Toxicology – First-Generation OTC Antihistamines

Core Concept

Most traditional over-the-counter antihistamines are first-generation H1 receptor antagonists. Important examples include:

• Diphenhydramine
• Doxylamine
• Chlorpheniramine
• Brompheniramine
• Dimenhydrinate
• Meclizine
• Cyclizine
• Clemastine
• Cyproheptadine
• Triprolidine

Some older drugs listed in historical references are now rarely used, prescription-only in many regions, or discontinued.

These agents cross the blood–brain barrier much more readily than second-generation antihistamines.

Their overdose syndrome is primarily:

CNS toxicity + antimuscarinic toxicity

Large overdoses of certain agents, particularly diphenhydramine, can additionally produce:

Cardiac sodium-channel blockade → QRS widening → ventricular dysrhythmia

Severe poisoning may cause seizures, hyperthermia, rhabdomyolysis, coma, hypotension, and cardiac arrest.

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Mechanism

Therapeutically, these drugs competitively block H1 histamine receptors.

In overdose, many also antagonize muscarinic acetylcholine receptors.

This produces the classic antimuscarinic syndrome:

• Agitation/delirium
• Mydriasis
• Dry mucous membranes
• Dry, flushed skin
• Tachycardia
• Hyperthermia
• Reduced bowel motility
• Urinary retention

Some first-generation antihistamines also affect cardiac ion channels at high concentrations.

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CNS Effects

Because these agents readily enter the CNS, both depression and excitation can occur.

Possible manifestations include:

• Drowsiness
• Confusion
• Dysarthria
• Ataxia
• Agitation
• Hallucinations
• Delirium
• Seizures
• Coma

The clinical pattern varies with agent, dose, age, and coingestants.

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Antimuscarinic Delirium

Severe poisoning may produce a characteristic delirium with:

• Severe agitation
• Visual hallucinations
• Incoherent speech
• Disorientation
• Picking at imaginary objects
• Paranoia
• Repeated attempts to climb out of bed

Peripheral antimuscarinic findings often accompany the delirium.

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Classic Antimuscarinic Findings

A useful memory pattern is:

• Dilated pupils
• Dry mouth
• Dry skin
• Flushing
• Tachycardia
• Hyperthermia
• Reduced bowel sounds
• Urinary retention
• Delirium

However, not every finding must be present.

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Sedation vs Excitation

First-generation antihistamines can produce either:

CNS depression

• Somnolence
• Ataxia
• Coma
• Respiratory compromise in severe poisoning

CNS excitation

• Restlessness
• Agitation
• Hallucinations
• Tremor
• Seizures

Children may sometimes demonstrate prominent excitation, but this pattern is not exclusive to children.

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Diphenhydramine – Particularly Important

Diphenhydramine deserves special attention because a large overdose can produce more than a simple antimuscarinic syndrome.

It can cause:

• Severe delirium
• Seizures
• Fast sodium-channel blockade
• QRS widening
• Ventricular dysrhythmias
• QT abnormalities
• Hypotension
• Coma

Thus, severe diphenhydramine poisoning can resemble TCA poisoning.

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Doxylamine

Doxylamine is another important first-generation antihistamine found in some sleep and cold preparations.

Large exposures may cause:

• Antimuscarinic delirium
• Seizures
• Coma
• Rhabdomyolysis

Rhabdomyolysis may occasionally be substantial even without prolonged seizures.

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Dimenhydrinate

Dimenhydrinate is used for motion sickness.

It is pharmacologically related to diphenhydramine and can cause:

• Sedation
• Antimuscarinic delirium
• Hallucinations
• Seizures
• Cardiovascular toxicity after severe exposure

Some misuse occurs because of its psychoactive effects.

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Combination Products – Major Pitfall

Many OTC “cold,” “night,” “allergy,” and “sleep” products contain more than one active ingredient.

Possible coformulated substances include:

• Acetaminophen
• Dextromethorphan
• Pseudoephedrine
• Phenylephrine
• Other antihistamines

The accompanying ingredient can be more dangerous than the antihistamine itself.

Always identify the exact product and every active ingredient.

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Cardiovascular Effects

Mild/moderate toxicity commonly causes:

• Sinus tachycardia
• Mild hypertension

Severe poisoning may cause:

• QRS widening
• QT prolongation
• Ventricular ectopy
• Ventricular tachycardia
• Hypotension
• Cardiovascular collapse

The exact electrophysiologic effects differ among individual antihistamines.

