API

Relationship: 457

Title

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Increased Cholinergic Signaling leads to Respiratory distress/arrest

Upstream event

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Increased Cholinergic Signaling

Downstream event

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Respiratory distress/arrest

Key Event Relationship Overview

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AOPs Referencing Relationship

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AOP Name Adjacency Weight of Evidence Quantitative Understanding
Acetylcholinesterase inhibition leading to acute mortality adjacent High Low

Taxonomic Applicability

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Sex Applicability

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Life Stage Applicability

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Key Event Relationship Description

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Respiratory distress as a result of increased cholinergic signalling due to AChE inhibition occurs through combined peripheral and central cholinergic effects.

Evidence Supporting this KER

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Biological Plausibility

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  • The link between increased cholinergic signalling and respiratory distress/failure is based on respiratory manifestations observed in many organisms and what is well-understood about cholinergic signalling, which is mediated by both muscarinic and nicotinic receptors. 

1. Nicotinic Respiratory paralysis (Wadia 1974),

2. Muscarinic- Central respiratory depression (Costa, Peter 2014), rhinorrhea, bronchorrhea, bronchospasm (Peter 2014), increased bronchial secretions (Costa, Buels 2012), bronchoconstriction (Costa, de Candole 1953, Buels 2012), neuromuscular block at the diaphragm, potentially leading to inability to regulate movements of the diaphragm (de Candole 1953).

  • Nicotinic acetylcholine receptors (nAChRs) are expressed in brain and spinal cord regions in control of breathing, and mediate central cholinergic regulation of respiration. Activation of nAChRs in the the preBötzinger Complex (preBötC), an essential site for normal respiratory rhythm generation in mammals, modulates excitatory glutamatergic neurotransmission and depolarizes preBötC inspiratory neurons, leading to increases in respiratory frequency. nAChRs are also present in motor nuclei innervating respiratory muscles. Activation of post- and/or extra-synaptic alpha4* nAChRs on hypoglossal (XII) motor neurons depolarizes these neurons, potentiating tonic and respiratory-related rhythmic activity (Shao 2009).

  • In humans, early acute mixed central and peripheral respiratory failure. Early respiratory failure in humans involves depression of central respiratory drive from the respiratory center in the ventrolateral medulla, respiratory muscle weakness, and direct pulmonary effects such as bronchospasm and bronchorrhea. (Eddleston 2007). 

  • The first signs of OP poisoning to appear are usually muscarinic, followed by nicotinic signs. Early respiratory failure may not display clear cut symptoms (Costa). A study of neurological signs in humans exposed to OP compounds found impaired consciousness in 10%, fasciculations in 27%, convulsions in 1%, toxic delirium in 50%, and paralysis in 26%. Type 1 signs were present on admission, while type 2 signs appeared later.  Type 1 signs, such as impaired consciousness and bilateral pyramidal tract signs, respond to atropine. Of 36 cases with type 2 signs (proximal limb weakness, areflexia, and cranial nerve palsies), 15 died from respiratory paralysis after a variable period of artificial respiration (Wadia 1974).

  • A study of OP poisoning in humans found that of 376 patients, 90 (24%) required intubation: 52 (58%) within 2 h of admission while unconscious with cholinergic features. Twenty-nine (32%) were well on admission but then required intubation after 24 h while conscious and without cholinergic features. These two syndromes were not clinically distinct and had much overlap. In particular, some patients who required intubation on arrival subsequently recovered consciousness but could not be extubated, requiring ventilation for up to 6 days (Eddleston 2006).

  • In animal models, ventilation can be impaired through bronchoconstriction, neuromuscular block, and central respiratory failure, with central failure being the predominant factor (De Candole 1953, Peter 2014). Disruption of the normal firing pattern of medullary respiratory-related neurons is followed by changes in phrenic nerve activity, diaphragm EMG, diaphragm contraction and airflow (Rickett 1986).

  • In fish, reduced uptake of oxygen by the gills due to reduced respiratory surface area, as a result of direct toxicant effects on the gills. Inhibition of AChE in the gills would result in continuous stimulation of neural-muscular junctions and cause sphincters at the base of the efferent filamental arteries to constrict, reducing blood flow through the secondary lamellae (McKim 1987). 

Empirical Evidence

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  • A study in cats concluded that loss of central respiratory drive was the predominant cause of nerve agent-induced respiratory failure.  The diaphragm was tested by stimulating the phrenic nerve with 2 msec pulses of 500 msec duration at 10 Hz and at 100 Hz. Stimulation at 10 Hz consistently produced a frequency-following contraction, while stimulation at 100 Hz for 500 msec produced a tetanic contraction at the time of respiratory arrest (Rickett 1986).

  • Male quail (8-14 weeks old) were exposed to a single dose of either dichlorvos or fenitrothion via subcutaneous injection at four treatment levels.  Analysis of brain tissue showed an 80% reduction of AChE, and a concurrent significant increase in acetylcholine as compared to controls. At the highest doses, mortality was preceded by vigorous tremors, lacrimation, salivation, ataxia, and respiratory distress (Kobayashi 1983).

