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Cholinesterase Inhibitors
Indications
Cholinesterase inhibitors also have the following names: acetylcholinesterase (AChE) inhibitors or anticholinesterases. They are a group of drugs that block the normal breakdown of acetylcholine (ACh) into acetate and choline and increase both the levels and duration of actions of acetylcholine found in the central and peripheral nervous system. The acetylcholinesterase inhibitors have a variety of indications. Most commonly, their use is in treating neurogenerative diseases such as Alzheimer disease, Parkinson disease, and Lewy body dementia. Different physiological processes in these degenerative disorders destroy cells that produce ACh and reduce cholinergic transmission in different regions of the brain. The cholinesterase inhibitor drugs inhibit AChE activity and maintain the ACh level by decreasing its breakdown rate.[1]
Also, cholinesterase inhibitors have frequent use in patients with myasthenia gravis. The raised level of acetylcholine in the neuromuscular junction leads to increased activation of ACh receptors found on post-synaptic membranes resulting in improved muscle activation, contraction, and strength.
At the end of surgeries, cholinesterase inhibitors, most commonly neostigmine, are administered to reverse the effects of nondepolarizing muscle agents such as rocuronium.[2][3][4][5][6]
Cholinesterase inhibitors are also necessary to administer when anticholinergic poisoning is suspected. Symptoms of anticholinergic poisoning include vasodilation, anhidrosis, mydriasis, delirium, and urinary retention.[7]
Other less common indications of cholinesterase inhibitors include treating patients diagnosed with certain psychiatric disorders such as schizophrenia and treatment of glaucoma by relieving aqueous humor pressure.[8]
Mechanism of Action
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Mechanism of Action
Cholinesterase inhibitors function by inhibiting cholinesterase from hydrolyzing acetylcholine into its components of acetate and choline'; this allows for an increase in the availability and duration of action of acetylcholine in neuromuscular junctions. The cholinesterase enzyme has two active sites: an anionic site formed by tryptophan and an esteractic site formed by serine. Cholinesterase inhibitors such as organophosphates inhibit cholinesterase from cleaving acetylcholine by interacting with the serine esteractic site. As a result, acetylcholine will continue to accumulate and activate associated receptors.[9]
Cholinesterase inhibitors classify as reversible, irreversible, or pseudo-reversible. Reversible cholinesterase inhibitors are generally utilized for therapeutic purposes. In contrast, irreversible and pseudo-reversible inhibitors are often used in pesticides and biowarfare (nerve agents).[10][11]
Administration
Cholinesterase inhibitors come in many forms. The administration of many available cholinesterase inhibitors is by IM, IV, or oral routes. Different forms can be available for different types of cholinesterase inhibitors. For example, neostigmine has a solution form used to counteract muscle relaxants at the end of surgeries. For patients with myasthenia gravis, an oral form of neostigmine is available for treatment. Rivastigmine, used in patients with dementia, has a transdermal patch form that is also frequently used.[12]
Adverse Effects
Cholinesterase inhibitors increase the overall amount of acetylcholine available. Thus, symptoms of overstimulation of the parasympathetic nervous system, such as increased hypermotility, hypersecretion, bradycardia, miosis, diarrhea, and hypotension, may be present.
