihistamine and continue the infusion.
D. Give IV epinephrine and intubate immediately. Stop the N-acetylcysteine and switch to sodium bicarbonate IV infusion.
A
Penny, age 55, is brought to the hospital by her sister, who discovered she ingested an entire bottle of Tylenol Extra Strength about 6 hours ago. According to Penny’s medical history, she also struggled with alcohol use disorder and severe depression for which she has been treated with multiple medications in recent years. Penny’s acetaminophen levels are drawn, and the Rumack Matthew Nomogram results indicate that her risk is borderline. What is the management now and why?
A. Give N-acetylcysteine because she has multiple risk factors for toxicity.
B. Avoid N-actylcysteine because he may be malnourished and lack the necessary co-factors.
C. IV fluids and sodium bicarbonate
D. Gastric lavage
A
Which of these metabolic pathways is not a major route of
acetaminophen elimination?
A. Excretion unchanged in the urine
B. Sulfation by hepatic metabolism
C. Glucuronidation in the liver
D. Glutathione conjugates of the product of CYP metabolism
A
Which of the following is true with regard to Acetaminophen toxicity?
A. The Rumack-Matthew Normogram may be used for both acute and chronic ingestions.
B. The APAP level should ideally be checked within 1-4 hours of ingestion.
C. The Rumack-Matthew Normogram applies for ingestions up to 48 hours post-ingestion.
D. N-Acetylcysteine (NAC) should be started within 4-8 hours of ingestion if an APAP level cannot be obtained.
E. Activated Charcoal should be used for all sustained-release ingestions
D
A 24-year-old non-pregnant female presents 6 hours after ingestion of 40 g of standard release acetaminophen. She is vomiting and decided to seek care after telling her boyfriend about the ingestion. She has no significant medical history, is on oral contraceptives and denies drug use. Her vital signs are within normal limits and her exam is unremarkable other than she is tearful. Patients who ingest more than 10 g of acetaminophen per day are considered at risk for liver injury. How should this patient be risk stratified?
A. SDAC immediately and measure APAP levels at 4 hours. Plot on RM Nomogram. If above 150 mcg/mL start NAC
B. SDAC, start NAC and measure APAP and AST and ALT levels every 4 hours. Continue infusion till back to normal levels.
C. SDAC and discharge
D. Gastric lavage and discharge
B
15 months old child (wt. 10 kg) accidentally took full bottle of Tylenol 60cc (120mg/5cc) 30 minutes ago. Clinically looked well. What will be
your treatment plan? The toxic dose for this group is 200 mg/kg
A. Give 1g/kg activated charcoal
B Insert OGT and perform gastric lavage
C. Should be observed for 4h then to do drug level
D. None of the above
D
[(60*120/5) / 10] = 144 mg/kg. The toxic dose for his age group is 200mg/kg