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Sodium-Channel Blockade

Large diphenhydramine exposures can inhibit fast myocardial sodium channels.

This produces:

Na⁺-channel blockade → slowed ventricular conduction → QRS widening → ventricular dysrhythmia

The ECG may resemble that of a TCA overdose.

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ECG Findings

In significant poisoning, evaluate:

• Heart rate/rhythm
• PR interval
• QRS duration
• QT/QTc
• Ventricular ectopy
• Terminal QRS morphology

A prominent terminal R wave in aVR may occur with sodium-channel blockade but is not specific for a particular toxin.

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Sodium Bicarbonate

When clinically important sodium-channel blockade produces:

• QRS widening
• Ventricular conduction disturbance
• Ventricular dysrhythmia

Sodium bicarbonate is an important treatment.

It works through sodium loading and alkalinization.

Treatment should be guided by:

• ECG response
• Blood pressure
• Perfusion
• Acid–base status
• Electrolytes

Excessive alkalinization can cause complications and should be avoided.

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QT Prolongation

Some antihistamines can also interfere with cardiac potassium channels.

This can produce:

Delayed repolarization → QT prolongation → increased risk of polymorphic ventricular dysrhythmia

When important QT prolongation is present:

• Correct potassium
• Correct magnesium
• Correct other relevant electrolyte abnormalities
• Avoid additional QT-prolonging drugs

Torsades is managed with standard toxicologic resuscitation, including IV magnesium and electrical treatment when unstable.

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Seizures

Seizures are an important feature of severe first-generation antihistamine poisoning.

They can cause:

• Hypoxemia
• Lactic acidosis
• Hyperthermia
• Rhabdomyolysis
• Hyperkalemia
• Aspiration

Seizures and acidemia can also worsen cardiovascular toxicity.

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Seizure Treatment

Benzodiazepines are first-line.

Persistent toxicologic seizures may require:

• Additional benzodiazepines
• Phenobarbital
• Appropriate anesthetic treatment for refractory status epilepticus

Phenytoin is generally not preferred for toxicant-induced seizures, particularly when sodium-channel cardiotoxicity is also present.

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Hyperthermia

Hyperthermia can result from:

• Impaired sweating
• Severe agitation
• Seizures
• Excessive muscular activity

Severe hyperthermia can cause:

• Rhabdomyolysis
• Acute kidney injury
• Hepatic injury
• Coagulopathy
• CNS injury

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Hyperthermia Management

Priorities include:

• Control agitation
• Control seizures
• Remove excessive clothing
• Active external cooling
• Appropriate IV fluids
• Monitor core temperature

Antipyretics are ineffective because this is toxicologic hyperthermia, not a hypothalamic fever response.

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Rhabdomyolysis

Rhabdomyolysis may follow:

• Seizures
• Severe agitation
• Hyperthermia
• Prolonged immobilization
• Doxylamine toxicity itself

Evaluate significant cases with:

• CK
• Potassium
• Creatinine
• Urinalysis
• Urine output

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Urinary Retention

Antimuscarinic blockade can cause substantial bladder retention.

A distended bladder can worsen:

• Agitation
• Delirium
• Tachycardia

Clinically significant retention may require bladder decompression.

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GI Effects

Antimuscarinic activity reduces gastrointestinal motility.

Possible findings include:

• Reduced bowel sounds
• Constipation
• Abdominal distension
• Ileus in severe cases

Slowed gastric emptying may contribute to prolonged absorption after large ingestion.

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Respiratory Complications

Severe CNS depression or seizures may lead to:

• Loss of airway reflexes
• Hypoventilation
• Aspiration
• Hypoxemia

Airway management takes priority over decontamination.

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Diagnosis

The diagnosis is usually clinical.

Important history includes:

• Exact product
• All active ingredients
• Amount
• Timing
• Formulation
• Intent
• Coingestants

Do not assume every OTC “allergy” or “sleep” medication contains only an antihistamine.

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Laboratory Evaluation

A minimally symptomatic patient after a clearly identified small exposure may need little laboratory testing.

