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AOP: 559

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE.  More help

Inhibition of acetylcholinesterase (AChE) leading to arrhythmias

Short name
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Inhibition of acetylcholinesterase (AChE), arrhythmias
The current version of the Developer's Handbook will be automatically populated into the Handbook Version field when a new AOP page is created.Authors have the option to switch to a newer (but not older) Handbook version any time thereafter. More help
Handbook Version v2.7

Graphical Representation

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Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

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Sun-Woong Kanga, Myeong Hwa Song,Do-Sun Lim b and Kim Young Jun

aCenter for Biomimetic Research, Korea Institute of Toxicology, Daejeon 34114, Korea

bCardiovascular Center, Department of Cardiology, Korea University Anam Hospital, Korea University College of Medicine, Seoul, South Korea

cEnvironemental Safety Group, KIST Europe, campus E 71 Saarbruecken, Germany 

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section.   More help
Young Jun Kim   (email point of contact)

Contributors

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  • Young Jun Kim

Coaches

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OECD Information Table

Provides users with information concerning how actively the AOP page is being developed and whether it is part of the OECD Workplan and has been reviewed and/or endorsed. OECD Project: Assigned upon acceptance onto OECD workplan. This project ID is managed and updated (if needed) by the OECD. OECD Status: For AOPs included on the OECD workplan, ‘OECD status’ tracks the level of review/endorsement of the AOP . This designation is managed and updated by the OECD. Journal-format Article: The OECD is developing co-operation with Scientific Journals for the review and publication of AOPs, via the signature of a Memorandum of Understanding. When the scientific review of an AOP is conducted by these Journals, the journal review panel will review the content of the Wiki. In addition, the Journal may ask the AOP authors to develop a separate manuscript (i.e. Journal Format Article) using a format determined by the Journal for Journal publication. In that case, the journal review panel will be required to review both the Wiki content and the Journal Format Article. The Journal will publish the AOP reviewed through the Journal Format Article. OECD iLibrary published version: OECD iLibrary is the online library of the OECD. The version of the AOP that is published there has been endorsed by the OECD. The purpose of publication on iLibrary is to provide a stable version over time, i.e. the version which has been reviewed and revised based on the outcome of the review. AOPs are viewed as living documents and may continue to evolve on the AOP-Wiki after their OECD endorsement and publication.   More help
OECD Project # OECD Status Reviewer's Reports Journal-format Article OECD iLibrary Published Version
This AOP was last modified on December 03, 2024 09:29

Revision dates for related pages

Page Revision Date/Time
Acetylcholinesterase (AchE) Inhibition April 29, 2020 17:21
Increased Muscarinic Acetylcholine Receptors December 02, 2024 03:35
Altered, Action Potential March 31, 2022 06:49
Increased delay in heart electrical conduction November 26, 2024 12:31
Occurrence, cardiac arrhythmia September 16, 2017 10:17
AchE Inhibition leads to Activation, Muscarinic Acetylcholine Receptors November 22, 2024 09:45
Activation, Muscarinic Acetylcholine Receptors leads to Altered, Action Potential November 22, 2024 09:45
Altered, Action Potential leads to Prolonged atrioventricular (AV) November 22, 2024 09:46
Prolonged atrioventricular (AV) leads to Occurrence, cardiac arrhythmia November 20, 2024 11:15
Donepezil November 22, 2024 11:21
Neostigmine November 22, 2024 11:21
Pyridostigmine November 22, 2024 11:21
Parathion November 29, 2016 18:42
Malathion March 30, 2020 15:59
Chlorpyrifos July 27, 2022 04:02
Diazinon November 22, 2024 11:22
Sarin November 22, 2024 11:22
Tabun November 22, 2024 11:23
Carbaryl November 22, 2024 11:23
Aldicarb November 22, 2024 11:23
Physostigmine November 22, 2024 11:23
Ciprofloxacin December 04, 2018 04:26
Carbofuran November 22, 2024 11:24
Pilocarpine November 22, 2024 11:24
Bethanechol November 22, 2024 11:24

