Organophosphate Insecticides - Toxicology

What are the 8 organophosphate common names?

1. Chlorpyrifos 2. Coumaphos 3. Diazinon 4. Fenthion 5. Malathion 6. Methyl parathion 7. Temephos 8. Dichlorvos

An animal becomes tolerant to organophosphates when exposed continuously to what 3 things?

1. enzyme induction 2. decreased esterases 3. excessive amount of ACh, leading to downregulation of receptors

What is the sequela of nervous system dysfunction due to organophosphate poisoning?

1. excessive seizure activity results in hyperthermia which leads to metabolic acidosis that results in shock/multiple organ failure/SIRS/DIC 2. respiratory depression leading to respiratory acidosis and hypoxemia which results in further organ injury/death. 3. muscle activity may lead to myopathy (muscle hemorrhage/necrosis) 4. secondary bacterial/viral infection due to organophos impurities that suppress immune system. also pneumonia from poor airway control

How long can an organophosphate persist in the environment?

2-4 weeks

What is the full antidote used for organophosphate toxicity?

2-PAM

Organophosphates - water soluble?

NO, but they are very soluble in organic solvents/fats/oils and they penetrate skin and waxy coating of leaves and fruit

See acute clinical signs of excessive salivation, diarrhea, tremoring/muscle fasciculations and seizure like activity. Which 3 of the insecticides are the most likely the culprit

Organophosphates, Carbamates or Nicotine

What is the prognosis of organophosphate poisoning?

Poor. In severe cases treatment can be long due to irreversible inhibition. Intermediate syndrome can also be a long recovery. Delayed organophosphate toxicity effects may be permanent.

What is the antidote for organophosphate poisoning?

atropine is the partial antidote and 2PAM is full antidote

What is the partial antidote for organophosphate poisoning? How does it work?

atropine, it blocks muscarinic receptors only (that's why it's partial)

Why isn't atropine a good antidote in treating intermediate syndrome organophosphate toxicosis?

because it doesn't have muscarinic signs and that's all atropine treats

What does an organophosphate bind to once inside the body? Is it reversible or irreversible?

binds AChase, is irreversible at first because it lasts hours to days, and then later it is irreversible because of permanent "aging" of AChase by binding of phosphorus and hydrogen at an esteric site.

What are the uses of organophosphates?

broad pesticide (toxin kills insects, molluscs, fungus, plants and rodents), antiglaucoma drug

Organophosphates are teratogenic in which animal?

chicken

Parasympathetic stimulation displays as "DUMBELS"... what are these signs?

diarrhea, urination, miosis, bradycardia, emesis, lacrimation, salivation

What response to administering atropine will confirm a diagnosis of organophosphate poisoning?

give a low dose of atropine, if the animal doesn't respond and improve, the parasympathetic signs are likely due to organophosphate poisoning. a much higher dose is needed for response.

When muscle relaxants are used at the time of organophosphate poisoning, does this increase or decrease toxicity?

increase

When neuromuscular blockers are being used at the time of organophosphate poisoning, does this increase or decrease toxicity?

increase

When organophosphates undergo chemical changes during storage, does it increase or decrease their toxicity?

increase

If you add an organic solvent to an organophosphate, does it increase or decrease toxicity?

increases toxicity

How does 2-PAM work in reversing organophosphates?

is a cholinesterase reactivator but only works before the phosphorylated AChase is aged.

Describe the "intermediate syndrome" associated with organophosphate toxicity.

it is subacute toxicity that is less common. signs are seen in 24 to 72 hours or longer after an acute crisis or when given small amounts

What will the acetylcholinesterase level be in the bloodwork of an animal with organophosphate poisoning?

less than 25% of normal

When organophosphates are hydrolyzed by esterases, are they more or less toxic?

less toxic

Do the more lipid soluble forms or organophosphates have longer or shorter half lives?

longer half lives

Do organophosphates have a high or low risk factor?

low risk factor because the effective dose and toxic dose are very close in number, making the ratio small.

