Continuing Education Activity

Anticholinergic toxicity is commonly seen in the emergency department but is rarely fatal. According to the 2015 annual American Association of Poison Control Centers (AAPCC) report, there were just under 14,000 exposures reported to poison control centers that year, none of which led to mortality. However, in prior years, up to 51 cases have been reported as fatalities. This activity describes the causes, pathophysiology, and presentation and highlights the treatment and management of these patients.

Objectives:

• Identify the causes of anticholinergic toxicity.
• Outline the presentation of a patient with anticholinergic toxicity.
• Discuss the current treatment and management options for anticholinergic toxicity.
• Summarize how an interprofessional team can coordinate care to provide the best outcomes in patients with anticholinergic toxicity.

Introduction

Anticholinergic toxicity is common in the emergency department but rarely fatal.[1] According to the 2015 annual American Association of Poison Control Centers (AAPCC) report, there were just under 14,000 exposures reported to poison control centers that year, none of which lead to mortality.[1] However, in prior years, up to 51 cases have been reported as deadly.[2][3][4] Overdoses of compounds with anticholinergic activity can be accidental or intentional. This is an important topic as anticholinergics are readily accessible, and many medications have anticholinergic side effects. The mechanism of action of anticholinergic compounds is the antagonization of the neurotransmitter acetylcholine.  Many pharmaceuticals and substances found in plants contain anticholinergic activity.

Etiology

Substances with anticholinergic activity are used and misused extensively worldwide. Toxicity typically occurs secondary to an overdose of compounds with anticholinergic properties, although mild toxicity can even be seen as a side effect when the medication is taken appropriately. The vast majority of these agents are orally ingested. The naturally occurring compounds atropine, hyoscyamine, and hyoscine are the prototypical anticholinergics from which others are synthesized. Atropine is an antidote for cholinergic toxicity from organophosphates and nerve agents and acute treatment of bradyarrhythmias.[5]

Medications with anticholinergic properties include antidepressants, antihistamines, antiparkinson drugs, antipsychotics, antispasmodics, and mydriatics. Many medications possess anticholinergic activity as their primary pharmacologic effect, while others exhibit these properties as adverse effects. Ingestion of multiple medications with anticholinergic properties is synergistic. This is especially important for elderly patients on numerous medications.[6][7] The most common source of an anticholinergic drug overdose is antihistamines.[1]

Plants are also a common source of accidental and intentional anticholinergic ingestion.[8] Plants that contain belladonna alkaloids are often abused due to their hallucinogenic properties.[9] Illicit drugs, including cocaine and heroin, have been known to be contaminated with anticholinergics such as hyoscine or atropine.[10][11][12] Toxicity has also been reported with topical application.[13][14]

Epidemiology

In 2015, there were approximately 14,000 anticholinergic exposures reported to poison control centers.[1] The following year, there were 2,159,032 total cases of human exposure reported to poison control centers. Antihistamines were the sixth most frequently involved category of substances involved in human exposure at 4.19%.[15] These figures probably grossly underestimate the total number of exposures, as many go unreported to poison control centers.

Pathophysiology

Anticholinergic agents competitively block the binding of the neurotransmitter acetylcholine at muscarinic receptors. Anticholinergics cause minimal blockade at nicotinic receptor sites. Muscarinic acetylcholine receptors are located in smooth muscle, the ciliary body of the eye, salivary glands, sweat glands, and the central nervous system (CNS). Muscarinic receptors are not found at the neuromuscular junction.[16][17][18]

Toxicokinetics

Most anticholinergic agents are orally ingested, and their onset of action typically occurs within 2 hours.[19] Some topical agents, such as hyoscine, can have effects lasting for over 24 hours.[20] The effects of anticholinergic compounds on the central nervous system (CNS) can last over 8 hours, while the effects on the cardiovascular system are generally much shorter.[21]

History and Physical

A thorough history and physical exam are critical to the identification of patients with anticholinergic poisoning. Patients may present with a history of intentional ingestion of common anticholinergic agents such as antihistamines or jimson weed; however, the history is often less straightforward.[8] Patients may present after a suicide attempt and be unwilling or unable to disclose what they ingested. Young children may be brought in by a caretaker/parent with suspected ingestion of unknown etiology.

The clinician must be familiar with the anticholinergic toxidrome as a reliable history is not always obtainable. The mnemonic “red as a beet, dry as a bone, blind as a bat, mad as a hatter, hot as a hare, full as a flask” is helpful to remember the classic signs and symptoms of anticholinergic poisoning. Respectively, these include flushing, anhydrosis, dry mucous membranes, mydriasis, altered mental status, fever, and urinary retention. Decreased bowel sounds are also a common physical exam finding. Central nervous system effects may include delirium, hallucinations, agitation, restlessness, confusion, staccato speech, and picking at clothing and bedding. Seizures and jerking movements are possible.[22][23] Diphenhydramine, in particular, has been reported to be associated with wide-complex tachycardia and QT prolongation.[24][25]

Evaluation

The clinician should utilize a standard approach to any suspected poisoned patient. As with any potentially critically ill patient, evaluation of the patient’s airway, respiratory, and circulatory status should immediately be performed. Vital signs, including temperature, heart rate, respiratory rate, blood pressure, and oxygen saturation, should be obtained. The patient should be fully exposed to assess for topical sources of toxicity, such as a hyoscine patch. The patient should also be placed on continuous cardiac monitoring and have intravenous (IV) access established. 

