Reported levels of fumonisins

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Anticholinesterase Insecticides
? Organophosphates
? Carbamates
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Cholinesterase Inhibitors Organophosphates
and Carbamates
? Not persistent in the environment. ? Highly
toxic ? Commonly used on crops and animals ?
Rapidly absorbed and metabolized ? Short
biological half-life ? Inhibit enzyme
(cholinesterase) causing accumulation of
acetylcholine. Effects are essentially of
acetylcholine on synaptic junctions.
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3
Athens Diagnostic Laboratory (College of
Veterinary Medicine)

• Organophosphates Diazinon, Dursban, Phosmet,
  Disyston, Parathion.
• Carbamates Methomyl, Methocarb, Propoxur,
  Temik
• Chlorinated Hydrocarbons DDT, Endosulfan,
  Lindane

VPHY8300/Spring 04
4
Review of basic physiology
? Electrical vs. chemical neurotransmission. ?
Synthesis, metabolism and actions of
acetylcholine. ? Muscarinic vs. nicotinic
effects. ? Acetylcholinesterase enzyme ?
Consequences of acetyl cholinesterase inhibition
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Anticholinesterase Agents
? Organophosphate Insecticides
? Initially developed as chemical warfare agents
? Original compounds like Tabun, Sarin, and
Soman, are extremely toxic Nerve Gas.
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Neurohumoral Transmission





Na





Cholinesterase











K






















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9
Neurohumoral Transmission





Na





Cholinesterase






K






K





















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10
Neurohumoral Transmission





Na





Cholinesterase






K




























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Neurohumoral Transmission





Na





Cholinesterase






K






K





















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12
Neurohumoral Transmission





Na





No Cholinesterase




K








K





















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13
Neurohumoral Transmission





Na





No Cholinesterase




K








K





















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The label contains most of the relevant
information
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Organophosphates
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Organophosphates
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Organophosphates
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Acetylcholinesterase inhibitors
The biological effects of acetylcholinesterase
inhibition are essentially the effects of
increased amount of acetylcholine
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Atropine
Atropa belladonna
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Central effects of acetylcholine
Acetylcholine is a universal neurotransmitter in
CNS and autonomic ganglia. Accumulation will
cause increased firing of neurons
General hyperactivity
However, only the chemicals that can penetrate
the blood brain barrier are toxic in the nervous
system.
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Muscarinic effects of acetylcholine
Lungs
Acetylcholine increases bronchial secretions and
constricts the sphincter muscles of air passages
Dyspnea, pneumonia
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Muscarinic effects of acetylcholine
Heart
Acetylcholine is a vagal neurotransmitter and
decreases the activity of heart muscles
Bradycardia, vagal arrest, blood flow
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Muscarinic effects of acetylcholine
GI tract
Acetylcholine increases glandular secretions and
constricts the smooth muscles of the GI tract but
relaxes sphincters
Vomiting, diarrhea, dehydration, salivation,
cramps
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Muscarinic effects of acetylcholine
Eye
Acetylcholine increases tears and constricts the
sphincter muscle of iris
Lacrimation and miosis
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Nicotinic effects of acetylcholine
Ganglia
Acetylcholine is a universal neurotransmitter in
all ganglia and therefore increases tone and
activity
Generalized hyperactivity, tremors
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Death usually involves paralysis of diaphragm.
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Organophosphate insecticides

• Non-reversible inhibitors of acetylcholinesterase
  
• Produce phosphorylated enzyme
• Dealkylation leads to aging
• Blood cholinesterase activity is a good
  indicator of poisoning
• Use of 2-PAM within a short time (2 hrs) is
  useful
• Use care while handling vomited material, skin
• Stomach contents or skin useful for chemical
  analyses

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Symptoms of cholinesterase inhibition

• Vomiting, diarrhea, salivation, lacrimation
• Difficult breathing, congested trachea
• Miosis
• Bradycardia
• Muscle tremors, paralysis, respiratory failure
• Death by asphyxiation

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Treatment of cholinesterase inhibition

• Wash contaminated surfaces, pump stomach
• Tracheal tube, provide unobstructed respiration
• ATROPINE (for muscarinic effects)
• 2-PAM, only for organophosphates and shortly
  after poisoning
• Use care in cyanotic cats (no atropine)
• Intravenous feeding

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Organophosphate-induced delayed neuropathy (OPIDN)
? Ginger Paralysis Affected 20,000 people in
1930s. ? Tri-O-cresyl phosphate used to shine
ginger. ? Other reports 10,000 people in Morocco
by oil. ? Human, chicken, pig, cat susceptible. ?
Rodents and immature animals resistant. ? An
enzyme called Neurotoxic Esterase described ?
Only 4 of phosphorylable sites in most tissues.
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Organophosphate-induced delayed neuropathy
(OPIDN), continued

• Good correlation of NTE phosphorylation to
  ability of chemicals to OPIDN has been obtained.
• However, resistant species have similar NTE.
• Axonal degeneration may occur in insensitive
  species.
• NTE involves a two-step process inhibition and
  aging, similar to cholinesterases.
• No function of NTE is known.
• Esterase activity not essential for axonal health.

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Organophosphate-induced delayed neuropathy
(OPIDN), continued

• A dying-back phenomenon.
• Primary lesion is demyelination.
• Agents involved TOCP, DFP, Mipafox, EPN, etc.
• The condition is non-reversible.
• Some chemicals may cause reversible paralysis.
• TOCP is not a direct inhibitor, but metabolized
  to active compounds.

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Carbamates
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