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Veterinary Toxicology > Cholinergic and Anticholinesterase Toxicants > Flashcards

Cholinergic and Anticholinesterase Toxicants Flashcards

1
Q

Nervous system overview:

A
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2
Q

How do the parasympathetic and sympathetic preganglionic and postganglionic fibers?

A

PS = long preganglionic, short postganglionic

S = short preganglionic, long postganglionic

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3
Q

What neurotransmitter is released by preganglionic fibers of both parasympathetic and sympathetic nerves? What receptor does it bind to?

A

acetylcholine

nicotinic

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4
Q

What neurotransmitters are used at the postganglionic fibers of parasympathetic and sympathetic nerves? What receptors do they bind to?

A

PARASYMPATHETIC
- Ach —> M - cardiac and smooth muscles, gland cells, nerve terminals

SYMPATHETIC
- NE —> α, β - cardiac and smooth muscles, gland cells, nerve terminals
- Ach —> M - sweat glands
- D —> D1 - renal vasculature, smooth muscle
- Ach —> N - adrenal medulla, production of Epi

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5
Q

What is unique about the peripheral nervous system of horses?

A

sweat glands are predominantly under β-adrenergic control

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6
Q

What are the direct and indirect mechanisms of toxicity of autonomic nervous system toxicants?

A

DIRECT = impairment of neurotransmission, causing structural toxicoses —> neuronopathy, axonopathy, myelinopathy

INDIRECT = alteration of metabolism or blood supply with secondary neuronal dysfunction

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7
Q

What are the 5 steps in neurotransmission?

A
  1. synthesis of neurotransmitter
  2. storage of neurotransmitter in presynaptic cells
  3. calcium-dependent neurotransmitter release upon stimulation
  4. interaction with postsynaptic receptors
  5. termination of neurotransmitter action by reuptake/metabolism
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8
Q

How do cholinergic toxicants generally work?

A

target any point of neuronal transmission where acetylcholine is used as the neurotransmission

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9
Q

What is the structure of nicotinic and muscarinic receptors?

A

NICOTINIC = ligand-gated channels that open upon Ach binding (Nn, Nm)

MUSCARINIC = G-protein coupled (M1-M5)

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10
Q

Where are nicotinic receptors found?

A

Nn - autonomic ganglia firing of post-ganglionic neurons, adrenal medulla secretion of Epi

Nm - NMJ end-plate depolarization and skeletal muscle contraction

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11
Q

Where are muscarinic receptors found?

A

M1/M3 - glands, stomach, intestine,

M2 - heart

M3 - eye, bronchial muscle

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12
Q

What muscarinic receptors are excitatory? Inhibitory?

A

EXCITATORY = M1, M3, M5

INHIBITORY = M2, M4

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13
Q

What are the general signs of cholinergic stimulation? What receptors control these reactions?

A
  • Diarrhea, Dyspnea
  • Urination
  • Miosis
  • Bradycardia
  • Emesis
  • Lacrimation
  • Salivation

muscarinic

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14
Q

What is the source of slaframine? What toxicosis does it cause? In plants?

A

indolizidine alkaloid mycotoxin produced in red clovers (Trifolium spp.) infected with the fungus Rhizoctonia leguminicola

slobber syndrome, clover poisoning, salivary syndrome

Black Patch Disease

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15
Q

In what conditions favor slaframine toxicosis?

A

periods of wet weather and high humidity

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16
Q

What is the ultimate toxicant of slaframine? How is it produced?

A

activated by liver microsomal flavoprotein oxidase to a ketoimine metabolite that is chemically similar to acetylcholine

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17
Q

What 2 species are most affected by slaframine toxicosis?

A
  1. cattle
  2. horses
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18
Q

What is the mechanism of toxicity of slaframine?

A

parasympathomimetic - causes cholinergic stimulation of exocrine and endocrine glands with a high affinity for GI tract muscarinic (M3) receptors

19
Q

What clinical sign is most associated with slaframine toxicosis? What else is observed?

A

salivation (slobbers)

DUMBELS - lacrimation, anorexia, diarrhea, urination, bloating, stiffness, respiratory distress, bradycardia, decreased milk production, death is rare

20
Q

What is a common observation in horses with slaframine toxicosis?

A

if a horse is kept in the same spot for a decent amount of time, it will salivate so severely that a puddle will form

21
Q

In what 5 ways can slaframine toxicosis be diagnosed?

A
  1. salivation in animals consuming legumes, especially red clovers
  2. detection of black patch plant lesions
  3. recovery following removal of offending feedstuff
  4. detection of toxin in plant material by chemical analysis
  5. salivary response in guinea pig bioassay
22
Q

What 7 conditions fit into a differential diagnosis for slaframine toxicosis?`

A

clinical syndromes that cause salivation:
1. vesicular stomatitis
2. foot and mouth disease
3. ulcerative stomatitis
4. mechanical or chemical irritation of the mouth
5. dental problems
6. glossitis
7. oral foreign body

23
Q

How is slaframine toxicosis typically treated?

