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Toxicology > Toxicology of the Peripheral Nervous System (PNS) > Flashcards

Toxicology of the Peripheral Nervous System (PNS) Flashcards

1
Q

Nervous system overview
- consists of CNS and PNS
- CNS = brain, spinal chord. communicates with PNS via afferent and efferent division

A
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2
Q

All preganglionic fibers, both in the sympathetic division and the parasympathetic division are ___________ and use _________ as the neurotransmitter acting on ________ receptor.
Parasympathetic division: ACh acts on muscarinic receptors in _____ and ____ muscles, ____ cells and nerve terminals.
o Sympathetic division: ___ is released to act on _____ and ____-adrenergic receptors in cardiac and smooth muscles, gland cells and nerve terminals OR on _____ receptors in sweat glands.

A

cholinergic, acetylcholine, nicotinic

cardiac, smooth, gland, NE, alpha, beta, muscarinic

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3
Q

Equine sweat glands are under ____ adrenegic control

A

beta

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4
Q

The sympathetic division also regulates _______ vascular ____ muscle via ______ acting on ___ receptors

A

renal, smooth, dopamine, D1

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5
Q

_____ acting on ______ receptors in the adrenal medulla causes release of epinephrine into the blood circulation.

A

ACh, nicotinic

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6
Q

Motor nerves to skeletal muscle release _____ to act on _____ receptors at the motor endplate

A

ACh, nicotinic

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7
Q

Describe the two main mechanisms of toxicity of ANS.

A
  1. Direct
    - include Impairment of neurotransmission
    - Structural toxicoses that may involve
    neuronopathy, axonopathy, myelinopathy
  2. Indirect: alteration of metabolism or blood supply with 2 degree neuronal dysfunction
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8
Q

What are the Key Steps in Neurotransmission?

A
  1. Synthesis of neurotransmitter (NT). NT is then…
  2. Storage of NT in presynaptic cell.
  3. Ca2+-dependent NT release upon stimulation into synaptic cleft.
  4. Interaction with postsynaptic receptors
  5. Termination of NT action by reuptake/metabolism
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9
Q

Neurotransmission can be disrupted by a few toxicants. Name these toxicants.

A
  1. At the level of synthesis L-Dopa impairs the synthesis of dopamine.
  2. Reserpine on the other hand impairs storage of norepinephrine while
  3. botulinum neurotoxin inhibits the release of ACh.
  4. OPs/CMs inhibit the catabolism of ACh leading to accumulation of ACh and cholinergic crisis while
  5. atropine or nicotine impair the binding of ACh to cholinergic receptors.
  6. Moreover, 2nd messenger processes can also be disrupted as exemplified
    here by the impairment of processes mediated by cyclic AMP by caffeine.
  7. Lastly, the opening and closing of ion channels can be disrupted and an
    example is the opening of Na channel by pyrethroids/pyrethrins.
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10
Q

