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Some older drugs listed in historical references are now rarely used, prescription-only in many regions, or discontinued.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

Toxicology – Second-Generation (“Nonsedating”) Antihistamines

Core Concept

The older term “nonsedating antihistamines” generally refers to second-generation H1 antihistamines.

Modern examples include:

• Cetirizine
• Levocetirizine
• Loratadine
• Desloratadine
• Fexofenadine
• Acrivastine in some regions

These agents penetrate the CNS less readily than first-generation antihistamines and therefore usually produce less sedation and fewer antimuscarinic effects.

Most isolated overdoses are relatively mild.

The major cardiac toxicity emphasized in older literature—marked QT prolongation and torsades—was primarily associated with astemizole and terfenadine, drugs that have been withdrawn or are no longer routinely marketed in many countries.

Historical Agents – Astemizole and Terfenadine

Astemizole and terfenadine are important historically because they demonstrated that an apparently “nonsedating” antihistamine could still cause severe cardiac toxicity.

Both could block cardiac repolarizing potassium currents and produce:

QT prolongation → early afterdepolarizations → torsades de pointes → ventricular fibrillation/cardiac arrest

Risk became especially important when their metabolism was inhibited by interacting medications.

Modern second-generation antihistamines generally have a much more favorable cardiac safety profile.

Mechanism

Second-generation antihistamines primarily antagonize peripheral H1 receptors.

H1 blockade reduces allergic manifestations such as:

• Pruritus
• Sneezing
• Rhinorrhea
• Urticaria

Their limited CNS penetration accounts for less sedation compared with agents such as diphenhydramine.

However, “nonsedating” is not absolute.

Cetirizine

Cetirizine is relatively more likely than some other second-generation agents to cause:

• Drowsiness
• Fatigue
• Dizziness

Overdose usually produces mild CNS effects rather than severe cardiotoxicity.

Loratadine

Loratadine and its active metabolite desloratadine generally have limited CNS penetration.

Overdose may produce:

• Somnolence
• Headache
• Tachycardia

Serious isolated cardiotoxicity is uncommon.

Fexofenadine

Fexofenadine is the active metabolite related to the older drug terfenadine.

Unlike terfenadine, it has substantially less potential for clinically important cardiac potassium-channel blockade.

This explains why:

Terfenadine → important historical torsades risk

whereas:

Fexofenadine → much lower cardiac risk

Most isolated fexofenadine overdoses are mild.

Acrivastine

Acrivastine can produce:

• Drowsiness
• Dizziness
• Headache
• GI symptoms

Some preparations contain pseudoephedrine.

This distinction is crucial because toxicity from a combination product may reflect the sympathomimetic component rather than the antihistamine.

Combination Products

Always determine whether the preparation contains another active ingredient.

Examples include antihistamine products combined with:

• Pseudoephedrine
• Other decongestants
• Analgesics in some formulations

Pseudoephedrine can produce:

• Agitation
• Tremor
• Tachycardia
• Hypertension
• Insomnia

Therefore, a markedly hyperadrenergic presentation after an “antihistamine” ingestion should prompt inspection of the actual formulation.

Toxic Dose

There is no single useful toxic-dose threshold covering all second-generation antihistamines.

For currently used agents, isolated accidental overdose generally has a relatively wide safety margin.

Risk assessment should consider:

• Exact agent
• Amount
• Patient age/size
• Symptoms
• Coingestants
• Combination-product ingredients
• Renal/hepatic impairment where relevant

Historical astemizole and terfenadine toxicity should not be extrapolated directly to modern agents.

Clinical Features

Most uncomplicated overdoses produce only:

• Drowsiness
• Dizziness
• Headache
• Nausea
• Dry mouth
• Mild tachycardia

Large exposures may occasionally produce:

• Agitation
• Tremor
• Ataxia
• Significant somnolence

Severe neurologic or cardiovascular toxicity should prompt consideration of another agent or coingestant.

Sedation

The label “nonsedating” is misleading if interpreted literally.

Second-generation antihistamines cause less CNS H1 blockade, but some sedation remains possible.

Cetirizine is particularly associated with somnolence compared with fexofenadine.

Antimuscarinic Effects

Modern second-generation antihistamines generally have much weaker antimuscarinic effects than first-generation agents.

Prominent findings such as:

• Severe delirium
• Marked mydriasis
• Very dry skin
• Urinary retention
• Ileus
• Major QRS widening

should raise concern for:

• Diphenhydramine
• Doxylamine
• Another first-generation antihistamine
• TCA
• Another antimuscarinic/sodium-channel blocker
• Mixed ingestion

Cardiovascular Effects

With current second-generation agents, cardiovascular effects are usually limited.

Possible findings include:

• Mild tachycardia
• Occasionally palpitations

Major ventricular dysrhythmia is uncommon in isolated overdose of modern agents.

Astemizole Cardiotoxicity

Historical astemizole toxicity could produce:

• QT prolongation
• Syncope
• Torsades de pointes
• Ventricular dysrhythmia
• Hypotension
• Cardiovascular collapse

Its prolonged pharmacokinetics also allowed delayed toxicity.

These historical features explain the prolonged monitoring recommendations in older texts but should not automatically be applied to cetirizine, loratadine, or fexofenadine.

Drug Interactions – Historical Lesson

Astemizole and terfenadine depended heavily on hepatic metabolism.

Inhibition of their metabolism could increase parent-drug concentrations and markedly increase QT-related toxicity.

Historically important interacting drugs included some:

• Azole antifungals
• Macrolide antibiotics
• CYP inhibitors

This interaction was one of the major reasons these drugs disappeared from routine clinical use.

QT Prolongation – Modern Approach

If clinically important QT prolongation occurs:

• Review the exact antihistamine
• Look for coingestants
• Check potassium
• Check magnesium
• Consider calcium when appropriate
• Review other QT-prolonging medications
• Consider congenital/acquired long-QT conditions

Marked QT prolongation should not automatically be attributed to a modern second-generation antihistamine.

Torsades de Pointes

If torsades develops:

• Stop QT-prolonging drugs
• Correct hypokalemia
• Correct hypomagnesemia
• Give IV magnesium
• Treat unstable ventricular dysrhythmia electrically

Recurrent pause-dependent torsades associated with bradycardia may require heart-rate acceleration, including selected use of overdrive pacing.

Avoid adding medications that further prolong the QT interval.

Neurologic Effects

Large exposures may cause:

• Somnolence
• Dizziness
• Headache
• Tremor
• Agitation
• Ataxia

Seizures are unusual with modern second-generation antihistamines.

If seizures occur, evaluate for:

• Large/mixed ingestion
• First-generation antihistamine
• Sympathomimetic combination product
• Other proconvulsant
• Metabolic or neurologic cause

Seizure Treatment

Benzodiazepines are first-line therapy for toxicant-induced seizures.

Persistent seizures may require:

• Additional benzodiazepines
• Phenobarbital
• Appropriate anesthetic status-epilepticus treatment

The older recommendation to routinely progress to phenytoin is outdated; phenytoin is generally not preferred for toxicologic seizures.

Hepatic Effects

Rare liver injury has been reported with antihistamines, but it is not a defining manifestation of acute second-generation antihistamine overdose.

Liver testing should therefore be driven by:

• Symptoms
• Prolonged exposure
• Coingestants
• Other clinical concerns

rather than performed routinely after every uncomplicated exposure.

Diagnosis

Diagnosis is usually clinical.

Determine:

• Exact product
• Immediate vs combination formulation
• Amount
• Time
• Symptoms
• Coingestants
• Relevant medical conditions

Identifying the exact product is particularly important because a “non-drowsy allergy tablet” may contain a decongestant.

ECG

An ECG is reasonable when there is:

• Syncope
• Palpitations
• Significant tachycardia
• Intentional or substantial overdose
• Suspected QT-active drug
• Electrolyte abnormality
• Concerning coingestant
• Cardiovascular symptoms

Routine prolonged ECG monitoring is generally unnecessary after every small asymptomatic exposure to a modern second-generation antihistamine.

Laboratory Evaluation

Small uncomplicated exposures may require no laboratory testing.

When clinically indicated, consider:

• Glucose
• Electrolytes
• Potassium
• Magnesium
• Creatinine

Additional testing depends on:

• Intentional overdose
• Coingestants
• ECG abnormalities
• Altered mental status

Drug concentrations are not routinely useful.

Occult Coingestion

Intentional overdose should prompt evaluation for clinically important coingestants.

Acetaminophen testing is often relevant because early toxicity can be asymptomatic.

Other testing should be directed by history and clinical findings rather than performed mechanically.

Initial Management

Management is predominantly supportive:

Airway/breathing → mental status → circulation → identify exact formulation → ECG when indicated → treat complications

Most isolated modern second-generation antihistamine overdoses do not require aggressive intervention.

GI Decontamination

Do not induce vomiting.

Routine gastric lavage is obsolete.

Activated charcoal may occasionally be considered after a substantial recent ingestion when:

• The substance is adsorbable
• The airway is safe
• Aspiration risk is low
• Expected benefit justifies treatment

Routine decontamination is unnecessary after many minor accidental exposures.

Hypotension

Significant hypotension is unusual after isolated modern second-generation antihistamine overdose.

If it occurs, evaluate for:

• Coingestants
• Dysrhythmia
• Dehydration
• Another medical cause

Treatment may include appropriate isotonic crystalloid and, for persistent vasodilatory shock, a vasopressor such as norepinephrine.

Trendelenburg positioning and routine dopamine-first therapy are outdated.

Extracorporeal Elimination

Hemodialysis and hemoperfusion have no routine role in second-generation antihistamine poisoning.

Supportive care is generally sufficient.

Monitoring

Monitoring should be proportional to the exposure.

Mild modern-agent exposure

Monitor:

• Mental status
• Vital signs
• Development of unexpected symptoms

Significant or symptomatic exposure

Consider:

• ECG
• Cardiac rhythm
• Electrolytes
• Neurologic status

QT prolongation

Continue ECG monitoring until clinically important repolarization abnormalities and associated risk factors have resolved.

Observation

The historical blanket recommendation of:

• 6 hours for all uncomplicated exposures
• 24 hours for hospitalized patients

is too rigid.

Observation should depend on:

• Exact agent
• Amount
• Symptoms
• ECG
• Combination ingredients
• Coingestants
• Clinical trajectory

Historical prolonged monitoring for astemizole should not be automatically transferred to currently used agents.

Admission

Hospital admission may be appropriate for:

• Significant altered mental status
• Seizure
• Syncope with concerning ECG findings
• Important QT prolongation
• Ventricular dysrhythmia
• Persistent hypotension
• Significant coingestion

ICU care is appropriate for torsades, cardiovascular collapse, or other severe toxicity.

Pregnancy and Breastfeeding

The historical FDA pregnancy letter categories are obsolete.

Cetirizine and loratadine have substantial clinical experience in pregnancy, but medication decisions should consider:

• Specific drug
• Dose
• Gestational stage
• Clinical indication

The old blanket statement that cetirizine or loratadine should generally be avoided during breastfeeding is also too broad.

Drug transfer into milk and infant effects vary by agent, and current lactation-specific guidance should be used.

Safeguarding

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

Pediatric exposures should instead be assessed according to:

• Developmental capability
• Medication accessibility
• Exposure circumstances
• Consistency of history
• Recurrent unexplained exposures
• Broader safeguarding concerns

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

Prognosis

Most isolated overdoses involving currently used second-generation antihistamines have a favorable outcome.

Severe toxicity should prompt particular attention to:

• Combination products
• Coingestants
• Electrolyte disturbances
• Unexpected first-generation antihistamine exposure
• Historical QT-active agents

Important Modernization of the Older Source

• “Nonsedating” is better described as second-generation H1 antihistamines; sedation can still occur.
• Astemizole is largely historical and its severe QT toxicity should not define the entire modern class.
• Terfenadine is likewise largely historical because of serious interaction-mediated cardiotoxicity.
• Modern agents such as cetirizine, loratadine, and fexofenadine generally have a much wider cardiovascular safety margin.
• Fexofenadine lacks the major torsadogenic liability of its historical precursor terfenadine.
• Cetirizine can still cause clinically noticeable drowsiness.
• Combination products containing pseudoephedrine can produce a sympathomimetic syndrome.
• Severe antimuscarinic delirium or QRS widening is atypical for modern second-generation agents and should prompt a search for another toxicant.
• Routine prolonged cardiac monitoring is unnecessary after every minor modern-agent exposure.
• Phenytoin is generally not preferred for toxicologic seizures.
• Ipecac and routine gastric lavage are obsolete.
• Trendelenburg and dopamine-first shock treatment are outdated.
• Observation should be agent-, symptom-, ECG-, and coingestant-specific.
• There is no specific antidote.

Key Points

• Second-generation antihistamines usually cause mild toxicity in isolated overdose.
• Common effects are drowsiness, dizziness, headache, nausea, and mild tachycardia.
• Cetirizine is relatively more sedating; fexofenadine has very little CNS effect.
• Astemizole and terfenadine are historical exceptions with major QT/torsades toxicity.
• Marked QT prolongation with a modern agent should prompt evaluation for electrolytes, interactions, and coingestants.
• IV magnesium + electrolyte correction are central if torsades occurs.
• Benzodiazepines are first-line for the unusual toxicologic seizure.
• Always check whether the product also contains pseudoephedrine or another active drug.
• Management is primarily supportive.

Toxicology – Second-Generation (“Nonsedating”) Antihistamines

Core Concept

The older term “nonsedating antihistamines” generally refers to second-generation H1 antihistamines.

Modern examples include:

• Cetirizine
• Levocetirizine
• Loratadine
• Desloratadine
• Fexofenadine
• Acrivastine in some regions

These agents penetrate the CNS less readily than first-generation antihistamines and therefore usually produce less sedation and fewer antimuscarinic effects.

Most isolated overdoses are relatively mild.

The major cardiac toxicity emphasized in older literature—marked QT prolongation and torsades—was primarily associated with astemizole and terfenadine, drugs that have been withdrawn or are no longer routinely marketed in many countries.

Historical Agents – Astemizole and Terfenadine

Astemizole and terfenadine are important historically because they demonstrated that an apparently “nonsedating” antihistamine could still cause severe cardiac toxicity.

Both could block cardiac repolarizing potassium currents and produce:

QT prolongation → early afterdepolarizations → torsades de pointes → ventricular fibrillation/cardiac arrest

Risk became especially important when their metabolism was inhibited by interacting medications.

Modern second-generation antihistamines generally have a much more favorable cardiac safety profile.

Mechanism

Second-generation antihistamines primarily antagonize peripheral H1 receptors.

H1 blockade reduces allergic manifestations such as:

• Pruritus
• Sneezing
• Rhinorrhea
• Urticaria

Their limited CNS penetration accounts for less sedation compared with agents such as diphenhydramine.

However, “nonsedating” is not absolute.

Cetirizine

Cetirizine is relatively more likely than some other second-generation agents to cause:

• Drowsiness
• Fatigue
• Dizziness

Overdose usually produces mild CNS effects rather than severe cardiotoxicity.

Loratadine

Loratadine and its active metabolite desloratadine generally have limited CNS penetration.

Overdose may produce:

• Somnolence
• Headache
• Tachycardia

Serious isolated cardiotoxicity is uncommon.

Fexofenadine

Fexofenadine is the active metabolite related to the older drug terfenadine.

Unlike terfenadine, it has substantially less potential for clinically important cardiac potassium-channel blockade.

This explains why:

Terfenadine → important historical torsades risk

whereas:

Fexofenadine → much lower cardiac risk

Most isolated fexofenadine overdoses are mild.

Acrivastine

Acrivastine can produce:

• Drowsiness
• Dizziness
• Headache
• GI symptoms

Some preparations contain pseudoephedrine.

This distinction is crucial because toxicity from a combination product may reflect the sympathomimetic component rather than the antihistamine.

Combination Products

Always determine whether the preparation contains another active ingredient.

Examples include antihistamine products combined with:

• Pseudoephedrine
• Other decongestants
• Analgesics in some formulations

Pseudoephedrine can produce:

• Agitation
• Tremor
• Tachycardia
• Hypertension
• Insomnia

Therefore, a markedly hyperadrenergic presentation after an “antihistamine” ingestion should prompt inspection of the actual formulation.

Toxic Dose

There is no single useful toxic-dose threshold covering all second-generation antihistamines.

For currently used agents, isolated accidental overdose generally has a relatively wide safety margin.

Risk assessment should consider:

• Exact agent
• Amount
• Patient age/size
• Symptoms
• Coingestants
• Combination-product ingredients
• Renal/hepatic impairment where relevant

Historical astemizole and terfenadine toxicity should not be extrapolated directly to modern agents.

Clinical Features

Most uncomplicated overdoses produce only:

• Drowsiness
• Dizziness
• Headache
• Nausea
• Dry mouth
• Mild tachycardia

Large exposures may occasionally produce:

• Agitation
• Tremor
• Ataxia
• Significant somnolence

Severe neurologic or cardiovascular toxicity should prompt consideration of another agent or coingestant.

Sedation

The label “nonsedating” is misleading if interpreted literally.

Second-generation antihistamines cause less CNS H1 blockade, but some sedation remains possible.

Cetirizine is particularly associated with somnolence compared with fexofenadine.

Antimuscarinic Effects

Modern second-generation antihistamines generally have much weaker antimuscarinic effects than first-generation agents.

Prominent findings such as:

• Severe delirium
• Marked mydriasis
• Very dry skin
• Urinary retention
• Ileus
• Major QRS widening

should raise concern for:

• Diphenhydramine
• Doxylamine
• Another first-generation antihistamine
• TCA
• Another antimuscarinic/sodium-channel blocker
• Mixed ingestion

Cardiovascular Effects

With current second-generation agents, cardiovascular effects are usually limited.

Possible findings include:

• Mild tachycardia
• Occasionally palpitations

Major ventricular dysrhythmia is uncommon in isolated overdose of modern agents.

Astemizole Cardiotoxicity

Historical astemizole toxicity could produce:

• QT prolongation
• Syncope
• Torsades de pointes
• Ventricular dysrhythmia
• Hypotension
• Cardiovascular collapse

Its prolonged pharmacokinetics also allowed delayed toxicity.

These historical features explain the prolonged monitoring recommendations in older texts but should not automatically be applied to cetirizine, loratadine, or fexofenadine.

Drug Interactions – Historical Lesson

Astemizole and terfenadine depended heavily on hepatic metabolism.

Inhibition of their metabolism could increase parent-drug concentrations and markedly increase QT-related toxicity.

Historically important interacting drugs included some:

• Azole antifungals
• Macrolide antibiotics
• CYP inhibitors

This interaction was one of the major reasons these drugs disappeared from routine clinical use.

QT Prolongation – Modern Approach

If clinically important QT prolongation occurs:

• Review the exact antihistamine
• Look for coingestants
• Check potassium
• Check magnesium
• Consider calcium when appropriate
• Review other QT-prolonging medications
• Consider congenital/acquired long-QT conditions

Marked QT prolongation should not automatically be attributed to a modern second-generation antihistamine.

Torsades de Pointes

If torsades develops:

• Stop QT-prolonging drugs
• Correct hypokalemia
• Correct hypomagnesemia
• Give IV magnesium
• Treat unstable ventricular dysrhythmia electrically

Recurrent pause-dependent torsades associated with bradycardia may require heart-rate acceleration, including selected use of overdrive pacing.

Avoid adding medications that further prolong the QT interval.

Neurologic Effects

Large exposures may cause:

• Somnolence
• Dizziness
• Headache
• Tremor
• Agitation
• Ataxia

Seizures are unusual with modern second-generation antihistamines.

