API

Relationship: 450

Title

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AchE Inhibition leads to Respiratory distress/arrest

Upstream event

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AchE Inhibition

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 non-adjacent Moderate 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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  • Acetylcholinesterase (AchE) inhibition leads to respiratory distress and arrest via increased cholinergic signalling. AchE inhibition leads to accumulation of acetylcholine (Ach) within neural synaptic clefts and neuromuscular junctions. Respiratory failure follows as a consequence of a multifactor process resulting from physiological functions associated with both muscarinic and nicotinic cholinergic signalling. This process includes a direct depressant effect on the brain stem respiratory center, airway constriction, increased mucus secretion in the airways, and respiratory musculature paralysis (review in Carey, 2013).

Evidence Supporting this KER

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Biological Plausibility

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  • Respiratory failure involves central apnea as well as pulmonary dysfunction. Multiple mechanisms, including afferent pathways, central respiratory networks, and efferent pathways are involved (Carey 2013). From Costa, “When death occurs, this is believed to be due to respiratory failure as a result of inhibition of respiratory centers in the brainstem, bronchoconstriction, and increased bronchial secretion, and flaccid paralysis of respiratory muscles (Gallo and Lawryk, 1991; Lotti, 2000, 2010).” 

  • Central apnea- Ach is important in respiration; most aspects of respiratory control are influenced by cholinergic mechanisms. Central control of respiration occurs via a respiratory oscillator with both feedback and feed-forward afferent and efferent pathways. Cholinergic mechanisms contribute to chemosensitivity, efferent airway signaling, sub-mucosal glands, vagal afferent signaling, and rhythm generation (Carey 2013).

  • Pulmonary function-  Effects causing impairment of respiration include bronchoconstriction, changes in pulmonary blood flow, pulmonary edema, and bronchorrhea (Carey 2013).

  • Acute respiratory failure is the cause of death in most cases of poisoning with AChE inhibitors; however, the overall clinical picture can be complicated by a delayed intermediate syndrome, pneumonitis/pneumonia, the specific poisoning agent, as well as interactions with other chemical exposures (Hulse et al., 2014).

Empirical Evidence

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Mammals
  • In a study of suicidal ingestion of organophosphorus insecticides, 14 of 52 cases with paralysis had type 2 respiratory paralysis, that appeared later and was not present on admission, indicating nicotinic rather than muscarinic effects predominating (Wadia 1974).

  • In a clinical study of 52 patients diagnosed with organophosphate or carbamate poisoning, 27 subjects developed Type I and 7 had Type II respiratory failure. Mechanical ventilation was required in 31 subjects (Goswamy 1994).

  • In a study of 80 subjects hospitalized for OP poisoning and treated with intravenous atropine and pralidoxime, the mortality rate was 18% in patients treated with pralidoxime, while patients without pralidoxime had a mortality rate of 21%. Ten patients were mechanically ventilated and the mortality rate was 50%. In patients without ventilation the mortality rate was 11.7% (Noshad 2007).

  • A study on dichlorvos-induced acute lung injury in swine showed that anti-cholinergic treatment reduced wet to dry weight ratio of pulmonary tissue, apoptosis index, and mitigated injury to the structure of lung. Measures of acute lung injury were cardiac index and pulmonary vascular resistance indices (Cui 2013).

    • Another indicator for oxygenation problems, OI, was significantly downregulated (P <0.01) in the group exposed to dichlorvos; this may be a sign of partial anatomic shunting, ventilation/perfusion mismatch, and disturbance of gas diffusion from the “pulmonary alveolar capillary barrier” in OP poisoning (Karbing 2007 in Cui 2013).

    • Acute dichlorvos toxicity caused damage to pulmonary tissue, including interstitial and alveolar edema, but treatment with atropine and PHC had protective effects.

  • A study of OP exposure in cats, dogs, rabbits, monkeys, sheep, goats, mice, rats, and guinea pigs found the predominant effect of anticholinesterase poisoning to be respiratory failure. It was postulated that multiple mechanisms caused respiratory failure, namely bronchoconstriction, neuromuscular block, and central respiratory failure (De Candole 1953).

    • Rabbits dosed with sarin showed narrowing of the bronchi at all dosage levels.

    • The height of the tetanic response of the diaphragm to stimulation of the phrenic nerve was reduced, and the diaphragm ceased to respond tetanically ten seconds after injection.

    • At 40 ug/kg, impulse traffic in the phrenic nerve rapidly diminished, with no further traffic after diaphragm contractions have stopped, indicating that respiratory motor neurons have ceased firing and that diaphragm paralysis results from central action rather than peripheral (De Candole 1953).

