Anticholinergic and Cholingeric Toxicity

Primer

Anticholinergic and Cholinergic Drugs are commonly used in medicine and prescribed for many conditions. These medications work on the parasympathetic nervous system (PNS). Remember that the PNS compliments the sympathetic nervous system (SNS), and this combines to make up the autonomic nervous system (ANS). As a result, these medications can have a variety of side effects and toxicities due to their effects on the sympathetic and parasympathetic nervous systems. The toxic effects of these medications (depending on dose) can range from mild symptoms to severe autonomic impairment and delirium requiring intensive care.

Psychotropic Medications

Antidepressants and antipsychotic medications have anticholinergic properties, and this is often forgotten. On the flip side, dementia medications and acetylcholinesterase inhibitors have cholinergic effects. It is important to consider the impact of anticholinergic and cholinergic side effects; sometimes the side effects far outweigh the benefits of the medications!

Anticholinergics

Anticholinergics are also known as antimuscarinics, cholinergic blockers, or parasympatholytics. They block or inhibit the actions of acetylcholine, and reduce activity of the parasympathetic nervous system. The mechanism of action of anticholinergics can be one of the following:

  1. Competitive antagonists of acetylcholine at cholinergic receptor sites
  2. Inhibits the transmission of signals at cholinergic receptors

Naming Alert!

Anticholinergic medications really should be called antimuscarinics, since most drugs target muscarinic acetylcholine receptors (and rarely target the nicotinic receptors).

Contraindications

The following conditions can be absolute or relative contraindications to using an anticholinergic medication:
  • Older adults already with high anticholinergic burden (e.g. - already taking anticholinergic medications for urinary incontinence, COPD)
  • Dementia (dementia correlates with reduced acetylcholine in the brain and thus can become worse with the use of anticholinergics)
  • Glaucoma
  • Hyperthyroidism
  • Tachyarrhythmias
  • Prostate hypertrophy

Medications/Substances with Anticholinergic Effects

Classes Examples
Antidepressants Tricylic antidepressants, paroxetine (most antidepressants have very weak anticholinergic activity, e.g. -bupropion, mirtazapine, sertraline, fluoxetine, venlafaxine, citalopram, escitalopram)
Antipsychotics Low potency antipsychotics are higher risk (e.g. - clozapine,quetiapine), but all antipsychotics have some anticholinergic properties (e.g. - risperidone, aripiprazole, olanzapine)
Neurologic/psychiatric Carbamazepine, benztropine
Antihistamines Diphenhydramine (Benadryl), hydroxyzine
Antimuscarinic inhalers and bronchodilators Tiotropium (Spiriva), glycopyrronium (Seebri)
Antispasmodics Hyoscine (scopolamine), buscopan
Gastrointestinal Ranitidine, domperidone, Dimenhydrinate (Gravol)
Pain medications Tricylic antidepressants, cyclobenzaprine
Genitourinary Oxybutynin, tolterodine
Cardiac/surgical Atropine
Opioids All opioids (e.g. - codeine, methadone, morphine)

Adverse Effects

An excess of anticholinergic activity can cause a precipitous drop in acetylcholine, leading to a drop in parasympathetic nervous system (PNS) activity, making things as “dry as the dessert.”

Mnemonic

The mnemonic below can be used to remember the symptoms of anticholinergic toxicity:
  • ”Blind as a bat” (blurred vision, dilated pupils)
  • “Dry as a bone” (dry mouth and skin)
  • “Red as a beet” (vasodilation/flushing)
  • “Mad as a hatter” (confusion, cognitive impairment, delirium, agitation, hallucinations, tremors, ataxia)
  • “Hot as a hare” (hyperthermia)
  • “And the heart runs alone” (tachycardia)

Anticholinergic Effects on the Body

System Adverse Effects Clinical Questions To Ask
Neurological • Brain fog, cognitive impairment, “dementia”
• Hallucinations (visual/auditory) 		• This can be difficult to obtain from the patient, ask family members about cognitive changes
Dermatological • Decreased sweating • Do you notice having drier skin than normal?
Cardiac • Tachycardia -
Ocular • Dry eyes
• Pupil dilation 		• Do you have difficulty focusing your vision?
• Do you notice a sensitivity to bright lights?
Oral • Dry mouth, causing: halitosis (bad breath)
• Impaired speech articulation (from dry mouth)
• Severe tooth decay, gingival disease
• Difficulty swallowing due to lack of saliva 		• Do you have difficulty swallowing?
• Do you notice worsening bad breath or tooth decay (can occur from decreased saliva)?[1]
• Do you have trouble speaking? (Tip: Listen to speech articulation: if a patient's speech improves after wetting their mouth with water, then it’s likely dry mouth related to an anticholinergic medication)
Gastrointestinal • Impaired GI motility, causing: constipation, change in stool calibre, “heartburn” symptoms • Any new changes in bowel movements or constipation?
Genitourinary • Urinary retention
• Overflow incontinence 		• Do you have difficulty emptying your bladder completely?
• Do you have trouble with incontinence?

