Acetaminophen (paracetamol)

• At normal doses most of the drug is conjugated safely in the liver. A small amount is converted by CYP2E1 to the toxic metabolite NAPQI, which is neutralized by glutathione.
• In overdose, glutathione runs out → NAPQI binds liver cells → centrilobular hepatic necrosis. Chronic alcohol use, fasting or malnutrition, and some enzyme-inducing drugs raise the risk.
• Acetylcysteine (N-acetylcysteine, NAC) restores glutathione and helps detoxify NAPQI. It is almost completely protective when started within about 8–10 hours of ingestion and still helps when given late.

Salicylates (aspirin, methyl salicylate/oil of wintergreen)

• Stimulate the respiratory center → respiratory alkalosis first; uncouple oxidative phosphorylation → heat, lactic and ketoacids → anion-gap metabolic acidosis. Acidemia lets more salicylate enter the brain.

Opioids — mu-receptor agonists; overdose depresses the brainstem's response to CO₂ → slow, shallow breathing, hypoxia, and death. Naloxone is a competitive mu antagonist that displaces the opioid.

Benzodiazepines — enhance GABA-A chloride flow. Alone they rarely stop breathing in healthy adults; combined with opioids, alcohol, or other sedatives they cause serious respiratory depression. Flumazenil is a competitive benzodiazepine-site antagonist.

Acetaminophen assessment

• Toxic risk begins at an acute ingestion of about 150 mg/kg (lower threshold in high-risk clients).
• Draw the serum level at 4 hours or later after a single acute ingestion and plot on the Rumack–Matthew nomogram. In the US, a 4-hour level at or above the treatment line of 150 mcg/mL (993 µmol/L) calls for NAC. A level before 4 hours cannot be interpreted.
• The nomogram does not apply to repeated supratherapeutic ingestion, unknown time of ingestion, or late presentation — treat when the level is detectable or AST/ALT is raised. With extended-release products or co-ingested opioids or anticholinergics (slowed absorption), a second level is drawn.
• If the level cannot be obtained within 8 hours of ingestion, start NAC first and adjust later.

Acetylcysteine regimens (deliver at least 300 mg/kg in the first 20–24 hours)

NAC continues beyond the standard course until stopping criteria are met: the client is well, the acetaminophen level is below about 10 mcg/mL (66 µmol/L), INR is below 2, and AST/ALT are normal for the client or have fallen 25–50% from their peak. After a massive ingestion (e.g., a 4-hour-equivalent level of 300 mcg/mL [1,986 µmol/L] or more), a higher NAC dose is given as directed by a toxicologist.

Clinical stages of acetaminophen toxicity

1. 0–24 hours: none, or nausea, vomiting, malaise — a well-looking client can still be poisoned
2. 24–72 hours: right upper quadrant pain, rising AST/ALT
3. 72–96 hours: peak liver injury — jaundice, coagulopathy (rising INR), hypoglycemia, encephalopathy, kidney injury, lactic acidosis; transplant evaluation for fulminant failure
4. 4 days–2 weeks: recovery or death

• Acetylcysteine: no absolute contraindication in acetaminophen poisoning — even after an anaphylactoid reaction, it is usually restarted at a slower rate after antihistamine treatment. Caution with asthma. Safe in pregnancy; treatment protects the fetal liver too.
• Naloxone: use the smallest dose that restores breathing in opioid-dependent clients and those receiving opioids for pain (full reversal causes severe pain and withdrawal). Buprenorphine binds tightly and may need higher doses or an infusion. Xylazine sedation is not reversed, but naloxone is still given for the opioid component. Pregnancy: naloxone is given for maternal overdose; precipitated withdrawal may stress the fetus, so use titrated doses when possible.
• Flumazenil — avoid in chronic benzodiazepine users, clients with seizure disorders controlled by benzodiazepines, unknown mixed overdoses (especially tricyclic antidepressants), and signs of raised intracranial pressure. Its main safe use is reversing procedural oversedation in a benzodiazepine-naive client.
• Opioid + benzodiazepine, gabapentinoid, alcohol, or other CNS depressants → additive respiratory depression (boxed warning on opioids and benzodiazepines).
• Salicylate toxicity: avoid intubation if possible — if it is necessary, keep minute ventilation high, because letting CO₂ rise worsens acidemia and brain entry.
• Acetaminophen hidden in combination products (cold remedies, opioid combinations) leads to unintentional overdose.