If seizures occur, evaluate for:

• Large/mixed ingestion
• First-generation antihistamine
• Sympathomimetic combination product
• Other proconvulsant
• Metabolic or neurologic cause

Seizure Treatment

Benzodiazepines are first-line therapy for toxicant-induced seizures.

Persistent seizures may require:

• Additional benzodiazepines
• Phenobarbital
• Appropriate anesthetic status-epilepticus treatment

The older recommendation to routinely progress to phenytoin is outdated; phenytoin is generally not preferred for toxicologic seizures.

Hepatic Effects

Rare liver injury has been reported with antihistamines, but it is not a defining manifestation of acute second-generation antihistamine overdose.

Liver testing should therefore be driven by:

• Symptoms
• Prolonged exposure
• Coingestants
• Other clinical concerns

rather than performed routinely after every uncomplicated exposure.

Diagnosis

Diagnosis is usually clinical.

Determine:

• Exact product
• Immediate vs combination formulation
• Amount
• Time
• Symptoms
• Coingestants
• Relevant medical conditions

Identifying the exact product is particularly important because a “non-drowsy allergy tablet” may contain a decongestant.

ECG

An ECG is reasonable when there is:

• Syncope
• Palpitations
• Significant tachycardia
• Intentional or substantial overdose
• Suspected QT-active drug
• Electrolyte abnormality
• Concerning coingestant
• Cardiovascular symptoms

Routine prolonged ECG monitoring is generally unnecessary after every small asymptomatic exposure to a modern second-generation antihistamine.

Laboratory Evaluation

Small uncomplicated exposures may require no laboratory testing.

When clinically indicated, consider:

• Glucose
• Electrolytes
• Potassium
• Magnesium
• Creatinine

Additional testing depends on:

• Intentional overdose
• Coingestants
• ECG abnormalities
• Altered mental status

Drug concentrations are not routinely useful.

Occult Coingestion

Intentional overdose should prompt evaluation for clinically important coingestants.

Acetaminophen testing is often relevant because early toxicity can be asymptomatic.

Other testing should be directed by history and clinical findings rather than performed mechanically.

Initial Management

Management is predominantly supportive:

Airway/breathing → mental status → circulation → identify exact formulation → ECG when indicated → treat complications

Most isolated modern second-generation antihistamine overdoses do not require aggressive intervention.

GI Decontamination

Do not induce vomiting.

Routine gastric lavage is obsolete.

Activated charcoal may occasionally be considered after a substantial recent ingestion when:

• The substance is adsorbable
• The airway is safe
• Aspiration risk is low
• Expected benefit justifies treatment

Routine decontamination is unnecessary after many minor accidental exposures.

Hypotension

Significant hypotension is unusual after isolated modern second-generation antihistamine overdose.

If it occurs, evaluate for:

• Coingestants
• Dysrhythmia
• Dehydration
• Another medical cause

Treatment may include appropriate isotonic crystalloid and, for persistent vasodilatory shock, a vasopressor such as norepinephrine.

Trendelenburg positioning and routine dopamine-first therapy are outdated.

Extracorporeal Elimination

Hemodialysis and hemoperfusion have no routine role in second-generation antihistamine poisoning.

Supportive care is generally sufficient.

Monitoring

Monitoring should be proportional to the exposure.

Mild modern-agent exposure

Monitor:

• Mental status
• Vital signs
• Development of unexpected symptoms

Significant or symptomatic exposure

Consider:

• ECG
• Cardiac rhythm
• Electrolytes
• Neurologic status

QT prolongation

Continue ECG monitoring until clinically important repolarization abnormalities and associated risk factors have resolved.

Observation

The historical blanket recommendation of:

• 6 hours for all uncomplicated exposures
• 24 hours for hospitalized patients

is too rigid.

Observation should depend on:

• Exact agent
• Amount
• Symptoms
• ECG
• Combination ingredients
• Coingestants
• Clinical trajectory

Historical prolonged monitoring for astemizole should not be automatically transferred to currently used agents.

Admission

Hospital admission may be appropriate for:

• Significant altered mental status
• Seizure
• Syncope with concerning ECG findings
• Important QT prolongation
• Ventricular dysrhythmia
• Persistent hypotension
• Significant coingestion

ICU care is appropriate for torsades, cardiovascular collapse, or other severe toxicity.

Pregnancy and Breastfeeding

The historical FDA pregnancy letter categories are obsolete.

Cetirizine and loratadine have substantial clinical experience in pregnancy, but medication decisions should consider:

• Specific drug
• Dose
• Gestational stage
• Clinical indication

The old blanket statement that cetirizine or loratadine should generally be avoided during breastfeeding is also too broad.

Drug transfer into milk and infant effects vary by agent, and current lactation-specific guidance should be used.

Safeguarding

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

Pediatric exposures should instead be assessed according to:

• Developmental capability
• Medication accessibility
• Exposure circumstances
• Consistency of history
• Recurrent unexplained exposures
• Broader safeguarding concerns

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

Prognosis

Most isolated overdoses involving currently used second-generation antihistamines have a favorable outcome.

Severe toxicity should prompt particular attention to:

• Combination products
• Coingestants
• Electrolyte disturbances
• Unexpected first-generation antihistamine exposure
• Historical QT-active agents

Important Modernization of the Older Source

• “Nonsedating” is better described as second-generation H1 antihistamines; sedation can still occur.
• Astemizole is largely historical and its severe QT toxicity should not define the entire modern class.
• Terfenadine is likewise largely historical because of serious interaction-mediated cardiotoxicity.
• Modern agents such as cetirizine, loratadine, and fexofenadine generally have a much wider cardiovascular safety margin.
• Fexofenadine lacks the major torsadogenic liability of its historical precursor terfenadine.
• Cetirizine can still cause clinically noticeable drowsiness.
• Combination products containing pseudoephedrine can produce a sympathomimetic syndrome.
• Severe antimuscarinic delirium or QRS widening is atypical for modern second-generation agents and should prompt a search for another toxicant.
• Routine prolonged cardiac monitoring is unnecessary after every minor modern-agent exposure.
• Phenytoin is generally not preferred for toxicologic seizures.
• Ipecac and routine gastric lavage are obsolete.
• Trendelenburg and dopamine-first shock treatment are outdated.
• Observation should be agent-, symptom-, ECG-, and coingestant-specific.
• There is no specific antidote.

Key Points

• Second-generation antihistamines usually cause mild toxicity in isolated overdose.
• Common effects are drowsiness, dizziness, headache, nausea, and mild tachycardia.
• Cetirizine is relatively more sedating; fexofenadine has very little CNS effect.
• Astemizole and terfenadine are historical exceptions with major QT/torsades toxicity.
• Marked QT prolongation with a modern agent should prompt evaluation for electrolytes, interactions, and coingestants.
• IV magnesium + electrolyte correction are central if torsades occurs.
• Benzodiazepines are first-line for the unusual toxicologic seizure.
• Always check whether the product also contains pseudoephedrine or another active drug.
• Management is primarily supportive.

Toxicology – Antifungal Medications

Core Concept

Antifungal medications are a diverse group, so there is no single antifungal toxidrome. Toxicity depends strongly on the drug class, route, duration of exposure, renal/hepatic function, and interacting medications.

Important groups include:

• Polyenes – amphotericin B, nystatin
• Azoles – fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole, ketoconazole, and topical imidazoles
• Antimetabolite – flucytosine
• Echinocandins – caspofungin, micafungin, anidulafungin
• Allylamines – terbinafine

Major toxicologic concerns include:

• Amphotericin B → nephrotoxicity and electrolyte disturbances
• Flucytosine → bone-marrow suppression and GI toxicity
• Systemic azoles → hepatotoxicity, drug interactions, and agent-specific QT effects
• Most topical/vaginal antifungals → predominantly local or mild GI effects after accidental exposure

There is generally no specific antidote.

1. Amphotericin B

Amphotericin B is a polyene antifungal used for serious systemic fungal infections.

It binds fungal membrane ergosterol, forming membrane pores and disrupting cellular integrity.

Unfortunately, amphotericin can also interact with mammalian cell membranes and produce significant toxicity.

Amphotericin B – Major Toxicities

The principal adverse effects are:

• Nephrotoxicity
• Potassium wasting
• Magnesium wasting
• Infusion-related reactions
• Anemia
• Less commonly severe cardiovascular effects

Toxicity is more important after parenteral exposure than accidental oral ingestion because conventional amphotericin B is poorly absorbed from the GI tract.

Amphotericin B Nephrotoxicity

Amphotericin can cause:

• Renal vasoconstriction
• Reduced GFR
• Direct tubular injury

Clinical consequences include:

• Rising creatinine
• Azotemia
• Renal potassium wasting
• Renal magnesium wasting
• Renal tubular dysfunction
• Distal renal tubular acidosis in some patients

Renal injury is especially important with prolonged conventional amphotericin B therapy.

Liposomal Amphotericin

Modern lipid-associated formulations, particularly liposomal amphotericin B, generally cause less nephrotoxicity than conventional amphotericin B deoxycholate.

However, renal injury and electrolyte disturbances can still occur.

The formulation therefore matters when assessing toxicity.

Potassium and Magnesium

A major correction to the older source is that therapeutic amphotericin toxicity characteristically produces:

• Hypokalemia
• Hypomagnesemia

These abnormalities can themselves increase dysrhythmia risk.

Hyperkalemia is not the usual chronic electrolyte pattern, although acute severe cellular injury or massive administration errors can produce different abnormalities.

Amphotericin Infusion Reactions

Infusion-related reactions can include:

• Fever
• Chills/rigors
• Nausea
• Headache
• Hypotension
• Dyspnea

Rare severe infusion reactions may involve:

• Bronchospasm
• Severe hypotension
• Cardiovascular instability

Rapid or erroneous IV administration can be particularly dangerous.

“Red Man Syndrome” – Correction

The term red man syndrome is classically associated with rapid vancomycin infusion and is not the preferred description of amphotericin toxicity.

Amphotericin can certainly produce infusion-associated flushing and other reactions, but these should be described as amphotericin infusion reactions rather than equated with classic vancomycin infusion reaction.

Cardiovascular Toxicity

Severe amphotericin toxicity has been associated with:

• Hypotension
• Bradyarrhythmia
• Ventricular dysrhythmia
• Cardiac arrest

Potential contributors include:

• Electrolyte abnormalities
• Infusion-related reactions
• Severe renal dysfunction
• Administration errors

Continuous ECG monitoring is appropriate after a substantial IV overdose or when cardiovascular abnormalities develop.

Amphotericin Drug Interactions

Risk of renal injury increases when amphotericin is combined with other nephrotoxic exposures.

Examples can include:

• Aminoglycosides
• Calcineurin inhibitors
• Other nephrotoxic medications

Diuretics or other causes of potassium/magnesium loss may further increase electrolyte complications.

2. Flucytosine

Flucytosine is an antifungal antimetabolite.

Fungal cells convert it through metabolic pathways to compounds related to 5-fluorouracil, interfering with:

• DNA synthesis
• RNA function

Human cells do not efficiently perform the initial conversion, but excessive systemic exposure can still cause substantial toxicity.

Flucytosine – Major Toxicities

The main target organs are rapidly dividing tissues.

Important effects include:

• Bone-marrow suppression
• GI toxicity
• Hepatotoxicity

Possible hematologic abnormalities include:

• Leukopenia
• Neutropenia
• Thrombocytopenia
• Anemia
• Pancytopenia in severe cases

Flucytosine and Renal Function

Flucytosine is substantially eliminated by the kidneys.

Therefore:

Renal impairment → reduced clearance → accumulation → greater marrow and GI toxicity

Renal function is one of the most important determinants of toxicity during therapy.

Flucytosine GI Toxicity

Possible manifestations include:

• Nausea
• Vomiting
• Diarrhea
• Abdominal discomfort

Severe systemic exposure can produce significant mucosal injury, but the historical description that severe GI injury is universal is too strong.

Flucytosine Concentrations

Unlike the older blanket statement that antifungal concentrations are never clinically useful, therapeutic drug monitoring can be clinically useful for flucytosine, particularly during treatment when:

• Renal function is impaired
• High exposure is suspected
• Toxicity develops

This is primarily a therapeutic-monitoring issue rather than a reason to delay acute supportive care.

3. Azole Antifungals

Azoles inhibit fungal lanosterol 14-α-demethylase, disrupting ergosterol synthesis and fungal cell membranes.

Modern systemic azoles include:

• Fluconazole
• Itraconazole
• Voriconazole
• Posaconazole
• Isavuconazole

Ketoconazole remains historically important but systemic oral use has been greatly restricted in many settings because of toxicity.

Azole Toxicity

Accidental single ingestions are often relatively mild.

Possible acute effects include:

• Nausea
• Vomiting
• Abdominal discomfort
• Headache
• Dizziness

More clinically important problems during systemic therapy include:

• Hepatotoxicity
• Drug interactions
• QT effects with several agents
• Agent-specific endocrine or neurologic effects

Azole Hepatotoxicity

Systemic azoles can cause:

• Transaminase elevation
• Hepatitis
• Rare severe hepatic injury

Risk and frequency differ among individual drugs.

Significant symptoms such as jaundice, persistent vomiting, right-upper-quadrant discomfort, or unexplained systemic illness warrant liver assessment.

Ketoconazole

Oral ketoconazole is no longer treated as a routine systemic antifungal in many modern settings because it can cause serious:

• Hepatotoxicity
• Adrenal steroid synthesis inhibition
• Drug interactions

Endocrine effects can include:

• Adrenal insufficiency
• Reduced androgen synthesis
• Gynecomastia
• Sexual/reproductive effects during prolonged exposure

Topical ketoconazole has far less systemic exposure.

Voriconazole

Voriconazole can cause distinctive adverse effects including:

• Transient visual disturbances
• Hallucinations or other neuropsychiatric effects
• Hepatotoxicity
• QT prolongation
• Photosensitivity with prolonged use

Toxicity may become more likely when concentrations rise because of nonlinear pharmacokinetics and metabolic variability.

Therapeutic drug monitoring is clinically useful in selected patients.

Itraconazole

Itraconazole can cause:

• GI symptoms
• Hepatotoxicity
• Drug interactions
• Edema
• Negative inotropic effects

It can worsen or precipitate heart failure in susceptible patients.

This cardiac adverse effect is important during therapeutic use and is not simply an overdose phenomenon.

Fluconazole

Fluconazole is generally better tolerated than many older systemic azoles.

Possible toxicity includes:

• GI symptoms
• Hepatotoxicity
• Rash
• QT prolongation

Serious skin reactions such as Stevens–Johnson syndrome are rare but recognized.

Isavuconazole – Important Exception

Most clinically important systemic azoles can prolong the QT interval.

Isavuconazole is an important exception because it tends to shorten the QT interval.

This distinction can be useful when interpreting ECG findings.

QT Prolongation

For QT-prolonging antifungals, dysrhythmia risk increases with:

• Hypokalemia
• Hypomagnesemia
• Bradycardia
• Congenital long-QT syndrome
• Other QT-prolonging drugs

Management centers on:

• Stopping the offending agent
• Correcting electrolytes
• ECG monitoring when clinically indicated

Torsades is treated with standard measures including IV magnesium and electrical therapy when unstable.

Azole Drug Interactions

Drug interactions are among the most important hazards of systemic azole therapy.

Many azoles inhibit CYP enzymes to varying degrees.

Consequently, concentrations of other medications may rise.

Clinically important interactions can involve drugs such as:

• Certain anticoagulants
• Some statins
• Calcineurin inhibitors
• Some benzodiazepines
• Antiarrhythmics
• Antiseizure medications
• Some glucose-lowering drugs

The exact interaction profile differs substantially among individual azoles.

Important Correction – CYP Statement

The older source’s broad interaction description is oversimplified.

Azoles generally act as CYP inhibitors, not simply as nonspecific agents that raise a fixed list of drug concentrations.

The affected CYP pathways and interaction magnitude vary by antifungal.

Medication-specific interaction checking is therefore important.

4. Echinocandins

Modern echinocandins include:

• Caspofungin
• Micafungin
• Anidulafungin

They inhibit fungal β-(1,3)-D-glucan synthesis, impairing the fungal cell wall.

They were not represented adequately in older antifungal toxicology references.

Echinocandin Toxicity

These agents generally have a favorable toxicity profile.

Possible adverse effects include:

• Infusion reactions
• Histamine-mediated flushing
• Rash
• GI symptoms
• Transaminase elevation

Severe acute poisoning is uncommon.

Management is mainly supportive.

5. Nystatin

Nystatin is a polyene but is poorly absorbed from intact GI mucosa and skin.

Therefore, accidental oral exposure generally causes limited systemic toxicity.

Possible effects are mainly:

• Nausea
• Vomiting
• Diarrhea

Systemic toxicity is unusual with conventional topical/oral preparations.

6. Topical and Vaginal Antifungals

Agents include various formulations of:

• Clotrimazole
• Miconazole
• Terconazole
• Tioconazole
• Nystatin

Systemic absorption from ordinary topical use is generally limited.

Adverse effects are more commonly:

• Local burning
• Irritation
• Erythema
• Contact dermatitis

Accidental small oral exposures are usually much less concerning than systemic antifungal overdoses.

Diagnosis

There is no universal antifungal poisoning syndrome.

Assessment should identify:

• Exact drug
• Formulation
• Route
• Amount
• Timing
• Acute overdose vs chronic therapeutic toxicity
• Renal function
• Hepatic function
• Interacting medications

This distinction is particularly important because many serious antifungal toxicities develop during therapeutic treatment, not after a single overdose.

Laboratory Evaluation

Testing should be drug-specific.

Amphotericin B

Consider:

• Creatinine
• BUN
• Potassium
• Magnesium
• Bicarbonate
• Calcium
• ECG when significant toxicity is suspected
• CBC during prolonged treatment

Flucytosine

Consider:

• CBC with differential
• Platelets
• Creatinine
• Liver tests
• Electrolytes

Systemic azoles

Consider:

• Liver tests
• Electrolytes
• ECG for QT-risk situations
• Renal function where relevant

Therapeutic Drug Monitoring

The older statement that antifungal levels are universally useless is incorrect.

Drug concentrations can have clinical roles for selected systemic antifungals, particularly:

• Flucytosine
• Voriconazole
• Itraconazole
• Posaconazole in selected circumstances

This is especially relevant during prolonged therapy, treatment failure, organ dysfunction, suspected toxicity, or major drug interactions.

Acute stabilization should never be delayed while waiting for a concentration.

Initial Management

General priorities are:

Airway/breathing → circulation → identify exact antifungal → ECG/electrolytes when relevant → renal/hepatic/marrow assessment → supportive care

There is no universal antidote for antifungal poisoning.

GI Decontamination

Ipecac should not be used.

Induced vomiting is obsolete in poisoning management.

Routine gastric lavage is also inappropriate.

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

• The airway is safe
• Aspiration risk is low
• Expected benefit justifies treatment

Many accidental antifungal ingestions do not require GI decontamination.

Hypotension

Treat the cause.

Management may include:

• Appropriate isotonic crystalloid
• Treatment of severe infusion reactions
• Correction of electrolyte abnormalities
• Vasopressor support for persistent shock

Norepinephrine is generally favored for persistent vasodilatory shock.

Routine Trendelenburg positioning and a dopamine-first strategy are outdated.

