Acetominophen Flashcards

1
Q

What is the mechanism of action acetaminophen?

A
  1. Analgesic - inhibits COX-3 in CNS
    - Competitive central inhibition of COX-3 decreases production of prostaglandin E2 in CNS
    - Very weak anti-inflammatory activity due to weak inhibition of peripheral tissue COX-1, COX-2
    - Does not cause GI ulceration or inhibit platelet aggregation like aspirin
  2. Antipyretic
    - Direct effect on heat-regulating centres of the hypothalamus, leading to increased heat dissipation through vasodilation and sweating
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2
Q

How is APAP metabolized?

A
  1. Acetaminophen is metabolized into N-Acetyl-p-benzoquinoeimine (NAPQI) by CYP2E1
  2. Acetaminophen is metabolized into sulfate-acetaminophen (20-46%)
  3. Acetaminophen is metabolized into glucuronide-acetominophen (40-67%)
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3
Q

How does APAP overdose cause liver injury?

A

Up to 45% of APAP is converted into NAPQI by P450 2E1 (a.k.a CYP2E1).

Usually, glutathione (GSH) converts NAPQI into cysteinyl conjugate.

But if GSH is > 70% depleted, then excess NAPQI binds to SH groups in cellular proteins and causes cell injury which results in centrilobular hepatic necrosis.

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4
Q

What causes APAP toxicity?

A
  1. Induction of liver CYP2E1 or CYP3A4 isoenzymes
    - Results in increased formation of NAPQI
  2. Depletion of glutathione (GSH)
    - Decreased detoxification of NAPQI
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5
Q

What are the clinical conditions that may cause the induction of liver CYP2E1 or CYP3A4 isoenzymes?

A
  1. Long term treatment with enzyme inducing drugs
    - Carbamazepine, phenobarbital, phenytoin, primidone, rifampicin, rifabutin, efavirenz, nevirapine, and St John’s wart
  2. Regular consumption of ethanol in excess of recommended amounts
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6
Q

What are the clinical conditions that may cause the depletion of GSH?

A
  1. Malnourished
  2. Eating disorders
  3. Cystic fibrosis in children
  4. AIDS
  5. Alcoholism
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7
Q

What are the stages of acetaminophen poisoning with their associated times?

A

Stage I (0.5-24 h)
Stage II (18-48 h)
Stage III (72-96 h)
Stage IV (5d - 3w)

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8
Q

What are the symptoms of Stage I acetaminophen poisoning?

A

GI irritation

  1. Anorexia, nausea, vomiting
  2. Liver function tests normal
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9
Q

What are the symptoms of Stage II acetaminophen poisoning?

A

Latent period (onset of liver injury)

  1. Transient resolution of GI symptoms
  2. Right upper quadrant (RUQ) abdominal pain
  3. AST/ALT increased
  4. Prothrombin time/bilirubin sometimes elevated if severe
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10
Q

What are the symptoms of Stage III acetaminophen poisoning?

A

Maximal hepatotoxicity

  1. Symptoms of hepatotoxicity - vomiting reappears
  2. Fulminant hepatic failure may develop: liver tenderness, jaundice, hepatic encephalopathy & hemorrage
  3. AST/ALT > 10000 IU/L, bilirubin peak
  4. Sometimes renal failure or pancreatitis
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11
Q

What are the symptoms of Stage IV acetaminophen poisoning?

A

Recovery or death

  1. Resolution of hepatotoxicity
  2. AST ALT return to normal (5-7 days)
    OR progression to multiple organ failure (sometimes fatal)
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12
Q

What test for APAP poisoning?

A

Plasma acetaminophen level:
4 hours post ingestion - to determine probability of liver damage

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13
Q

What is the antidote for APAP poisoning? When is it used?

A

N-acetylcysteine (NAC, Mucomyst)

Decision of antidote treatment is based on timed plasma acetaminophen concentration - Rumack-Matthew nomogram

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14
Q

What are the Nomogram commandments?

A
  1. Only for single acute ingestion
    - APAP blood levels NOT obtained < 4 h after ingestion
    - Period of 4 h after ingestion was chosen to assume complete absorption & a peak plasma APAP level
  2. Unreliable when ingestion > 24 h
    - APAP levels may be undetectable even if significant hepatotoxicity
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15
Q

When is the APAP nomogram not applicable?

A
  1. Time of ingestion unknown
  2. Extended-release APAP
  3. Staggered overdose
  4. Chronic overdose exposure
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16
Q

What is the mechanism of NAC?

A
  1. NAC increases synthesis and availability of GSH
  2. Acts as intracellular GSH substitute by directly binding to NAPQI and detox
  3. Provides substrate for sulfation, which increases percentage of non-toxic detoxification
  4. Enhances reduction of NAPQI to APAP