Listed in priority order.

1. Breathing first in opioid or sedative overdose
   • Open the airway and ventilate with a bag-valve mask before or while naloxone is given
   • Naloxone: e.g., 0.4 mg IV/IM (or 4 mg intranasal in the community), repeated every 2–3 minutes; for clients on opioids for pain, dilute 0.4 mg to 10 mL and give 0.04 mg every 1–2 minutes until breathing improves
   • Target: respiratory rate and SpO₂ adequate, not full arousal; restrain the urge to "wake them fully"
2. Watch for recurrence — naloxone lasts about 30–90 minutes, shorter than many opioids (methadone, extended-release products, some fentanyl analogs). Monitor RR, SpO₂, sedation, and capnography; a naloxone infusion may be ordered. Methadone also prolongs QT — get an ECG.
3. Precipitated withdrawal — side-lying for vomiting, suction ready, reassurance; do not leave the client alone
4. Acetaminophen
   • Note the exact time of ingestion; draw the level at 4 hours or later, plus AST, ALT, INR, bilirubin, glucose, creatinine, and a salicylate level
   • Start NAC as ordered — do not wait for symptoms
   • IV NAC: infusion pump, check each bag's dose and time; watch closely during the first bag for flushing, rash, wheeze, hypotension → stop, notify, give antihistamine as ordered, then restart at a slower rate
   • Oral NAC: chill and mix with juice or soda, serve in a covered cup with a straw; repeat the dose if vomited within 1 hour; give antiemetic as ordered
   • Monitor for liver failure: glucose, mental status, bleeding, INR
5. Salicylate — serial levels (e.g., every 2 hours until falling), ABG, potassium, glucose (brain glucose can be low even with normal serum glucose); maintain urine pH about 7.5–8.0 with bicarbonate; replace potassium (alkalinization fails when K⁺ is low); prepare for dialysis
6. Benzodiazepine — airway, positioning, aspiration prevention; flumazenil only as ordered with seizure precautions
7. Safety and mental health — suicide precautions after intentional overdose; psychiatric evaluation when medically clear

• Adults: do not exceed the labeled maximum of acetaminophen (4 g/day; lower, often 2–3 g/day, with liver disease, heavy alcohol use, or low body weight) and read every label for acetaminophen or paracetamol in combination products
• Liquid pediatric products: use the syringe that comes with the product and dose by weight
• Opioids: never combine with alcohol, sleeping pills, or benzodiazepines unless the prescriber directs; store locked; dispose of leftovers safely
• Keep naloxone at home when someone uses opioids; family learns to recognize overdose (no response, slow or no breathing, blue lips, pinpoint pupils), give naloxone, call emergency services, give rescue breaths, and stay — a second dose may be needed
• Benzodiazepines: do not stop suddenly after long use (withdrawal seizures)
• Aspirin and oil of wintergreen: keep away from children; small amounts of oil of wintergreen are highly toxic

• Acetaminophen → acetylcysteine; best within 8–10 hours but never withheld for late presentation
• Draw the acetaminophen level at 4 hours or later; US treatment line 150 mcg/mL (993 µmol/L) at 4 hours
• Nomogram only for a single acute ingestion with a known time
• Early acetaminophen poisoning may look normal; liver injury peaks at 72–96 hours
• IV NAC reactions → stop, antihistamine, restart slower
• Opioid → naloxone, titrated to breathing; ventilate first; watch for resedation
• Naloxone lasts shorter than many opioids; methadone is long-acting
• Flumazenil can cause seizures — avoid in chronic benzodiazepine users and mixed overdoses
• Salicylates: tinnitus + tachypnea + mixed respiratory alkalosis/metabolic acidosis → bicarbonate, dialysis
• Check acetaminophen and salicylate levels in every intentional overdose