Can the tachycardia in my 16‑year‑old patient taking chlorpromazine (Thorazine) 100 mg daily and diphenhydramine (Benadryl) 50 mg daily be due to anticholinergic effects?

Can Tachycardia in a 16-Year-Old on Chlorpromazine and Diphenhydramine Be Due to Anticholinergic Effects?

Yes, the tachycardia in your patient is very likely due to additive anticholinergic effects from the combination of chlorpromazine (Thorazine) and diphenhydramine (Benadryl), both of which possess significant anticholinergic properties that can cause sinus tachycardia.

Mechanism of Anticholinergic-Induced Tachycardia

• Anticholinergic medications block muscarinic receptors in the heart, removing parasympathetic (vagal) tone on the sinoatrial node, which directly increases heart rate 1
• Chlorpromazine (phenothiazine antipsychotic) has well-documented anticholinergic properties including dry mouth, constipation, urinary retention, and tachycardia 1
• Diphenhydramine is a potent anticholinergic agent that commonly causes tachycardia as part of the classic anticholinergic toxidrome (hyperthermia, mydriasis, dry flushed skin, altered mental status, urinary retention, and tachycardia) 2, 3

Additive Risk from Combination Therapy

• The concurrent use of chlorpromazine 100 mg daily plus diphenhydramine 50 mg daily creates additive anticholinergic burden, exponentially increasing the risk of anticholinergic side effects including tachycardia 1
• Antipsychotics with higher binding affinity to muscarinic M2 receptors (the cardiac subtype) carry greater risk of tachycardia and atrial fibrillation 1
• Young age (16 years) is a risk factor for acute dystonic reactions from antipsychotics, which may explain why diphenhydramine was prescribed, but this creates the problematic anticholinergic combination 4

Critical Differential Considerations

While anticholinergic effects are the most likely explanation, you must also consider:

• Sodium channel blockade: Both diphenhydramine and chlorpromazine possess sodium channel-blocking properties that can cause wide-complex tachycardia, QRS prolongation, and ventricular arrhythmias at toxic doses 2, 3, 5
• QTc prolongation: Chlorpromazine has significant QTc effects and can cause drug-induced atrial fibrillation, particularly in patients with hypertension, diabetes, or coronary artery disease 1, 6
• Diphenhydramine can prolong the QTc interval and has been associated with torsades de pointes-like ventricular arrhythmias in overdose 7

Immediate Assessment Algorithm

Step 1: Obtain a 12-lead ECG immediately 6

• Measure the QTc interval (normal <450 ms in males, <460 ms in females) 6
• Assess QRS duration (normal <120 ms); widening suggests sodium channel blockade 2, 3
• Look for a terminal R wave in aVR, which indicates sodium channel toxicity 2

Step 2: Check vital signs and anticholinergic signs 2, 3

• Document heart rate, blood pressure, temperature
• Examine pupils (mydriasis?), skin (dry, flushed?), mucous membranes (dry mouth?)
• Assess for urinary retention, decreased bowel sounds

Step 3: Obtain serum electrolytes 1, 6

• Hypokalemia and hypomagnesemia potentiate QTc prolongation and arrhythmias 1, 6
• Correct potassium to >4.5 mEq/L and normalize magnesium before attributing tachycardia solely to medications 6

Management Recommendations

If tachycardia is simple sinus tachycardia with normal QRS and QTc <500 ms:

• Discontinue diphenhydramine immediately 1, 6
• Consider reducing chlorpromazine dose or switching to aripiprazole (0 ms QTc prolongation, minimal anticholinergic effects) 6
• Benztropine 1-2 mg IM/IV can be used for dystonia prophylaxis if that was the indication for diphenhydramine, avoiding the anticholinergic burden of chronic diphenhydramine 4

If QTc >500 ms or QRS >120 ms:

• Stop both chlorpromazine and diphenhydramine immediately 6
• Administer sodium bicarbonate 1-2 mEq/kg IV if QRS prolongation is present (evidence of sodium channel blockade) 2, 3, 5
• Implement continuous cardiac monitoring 6
• Correct all electrolyte abnormalities urgently 6

If wide-complex tachycardia or ventricular arrhythmia:

• Treat as sodium channel blockade toxicity with IV sodium bicarbonate boluses until QRS narrows 2, 3, 5
• Avoid class IA and IC antiarrhythmics, which will worsen sodium channel blockade 1
• Consider ICU admission for continuous monitoring 3

Long-Term Antipsychotic Strategy

• Switch from chlorpromazine to aripiprazole (0 ms mean QTc prolongation, no anticholinergic effects, lowest risk profile for cardiovascular complications in adolescents) 6
• If dystonia prophylaxis is needed, use scheduled benztropine 1-2 mg daily rather than diphenhydramine, as it provides targeted anticholinergic effect without the excessive sedation and cardiac risks 4
• Obtain baseline and follow-up ECGs at 7-15 days after any antipsychotic change 6

Common Pitfalls to Avoid

• Never combine multiple anticholinergic medications without recognizing the additive cardiac effects 1, 6
• Do not attribute tachycardia solely to anxiety or agitation without obtaining an ECG to rule out QTc prolongation or wide-complex rhythms 6, 2
• Failing to correct electrolyte abnormalities before attributing QTc changes to medication can lead to inappropriate management decisions 6
• Do not use physostigmine (a cholinesterase inhibitor sometimes used for anticholinergic toxicity) if there is any evidence of QRS widening, as it can precipitate seizures and asystole 3

High-Risk Features Requiring Immediate Action

• QTc >500 ms: discontinue all QT-prolonging medications immediately 6
• QRS >120 ms: administer sodium bicarbonate and prepare for possible advanced cardiac life support 2, 3
• Female gender and electrolyte abnormalities significantly increase risk of torsades de pointes 1, 6
• Seizures in the setting of anticholinergic toxicity suggest severe diphenhydramine toxicity requiring aggressive airway management and benzodiazepines (not physostigmine) 3