Dysrhythmias

When dysrhythmias occur:

• Stop the causative drug
• Correct potassium
• Correct magnesium
• Correct significant calcium abnormalities
• Treat hypoxemia/acidemia
• Follow standard resuscitation principles

For torsades associated with QT prolongation:

• IV magnesium
• Correction of electrolytes
• Electrical treatment if unstable

Bone-Marrow Suppression

This is particularly important with flucytosine.

Monitor:

• Hemoglobin
• Leukocyte/neutrophil count
• Platelets

Clinically important marrow suppression may require:

• Discontinuation of the drug
• Supportive hematologic care
• Management of infection or bleeding complications

Recovery depends partly on exposure severity and renal clearance.

Renal Injury

Amphotericin-associated renal toxicity requires:

• Serial renal function
• Careful volume assessment
• Potassium monitoring
• Magnesium monitoring
• Review of other nephrotoxic drugs

Electrolyte abnormalities may persist even when creatinine changes are modest.

Hepatic Injury

Systemic azoles and, less commonly, other antifungals may produce clinically significant liver injury.

Evaluate significant cases with:

• AST/ALT
• Bilirubin
• Coagulation studies when severe

Severe hepatic dysfunction warrants specialist assessment.

Extracorporeal Treatment

There is no general role for dialysis simply because an antifungal overdose has occurred.

Potential usefulness depends on the specific agent and its:

• Protein binding
• Volume of distribution
• Molecular characteristics
• Renal clearance

Dialysis may still be required for conventional indications such as severe renal failure or dangerous electrolyte abnormalities.

Monitoring

Monitoring should match the causative drug.

Important parameters may include:

• Vital signs
• ECG
• Potassium
• Magnesium
• Renal function
• Liver function
• CBC
• Platelets

A patient receiving amphotericin requires a very different monitoring strategy from someone with a small accidental topical azole ingestion.

Observation and Disposition

A universal 6-hour observation period is not appropriate for every antifungal exposure.

Disposition depends on:

• Agent
• Route
• Formulation
• Amount
• Symptoms
• Organ function
• Laboratory abnormalities
• Drug interactions
• Intentional vs accidental exposure

Many small accidental topical or oral exposures can be managed conservatively, whereas significant amphotericin administration errors, marrow toxicity, hepatic injury, or cardiac abnormalities require monitored care.

Admission

Hospital management may be required for:

• Significant amphotericin overdose
• Dysrhythmia
• Important electrolyte abnormalities
• Acute kidney injury
• Persistent hypotension
• Severe vomiting/dehydration
• Significant marrow suppression
• Hepatitis
• Coagulopathy
• Severe drug interaction

ICU care is appropriate for severe cardiovascular instability or multiorgan toxicity.

Pregnancy

The old FDA A/B/C/D/X pregnancy categories are obsolete.

Antifungal selection during pregnancy depends strongly on:

• Specific agent
• Route
• Dose
• Duration
• Gestational stage
• Severity of fungal infection

The historical claim that all vaginal antifungals are automatically safe in pregnancy is too broad.

Topical azoles have extensive use in pregnancy, but treatment decisions should still be agent- and formulation-specific.

Similarly, breastfeeding recommendations cannot accurately be reduced to “avoid all azoles.”

Safeguarding

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

Pediatric exposure should instead be assessed according to:

• Developmental capability
• Access to medication
• Exposure circumstances
• Consistency of history
• Recurrent unexplained events
• Broader safeguarding concerns

Prognosis

Most small accidental antifungal exposures have a favorable outcome.

Prognosis becomes more concerning with:

• Major amphotericin administration errors
• Severe renal injury
• Dangerous electrolyte abnormalities
• Dysrhythmias
• Severe flucytosine-associated marrow suppression
• Significant azole hepatotoxicity
• Serious drug interactions

Important Modernization of the Older Source

• Antifungals should not be divided simply into polyenes, flucytosine, and “imidazoles”; modern therapy includes triazoles, echinocandins, allylamines, and other agents.
• Amphotericin B primarily causes nephrotoxicity with potassium and magnesium wasting.
• Liposomal amphotericin generally causes less nephrotoxicity than conventional amphotericin B.
• Amphotericin infusion reactions should not simply be called “red man syndrome.”
• Flucytosine toxicity is strongly influenced by renal clearance and can cause severe marrow suppression.
• Flucytosine concentrations can be clinically useful; the blanket statement that antifungal levels have no value is incorrect.
• Selected azoles also use therapeutic drug monitoring.
• Systemic azoles can produce clinically important hepatotoxicity and CYP-mediated drug interactions.
• Several azoles can prolong QT, whereas isavuconazole characteristically shortens QT.
• Oral ketoconazole has been greatly restricted because of serious hepatic, endocrine, and interaction risks.
• Itraconazole can worsen heart failure because of negative inotropic effects.
• Modern echinocandins generally have relatively low acute toxicity.
• Nystatin has little systemic absorption with conventional oral/topical use.
• Ipecac and routine gastric lavage are obsolete.
• Trendelenburg and dopamine-first shock management are outdated.
• Observation and laboratory testing should be drug-specific, not based on a universal antifungal protocol.
• There is generally no specific antidote.

Key Points

• Antifungal toxicity varies dramatically by drug class.
• Amphotericin B → kidney injury + hypokalemia + hypomagnesemia + infusion reactions.
• Flucytosine → bone-marrow suppression + GI toxicity, especially with renal impairment.
• Systemic azoles → liver injury + major drug interactions + agent-specific cardiac effects.
• Topical agents and nystatin usually have limited systemic toxicity.
• Check ECG and electrolytes when QT-active drugs or amphotericin-related electrolyte disturbances are involved.
• Monitor CBC during significant flucytosine toxicity.
• Monitor renal function, potassium, and magnesium with amphotericin.
• Monitor liver function with clinically significant systemic azole toxicity.
• Management is predominantly supportive and agent-specific.

Toxicology – Class IB Antidysrhythmic Agents

Core Concept

Class IB antidysrhythmic drugs are fast sodium-channel blockers. Historically important examples include:

• Lidocaine
• Mexiletine
• Tocainide — now largely obsolete/discontinued in many regions

Phenytoin also has Class IB-like electrophysiologic properties but is better considered separately.

The most important modern toxicology distinction is that lidocaine toxicity is also local anesthetic systemic toxicity (LAST).

Major manifestations include:

• Early neurologic excitation
• Circumoral or tongue paresthesia
• Tinnitus
• Dizziness
• Seizures
• CNS depression/coma
• Hypotension
• Bradycardia
• Conduction disturbances
• Ventricular dysrhythmias
• Cardiovascular collapse

Severe local-anesthetic toxicity has an important modern rescue treatment:

Intravenous lipid emulsion (ILE)

Thus, the historical statement that there is “no specific antidote” requires qualification for severe lidocaine-associated LAST.

Mechanism

Class IB drugs block fast voltage-gated sodium channels.

Their effects are particularly prominent in:

• Depolarized tissue
• Ischemic myocardium
• Rapidly firing sodium channels

At therapeutic concentrations they can suppress abnormal ventricular automaticity.

With excessive exposure, sodium-channel blockade extends to normal cardiac and nervous tissue.

CNS Sodium-Channel Toxicity

Local anesthetics inhibit neuronal sodium channels.

As concentrations rise, inhibitory CNS pathways may be affected first, producing an initial excitatory phase.

Early symptoms may include:

• Circumoral numbness
• Tongue paresthesia
• Metallic or abnormal taste
• Tinnitus
• Dizziness
• Lightheadedness
• Visual disturbance
• Restlessness
• Tremor
• Confusion

This can progress to:

Agitation → seizure → CNS depression → coma → respiratory arrest

Cardiac Sodium-Channel Toxicity

At higher concentrations:

Na⁺-channel blockade → impaired conduction + reduced myocardial excitability/contractility

Possible consequences include:

• PR prolongation
• QRS widening
• AV block
• Bradycardia
• Ventricular dysrhythmias
• Hypotension
• Cardiogenic shock
• Asystole

Lidocaine

Lidocaine is used as:

• Local anesthetic
• Regional anesthetic
• Topical anesthetic
• Selected ventricular antiarrhythmic therapy

Toxicity may follow:

• Excessive injection
• Accidental intravascular administration
• Rapid systemic absorption
• Excessive topical exposure
• Impaired metabolism
• Medication error
• Rare oral exposure

Acute intravascular exposure can produce toxicity within minutes.

Local Anesthetic Systemic Toxicity – LAST

The modern syndrome of serious systemic toxicity from lidocaine or another local anesthetic is termed:

Local Anesthetic Systemic Toxicity (LAST)

LAST can produce both:

Neurologic toxicity

• Paresthesia
• Tinnitus
• Agitation
• Seizure
• Coma

Cardiovascular toxicity

• Hypotension
• Bradycardia
• Conduction block
• Ventricular dysrhythmia
• Cardiovascular collapse

The traditional progression from neurologic symptoms to cardiovascular toxicity is useful but not universal.

Some patients can present primarily with cardiovascular collapse.

Why Toxicity May Occur at Therapeutic Use

Risk depends on more than the total administered dose.

Important factors include:

• Injection site vascularity
• Accidental intravascular administration
• Rate of administration
• Patient size
• Age
• Cardiac output
• Hepatic function
• Protein binding
• Acid–base status
• Concomitant drugs

Therefore, a single rigid “toxic dose” cannot reliably predict LAST.

Lidocaine Metabolism

Lidocaine is predominantly metabolized in the liver.

Reduced clearance can occur with:

• Severe hepatic dysfunction
• Reduced hepatic blood flow
• Heart failure
• Shock

Repeated dosing or prolonged infusion can therefore cause accumulation.

Acidemia

Acidemia is particularly undesirable in severe local-anesthetic toxicity.

It may increase the active drug fraction and worsen:

• CNS toxicity
• Sodium-channel blockade
• Myocardial depression

Therefore, adequate oxygenation and ventilation are important during resuscitation.

Mexiletine

Mexiletine is an orally active Class IB sodium-channel blocker structurally and pharmacologically related to lidocaine.

Toxicity may produce:

• Nausea/vomiting
• Tremor
• Dizziness
• Ataxia
• Confusion
• Seizures
• Bradycardia
• Hypotension
• Conduction abnormalities
• Ventricular dysrhythmias

Neurologic toxicity may be prominent.

Tocainide

Tocainide is an older orally active lidocaine-like drug.

It has largely disappeared from contemporary clinical practice because of safety concerns and availability of alternatives.

Older toxicology descriptions remain historically relevant but are less important for current practice.

Neurologic Warning Signs

One of the important characteristics of Class IB toxicity is that neurologic symptoms may precede cardiovascular deterioration.

Early findings can include:

• Restlessness
• Dizziness
• Paresthesias
• Tinnitus
• Tremor
• Confusion
• Visual disturbances

These symptoms should not automatically be attributed to anxiety or hyperventilation when systemic local-anesthetic exposure is possible.

Seizures

Seizures are a major manifestation of severe lidocaine/LAST toxicity.

Seizures worsen toxicity by producing:

• Hypoxemia
• Hypercarbia
• Lactic acidosis
• Increased metabolic demand

These changes can intensify cardiovascular toxicity.

Therefore:

Rapid seizure control + oxygenation + ventilation are critical.

Seizure Treatment

Benzodiazepines are generally first-line therapy.

Persistent seizures may require escalation with appropriate anticonvulsant/anesthetic therapy.

Large doses of medications that significantly depress myocardial function should be used cautiously in a patient already developing cardiovascular collapse.

CNS Depression

As toxicity progresses, initial CNS excitation may transition to:

• Drowsiness
• Respiratory depression
• Coma
• Apnea

Airway and ventilation support may therefore become necessary rapidly.

Cardiovascular Findings

Severe toxicity may produce:

• Hypotension
• Bradycardia
• AV block
• QRS widening
• Ventricular dysrhythmias
• Cardiac arrest

Unlike Class IA agents, therapeutic Class IB drugs do not characteristically produce major QT prolongation.

Marked QT prolongation should therefore prompt consideration of:

• Coingestants
• Electrolyte abnormalities
• Another drug mechanism

ECG

Obtain an ECG in significant systemic toxicity.

Assess:

• Rate
• Rhythm
• PR interval
• QRS duration
• QT/QTc
• AV conduction
• Ventricular ectopy

However:

A normal ECG does not exclude early lidocaine toxicity.

Neurologic symptoms may occur before obvious ECG abnormalities.

Methemoglobinemia – Important Clarification

Methemoglobinemia is classically associated with certain local anesthetics, especially:

• Benzocaine
• Prilocaine

Lidocaine can cause methemoglobinemia, but it is substantially less characteristic than with benzocaine or prilocaine.

Consider it when there is:

• Cyanosis disproportionate to respiratory findings
• Low pulse-oximetry readings that do not normalize as expected with oxygen
• Chocolate-brown blood
• An exposure capable of oxidizing hemoglobin

Confirm with co-oximetry.

Laboratory Evaluation

Significant poisoning may warrant:

• Glucose
• Electrolytes
• Potassium
• Magnesium
• Calcium
• Bicarbonate
• Creatinine

Severe poisoning may additionally require:

• Blood gas
• Lactate
• Serial acid–base assessment

Co-oximetry is appropriate if methemoglobinemia is suspected.

Serum Drug Concentrations

Lidocaine or mexiletine concentrations can occasionally support a diagnosis but should not delay treatment.

Clinical toxicity correlates imperfectly with an isolated serum concentration.

Management should be based primarily on:

• Neurologic findings
• ECG
• Hemodynamics
• Respiratory status
• Exposure history

Routine serial drug levels are generally not required to determine recovery in most poisoning cases.

Initial Management

Priorities are:

Stop exposure → airway/oxygenation → control seizures → ECG/circulation → treat cardiovascular toxicity

For suspected LAST, preparation for lipid-emulsion therapy should occur early when severe neurologic or cardiovascular toxicity develops.

Stop Local Anesthetic Administration

If toxicity develops during local or regional anesthesia:

Immediately stop administration of the local anesthetic.

Preventing further systemic exposure is the first intervention.

Oxygenation and Ventilation

Avoid:

• Hypoxemia
• Hypercarbia
• Severe acidemia

These physiologic abnormalities can worsen local-anesthetic cardiotoxicity.

Early airway support may be necessary with:

• Recurrent seizures
• Coma
• Apnea
• Severe cardiovascular collapse

Intravenous Lipid Emulsion

This is the major modern addition missing from the older source.

IV lipid emulsion is an established rescue therapy for severe local anesthetic systemic toxicity, particularly when cardiovascular instability is present.

Its proposed mechanisms include:

• Sequestration/redistribution of lipophilic local anesthetic
• Improved myocardial substrate availability
• Direct beneficial effects on myocardial function

It is especially relevant to severe toxicity from highly lipophilic local anesthetics, but it is also used for severe lidocaine-associated LAST.

Exact administration should follow a current LAST resuscitation protocol.

Cardiac Arrest in LAST

Resuscitation differs somewhat from ordinary cardiac arrest because the myocardium is profoundly affected by the local anesthetic.

Priorities include:

• High-quality CPR
• Adequate oxygenation and ventilation
• Seizure control
• Correction of acidemia
• Early lipid emulsion for severe LAST
• Appropriate defibrillation when indicated

Resuscitation may need to be prolonged because severe local-anesthetic cardiotoxicity can be reversible as the drug redistributes and is metabolized.

Vasopressors

Vasopressor therapy may be required for severe hypotension.

In LAST, standard resuscitation drugs may need modification because excessive catecholamine exposure can worsen arrhythmogenicity and interfere with successful resuscitation.

Current LAST-specific resuscitation guidance should therefore be followed rather than simply applying an old dopamine-first algorithm.

Trendelenburg – Obsolete

Routine Trendelenburg positioning is not recommended as treatment for hypotension.

It does not provide reliable sustained improvement in perfusion and may worsen respiratory mechanics.

Sodium Bicarbonate

Sodium bicarbonate may be considered when significant sodium-channel-blocker physiology is present, particularly with:

• QRS widening
• Severe conduction slowing
• Acidemia

However, in severe LAST it does not replace lipid emulsion and comprehensive resuscitation.

Bradycardia and AV Block

Management centers on:

• Correcting hypoxemia/acidemia
• Treating systemic local-anesthetic toxicity
• Hemodynamic support

Temporary pacing may be considered for refractory severe bradycardia or high-grade block.

However, electrical pacing may be ineffective when myocardial sodium-channel blockade and contractile depression are profound.

Ventricular Dysrhythmias

Management includes:

• Correction of hypoxemia
• Correction of acidemia
• Treatment of electrolyte abnormalities
• Defibrillation/cardioversion when clinically indicated
• LAST-specific resuscitation

Avoid reflexively adding additional sodium-channel-blocking antiarrhythmics because they may worsen the underlying toxicity.

Antiarrhythmics in LAST

The older recommendation to treat lidocaine-induced dysrhythmia with additional Class I drugs should be approached cautiously.

Agents that further impair myocardial conduction can aggravate toxicity.

Treatment should instead focus on reversing the toxic physiology and following contemporary LAST resuscitation guidance.

Torsades de Pointes

Torsades is not the defining dysrhythmia of typical Class IB poisoning.

If polymorphic VT with prolonged QT occurs:

• Correct potassium
• Correct magnesium
• Remove QT-prolonging agents
• Give IV magnesium
• Electrically treat unstable dysrhythmia

Consider another drug or electrolyte abnormality if major QT prolongation dominates the presentation.

GI Decontamination

GI decontamination applies primarily to oral drugs such as mexiletine.

Do not induce vomiting.

Routine gastric lavage is obsolete.

Activated charcoal may occasionally be considered after a substantial recent oral ingestion when:

• The substance is adsorbable
• The airway is safe
• Aspiration risk is acceptable

It has no role in an already absorbed parenteral lidocaine exposure.

Extracorporeal Removal

Routine:

• Hemodialysis
• Hemoperfusion
• Hemofiltration
• Forced diuresis
• Urinary manipulation

do not represent standard toxin-removal strategies for lidocaine poisoning.

In catastrophic refractory cardiovascular collapse, the relevant extracorporeal intervention is circulatory support, not conventional dialysis.

VA-ECMO

Severe LAST is potentially reversible.

When cardiovascular collapse remains refractory despite appropriate resuscitation and lipid therapy, VA-ECMO may be considered at an experienced center.

This modernizes the older concept of emergency cardiopulmonary bypass.

ECMO supports circulation while the local anesthetic redistributes and is metabolized.

Differential Diagnosis

The combination of neurologic toxicity, seizures, and cardiovascular abnormalities can also occur with:

• Other Class I antiarrhythmics
• Tricyclic antidepressants
• Diphenhydramine
• Cocaine
• Chloroquine
• β-blockers
• Calcium-channel blockers
• Other local anesthetics

Nontoxicologic causes include:

• Hypoglycemia
• Electrolyte abnormalities
• Intracranial pathology
• CNS infection
• Primary seizure disorders

Monitoring

Significant toxicity requires monitoring of:

• Mental status
• Respiratory function
• Oxygenation
• Heart rate
• Blood pressure
• Continuous ECG
• Acid–base status when severe

Monitor severe cases for recurrent:

• Seizures
• Dysrhythmias
• Hypotension
• Respiratory failure

Observation

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

Observation depends on:

• Drug
• Route
• Formulation
• Amount
• Timing
• Neurologic findings
• ECG
• Hemodynamics
• Coingestants

Parenteral intravascular lidocaine toxicity generally develops rapidly, whereas oral Class IB agents may have a different time course.