A major concern when prescribing cholinesterase inhibitors or exposure to organophosphates is potentially developing a cholinergic crisis, also known as SLUDGE syndrome.[13]
SLUDGE is a mnemonic that stands for the following:
- S: Salivation
- L: Lacrimation
- U: Urination
- D: Diaphoresis
- G: Gastrointestinal upset
- E: Emesis
Temporary adverse effects when starting patients on cholinesterase inhibitors include headaches, insomnia, and minor GI issues. Other more concerning effects include lightheadedness, weakness, and weight loss. Prolonged muscle contraction may also be a presenting feature in patients exposed to cholinesterase inhibitors.[14][15]
Cholinesterase inhibitors such as neostigmine used post-operatively for reversal of neuromuscular blockade can result in a potential residual neuromuscular block.[16]
Contraindications
Due to the ability to increase vagal tone through activation of the parasympathetic nervous system, caution is necessary when administering cholinesterase inhibitors to individuals who have bradycardia or cardiac conduction diseases such as sick sinus syndrome. These individuals are at risk for syncope and falls. Caution is also advised in patients on antihypertensive medications due to the possibility of developing severe hypotension.[17]
Moreover, cholinesterase inhibitors are also contraindicated in patients with gastric ulcers due to the increased risk of gastrointestinal bleeding. Patients with urinary retention should also not receive cholinesterase inhibitors due to the risk of increased retention. This effect is especially notable in patients undergoing treatment for dementia and Alzheimer disease as urinary incontinence is a frequent clinical feature in these patients.[18]
Administration to patients with previous allergies or hypersensitivities to cholinesterase inhibitors and their derivatives is also contraindicated.[19]
Monitoring
The therapeutic index for each class of cholinesterase inhibitors varies. Physostigmine has a short half-life with a small therapeutic index and is known to cause adverse effects of nausea, vomiting, stomach cramps, and diarrhea; it is not currently recommended to treat dementia. Donepezil, which can also be used in Alzheimer disease, is well absorbed and relatively tolerated but produces adverse effects at higher dosages. The oral capsule form of rivastigmine was known to cause gastrointestinal upset. However, research led to developing a transdermal version, which was proven well-tolerated in many studies. Donepezil and rivastigmine are FDA approved and associated with fewer adverse effects than older generations of cholinesterase inhibitors. The efficacy and adverse effects of newer generations of cholinesterase inhibitors such as metrifonate are currently under investigation. Blood can be drawn to measure RBC cholinesterase activity if there is difficulty confirming the diagnosis.[20][21] Galantamine is used for the treatment of cognitive decline in mild to moderate Alzheimer disease. Galantamine is a potent allosteric potentiating ligand of human nicotinic acetylcholine receptors. Galantamine also works as a weak competitive and reversible cholinesterase inhibitor in all areas of the body.
Toxicity
The potential toxicity of cholinesterase inhibitors is due to their mechanism of action. The spectrum of toxicity can vary from patient to patient, which is also complicated by the type of cholinesterase inhibitor to which a patient suffers exposure. SLUDGE syndrome, as described above, is the most recognized form of toxicity for cholinesterase inhibitors. Severe respiratory depression can also present.
Involuntary movements due to increased acetylcholine at neuromuscular junctions can also be a sign of toxicity. Muscle fibrillation, fasciculations, and paralysis should raise the suspicion of toxicity.[22]
Miosis is a common sign of cholinergic toxicity. The excess acetylcholine causes the contraction of the sphincter pupillae muscle that encompasses the iris. Miosis is considered one of the most sensitive signs of exposure to aerosol cholinesterase inhibitors (organophosphates, pesticides).[23]
First-line treatments for suspected cholinesterase inhibitor toxicity include atropine, 2-PAM (pralidoxime), and diazepam. Atropine occupies muscarinic receptor sites, therefore reducing the binding of acetylcholine. However, it does not counteract nicotinic effects such as muscle fasciculations and weakness, so ventilation may still be necessary.[24]
2-PAM functions by reversing the binding of cholinesterase inhibitors to acetylcholinesterase. When administered together, 2-PAM and atropine have a synergistic effect.[25]
Seizures due to cholinesterase inhibitor toxicity are more apparent in pediatric patients and adults exposed to nerve agents, hence requiring immediate management with diazepam.
Enhancing Healthcare Team Outcomes
An interprofessional team is required to manage patients who are being treated with cholinesterase inhibitors successfully. Since most patients with cholinesterase inhibitor toxicity first present to the emergency department, the triage nurse must be familiar with the symptoms; these patients need immediate admission to a monitored unit. To improve outcomes, a team of nurses, laboratory technicians, pharmacists, physicians, and other healthcare professionals are essential to optimize care, especially when considering cholinesterase inhibitor toxicity. Patients admitted under these circumstances need close monitoring by the nurses and other clinicians. Ordering labs, understanding patient symptoms, and being vigilant to the next treatment steps are necessary to manage patients who are experiencing toxicity due to cholinesterase inhibitor use. Pharmacists should be consulted about the use of atropine, pralidoxime, and benzodiazepines if cholinesterase inhibitor-toxicity is suspected. A toxicologist consult should also occur, with an intensivist, to further manage a patient as many of these cases require further interventional management during the hospital course. Only through this type of interprofessional coordination can patients experiencing cholinergic toxicity achieve optimal clinical results. [Level 5]
Apart from toxicity, cholinesterase inhibitor therapy for conditions such as dementia and Alzheimer disease also requires interprofessional collaboration. Given the status of patients with these conditions being unable to participate in their treatment, the dosing clinician, the administering nursing staff, and the pharmacist must have input and cross-communication to ensure proper agent selection, dosing, administration, and monitoring of side effects. Again, interprofessional collaboration is crucial to patient outcomes. [Level 5]
Outcomes
Patients who are managed immediately after poisoning have good outcomes, but delays in treatment can lead to adverse outcomes.
