August 31, 2015 - Acetaminophen

Question 1

Dose-Dependent Toxicity

Answer 1

Is a small list of drugs that have a predictable injury.

Question 2

Dose-Independent Toxicity

Answer 2

Are unpredictable and idiosyncratic. There is a long list of drugs that can cause this.

Question 3

Anti-Pyretic

Answer 3

A drug that counteracts a fever. Tylenol is an example of this.

Question 4

Maximum Daily Dose of Acetaminophen

Answer 4

4000mg

Doses of 7-10 grams may cause toxicity.

Doses of >12g will likely cause toxicity.

Question 5

Phases of Drug Metabolism

Answer 5

Phase I: Alters the parent molecule through oxidation / reduction / hydrolysis

Phase II: Conjugates the molecule/metabolite with a water-soluble moiety

Phase III: Excretes the molecule/metabolite/conjugate into bile

~90% of acetaminophen is metabolized via conjucation (phase II). Specifically glucoronidation and sulfation.

Question 6

Acetaminophen and Cytochrome P450

Answer 6

Around 10% of acetaminophen is metablozed by oxidative processes (phase I) by using the cytochrome P450 complex. This yields a toxic metabolite No-acetyl-p-benzo-quinone-imine (NAPQI).

NAPQI is rapidly conjugated with glutathione forming non-toxic compounds.

With toxic doses, more acetaminophen is converted to the toxic NAPQI and the glutathione stores are depleted, allowing NAPQI to cause oxidative injury and hepatocellular necrosis.

Question 7

Clinical Course of Acetaminophen Toxicity

Answer 7

Stage 1 (0.5 - 24 hours): asymptomatic, N/V, diaphoresis, lethargy, normal laboratory studies

Stage 2 (24-72 hours): initial symptom improvement, then RUQ pain, AST/ALT, INR and bilirubin elevation begins, as well as nephrotoxicity.

Stage 3 (72-96 hours): N/V reappears along with jaundice, encephalopathy, bleeding diathesis, hypoglycemia, lactic acidosis, renal failure, and potentially death.

Stage 4 (4-14 days): Recovery, which is typically complete.

Question 8

Chronic Alcohol and Acetaminophen

Answer 8

Cytochrome P450 also metabolizes ethanol. This upregulates the enzymes which causes more acetaminophen to be converted to NAPQI. As a double-whammy, alcohols also have a decreased level of glutathione which causes NAPQI to stick around longer and cause liver injury.

Question 9

Therapeutic Misadventure

Answer 9

An unintentional overdose.

Question 10

Management of Acetaminophen Toxicity

Answer 10

Take a serum [acetaminophen] as well as a good patient history.

Consider administering N-acetylcysteine (NAC). This can seriously reduce the risk of complications. Use the nomogram to determine if NAC administration is required.

Acetaminophen is the #1 cause of acute liver failure.