Anticholinergic Toxicity: The Wacky, Tachy Patient
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Example Case
A female patient presents with altered mental status. She is accompanied by her mother who provides much of the history as the patient loses focus and attention when conversing.
Her mother states that the patient was not acting herself yesterday, and that it has since worsened today. Her mother then tells you, “I am really worried about her. We just saw her family doctor 3 days ago for neck pain and anxiety. The doctor thought that her neck pain was musculoskeletal from tension, stress, and anxiety. He prescribed hydroxyzine for her anxiety and cyclobenzaprine for her muscular pain. She continues to take her antidepressants the way she is supposed to. We are doing everything we are told, and I just don’t get it.”
You notice the patient’s heart rate on the monitor is 128 and she is hypertensive despite her resting comfortably on the bed. The nurse in the room also makes you aware that her temperature on arrival was 101.9.
Anticholinergic Toxicity
Anticholinergic toxicity can be challenging to manage.
First, many patients are unable provide a history due to their symptoms or altered mental status, and family members are not always present to give additional information.
Second, anticholinergic toxicity can mimic other disease states.
Third, we often do not initially think of toxicology as a cause to the patient’s symptoms unless there is an obvious presentation.
Therefore, it is important to always keep medications, adverse pharmacologic reactions, and toxicologic etiologies in mind when creating a differential.
For example, in the case above it would be easy to prematurely conclude an infectious etiology since the patient is febrile, tachycardic, and altered.
To complicate matters, she recently had neck pain and meningitis would be very reasonable to have high on the differential (and should be).
However, today we are going to focus on anticholinergic toxicity.
As with every EZmed blog, you will learn easy tricks to remember the content.
This post will provide you with an easy method for recalling anticholinergic symptoms.
Causes
There are numerous medications that have anticholinergic properties.
It is easiest to remember them by drug classes rather than memorizing each one individually.
Antidepressants, antihistamines, antipsychotics, and muscle relaxants are all commonly prescribed medications that have anticholinergic effects.
Plants are commonly tested on licensure and board exams, and although rarely seen in real life, Jimson weed can also cause anticholinergic toxicity.
Autonomic Nervous System
I’m going to briefly discuss the autonomic nervous system as this will help to better understand the symptoms and treatment for anticholinergic toxicity.
The autonomic nervous system has 2 main components: the sympathetic and parasympathetic nervous system.
The sympathetic nervous system is involved in the fight or flight response.
Norepinephrine and epinephrine is released and binds to alpha adrenergic receptors and beta adrenergic receptors. The critical body actions for immediate survival are upregulated while the bodily functions less critical are downregulated.
Therefore, the sympathetic nervous system will dilate the pupils, increase heart rate and cardiac output, dilate the bronchi, increase blood pressure, increase gluconeogenesis, and cause diaphoresis while decreasing salivation, lacrimation, digestion, defecation, and urination.
The parasympathetic nervous system is essentially the opposite, and it is often referred to as the rest and digest state.
Acetylcholine binds to cholinergic muscarinic receptors. The critical actions for immediate survival are downregulated while bodily functions less critical are upregulated.
Therefore, the parasympathetic nervous system will increase digestion, urination, defecation, salivation, and lacrimation while decreasing the heart rate and constricting the bronchi.
The sympathetic nervous system causes a fight or flight response in which the critical actions for immediate survival are upregulated and other functions are downregulated. Alternatively, the parasympathetic nervous system upregulates functions important during the rest and digest state while normalizing or decreasing the other functions.
Anticholinergic Presentation
As discussed above, the sympathetic and parasympathetic nervous systems counteract one another and are constantly producing responses.
Therefore, blocking either the sympathetic or parasympathetic system will result in overactivity of the other.
Inhibiting the cholinergic receptors of the parasympathetic nervous system, as seen in anticholinergic toxicity, will lead to unopposed sympathetic activity and activation of the adrenergic receptors.
Simply put, anticholinergic toxicity inhibits the parasympathetic system and leaves only the sympathetic response present.