References
Colović MB, Krstić DZ, Lazarević-Pašti TD, Bondžić AM, Vasić VM. Acetylcholinesterase inhibitors: pharmacology and toxicology. Current neuropharmacology. 2013 May:11(3):315-35. doi: 10.2174/1570159X11311030006. Epub [PubMed PMID: 24179466]
Ma SL, Tang NLS, Wat KHY, Tang JHY, Lau KH, Law CB, Chiu J, Tam CCW, Poon TK, Lin KL, Kng CPL, Kong HL, Chan TY, Chan WC, Lam LCW. Effect of CYP2D6 and CYP3A4 Genotypes on the Efficacy of Cholinesterase Inhibitors in Southern Chinese Patients With Alzheimer's Disease. American journal of Alzheimer's disease and other dementias. 2019 Aug:34(5):302-307. doi: 10.1177/1533317519848237. Epub 2019 May 7 [PubMed PMID: 31064198]
Lin YW, Truong D. Diffuse Lewy body disease. Journal of the neurological sciences. 2019 Apr 15:399():144-150. doi: 10.1016/j.jns.2019.02.021. Epub 2019 Feb 20 [PubMed PMID: 30807982]
Meng YH, Wang PP, Song YX, Wang JH. Cholinesterase inhibitors and memantine for Parkinson's disease dementia and Lewy body dementia: A meta-analysis. Experimental and therapeutic medicine. 2019 Mar:17(3):1611-1624. doi: 10.3892/etm.2018.7129. Epub 2018 Dec 24 [PubMed PMID: 30783428]
Level 1 (high-level) evidenceMasuda M, Utsumi H, Tanaka S, Maeno A, Yamamoto M, Sugiyama K, Hirano T, Aizawa H. Treatment of Myasthenia Gravis With High-Dose Cholinesterase Inhibitors and Calcineurin Inhibitors Caused Spontaneous Muscle Cramps in Patients. Clinical neuropharmacology. 2018 Sep/Oct:41(5):164-170. doi: 10.1097/WNF.0000000000000295. Epub [PubMed PMID: 30130259]
Shoja Shafti S, Azizi Khoei A. Effectiveness of rivastigmine on positive, negative, and cognitive symptoms of schizophrenia: a double-blind clinical trial. Therapeutic advances in psychopharmacology. 2016 Oct:6(5):308-316 [PubMed PMID: 27721970]
Level 3 (low-level) evidenceAhmad J, Hasan MJ, Anam AM, Barua DK. Donepezil: an unusual therapy for acute diphenhydramine overdose. BMJ case reports. 2019 Mar 20:12(3):. doi: 10.1136/bcr-2018-226836. Epub 2019 Mar 20 [PubMed PMID: 30898954]
Level 3 (low-level) evidenceOstergaard D, Engbaek J, Viby-Mogensen J. Adverse reactions and interactions of the neuromuscular blocking drugs. Medical toxicology and adverse drug experience. 1989 Sep-Oct:4(5):351-68 [PubMed PMID: 2682131]
Oliveira C, Bagetta D, Cagide F, Teixeira J, Amorim R, Silva T, Garrido J, Remião F, Uriarte E, Oliveira PJ, Alcaro S, Ortuso F, Borges F. Benzoic acid-derived nitrones: A new class of potential acetylcholinesterase inhibitors and neuroprotective agents. European journal of medicinal chemistry. 2019 Jul 15:174():116-129. doi: 10.1016/j.ejmech.2019.04.026. Epub 2019 Apr 17 [PubMed PMID: 31029943]
Wang P, Li H, Hassan MM, Guo Z, Zhang ZZ, Chen Q. Fabricating an Acetylcholinesterase Modulated UCNPs-Cu(2+) Fluorescence Biosensor for Ultrasensitive Detection of Organophosphorus Pesticides-Diazinon in Food. Journal of agricultural and food chemistry. 2019 Apr 10:67(14):4071-4079. doi: 10.1021/acs.jafc.8b07201. Epub 2019 Mar 27 [PubMed PMID: 30888170]
Bajgar J, Kassa J, Kucera T, Musilek K, Jun D, Kuca K. Some Possibilities to Study New Prophylactics against Nerve Agents. Mini reviews in medicinal chemistry. 2019:19(12):970-979. doi: 10.2174/1389557519666190301112530. Epub [PubMed PMID: 30827238]
Chou PS, Jhang KM, Huang LC, Wang WF, Yang YH. Skinfold thickness for rivastigmine patch application in Alzheimer's disease. Psychopharmacology. 2019 Apr:236(4):1255-1260. doi: 10.1007/s00213-018-5135-x. Epub 2019 Jan 15 [PubMed PMID: 30645680]