Admission

Monitored admission is appropriate for:

• Seizures
• Significant altered mental status
• Respiratory depression
• Hypotension
• Bradycardia
• AV block
• QRS widening
• Ventricular dysrhythmia
• Any clinically significant LAST

Severe cardiovascular or neurologic toxicity warrants intensive care.

Pregnancy

The historical FDA pregnancy letter categories are obsolete.

Management of severe poisoning during pregnancy prioritizes maternal:

• Airway
• Oxygenation
• Ventilation
• Seizure control
• Hemodynamics

Maternal stabilization is also fundamental to fetal oxygenation and perfusion.

Safeguarding

Rigid historical age cutoffs for neglect, abuse, or intentional poisoning are outdated.

Pediatric exposures should instead be assessed according to:

• Developmental capability
• Access
• Circumstances
• Consistency of history
• Recurrent unexplained exposure
• Broader safeguarding concerns

Prognosis

Early neurologic toxicity is often completely reversible when recognized and treated promptly.

Poor outcomes are associated with:

• Prolonged seizures
• Severe hypoxemia
• Acidemia
• Refractory ventricular dysrhythmia
• Prolonged cardiovascular collapse
• Hypoxic brain injury

Even severe LAST can be reversible with prolonged, aggressive resuscitation.

Important Modernization of the Older Source

• Lidocaine toxicity should be recognized within the modern syndrome of local anesthetic systemic toxicity (LAST).
• Neurologic manifestations often precede cardiovascular toxicity, but this sequence is not universal.
• A normal early ECG does not exclude LAST.
• Severe toxicity can cause seizures, conduction block, ventricular dysrhythmias, and cardiovascular collapse.
• IV lipid emulsion is a major modern rescue treatment for severe LAST and is absent from the historical source.
• Avoid hypoxemia, hypercarbia, and acidemia because they worsen toxicity.
• Benzodiazepines are first-line for seizures.
• Sodium bicarbonate may have a role in significant conduction toxicity but does not replace LAST-specific resuscitation.
• Additional sodium-channel-blocking antiarrhythmics can worsen toxicity.
• Major QT prolongation/torsades is less characteristic of Class IB poisoning than Class IA poisoning.
• Methemoglobinemia is much more strongly associated with benzocaine/prilocaine than with lidocaine.
• Routine gastric lavage is obsolete.
• Dialysis is not a useful primary toxin-removal strategy.
• Trendelenburg and dopamine-first hypotension management are outdated.
• “Cardiac bypass” is better conceptualized today as VA-ECMO for selected refractory, potentially reversible cardiovascular collapse.
• Fixed observation periods should be replaced by agent-, route-, formulation-, and symptom-based monitoring.

Key Points

• Class IB drugs block fast Na⁺ channels.
• Major examples are lidocaine and mexiletine; tocainide is largely historical.
• Lidocaine systemic toxicity = LAST.
• Early LAST may cause circumoral paresthesia, tinnitus, dizziness, agitation, and tremor.
• Severe toxicity progresses to seizures, coma, respiratory depression, bradycardia, conduction block, ventricular dysrhythmias, and cardiovascular collapse.
• Control seizures rapidly and prevent hypoxemia, hypercarbia, and acidemia.
• IV lipid emulsion is an important rescue therapy for severe LAST.
• ECG abnormalities may occur late; a normal ECG does not exclude early neurologic toxicity.
• Avoid adding drugs that worsen sodium-channel blockade.
• Severe refractory cardiovascular collapse may require VA-ECMO.

Toxicology – Class IA Antidysrhythmics: Quinidine and Disopyramide

Core Concept

Quinidine and disopyramide are Class IA sodium-channel-blocking antidysrhythmics. Their use has declined substantially because safer or more effective alternatives are available for many arrhythmias.

In overdose, the major dangers are:

• Fast sodium-channel blockade → QRS widening
• Potassium-channel blockade → QT prolongation
• Ventricular dysrhythmias
• Torsades de pointes
• Hypotension
• Bradycardia/AV block
• Seizures and CNS depression

Quinidine additionally produces cinchonism, while disopyramide has particularly prominent antimuscarinic and negative-inotropic effects.

There is no specific antidote.

⸻

Mechanism – Class IA

Class IA agents block fast myocardial sodium channels.

This slows phase-0 depolarization:

Na⁺-channel blockade → slowed conduction → QRS widening

They also inhibit repolarizing potassium currents:

K⁺-channel blockade → prolonged repolarization → QT prolongation

Thus, Class IA poisoning can produce the dangerous combination of:

Wide QRS + prolonged QT

⸻

Electrophysiologic Effects

Toxicity may cause:

• Slowed atrial conduction
• Slowed AV/intraventricular conduction
• QRS widening
• QT prolongation
• Bradyarrhythmias
• Ventricular tachycardia
• Ventricular fibrillation
• Torsades de pointes

These abnormalities may deteriorate rapidly.

⸻

Quinidine

Quinidine is closely related to quinine.

In addition to sodium- and potassium-channel effects, it can produce:

• α-adrenergic blockade
• Hypotension
• GI symptoms
• Cinchonism

Its role in contemporary rhythm management is much narrower than suggested by older toxicology texts.

⸻

Disopyramide

Disopyramide has important:

• Sodium-channel-blocking activity
• Potassium-channel effects
• Antimuscarinic activity
• Negative inotropic effects

Consequently, toxicity can include:

• Dry mouth
• Mydriasis
• Urinary retention
• Ileus
• Tachycardia
• Delirium
• Hypotension
• Heart failure/cardiogenic shock
• Conduction abnormalities

⸻

Toxic Dose

There is no reliable universal toxic-dose threshold.

Toxicity can occur relatively close to therapeutic concentrations, especially when clearance is impaired or interacting medications are present.

Risk depends on:

• Agent
• Formulation
• Amount
• Renal/hepatic function
• Baseline conduction disease
• Electrolytes
• Drug interactions
• Coingestants

Clinical status and serial ECG findings are more important than the reported dose alone.

⸻

Sustained-Release Preparations

Modified-release formulations can produce:

• Delayed absorption
• Delayed peak toxicity
• Prolonged cardiotoxicity

Antimuscarinic slowing of GI motility may further delay absorption.

An initially normal ECG therefore does not necessarily exclude later deterioration after a substantial sustained-release exposure.

⸻

Cinchonism

Quinidine can produce a syndrome known as cinchonism.

Possible manifestations include:

• Tinnitus
• Hearing disturbance
• Headache
• Dizziness
• Nausea/vomiting
• Visual disturbance
• Confusion

More severe toxicity may cause marked visual impairment and serious neurologic or cardiovascular abnormalities.

Sudden tinnitus or visual symptoms in a patient taking quinidine should raise concern for toxicity.

⸻

Neurologic Toxicity

Severe poisoning may produce:

• Confusion
• Somnolence
• Seizures
• Coma
• Respiratory depression

Seizures can worsen cardiotoxicity through:

Seizure → lactic acidosis → acidemia → increased sodium-channel toxicity

Rapid seizure control is therefore important.

⸻

Cardiovascular Toxicity

Major manifestations include:

• QRS widening
• QT prolongation
• AV conduction delay
• Bradycardia
• Hypotension
• Ventricular tachycardia
• Ventricular fibrillation
• Torsades de pointes

Severe poisoning can progress to shock or cardiac arrest.

⸻

Why Hypotension Occurs

Hypotension may result from several simultaneous mechanisms:

• Myocardial depression
• Sodium-channel blockade
• Dysrhythmia
• α-adrenergic blockade, particularly with quinidine
• Negative inotropy, particularly with disopyramide
• Acidemia

Therefore, treatment must address both circulation and the underlying electrical toxicity.

⸻

ECG – Essential Test

Obtain an ECG promptly in suspected significant poisoning.

Assess:

• Heart rate
• Rhythm
• PR interval
• QRS duration
• QT/QTc
• AV conduction
• Ventricular ectopy

Symptomatic or significant exposures require continuous cardiac monitoring.

⸻

QRS Widening

QRS widening reflects myocardial sodium-channel blockade.

Increasing QRS duration suggests increasing conduction toxicity and greater risk of ventricular dysrhythmia.

The ECG and clinical trajectory are more useful than a serum drug concentration for acute management.

⸻

QT Prolongation

Class IA agents delay ventricular repolarization.

This produces:

QT prolongation → early afterdepolarizations → polymorphic VT → torsades de pointes

Risk increases with:

• Hypokalemia
• Hypomagnesemia
• Bradycardia
• Other QT-prolonging drugs
• Congenital long-QT susceptibility

⸻

Quinidine and Diarrhea

Quinidine commonly causes gastrointestinal adverse effects, including diarrhea.

Significant diarrhea can cause:

K⁺ loss → hypokalemia → increased QT-related dysrhythmia risk

Thus electrolyte abnormalities can convert otherwise modest drug exposure into a more dangerous electrophysiologic situation.

⸻

Syncope

Syncope in a patient receiving a QT-prolonging Class IA agent should prompt urgent consideration of a transient ventricular dysrhythmia, including torsades.

However, it should not be assumed automatically; other causes of syncope still require evaluation.

⸻

Laboratory Evaluation

Important tests in significant poisoning include:

• Potassium
• Magnesium
• Calcium
• Bicarbonate
• Creatinine
• Glucose

Severe cases may additionally require:

• Blood gas
• Lactate
• Renal and hepatic assessment

Renal function is particularly relevant to drugs with substantial renal elimination.

⸻

Serum Drug Concentrations

Quinidine or disopyramide concentrations may occasionally provide supportive information, but they generally do not determine emergency treatment.

Management should be guided by:

• ECG
• Blood pressure
• Mental status
• Seizures
• Perfusion
• Electrolytes

Do not delay treatment while awaiting a drug level.

⸻

Initial Management

Priorities are:

Airway/breathing → ECG → circulation → correct electrolytes → control seizures → treat conduction abnormalities/torsades

Continuous monitoring is important because deterioration can be abrupt.

⸻

Sodium Bicarbonate

Sodium bicarbonate is an important treatment when significant sodium-channel blockade is present.

Clinical indications include:

• Significant QRS widening
• Ventricular conduction toxicity
• Ventricular dysrhythmia associated with sodium-channel blockade
• Cardiovascular instability in the appropriate toxicologic context

Its effects come from:

• Sodium loading
• Alkalinization
• Reduced drug interaction with myocardial sodium channels

Treatment is guided by ECG response, hemodynamics, and acid–base/electrolyte status rather than blindly targeting a fixed dose.

⸻

Avoid Acidemia

Acidemia can intensify sodium-channel-blocker cardiotoxicity.

Therefore:

• Treat seizures promptly
• Maintain adequate ventilation
• Correct hypoperfusion
• Address severe metabolic abnormalities

Excessive alkalinization should also be avoided because it can cause clinically important electrolyte disturbances.

⸻

Torsades de Pointes

Management priorities include:

• Stop QT-prolonging drugs
• Correct hypokalemia
• Correct hypomagnesemia
• Correct other important electrolyte abnormalities
• IV magnesium
• Electrical defibrillation/cardioversion if unstable

For recurrent pause-dependent torsades associated with bradycardia, increasing the heart rate with overdrive pacing may be appropriate.

Isoproterenol has selected roles in acquired bradycardia-dependent torsades but is not appropriate for every prolonged-QT situation.

⸻

Drugs to Avoid in Torsades

Avoid adding medications that further prolong repolarization.

In particular, additional Class IA drugs are inappropriate.

Other QT-prolonging antiarrhythmics may also worsen acquired long-QT-associated torsades.

The older recommendation lists should therefore be interpreted according to the mechanism rather than memorized as isolated drug names.

⸻

Bradycardia and AV Block

Severe sodium-channel toxicity can produce:

• Bradycardia
• AV block
• Intraventricular conduction delay

Standard bradycardia measures may be attempted as clinically appropriate, but severe toxicologic conduction blockade may respond poorly.

Temporary pacing may be considered when clinically significant bradycardia or high-grade block persists despite correction of the toxicologic abnormalities.

⸻

Important Pacing Limitation

Electrical capture does not guarantee effective mechanical cardiac output in profound sodium-channel-blocker poisoning.

Therefore, pacing should not distract from:

• Sodium bicarbonate therapy
• Correction of acidemia
• Electrolyte correction
• Hemodynamic support

⸻

Hypotension

Management includes:

• Appropriate isotonic crystalloid when volume responsive
• Treatment of the dysrhythmia
• Sodium bicarbonate when sodium-channel cardiotoxicity is present
• Correction of acidemia

Persistent shock may require vasopressor therapy.

Norepinephrine is generally more appropriate than the historical routine dopamine-first approach for persistent vasodilatory hypotension.

Disopyramide-associated myocardial depression may complicate the hemodynamic picture.

⸻

Seizures

Benzodiazepines are first-line therapy.

Persistent seizures may require:

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

⸻

Phenytoin – Modern Correction

The historical recommendation to use phenytoin/fosphenytoin for refractory ventricular dysrhythmias is not part of routine modern management of Class IA poisoning.

Phenytoin itself interacts with sodium channels and can produce cardiovascular toxicity during IV administration.

It is also generally not preferred for toxicant-induced seizures.

⸻

Lidocaine

Lidocaine may have a specialist-guided role in refractory ventricular dysrhythmias caused by sodium-channel blockers after appropriate sodium bicarbonate therapy.

It should not replace bicarbonate as the fundamental treatment of significant Class IA sodium-channel toxicity.

⸻

Other Class I Antiarrhythmics

Avoid using additional Class IA agents because they can worsen:

• Sodium-channel blockade
• QRS widening
• QT prolongation
• Hypotension

Class IC sodium-channel blockers can likewise worsen conduction toxicity.

⸻

GI Decontamination

Do not induce vomiting.

Seizures, dysrhythmias, or altered consciousness may develop abruptly.

Routine gastric lavage is obsolete.

⸻

Activated Charcoal

A single dose of activated charcoal may be considered after a substantial recent oral exposure when:

• The drug is adsorbable
• The airway is safe
• Aspiration risk is acceptable

It should never delay cardiovascular stabilization.

Routine repeat-dose charcoal solely because GI motility is slowed is not established.

⸻

Whole-Bowel Irrigation

Whole-bowel irrigation is not routine.

It may occasionally be considered after a substantial sustained-release ingestion when:

• The patient is sufficiently stable
• Bowel function is adequate
• The airway is protected
• There is no obstruction, ileus, or perforation

Because antimuscarinic effects can impair GI motility, WBI may sometimes be impractical or inappropriate.

⸻

Extracorporeal Removal

Quinidine is generally poorly suited to routine extracorporeal removal because of its pharmacokinetic characteristics.

Historical suggestions that disopyramide should routinely undergo hemodialysis should also be interpreted cautiously.

Extracorporeal treatment is not the primary strategy for Class IA cardiotoxicity and should not delay:

• Sodium bicarbonate
• Dysrhythmia treatment
• Vasopressor support
• Electrolyte correction

⸻

Refractory Cardiovascular Collapse

Massive sodium-channel-blocker poisoning may rarely cause shock or dysrhythmia refractory to conventional therapy.

Selected severe cases may require advanced rescue measures such as VA-ECMO at an experienced center.

The older reference to “cardiac bypass” is better understood in modern practice as temporary extracorporeal circulatory support for potentially reversible poisoning.

⸻

Chronic Quinidine Adverse Effects

Therapeutic quinidine can rarely cause immune-mediated complications such as:

• Thrombocytopenia
• Hemolytic anemia
• Drug-induced lupus-like reactions

These are distinct from the acute electrophysiologic toxicity of overdose.

⸻

Drug Interactions

Risk increases when Class IA agents are combined with:

• Other QT-prolonging medications
• Other sodium-channel blockers
• Drugs altering their metabolism
• Drugs causing hypokalemia or hypomagnesemia

A medication review is therefore particularly important when toxicity occurs at apparently therapeutic dosing.

⸻

Differential Diagnosis

The combination of:

CNS toxicity + seizure + QRS widening

can also occur with:

• Tricyclic antidepressants
• Diphenhydramine and some other antihistamines
• Cocaine
• Flecainide/propafenone
• Chloroquine
• Other sodium-channel-blocking xenobiotics

QT prolongation and torsades have their own broad drug and electrolyte differential.

⸻

Monitoring

Significant poisoning requires:

• Continuous ECG
• Blood pressure monitoring
• Respiratory monitoring
• Serial electrolytes
• Renal function
• Serial assessment of QRS and QT

Severe cases also require monitoring for:

• Seizures
• Acidemia
• Shock
• End-organ hypoperfusion

⸻

Observation

A fixed 6-hour rule should not be applied universally.

Observation depends on:

• Agent
• Immediate- vs sustained-release formulation
• Amount
• ECG findings
• Symptoms
• Electrolytes
• Coingestants
• Clinical trajectory

Sustained-release products can produce delayed and prolonged toxicity.

⸻

Admission

Monitored inpatient care is appropriate for:

• QRS widening
• Significant QT prolongation
• Dysrhythmia
• Syncope concerning for dysrhythmia
• Hypotension
• Bradycardia/high-grade AV block
• Seizures
• Altered mental status
• Significant cinchonism
• Large sustained-release exposure

Severe cardiovascular instability warrants ICU care.

⸻

Pregnancy

Historical FDA pregnancy letter categories are obsolete.

Clinically significant poisoning during pregnancy should be managed according to maternal physiology, with priority given to:

• Airway
• Oxygenation
• Cardiac rhythm
• Blood pressure
• Seizure control

Maternal dysrhythmia and shock also threaten fetal perfusion.

⸻

Safeguarding

Rigid historical age cutoffs for neglect, abuse, or intentional poisoning are outdated.

Pediatric exposure should instead be assessed according to developmental capability, access, circumstances, history consistency, recurrent events, and other safeguarding concerns.

⸻

Prognosis

Mild poisoning may resolve with monitoring and supportive treatment.

Severe poisoning carries risk of:

• Ventricular dysrhythmia
• Torsades
• Cardiogenic/vasodilatory shock
• Seizures
• Respiratory failure
• Cardiac arrest
• Hypoxic brain injury

Outcome is strongly influenced by early recognition and correction of electrophysiologic toxicity.

⸻

Important Modernization of the Older Source

• Quinidine and disopyramide are now used much less commonly than historically.
• Class IA = sodium-channel blockade + potassium-channel blockade.
• Therefore, poisoning can produce both QRS widening and QT prolongation.
• Quinidine can cause cinchonism.
• Disopyramide has prominent antimuscarinic and negative-inotropic effects.
• Sodium bicarbonate is central when clinically important sodium-channel blockade is present.
• Correct K⁺ and Mg²⁺ aggressively when QT-related dysrhythmia risk is present.
• IV magnesium is central to torsades management.
• Overdrive pacing may help selected recurrent bradycardia-dependent torsades.
• Phenytoin/fosphenytoin is not routine modern therapy for Class IA cardiotoxicity or toxicologic seizures.
• Additional Class IA/IC sodium-channel blockers should generally be avoided.
• Norepinephrine is generally favored over routine dopamine-first treatment for persistent vasodilatory shock.
• Routine gastric lavage is obsolete.
• Repeated charcoal is not automatically indicated because of slowed GI motility.
• WBI has only a selective role in substantial sustained-release exposure.
• Drug concentrations should not delay ECG-directed treatment.
• Severe refractory cardiovascular collapse may warrant advanced extracorporeal circulatory support.