Abstract

A concise and informative summation of the AOP under development that can stand-alone from the AOP page. The aim is to capture the highlights of the AOP and its potential scientific and regulatory relevance. More help

Inhibition of acetylcholinesterase (AChE) can lead to arrhythmias by disrupting parasympathetic regulation of cardiac activity. AChE normally terminates the action of acetylcholine (ACh) at muscarinic M2 receptors in the heart, maintaining a balance in autonomic control. Inhibition of AChE, such as in organophosphate poisoning or carbamate toxicity, results in excessive ACh accumulation, causing prolonged parasympathetic stimulation. This leads to bradyarrhythmias, including sinus bradycardia, atrioventricular (AV) block, and in severe cases, asystole. Excessive vagal stimulation also contributes to electrical instability through early and delayed afterdepolarizations, increasing the risk of polymorphic ventricular tachycardia, such as Torsades de Pointes (TdP), and ventricular fibrillation (VF). Additionally, autonomic imbalance caused by prolonged parasympathetic overdrive may predispose to alternating bradyarrhythmias and tachyarrhythmias. Clinical scenarios such as organophosphate poisoning and the therapeutic use of cholinesterase inhibitors in myasthenia gravis or Alzheimer’s disease illustrate the potential cardiac effects of AChE inhibition. While mild bradycardia is manageable in controlled settings, severe AChE inhibition can cause life-threatening arrhythmias, emphasizing the importance of understanding these mechanisms for effective management of AChE-related cardiac dysfunction.

AOP Development Strategy

Context

Used to provide background information for AOP reviewers and users that is considered helpful in understanding the biology underlying the AOP and the motivation for its development.The background should NOT provide an overview of the AOP, its KEs or KERs, which are captured in more detail below. More help

AOP: Inhibition of Acetylcholinesterase (AChE) Leading to Arrhythmias provides a mechanistic framework linking the disruption of acetylcholine (ACh) regulation at synapses to the development of cardiac arrhythmias. AChE is a critical enzyme responsible for breaking down ACh, a neurotransmitter that mediates parasympathetic signaling in the autonomic nervous system. When AChE is inhibited, ACh accumulates excessively at synaptic junctions, particularly within the cardiac parasympathetic system, leading to overstimulation of muscarinic acetylcholine receptors (M2 receptors) in the heart. The overstimulation of M2 receptors triggers potassium efflux through G-protein-coupled inwardly rectifying potassium channels (IK,ACh), resulting in hyperpolarization of cardiac cells. This disrupts the normal electrical activity of the heart by prolonging or destabilizing cardiac action potentials. The altered electrical signaling can cause conduction delays, reentrant circuits, and early afterdepolarizations (EADs), which ultimately manifest as bradyarrhythmias, tachyarrhythmias, or fibrillation.  This AOP has applications in regulatory toxicology, where it can be used to screen for cardiotoxic effects of environmental toxins and pharmaceuticals, and in therapeutic development, where targeting intermediate key events (e.g., using muscarinic receptor antagonists) can help mitigate arrhythmias. It also provides a framework for assessing combined risks from multiple stressors affecting AChE activity or parasympathetic signaling.

Strategy

Provides a description of the approaches to the identification, screening and quality assessment of the data relevant to identification of the key events and key event relationships included in the AOP or AOP network.This information is important as a basis to support the objective/envisaged application of the AOP by the regulatory community and to facilitate the reuse of its components.  Suggested content includes a rationale for and description of the scope and focus of the data search and identification strategy/ies including the nature of preliminary scoping and/or expert input, the overall literature screening strategy and more focused literature surveys to identify additional information (including e.g., key search terms, databases and time period searched, any tools used). More help

1. Problem Formulation

Objective

To describe the mechanistic progression from AChE inhibition to arrhythmias.

To identify key events (KEs), key event relationships (KERs), and modulating factors influencing this pathway.

To enable applications in toxicology, pharmacology, and therapeutic development.

Relevance

AChE inhibitors, such as organophosphates and carbamates, are widely used pesticides and chemical warfare agents, posing risks of cardiac arrhythmias.

