What toxicities can cause anticholinergic effects and seizures?

Toxicities Causing Both Anticholinergic Effects and Seizures

Tricyclic antidepressants (TCAs), diphenhydramine, and other sodium channel blockers are the primary toxicities that cause both anticholinergic effects and seizures. 1

Primary Offending Agents

Tricyclic and Tetracyclic Antidepressants

• TCAs are the most commonly described and best-studied agents causing this dual toxicity, including amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, maprotiline, nortriptyline, protriptyline, and trimipramine 1
• These agents block cardiac sodium channels while simultaneously producing potent anticholinergic effects 1
• Seizures occur as a direct CNS toxic effect, while anticholinergic manifestations include dry mouth, blurred vision, dilated pupils, urinary retention, and decreased bowel sounds 2, 3
• Dosulepin (dothiepin) and amitriptyline appear particularly likely to cause seizures and are more toxic than other TCAs 4

Antihistamines

• Diphenhydramine is a well-documented cause of both anticholinergic toxicity and seizures, with status epilepticus reported in overdose 5
• The serum diphenhydramine concentration in documented cases of status epilepticus has reached 1200 ng/mL (therapeutic range 9-120 ng/mL) 5
• Diphenhydramine produces sodium channel blockade in addition to anticholinergic and antihistaminergic effects 5

Other Sodium Channel Blockers with Anticholinergic Properties

• Carbamazepine, lamotrigine, and other anticonvulsants listed as sodium channel blockers can produce both seizures and anticholinergic effects 1
• Cocaine causes seizures through sodium channel blockade and can produce anticholinergic-like sympathomimetic effects 1

Clinical Presentation Algorithm

Anticholinergic Features to Identify

• Central effects: Agitated delirium, confusion, hallucinations, altered mental status 1, 6
• Cardiovascular: Tachycardia, mild hypertension 1, 6
• Pupils: Mydriasis (dilated pupils) 1, 6
• Skin: Hot, dry, erythematous skin with absent sweating 1, 6
• Mucous membranes: Dry mouth and mucous membranes 1, 6
• Gastrointestinal: Hypoactive or absent bowel sounds, decreased motility 1, 6
• Genitourinary: Urinary retention 6, 7
• Temperature: Mild hyperthermia (typically <38.8°C) 1

Seizure Characteristics

• Generalized tonic-clonic seizures are most common with TCA and diphenhydramine toxicity 2, 5
• Status epilepticus can occur, particularly with diphenhydramine overdose 5
• Seizures typically occur within 4 hours of overdose with TCAs 2
• Coma is the most useful predictor of severe toxic complications including seizures 4

Distinguishing ECG Features

• QRS prolongation >100 ms is characteristic of sodium channel blocker toxicity and helps distinguish these agents from pure anticholinergic toxins 1, 8
• Terminal rightward axis deviation in lead aVR is highly specific for sodium channel blockade 1
• PR and QT interval prolongation occur with TCAs 2, 3
• Wide-complex tachycardia may develop 5, 8

Management Priorities

Immediate Interventions

• Secure airway, breathing, and circulation as rapid deterioration is common 6, 3
• Administer benzodiazepines (diazepam or lorazepam) as first-line therapy for seizures 1, 6
• Obtain 12-lead ECG immediately to assess QRS duration 6, 8

Sodium Bicarbonate Administration

• Administer 1-2 mEq/kg IV boluses of sodium bicarbonate if QRS duration >100 ms or ventricular dysrhythmias present 1
• Target arterial pH >7.45, or 7.50-7.55 in severe intoxication 1
• Sodium bicarbonate is indicated even for diphenhydramine toxicity with wide-complex tachycardia 5
• Repeat boluses as needed and consider continuous infusion (150 mEq NaHCO3 per liter D5W) 1

Physostigmine Considerations

• Physostigmine is CONTRAINDICATED when QRS prolongation or wide-complex tachycardia is present 6, 2, 5
• This is a critical pitfall: while physostigmine reverses anticholinergic effects, it can worsen cardiac conduction abnormalities and precipitate asystole in sodium channel blocker toxicity 2, 5
• Physostigmine may only be considered for pure anticholinergic toxicity without cardiac conduction abnormalities 6, 9
• Adult dosing when appropriate: 1-2 mg IV slowly over 5 minutes 6
• Pediatric dosing: 0.02 mg/kg IV (maximum 0.5 mg/dose) 6

Seizure Management

• Benzodiazepines remain first-line for seizure control (diazepam or lorazepam) 1, 6
• If seizures persist despite benzodiazepines, proceed to endotracheal intubation with propofol infusion 5
• Avoid physostigmine for seizure control when sodium channel blockade is present 2, 5
• Muscular paralysis and mechanical ventilation may be required for refractory status epilepticus, but avoid succinylcholine 1, 6

Hypotension Management

• Administer 10-20 mL/kg boluses of normal saline initially 1, 8
• Norepinephrine or epinephrine are more effective than dopamine for TCA-induced hypotension 1
• Direct-acting vasopressors are preferred over indirect agents 1

Additional Supportive Measures

• Activated charcoal 30-50 g if recent ingestion and airway protected 6, 8
• Avoid Class IA (quinidine, procainamide), Class IC (flecainide, propafenone), and Class III (amiodarone, sotalol) antiarrhythmics as they exacerbate sodium channel blockade 1
• External cooling for hyperthermia 6
• Bladder catheterization for urinary retention 6
• Consider ECMO for refractory cardiogenic shock 1

Critical Pitfalls to Avoid

The Physostigmine Trap

• Never administer physostigmine when ECG shows QRS prolongation, conduction delays, or dysrhythmias 6, 2, 5
• The presence of anticholinergic signs does not automatically indicate physostigmine use—always check the ECG first 5
• Physostigmine has short duration of action (45-60 minutes) and can produce dangerous bradycardia and asystole in sodium channel blocker toxicity 9, 2

Monitoring Duration

• Life-threatening complications typically occur within 24 hours of ingestion but ECG changes may take up to one week to fully resolve 3
• Continuous cardiac monitoring for at least 6 hours after symptom resolution 6
• Maximal QRS prolongation usually present within 12 hours 3

Distinguishing from Other Syndromes

• Unlike serotonin syndrome, anticholinergic toxicity presents with dry skin (not diaphoretic), absent bowel sounds (not hyperactive), and normal muscle tone (not increased rigidity with clonus) 1, 10
• Unlike neuroleptic malignant syndrome, onset is rapid (minutes to hours vs. days) and muscle tone is normal rather than "lead pipe" rigid 1