Diagnostics, including urinalysis, urine drug screen, finger-stick glucose, salicylate and acetaminophen levels, electrocardiogram, and pregnancy test for females, should be obtained. If seizures or significant hyperthermia are present, the clinician should obtain further laboratory evaluation, including a metabolic panel, liver enzymes, and creatine kinase. However, it is important to understand that anticholinergic toxicity is a clinical diagnosis. Anticholinergic toxicity can be confused with sympathomimetic toxicity. However, the absence of sweating indicates anticholinergic toxicity.[22]

Treatment / Management

Supportive care is usually all that is required for the treatment of anticholinergic toxicity. The most difficult therapeutic challenge is treating the agitation that can be severe in patients with anticholinergic toxicity. Benzodiazepines administered intravenously should be the first-line therapy for agitation. This may require large doses but is necessary to avoid making symptoms such as hyperthermia and rhabdomyolysis worse. Physostigmine may be indicated in severe cases refractory to benzodiazepines.[26] IV fluids should be administered in the case of hypotension, or rhabdomyolysis is suspected. Cooling measures should be initiated if significant hyperthermia is present.[27] Activated charcoal should be considered if the ingestion occurred within one hour before the patient presents. However, administration somewhat outside this window may be appropriate, as anticholinergics decrease gastrointestinal motility.[28][29] If wide-complex dysrhythmias develop, IV sodium bicarbonate should be administered.[25][30]

Physostigmine is usually only given in the case of both peripheral and central signs and symptoms of anticholinergic poisoning.[26] Physostigmine is an acetylcholinesterase inhibitor active in both the central and peripheral nervous systems. Resuscitation equipment, including atropine, should be readily available before physostigmine is given. The recommended dose is 0.5 to 2 mg IV for adults and 0.02 mg/kg IV for pediatric patients, with a maximum pediatric dose of 0.5 mg.[31] Repeat dosing may be required after approximately 30 minutes if symptoms recur.[32] In general, physostigmine is only recommended for pure anticholinergic poisoning.[33] Intravenous fat emulsion has been reported as a successful treatment for severe diphenhydramine overdose refractory to other interventions.[34]

Alternatives to physostigmine are rivastigmine and pyridostigmine. Rivastigmine is only available in oral and transdermal formulations. Pyridostigmine is available in an oral and intravenous formulations. Neither has FDA approval for this indication.

Differential Diagnosis

Many conditions can cause agitated delirium, especially in the elderly. Side effects of other medications and polypharmacy should be considered. Meningitis, sepsis, uremia, sympathomimetic toxicity, salicylate toxicity, and serotonin syndrome can all present similarly to anticholinergic poisoning.[35] Pure anticholinergic toxicity versus mixed toxicity, as seen with tricyclic antidepressants and phenothiazines, should be considered.

Prognosis

Overall, with early identification and adequate supportive care, the prognosis of anticholinergic toxicity is good.

Complications

• Respiratory failure
• Cardiovascular collapse
• Rhabdomyolysis
• Seizures
• Coma
• Permanent disability
• Death

Consultations

Depending on the severity, the following consults may be indicated:

• Poison Control can be reached 24 hours a day in the United States at 1-800-222-1222.
• Intensivist for intensive care unit (ICU) admission
• Psychiatry if the ingestion was intentional self-harm
• Nephrology, if dialysis is necessary

Deterrence and Patient Education

Patients taking multiple medications should be educated that anticholinergic side effects are common. Parents and guardians should be encouraged to keep all medications in a safe place, inaccessible to children. This includes over-the-counter medications in addition to prescription medications. All patients should be informed not to take their medications more frequently than prescribed and not to take more than the recommended dose of over-the-counter medications. Patients should also be counseled not to drive after taking sedating anticholinergics such as antihistamines.

Pearls and Other Issues

• Always consider anticholinergic toxicity in patients taking multiple medications, especially older patients.
• Always consider anticholinergic toxicity in young children who present somnolent or lethargic.
• Remember the mnemonic "red as a beet, dry as a bone, blind as a bat, mad as a hatter, hot as a hare, full as a flask."
• Confirmatory testing is not usually readily available in the emergency setting. Anticholinergic toxicity is a clinical diagnosis.

Enhancing Healthcare Team Outcomes

The prevention and treatment of anticholinergic toxicity can be maximized by adopting an interprofessional team-based approach. This interprofessional team will include clinicians, mid-level practitioners, nurses, pharmacists, and any needed specialists. Psychiatry services should see any patient with anticholinergic poisoning as an inpatient and refer to outpatient behavioral health resources if the ingestion is due to intentional self-harm. Pharmacists in the hospital and the community are excellent resources for educating patients and the community regarding medication side effects, dosage, and synergistic effects of taking more than one anticholinergic agent. In many emergency departments, pharmacists perform routine reconciliation of patients’ home medications. Thus, pharmacists have a prime opportunity to recognize and alert providers of potential drug interactions, which would place a patient at higher risk for anticholinergic toxicity. Both nursing staff and pharmacy staff can play an increased role in patient education at the time of discharge from the hospital regarding the appropriate consumption of anticholinergic drugs. Nursing staff should also assist in educating all patients on anticholinergic agents and stress the importance of keeping them out of the reach of children. Prehospital providers can also aid clinicians in making the diagnosis of anticholinergic poisoning by interviewing bystanders and observing the scene for any medications or substances that may have been available to the patient.[36][37][38][39] [Level 5]