Therapeutic agents like donepezil for Alzheimer's disease also inhibit AChE and may induce adverse cardiac effects.

2. Identification of Key Events (KEs)

The pathway begins with the Molecular Initiating Event (MIE) of AChE inhibition and progresses through several KEs to the adverse outcome (AO):

MIE: Inhibition of AChE

Prevents the breakdown of acetylcholine (ACh), leading to its accumulation at synaptic junctions.

KE1: Increased ACh Levels

Accumulated ACh overstimulates parasympathetic signaling.

KE2: Overactivation of Muscarinic Receptors

Activation of M2 receptors in the heart disrupts ionic balance and electrical signaling.

KE3: Altered Cardiac Action Potential

Hyperpolarization and increased potassium efflux through IK,ACh channels impair excitation-contraction coupling.

KE4: Prolonged atrioventricular (AV) conduction time

Conduction blocks and reentrant circuits emerge, causing electrical instability.

AO: Arrhythmias

Sustained electrical instability leads to bradyarrhythmias, tachyarrhythmias, or fibrillation.

3. Evidence Collection and Screening

Data Sources

In Vitro Studies:

Cardiac cell models assessing ACh accumulation, muscarinic receptor activation, and ionic currents.

In Vivo Studies:

Animal models exposed to AChE inhibitors to monitor cardiac electrophysiology and arrhythmic patterns.

Clinical Data:

Observations of arrhythmias in patients exposed to pesticides or receiving therapeutic AChE inhibitors.

Computational Models:

Simulations of parasympathetic signaling and cardiac action potential dynamics.

Screening Criteria

Relevance: Data must address the MIE or KEs in the pathway.

Quality: Prioritize studies with robust experimental designs and reproducibility.

Consistency: Focus on findings that align with the proposed mechanistic progression.

4. Validation and Refinement

Validate the AOP using experimental, computational, and clinical data.

Refine KERs and quantitative models based on emerging evidence.

Summary of the AOP

This section is for information that describes the overall AOP.The information described in section 1 is entered on the upper portion of an AOP page within the AOP-Wiki. This is where some background information may be provided, the structure of the AOP is described, and the KEs and KERs are listed. More help

Events:

Molecular Initiating Events (MIE)
An MIE is a specialised KE that represents the beginning (point of interaction between a prototypical stressor and the biological system) of an AOP. More help
Key Events (KE)
A measurable event within a specific biological level of organisation. More help
Adverse Outcomes (AO)
An AO is a specialized KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help
Type Event ID Title Short name
KE 1602 Increased Muscarinic Acetylcholine Receptors Activation, Muscarinic Acetylcholine Receptors
KE 698 Altered, Action Potential Altered, Action Potential
KE 2280 Increased delay in heart electrical conduction Prolonged atrioventricular (AV)
AO 1106 Occurrence, cardiac arrhythmia Occurrence, cardiac arrhythmia

Relationships Between Two Key Events (Including MIEs and AOs)

This table summarizes all of the KERs of the AOP and is populated in the AOP-Wiki as KERs are added to the AOP.Each table entry acts as a link to the individual KER description page. More help

Network View

This network graphic is automatically generated based on the information provided in the MIE(s), KEs, AO(s), KERs and Weight of Evidence (WoE) summary tables. The width of the edges representing the KERs is determined by its WoE confidence level, with thicker lines representing higher degrees of confidence. This network view also shows which KEs are shared with other AOPs. More help

Prototypical Stressors

A structured data field that can be used to identify one or more “prototypical” stressors that act through this AOP. Prototypical stressors are stressors for which responses at multiple key events have been well documented. More help

Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help
Life stage Evidence
Not Otherwise Specified Moderate

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available. More help
Term Scientific Term Evidence Link
human and other cells in culture human and other cells in culture High NCBI
Rattus norvegicus Rattus norvegicus High NCBI
dogs Canis lupus familiaris High NCBI
Sus scrofa Sus scrofa Moderate NCBI
zebrafish Danio rerio Moderate NCBI
Insecta sp. BOLD:AAN5199 Insecta sp. BOLD:AAN5199 Moderate NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help
Sex Evidence
Mixed Moderate

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help
Contents Evaluation
Biological Plausibility Strong: Mechanisms linking AChE inhibition to arrhythmias are well-established.
Empirical Evidence Robust: Consistent support across experimental and clinical studies.
Quantitative Understanding Moderate: Well-characterized for early events; limited for late-stage effects.
Modulating Factors Identified: Age, genetics, comorbidities, and stress influence outcomes.
Regulatory Relevance High: Applicable to toxicology, drug safety, and therapeutic development.