This is exactly why most of the symptoms seen with anticholinergic toxicity mimic a sympathetic response, and the patient will appear to be in a fight or flight state.
The patient will have mydriasis, tachycardia, hypertension, and bronchodilation as a result of the unopposed adrenergic receptor activity that is not affected by anticholinergic toxicity.
Alternatively, the body functions that primarily rely on cholinergic activation, such as salivation, urination, digestion, and defecation, will be decreased secondary to inhibition of the cholinergic receptors.
As a result, a patient with anticholinergic toxicity may present with dry mucous membranes, urinary retention, decreased bowel sounds, and constipation.
Anticholinergic toxicity inhibits the parasympathetic response leaving unopposed sympathetic activity only.
Anticholinergic vs Sympathomimetic
It is evident that anticholinergic toxicity will present a lot like sympathomimetic toxicity from cocaine or stimulant use secondary to unopposed action of the sympathetic nervous system.
However, there are 2 physical exam findings that help to delineate anticholinergic toxicity from sympathomimetic toxicity.
First, assess the pupils. Mydriasis will be present in both sympathomimetic and anticholinergic toxicity, however the pupils will only react to light in sympathomimetic toxicity and not anticholinergic toxicity.
The reason for this finding is that pupillary constriction is a parasympathetic response which has been blocked in anticholinergic toxicity but not in sympathomimetic toxicity.
Second, assess the patient’s skin. Patient’s with anticholinergic toxicity will be very dry, and patient’s from sympathomimetic toxicity will be diaphoretic.
Both anticholinergic and sympathetic toxicity can cause hyperthermia but the ability to sweat is lost in anticholinergic toxicity.
The reason for this finding is that the sympathetic innervation of sweat glands is unique. Normally the sympathetic nervous system releases norepinephrine and epinephrine onto adrenergic receptors. However, the sympathetic innervation on sweat glands is an exception in that sweat glands have muscarinic cholinergic receptors, and postganglionic sympathetic fibers release acetylcholine onto these receptors.
Therefore, in a sympathomimetic response there will be diaphoresis as a result of hyperthermia and the sympathetic surge.
Alternatively, in anticholinergic toxicity the sweat gland cholinergic receptors are blocked so these patients will have anhidrosis, the inability to sweat despite unopposed sympathetic activity.
Anticholinergic Toxicity Vs Sympathomimetic Toxicity
Mydriasis Nonreactive to Light (Anticholinergic)
Mydriasis Reactive to Light (Sympathomimetic)
Anhidrosis/Inability to Sweat (Anticholinergic)
Diaphoresis (Sympathomimetic)
We’ve hit most of the anticholinergic symptoms above: mydriasis, dry mucous membranes, tachycardia, constipation, urinary retention, and anhidrosis.
The last 2 main ones to discuss are hyperthermia and altered mental status.
Hyperthermia is typically secondary to increased heat production from agitation and activity, decreased heat loss from absence of sweating, and CNS temperature dysregulation.
Altered mental status, agitation, and delerium may also occur. There are cholinergic receptors (M1 muscarinic receptors) in the central nervous system that are involved with attention, perception, and cognitive functioning.
Blocking these receptors can be deleterious to the patient’s cognition. Anticholinergic toxicity will often cause attention deficits when conversing. Visual perception may also be impacted, and patient’s can often be seen picking at objects.
Anticholinergic Toxicity
Mad as a Hatter = Agitation, Delirium, Picking at Objects
Hot as a Hare = Hyperthermia
Blind as a Bat = Mydriasis Nonreactive to Light
Dry as a Bone = Dry Mucous Membranes, Anhidrosis
Full as a Flask = Urinary Retention
Red as a Beet = Flushing
Work Up Considerations
The differential diagnosis for a patient who presents with fever, altered mental status, and tachycardia is broad.
It includes infectious etiologies such as urinary tract infection, pneumonia, meningitis, encephalitis, sepsis, spontaneous bacterial peritonitis, or brain abscess among others.
It also includes noninfectious etiologies such as thyroid storm/hyperthyroidism, malignant hyperthermia, neuroleptic malignant syndrome, serotonin syndrome, drug toxicity, and withdrawal among others.
