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.