ANTICHOLINERGIC EFFECT	SYMPTOMS
Central inhibition of muscarinic acetylcholine receptors	Confusion, disorientation, psychomotor agitation, ataxia, myoclonus, tremor, picking movements, abnormal speech, visual and auditory hallucinations, psychosis, seizures, cardiovascular collapse, coma
Inhibition of postsynaptic sympathetic muscarinic acetylcholine receptors in the sweat glands, as well as vasodilation of peripheral blood vessels	Dry, flushed skin
Inhibition of postsynaptic parasympathetic muscarinic acetylcholine receptors in the:
Salivary glands	Dry mucous membranes
Eye	Paralysis of the sphincter muscle of the iris and the ciliary muscle of the lens resulting in mydriasis, cycloplegia, and blurred vision
Heart (vagus nerve)	Tachycardia
Bladder	Urinary retention and overflow incontinence
Bowel	Adynamic ileus

Muscarinic acetylcholine receptor antagonists competitively inhibit muscarinic acetylcholine receptors. These agents cause the classic anticholinergic poisoning syndrome, which perhaps may be more appropriately designated the antimuscarinic poisoning syndrome because nicotinic acetylcholine receptors are not affected. Muscarinic receptors in different organs are not equally sensitive to antimuscarinic agents.

Tricyclic antidepressants are a unique subset of antimuscarinic agents that deserve special attention. Their antidepressant effect is achieved pharmacologically through blockade of the reuptake of norepinephrine, dopamine, and serotonin in the CNS. Additionally, tricyclic antidepressants interact with other channels and receptors and cause considerably more profound clinical toxicity in overdose than occurs with most other agents that exhibit anticholinergic effects. Adverse effects of a tricyclic antidepressant overdose include competitive inhibition at both central and peripheral muscarinic acetylcholine receptors (antimuscarinic poisoning syndrome); histamine receptor antagonism (sedation); sodium channel blockade in the myocardium (widening of the QRS complex or wide-complex dysrhythmias, atrioventricular block, QT prolongation, and rightward shift of the terminal 40-msec QRS axis on an electrocardiogram [ECG], as well as negative inotropy leading to hypotension); α-adrenergic receptor antagonism on vascular smooth muscle (vasodilation leading to hypotension); and although the mechanism of this effect is unclear, γ-aminobutyric acid (GABA) antagonism (seizures). In the right clinical setting, anticholinergic syndrome is a key clinical finding leading to the diagnosis of tricyclic antidepressant poisoning (Table 145.2).

Table 145.2 Pathophysiology of Tricyclic Antidepressants and Associated Symptoms

EFFECT	SYMPTOMS
Blockade of reuptake of norepinephrine, dopamine, and serotonin in the central nervous system	Mood elevation
Competitive inhibition at both central and peripheral muscarinic acetylcholine receptors	Antimuscarinic poisoning syndrome
Histamine receptor antagonism	Sedation
Sodium channel blockade in the myocardium	QRS complex widening or wide-complex dysrhythmias, atrioventricular block, QT prolongation and rightward shift of the terminal 40-msec QRS axis on the electrocardiogram, as well as negative inotropy leading to hypotension
α-Adrenergic receptor antagonism on vascular smooth muscle	Vasodilation leading to hypotension
γ-Aminobutyric acid antagonism	Seizures

Presenting Signs and Symptoms

Central inhibition of muscarinic acetylcholine receptors results in confusion, disorientation, psychomotor agitation, ataxia, myoclonus, tremor, picking movements, abnormal speech, visual and auditory hallucinations, psychosis, seizures, cardiovascular collapse, and coma.