If there is a known history of recent drug ingestion, then the case becomes simpler. However, if the patient is too confused to provide the history or the patient unknowingly was taking too many anticholinergics, then the case could be more challenging.
In the undifferentiated patient with fever, altered mental status, and tachycardia an infectious work up should be performed including but not limited to complete blood count, chemistry, liver function tests, urine and urine cultures, blood cultures, lactate, blood gas, chest X-ray, and EKG.
Procedures such as lumbar puncture or paracentesis, other labs, and other advanced imaging may be necessary depending on the potential source of infection.
Noninfectious work up should also be performed on the undifferentiated altered patient including but not limited to thyroid studies, troponin, drug screen, ammonia, ethanol level, salicylate level, acetaminophen level, and blood gas. CT head and other advanced imaging may also need to be performed.
The take home point is to always consider toxicologic etiologies and adverse medication events in your differential as it applies. Below are example work up considerations for the febrile, altered, tachycardic patient.
Treatment - Supportive Care Measures
Management of a patient with anticholinergic toxicity should be discussed with the poison center or a toxicologist. If the patient intentionally ingested medications, then psychiatry should also be consulted.
Treatment for most cases will be supportive care.
Mild to moderate agitation or delirium can be treated using verbal deescalation and having family members at the bedside for support and reassurance. The room should be kept quiet with minimal stimuli.
Hyperthermia can be treated with antipyretics and cooling measures although this may not always be successful.
IV fluids may also be used for supportive care.
Supportive Care
Toxicology and Psychiatry (if intentional ingestion)
Verbal deescalation of agitation
Quiet room
IV fluids
Antipyretics
Cooling measures
Treatment - Medication Options
If the patient presents within 2 hours of ingestion of medication, then GI decontamination using activated charcoal can be considered in consultation with toxicology.
Benzodiazepines can be used for seizures, prevention of hyperthermia, prevention of rhabdomyolysis injuries, and agitation and delirium refractory to verbal deescalation.
If there are conduction abnormalities on EKG such as QRS widening to raise concern for sodium channel blockade, coingestion, or TCA ingestion, then sodium bicarbonate could also be considered in addition to supportive care.
Medication Options
Activated Charcoal
Benzodiazepines
Sodium Bicarbonate
Treatment - Antidote
In cases of severe delirium, significant tachydysrhythmias, and hemodynamic instability then physostigmine can be considered.
Physostigmine is an acetylcholinesterase inhibitor.
Acetylcholinesterase is an enzyme that breaks down synaptic acetylcholine, and therefore its inhibition will lead to increased synaptic acetylcholine levels which will augment cholinergic effects.
Physostigmine should be used in consultation with a toxicologist or poison center.
It is also wise to have atropine at the bedside when administering physostigmine, as too much physostigmine could overshoot the cholinergic effects leading to increased secretions, respiratory distress, bradycardia, along with other potential detrimental side effects.
Antidote
Physostigmine = Acetylcholinesterase Inhibitor
Physostigmine inhibits acetylcholinesterase, an enzyme that normally breaks down acetylcholine. This increases synaptic acetylcholine levels to augment the cholinergic parasympathetic response.
Conclusion
Always consider toxidromes in the differential, especially when a patient presents with vague symptoms or a history that is difficult to elicit.
It can be easy to prematurely jump to conclusions, such as an infectious etiology, which could lead to incorrect management of the patient.
Anticholinergic toxicity will present much like a sympathomimetic response. The main difference is that patient’s with anticholinergic toxicity will have mydriasis not reactive to light as well as anhidrosis.
Treatment involves any combination of supportive care, toxicology and psychiatry consultation, benzodiazepines, and physostigmine depending on the severity of the case.
I have created a table below comparing anticholinergic toxicity to cholinergic, sympathomimetic, and opioid toxidromes which will be discussed in future blog posts.
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AChEI = Acetylcholinesterase Inhibitor
Resources
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5606458/
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767198/#bcp12839-sec-0002title