Physiology, Anticholinergic Reaction
Acetylcholine (ACh) is a neurotransmitter that acts on the central nervous system (CNS), the autonomic nervous system (ANS), and at the neuromuscular junction (NMJ). Generally, ACh receptors at the NMJ are nicotinic type while in the CNS and ANS they are usually muscarinic type. As a reminder, these receptors are functionally and structurally different; nicotinic ACh receptors are ligand-gated ion channels, whereas muscarinic ACh receptors are G-protein coupled receptors. Processes that enhance ACh function are termed “cholinergic” while processes that inhibit the action of ACh at its receptors are termed “anticholinergic.” Anticholinergic effects are most commonly the result of medication. These medications should be more appropriately termed "antimuscarinics," as they usually block muscarinic but not nicotinic receptors. At least 600 drugs/medicinal products are recognized to have anticholinergic activity, and the most common of these are responsible for a significant amount of poisoning admissions. Many also contribute to the development of an anticholinergic reaction: a constellation of symptoms resulting from the antagonism of muscarinic receptors throughout the body. The features of the anticholinergic reaction are deducible from an understanding of the normal function of muscarinic receptors at various organs, and the following mnemonic summarizes these effects:
- Mad as a hatter (delirium)
- Blind as a bat (ocular symptoms)
- Dry as a bone (anhidrosis/dry mouth/dry skin)
- Hot as a hare (fever)
- Bloated as a toad (constipation)
- The heart runs alone (tachycardia)
- Full as a flask (urinary retention)
- Red as a beet (cutaneous vasodilation)
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Acetylcholine (ACh) is a neurotransmitter found within synaptic vesicles in presynaptic cholinergic neurons present in the central nervous system (CNS), autonomic nervous system (ANS), and neuromuscular junction (NMJ). It is synthesized within the cytosol of the presynaptic neuron from acetyl-coenzyme A and choline by the enzyme choline acetyltransferase. It is subsequently transferred to vesicles within the presynaptic neuron for storage. Upon stimulation of the neuron, ACh vesicles are exocytosed, out of the neuron, and into the synaptic cleft, where it can act on receptors present on postsynaptic neurons. In general, the ACh binds to ACh receptors are nicotinic-type at the NMJ, and muscarinic-type at the CNS and ANS, although some exceptions exist.
Acetylcholinesterase is an enzyme in the synaptic cleft, functioning to degrade acetylcholine and decrease its concentration, thereby, decreasing its action on its receptors.
Any process that attenuates the effects of acetylcholine at its receptors, whether by reducing its synthesis or release, increasing acetylcholinesterase activity, or inhibiting the receptor, is termed an anticholinergic effect. This activity can result from normal physiology, abnormal pathology, or medication.
Medications with anticholinergic activity usually affect muscarinic receptors but not nicotinic receptors. There are a limited number of medication classes with antinicotinic properties. Therefore the remainder of this article, "anticholinergic" is used synonymously with "antimuscarinic."
There are at least five subtypes of muscarinic receptors (M1, M2, M3, M4, and M5) present throughout the body. Understanding the general function of each muscarinic receptor at each organ system is necessary to understand the anticholinergic reaction. Additionally, although the general patterns of distribution/function listed below are accepted, new research is still being performed to identify additional locations and functions of the receptor subtypes.
- Brain: All five (M1-M5) muscarinic receptor subtypes are distributed throughout the brain. However, several studies suggest that the receptor most significantly implicated in the anticholinergic reaction is the M1 receptor. Components of the reaction include delirium, cognitive impairment, dizziness, sedation, and confusion.
- Eye: M1-M5 are present throughout the eye, but M3 predominates. The stimulation of M3 by ACh causes iris sphincter contraction, leading to pupillary constriction (miosis). Anticholinergic toxicity, therefore, leads to improperly-timed pupillary dilation (mydriasis) and blurred vision.
- Salivary Glands: M1 and M3 receptors predominate, and stimulation by ACh leads to increased salivation. Anticholinergic toxicity leads to decreased salivation and dry mouth with difficulty swallowing. M4 is possibly present at the parotid glands, but its full effect is currently unclear.
- Sweat Glands: The M3 receptor predominates at the sweat glands of the skin and stimulation by ACh leads to increased sweating. The anticholinergic reaction leads to a decreased ability to sweat, and therefore, a decreased ability to dissipate heat.
- Heart: The M2 receptor predominates in the heart and modulates several aspects of cardiac function; slowing down pacemaker activity and atrioventricular conduction (chronotropic), and decreasing cardiac inotropy (contractility). An anticholinergic effect at the M2 cardiac receptor would lead to sinus tachycardia and increased contractility.