Significant poisoning may warrant:

• Glucose
• Electrolytes
• Bicarbonate
• Creatinine
• CK
• Blood gas/lactate in severe cases

Acetaminophen testing is often appropriate after intentional ingestion because combination products and occult coingestion are common.

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Urine Drug Screening

Routine urine toxicology screening is generally not useful for diagnosing antihistamine poisoning.

Immunoassays have:

• False positives
• False negatives
• Cross-reactivity
• Limited ability to establish causation

A positive urine result demonstrates possible exposure, not necessarily the cause of the syndrome.

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Neurodiagnostic Testing

Head CT, lumbar puncture, cultures, or other neurologic investigations are not routinely required when the toxidrome and exposure are clear.

Consider them when:

• Diagnosis is uncertain
• Focal neurologic findings occur
• Trauma is possible
• CNS infection is suspected
• Seizures or altered consciousness have an atypical course

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Initial Management

Priorities are:

Airway/breathing → agitation/seizure control → core temperature → ECG → circulation → complications

A calm, low-stimulation environment can reduce worsening agitation.

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Agitation

Benzodiazepines are appropriate for significant agitation, particularly when:

• The exposure is uncertain
• Seizures are a concern
• A mixed overdose is possible
• Physostigmine is inappropriate

Physical restraint alone can worsen:

• Muscular activity
• Hyperthermia
• Acidosis
• Rhabdomyolysis

If restraint is temporarily required for safety, adequate chemical sedation and frequent reassessment are important.

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Physostigmine – Modern Role

The older description of physostigmine primarily as a diagnostic test is outdated.

Physostigmine can be a therapeutic treatment for carefully selected patients with severe, predominantly pure antimuscarinic delirium.

It may rapidly reverse:

• Delirium
• Hallucinations
• Severe agitation
• Confusion

Its use requires careful patient selection and monitoring.

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When Physostigmine May Be Considered

The patient should have a convincing antimuscarinic syndrome with significant central delirium and no strong evidence of another dangerous toxic mechanism.

Before considering it, evaluate:

• ECG
• QRS duration
• Rhythm
• Coingestants
• Seizure risk

Toxicology/poison-center guidance is appropriate.

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When Physostigmine Should Be Avoided

Avoid or use extreme caution with:

• QRS widening
• Suspected TCA poisoning
• Significant sodium-channel blockade
• Important conduction disease
• Bradycardia
• High-risk proconvulsant ingestion
• Uncertain mixed overdose

These are much more clinically important contraindications than some of the broad historical lists involving conditions such as diabetes.

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Physostigmine Adverse Effects

Excessive cholinergic activity may cause:

• Bradycardia
• Salivation
• Sweating
• Bronchial secretions
• Nausea/vomiting
• Diarrhea
• Hypotension
• Seizures

It should therefore be used in a monitored environment with resuscitation capability.

Symptoms may recur because physostigmine can have a shorter duration than the causative antihistamine.

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Hypotension

Potential causes include:

• Severe sodium-channel toxicity
• Dysrhythmia
• Dehydration
• Acidemia
• Coingestants

Management includes:

• Appropriate isotonic crystalloid
• Correction of cardiotoxicity
• Treatment of dysrhythmia
• Vasopressor support when required

For persistent vasodilatory shock, norepinephrine is generally favored over an automatic dopamine-first strategy.

Trendelenburg positioning is obsolete.

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GI Decontamination

Do not induce vomiting.

Ipecac has no modern role.

Routine gastric lavage is obsolete.

A single dose of activated charcoal may occasionally be considered after a substantial recent ingestion when:

• The drug is adsorbable
• The airway is reliably protected
• Aspiration risk is acceptable

Delayed gastric emptying from antimuscarinic effects does not automatically justify late lavage or repeated charcoal.

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Extracorporeal Elimination

Hemodialysis and hemoperfusion are generally ineffective for first-generation antihistamine poisoning because these drugs typically have pharmacokinetic characteristics unfavorable for extracorporeal removal.

Treatment remains primarily supportive.

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Differential Diagnosis

Antimuscarinic-like toxicity can occur with:

• Atropine/scopolamine
• TCAs
• Antipsychotics
• Antiparkinsonian drugs
• Antispasmodics
• Datura species
• Other antimuscarinic plants or medications

Agitated patients with tachycardia and mydriasis may instead have:

• Amphetamine toxicity
• Cocaine toxicity
• Serotonin toxicity

A useful distinction is:

Antimuscarinic → usually dry

Sympathomimetic → usually sweaty

But no single sign is completely reliable.

