In this episode I’ll focus on 2 examples of medication overdose that require more than supportive care to treat effectively:

1. Acetaminophen poisoning

2. Methanol & ethylene glycol poisoning

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A special shout out to my kids for the artwork & audio bumper for this episode!

Many poisons, few antidotes

Expert Consensus Guidelines for Stocking of Antidotes in Hospitals That Provide Emergency Care list just 21 antidotes to medications for stocking. Compare that to the over 1500 medications that have been approved by the FDA and it is readily apparent that most medications do not have antidotes.

Supportive care is the mainstay of treatment for overdose patients. Most medications, even when taken in overdose, will be safely cleared if a patient’s vital organ systems can be supported long enough.

But some overdose situations require an antidote in addition to supportive care for the the patient to survive.

Two common examples are acetaminophen poisoning and methanol or ethylene glycol poisoning.

Acetaminophen poisoning

At therapeutic doses, most acetaminophen is metabolized via sulfation and glucuronidation into safe metabolites and eliminated in the urine. About 8 % is metabolized via the hepatic cytochrome P450 pathway into the hepatotoxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI). This toxic metabolite is readily and safely neutralized by hepatic glutathione before any damage to hepatocytes can occur.

After the administration of a toxic dose of acetaminophen (generally considered to be 7.5 g or more in adults), the safe metabolic pathways of sulfation and glucuronidation are saturated, and more of the toxic NAPQI is produced. Hepatic glutathione stores eventually deplete and NAPQI begins to damage hepatocytes.

If only supportive care is given, NAPQI will continue to be formed and fulminant hepatic failure and death will ensue.

Antidote for acetaminophen

The antidote for acetaminophen toxicity – N-acetylcysteine (NAC) – restores hepatic glutathione stores, allowing NAPQI to be safely neutralized and preventing hepatic damage.

If N-acetylcysteine is given within 10 hours of ingestion of toxic doses of acetaminophen, prognosis is excellent.

N-acetylcysteine can be given IV or orally using either a 20 hour or 72 hour protocol.

The 20 hour protocol involves compounding three different bags of N-acetylcysteine for IV infusion:

1. A loading dose of 150 mg/kg IV over 60 minutes followed by:

2. 50 mg/kg IV over 4 hours followed by:

3. 100 mg/kg IV over 16 hours.

The 72 hour oral N-acetylcysteine protocol involves:

1. A loading dose of 140 mg/kg orally followed by:

2. 70 mg/kg orally every four hours for a total of 17 doses.

Oral N-acetylcysteine has a particularly unpleasant smell & taste which can be masked by mixing with ice, cola, and drinking quickly through a straw.

No study has compared the IV vs. oral protocols head-to-head.

The IV protocol is attractive because it takes less time and avoids the unpleasant taste of oral N-acetylcysteine. IV administration does carry a risk of anaphylactoid reaction which is rarely serious.

Interestingly, the hepatic first-pass effect brings oral N-acetylcysteine directly to the desired site of action.

Duration of treatment

Regardless of which protocol is used, N-acetylcysteine treatment should be extended if the acetaminophen level remains elevated when N-acetylcysteine treatment is scheduled to end. Shout out to Pharmacy Student Kaitlin who will be presenting on this topic in the near future!

If there is any doubt about whether to end or extend treatment with N-acetylcysteine, I always consult with poison control by calling 1-800-222-1222 from within the US.

Methanol or ethylene glycol poisoning

Until they are metabolized, methanol and ethylene glycol cause sedation but are otherwise non-toxic. However alcohol dehydrogenase converts these alcohols into highly toxic metabolites that lead to hypoxia and metabolic acidosis. In the case of methanol the metabolites also lead to permanent blindness and in the case of ethylene glycol the metabolites also lead to acute kidney injury.

If only supportive care is given toxic metabolites will continue to form. Antidote treatment involves inhibiting alcohol dehydrogenase.

Antidote for methanol or ethylene glycol

Two options are available for inhibiting alcohol dehydrogenase and the formation of toxic metabolites:

1. Fomepizole

2. Ethanol

Fomepizole

Fomepizole is highly effective, has few side effects, is simple to dose, but is expensive.

Give a 15 mg/kg IV loading dose followed by 10 mg/kg every 12 hours until the blood pH is normal and serum alcohol concentration is less than 20 mg/dL.

Ethanol

Using ethanol to treat methanol or ethylene glycol poisoning is problematic. Ethanol is irritating to veins and has significant CNS effects. Most troubling though is getting the ethanol dose right. Kyle DeWitt of EMPharmD.blogspot.com said it best:

Ethanol is a pharmacokinetic nightmare.

If I ever find myself needing to dose ethanol I’ll be starting with Kyle’s detailed post on the subject.

Cofactor use in methanol or ethylene glycol poisoning

In addition to inhibiting alcohol dehydrogenase, cofactors are administered to allow for maximal elimination of toxic metabolites by nontoxic pathways.

In the case of methanol poisoning, leucovorin 50 mg IV every 6 hours is given. In the case of methanol and ethylene glycol poisoning, 100 mg IV thiamine and 50 mg IV pyridoxine should be considered.

If you like this post, check out my book – A Pharmacist’s Guide to Inpatient Medical Emergencies: How to respond to code blue, rapid response calls, and other medical emergencies.

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