Nomenclature of ANS Toxicants- Cholinergic

A

– Cholinomimetic
– Parasympatho-
mimetic

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11
Q

Nomenclature of ANS Toxicants- Anticholinergic

A

– Cholinolytic
– Parasympatholytic

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12
Q

Nomenclature of ANS Toxicants- Adrenergic

A

– Adrenomimetic
– Sympathomimetic

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13
Q

Nomenclature of ANS Toxicants- Antiadrenergic

A

– Adrenolytic
– Sympatholytic

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14
Q

Nomenclature of ANS Toxicants- Antiadrenergic

A

– Adrenolytic
– Sympatholytic

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15
Q

Cholinergic Toxicants

A
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16
Q
  1. Cholinergic receptors are divided into?
  2. Nicotinic receptors are further divided into?
  3. What type of receptors are Nicotinic receptors?
  4. Where are Nicotinic neuronal receptors found? Nicotinic muscular?
A
  1. Cholinergic receptors are divided into two, nicotinic and muscarinic.
  2. Nicotinic receptors are further divided into two, nicotinic neuronal and nicotinic muscular.
  3. Nicotinic receptors are ligand-gated ion channels that open in response to the binding of a chemical messenger. The prototypic ligand-gated ion channel is the nicotinic acetylcholine receptor. Nicotinic neuronal receptors are found in
    the autonomic ganglia where they mediate the depolarization and firing of the post-ganglionic neuron. They are also found in the adrenal medulla where their stimulation causes secretion of catecholamines particularly epinephrine. Nicotinic muscular receptors are also found at the NMJ where they mediate
    the depolarization of the motor endplate and contraction of skeletal muscle.
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17
Q

What are the General Clinical Signs of Cholinergic Stimulation?
These clinical signs are consistent with?

A

muscarinic receptors
Clinical signs are consistent with stimulation of Muscarinic receptors

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18
Q

Muscarinic Toxicants
(Parasympathomimetics) are divided into..

A
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19
Q

Slaframine causes ?

A

Slaframine (Slobber syndrome, Clover
Poisoning, Salivary Syndrome)

Black Patch Disease in Plants = black spots/rings on leaves and stems of red clovers when infected.

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20
Q

Where is Slaframine sourced from?

A

An indolizidine alkaloid mycotoxin produced
in red clovers (Trifolium spp.) infected with the
fungus Rhizoctonia leguminicola
* Also associated with other legumes: white clover,
soybean, kudzu, cowpea, blue lupine, alfalfa

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21
Q

What are the risk factors associated with slaframine toxicity?

A

Encountered most often in
periods of wet weather and high humidity

22
Q
  1. The effects of Slaframine are?
  2. What is Slaframine activated by?
  3. It’s metabolite is similar to?
  4. Which species are affected by Slaframine toxicity?
A
  1. Absorbed and produces effects rapidly.
  2. Slaframine is activated by liver microsomal flavoprotein oxidase to a ketoimine metabolite
  3. The ketoimine metabolite is chemically (and physiologically) similar to acetylcholine and is responsible for the toxicosis
  4. Species affected: cattle, horse, sheep, goats, swine, chickens
    - cattle and horses are primarily effected
23
Q

What is the toxic dose of Slaframine?
1. In chicks
2. In cats
3. In cattle
4. In guinea pigs

A

See below

24
Q

What is the MOT of Slaframine?

A
  • Cholinergic stimulation of exocrine and endocrine glands
    – Slaframine has high affinity for GI tract muscarinic (M3)
    receptors

No effect on ganglionic transmission, peripheral blood flow or neuromuscular
transmission

25
Q

What are the clinical signs associated with Slaframine?

A

– Natural cases reported only in horses and
ruminants
– Excessive salivation (slobbers), lacrimation,
anorexia, diarrhea, frequent urination, bloating,
stiffness, respiratory distress, bradycardia,
decreased milk production. Death is rare. (DUMBELS)

Salivation = main sign

26
Q

Horses with significant toxicoses have been observed to __________, so severely, that after being tied to a post for a few minutes a ________ of _______ accumulates in the soil beneath their heads.
In spite of this, the horses perform _______ and do not
appear to experience other adverse effect.

A

Horses with significant toxicoses have been observed to salivate, so severely, that after being tied to a post for a few minutes a puddle of saliva accumulates in the soil beneath their heads.
In spite of the severe salivation, the horses perform normally and do not appear to experience other adverse effect

27
Q

How can you diagnose Slaframine toxicity?

A
  • Clinical signs (↑salivation) in animals
    consuming legumes esp. red clovers
  • Detection of plant lesions (black patches)
  • Recovery following removal of offending
    feedstuff
  • Detection of toxin in plant material by
    chemical analysis
  • Salivary response in guinea pig bioassay (uncommon)
28
Q

What are the DDX for Slaframine toxicity?

A
  • Clinical syndromes that cause salivation:
    – Vesicular stomatitis
    – Foot and mouth disease
    – Ulcerative stomatitis
    – Mechanical or chemical irritation of the mouth
    – Dental problems
    – Glossitis
    – Oral foreign body
29
Q

Is Slaframine toxicosis life threatening?