Inhibition of postsynaptic sympathetic muscarinic acetylcholine receptors in the sweat glands, as well as vasodilation of peripheral blood vessels, gives rise to dry, flushed skin. Inability to sweat, particularly in the presence of altered CNS regulation, may lead to hyperthermia. Inhibition of these receptors in the salivary glands results in dry mucous membranes, whereas inhibition of these receptors in the eye (which cause pupillary constriction when activated) leads to paralysis of the sphincter muscle of the iris and the ciliary muscle of the lens with subsequent mydriasis, cycloplegia, and blurred vision. Tachycardia is caused by inhibition of postsynaptic parasympathetic muscarinic acetylcholine receptors on the vagus nerve. Dysrhythmias may be caused by antimuscarinic agents that possess additional pharmacologic effects. For example, agents that produce sodium channel blockade in the myocardium (i.e., tricyclic antidepressants, diphenhydramine, pheniramine, orphenadrine, pyrilamine) cause widening of the QRS complex or wide-complex dysrhythmias, atrioventricular block, QT prolongation, and rightward shift of the terminal 40-msec QRS axis on the ECG, as well as negative inotropy leading to hypotension. Inhibition of postsynaptic parasympathetic muscarinic acetylcholine receptors in the bladder results in urinary retention and overflow incontinence, and in the bowel it causes adynamic ileus.

Frequently, patients with anticholinergic (antimuscarinic) poisoning do not have all the previously mentioned characteristics of the classic syndrome, especially the elderly and patients with organic brain syndrome, in whom central anticholinergic (antimuscarinic) poisoning syndrome is often more pronounced than or outlasts the peripheral syndrome.

See Tables 145.1 and 145.2, which detail the pathophysiology associated with the signs and symptoms of antimuscarinic poisoning syndrome and tricyclic antidepressants.

Differential Diagnosis and Medical Decision Making

Diagnostic Features

Patients who overdose with an anticholinergic (antimuscarinic) agent often have sufficient clinical findings to make the diagnosis apparent. However, the symptoms and signs in others may be less overt, and thus a substantially broader differential diagnosis is required.

Although patients with both adrenergic (sympathomimetic) and anticholinergic (antimuscarinic) poisoning may exhibit confusion, disorientation, psychomotor agitation, seizures, flushed skin, hyperthermia, mydriasis, and tachycardia, the two syndromes may be differentiated through examination of the skin and observation of the symptoms associated with the altered mental status. Patients with anticholinergic poisoning have dry skin and mucous membranes, and the alteration in mental status is characterized by mumbling speech, delirium, and tactile or visual hallucinations. In contrast, patients poisoned by sympathomimetic agents, such as cocaine toxicity, are typically, though not always, diaphoretic with agitated or violent behavior and hallucinations that are more commonly paranoid.

Multiple other toxicologic entities are associated with autonomic dysfunction (i.e., dysregulation of the heart rate, blood pressure, temperature, gastrointestinal secretion, metabolic and endocrine responses to stress). Acute withdrawal syndromes may be differentiated from anticholinergic (antimuscarinic) syndrome by a history of recent cessation of ethanol or another sedative-hypnotic agent, serotonin syndrome may be differentiated by a history of recent (minutes to hours) exposure to a serotonergic agent, and neuroleptic malignant syndrome may be differentiated by a history of exposure (within 3 to 9 days) to an agent capable of producing central dopamine blockade. Drug-induced psychosis mimicking central anticholinergic syndrome may be due to hallucinogens, phencyclidine, amphetamines, or corticosteroids.

Medical diseases that produce confusion, seizures, and tachycardia, such as hypoxia, hypoglycemia, and heat stroke, or those that cause hyperthermia, hypertension, tachycardia, and mydriasis, such as thyrotoxicosis and pheochromocytoma, may also be confused with anticholinergic toxicity.

Finally, diseases that may be manifested similar to central anticholinergic syndrome include schizophrenia and other psychotic disorders, cerebral vasculitis, CNS infection (e.g., encephalitis), sepsis, and psychiatric disease.

Diagnostic Testing

In the setting of anticholinergic (antimuscarinic) poisoning, results of the fingerstick serum glucose test and pulse oximetry analysis should be normal.

The ECG typically demonstrates sinus tachycardia. Some agents with anticholinergic (antimuscarinic) effects also have type IA antidysrhythmic effects that result in blockade of myocardial sodium channels. The blockade is seen on the ECG as prolongation of the QRS interval. Such agents include diphenhydramine, cyclobenzaprine, carbamazepine, and the tricyclic antidepressants.

