Pesticides: Organophosphates Dr. Bergfelt Flashcards
Would tetanus be considered a Ddx for organochlorine toxicity?
Yes!
What are some important characteristics of Organophosphates (OP) to know
Irreversibly inactivates acetylcholinesterase (ACh)
Major cause of animal poisoning
Malathion is most common
Has various degrees of water & lipid solubility
What are some chemical properties of OP
Thiophosphate OPs more lipid soluble than phosphate OPs
Subject to “storage activation” - If sealed & stored 1-2 years, more toxic they become!
Impurities = More toxicity - technical grade less pure than reagent grade
Toxicokinetics of OP
Lipophilic - readily absorbed through skin & mucous membranes, GIT & inhalation
Well distributed including CNS
Tissue accumulation varies with type of OP - generally thiophosphates more lipophilic than phosphates
Extensively metabolized in liver - excretion/bioactivation
Lethal synthesis - CYP450 (liver enzymes) metabolize or bioactivate thiophospate OPs
Continued exposure can lead to adaptation to decr ACh
Differences of types of OPs:
Phosphates (P=O) are biologically active
Thiophosphates (P=S) require hepatic bioactivation
Thiophosphate OP particulars
Biologically inactive until transformed by liver to -oxon metabolites
Highly lipid soluble and rapidly absorbed in adipose tissue
Slow release from fat may lead to delayed and/or prolonged
cholinesterase inhibition
Slow redistribution or activation may have implications for
diagnosis and treatment
Major route of elimination is paraoxonase – a serum bound
enzyme
MoA of OP
Irreversible inhibition of cholinesterases
High exposure can result in respiratory failure or paralysis & death
Delayed neurotoxicity is possible - OP induced delayed polyneuropathy
Visual aid for MoA of OP
ACh accumulates throughout CNS resulting in overstimulation of muscarinic & nicotinic receptors
Muscarinic effects of OPs
DUMBELS
Diarrhea
Urination
Miosis
Bronchospasm
Emesis
Lacrimation
Salivation
Nicotinic effects of OPs
Acetylcholine accumulation at neuromuscular junction &
preganglionic synapses
initial stimulation→ fasciculations in muscle (incl
tongue) ⇒paralysis due to failure (blockade)
CS of stimulation →
sweating, hypertension and tachycardia
CNS effects of OPs
Crosses BBB
Respiratory failure usual COD
Recovery depends ultimately on generation of new enzyme or ACh-esterase in critical tissues
Delayed effects of OPs
OP-induced delayed polyneuropathy
10-14 days post exposure
CS - muscle weakness, ataxia, rear limb paralysis
Chickens are most sensitive
OP-induced intermediate syndrome
2-4 days after acute cholinergic effectand signs of the acute
effects are no longer obvious
CS occur after apparent recovery from the acute effects
NO muscarinic signs or muscle fasciculations
Weakness of respiratory muscles (diaphragm, intercostal) and accessory muscles, including neck muscles and of proximal limb muscles
special MoA of OP
Ageing: conformational change in OP – Ach-esterase
complex that results in increased or irreversible binding
of the complex
Various aging times range from 2 min to 72 h depending on OP
Irreversible inhibition of cholinesterases
Non-competitive inhibition
CS of OPs
Onset is rapid! 15min -1 hr
Pathology of OP
Acute death, no specific lesions
Few nonspecific lesions
Delayd or intermediate effects: degeneration & demyelination of peripheral & spinal motor neurons
Tx of OP
Px
Acute tx:
Decontaminate, Supportive care
Avoid phenothiazines, aminoglycosides, muscle relaxants, drugs that depress respiration (opioids)
Atropine - specific physiologic antagonist
Cholinesterase reactivators - “oximes”
Pralidoxime or 2-PAM
may or may not be effective depending on OP and if ageing has occurred
OP induced delayed polyneuropathy:
symptomatic tx only
OP induced intermediate syndrome
supportive care
PX: GUARDED
presented alive w/ no CS Px = good
alive w/ mild-moderate CS = generally treatable
acute cases that respond to tx can recover in 24 hr
presented w/ multiple CS = depends on $