A
  • Slaframine toxicosis is generally not life-
    threatening
    – Animals usually recover spontaneously
    once the offending forage is removed
30
Q

What can be given to reduce clinical signs of Slaframine toxicity?

A
  • Atropine reverses muscarinic signs if given
    early. It is not effective once salivation has
    become excessive
  • Antihistamines may alleviate some clinical
    signs
31
Q

What are the common sources of Organophosphates?

A

Sources: Organophosphates
* Pesticides used on yards, gardens, homes or
directly on animals
* Parasiticides in vet medicine (wormers)
* Chemical weapons of mass destruction (nerve
gases: soman, sarin, tabun, VX, VR)

Commonly used in
agriculture as insecticides
on forage, grain, crops,
soils and stored grain.
OPs have replaced the
banned organochlorine
compounds and are a major
cause of animal poisoning.
Formulation: powder, spray,
granules, emulsions, flea
collars
Agricultural OPs are very
toxic: malicious poisoning

32
Q

What are the common sources of Carbamates?

A

Carbamates: derivatives of carbamic acid with
similar uses as the OPs

33
Q

Compare the struutre of organophosphates and carbamates?

A

OPs are esters of phosphoric acid
Carbamates are esters of carbamic acid. Acetylcholine is an ester of choline and acetic acid
This structural similarity is the reason why the affect the same cellular
process.

34
Q

List some examples of organophosphates?

A
  • Chlorpyrifos (Dursban)
  • Coumaphos (CoRal)
  • Diazinon
  • Fenthion (Pro-Spot)
  • Malathion
  • Parathion
  • Disulfoton
  • Terbufos
  • Phorate

Liquids, powders, collars,
sprays, dips, lotions, baits.
Most OPs are very insoluble in water and are formulated with oily vehicles or organic
solvents

35
Q

List some examples of carbamates?

A
  • Aldicarb (Temik)
  • Carbaryl (Sevin)
  • Carbofuran (Furadan)
  • Methiocarb
  • Methomyl
  • Propoxur (Baygon)

They are prefered as pesticides

36
Q

Describe the susceptibility of animal species to OPs and carbamates

A
  • Exposures are mostly food-related (80% of
    all food animal exposures)
  • Improper/careless use
  • Dose miscalculation and use on stressed
    animals
  • Malicious poisoning
  • All species are susceptible. Cats, fish and
    birds are more susceptible
37
Q

What is the toxicity and risk associated with OP and carbamate toxicity?

A
38
Q
  1. The rate of absorption of OPs and carbamates is influenced by?
  2. Water soluble metabolites are excreted via ?
  3. OPs and Carbamates are readily absorbed via?
  4. OPs undergo which processes?
A
  1. Rate of absorption is influenced by lipid solubility and formulation
  2. Water soluble metabolites are excreted via urine
  3. Absorbed readily via skin, GI & resp. tracts. Influenced by liquid solubility and formulation.
  4. The OPs undergo oxidation and hydrolysis by esterases in plasma and liver followed
    by conjugation reactions. Excreted via urine and feces
    * Many OPs undergo “lethal synthesis” in the
    liver
39
Q
  1. Lethal synthesis of OPs is another term for?
A
  1. Toxication
    Here it is a desulfuration reaction where sulfur in the OP is replace with oxygen. This reaction is catalyzed by cytochrome P450 or flavin monooxygenase in the
    liver. Examples include the conversion of parathion to paraoxon and malathion to
    malaoxon. Both of these metabolites are more toxic than the parent OPs.
40
Q

What are the mechanisms of toxicity of OPs and carbamates?