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Observation

The historical universal 6–12-hour rule should not be applied mechanically.

Observation depends on:

• Exact antihistamine
• Formulation
• Amount
• Symptoms
• ECG
• Mental-status trajectory
• Seizures
• Coingestants
• Combination-product ingredients

Large antimuscarinic ingestions can have prolonged effects because GI motility is reduced.

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Admission

Monitored admission is appropriate for:

• Significant delirium
• Persistent altered mental status
• Seizure
• Hyperthermia
• QRS widening
• Important QT prolongation
• Ventricular dysrhythmia
• Persistent hypotension
• Rhabdomyolysis
• Respiratory compromise

Severe cardiotoxicity, recurrent seizures, extreme hyperthermia, or coma warrants ICU care.

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Pregnancy

Historical FDA pregnancy letter categories are obsolete.

Management of significant poisoning during pregnancy prioritizes maternal:

• Airway
• Oxygenation
• Temperature
• Seizure control
• Hemodynamics
• Cardiac rhythm

Treatment decisions should be based on the specific drug and clinical situation rather than the old A/B/C/D/X categories.

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Safeguarding

Rigid historical age thresholds for assuming neglect, abuse, or intentional poisoning are inappropriate.

Pediatric poisoning should instead be assessed according to:

• Developmental capability
• Medication access
• Exposure circumstances
• Consistency of the history
• Recurrent unexplained events
• Broader safeguarding concerns

Intentional self-poisoning requires appropriate safety assessment after medical stabilization.

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Prognosis

Most mild and moderate antihistamine poisonings recover completely with supportive care.

Severe complications include:

• Status epilepticus
• Extreme hyperthermia
• Aspiration
• Rhabdomyolysis
• Acute kidney injury
• QRS widening
• Ventricular dysrhythmia
• Shock
• Hypoxic brain injury

Large diphenhydramine or doxylamine exposures deserve particular caution.

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Important Modernization of the Older Source

• The clinically important OTC agents are predominantly first-generation H1 antihistamines.
• Toxicity is not purely antimuscarinic; some agents, especially diphenhydramine, also block myocardial sodium channels.
• Severe diphenhydramine poisoning can resemble TCA poisoning.
• Doxylamine is particularly associated with severe CNS toxicity and rhabdomyolysis after substantial exposure.
• Combination products are a major source of additional toxicity; always identify every active ingredient.
• Benzodiazepines are first-line for agitation and seizures.
• Phenytoin is generally not preferred for toxicologic seizures.
• Sodium bicarbonate is important for clinically significant antihistamine-associated sodium-channel blockade/QRS widening.
• Physostigmine is a therapeutic option for carefully selected pure antimuscarinic delirium, not merely a diagnostic test.
• Physostigmine should generally be avoided when QRS widening, TCA exposure, significant sodium-channel blockade, or a dangerous mixed ingestion is suspected.
• Routine urine drug screening has limited diagnostic value.
• Antipyretics do not treat toxicologic hyperthermia.
• Ipecac and routine gastric lavage are obsolete.
• Antimuscarinic delayed gastric emptying does not justify routine late lavage or repeated charcoal.
• Trendelenburg and routine dopamine-first treatment of shock are outdated.
• Fixed observation periods should be replaced by agent-, symptom-, ECG-, and trajectory-based assessment.

Key Points

• First-generation antihistamine overdose = antimuscarinic + CNS toxicity.
• Typical findings: tachycardia, mydriasis, dry skin/mouth, hyperthermia, urinary retention, agitation, hallucinations, and delirium.
• Severe poisoning can cause seizures, coma, QRS widening, ventricular dysrhythmias, hypotension, and rhabdomyolysis.
• Diphenhydramine can cause clinically important sodium-channel blockade.
• Benzodiazepines are first-line for agitation and seizures.
• Sodium bicarbonate is used for significant QRS widening/sodium-channel cardiotoxicity.
• Physostigmine is reserved for carefully selected predominantly pure antimuscarinic delirium.
• Always check for acetaminophen, dextromethorphan, decongestants, or other ingredients in combination products.
• Management is primarily supportive, ECG-directed, and complication-focused.