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help
Domain Description
Taxonomic Relevance Humans, rodents, and dogs are most relevant; pigs and zebrafish are moderately applicable.
Life Stage Highly relevant to adults and elderly; moderately applicable to neonates and children.
Sex Applicable to both sexes, with potential hormonal modulation of outcomes.
Molecular/Cellular Level Focuses on AChE, M2 muscarinic receptors, and cardiac myocytes.
Stressors Includes organophosphates, carbamates, therapeutic AChE inhibitors, and physiological vagal activation.

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help
Key Event Essentiality Evidence
MIE: AChE Inhibition High Directly causes ACh accumulation, initiating downstream effects.
KE1: Overactivation of M2 Receptors High Necessary for potassium efflux and action potential disruption.
KE2: Altered Cardiac Action Potential High Central to the development of conduction blocks and arrhythmic activity.
KE3: Prolonged atrioventricular (AV) conduction time Moderate-High Directly leads to arrhythmias but can be modulated by other factors.
AO: Arrhythmias Endpoint Result of sustained electrical instability.

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help
Key Event  Biological Plausibility Evidence Assessment
MIE: AChE Inhibition Strong Numerous studies have demonstrated that exposure to AChE inhibitors, such as organophosphates and carbamates, results in dose-dependent increases in ACh levels. Measurement tools such as Ellman’s assay provide reliable quantification of AChE activity.
KE1: Overactivation of M2 Receptors Strong Electrophysiological studies in isolated cardiac myocytes demonstrate M2 receptor-mediated activation of inwardly rectifying potassium channels (IK,ACh). Muscarinic agonists mimic the effects of AChE inhibitors, supporting the role of receptor overactivation.
KE2: Altered Cardiac Action Potential Strong Patch-clamp recordings show alterations in action potential duration and repolarization under conditions of muscarinic receptor overstimulation. Clinical ECG data from organophosphate poisoning cases reveal bradyarrhythmias and conduction delays.
KE3: Prolonged atrioventricular (AV) conduction time Moderate In vivo studies in animal models exposed to organophosphates demonstrate conduction blocks and reentrant arrhythmias. Human clinical reports support associations between AChE inhibitor exposure and conduction disturbances.
AO: Arrhythmias Strong Extensive clinical documentation links AChE inhibitor exposure to arrhythmias. Animal studies confirm dose-dependent progression from conduction disturbances to arrhythmias.

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help
Modulating Factor (MF) Influence or Outcome KER(s) involved

Age

Genetic Variants

Electrolyte Imbalances

Chemical Interactions

Older individuals are more susceptible to arrhythmias due to reduced cardiac plasticity and slower compensatory responses to parasympathetic overstimulation.

Variants in muscarinic receptors or ion channels can affect the sensitivity of key cellular processes, amplifying or reducing responses to AChE inhibitors.

Hypokalemia (low potassium) and hypercalcemia (high calcium) exacerbate ionic imbalances caused by AChE inhibition, worsening conduction abnormalities and arrhythmias.

Co-administration of β-adrenergic agonists (e.g., isoproterenol) or other parasympathomimetic agents exacerbates the effects of AChE inhibitors.

Conversely, muscarinic antagonists (e.g., atropine) can mitigate these effects

Inhibition of AChE → Prolonged atrioventricular (AV) conduction time

Increased ACh → Overactivation of Muscarinic Receptors

Overactivation of Muscarinic Receptors → Altered Action Potential

Overactivation of Muscarinic Receptors → Altered Action Potential

Overactivation of Muscarinic Receptors → Altered Action Potential

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors.  More help

MIE: Inhibition of AChE

Quantitative Relationship:

AChE inhibition is directly proportional to the dose of the stressor (e.g., organophosphates, carbamates).

