15. Drug toxicities

7.5 g/day in adults

Ingestion of ≥ 12 g in 24 hours is associated with a high risk of hepatotoxicity

• Exhaustion of hepatic metabolic pathways causes increased formation of a toxic metabolite of acetaminophen, N-acetyl-p-benzoquinoneimine (NAPQI).

  • Glutathione initially inactivates NAPQI, but its reserves are eventually depleted, leading to NAPQI build-up.

  • NAPQI → irreversible oxidative hepatocyte injury → liver cell necrosis

• Nonspecific symptoms (nausea, vomiting, pallor lethargy) or asymptomatic in the first 24 hours after ingestion

• Progressive liver impairment (RUQ pain, liver enlargement and tenderness, abnormal liver function tests)

• If acute liver failure does not develop, patients typically begin to recover within 2 weeks after ingestion.

• Acute kidney failure occurs in approx. 50% of patients with acute hepatic failure.

• Activated charcoal administered < 4 hours after ingestion (1 g/kg (maximum dose 50 g))

• Measure acetaminophen (APAP) levels 4 hours after ingestion (or immediately, if ingestion occurred > 4 hours prior to presentation)

• Antidote: PO or IV N-acetylcysteine (NAC)

• Administered 4–24 hours after ingestion

• NAC replenishes glutathione stores in the liver

• Indications

  • Serum acetaminophen level above the treatment line when measured 4 hours after ingestion

  • Single ingestion of acetaminophen > 150 mg/kg (7.5 g irrespective of patient weight) if the acetaminophen level cannot be assessed within 8 hours of ingestion

  • History of acetaminophen ingestion with signs of liver injury

  • High serum acetaminophen level (> 10 mcg/mL) with an unknown time of ingestion

• Treatment of liver failure

• Liver transplant in severe cases

a life-threatening condition caused by serotonergic overactivity

drugs that increase serotonin levels

• Antidepressants (e.g., MAOIs, SSRIs, SNRIs, TCAs,vortioxetine, vilazodone, trazodone)

• Anxiolytics (e.g., buspirone)

• Opioids (e.g., tramadol, meperidine)

• NMDA receptor antagonists (e.g., dextrometorphan)

• Recreational stimulants (e.g., MDMA, cocaine)

• Serotonin receptor antagonists (e.g., ondansetron)

• Serotonin receptor agonists (e.g., triptane)

• Antibiotics (e.g., linezolid)

• Herbals (e.g., St. John's wort)

• Risk-increasing factors

  • Concurrent use of two or more serotonergic drugs

  • Switching from one serotonergic drug to another without tapering

acute symptom onset (< 24 hours after intake of a drug that increases serotonin levels) [19]

• Classic triad

  • Neuromuscular excitability

  • Autonomic dysfunction

  • Altered mental status

• General: diaphoresis, hyperthermia

• Cardiovascular: hypertension, tachycardia

• Gastrointestinal: nausea, vomiting, diarrhea

• Psychiatric: delirium, psychomotor agitation, anxiety

• Neurological: hypertonia (especially in the lower extremities), hyperreflexia, myoclonus, tremor, clonus, horizontal ocular clonus, mydriasis, seizure, coma

• Diagnosis: is primarily based on patient history and clinical features.

• Differential diagnoses

  • See differential diagnosis of drug-induced hyperthermia

  • Meningitis

  • Encephalitis

• Immediate discontinuation of serotonergic drugs

• Supportive care

  • Antihypertensives, fluid replacement

  • Benzodiazepines for sedation

  • Cyproheptadine

    • H1, 5-HT1A, and 5-HT2A receptor antagonists

    • Used for cases of serotonin syndrome that do not respond to supportive care

  • Cooling measures: ice packs and cold compresses

• Prognosis: resolves within 24 hours with treatment

• Belladonna poisoning

• Jimson weed/Angel's trumpet (Datura stramonium) poisoning: The plant contains alkaloids, such as atropine and scopolamine, which lead to anticholinergic intoxication and mydriasis (“gardener's pupil”).

• Medications

  • Anticholinergic agents (e.g., atropine, benztropine, trihexyphenidyl)

  • Drugs with anticholinergic properties

    • Tricyclic antidepressives (predominantly doxepin, amitriptyline, imipramine, and trimipramine)

    • Antipsychotics (e.g., clozapine, quetiapine)

    • First-generation antihistamines (e.g., promethazine, dimenhydrinate)

• Dry mouth, warm, flushed skin, thirst, tachycardia, arrhythmias, mydriasis, confusion, and agitation

• Possibly anticholinergic delirium: Excessive use of tricyclic antidepressants (or other medications with significant anticholinergic effects) can cause life-threatening delirium, hallucinations, and psychomotor symptoms.

antidote for purely anticholinergic poisoning (e.g. atropine): physostigmine

Physostigmine is contraindicated in toxicity with tricyclic antidepressants, even in the case of severe anticholinergic symptoms, because it can cause cardiac arrest.

tinnitus, nausea, vomiting, tachypnea, hyperpnea

hyperthermia, agitation, delirium, seizures, noncardiogenic pulmonary edema

• ABG: mixed respiratory alkalosis and increased anion gap metabolic acidosis [2]

• Serum salicylate level: > 40 mg/dL [1]

• BMP: hypokalemia, ↑ BUN, ↑ creatinine

• Toxicology screen: evaluate for concurrent ingestions

• Stabilization of vitals

• Oral/orogastric activated charcoal

• IV sodium bicarbonate

• Hemodialysis