Key Points

• Class IA toxicity = Na⁺ blockade + K⁺ blockade.
• Na⁺ blockade → QRS widening and conduction slowing.
• K⁺ blockade → QT prolongation and torsades risk.
• Quinidine additionally causes cinchonism.
• Disopyramide has strong antimuscarinic and myocardial-depressant effects.
• Obtain an early ECG and continuously monitor significant poisoning.
• Sodium bicarbonate is first-line for important sodium-channel cardiotoxicity.
• Magnesium and electrolyte correction are central for torsades.
• Benzodiazepines are first-line for seizures.
• Avoid additional Class IA/IC agents that worsen conduction.
• Sustained-release formulations may cause delayed toxicity.
• There is no specific antidote.

Toxicology – Tricyclic Antidepressants (TCAs)

Core Concept

Tricyclic antidepressants are highly important toxicologic drugs because substantial overdose can rapidly produce:

• Myocardial sodium-channel blockade
• Hypotension
• Ventricular dysrhythmias
• Seizures
• CNS depression/coma
• Antimuscarinic effects

A patient who initially appears relatively stable can deteriorate abruptly.

The central treatment principle is:

Suspected TCA cardiotoxicity + QRS widening/hypotension/ventricular dysrhythmia → sodium bicarbonate

There is no single specific antidote that reverses all TCA toxicity.

Important TCAs

Examples include:

• Amitriptyline
• Nortriptyline
• Imipramine
• Desipramine
• Clomipramine
• Doxepin
• Trimipramine
• Protriptyline

Some older agents such as dosulepin/dothiepin remain relevant in certain regions but are used less widely.

Therapeutic Uses

Although TCAs were developed as antidepressants, modern uses can include:

• Depression
• Neuropathic pain
• Migraine/headache prevention
• Selected chronic pain syndromes
• Sleep-related/off-label indications
• Enuresis with selected agents

Their narrow therapeutic index makes overdose substantially more dangerous than overdose with many newer antidepressants.

Mechanisms of Toxicity

TCA poisoning is not caused by a single receptor effect.

Important mechanisms include:

1. Fast sodium-channel blockade
2. Muscarinic receptor antagonism
3. α₁-Adrenergic blockade
4. Norepinephrine and serotonin reuptake inhibition
5. Potassium-channel effects contributing to repolarization abnormalities

The most immediately life-threatening mechanism is usually cardiac sodium-channel blockade.

Sodium-Channel Blockade

TCAs inhibit fast sodium channels in myocardial tissue.

This slows phase-0 depolarization:

Na⁺ channel blockade → slowed conduction → QRS widening → ventricular dysrhythmia/cardiovascular collapse

Sodium-channel blockade also contributes to neurologic toxicity.

Importantly, TCA binding to sodium channels becomes more problematic with acidemia.

Why Acidemia Is Dangerous

Acidemia can:

• Increase the pharmacologically active fraction of TCA
• Enhance sodium-channel binding
• Worsen conduction slowing
• Increase hypotension and dysrhythmia risk

This creates a dangerous cycle:

Seizure/shock → lactic acidosis → greater TCA cardiotoxicity → worsening shock

Rapid control of seizures, adequate ventilation, and correction of clinically important acidemia are therefore critical.

Antimuscarinic Effects

TCAs may produce:

• Mydriasis
• Dry mouth
• Tachycardia
• Flushing
• Reduced bowel sounds
• Urinary retention
• Delirium

However, the full classic antimuscarinic toxidrome is not required.

Life-threatening sodium-channel toxicity can occur whether or not peripheral antimuscarinic findings are dramatic.

α₁-Adrenergic Blockade

Peripheral α₁ blockade causes vasodilation and contributes to:

• Orthostatic hypotension
• Severe hypotension in overdose

TCA-related shock may therefore combine:

• Vasodilation
• Myocardial depression
• Dysrhythmia
• Acidemia

Toxic Dose

There is no perfectly reliable dose threshold for an individual patient.

Risk generally increases with:

• Larger mg/kg exposure
• Potent cardiotoxic TCAs
• Coingestants
• Delayed treatment
• Acidemia
• Underlying cardiac disease

Because the consequences can be severe, suspected significant pediatric ingestion deserves particular caution.

Clinical findings and the ECG are more important than the reported dose alone.

Clinical Presentation

A useful way to remember serious TCA poisoning is:

“3 Cs”

• Coma
• Convulsions
• Cardiotoxicity

Additional findings include:

• Tachycardia
• Hypotension
• Antimuscarinic findings
• Respiratory depression
• Hyperthermia
• Metabolic acidosis

Neurologic Toxicity

Possible manifestations include:

• Drowsiness
• Confusion
• Agitation
• Delirium
• Seizures
• Coma

Neurologic and cardiovascular toxicity often occur together because sodium-channel blockade affects both tissues.

Seizures

TCA-associated seizures may occur abruptly.

Complications include:

• Hypoxemia
• Aspiration
• Lactic acidosis
• Hyperthermia
• Rhabdomyolysis
• Worsening cardiotoxicity

Because acidosis increases TCA cardiotoxicity, seizure control has direct cardiovascular importance.

Seizure Treatment

Benzodiazepines are first-line therapy.

Persistent toxicologic seizures may require:

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

The historical recommendation for phenytoin is outdated.

Phenytoin is generally not preferred in TCA-induced seizures, particularly because it has sodium-channel-blocking properties and does not address the toxicologic mechanism effectively.

Cardiovascular Toxicity

Common findings include:

• Sinus tachycardia
• QRS widening
• Hypotension

Severe poisoning can progress to:

• AV/intraventricular conduction disturbances
• Ventricular tachycardia
• Ventricular fibrillation
• Profound shock
• Cardiac arrest

Abrupt deterioration is characteristic of serious TCA poisoning.

ECG – One of the Most Important Tests

Obtain an ECG promptly after suspected significant TCA poisoning.

Assess:

• Heart rate and rhythm
• QRS duration
• QT/QTc
• Terminal QRS morphology
• Lead aVR

Continuous cardiac monitoring is appropriate for clinically important poisoning.

QRS Widening

A QRS around or above 100 ms increases concern for clinically meaningful sodium-channel blockade.

Increasing QRS duration generally correlates with increasing toxicity.

Historical studies associated progressively wider QRS complexes with greater risks of:

• Seizures
• Ventricular dysrhythmias

However, old thresholds such as 100, 120, or 160 ms should not be interpreted as absolute biological cutoffs.

Treat the ECG, clinical condition, and trajectory, not a single number.

Lead aVR

TCA sodium-channel blockade may produce:

• Prominent terminal R wave in aVR
• Increased R/S ratio in aVR

These findings support sodium-channel toxicity but should not be interpreted in isolation.

QRS duration and the overall clinical syndrome remain important.

QT Prolongation

TCAs can also prolong ventricular repolarization.

QT prolongation may reflect potassium-channel effects and can increase dysrhythmia risk.

Correct important:

• Hypokalemia
• Hypomagnesemia
• Hypocalcemia

and avoid additional QT-prolonging drugs when possible.

Sodium Bicarbonate

Sodium bicarbonate is the cornerstone of treatment for significant TCA cardiotoxicity.

Important indications include:

• Clinically significant QRS widening
• Ventricular dysrhythmia due to sodium-channel blockade
• Hypotension associated with TCA cardiotoxicity
• Other convincing evidence of serious myocardial sodium-channel blockade

It should not be reserved only for cardiac arrest.

How Sodium Bicarbonate Works

Two major mechanisms are important:

1. Sodium loading

Increasing extracellular sodium helps overcome sodium-channel blockade.

2. Alkalemia

Increasing serum pH reduces the active free fraction and decreases drug interaction with myocardial sodium channels.

Clinical effects may include:

• QRS narrowing
• Improved blood pressure
• Reduced ventricular ectopy
• Improved conduction

Bicarbonate Endpoints

Treatment is guided by:

• QRS narrowing
• Rhythm
• Blood pressure
• Perfusion
• Acid–base status
• Serum sodium and potassium

Excessive treatment can cause:

• Severe alkalemia
• Hypernatremia
• Hypokalemia
• Reduced ionized calcium
• Volume overload

Therefore, therapy requires repeated ECG and laboratory reassessment.

Ventilation

Adequate ventilation is especially important because hypercapnia produces respiratory acidosis and may worsen TCA cardiotoxicity.

If intubation is required, avoid unnecessary hypoventilation and abrupt development of acidemia.

At the same time, excessive combined hyperventilation and bicarbonate can produce dangerous alkalemia.

Hypotension

TCA-associated hypotension can result from:

• α₁ blockade
• Myocardial depression
• Sodium-channel blockade
• Dysrhythmia
• Acidemia
• Relative volume depletion

Management must therefore address more than simple fluid loss.

Management of TCA Hypotension

Initial measures include:

• Airway and oxygenation support
• Appropriate isotonic crystalloid
• Sodium bicarbonate when cardiotoxicity is present
• Correction of seizures and acidemia

Persistent hypotension may require a vasopressor.

Norepinephrine is generally favored for persistent TCA-associated vasodilatory shock.

Routine dopamine-first therapy is outdated.

Routine Trendelenburg positioning is also obsolete.

Ventricular Dysrhythmias

First priorities include:

• Sodium bicarbonate
• Correction of hypoxemia
• Correction of acidemia
• Control of seizures
• Correction of major electrolyte abnormalities

If serious ventricular dysrhythmia persists despite appropriate alkalinization/sodium therapy, specialist-guided additional antiarrhythmic therapy may be considered.

Antiarrhythmics to Avoid

Drugs that further inhibit cardiac sodium channels can worsen TCA toxicity.

Particularly avoid routine use of:

• Class IA agents
• Class IC agents

Examples include:

• Quinidine
• Procainamide
• Flecainide
• Propafenone

Lidocaine

Lidocaine has historically been used for refractory ventricular dysrhythmias after adequate sodium bicarbonate treatment.

Its use is secondary to correction of the underlying sodium-channel toxicity and should be guided by toxicology/cardiology expertise.

The historical antiarrhythmic algorithms in older references should not replace current toxicologic resuscitation practice.

Physostigmine – Avoid

Despite antimuscarinic findings, physostigmine should generally not be used in significant TCA poisoning.

TCA overdose carries risks of:

• QRS widening
• Conduction block
• Ventricular dysrhythmia
• Seizures

Increasing cholinergic activity in this setting can produce dangerous bradyarrhythmia or other complications.

Antimuscarinic delirium in a suspected TCA overdose should therefore not be treated as though it were a pure atropine-like poisoning.

Flumazenil – Avoid

Flumazenil should generally be avoided in suspected TCA or mixed antidepressant overdose.

If a benzodiazepine has been coingested, its anticonvulsant activity may actually be protective.

Flumazenil can remove this protection and precipitate:

• Seizures
• Severe withdrawal
• Increased cardiotoxic complications

Pulmonary Complications

Severe poisoning can cause:

• Respiratory depression
• Loss of airway reflexes
• Aspiration pneumonitis
• Acute lung injury

Early airway control may be appropriate when severe CNS depression or recurrent seizures compromise ventilation or airway protection.

Rhabdomyolysis

Rhabdomyolysis can follow:

• Recurrent seizures
• Hyperthermia
• Prolonged coma
• Severe agitation

Monitor selected severe cases with:

• CK
• Potassium
• Creatinine
• Urinalysis
• Urine output

Metabolic Acidosis

Lactic acidosis can result from:

• Seizures
• Shock
• Hypoxemia

Because acidemia potentiates sodium-channel toxicity, it is especially dangerous in TCA overdose.

Treatment focuses on correcting the underlying seizure, ventilation, and circulatory failure while using sodium bicarbonate when indicated for TCA cardiotoxicity.

Diagnosis

Diagnosis is based on:

• Medication history
• Clinical syndrome
• ECG
• Coingestant assessment

A quantitative serum TCA concentration is generally not useful for guiding acute treatment.

A severely toxic patient can require aggressive treatment regardless of the measured serum concentration.

Laboratory Evaluation

Significant poisoning may require:

• Electrolytes
• Bicarbonate
• Glucose
• Creatinine
• Blood gas
• CK after prolonged seizure/coma
• Lactate in severe shock or seizures

Serial testing is more useful than isolated values when severe toxicity is evolving.

Occult Coingestion

Intentional TCA overdose commonly requires evaluation for additional substances.

Acetaminophen testing is often appropriate because early acetaminophen poisoning may be clinically silent.

Other testing should be directed by history and clinical findings.

Neuroimaging and Lumbar Puncture

Head CT, lumbar puncture, cultures, and other neurologic investigations are not automatically required simply because TCA poisoning causes coma or seizures.

They are appropriate when:

• Diagnosis remains uncertain
• Trauma is possible
• Focal findings are present
• Infection is suspected
• Clinical course is inconsistent with poisoning

GI Decontamination

Do not induce vomiting.

Abrupt seizures and coma make emesis particularly dangerous.

Gastric Lavage

Routine gastric lavage is obsolete and should not be performed simply because the ingestion is large.

Potential harms include:

• Aspiration
• Mechanical injury
• Delays in resuscitation

Airway, ECG, seizures, and circulation take priority.

Activated Charcoal

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

• The airway is protected or reliably intact
• Aspiration risk is acceptable
• The drug remains potentially available for adsorption

TCAs slow gastric motility, so delayed absorption may occur.

However, this does not justify routine repeated charcoal administration.

Extracorporeal Removal

Hemodialysis and hemoperfusion do not meaningfully enhance TCA elimination because TCAs generally have:

• Large volumes of distribution
• Extensive tissue distribution
• High protein binding

Extracorporeal therapy should therefore not delay proven supportive and sodium-bicarbonate-based treatment.

Refractory Cardiovascular Collapse

Rare massive TCA poisoning can produce profound shock or cardiac arrest despite conventional therapy.

Selected refractory cases may involve specialist consideration of:

• Intravenous lipid emulsion as rescue therapy
• VA-ECMO or other extracorporeal circulatory support

Evidence for lipid emulsion outside established indications is limited, so it is not routine first-line treatment.

ECMO provides temporary cardiopulmonary support while the toxin redistributes and is metabolized; it does not directly remove the TCA.

Monitoring

Clinically significant TCA poisoning requires close monitoring of:

• Airway and ventilation
• Mental status
• Heart rate
• Blood pressure
• Continuous ECG
• QRS duration
• Temperature
• Acid–base status
• Electrolytes

Severe cases also require monitoring for:

• Rhabdomyolysis
• Renal injury
• Recurrent seizures
• Shock

Observation

Most serious TCA toxicity becomes evident relatively early after a substantial immediate-release ingestion, but the older universal “6-hour rule” should not be treated as absolute.

Disposition depends on:

• Agent and formulation
• Estimated exposure
• Symptoms
• Serial ECGs
• Hemodynamics
• Mental status
• Coingestants
• Clinical trajectory

Persistent tachycardia alone should be interpreted in the overall clinical context rather than automatically defining severe poisoning.

Admission

ICU-level care is appropriate for:

• QRS widening
• Significant hypotension
• Ventricular dysrhythmia
• Recurrent seizures
• Coma
• Respiratory failure
• Severe acidemia
• Other evidence of major cardiotoxicity

Pregnancy

Historical FDA pregnancy letter categories are obsolete.

In maternal TCA poisoning, priorities remain:

• Airway and ventilation
• Seizure control
• Hemodynamic stabilization
• Correction of cardiotoxicity

Maternal hypoxemia, hypotension, seizures, and dysrhythmias also threaten fetal perfusion and oxygenation.

Life-saving sodium bicarbonate and resuscitative treatment should not be withheld because of pregnancy.

Safeguarding

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

Pediatric poisoning should instead be assessed according to:

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

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

Prognosis

Patients who survive the acute cardiotoxic phase without major hypoxic or ischemic complications can recover completely.

Poor outcomes are generally associated with:

• Prolonged hypotension
• Refractory ventricular dysrhythmia
• Cardiac arrest
• Recurrent/prolonged seizures
• Severe acidemia
• Hypoxic brain injury

Important Modernization of the Older Source

• TCA lethality is driven particularly by fast myocardial sodium-channel blockade, not simply monoamine-reuptake inhibition.
• QRS widening is one of the most useful bedside markers of serious toxicity.
• Historical QRS thresholds predict increasing risk but are not absolute treatment boundaries.
• Lead aVR abnormalities support the diagnosis but should not be interpreted alone.
• Acidemia potentiates TCA cardiotoxicity.
• Sodium bicarbonate is first-line for significant QRS widening, ventricular conduction toxicity, and TCA-associated hypotension/cardiotoxicity.
• Phenytoin is generally not preferred for TCA-induced seizures.
• Class IA and IC antiarrhythmics can worsen sodium-channel blockade and should generally be avoided.
• Physostigmine should generally be avoided in significant TCA poisoning.
• Flumazenil is hazardous in TCA/mixed overdose because it may precipitate seizures.
• Norepinephrine is generally preferred over the historical dopamine-first strategy for persistent shock.
• Trendelenburg positioning is obsolete.
• Ipecac and routine gastric lavage have no modern role.
• Routine repeated activated charcoal is not established.
• Hemodialysis and hemoperfusion do not meaningfully remove TCAs.
• Selected refractory cardiovascular collapse may require rescue therapies such as ECMO.
• Serum TCA concentrations do not guide acute treatment.

Key Points

• TCA overdose = coma + convulsions + cardiotoxicity.
• Na⁺-channel blockade → QRS widening → ventricular dysrhythmia and shock.
• Acidemia worsens sodium-channel blockade.
• Sodium bicarbonate is the cornerstone of cardiotoxicity treatment.
• Benzodiazepines are first-line for seizures.
• Avoid phenytoin as routine seizure therapy, physostigmine, flumazenil, and class IA/IC antiarrhythmics in significant TCA toxicity.
• Obtain an early ECG and follow serial QRS/rhythm changes.
• Significant hypotension, QRS widening, seizure, coma, or dysrhythmia warrants intensive monitoring.
• Serum TCA levels are not useful for bedside treatment decisions.
• Patients can deteriorate abruptly, so early recognition and aggressive supportive care are critical.

241. Toxicology – Tricyclic Antidepressants (TCAs)

Core Concept

Tricyclic antidepressants are highly important toxicologic drugs because substantial overdose can rapidly produce:

Myocardial sodium-channel blockade   Hypotension   Ventricular dysrhythmias   Seizures   CNS depression/coma   Antimuscarinic effects

A patient who initially appears relatively stable can deteriorate abruptly.

The central treatment principle is:

Suspected TCA cardiotoxicity + QRS widening/hypotension/ventricular dysrhythmia → sodium bicarbonate

There is no single specific antidote that reverses all TCA toxicity.

⸻

Important TCAs

Examples include:

Amitriptyline   Nortriptyline   Imipramine   Desipramine   Clomipramine   Doxepin   Trimipramine   Protriptyline

Some older agents such as dosulepin/dothiepin remain relevant in certain regions but are used less widely.

⸻

Therapeutic Uses

Although TCAs were developed as antidepressants, modern uses can include:

Depression   Neuropathic pain   Migraine/headache prevention   Selected chronic pain syndromes   Sleep-related/off-label indications   Enuresis with selected agents

Their narrow therapeutic index makes overdose substantially more dangerous than overdose with many newer antidepressants.

⸻

Mechanisms of Toxicity

TCA poisoning is not caused by a single receptor effect.

Important mechanisms include:

Fast sodium-channel blockade   Muscarinic receptor antagonism   α₁-Adrenergic blockade   Norepinephrine and serotonin reuptake inhibition   Potassium-channel effects contributing to repolarization abnormalities

The most immediately life-threatening mechanism is usually cardiac sodium-channel blockade.

⸻

Sodium-Channel Blockade

TCAs inhibit fast sodium channels in myocardial tissue.