Which 2 organophosphates are synergistic with each other?

malathion and coumaphos

Which 2 organophosphates are antagonistic to each other?

malathion and parathion

Which 2 organophosphates undergo lethal synthesis?

malathion and parathion

What is "intermediate syndrome" associated with organophosphate toxicity?

may occur after an acute crisis, prolonged exposure to small amounts, or with organophosphates that are more lipid soluble. mainly causes nicotinic stimulation, not muscarinic b/c they downregulate

How much time does it take for onset of clinical signs from organophosphate poisoning?

most commonly acute onset. Within 10 min with oral dose, 12-24 hr with dermal dose

How are most organophosphates metabolized?

most undergo lethal synthesis in the liver, via an MFO "mixed function oxidase" reaction which is when a sulfur atom replaces an oxygen and leads to activation.

Which cholinergic receptors are stimulated by organophosphate poisoning first?

muscarinic are stimulatic first because they are more sensitive than nicotinic receptors.

Which neuro receptors are most sensitive to increased ACh and are most effected by organophosphate toxicity?

muscarinic receptors are most sensitive so parasympathetic stim first.

What are the CNS signs of organophosphate poisoning in OPIDN?

muscle weakness, ataxia (rear limbs) that may or may not be reversible. May see degeneration and demyelination of peripheral and spinal motor neurons.

What 5 drugs compete for esterases and increase toxicity of organophosphates?

neostigmine, physostigmine, succinylcholine, phenothiazines, procaine

What are the main organs affected by organophosphate poisoning?

nervous system excitement, muscarinic stimulation, followed by neuromuscular depression

What is OPIDN?

organophosphate induced delayed neurotoxicosis. animals that survive acute toxicity may develop delayed toxicity depending on the species and compound. may be due to inhibition of neuronal esterases. NO muscarinic signs. can see paresis/paralysis of hind limbs that may not be reversible.

Which type of organophosphates are more toxic to young animals? Which are less toxic?

organophosphates that undergo lethal synthesis are LESS toxic to young animals because they do less biotransformation, while the organophosphates that do not undergo lethal synthesis (meaning the original compound is already very toxic) are more toxic to young animals

What are the 2 major insecticides that can result in posterior paralysis in delayed neurotoxicosis?

organophosphates, bromethalin

Which three insecticides specifically target parasympathetic system and cause stimulation?

organophosphates, nicotine, carbamates

Muscarinic stimulation leads to what clinical signs?

parasympathetic signs "DUMBELS"

When organophosphates progress to affect muscarinic and nicotinic receptors, which clinical signs predominate?

parasympathetic signs predominate "DUMBELS", except for blood vessels are usually under sympathetic vasoconstriction.

Which 3 insecticides cause neurologic excitement (in general, not specifically SNS or PNS)

pyrethrins, organochlorides, strychnine

Systemic organophosphates have a faster or slower onset of action?

slower onset, they cause MORE neuromuscular and CNS excitement similar to organochlorines

Which has a longer onset of action: non-systemic organophosphates like malathion or parathion, or systemic organophosphates like coumophos or dichlorvos?

systemic organophos have a longer onset of action (18-36 hours)

Which is more toxic: technical grades or pure compounds of organophosphates?

technical grades because of heat isomerization and impurities

When total CNS stimulation is occuring with organophosphate poisoning, where do you see sympathetic stim signs and where do you see parasympathetic stim signs?

the sympathetic predominates in blood vessels (vasoconstriction) and the parasympathetic system predominates everywhere else (DUMBELS).

Why are organophosphates more toxic than many other insecticides?

there is a narrow margin between dose that kills insects and dose that causes toxicity in mammals.

Are seizures a feature of organophosphate poisoning?

they are a common sequelae of the CNS stimulation due to organophosphate poisoning, seen in small animals and horses, but NOT cows.

When do phenobarbitol or chlorinated hydrocarbon insecticides increase toxicity? When do they decrease toxicity?

they are enzyme INDUCERS and increase toxicity when the organophosphates undergo lethal synthesis (malathion or parathion). They decrease toxicity when seen the organophosphate does NOT undergo lethal synthesis, the enzyme inducer will inactivate them.

Why are neurological signs seen with acute toxicity of organophosphate poisoning? (explain mechanism)

they irreversibly bind to AChase which results in increase in ACh at all cholinergic sites (nicotinic and muscarinic). The parasympathetic, sympathetic and somatic systems are activated.

What is "aging" acetylcholinesterase?

when there is permanent binding by a phosphorus and hydrogen molecule at an esteric site. It is an unbreakable bond and renders AChase no longer functional.