With tricyclic antidepressant overdose in particular, the extent of prolongation of the QRS interval on an ECG is especially useful in predicting the severity of toxicity.

Facts and Formulas

A QRS duration shorter than 100 msec predicts that no serious clinical toxicity will occur, a QRS duration longer than 100 msec is associated with a 30% incidence of seizures, and a QRS duration longer than 160 msec is associated with a 50% likelihood of the development of ventricular dysrhythmia.² Additionally, an R wave in lead aVR measuring 3 mm or greater³ or a terminal 40-msec right axis deviation between 130 and 270 degrees⁴ is a predictor of tricyclic antidepressant–induced toxicity.

Prolonged agitation and seizures can lead to the development of acidosis and rhabdomyolysis. Measurement of serum creatine phosphokinase and urine myoglobin aids in the recognition of patients at risk for the development of acute renal failure.

Red Flags

Cautions for Physicians

Physostigmine is contraindicated in patients after a tricyclic antidepressant overdose with a QRS interval longer than 100 msec because it may cause cardiac arrhythmias and profound hypotension.

Flumazenil should not generally be administered to patients with anticholinergic (antimuscarinic) toxicity because it may cause seizures or other complications.

Failure to become cholinergic (bradycardia, bronchorrhea, diaphoretic, drooling) after the administration of physostigmine is essentially diagnostic of anticholinergic toxicity.

Physostigmine will prolong the action of drugs metabolized by cholinesterases, such as succinylcholine. A nondepolarizing agent should be used instead.

Treatment

Most patients with anticholinergic (antimuscarinic) toxicity can be treated adequately with general supportive care of the airway, breathing, and circulation, followed by frequent reassessment and close observation (Fig. 145.1). To avoid the risk for aspiration, activated charcoal (1 g/kg) is recommended only for patients who are capable of spontaneously drinking and protecting their own airway. It may also be administered cautiously via a nasogastric tube to patients who are endotracheally intubated. Because anticholinergic (antimuscarinic) agents may slow gastrointestinal transit, activated charcoal may be useful several hours after ingestion.⁵ The specific role of activated charcoal in most of these poisonings has not been studied.

Fig. 145.1 Algorithm for the recognition and treatment of anticholinergic toxicity.

CPK, Creatine phosphokinase; D₅W, 5% dextrose in water; ECG, electrocardiogram; IV, intravenous line; TCA, tricyclic antidepressant.

The initial therapy for cardiovascular toxicity secondary to sodium channel blockade is hypertonic sodium bicarbonate in 1- to 2-mEq/kg boluses.⁶ Treatment with sodium bicarbonate is indicated for patients with a QRS complex longer than 100 to 120 msec or a wide-complex or ventricular tachycardia until the abnormality is reversed or serum pH reaches 7.55. The ECG should be repeated within 60 seconds after a bolus of sodium bicarbonate to check for narrowing of the QRS complex. If narrowing has occurred, a continuous infusion at 1.5 times the maintenance intravenous fluid rate (three ampules [132 mEq] of sodium bicarbonate in 1 L of 5% dextrose in water [D₅W]) should be administered. Profound cardiovascular toxicity may require more aggressive interventions, such as the initiation of vasopressors or use of an intraaortic balloon pump.

Agitation should be addressed aggressively to prevent the development of more serious sequelae, such as hyperthermia, acidosis, and rhabdomyolysis. It is best controlled with benzodiazepines. The emergency physician should start with standard doses (i.e., diazepam, 5 to 10 mg intravenously) and repeat them until sedation (relief of agitation, myoclonus, tremor, picking movements, abnormal speech, and hallucinations) is achieved. Administration of physostigmine should also be considered for the treatment of agitation caused by an anticholinergic agent (see later).

Anticholinergic (antimuscarinic) agent–induced seizures should also be treated with standard doses of benzodiazepines (i.e., lorazepam, 2 mg intravenously) or with physostigmine. If this therapy fails, barbiturates or other GABAergic anticonvulsants should be administered. Phenytoin is rarely useful for toxin-induced seizures.