A
41
Q
  • After OP binding, enzyme is ______________ and unavailable to participate in catabolism
    of ACh.
  • Most OPs bind __________ to ChEs
  • OP-ChE bond is enhanced through ‘______’ caused by the loss of an ______ group
    – or? groups
A
  • After OP binding, enzyme is phosphorylated
    and unavailable to participate in catabolism
    of ACh
  • Most OPs bind irreversibly to ChEs
  • OP-ChE bond is enhanced through ‘aging’
    caused by the loss of an alkyl group
    – Methyl, ethyl or propyl group
42
Q
  • Similar to OPs except that the ChEs undergo _____________
  • Carbamates are poor substrates for _____ because they have a ______ affinity for enzyme binding site than OPs. Also, have _________ ChE inhibition: CMs _____________ dislodge from the enzyme

This is why carbamates are preferred then OP

A
  • Similar to OPs except that the ChEs
    undergo carbamylation
  • Carbamates are poor substrates for ChEs
    – Lower affinity for enzyme binding site than
    OPs
    – Reversible ChE inhibition: CMs spontaneously
    dislodge from the enzyme
    This is why carbamates are preferred then OP
43
Q
  1. Describe the rate of the first reaction.
A

This diagram summarizes the interactions of OPs, CMs and ACh with acetylcholinesterase (AChE).
Remember that the structure of these compounds is similar and that is why they all interact with acetylcholinesterase.
1. The first reaction which is the binding of ACh, CM or OPs to AChE is very fast. The difference is at the level of hydrolysis where for the acetylated enzymes it occurs within 150 uSec.
For the carbamylated enzyme the half-life for hydrolysis is 15-30 min while for the phosphorylated enzyme this can take days, or it can be irreversible. The irreversibility occurs through the process of aging where an alkyl group is lost from the phosphorylated enzyme.
In this case a methyl group is lost and once that happens the bond between the OP and the AChE is permanent and cannot be reversed.

44
Q

Consequence of ChE Inhibition
* As a result of the phosphorylation or carbamylation, AChE _____ normal function, i.e., there is ______ catabolism of ACh
– ACh builds up in nerve synapses and _____ resulting in _______ stimulation of ?

A

ceases, impaired, NMJs, continuous, nervous,
glandular, GI tract and muscular cholinergic receptors

45
Q

What can be seen in the diagram below?

A

This diagram summarizes the mechanism of action of OPs/CMs.
The left side is the normal situation where ACh is released from the presynaptic cell into the synaptic cleft or NMJ.
It then binds to receptors on the postsynaptic cell, and it is quickly thereafter broken down by AChE resulting in a measured response.
On the right side when you have exposure to OPs or CMs which are anti- AChE, the ACh is not quickly removed from the synaptic cleft or the NMJ
because the enzyme that breaks it down is inhibited.
Therefore, ACh binds to a lot more receptors on the postsynaptic cell causing
massive stimulation of cholinergic receptors.

46
Q
A
47
Q

List the clinical signs of cholinergic crisis?

A

Clinical Signs: Cholinergic crisis
* Signs of acute poisoning can occur within
30 minutes, usually within 6h of exposure
* There are 3 categories of clinical signs:
muscarinic, nicotinic and CNS. Signs are
highly variable among individuals

48
Q

List the muscarinic signs of cholinergic crisis

A

– These are usually the first signs to appear and
are preceded by apprehension/uneasiness
– DUMBELS

49
Q

List the nicotinic signs of cholinergic crisis

A

Stimulation of skeletal muscle
* Twitching of facial muscles, eyelids, tongue,
and eventually general musculature
* Tremors are followed by convulsions and
seizures
* Tachycardia and mydriasis
* Weakness, paresis or paralysis
– Paralysis of respiratory muscles –> death

50
Q

List the CNS signs of cholinergic crisis

A

CNS Signs
* Stimulation, then severe depression of CNS
with coma and death terminally
* Anxiety, restlessness, stiffness and ataxia
* Food animals often exhibit hyperactivity and
rarely seizures
* Dogs and cats have clonic-tonic seizures and
hyperactivity
* Centrally mediated respiratory paralysis

Toxicology (32 decks)

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