Ohbe H, Jo T, Matsui H, Fushimi K, Yasunaga H. Cholinergic Crisis Caused by Cholinesterase Inhibitors: a Retrospective Nationwide Database Study. Journal of medical toxicology : official journal of the American College of Medical Toxicology. 2018 Sep:14(3):237-241. doi: 10.1007/s13181-018-0669-1. Epub 2018 Jun 15 [PubMed PMID: 29907949]
Level 2 (mid-level) evidenceObara K, Ogawa T, Chino D, Tanaka Y. The Long-Lasting Enhancing Effect of Distigmine on Acetylcholine-Induced Contraction of Guinea Pig Detrusor Smooth Muscle Correlates with Its Anticholinesterase Activity. Biological & pharmaceutical bulletin. 2017:40(7):1092-1100. doi: 10.1248/bpb.b17-00175. Epub [PubMed PMID: 28674252]
Inglis F. The tolerability and safety of cholinesterase inhibitors in the treatment of dementia. International journal of clinical practice. Supplement. 2002 Jun:(127):45-63 [PubMed PMID: 12139367]
Luo J, Chen S, Min S, Peng L. Reevaluation and update on efficacy and safety of neostigmine for reversal of neuromuscular blockade. Therapeutics and clinical risk management. 2018:14():2397-2406. doi: 10.2147/TCRM.S179420. Epub 2018 Dec 10 [PubMed PMID: 30573962]
Gill SS, Anderson GM, Fischer HD, Bell CM, Li P, Normand SL, Rochon PA. Syncope and its consequences in patients with dementia receiving cholinesterase inhibitors: a population-based cohort study. Archives of internal medicine. 2009 May 11:169(9):867-73. doi: 10.1001/archinternmed.2009.43. Epub [PubMed PMID: 19433698]
Level 2 (mid-level) evidenceTriantafylidis LK, Clemons JS, Peron EP, Roefaro J, Zimmerman KM. Brain Over Bladder: A Systematic Review of Dual Cholinesterase Inhibitor and Urinary Anticholinergic Use. Drugs & aging. 2018 Jan:35(1):27-41. doi: 10.1007/s40266-017-0510-6. Epub [PubMed PMID: 29350336]
Level 1 (high-level) evidenceBonner LT, Peskind ER. Pharmacologic treatments of dementia. The Medical clinics of North America. 2002 May:86(3):657-74 [PubMed PMID: 12171061]
Mehta M, Adem A, Sabbagh M. New acetylcholinesterase inhibitors for Alzheimer's disease. International journal of Alzheimer's disease. 2012:2012():728983. doi: 10.1155/2012/728983. Epub 2011 Dec 15 [PubMed PMID: 22216416]
Gupta S, Belle VS, Kumbarakeri Rajashekhar R, Jogi S, Prabhu RK. Correlation of Red Blood Cell Acetylcholinesterase Enzyme Activity with Various RBC Indices. Indian journal of clinical biochemistry : IJCB. 2018 Oct:33(4):445-449. doi: 10.1007/s12291-017-0691-0. Epub 2017 Sep 4 [PubMed PMID: 30319191]
Pope CN, Brimijoin S. Cholinesterases and the fine line between poison and remedy. Biochemical pharmacology. 2018 Jul:153():205-216. doi: 10.1016/j.bcp.2018.01.044. Epub 2018 Jan 31 [PubMed PMID: 29409903]
Mattio TG, Richardson JS, Giacobini E. Effects of DFP on iridic metabolism and release of acetylcholine and on pupillary function in the rat. Neuropharmacology. 1984 Oct:23(10):1207-14 [PubMed PMID: 6521855]
Level 3 (low-level) evidenceSingh S, Batra YK, Singh SM, Wig N, Sharma BK. Is atropine alone sufficient in acute severe organophosphorus poisoning?: experience of a North West Indian Hospital. International journal of clinical pharmacology and therapeutics. 1995 Nov:33(11):628-30 [PubMed PMID: 8688989]
Burillo-Putze G, Hoffman RS, Howland MA, Duenas-Laita A. Late administration of pralidoxime in organophosphate (fenitrothion) poisoning. The American journal of emergency medicine. 2004 Jul:22(4):327-8 [PubMed PMID: 15258887]
Level 3 (low-level) evidence