This slows phase-0 depolarization:

Na⁺ channel blockade → slowed conduction → QRS widening → ventricular dysrhythmia/cardiovascular collapse

Sodium-channel blockade also contributes to neurologic toxicity.

Importantly, TCA binding to sodium channels becomes more problematic with acidemia.

⸻

Why Acidemia Is Dangerous

Acidemia can:

Increase the pharmacologically active fraction of TCA   Enhance sodium-channel binding   Worsen conduction slowing   Increase hypotension and dysrhythmia risk

This creates a dangerous cycle:

Seizure/shock → lactic acidosis → greater TCA cardiotoxicity → worsening shock

Rapid control of seizures, adequate ventilation, and correction of clinically important acidemia are therefore critical.

⸻

Antimuscarinic Effects

TCAs may produce:

Mydriasis   Dry mouth   Tachycardia   Flushing   Reduced bowel sounds   Urinary retention   Delirium

However, the full classic antimuscarinic toxidrome is not required.

Life-threatening sodium-channel toxicity can occur whether or not peripheral antimuscarinic findings are dramatic.

⸻

α₁-Adrenergic Blockade

Peripheral α₁ blockade causes vasodilation and contributes to:

Orthostatic hypotension   Severe hypotension in overdose

TCA-related shock may therefore combine:

Vasodilation   Myocardial depression   Dysrhythmia   Acidemia

⸻

Toxic Dose

There is no perfectly reliable dose threshold for an individual patient.

Risk generally increases with:

Larger mg/kg exposure   Potent cardiotoxic TCAs   Coingestants   Delayed treatment   Acidemia   Underlying cardiac disease

Because the consequences can be severe, suspected significant pediatric ingestion deserves particular caution.

Clinical findings and the ECG are more important than the reported dose alone.

⸻

Clinical Presentation

A useful way to remember serious TCA poisoning is:

“3 Cs”

Coma   Convulsions   Cardiotoxicity

Additional findings include:

Tachycardia   Hypotension   Antimuscarinic findings   Respiratory depression   Hyperthermia   Metabolic acidosis

⸻

Neurologic Toxicity

Possible manifestations include:

Drowsiness   Confusion   Agitation   Delirium   Seizures   Coma

Neurologic and cardiovascular toxicity often occur together because sodium-channel blockade affects both tissues.

⸻

Seizures

TCA-associated seizures may occur abruptly.

Complications include:

Hypoxemia   Aspiration   Lactic acidosis   Hyperthermia   Rhabdomyolysis   Worsening cardiotoxicity

Because acidosis increases TCA cardiotoxicity, seizure control has direct cardiovascular importance.

⸻

Seizure Treatment

Benzodiazepines are first-line therapy.

Persistent toxicologic seizures may require:

Additional benzodiazepines   Phenobarbital   Appropriate anesthetic therapy for refractory status epilepticus

The historical recommendation for phenytoin is outdated.

Phenytoin is generally not preferred in TCA-induced seizures, particularly because it has sodium-channel-blocking properties and does not address the toxicologic mechanism effectively.

⸻

Cardiovascular Toxicity

Common findings include:

Sinus tachycardia   QRS widening   Hypotension

Severe poisoning can progress to:

AV/intraventricular conduction disturbances   Ventricular tachycardia   Ventricular fibrillation   Profound shock   Cardiac arrest

Abrupt deterioration is characteristic of serious TCA poisoning.

⸻

ECG – One of the Most Important Tests

Obtain an ECG promptly after suspected significant TCA poisoning.

Assess:

Heart rate and rhythm   QRS duration   QT/QTc   Terminal QRS morphology   Lead aVR

Continuous cardiac monitoring is appropriate for clinically important poisoning.

⸻

QRS Widening

A QRS around or above 100 ms increases concern for clinically meaningful sodium-channel blockade.

Increasing QRS duration generally correlates with increasing toxicity.

Historical studies associated progressively wider QRS complexes with greater risks of:

Seizures   Ventricular dysrhythmias

However, old thresholds such as 100, 120, or 160 ms should not be interpreted as absolute biological cutoffs.

Treat the ECG, clinical condition, and trajectory, not a single number.

⸻

Lead aVR

TCA sodium-channel blockade may produce:

Prominent terminal R wave in aVR   Increased R/S ratio in aVR

These findings support sodium-channel toxicity but should not be interpreted in isolation.

QRS duration and the overall clinical syndrome remain important.

⸻

QT Prolongation

TCAs can also prolong ventricular repolarization.

QT prolongation may reflect potassium-channel effects and can increase dysrhythmia risk.

Correct important:

Hypokalemia   Hypomagnesemia   Hypocalcemia

and avoid additional QT-prolonging drugs when possible.

⸻

Sodium Bicarbonate

Sodium bicarbonate is the cornerstone of treatment for significant TCA cardiotoxicity.

Important indications include:

Clinically significant QRS widening   Ventricular dysrhythmia due to sodium-channel blockade   Hypotension associated with TCA cardiotoxicity   Other convincing evidence of serious myocardial sodium-channel blockade

It should not be reserved only for cardiac arrest.

⸻

How Sodium Bicarbonate Works

Two major mechanisms are important:

1. Sodium loading

Increasing extracellular sodium helps overcome sodium-channel blockade.

2. Alkalemia

Increasing serum pH reduces the active free fraction and decreases drug interaction with myocardial sodium channels.

Clinical effects may include:

QRS narrowing   Improved blood pressure   Reduced ventricular ectopy   Improved conduction

⸻

Bicarbonate Endpoints

Treatment is guided by:

QRS narrowing   Rhythm   Blood pressure   Perfusion   Acid–base status   Serum sodium and potassium

Excessive treatment can cause:

Severe alkalemia   Hypernatremia   Hypokalemia   Reduced ionized calcium   Volume overload

Therefore, therapy requires repeated ECG and laboratory reassessment.

⸻

Ventilation

Adequate ventilation is especially important because hypercapnia produces respiratory acidosis and may worsen TCA cardiotoxicity.

If intubation is required, avoid unnecessary hypoventilation and abrupt development of acidemia.

At the same time, excessive combined hyperventilation and bicarbonate can produce dangerous alkalemia.

⸻

Hypotension

TCA-associated hypotension can result from:

α₁ blockade   Myocardial depression   Sodium-channel blockade   Dysrhythmia   Acidemia   Relative volume depletion

Management must therefore address more than simple fluid loss.

⸻

Management of TCA Hypotension

Initial measures include:

Airway and oxygenation support   Appropriate isotonic crystalloid   Sodium bicarbonate when cardiotoxicity is present   Correction of seizures and acidemia

Persistent hypotension may require a vasopressor.

Norepinephrine is generally favored for persistent TCA-associated vasodilatory shock.

Routine dopamine-first therapy is outdated.

Routine Trendelenburg positioning is also obsolete.

⸻

Ventricular Dysrhythmias

First priorities include:

Sodium bicarbonate   Correction of hypoxemia   Correction of acidemia   Control of seizures   Correction of major electrolyte abnormalities

If serious ventricular dysrhythmia persists despite appropriate alkalinization/sodium therapy, specialist-guided additional antiarrhythmic therapy may be considered.

⸻

Antiarrhythmics to Avoid

Drugs that further inhibit cardiac sodium channels can worsen TCA toxicity.

Particularly avoid routine use of:

Class IA agents   Class IC agents

Examples include:

Quinidine   Procainamide   Flecainide   Propafenone

⸻

Lidocaine

Lidocaine has historically been used for refractory ventricular dysrhythmias after adequate sodium bicarbonate treatment.

Its use is secondary to correction of the underlying sodium-channel toxicity and should be guided by toxicology/cardiology expertise.

The historical antiarrhythmic algorithms in older references should not replace current toxicologic resuscitation practice.

⸻

Physostigmine – Avoid

Despite antimuscarinic findings, physostigmine should generally not be used in significant TCA poisoning.

TCA overdose carries risks of:

QRS widening   Conduction block   Ventricular dysrhythmia   Seizures

Increasing cholinergic activity in this setting can produce dangerous bradyarrhythmia or other complications.

Antimuscarinic delirium in a suspected TCA overdose should therefore not be treated as though it were a pure atropine-like poisoning.

⸻

Flumazenil – Avoid

Flumazenil should generally be avoided in suspected TCA or mixed antidepressant overdose.

If a benzodiazepine has been coingested, its anticonvulsant activity may actually be protective.

Flumazenil can remove this protection and precipitate:

Seizures   Severe withdrawal   Increased cardiotoxic complications

⸻

Pulmonary Complications

Severe poisoning can cause:

Respiratory depression   Loss of airway reflexes   Aspiration pneumonitis   Acute lung injury

Early airway control may be appropriate when severe CNS depression or recurrent seizures compromise ventilation or airway protection.

⸻

Rhabdomyolysis

Rhabdomyolysis can follow:

Recurrent seizures   Hyperthermia   Prolonged coma   Severe agitation

Monitor selected severe cases with:

CK   Potassium   Creatinine   Urinalysis   Urine output

⸻

Metabolic Acidosis

Lactic acidosis can result from:

Seizures   Shock   Hypoxemia

Because acidemia potentiates sodium-channel toxicity, it is especially dangerous in TCA overdose.

Treatment focuses on correcting the underlying seizure, ventilation, and circulatory failure while using sodium bicarbonate when indicated for TCA cardiotoxicity.

⸻

Diagnosis

Diagnosis is based on:

Medication history   Clinical syndrome   ECG   Coingestant assessment

A quantitative serum TCA concentration is generally not useful for guiding acute treatment.

A severely toxic patient can require aggressive treatment regardless of the measured serum concentration.

⸻

Laboratory Evaluation

Significant poisoning may require:

Electrolytes   Bicarbonate   Glucose   Creatinine   Blood gas   CK after prolonged seizure/coma   Lactate in severe shock or seizures

Serial testing is more useful than isolated values when severe toxicity is evolving.

⸻

Occult Coingestion

Intentional TCA overdose commonly requires evaluation for additional substances.

Acetaminophen testing is often appropriate because early acetaminophen poisoning may be clinically silent.

Other testing should be directed by history and clinical findings.

⸻

Neuroimaging and Lumbar Puncture

Head CT, lumbar puncture, cultures, and other neurologic investigations are not automatically required simply because TCA poisoning causes coma or seizures.

They are appropriate when:

Diagnosis remains uncertain   Trauma is possible   Focal findings are present   Infection is suspected   Clinical course is inconsistent with poisoning

⸻

GI Decontamination

Do not induce vomiting.

Abrupt seizures and coma make emesis particularly dangerous.

⸻

Gastric Lavage

Routine gastric lavage is obsolete and should not be performed simply because the ingestion is large.

Potential harms include:

Aspiration   Mechanical injury   Delays in resuscitation

Airway, ECG, seizures, and circulation take priority.

⸻

Activated Charcoal

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

The airway is protected or reliably intact   Aspiration risk is acceptable   The drug remains potentially available for adsorption

TCAs slow gastric motility, so delayed absorption may occur.

However, this does not justify routine repeated charcoal administration.

⸻

Extracorporeal Removal

Hemodialysis and hemoperfusion do not meaningfully enhance TCA elimination because TCAs generally have:

Large volumes of distribution   Extensive tissue distribution   High protein binding

Extracorporeal therapy should therefore not delay proven supportive and sodium-bicarbonate-based treatment.

⸻

Refractory Cardiovascular Collapse

Rare massive TCA poisoning can produce profound shock or cardiac arrest despite conventional therapy.

Selected refractory cases may involve specialist consideration of:

Intravenous lipid emulsion as rescue therapy   VA-ECMO or other extracorporeal circulatory support

Evidence for lipid emulsion outside established indications is limited, so it is not routine first-line treatment.

ECMO provides temporary cardiopulmonary support while the toxin redistributes and is metabolized; it does not directly remove the TCA.

⸻

Monitoring

Clinically significant TCA poisoning requires close monitoring of:

Airway and ventilation   Mental status   Heart rate   Blood pressure   Continuous ECG   QRS duration   Temperature   Acid–base status   Electrolytes

Severe cases also require monitoring for:

Rhabdomyolysis   Renal injury   Recurrent seizures   Shock

⸻

Observation

Most serious TCA toxicity becomes evident relatively early after a substantial immediate-release ingestion, but the older universal “6-hour rule” should not be treated as absolute.

Disposition depends on:

Agent and formulation   Estimated exposure   Symptoms   Serial ECGs   Hemodynamics   Mental status   Coingestants   Clinical trajectory

Persistent tachycardia alone should be interpreted in the overall clinical context rather than automatically defining severe poisoning.

⸻

Admission

ICU-level care is appropriate for:

QRS widening   Significant hypotension   Ventricular dysrhythmia   Recurrent seizures   Coma   Respiratory failure   Severe acidemia   Other evidence of major cardiotoxicity

⸻

Pregnancy

Historical FDA pregnancy letter categories are obsolete.

In maternal TCA poisoning, priorities remain:

Airway and ventilation   Seizure control   Hemodynamic stabilization   Correction of cardiotoxicity

Maternal hypoxemia, hypotension, seizures, and dysrhythmias also threaten fetal perfusion and oxygenation.

Life-saving sodium bicarbonate and resuscitative treatment should not be withheld because of pregnancy.

⸻

Safeguarding

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

Pediatric poisoning should instead be assessed according to:

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

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

⸻

Prognosis

Patients who survive the acute cardiotoxic phase without major hypoxic or ischemic complications can recover completely.

Poor outcomes are generally associated with:

Prolonged hypotension   Refractory ventricular dysrhythmia   Cardiac arrest   Recurrent/prolonged seizures   Severe acidemia   Hypoxic brain injury

⸻

Important Modernization of the Older Source

TCA lethality is driven particularly by fast myocardial sodium-channel blockade, not simply monoamine-reuptake inhibition.   QRS widening is one of the most useful bedside markers of serious toxicity.   Historical QRS thresholds predict increasing risk but are not absolute treatment boundaries.   Lead aVR abnormalities support the diagnosis but should not be interpreted alone.   Acidemia potentiates TCA cardiotoxicity.   Sodium bicarbonate is first-line for significant QRS widening, ventricular conduction toxicity, and TCA-associated hypotension/cardiotoxicity.   Phenytoin is generally not preferred for TCA-induced seizures.   Class IA and IC antiarrhythmics can worsen sodium-channel blockade and should generally be avoided.   Physostigmine should generally be avoided in significant TCA poisoning.   Flumazenil is hazardous in TCA/mixed overdose because it may precipitate seizures.   Norepinephrine is generally preferred over the historical dopamine-first strategy for persistent shock.   Trendelenburg positioning is obsolete.   Ipecac and routine gastric lavage have no modern role.   Routine repeated activated charcoal is not established.   Hemodialysis and hemoperfusion do not meaningfully remove TCAs.   Selected refractory cardiovascular collapse may require rescue therapies such as ECMO.   Serum TCA concentrations do not guide acute treatment.

Key Points

TCA overdose = coma + convulsions + cardiotoxicity.   Na⁺-channel blockade → QRS widening → ventricular dysrhythmia and shock.   Acidemia worsens sodium-channel blockade.   Sodium bicarbonate is the cornerstone of cardiotoxicity treatment.   Benzodiazepines are first-line for seizures.   Avoid phenytoin as routine seizure therapy, physostigmine, flumazenil, and class IA/IC antiarrhythmics in significant TCA toxicity.   Obtain an early ECG and follow serial QRS/rhythm changes.   Significant hypotension, QRS widening, seizure, coma, or dysrhythmia warrants intensive monitoring.   Serum TCA levels are not useful for bedside treatment decisions.   Patients can deteriorate abruptly, so early recognition and aggressive supportive care are critical.

Toxicology – Venlafaxine and Related SNRIs

Core Concept

The historical term “bicyclic antidepressants” is no longer a useful modern toxicology classification for venlafaxine.

Venlafaxine is now classified as a serotonin–norepinephrine reuptake inhibitor (SNRI). Its active metabolite, desvenlafaxine, is also marketed as an antidepressant.

Venlafaxine overdose is clinically important because substantial poisoning can cause:

• Seizures
• Serotonin toxicity
• Tachycardia and hypertension
• CNS depression
• QRS or QT abnormalities
• Ventricular dysrhythmias
• Hypotension and cardiogenic shock in severe cases

The older description of venlafaxine overdose as predominantly “mild CNS depression” substantially understates its potential severity.

There is no specific antidote.

Historical Drugs

Older literature grouped several structurally related drugs together.

Venlafaxine

Remains widely used and is the principal clinically relevant drug in this older chapter.

Viloxazine

The source describes viloxazine as investigational. This is outdated.

Viloxazine has subsequently been used clinically in some jurisdictions, including as a nonstimulant treatment for ADHD. Its modern pharmacology and overdose profile should not simply be assumed to be identical to venlafaxine.

Zimelidine

Withdrawn decades ago after association with serious neurologic adverse effects, including Guillain–Barré syndrome. It is primarily of historical interest.

Mechanism of Venlafaxine

Venlafaxine inhibits reuptake of:

• Serotonin (5-HT)
• Norepinephrine (NE)

This increases synaptic monoamine concentrations.

At lower therapeutic exposure, serotonergic effects predominate; noradrenergic effects become more prominent as exposure increases.

It has relatively little direct muscarinic, histamine, or α₁-antagonist activity compared with classic TCAs.

Metabolism

Venlafaxine undergoes hepatic metabolism, importantly through CYP2D6, producing the active metabolite:

O-desmethylvenlafaxine = desvenlafaxine

Both parent drug and active metabolite contribute to clinical effects.

Renal elimination is important for the drug and its metabolites, so renal impairment can prolong exposure.

Immediate-Release vs Extended-Release

Venlafaxine is available in immediate- and extended-release formulations.

This distinction matters in overdose because modified-release products can produce:

• Delayed absorption
• Delayed peak toxicity
• Prolonged symptoms
• Delayed seizures

Therefore, a patient who initially appears well may not necessarily remain asymptomatic after a substantial extended-release ingestion.

Toxic Dose

There is no single reliable dose threshold that predicts an individual’s course.

In general:

Increasing exposure → increasing risk of seizures and cardiovascular toxicity

Very large overdoses can cause severe or fatal poisoning.

The historical statement that death had not been reported is obsolete.

Modern experience confirms that venlafaxine overdose can be fatal, particularly after massive ingestion or severe cardiovascular toxicity.

Neurologic Toxicity

Possible manifestations include:

• Dizziness
• Tremor
• Agitation
• Confusion
• Somnolence
• Myoclonus
• Seizures
• Coma

Seizures are one of the hallmark complications of significant venlafaxine overdose.

They may occur after an initially relatively benign period.

Seizures

Venlafaxine lowers the seizure threshold.

Seizures may be:

• Generalized
• Recurrent
• Delayed, especially with modified-release formulations

Complications include:

• Hypoxemia
• Aspiration
• Lactic acidosis
• Hyperthermia
• Rhabdomyolysis
• Acute kidney injury

Seizure Management

Benzodiazepines are first-line treatment for toxicant-induced seizures.

Persistent seizures may require:

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

Phenytoin is generally not preferred for toxicologic seizures.

Serotonin Toxicity

Venlafaxine can produce serotonin syndrome, particularly after substantial overdose or combination with other serotonergic drugs.

Important findings include:

• Agitation
• Diaphoresis
• Tremor
• Hyperreflexia
• Inducible or spontaneous clonus
• Ocular clonus
• Increased bowel activity
• Hyperthermia in severe cases

Severe toxicity may cause:

• Marked hyperthermia
• Rhabdomyolysis
• Coagulopathy
• Metabolic acidosis
• Multiorgan failure

Important Drug Interactions

Serotonin toxicity risk increases with other serotonergic agents, including:

• MAO inhibitors
• SSRIs
• Other SNRIs
• Certain serotonergic analgesics
• Some other serotonergic medications

Combination with an MAO inhibitor is particularly hazardous.

