What are the symptoms of an antihistamine (anti-allergic medication) overdose in different patient populations, such as the elderly, young children, and individuals with pre-existing liver or kidney disease?

Antihistamine Overdose Symptoms

Antihistamine overdose presents primarily with anticholinergic toxicity, manifesting as central nervous system effects (sedation, confusion, psychosis, seizures), autonomic dysfunction (tachycardia, hyperthermia, dry mucous membranes, urinary retention), and potentially life-threatening cardiac dysrhythmias, with symptom severity and specific manifestations varying by generation of antihistamine and patient vulnerability. 1, 2, 3

Core Anticholinergic Syndrome

The hallmark presentation of first-generation antihistamine overdose includes:

• Central nervous system effects: Sedation progressing to confusion, agitation, hallucinations, psychosis, and potentially seizures 1, 2, 4
• Autonomic effects: Tachycardia, hyperthermia, dry mouth and eyes, flushed skin, and urinary retention 1, 2
• Pupillary changes: Typically mydriasis (dilated pupils), though miotic pupils have been paradoxically reported with cyproheptadine overdose 4

Cardiac Complications

Direct cardiac toxicity represents a critical concern, particularly with second-generation antihistamines (terfenadine, astemizole) but also occurring with first-generation agents:

• QT interval prolongation leading to torsades de pointes and potentially fatal dysrhythmias, especially with terfenadine and astemizole 2, 3
• Diphenhydramine-induced prolonged QT has been documented even with first-generation agents 3
• Second-generation antihistamines inhibit delayed outward rectifier potassium channels in myocardium, predisposing to dysrhythmias 2

Rare but Serious Complications

• Rhabdomyolysis: Non-traumatic muscle breakdown leading to myoglobinuria and acute renal failure, reported with diphenhydramine and doxylamine overdoses 1, 3
• Acute renal failure: Secondary to rhabdomyolysis 1
• Combined rhabdomyolysis and QT prolongation: Documented in diphenhydramine overdose cases 3

Population-Specific Symptom Patterns

Elderly Patients

Older adults demonstrate heightened sensitivity to antihistamine toxicity with distinct manifestations:

• Enhanced psychomotor impairment with increased fall risk, fractures, and subdural hematomas even at therapeutic doses 5, 6
• Severe anticholinergic effects: Pronounced dry mouth, constipation, urinary retention (especially problematic in men with prostatic hypertrophy), and narrow-angle glaucoma precipitation 5, 6
• Cognitive impairment and confusion that may be mistaken for dementia or delirium 5, 6
• Next-day sedation persisting beyond plasma drug levels, causing performance impairment without subjective awareness 5, 6

Young Children

• Sedation affecting learning ability occurs in more than 50% of children receiving therapeutic doses of first-generation antihistamines 2
• Life-threatening adverse events are unusual but have been described in pediatric overdoses 2
• School performance impairment with sedating antihistamines 5

Patients with Hepatic Impairment

Cirrhotic patients face unique and potentially catastrophic risks:

• Hepatic encephalopathy precipitation: First-generation antihistamines like hydroxyzine act as CNS depressants that can trigger life-threatening encephalopathy in cirrhosis 6
• Symptoms include: Confusion, asterixis, altered sleep-wake cycle 6
• Absolute contraindication in severe liver disease (Child-Pugh C) 6, 7

Patients with Renal Impairment

• Enhanced toxicity due to impaired drug clearance 7
• Dose-dependent symptom severity requiring 50% dose reduction in moderate renal impairment (creatinine clearance 10-20 mL/min) 7
• Complete avoidance necessary in severe renal impairment (creatinine clearance <10 mL/min) 7

Generation-Specific Toxicity Profiles

First-Generation Antihistamines (Diphenhydramine, Hydroxyzine, Cyproheptadine)

• Dominant anticholinergic syndrome with sedation exceeding 50% at therapeutic doses 5, 2
• Serious adverse events uncommon but life-threatening complications documented 2
• Rhabdomyolysis risk particularly with diphenhydramine and doxylamine 1, 3

Second-Generation Antihistamines (Terfenadine, Astemizole)

• Cardiotoxicity predominates with torsades de pointes as primary concern 2
• Requires immediate medical attention for excessive ingestions 2
• Ion channel inhibition causing dysrhythmias 2

Third-Generation Antihistamines (Fexofenadine, Loratadine, Desloratadine)

• Minimal toxicity in overdose 2
• Home management appropriate for accidental ingestions unless >3-4 times therapeutic daily dose 2
• Cetirizine exception: May cause sedation even at recommended doses, requiring monitoring 6, 2

Critical Clinical Pitfalls

Performance impairment occurs without subjective awareness of sedation, making patients unaware of their compromised state, particularly dangerous for driving and operating machinery 5, 6. This effect persists beyond measurable plasma drug levels, causing next-day impairment even with bedtime dosing 5, 6.

Concomitant CNS-active substances (alcohol, sedatives) dramatically enhance toxicity and performance impairment 5.

Antihistamines were found in 15% of all US drug overdose deaths from 2019-2020, often co-administered with fentanyl, with diphenhydramine being the most common antihistamine in these deaths 8.

Monitoring Requirements

No specific antidote exists for antihistamine overdose, making recognition of symptoms critical 2, 8:

• EKG monitoring essential if toxicity suspected, particularly for QT interval assessment 3
• Observation period: 2-3 hours minimum for third-generation overdoses 2
• Renal function monitoring for rhabdomyolysis (creatine kinase, myoglobin, renal function tests) 1, 3