Risks

There is a noted observation between cumulative anticholinergic burden and dementia risk in observational studies.[2][3]

Cholinergics

Cholinergic drugs are also known as cholinergic agonists. They mimic the effects of acetylcholine and stimulate the parasympathetic nervous system. The mechanism of action of cholinergics can be one of the following:

  1. Direct-acting cholinergic agonists
    • e.g. - Pilocarpine for glaucoma to reduce intraocular pressure
    • e.g. - Ethanechol to increase the tone and motility of the bladder in neurogenic bladder
  2. Indirect-acting cholinergic agonists
    • Work by inhibiting the enzyme cholinesterase which breaks down acetylcholine, causing an increase in acetylcholine at the receptors)
    • e.g. - Pyridostigmine for myasthenia gravis to help with muscle contraction and inhibits the breakdown of acetylcholine
    • e.g. - Donepezil for Alzheimer's Disease to reduce cognitive deterioration

Contraindicated Conditions

The following conditions can be absolute or relative contraindications to using a cholinergic medication:[4]
  • Pulmonary disease (COPD/bronchial asthma)
  • Peptic ulcer disease (may use with caution)
  • Arrhythmias (atrial fibrillation)
  • Coronary vascular disease
  • Angle-closure glaucoma
  • Hyperthyroidism
  • Intestinal resection or anastomosis
  • Urinary obstruction
  • Orthostatic hypotension
  • Severe miosis

Medications/Substances with Cholinergic Effects

Classes Examples
(Acetyl)cholinesterase Inhibitors Donepezil, galantamine, rivastigmine, pyridostigmine
Ocular medications Pilocarpine (for glaucoma)
Respiratory agents Methacholine (bronchoprovocation test to diagnose asthma)
Organophosphate insecticides Sarin gas

Adverse Effects

As one might expect, the side effects from cholinergic medications are usually the opposite from that of anticholinergics. Cholinergics cause a “flood” of acetylcholine, making things as “wet as the ocean.”

Mnemonic

The mnemonic SLUDGE can be used to remember the symptoms of cholinergic overload and toxicity:
  • S - Salivation
  • L - Lacrimation
  • U - Urination
  • D - Diaphoresis
  • G - GI Upset
  • E - Emesis
  • Bradycardia and pin-point pupils can result as well!

Cholinergic Effects on the Body

System Adverse Effects
Neurological • Dizziness
• Drowsiness
Dermatological and Glands • Increased sweating, salivation, lacrimation, gastric, and tracheobronchial secretions
Cardiac • Bradycardia
• Cardiac arrest
Respiatory • Bronchospasms, asthma attacks
Ocular • Contraction of the iris (miosis) and accommodation spasm
Vascular • Hypotension
Gastrointestinal • Increased GI motility, causing: peristalsis increase, sphincters relaxing, resulting in abdominal cramps, vomiting, diarrhea, and increased voiding
Genitourinary • The detrusor muscle contracts, while the bladder trigone and sphincter relax, causing voiding of the bladder

Cholinergic-Anticholinergic Interactions

The concurrent administration of both anticholinergic and cholinergic drugs can cause an antagonistic response, and reduce the pharmacodynamic effects of one or both of the medications. Older adults are particularly susceptible, due to age-related decreases in endogenous acetylcholine.

Management and Treatment

Symptomatic

If a patient is symptomatic and you suspect anticholinergic or cholinergic side effects, the most important thing is to review the indication for the use of the medications! Afterwards, if the medication is still felt to be necessary, either try to reduce the dose of the medication, or try to manage symptomatically (e.g. - use of stool softeners, eye drops, etc.).

Overdose

Anticholinergic vs. Cholinergic Overdose Management

Anticholinergic Overdose Cholinergic Overdose
Summary A precipitous drop in acetylcholine, leading to a drop in PNS activity, making things as “dry as the dessert” A flood of acetylcholine, making things as “wet as the ocean”
Treatment • Benzodiazepines for seizures and agitation
• Physostigmine is the main treatment: it inhibits acetylcholinesterase activity to increase the amount ACh available (EXCEPT in cases of TCA overdose, where it is CONTRAINDICATED, because it will lead to life-threatening bradyarrhythmias)[5][6] 		• Atropine 2mg every few minutes until symptoms are relieved
• Since atropine only targets muscarinic receptors, the flooded nicotinic receptors are left untouched. Therefore to treat the neuromuscular symptoms (weakness/fasciculations) you need to add pralidoxime which inactivates the agent at the neuromuscular junction (NMJ)

Resources

For Providers
Reading

References

1) Peeters, F. P. M. L., DeVries, M. W., & Vissink, A. (1998). Risks for oral health with the use of antidepressants. General hospital psychiatry, 20(3), 150-154.
2) Coupland, C. A., Hill, T., Dening, T., Morriss, R., Moore, M., & Hippisley-Cox, J. (2019). Anticholinergic drug exposure and the risk of dementia: a nested case-control study. JAMA internal medicine, 179(8), 1084-1093.
3) Gray, S. L., Anderson, M. L., Dublin, S., Hanlon, J. T., Hubbard, R., Walker, R., ... & Larson, E. B. (2015). Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study. JAMA internal medicine, 175(3), 401-407.
4) Pakala, R. S., & Brown, K. N. (2019). Cholinergic Medications.
5) Dawson, A. H., & Buckley, N. A. (2016). Pharmacological management of anticholinergic delirium‐theory, evidence and practice. British journal of clinical pharmacology, 81(3), 516-524.
6) Mad as a Hatter: Physostigmine for Delirium Control in Anticholinergic Toxicity