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. 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 :
Acetylcholine (ACh) is a neurotransmitter found 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 gets released from the vesicles, out of the neuron and into the synaptic cleft, where it can act on receptors present on postsynaptic neurons or organs. In general, the 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.
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 to evaluate 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.
|||Ferreira-Vieira TH,Guimaraes IM,Silva FR,Ribeiro FM, Alzheimer's disease: Targeting the Cholinergic System. Current neuropharmacology. 2016; [PubMed PMID: 26813123]|
|||Dawson AH,Buckley NA, Pharmacological management of anticholinergic delirium - theory, evidence and practice. British journal of clinical pharmacology. 2016 Mar; [PubMed PMID: 26589572]|
|||Durán CE,Azermai M,Vander Stichele RH, Systematic review of anticholinergic risk scales in older adults. European journal of clinical pharmacology. 2013 Jul; [PubMed PMID: 23529548]|
|||Abrams P,Andersson KE,Buccafusco JJ,Chapple C,de Groat WC,Fryer AD,Kay G,Laties A,Nathanson NM,Pasricha PJ,Wein AJ, Muscarinic receptors: their distribution and function in body systems, and the implications for treating overactive bladder. British journal of pharmacology. 2006 Jul; [PubMed PMID: 16751797]|
|||Gerretsen P,Pollock BG, Rediscovering adverse anticholinergic effects. The Journal of clinical psychiatry. 2011 Jun; [PubMed PMID: 21733482]|
|||Price D,Fromer L,Kaplan A,van der Molen T,Román-Rodríguez M, Is there a rationale and role for long-acting anticholinergic bronchodilators in asthma? NPJ primary care respiratory medicine. 2014 Jul 17; [PubMed PMID: 25030457]|
|||Lampela P,Paajanen T,Hartikainen S,Huupponen R, Central Anticholinergic Adverse Effects and Their Measurement. Drugs [PubMed PMID: 26518014]|
|||Tune LE, Anticholinergic effects of medication in elderly patients. The Journal of clinical psychiatry. 2001; [PubMed PMID: 11584981]|
|||Ueki T,Nakashima M, Relationship Between Constipation and Medication. Journal of UOEH. 2019; [PubMed PMID: 31292358]|
|||Torres NE,Zollman PJ,Low PA, Characterization of muscarinic receptor subtype of rat eccrine sweat gland by autoradiography. Brain research. 1991 May 31; [PubMed PMID: 1888990]|
|||Golding JF,Wesnes KA,Leaker BR, The effects of the selective muscarinic M3 receptor antagonist darifenacin, and of hyoscine (scopolamine), on motion sickness, skin conductance [PubMed PMID: 29522648]|
|||Black CE,Huang N,Neligan PC,Levine RH,Lipa JE,Lintlop S,Forrest CR,Pang CY, Effect of nicotine on vasoconstrictor and vasodilator responses in human skin vasculature. American journal of physiology. Regulatory, integrative and comparative physiology. 2001 Oct; [PubMed PMID: 11557615]|
|||Cooke JP,Ghebremariam YT, Endothelial nicotinic acetylcholine receptors and angiogenesis. Trends in cardiovascular medicine. 2008 Oct; [PubMed PMID: 19232953]|
|||Fujii N,Louie JC,McNeely BD,Zhang SY,Tran MA,Kenny GP, Nicotinic receptor activation augments muscarinic receptor-mediated eccrine sweating but not cutaneous vasodilatation in young males. Experimental physiology. 2017 Feb 1; [PubMed PMID: 27859779]|
|||Yates C,Manini AF, Utility of the electrocardiogram in drug overdose and poisoning: theoretical considerations and clinical implications. Current cardiology reviews. 2012 May; [PubMed PMID: 22708912]|
|||Shi S,Klotz U, Age-related changes in pharmacokinetics. Current drug metabolism. 2011 Sep; [PubMed PMID: 21495970]|
|||Stegemann S,Ecker F,Maio M,Kraahs P,Wohlfart R,Breitkreutz J,Zimmer A,Bar-Shalom D,Hettrich P,Broegmann B, Geriatric drug therapy: neglecting the inevitable majority. Ageing research reviews. 2010 Oct; [PubMed PMID: 20478411]|
|||de Leon J, Paying attention to pharmacokinetic and pharmacodynamic mechanisms to progress in the area of anticholinergic use in geriatric patients. Current drug metabolism. 2011 Sep; [PubMed PMID: 21495973]|
|||Patel T,Slonim K,Lee L, Use of potentially inappropriate medications among ambulatory home-dwelling elderly patients with dementia: A review of the literature. Canadian pharmacists journal : CPJ = Revue des pharmaciens du Canada : RPC. 2017 May-Jun; [PubMed PMID: 28507653]|
|||Sheu JJ,Tsai MT,Erickson SR,Wu CH, Association between Anticholinergic Medication Use and Risk of Dementia among Patients with Parkinson's Disease. Pharmacotherapy. 2019 Aug; [PubMed PMID: 31251824]|
|||Hafdi M,Hoevenaar-Blom MP,Beishuizen CRL,Moll van Charante EP,Richard E,van Gool WA, Association of Benzodiazepine and Anticholinergic Drug Usage With Incident Dementia: A Prospective Cohort Study of Community-Dwelling Older Adults. Journal of the American Medical Directors Association. 2019 Jul 9; [PubMed PMID: 31300339]|
|||Andrade C, Anticholinergic Drug Exposure and the Risk of Dementia: There Is Modest Evidence for an Association but Not for Causality. The Journal of clinical psychiatry. 2019 Aug 6; [PubMed PMID: 31390497]|
|||OʼNeil CA,Krauss MJ,Bettale J,Kessels A,Costantinou E,Dunagan WC,Fraser VJ, Medications and Patient Characteristics Associated With Falling in the Hospital. Journal of patient safety. 2018 Mar; [PubMed PMID: 25782559]|
|||Mirrakhimov AE,Ayach T,Barbaryan A,Talari G,Chadha R,Gray A, The Role of Sodium Bicarbonate in the Management of Some Toxic Ingestions. International journal of nephrology. 2017; [PubMed PMID: 28932601]|