Sedative coingestants may increase CNS and respiratory depression.

Cardiovascular Effects

Mild or moderate poisoning commonly produces:

• Sinus tachycardia
• Mild hypertension

Increasing toxicity may produce:

• Hypotension
• QRS prolongation
• QT prolongation
• Ventricular dysrhythmias
• Myocardial dysfunction

Massive poisoning can produce profound cardiovascular collapse.

Severe Cardiovascular Toxicity

In very large overdose, venlafaxine may produce:

• Reduced myocardial contractility
• Cardiogenic shock
• Ventricular dysrhythmias
• Severe hypotension

This is clinically distinct from the usually mild cardiovascular effects of many SSRI overdoses.

ECG

An ECG is important after significant venlafaxine overdose.

Assess:

• Heart rate
• Rhythm
• QRS duration
• QT/QTc
• Conduction abnormalities

Continuous cardiac monitoring is appropriate for symptomatic or substantial poisoning.

QRS Widening

Marked QRS widening after venlafaxine overdose suggests clinically significant myocardial conduction toxicity.

Sodium bicarbonate has been used when substantial sodium-channel-like conduction toxicity is present, particularly with:

• Significant QRS widening
• Ventricular dysrhythmia associated with conduction slowing

However, venlafaxine cardiotoxicity can involve more than a simple TCA-like sodium-channel mechanism, so bicarbonate should not be assumed to reverse every cardiovascular manifestation.

QT Prolongation

QT prolongation may occur, particularly in severe poisoning or when additional risk factors are present.

Correct:

• Hypokalemia
• Hypomagnesemia
• Hypocalcemia when clinically significant

Avoid additional QT-prolonging medications when possible.

Torsades de pointes is managed according to standard toxicologic resuscitation principles.

Blood Pressure

Early findings may include hypertension because of increased noradrenergic activity.

Severe poisoning may instead progress to:

• Vasodilatory hypotension
• Myocardial dysfunction
• Cardiogenic shock

Thus, the blood-pressure pattern can change as toxicity becomes more severe.

Hypotension

Management includes assessment of:

• Volume status
• Cardiac function
• Rhythm
• Acid–base status
• Coingestants

Appropriate isotonic crystalloid may be used when indicated.

Persistent shock may require vasopressor support, commonly with norepinephrine, while severe myocardial dysfunction may require more advanced hemodynamic support.

Routine Trendelenburg positioning and a dopamine-first approach are outdated.

Refractory Cardiogenic Shock

Massive venlafaxine poisoning can occasionally cause profound reversible myocardial failure.

Severe refractory cases may require advanced critical-care support, including consideration of mechanical circulatory support such as VA-ECMO in appropriately selected patients.

ECMO supports circulation while the drug is metabolized; it does not function as a venlafaxine antidote.

Hyperthermia

Hyperthermia should raise concern for:

• Serotonin toxicity
• Recurrent seizures
• Severe agitation

Marked hyperthermia is an emergency because it can rapidly cause:

• Rhabdomyolysis
• Hepatic injury
• Coagulopathy
• Renal failure
• CNS injury

Management emphasizes sedation, control of muscular activity, and active cooling.

Antipyretics are not useful for serotonin-mediated hyperthermia.

Hyponatremia / SIADH

SNRIs can be associated with:

• SIADH
• Hyponatremia

This is particularly relevant during therapeutic use in susceptible patients, such as older adults or those taking other medications that promote hyponatremia.

Severe hyponatremia can itself produce:

• Confusion
• Seizures
• Coma

Therefore, electrolytes are important when neurologic findings are present.

Gastrointestinal Effects

Possible findings include:

• Nausea
• Vomiting
• Dry mouth
• Abdominal discomfort

These are generally secondary concerns compared with neurologic and cardiovascular toxicity.

Diagnosis

Diagnosis is primarily based on:

• Drug and formulation
• Amount
• Time of ingestion
• Symptoms
• ECG
• Coingestants

Serum venlafaxine concentrations are not routinely useful for emergency management.

Laboratory Evaluation

Mild uncomplicated exposure may require limited testing.

Significant poisoning may warrant:

• Electrolytes
• Sodium
• Potassium
• Bicarbonate
• Creatinine
• Glucose
• CK if seizures/hyperthermia occur
• Blood gas and lactate in severe poisoning

Severe hyperthermia or shock may additionally require:

• Liver tests
• Coagulation studies
• Serial renal assessment

Occult Coingestion

Intentional antidepressant overdose should prompt assessment for important coingestants.

Acetaminophen testing is often appropriate because clinically important early poisoning can be asymptomatic.

Salicylate testing should be based on the circumstances and clinical/acid–base findings rather than used mechanically in every case.

Imaging and Lumbar Puncture

Head CT, lumbar puncture, and cultures are not routinely required merely because venlafaxine causes altered mental status or a seizure.

They should be considered when:

• The diagnosis remains uncertain
• Focal neurologic deficits occur
• Trauma is possible
• CNS infection is suspected
• Mental status fails to follow the expected toxicologic course

Initial Management

Priorities are:

Airway/breathing → seizure control → temperature → ECG/circulation → identify serotonin toxicity → monitor for delayed deterioration

Supportive care remains the foundation of treatment.

Physostigmine

Physostigmine has no routine role in venlafaxine poisoning.

Venlafaxine does not produce a classic pure antimuscarinic syndrome, and significant poisoning carries seizure and cardiovascular risks.

GI Decontamination

Do not induce vomiting.

Routine gastric lavage is obsolete.

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

• The airway is reliably protected
• Aspiration risk is acceptable
• Expected benefit justifies treatment

It should never delay stabilization of seizures, hyperthermia, or cardiovascular toxicity.

Extended-Release Ingestion

Because extended-release venlafaxine can remain within the GI tract for prolonged periods, substantial ingestion may require longer monitoring than an immediate-release exposure.

Selected very large modified-release ingestions may warrant specialist discussion regarding additional GI decontamination strategies, but these are not routine measures for every overdose.

Hemodialysis and Hemoperfusion

Conventional hemodialysis and hemoperfusion do not provide useful routine venlafaxine elimination because of its pharmacokinetic characteristics.

Dialysis may still be required for a separate indication such as severe renal failure, but it should not be viewed as the primary antidotal treatment.

Monitoring

Significant poisoning requires monitoring of:

• Mental status
• Respiratory function
• Heart rate
• Blood pressure
• ECG
• Core temperature
• Seizure activity

Severe cases additionally require monitoring of:

• CK
• Electrolytes
• Renal function
• Lactate/acid–base status
• Liver function
• Coagulation

Observation

The older assumption that toxicity simply appears within a few hours and resolves within 24–48 hours is too rigid.

Observation should consider:

• Immediate- vs extended-release preparation
• Estimated exposure
• Symptoms
• ECG
• Seizures
• Serotonin toxicity
• Coingestants
• Clinical trajectory

Delayed seizures are particularly important after extended-release venlafaxine.

Admission

Hospital admission is appropriate for:

• Seizure
• Persistent altered mental status
• Serotonin toxicity
• Hyperthermia
• Significant QRS or QT abnormality
• Dysrhythmia
• Persistent hypotension
• Evidence of myocardial dysfunction
• Significant metabolic or end-organ injury

Severe cardiovascular toxicity, recurrent seizures, or marked hyperthermia warrants intensive care.

Pregnancy

The historical FDA pregnancy letter category is obsolete.

Management of significant overdose during pregnancy prioritizes maternal:

• Airway
• Oxygenation
• Blood pressure
• Temperature
• Seizure control

Severe maternal hypoxemia, shock, hyperthermia, or seizures also threaten fetal well-being.

Safeguarding

The historical rigid age thresholds for neglect or intentional poisoning are inappropriate.

Pediatric exposures should instead be evaluated according to:

• Developmental capability
• Medication accessibility
• Circumstances
• Consistency of history
• Recurrent unexplained exposures
• Broader safeguarding concerns

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

Prognosis

Most mild venlafaxine overdoses recover with supportive treatment.

Increasingly severe poisoning carries risk of:

• Recurrent seizures
• Serotonin toxicity
• Hyperthermia
• Rhabdomyolysis
• Ventricular dysrhythmias
• Cardiogenic shock
• Multiorgan injury

Massive venlafaxine overdose can be fatal, contrary to the historical source.

Important Modernization of the Older Source

• “Bicyclic antidepressant” is an outdated classification for venlafaxine; it is an SNRI.
• Desvenlafaxine is its pharmacologically active metabolite and also a marketed drug.
• Venlafaxine overdose is not simply a mild CNS-depressant syndrome.
• Seizures are a major hallmark of significant poisoning.
• Extended-release preparations can cause delayed seizures and prolonged toxicity.
• Serotonin syndrome is an important complication, especially with serotonergic coexposure.
• Massive overdose can cause QRS/QT abnormalities, ventricular dysrhythmias, myocardial dysfunction, cardiogenic shock, and death.
• Zimelidine is historical; viloxazine should not simply be treated as interchangeable with venlafaxine.
• Phenytoin is generally not preferred for toxicologic seizures.
• Trendelenburg and routine dopamine-first shock treatment are outdated.
• Severe reversible cardiogenic shock may occasionally require advanced mechanical circulatory support.
• Routine gastric lavage is obsolete.
• Activated charcoal has a selective role when the airway is safe.
• Hemodialysis does not meaningfully enhance venlafaxine elimination.
• Observation should account for formulation and delayed toxicity rather than follow a fixed short period.
• There is no specific antidote.

Key Points

• Venlafaxine = SNRI, not a clinically useful “bicyclic” category.
• Major overdose risks = seizures + serotonin toxicity + cardiovascular toxicity.
• Mild poisoning often causes tachycardia, hypertension, tremor, and CNS symptoms.
• Severe poisoning can progress to hyperthermia, QRS/QT abnormalities, dysrhythmias, hypotension, and cardiogenic shock.
• Extended-release venlafaxine can produce delayed toxicity.
• Benzodiazepines are first-line for seizures.
• Significant hyperthermia requires control of muscular activity and active cooling.
• Obtain ECG monitoring after substantial or symptomatic overdose.
• Dialysis is not useful for routine toxin removal.
• No specific antidote exists.

Toxicology – Anticholinergic (Antimuscarinic) Compounds

Core Concept

A wide range of prescription drugs, OTC medications, plants, and other substances can produce antimuscarinic toxicity, traditionally called the anticholinergic syndrome.

The classic toxidrome consists of:

Delirium + mydriasis + dry skin/mucosa + tachycardia + hyperthermia + decreased bowel activity + urinary retention

Severe poisoning may cause:

• Extreme agitation
• Hallucinations
• Seizures
• Coma
• Hyperthermia
• Rhabdomyolysis
• Cardiovascular toxicity

Most cases are diagnosed clinically from the toxidrome, rather than by serum drug concentrations.

Terminology

“Anticholinergic” is commonly used, but antimuscarinic is more pharmacologically precise for this syndrome.

These drugs competitively antagonize acetylcholine primarily at muscarinic receptors.

They do not simply block every cholinergic receptor.

Common Causes

Important antimuscarinic drugs include:

• Atropine
• Scopolamine
• Benztropine
• Trihexyphenidyl
• Oxybutynin
• Tolterodine
• Solifenacin
• Trospium
• Dicyclomine
• Glycopyrrolate
• Cyclopentolate
• Tropicamide
• Ipratropium

Many other medications have clinically important antimuscarinic properties, including:

• Diphenhydramine
• Doxylamine
• Tricyclic antidepressants
• Some antipsychotics
• Some skeletal-muscle relaxants
• Some antiparkinsonian drugs

Certain plants containing atropine-like alkaloids can produce the same syndrome.

Muscarinic Physiology

Acetylcholine acting at muscarinic receptors normally contributes to:

• Salivation
• Lacrimation
• Sweating
• Pupillary constriction
• Accommodation
• GI motility
• Bladder contraction
• Parasympathetic cardiac regulation

Blocking these actions produces the characteristic toxidrome.

Central vs Peripheral Effects

Antimuscarinic toxicity can be divided conceptually into:

Central effects

• Agitation
• Confusion
• Delirium
• Hallucinations
• Disorganized behavior
• Seizures
• Coma

Peripheral effects

• Mydriasis
• Blurred vision
• Dry mouth
• Dry skin
• Flushing
• Tachycardia
• Reduced bowel sounds
• Ileus
• Urinary retention
• Hyperthermia

Not every patient develops every finding.

Classic Clinical Mnemonic

The traditional descriptions remain useful:

• “Mad as a hatter” → delirium
• “Blind as a bat” → mydriasis/cycloplegia
• “Dry as a bone” → dry skin and mucosa
• “Red as a beet” → flushing
• “Hot as a hare” → hyperthermia
• “Full as a flask” → urinary retention

These are memory aids rather than diagnostic criteria.

Mental Status

Central antimuscarinic toxicity commonly produces a distinctive agitated delirium.

Features can include:

• Confusion
• Disorientation
• Inattention
• Picking at imaginary objects
• Visual hallucinations
• Paranoia
• Incoherent speech
• Restlessness
• Attempting to climb from bed

The patient may interact with objects or people that are not present.

Severe poisoning may progress from agitation to:

• Somnolence
• Seizures
• Coma

Tachycardia

Sinus tachycardia is common because vagal muscarinic influence on the heart is reduced.

However, the older statement that absence of tachycardia should strongly call the diagnosis into question is too rigid.

Heart rate can be influenced by:

• Age
• Coingestants
• β-blockers
• Baseline conduction disease
• Specific antimuscarinic agent
• Timing of examination

Diagnosis should be based on the entire syndrome.

Eyes

Typical findings include:

• Mydriasis
• Reduced pupillary response
• Cycloplegia
• Blurred near vision
• Photophobia

Ophthalmic antimuscarinic medications can occasionally cause systemic toxicity, particularly in susceptible patients.

Unilateral Mydriasis

Accidental exposure of only one eye to:

• Atropine
• Tropicamide
• Cyclopentolate
• Scopolamine-like substances

can produce unilateral pharmacologic mydriasis.

This can mimic a neurologic emergency.

However, unexplained new anisocoria should not automatically be attributed to a medication unless the exposure history and examination are convincing.

Skin and Secretions

Typical findings include:

• Warm skin
• Dry skin
• Flushing
• Dry mouth
• Reduced salivation

Sweating is impaired because eccrine sweat glands use muscarinic cholinergic signaling, despite belonging anatomically to the sympathetic nervous system.

This is an important physiologic exception.

Hyperthermia

Hyperthermia can result from:

• Impaired sweating
• Reduced heat dissipation
• Agitation
• Excessive muscular activity

Severe hyperthermia can cause:

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

Children may be particularly susceptible to impaired heat dissipation.

Gastrointestinal Effects

Muscarinic blockade reduces GI motility.

Possible findings include:

• Reduced bowel sounds
• Constipation
• Abdominal distension
• Ileus

Slowed GI motility can also delay absorption of an ingested drug, contributing to prolonged or delayed toxicity.

Urinary Retention

Muscarinic blockade interferes with detrusor contraction and may cause:

• Difficulty voiding
• Bladder distension
• Urinary retention

A distended bladder can itself worsen agitation and delirium.

Bladder assessment is therefore useful in a persistently agitated patient.

Sympathomimetic vs Antimuscarinic Toxicity

Both syndromes can cause:

• Agitation
• Tachycardia
• Hypertension
• Mydriasis
• Hyperthermia

A useful distinction is:

Sympathomimetic toxicity → usually sweaty

Antimuscarinic toxicity → usually dry

Sympathomimetic poisoning also tends to preserve or increase bowel activity, whereas antimuscarinic toxicity tends to reduce it.

No single finding is perfectly diagnostic.

Cardiovascular Toxicity

Pure antimuscarinic poisoning usually produces:

• Sinus tachycardia

Major dysrhythmias are uncommon with drugs whose only important mechanism is muscarinic blockade.

Therefore:

QRS widening, major QT abnormalities, ventricular dysrhythmias, or severe hypotension should raise concern for additional toxic mechanisms or coingestants.

Diphenhydramine – Important Exception

Large diphenhydramine overdoses can cause both:

• Antimuscarinic delirium
• Myocardial sodium-channel blockade

This can produce:

• QRS widening
• Ventricular dysrhythmias
• Seizures

Therefore, a patient may appear strongly antimuscarinic while simultaneously having potentially dangerous cardiotoxicity.

Tricyclic Antidepressants

TCAs can cause:

• Antimuscarinic findings
• CNS toxicity
• Seizures
• α₁ blockade
• Sodium-channel blockade

A patient with antimuscarinic delirium plus:

• QRS widening
• Hypotension
• Ventricular dysrhythmia
• Significant terminal R-wave abnormalities in aVR

should be evaluated for TCA or another sodium-channel-blocking drug.

Seizures

Seizures can occur in severe poisoning or when the causative drug has additional proconvulsant properties.

Management includes:

• Airway and oxygenation assessment
• Benzodiazepines as first-line anticonvulsant therapy
• Correction of glucose and important metabolic abnormalities
• Escalation according to toxicologic status-epilepticus management if persistent

Rhabdomyolysis

Severe agitation, hyperthermia, or seizures can produce rhabdomyolysis.

Evaluate significant cases with:

• CK
• Potassium
• Creatinine
• Urinalysis
• Urine output

Prompt control of agitation and temperature helps prevent this complication.

Diagnosis

Antimuscarinic poisoning is primarily a clinical diagnosis.

Important clues include:

• Characteristic toxidrome
• Medication history
• Plant exposure
• OTC medication access
• Prescription medications
• Coingestants

Routine measurement of serum concentrations is usually unnecessary for pure antimuscarinic agents.

Laboratory Evaluation

Mild uncomplicated cases may require little testing.

In significant toxicity, useful studies may include:

• Glucose
• Electrolytes
• Bicarbonate
• Creatinine
• CK
• Urinalysis
• Temperature measurement

Additional testing depends on the differential diagnosis and suspected drug.

ECG

An ECG is particularly important when:

• The exact drug is uncertain
• Intentional overdose occurred
• Diphenhydramine is suspected
• TCA exposure is possible
• Seizures occur
• Significant tachycardia or hypotension is present

Look for:

• QRS widening
• QT prolongation
• Conduction abnormalities
• Ventricular dysrhythmias

The ECG is also critical when considering physostigmine.

Occult Coingestion

Intentional poisoning should prompt evaluation for clinically important coingestants.

Acetaminophen screening is often relevant because early acetaminophen poisoning may be asymptomatic.

Other testing should be directed by history, examination, ECG, and acid–base findings rather than performed indiscriminately.

Initial Management

The priorities are:

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

Most patients improve with supportive care.

Environmental Management

Patients with delirium benefit from:

• A calm environment
• Reduced unnecessary stimulation
• Close observation
• Protection from falls and trauma

Physical restraints alone can increase:

• Muscular activity
• Hyperthermia
• Acidosis
• Rhabdomyolysis

If restraints are temporarily necessary for immediate safety, adequate chemical sedation and continuous reassessment are important.

Agitation

Benzodiazepines can be used for significant agitation, particularly when:

• The diagnosis is uncertain
• Seizures are possible
• Physostigmine is inappropriate
• Mixed poisoning is suspected

Excessive nonspecific sedation should be avoided when a more targeted and appropriate treatment is available.