Fish
  • A study of the overall respiratory-cardiovascular responses of rainbow trout to acutely lethal concentrations of malathion and carbaryl showed immediate decreases in oxygen utilization and heart rate. Ventilation volume increased, but oxygen consumption did not. A moderate to low increase in ventilation volume and oxygen consumption was followed at 50 to 60% survival time by sudden decreases in ventilation volume and oxygen consumption until death. Ventilation rate, oxygen utilization and heart rate showed a steady downward trend over the entire survival period (McKim et al., 1987b).

​Birds
  • Within one hour of exposure of broiler chicks to dichlorvos or diazinon symptoms indicative of cholinergic poisoning were observed including respiratory difficulty (gasping), tremors and convulsions (Al-Zubaidy et al. 2011.

 

 

Uncertainties and Inconsistencies

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Quantitative Understanding of the Linkage

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  • Symptoms of respiratory failure varied with the species studied, drugs used, and administered dose (De Candole).

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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  • The effects of anticholinesterase drugs on respiratory response varied by species. In rabbits, respiratory failure resulted from a combined central respiratory response with neuromuscular block at the diaphragm, while bronchoconstriction was less severe. Cats showed immediate bronchoconstriction and consequent anoxia, followed by central respiratory effects. In monkeys, respiratory failure was almost entirely caused by inhibition of central respiratory mechanism (De Candole).

  •  Studies across multiple species show that the relative role of local pulmonary effects, central respiratory depression, and respiratory muscle paralysis may vary, but the central effects predominate in nonhuman primates (and by extension humans).  Maintenance of ventilation and treatment with muscarinic blockers and reactivating agents are shown to reduce mortality in animal studies and continue to be the standard clinical treatment (Hulse et al., 2014).

  • In fish, the mechanism for respiratory-cardiovascular response in fish is likely explained by a decrease in respiratory surface area of the gills, or vasoconstriction. AChE inhibition in the gills would result in continuous stimulation at neuromuscular junctions, causing arterial sphincters to constrict and reduced blood flow to secondary lamellae. Oxygen utilization decreased as a result (McKim).

  • In birds, respiratory failure occurs after continued cholinergic stimulation exhausts the respiratory muscles. Other respiratory symptoms include muscle tremors and increased respiratory tract secretions (Blackwell's Five-Minute Veterinary Consult: Avian).

References

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  • Al‐Zubaidy, M.H.I., Mousa, Y.J., Hasan, M.M., Mohammad, F.K. 2011. Acute toxicity of veterinary and agricultural formulations of organophosphates dichlorvos and diazinon in chicks. Arh Hig Rada Toksikol 62:317–323.

  • Carey, J.L., Dunn, C., Gaspari, R.J. 2013. Central respiratory failure during acute organophosphate poisoning. Respiratory Physiology & Neurobiology. 189(2), 403-410.

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

  • Cui,J., C.S. Li, X.H. He, and Y.G. Song. 2013. Protective Effects of Penehyclidine Hydrochloride on Acute Lung Injury Caused by Severe Dichlorvos Poisoning in Swine. Chin. Med. J.126(24): 4764-4770.

  • 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. 

  • Giyanwani PR, Zubair U, Salam O, Zubair Z., Respiratory Failure Following Organophosphate Poisoning: A Literature Review. Cureus. 2017 Sep 3;9(9):e1651. doi: 10.7759/cureus.1651.

  • Goswamy, R., Chaudhuri, A., Mahashur, A.A. 1994. Study of respiratory failure in organophosphate and carbamate poisoning. Heart Lung. 23(6):466-72.

  • Graham, J.E.  2016. Blackwell's Five-Minute Veterinary Consult: Avian.

  • Hulse, E.J., Davies, J.O., John Simpson, A., Sciuto, A.M., Eddleston, M. 2013. Respiratory Complications of Organophosphorus Nerve Agent and Insecticide Poisoning. Implications for Respiratory and Critical Care. American Journal of Respiratory and Critical Care Medicine. 190(12).

  • 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.

  • Noshad, H., Ansarin, K., Ardalan, M.R., Ghaffari, A.R., Safa, J., Nezami, N. 2007 Respiratory failure in organophosphate insecticide poisoning. Saudi Med J. 28(3):405-7.

  • Rivera JA1, Rivera M., Organophosphate poisoning. Bol Asoc Med P R. 1990 Sep;82(9):419-22.

  • Shao, X. M., & Feldman, J. L. 2009. Central cholinergic regulation of respiration: nicotinic receptors. Acta pharmacologica Sinica, 30(6), 761–770. 

  • Wadia, R. S., Sadagopan, C., Amin, R. B., and Sardesai, H.V. 1974. Neurological manifestations of organophosphorus insecticide poisoning. J Neurol Neurosurg Psychiatry. 37(7): 841–847.