Patients with rhabdomyolysis should be administered saline intravenously at a rate sufficient to maintain brisk urine output (generally 3 to 5 mL/kg/hr after any lost intravascular volume has been replaced). If urinary pH is less than 6.0, urine alkalinization is necessary and is achieved with the use of a sodium bicarbonate infusion at 1.5 times the maintenance intravenous fluid rate (three ampules [132 mEq] of sodium bicarbonate in 1 L of D₅W). Serum pH must be monitored during the sodium bicarbonate infusion, which should be stopped if the pH reaches 7.55 or higher.

Antidotal Therapy—Physostigmine

Physostigmine is a tertiary amine carbamate that penetrates into the CNS. It reversibly inhibits cholinesterases in both the central and peripheral nervous systems, thereby allowing acetylcholine to accumulate within the synapse. Accumulation of acetylcholine directly antagonizes the anticholinergic effects of antimuscarinic agents.

In the setting of a clear diagnosis of anticholinergic toxicity, physostigmine should be administered. It is beneficial in the treatment of agitation and delirium and also shortens the time to recovery after agitation. This agent should not be given once a benzodiazepine has been administered because the end point of clear mental status has been lost.⁷

During and immediately after the administration of physostigmine, patients must be monitored for early signs of cholinergic toxicity, such as diaphoresis and slowing of the heart rate. Atropine should be kept at the bedside and should be given in titrated doses if needed for cholinergic toxicity (development of bronchorrhea, hypoxia, bradycardia).

Physostigmine is indicated for patients with central (and perhaps peripheral) anticholinergic manifestations. It is contraindicated in patients with a QRS interval longer than 100 msec if the history suggests overdose of tricyclic antidepressant or other cardiotoxic agents. The latter contraindication is based on two case reports of patients with tricyclic antidepressant overdose in whom asystole developed after the administration of physostigmine. The cause of the asystole was theorized to be physostigmine-induced bradycardia that resulted in cardiac conduction defects and decreased cardiac output in the presence of tricyclic antidepressant–induced sodium channel blockade.⁸ Other contraindications to the use of physostigmine are bronchospastic disease, peripheral vascular disease, intestinal or bladder obstruction, intraventricular conduction defects, and atrioventricular block.

Physostigmine is administered intravenously over a 5-minute period, 1 to 2 mg in adults and 0.02 mg/kg (maximum of 0.5 mg) in children. Its onset of action occurs within minutes.⁹ This initial dose can be repeated in 5 to 10 minutes if an adequate response is not achieved and muscarinic effects are not noted. Failure of the patient to become cholinergic after the administration of physostigmine is essentially diagnostic of anticholinergic toxicity. Although the total effective dose of physostigmine depends on the individual, as well as the dose and duration of action of the anticholinergic (antimuscarinic) agent, 4 mg is usually a sufficient dose for most patients.¹⁰ The half-life of physostigmine is 16 minutes, and its usual duration of action exceeds 1 hour.¹¹

Adverse effects may occur if physostigmine is administered rapidly, in an excessive dose, or in the absence of an anticholinergic (antimuscarinic) agent. In all these instances, an excess of acetylcholine occurs at various sites within the body and has various effects, as follows:

• At nicotinic receptors: muscle fasciculations, weakness, and paralysis

• At muscarinic receptors: bronchospasm, bronchorrhea, bradycardia, salivation, lacrimation, urination, defecation, and emesis

• At CNS sites: anxiety, dizziness, tremors, confusion, ataxia, coma, and seizures

Accordingly, overdoses of physostigmine may require atropine to control the bronchial secretions, and mechanical ventilation may be needed for neuromuscular weakness because no specific antidote is available for the excess nicotinic activity.

Additionally, it is important to note that when other cholinergic agents are used concurrently with physostigmine, the effects may be additive. Examples of such agents are pilocarpine, carbamates, organophosphates, pyridostigmine, and depolarizing neuromuscular blocking agents. Because physostigmine is an acetylcholinesterase inhibitor, it also prolongs the action of drugs metabolized by plasma cholinesterases, such as cocaine, succinylcholine, and mivacurium.