- Lungs: The lung contains M1-M4 receptors which play an important role in lung/bronchial function as well as treatment of lung disease. The muscarinic receptor antagonists play an important role in treating pathology related to the lungs and are not classically associated with an anticholinergic reaction.
- Gastrointestinal System: M2 and M3 receptors predominate and under ACh stimulation, increase gastric motility. In the anticholinergic reaction, the motility slows down, which can result in gastric stasis and constipation.
- Bladder: M3 is predominantly responsible for detrusor/bladder contraction. M2 may be responsible for inhibiting detrusor relaxation, but the exact role is still unclear. Inhibition during an anticholinergic reaction leads to an inability to contract the bladder, causing urinary stasis and retention. 
- Skin: Although M3 is the primary receptor at the skin, there is no clear relationship between ACh and vasodilation. ACh can stimulate muscarinic receptors in vascular endothelium, leading to increased nitric oxide synthesis and vasodilation. ACh also acts on nicotinic receptors in the vascular endothelium, leading to vasoconstriction. There is a complex interaction at the vascular endothelium between nicotinic and muscarinic receptors, as well as other factors including norepinephrine and prostaglandins. The anticholinergic reaction generally results in vasodilation at the skin despite the complexity of factors involved, likely to dissipate excess body heat.
The anticholinergic reaction is thought to be due to both central and peripheral antagonism of ACh at muscarinic receptors. The mechanism of each specific symptom derives from the normal function of ACh at each of its muscarinic receptors (see Organ Systems Involved, above).
Testing is not available to aid in the diagnosis of anticholinergic toxicity. It is a clinical diagnosis based on a thorough history and physical exam. The anticholinergic reaction can present with symptoms of non-muscarinic drug effects that can further complicate the syndrome. Clinical exam and testing focus on patient presentation and evaluation for all possible causes of delirium. Basic screening tests should include a pregnancy test in childbearing age women, drug levels of acetaminophen, and salicylates to rule out common co-ingestions and fingerstick glucose. Electrocardiogram (ECG) is crucial to evaluate the QT and QRS intervals to rule out cardiotoxicity.
There are over 600 identified medications and medicinal products with anticholinergic activity. Toxicity leads to a significant number of hospital admissions and up to 40% of intensive care unit admissions. The geriatric population is at the highest risk for anticholinergic poisoning. Treatment of anticholinergic toxicity is associated with its additional adverse effects.
Elderly Patients: The elderly population is most sensitive to the effects of anticholinergic medications. Age is the most significant patient predictor associated with the severity of an anticholinergic reaction. As age increases, there are changes in metabolism, leading to different drug pharmacokinetics and pharmacodynamics. Additionally, many elderly patients may have comorbidities such as pre-existing psychiatric disease that increase their sensitivities to anticholinergic medications and increased risk of drug-drug interaction with other medications. It merits noting that the relationship between age and anticholinergic sensitivity is an association without established causality. Regardless, delirium and other effects of the anticholinergic reaction are significant in the elderly as it can lead to increased anxiety, falls, decreased activities of daily living, urinary incontinence, decreased nutritional status, and decreased independence.
Treatment: Management of anticholinergic toxicity starts with stabilization of any emergent conditions related to airway, breathing, and circulation. Specific treatment available for poisoning includes sodium bicarbonate for prolonged QRS intervals on ECG. Delirium is treatable with benzodiazepines. Cooling methods can treat hyperthermia. If the patient is awake and cooperative, activated charcoal can be a consideration. Supportive treatment is typically sufficient for anticholinergic toxicity. Physostigmine is an available antidote, a drug that inhibits the enzyme acetylcholinesterase in the synaptic cleft; this increases ACh in the synapse and allows for competition for inhibited muscarinic receptors.
Effects of Treatment: Clinicians should also monitor patients for effects related to treatment. Physostigmine use is controversial given excessive inhibition of acetylcholinesterase which can lead to additional toxicity. Potential symptoms of toxicity categorize into effects on the CNS (coma and seizures), effects on peripheral muscarinic receptors (bradycardia, bronchospasm, gland overactivity, nausea, and vomiting), and effects on peripheral nicotinic receptors (neuromuscular symptoms). The adverse effects of cholinesterase inhibitors should be considered before administration and require close monitoring after administration. Sodium bicarbonate can lead to metabolic alkalosis, electrolyte abnormalities, volume overload, causing worsening of heart failure and respiratory status. Benzodiazepines can cause respiratory depression if used in excessive amounts, although they have a high safety threshold.
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