IC50 values for AChE inhibition are well-established for various chemicals, ranging from nanomolar to micromolar concentrations depending on the compound.

Measurement:

AChE activity can be quantified using Ellman’s assay or biosensor-based techniques.

Thresholds:

Substantial ACh accumulation occurs when AChE activity is reduced by >50%.

Time Course:

AChE inhibition is rapid, occurring within minutes to hours following exposure.

KE1: Overactivation of Muscarinic Receptors

Quantitative Relationship:

Muscarinic receptor activation depends on the concentration of ACh. EC50 for M2 receptor activation by ACh is approximately 1 µM.

Overactivation occurs when ACh levels exceed the physiological range (e.g., >10 µM).

Measurement:

Muscarinic receptor activity is assessed using radioligand binding assays or electrophysiological recordings of IK,ACh currents.

Thresholds:

Overactivation of M2 receptors is correlated with prolonged IK,ACh channel opening and increased potassium efflux.

Time Course:

Receptor activation occurs within seconds to minutes after ACh levels rise.

KE2: Altered Cardiac Action Potential

Quantitative Relationship:

The degree of action potential alteration (e.g., prolongation, amplitude reduction) is proportional to M2 receptor activation and potassium efflux through IK,ACh.

Dose-response studies demonstrate significant changes in action potential duration at ACh concentrations >10 µM.

Measurement:

Patch-clamp techniques are used to measure action potential duration (APD) and ionic currents in cardiac myocytes.

ECG analysis provides indirect measurements of action potential changes (e.g., QT prolongation).

Thresholds:

A >20% change in APD is associated with electrical instability.

Time Course:

Action potential alterations manifest within minutes to hours of AChE inhibition.

KE3: Prolonged atrioventricular (AV) conduction time

Quantitative Relationship:

Electrical conduction delays increase with the degree of action potential alteration and ionic imbalance.

Conduction blocks are observed at higher ACh concentrations (>50 µM) or prolonged receptor overstimulation.

Measurement:

ECG analysis detects conduction blocks, PR interval prolongation, and QRS widening.

Thresholds:

Prolonged PR intervals (>200 ms) and QRS widening (>120 ms) are indicative of conduction delays.

Time Course:

Conduction disruptions are observed shortly after action potential changes, often within hours.

AO: Arrhythmias

Quantitative Relationship:

The likelihood of arrhythmias increases with the severity of conduction disruption and action potential instability.

Dose-response studies in animal models link higher AChE inhibitor concentrations with increased incidence of bradyarrhythmias, tachyarrhythmias, or fibrillation.

Measurement:

Arrhythmias are diagnosed using ECG, measuring irregularities in heart rate, rhythm, and intervals (e.g., bradycardia, tachycardia, QT prolongation).

Thresholds:

Severe arrhythmias typically occur when ACh levels are >10-fold above physiological levels.

Time Course:

Arrhythmias can occur within hours of exposure, depending on the dose and stressor.

Key Event or Relationship Quantitative Relationship Measurement Tools
MIE: AChE Inhibition Dose-response (IC50 well-characterized) Ellman’s assay, LC-MS
KE1: Increased ACh Levels Linear relationship with AChE inhibition LC-MS, ELISA
KE2: Overactivation of M2 Receptors ACh EC50 (~1 µM) for receptor activation Radioligand binding, IK,ACh
KE3: Altered Cardiac Action Potential Dose-response for APD changes with ACh >10 µM Patch-clamp,  Electrocardiogram
KE4: Prolonged atrioventricular (AV) conduction time Conduction blocks proportional to APD changes  Electrocardiogram
AO: Arrhythmias Incidence correlates with severity of conduction disruptions  Electrocardiogram

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

Potential applications of this AOP include hazard identification, chemical screening, and prioritization of AChE inhibitors, as well as preclinical drug safety evaluations. In regulatory toxicology, it can assess the cardiotoxic risks of pesticides and environmental toxins. For therapeutic development, it supports the design of safer cholinesterase inhibitors and post-exposure treatments targeting intermediate key events. Personalized medicine applications include genetic risk stratification and precision therapies for at-risk populations. This AOP framework advances the understanding of how AChE inhibition leads to arrhythmias, with significant implications for toxicology, pharmacology, and regulatory science. It enables predictive risk assessments, therapeutic innovation, and enhanced regulatory decision-making to mitigate the cardiotoxic effects of AChE inhibition.