A

generally not life-threatening and animals recover spontaneously once the offending forage is removed so treatment is not always necessary

24
Q

What 2 drugs can be used to alleviate clinical signs of slaframine toxicosis?

A
  1. Atropine can only reverse muscarinic signs if given early and is not effective once salivation occurs
  2. antihistamines
25
Q

What are 3 anticholinesterase toxicants?

A
  1. organophosphates
  2. carbamates
  3. anatoxin-a(s) - naturally produced by blue-green algae
26
Q

What are 3 major sources of organophosphates?

A
  1. pesticides used on yards, gardens, homes, or directly on animals
  2. parasiticides
  3. chemical weapons of mass destruction (nerve gases)
27
Q

How do the structures of organophosphates and carbamates compare? What are they similar to?

A

OP = esters of phosphate

CM = esters of carbamic acid

acetylcholine, an ester of choline and acetic acid

28
Q

What are some examples of organophosphates and carbamates?

A

OP
- Diazinon
- Fenthion (Pro-Spot)
- Malathion
- Parathion

CM
- Aldicarb
- Carbaryl
- Carbofuran
- Methiocarb

29
Q

What is the most common cause of exposure to organophosphates and carbamates? What else can lead to exposure?

A

food-related (oral route)

  • improper/careless use: misidentification of pesticides/parasiticides as supplements
  • dose miscalculation and use on stressed animals
  • malicious poisoning
30
Q

What 3 species are most susceptible to organophosphate and carbamate toxicosis?

A
  1. cats
  2. fish
  3. birds
31
Q

What is the lethal dose for the most toxic organophosphates can carbamates?

A

< 1 mg/kg

32
Q

How can species, sex, and age affect toxicity of organophosphates and carbamates?

A

SPECIES: cats are sensitive because a majority of their cholinesterase activity is in the blood

SEX: bulls are very susceptible to chlorpyrifos due to high testosterone levels

AGE: young animals are poisoned at lower doses due to their immature hydrolyzing enzyme systems

33
Q

Where are organophosphates and carbamates absorbed? What happens once they reach the liver?

A

skin, GI tract, respiratory tract

oxidation and hydrolysis by esterases followed by conjugation

34
Q

Where do organophosphates undergo lethal synthesis? What is this?

A

liver

CYP450 or flavin monooxygenase induced desulfuration where the sulfur is replaced by an oxygen molecule, making the new product more toxic

Parathion —> paraoxon
Malathion —> malaoxon

35
Q

How do anticholinesterases work?

A

bind to acetylcholinesterase and other cholinesterases to impair acetylcholine catabolism, allowing it to accumulate at nerve synapses and NMJ —-> continuous stimulation of nervous, glandular, GI tract, and muscular cholinergic receptors

36
Q

How does the action of organophosphates compare to carbamates?

A

OP - bind irreversibly to cholinesterases and phosphorylate them to make it unavailable to participate in acetylcholine catabolism

CM - bind to cholinesterases and have them undergo carbamylation

37
Q

How can the organophosphate-cholinesterase bond be enhanced?

A

aging - loss of an alkyl group, like methyl, ethyl, or propyl

38
Q

What are 2 reasons that carbamates are preferred as pesticides?

A

poor substrates for cholinesterases
1. lower affinity for enzyme binding site compare to OP
2. reversibly inhibits cholinesterases, allowing them to spontaneously dislodge from the enzyme

39
Q

How is the half-life/hydrolysis of acetylcholine affected by organophosphates and carbamates?

A

JUST AChE = 150 µs

CM = 15-30 min

OP = days/irreversible

(ACh lasts longer in the synaptic cleft once these drugs attach to AChE)

40
Q

What is the general 4 steps in the pathogenesis of organophosphates and carbamates?

A
  1. inhibit AChE
  2. ACh accumulates at nerve synapses and NMJ
  3. continued stimulation of muscarinic and nicotinic receptors
  4. cholinergic crisis
41
Q

What are the 3 categories of clinical signs in the cholinergic crisis caused by organophosphates and carbamates?

A
  1. MUSCARINIC SIGNS - first to appear, preceded by apprehension/uneasiness; DUMBELS
  2. NICOTINIC SIGNS - stimulation of skeletal muscle resulting in facial muscle, eyelid, tongue, and general musculature twitching, convulsions, seizures, tachycardia, mydriasis, weakness, paresis, paralysis
  3. CNS SIGNS - anxiety, restlessness, stiffness, ataxia, centrally mediated respiratory paralysis, coma, death
42
Q

What aspect of nicotinic signs of organophosphate and carbamate toxicosis can result in death?

A

paralysis of respiratory muscles

43
Q

What CNS signs do food animals and dogs/cats typically present with in organophosphate and carbamate toxicity?

A

hyperactivity, rarely seizures

clonic-tonic seizures and hyperactivity

Veterinary Toxicology (29 decks)

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