What Is A Cholinergic Crisis?
Cholinergic crisis is a medical condition characterized by excess stimulation of the neuromuscular junction. The neuromuscular junction is between the axon of a motor neuron and a muscle fiber[^1].
This phenomenon occurs due to excess activity of the neurotransmitter acetylcholine (Ach). It results from inhibition or inactivation of the enzyme acetylcholinesterase. Acetylcholinesterase normally breaks down the neurotransmitter within the neuromuscular junction[^1].
Fun fact: acetylcholinesterase has a high catalytic activity. One acetylcholinesterase can degrade 25000 molecules of acetylcholine per second.
Cholinergic crisis is also referred to as cholinergic syndrome and cholinergic toxidrome.
What Is The Neuromuscular Junction?
The neuromuscular junction is a chemical synapse formed by the contact of a motor neuron and a muscle fiber[^2].
The motor neuron transmits a chemical signal to the muscle fiber causing it to contract[^2]. Specifically, the motor neuron releases Ach which acts on proteins known as Ach-receptors expressed on the surface of muscle fibers[^2]. There are two types of Ach-receptors:
- Nicotinic Acetylcholine Receptors
- Mostly present on the surface of skeletal muscles.
- Their activation leads to their twitching[^3]. -
- Nicotinic Ach-receptors are expressed on the skeletal muscles of the diaphragm and their activation mediates the process of breathing[^3].
- Muscarinic-Acetylcholine Receptors
- Present on the surface of the muscles of various visceral organs.
- Their activation leads to modulation of innate contractile activity[^4].
- Muscarinic-Ach receptors are also present on the surface of glands (such as the lacrimal glands) where they stimulate the production and secretion of bodily fluids[^4].
What Causes A Cholinergic Crisis?
Two major causes of cholinergic crisis are:
- Overdose with a cholinesterase inhibitor
- Exposure to nerve agents known as organophosphates
Cholinesterase inhibitors are a class of drugs used for a variety of conditions. Cholinesterase inhibitors treat Myasthenia-Gravis, an autoimmune disorder leading to skeletal muscle weakness. They also reverse residual muscle paralysis following a surgical procedure[^5]. Cholinesterase inhibitors are also used for the treatment of dementia (e.g., Donepezil).
Even some over-the-counter supplements inhibit acetylcholinesterase. For example, Huperzine A is a potent and irreversible acetylcholinesterase inhibitor.
Organophosphates are compounds used for their insecticidal and herbicidal properties. Organophosphates irreversibly inactivate acetylcholinesterase, inhibiting the metabolism of acetylcholine and leading to the SLUDGE syndrome [^5].
Classification of Cholinergic Crisis
Cholinergic crisis can be sub-divided into:
- Nicotinic Crisis
- Arises from excessive activation of the nicotinic acetylcholine receptor system
- Associated with the following side effects: muscle weakness, involuntary muscle twitches, inability to swallow and cramping 
- Muscarinic Crisis
- Arises from excess activation of the muscarinic acetylcholine receptors
- Associated with: blurry vision, pain in the abdomen, vomiting, nausea, diarrhea and secretion of tears and mucus [^5].
- Arises from excess activation of the muscarinic acetylcholine receptors
What are the Signs and Symptoms of a Cholinergic Crisis?
The signs and symptoms of cholinergic crisis result from excess activation of the muscarinic receptor system. The cluter of symptoms is best described with the acronym SLUDGE:
- Salivation: due to stimulation of the salivary glands
- Lacrimation: due to stimulation of the lacrimal glands
- Urination: due to relaxation of the internal sphincter muscle of urethra, and contraction of the detrusor muscles
- Gastrointestinal Distress: due to changes in smooth muscle tone of the gastrointestinal tract leading to gastrointestinal problems, including cramping
Other symptoms indicative of a cholinergic crisis are:
- excess bronchial mucus production and secretion
- constriction of pupils
- skeletal muscle spasms[^6]
What are the Complications of a Cholinergic Crisis?
If left untreated cholinergic crisis can be life-threatening because muscles stop responding to Ach. This occurs as a protective, physiological response to excess Ach activity[^6].
Specifically due to decreased nicotinic receptor activity, cholinergic crisis is associated with the following life-threatening events[^6]:
- Respiratory system failure as a result of insufficient gas exchange
- Decrease in muscle tone caused by paralysis or enfeeblement, also known as flaccid paralysis
Cholinergic Crisis vs Myasthenia Gravis
Cholinergic crisis can often be confused with another medical condition known as myasthenic crisis.
The distinction between these conditions is nebulous because they have a similar presentation.
But distinguishing cholinergic vs myasthenic crisis is crucial since the underlying pathology differs, in that they are exactly opposite, and administration of the wrong medication can be fatal[^7].
Myasthenic crisis is a life-threatening form of myasthenia gravis where the muscles used for breathing become weak. If untreated, this can lead to breathing difficulties and ultimately lung failure[^7].
While cholinergic crisis is associated with excess activity of the neurotransmitter Ach, myasthenic gravis is associated with declined Ach activity due to auto-reactive antibodies that 'attack' the nicotinic-Ach receptor system[^7].
What Drugs Treat Cholinergic Crisis?
Cholinergic chrisis is managed with anticholinergic drugs like atropine, oximes like pralidoxime, and benzodiazepines like diazepam.
Edrophonium inhibits the action of the enzyme AchE and can help discriminate between a cholinergic and a myasthenic crisis[^7].
When edrophonium exacerbates paralysis it indicates that a true cholinergic crisis is present [^7]. But muscle strength improvement after intake of edrophonium suggests myasthenic crisis[^7].
Once cholinergic crisis has been identified it can be managed with the anticholinergic drug atropine.
Atropine's blockade of muscarinic-Ach receptors, normalizes excessive Ach activity [^7].
While atropine treats the effects of muscarinic receptor activity, it has no effect on nicotinic receptors[^7]. Thus the key element of a cholinergic crisis, muscle paralysis, which is linked to life threatening respiratory arrest does not improve with atropine.
Patients with respiratory toxicity require mechanical ventilation, i.e., intubation to support breathing until the crisis resolves.
Pralidoxime is an oxime that binds acetylcholinesterase enzymes that have been inactivated by organophosphates. Hence it comes as no surprise that pralidoxime is used clinically to combat organophosphate poisoning in conjunction with
atropine and diazepam.
[^1]: Kaminski, Henry J. (2009) Myasthenia Gravis and Related Disorders. Springer Science & Business Media. [^2]: Levitan, Irwin. Kaczmarek, Leonard. (2015) Intercellular communication. The Neuron: Cell and Molecular Biology (4th ed.). New York, NY: Oxford Univerty Press. pp. 153–328._ [^3]: Itier V, Bertrand D. (2001) Neuronal nicotinic receptors: from protein structure to function. FEBS Letters._ _ 504 _ (3): 118–25. [^4]: Eglen RM (July 2006). "Muscarinic receptor subtypes in neuronal and non-neuronal cholinergic function". Auton Autacoid Pharmacol._ _ 26 _ (3): 219–33. [^5]: Marx, John A. Marx (2014). Rosen's emergency medicine: concepts and clinical practice (8th ed.). Philadelphia, PA: Elsevier/Saunders. pp. 1441–1444. [^6]: Mary Jo Wagner; Susan B. Promes. (2007)_ Last Minute Emergency Medicine: A Concise Review for the Specialty Boards. McGraw Hill Professional. p. 12. [^7]: Hetherington KA, Losek JD. (2005) Myasthenia gravis: myasthenia vs. cholinergic crisis. Pediatr Emerg Care.21(8):546-8