References

List of the literature that was cited for this AOP. More help

Taylor P. The cholinesterases. Journal of Biological Chemistry. 1991;266(7):4025–4028.

López-Arrieta JM, Birks J. Donepezil for Alzheimer's disease. Cochrane Database of Systematic Reviews. 2002;(4):CD001190.

Karczmar AG. The mode of action of anticholinesterase agents. Annual Review of Pharmacology. 1967;7:139–160.

Clegg DJ, van Gemert M. Determination of the relative cholinesterase-inhibiting potency of carbamate insecticides. Toxicological Sciences. 1999;51(1):66–70

Bajgar J. Organophosphates/nerve agent poisoning: Mechanism of action, diagnosis, prophylaxis, and treatment. Advances in Clinical Chemistry. 2004;38:151–216

Brock-Utne JG. Bradyarrhythmias: Causes, recognition, and treatment. Journal of Cardiothoracic and Vascular Anesthesia. 2007;21(6):990–996.

Gralinski MR, Diederich DA, Severson D. Cardiotoxicity of organophosphates in rats. Toxicology and Applied Pharmacology. 1996;140(2):356–363.

Bernsten L, Ueda N, Yamanaka T. Muscarinic receptor activation and its role in arrhythmias. American Journal of Physiology-Heart and Circulatory Physiology. 2006;290(5):H2007–H2016.

Costa LG. Current issues in organophosphate toxicology. Clinica Chimica Acta. 2006;366

Cherian AM, Peter JV, Samuel BU, et al. Effectiveness of oximes in the management of organophosphorus poisoning. Clinical Toxicology. 2005;43(4):309–315.

Murray V, Rabergh C, Boman A, et al. Acetylcholinesterase inhibitors and their influence on cardiac autonomic function. Journal of Cardiovascular Pharmacology. 1995;26(Suppl 2):S79–S85.

Silverthorn DU. Human Physiology: An Integrated Approach. 8th Edition. Pearson Education; 2019.

Shen MJ, Zipes DP. Role of the autonomic nervous system in modulating cardiac arrhythmias. Circulation Research. 2014;114(6):1004–1021

Nagy L, Kovacs D, Szilvassy Z, et al. The role of cardiac M2 muscarinic receptors in arrhythmias. Experimental Physiology. 2009;94(9):983–991.

Gandhi PJ, Emani VR, Shah NK. Cholinesterase inhibitors and cardiac complications. Annals of Pharmacotherapy. 2001;35(4):439–442

Rickett DL, Glenn JF, Beers ET. Central respiratory and cardiovascular effects of organophosphate poisoning. Toxicology and Applied Pharmacology. 1986;82(2):190–197.

Hajjo R, Sabbah DA, Bardaweel SK, Tropsha A. Shedding the light on adverse effects of cholinesterase inhibitors used in dementia: A postmarketing surveillance study. Scientific Reports. 2021;11:2399.

Shibata N, Kobayashi M. Acetylcholinesterase inhibitors for the treatment of Alzheimer's disease: Molecular and clinical perspectives. Current Alzheimer Research. 2008;5(4):411–421.

Orr CF, Rowe DB, Halliday GM. An inflammatory review of cholinergic neuroprotection in Parkinson’s disease. Experimental Neurology. 2002;184(Suppl 1):S97–S113

Thiermann H, Szinicz L, Eyer P, et al. Modern strategies in therapy of organophosphate poisoning. Toxicology Letters. 1999;107(1-3):233–239.