Physostigmine

Physostigmine is a reversible acetylcholinesterase inhibitor that crosses the blood–brain barrier.

It increases acetylcholine in both the CNS and peripheral nervous system.

In a carefully selected patient, it can rapidly reverse:

• Delirium
• Hallucinations
• Agitation
• Confusion

and may improve peripheral antimuscarinic findings.

Modern Role of Physostigmine

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

Its modern role is mainly therapeutic in selected patients with severe, predominantly pure antimuscarinic delirium.

It should not be used merely to prove the diagnosis or to avoid otherwise clinically necessary diagnostic evaluation.

When Physostigmine May Be Appropriate

Consider it when there is:

• Convincing antimuscarinic delirium
• Significant agitation or hallucinations
• A predominantly pure antimuscarinic exposure
• No important ECG evidence of sodium-channel blockade
• No major contraindicating coingestion

Selection should be cautious and ideally involve toxicology/poison-center guidance.

When Physostigmine Should Be Avoided

Avoid or use extreme caution when there is:

• Significant QRS widening
• Suspected TCA poisoning
• Significant sodium-channel blockade
• Important conduction disease
• Bradycardia
• High-risk proconvulsant coingestion
• Uncertain mixed overdose where dangerous cardiotoxicity is plausible

The older blanket contraindication lists involving conditions such as diabetes or all asthma are not the main modern toxicologic decision points.

Physostigmine Adverse Effects

Excessive acetylcholinesterase inhibition can produce cholinergic toxicity.

Possible effects include:

• Bradycardia
• Bronchorrhea
• Bronchospasm
• Sweating
• Salivation
• Nausea
• Vomiting
• Diarrhea
• Hypotension
• Seizures

Administration should therefore occur in an appropriately monitored setting with resuscitation capability.

Recurrence After Physostigmine

Physostigmine may have a shorter duration than the causative drug.

Therefore:

Initial improvement does not necessarily mean the poisoning has resolved.

Antimuscarinic delirium may recur and require continued observation and reassessment.

Sodium Bicarbonate

If an antimuscarinic-appearing overdose also produces significant sodium-channel blockade, sodium bicarbonate may be indicated.

Examples include severe poisoning with:

• Diphenhydramine
• Tricyclic antidepressants
• Other sodium-channel-blocking agents

Treatment is directed at the conduction toxicity, not at muscarinic blockade itself.

GI Decontamination

Ipecac is obsolete and should not be used.

Inducing vomiting is particularly dangerous because delirium, seizures, and CNS depression can develop unexpectedly.

Gastric Lavage

Routine gastric lavage is not recommended.

The historical idea that antimuscarinic-induced delayed gastric emptying automatically justifies lavage many hours after ingestion is not supported as a routine modern strategy.

Risks include:

• Aspiration
• Airway complications
• Mechanical injury

Activated Charcoal

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

• The substance is adsorbable
• The airway is safe
• Expected benefit outweighs aspiration risk

Because antimuscarinic drugs may slow gastric emptying, useful drug may occasionally remain in the stomach longer than expected, but this does not justify routine late charcoal.

Repeat-dose charcoal is not routinely indicated simply because a drug is antimuscarinic.

Hyperthermia Management

Management includes:

• Control of agitation
• Removal of excess clothing
• External cooling
• Appropriate IV fluids
• Treatment of seizures

Antipyretics are not effective because antimuscarinic hyperthermia is not caused by an elevated hypothalamic fever set point.

Urinary Retention

Clinically significant bladder distension may require bladder decompression.

This can sometimes substantially improve agitation and discomfort.

Monitoring

Significant poisoning warrants monitoring of:

• Mental status
• Heart rate
• Blood pressure
• Core temperature
• ECG when appropriate
• Hydration
• Urine output

Severe cases additionally require monitoring for:

• CK elevation
• Renal injury
• Electrolyte abnormalities
• Hyperthermic complications

Observation

Antimuscarinic toxicity may persist longer than expected because:

• Some causative drugs have long half-lives
• GI motility is reduced
• Absorption may be delayed
• Active metabolites may persist

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

Observation should depend on:

• Agent
• Formulation
• Amount
• Symptoms
• Mental status trajectory
• ECG
• Coingestants
• Need for sedatives or physostigmine

Differential Diagnosis

Other causes of delirium, tachycardia, mydriasis, or hyperthermia include:

• Sympathomimetic poisoning
• Serotonin syndrome
• Alcohol or sedative withdrawal
• Mania or psychosis
• Hyperthyroidism/thyroid storm
• CNS infection
• Sepsis
• Hypoglycemia
• Intracranial hemorrhage
• Postictal states

The toxidrome should guide evaluation, but alternative dangerous diagnoses should not be ignored.

Pregnancy

The historical FDA pregnancy letter categories are obsolete.

Management of clinically significant poisoning during pregnancy focuses on:

• Maternal airway
• Oxygenation
• Temperature
• Hemodynamics
• Seizure control

Medication-specific fetal considerations can then be addressed according to the actual causative drug.

Safeguarding

Rigid age cutoffs for presumed neglect, abuse, or intentional poisoning are outdated.

Pediatric exposure should instead be evaluated according to:

• Developmental capability
• Access to medications
• Circumstances
• Consistency of the history
• Recurrent unexplained exposures
• Broader safeguarding concerns

Prognosis

Most uncomplicated antimuscarinic poisonings resolve completely with supportive care.

Severe outcomes are more likely when there is:

• Extreme hyperthermia
• Refractory agitation
• Seizures
• Rhabdomyolysis
• Aspiration
• Trauma during delirium
• Sodium-channel cardiotoxicity from the particular drug
• Significant coingestion

Important Modernization of the Older Source

• Antimuscarinic is the more precise term for the classic “anticholinergic” toxidrome.
• Diagnosis is clinical and does not require every classic feature.
• Absence of tachycardia does not absolutely exclude the syndrome.
• Sympathomimetic toxicity usually causes diaphoresis, whereas antimuscarinic poisoning usually produces dry skin and mucosa.
• Major QRS widening or ventricular dysrhythmia suggests an additional mechanism such as sodium-channel blockade.
• Diphenhydramine and TCAs can produce both antimuscarinic findings and dangerous cardiotoxicity.
• Physostigmine is no longer viewed merely as a diagnostic challenge; it can be a targeted therapeutic antidote in carefully selected pure antimuscarinic delirium.
• Avoid physostigmine when significant sodium-channel blockade, TCA toxicity, or another major contraindicating mechanism is suspected.
• Benzodiazepines remain important for seizures and selected agitation.
• Ipecac is obsolete.
• Routine gastric lavage is inappropriate.
• Delayed gastric emptying does not automatically justify late lavage or repeated charcoal.
• Physical restraint alone can worsen hyperthermia and rhabdomyolysis.
• Antipyretics do not treat antimuscarinic hyperthermia.
• Observation should be based on the specific drug, formulation, symptoms, ECG, and clinical course rather than a fixed time.

Key Points

• Muscarinic blockade → dry, dilated, tachycardic, delirious, hot, urinary-retaining patient.
• Central toxicity produces delirium, hallucinations, agitation, seizures, and occasionally coma.
• Peripheral toxicity produces mydriasis, dry mucosa/skin, tachycardia, ileus, urinary retention, and impaired sweating.
• Dry skin helps distinguish antimuscarinic from sympathomimetic toxicity.
• Obtain an ECG when the drug is uncertain or cardiotoxic coeffects are possible.
• QRS widening suggests sodium-channel blockade, not simple muscarinic antagonism.
• Benzodiazepines are first-line for toxicologic seizures.
• Physostigmine can reverse severe pure antimuscarinic delirium in appropriately selected patients.
• Hyperthermia requires sedation, cooling, and supportive care—not antipyretics.
• Ipecac and routine gastric lavage have no modern role.

Toxicology – Angiotensin-Converting Enzyme (ACE) Inhibitors

Core Concept

ACE inhibitors are widely used cardiovascular and renal medications. Important examples include:

• Captopril
• Enalapril
• Lisinopril
• Ramipril
• Benazepril
• Fosinopril
• Perindopril
• Quinapril
• Trandolapril

They are used for conditions such as:

• Hypertension
• Heart failure with reduced ejection fraction
• Post-myocardial-infarction ventricular dysfunction
• Selected chronic kidney disease, particularly with albuminuria
• Other conditions involving the renin–angiotensin–aldosterone system (RAAS)

Most isolated ACE-inhibitor overdoses produce mild or moderate hypotension, but severe vasodilatory shock can occur after a very large exposure or when important coingestants or comorbidities are present.

There is no routinely required specific antidote.

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Renin–Angiotensin–Aldosterone System

The RAAS helps maintain:

• Blood pressure
• Vascular tone
• Sodium balance
• Extracellular fluid volume
• Renal perfusion

Reduced renal perfusion stimulates renin release.

The sequence is:

Angiotensinogen → angiotensin I → ACE → angiotensin II

Angiotensin II then:

• Produces vasoconstriction
• Stimulates aldosterone secretion
• Promotes sodium retention
• Supports blood pressure and renal hemodynamics

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Mechanism of ACE Inhibition

ACE inhibitors block conversion of:

Angiotensin I → Angiotensin II

Consequences include:

• Reduced vasoconstriction
• Reduced aldosterone secretion
• Reduced sodium retention
• Reduced systemic vascular resistance
• Lower blood pressure

In overdose, excessive loss of angiotensin-II-mediated vascular tone can cause significant hypotension.

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Bradykinin

ACE also normally degrades bradykinin.

ACE inhibition therefore increases bradykinin activity.

This contributes to:

• Vasodilation
• Dry cough
• ACE-inhibitor-associated angioedema

This mechanism is clinically important because ACE-inhibitor angioedema is bradykinin-mediated, rather than a conventional histamine-mediated allergic reaction.

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Toxic Dose

There is no reliable universal toxic dose.

Many isolated ingestions, including some apparently large ones, produce only limited hypotension.

Severity depends on:

• Specific ACE inhibitor
• Amount and formulation
• Baseline blood pressure
• Hydration status
• Renal function
• Age and frailty
• Coingestants
• Concurrent antihypertensive therapy

Clinical findings are more useful than the reported dose alone.

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Principal Acute Toxicity – Hypotension

The major manifestation of acute overdose is:

Reduced angiotensin II → vasodilation → decreased systemic vascular resistance → hypotension

Possible symptoms include:

• Dizziness
• Weakness
• Lightheadedness
• Orthostatic symptoms
• Syncope

Severe poisoning may produce:

• Persistent hypotension
• Altered mental status
• Oliguria
• Acute kidney injury
• Shock

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Heart Rate

Tachycardia may accompany hypotension, but the response is variable.

Bradycardia is not usually the defining feature of isolated ACE-inhibitor overdose.

If substantial bradycardia occurs, consider:

• β-blocker coingestion
• Calcium-channel blocker coingestion
• Digoxin
• Clonidine
• Conduction disease
• Hyperkalemia
• Other causes

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Hyperkalemia

ACE inhibition reduces aldosterone activity.

This decreases renal potassium excretion and can produce:

Hyperkalemia

Risk is greatest with:

• Chronic kidney disease
• Acute kidney injury
• Potassium supplements
• Potassium-sparing diuretics
• Other RAAS inhibitors
• Significant dehydration or renal hypoperfusion

Hyperkalemia may be more clinically important than the initial blood-pressure abnormality in susceptible patients.

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Renal Effects

Angiotensin II normally constricts the efferent arteriole, helping maintain glomerular filtration when renal perfusion falls.

ACE inhibition reduces this compensatory effect.

Consequently, renal function may deteriorate in settings such as:

• Severe volume depletion
• Renal hypoperfusion
• Bilateral renal artery stenosis
• Advanced kidney disease
• Severe hypotension

Monitor creatinine and urine output in clinically significant poisoning.

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ACE-Inhibitor Angioedema

One of the most important adverse effects is bradykinin-mediated angioedema.

It can involve:

• Lips
• Tongue
• Floor of mouth
• Oropharynx
• Larynx

Severe swelling can cause life-threatening airway obstruction.

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Clinical Pattern of Angioedema

Typical findings include:

• Nonpitting swelling
• Lip or tongue enlargement
• Voice change
• Dysphagia
• Drooling
• Throat tightness
• Stridor in advanced disease

Unlike histamine-mediated anaphylaxis, ACE-inhibitor angioedema often occurs without urticaria or generalized pruritus.

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Timing of Angioedema

Angioedema can occur:

• Soon after starting therapy
• Months later
• Even after years of previously tolerated treatment

Therefore, long-term uneventful use does not exclude an ACE inhibitor as the cause.

Angioedema is an adverse drug reaction and does not require an overdose.

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Airway Management

Airway assessment is the highest priority in significant ACE-inhibitor angioedema.

Concerning findings include:

• Progressive tongue swelling
• Floor-of-mouth swelling
• Voice change
• Drooling
• Dysphagia
• Stridor
• Respiratory distress

If airway compromise is developing:

Secure the airway before swelling progresses to the point that intubation becomes extremely difficult.

Severe cases may require advanced airway expertise and preparation for a surgical airway.

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Epinephrine, Antihistamines, and Steroids

A critical distinction is that ACE-inhibitor angioedema is primarily bradykinin-mediated.

Therefore:

• Antihistamines
• Corticosteroids
• Epinephrine

do not directly reverse the underlying bradykinin mechanism and may have limited benefit in isolated ACE-inhibitor angioedema.

However, if the diagnosis is uncertain and anaphylaxis is possible, epinephrine should not be withheld from a patient with a compatible life-threatening allergic reaction.

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Bradykinin-Targeted Therapies

Several therapies have been studied or used for severe ACE-inhibitor angioedema, including agents that target bradykinin pathways and, in some settings, plasma-derived products.

Evidence has been mixed, and no pharmacologic treatment should delay definitive airway management.

The key principle is:

Airway protection takes precedence over medication.

⸻

ACE-Inhibitor Cough

A persistent dry cough can occur during therapeutic treatment.

This is associated with increased bradykinin and related mediators.

The cough is:

• Usually nonproductive
• Not evidence of pulmonary edema by itself
• Reversible after discontinuation, although resolution may take longer than only a few days in some patients

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Other Chronic Adverse Effects

Less common adverse effects include:

• Dysgeusia, particularly with captopril
• Rash
• Renal dysfunction
• Rare hepatic injury
• Rare hematologic abnormalities

These are not the defining findings of acute overdose.

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Diagnosis

ACE-inhibitor poisoning is usually a clinical diagnosis based on:

• Medication history
• Amount and timing
• Vital signs
• Renal function
• Potassium
• Coingestants

Serum ACE-inhibitor concentrations are not useful for routine emergency management.

⸻

Laboratory Evaluation

A small, asymptomatic isolated exposure may require little testing.

For symptomatic or substantial poisoning, useful tests include:

• Electrolytes
• Potassium
• Bicarbonate
• Creatinine
• Glucose

Additional testing depends on clinical severity and suspected coingestants.

⸻

ECG

An ECG is appropriate when there is:

• Significant hypotension
• Hyperkalemia
• Syncope
• Intentional overdose
• Suspected cardiovascular coingestion

Marked conduction abnormalities are not typical of isolated ACE-inhibitor poisoning and should prompt investigation for:

• Hyperkalemia
• β-blockers
• Calcium-channel blockers
• Sodium-channel blockers
• Other coingestants

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Differential Diagnosis of Hypotension

Toxicologic possibilities include:

• β-blockers
• Calcium-channel blockers
• α₁ antagonists
• Clonidine and other imidazolines
• Nitrates
• Tricyclic antidepressants
• Other vasodilators

Nontoxicologic possibilities include:

• Dehydration
• Sepsis
• Hemorrhage
• Cardiogenic shock
• Adrenal crisis
• Anaphylaxis
• Autonomic dysfunction

Severe or unusual findings should not automatically be attributed to the ACE inhibitor.

⸻

Initial Management

Management centers on:

Airway assessment → circulation/perfusion → renal and potassium evaluation → supportive care

For uncomplicated isolated overdose, supportive treatment is usually sufficient.

⸻

IV Fluids

Hypotension may respond to appropriate isotonic crystalloid, especially when volume depletion is contributing.

However, fluid administration should be individualized in patients with:

• Heart failure
• Renal impairment
• Pulmonary edema

The goal is restoration of adequate perfusion rather than administration of a fixed volume.

⸻

Trendelenburg – Modern Correction

Routine Trendelenburg positioning is obsolete for treatment of hypotension.

It provides no reliable sustained improvement in organ perfusion and may worsen respiratory mechanics.

⸻

Vasopressors

Persistent shock despite appropriate initial fluid resuscitation may require vasopressor therapy.

Norepinephrine is generally a reasonable first-line vasopressor for persistent vasodilatory shock.

The historical dopamine-first approach is no longer routinely preferred.

⸻

Refractory ACE-Inhibitor Shock

Rare severe overdose can produce hypotension that is unusually resistant to conventional vasopressors because the RAAS pathway itself is blocked.

Angiotensin II has been used in selected cases of severe refractory ACE-inhibitor-associated vasodilatory shock.

This is a specialist/critical-care intervention rather than routine therapy for ordinary ACE-inhibitor ingestion.

⸻

Atropine

Atropine is useful only when clinically significant bradycardia contributes to poor perfusion.

It is not an antidote to ACE inhibition and should not be routinely administered simply because the patient is hypotensive.

⸻

Hyperkalemia Management

Clinically important hyperkalemia should be managed according to severity.

Principles include:

• ECG assessment
• Cardiac membrane stabilization when indicated
• Intracellular potassium shifting
• Correction of contributing abnormalities
• Potassium removal when required
• Dialysis in selected severe cases, particularly with renal failure

Treatment is based on the potassium level, ECG, clinical condition, renal function, and trajectory.

⸻

GI Decontamination

Do not induce vomiting.

Routine gastric lavage is obsolete.

Activated charcoal may occasionally be considered after a substantial recent ingestion when:

• Presentation is sufficiently early
• The airway is safe
• Expected benefit outweighs aspiration risk

Most uncomplicated ACE-inhibitor exposures do not require aggressive GI decontamination.

⸻

No Routine Specific Antidote

There is no standard antidote required for ordinary ACE-inhibitor poisoning.

Management consists primarily of:

• Hemodynamic support
• Renal monitoring
• Hyperkalemia treatment when necessary
• Airway management for angioedema
• Treatment of coingestants

⸻

Observation

The older universal 4–6-hour observation rule should not be applied mechanically.

Observation depends on:

• Specific agent
• Amount
• Formulation
• Symptoms
• Blood-pressure trajectory
• Renal function
• Potassium
• Coingestants

Clinically important hypotension usually develops relatively early after immediate-release ingestion, but persistent toxicity can occur after substantial exposures or in patients with impaired physiology.

⸻

Admission

Hospital management is appropriate for:

• Persistent hypotension
• Shock
• Significant hyperkalemia
• Acute kidney injury
• Altered mental status
• Significant coingestion
• Angioedema involving the tongue, floor of mouth, pharynx, or larynx
• Any threatened airway

Severe shock or airway compromise warrants intensive care.

⸻

Pregnancy – Major Modern Correction

The historical FDA pregnancy letter categories are obsolete.

ACE inhibitors are generally avoided during pregnancy, particularly because fetal RAAS blockade later in pregnancy can cause serious fetal toxicity.

Potential complications include:

• Fetal renal dysfunction
• Oligohydramnios
• Impaired skull ossification
• Pulmonary developmental complications secondary to oligohydramnios
• Neonatal renal failure
• Fetal or neonatal death in severe exposure