  • An acute (24-h) exposure of fingerling rainbow trout to acephate found a dose-dependent relationship between inhibition of AChE, respiratory activity, and mortality.  The LC50 values ranged from 1880-3160 mg/L, with 76-89% inhibition of AChE in dead fish (at a concentration of 950-4000 mg/L), and significant effects on the heart rate (significant decrease) and respiration rates (significant increase) at a concentration of 2,000 mg/L (Duangsawasdi 1977, 1979).

Uncertainties and Inconsistencies

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  • There is abundant evidence that increased cholinergic signalling leads to respiratory failure in many organisms. There is one area of uncertainty, which relates to how the balance of nicotinic and muscarinic effects lead to respiratory failure. It is unclear which mechanism predominates and greater understanding of these mechanisms could help inform therapeutic intervention strategies.

Quantitative Understanding of the Linkage

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  • We are unaware of any correlative relationships of significant predictive value with regard to this KER.

  • Predominance of nicotinic vs muscarinic responses seems to depend on the time post-OP exposure in humans

Response-response Relationship

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Time-scale

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Known modulating factors

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Known Feedforward/Feedback loops influencing this KER

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Domain of Applicability

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  • Cats - see Rickett 1986, cited above

References

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  • Buels, K.S., Fryer, A.D. 2014. Muscarinic Receptor Antagonists: Effects on Pulmonary Function. Handb Exp Pharmacol. 2012; (208): 317–341.

  • Costa.  Toxic effects of pesticides.  In Casarett and Doull's Toxicology: The Basic Science of Poisons. 9th ed. pp 1055-1106.

  • De Candole, C.A., Douglas, W.W., Evans, C.L., Holmes, R., Spencer, K.E., Torrance, R.W., Wilson, K.M. 1953. The failure of respiration in death by anticholinesterase poisoning. Br J Pharmacol Chemother. 8(4):466-75.

  • Eddleston M, Mohamed F, Davies JO, Eyer P, Worek F, Sheriff MH, Buckley NA. 2006. Respiratory failure in acute organophosphorus pesticide self-poisoning. QJM. 99(8):513-22. 

  • McKim, J.M., Schmieder, P.K., Niemi, G.J., Carlson, R.W., Henry, T.R. 1987. Use of respiratory‐cardiovascular responses of rainbow trout (Salmo gairdneri) in identifying acute toxicity syndromes in fish: Part 2. Malathion, carbaryl, acrolein, and benzaldehyde. Environ Toxicol Chem 6:313–328.

  • Peter, J.V., Sudarsan, T.I. and Moran, J.L. 2014. vas. Indian J Crit Care Med. 18(11): 735–745.

  • Rickett, D.L., Glenn, J.F., Beers, E.T. 1986. Central respiratory effects versus neuromuscular actions of nerve agents. Neurotoxicology. 7(1): 225-36.

  • Shao, X.M., Feldman, J.L. 2009. Central cholinergic regulation of respiration: nicotinic receptors. Acta Pharmacol Sin. 30(6):761-70. 

  • Wadia RS, Sadagopan C, Amin RB, Sardesai HV. Neurological manifestations of organophosphorous insecticide poisoning. J Neurol Neurosurg Psychiatry. 1974 Jul;37(7):841-7.

  • Dickson EW, Bird SB, Gaspari RJ, Boyer EW, Ferris CF. Diazepam inhibits organophosphate-induced central respiratory depression. Acad Emerg Med. 2003 Dec;10(12):1303-6.

  • Senanayake N, Karalliedde L. Neurotoxic effects of organophosphate insecticides: an intermediate syndrome. N Engl J Med. 1987;316:761–3.

  • de Bleecker JL. The intermediate syndrome in organophosphate poisoning: an overview of experimental and clinical observations. J Toxicol Clin Toxicol. 1995;33:683.

  • Pitcher JA, Freedman NJ, Lefkowitz RJ. G protein-coupled receptor kinases. Annu Rev Biochem. 1998;67:653–92. 

  • Gainetdinov RR, Premont RT, Bohn LM, Lefkowitz RJ, Caron MG. Desensitization of G protein-coupled receptors and neuronal functions. Annu Rev Neurosci. 2004;27:107–44.

  • Kobayashi, H., Yuyama, A., Kudo, M., and Matsusaka, N. 1983. Effects of Organophosphorus Compounds, O,O-Dimethyl O-(2,2-Dichlorovinyl)Phosphate (DDVP) and O,O-Dimethyl O-(3-Methyl 4-Nitrophenyl)Phosphorothioate (Fenitrothion), on Brain Acetylcholine Content and Acetylcholinesterase Activity in Japanese Quail. Toxicology 28[3], 219-227.

  • Duangsawasdi M. 1977. Organophosphate insecticide toxicity in rainbow trout (Salmo gairdneri). Effects of temperature and investigations on the sites of action. PhD thesis. University of Manitoba, Manitoba, Canada.

  • Duangsawasdi M, Klaverkamp JF. 1979. Acephate and fenitrothion toxicity in rainbow trout: Effects of temperature stress and investigations on the sites of action. In Aquatic Toxicology, Vol 2, STP 667. ASTM International, Philadelphia, PA, USA, pp 35–51.