PNS III - Neuromuscular Flashcards
Briefly discuss the physiology of the neuromuscular junction.
- the neuromuscular junction is a cholinergic synapse between a motor neuron and skeletal muscle
- action potential arrives at terminal button of motor neuron causing the opening of Ca channels
- this causes the release of ACh which binds to nicotinic receptors on the muscle fiber
- binding to these causes the opening of Na channels and sodium rushes back into the fiber and stimulates the action potential
What is the origin of the phrase ‘black widow spider’?
- the female eats the male after mating
Name the black widow spider toxin. What is the mechanism of action of this toxin?
- a-latrotoxin
- binds to 2 neuronal receptors (neurexins, calcium independent receptor for latrotoxin [CIRL]) causing release of neurotransmitters via 2 mechanisms
- Ca-independent and Ca- dependent
- this inhibits presynaptic neurotransmitter reuptake
Differentiate the Ca-dependent and Ca-independent mechanisms of action of a-latrotoxin.
- Ca dependent
- affects ACh, GABA, glutamate
- direct action via CIRL
- Ca independent
- catecholamines (dopamine, EPI, NE)
- neurexin receptor, pore formation - Ca entry
Name the drugs recommended for control of muscle cramping in black widow toxicosis.
- benzodiazepines (diazepam)
- methocarbamol
Is there an antivenin for black widow venom?
- yes, Lyovac Antivenin
- used for high risk patients (neonates, geriatric) or those not responding to symptomatic treatment
- be prepared to respond to anaphylactic reaction
Name the sources of botulinum neurotoxin toxin.
- Clostridium botulinum
Which botulinum toxin subtype(s) most commonly affect animals and birds?
- A, B, C, D - most important in animals
- cattle - B, C, D
- horse - A, B, C
- avian - A, B, C, E
Provide the mechanism of toxicity of botulinum toxin and the resulting clinical signs.
- toxins enter presynaptic nerve endings by endocytosis, light chain bonds to synaptotagmin
- blocks release of ACh at neuromuscular junction - flaccid paralysis
- inhibits exocytosis of ACh by cleaving proteins essential for fusion of the vesicle membrane with the neuronal cell membrane
- clinical signs
- sudden death progressive neuromuscular dysfunction, progressive flaccid paralysis
- ataxia, depression, weakness of tongue and tail
- poor reflexes of eyes and throat - mydriasis, slow pupillary light response, decreased palpebral reflex, decreased gag reflex, weak vocalization
- ANS signs - bradycardia, vomiting, inability to swallow, ileus, constipation, ruminal atony, frequent attempts to urinate (horses)
Name the proteins involved in the docking of ACh vesicles at the presynaptic cell membrane. Identify the botulinum toxin subtypes that affect these proteins.
- SNARE and NSF proteins
- SNARE includes synaptobrevin (VAMP), SNAP-25, syntaxin
- A, B, C, D, E, F, G
- B, D, F, G - cleave synaptobrevin (VAMP)
- A, C, E - cleave SNAP
- C - cleaves syntaxin
What are the characteristic signs of botulism in foals and waterfowl?
- foals - tremors, shaker foal syndrome
- waterfowl - progressive paralysis of neck (limberneck), wings, legs
- death by drowning
What is the diagnosis of botulinum toxicosis based on?
- analysis of serum, GI contents, vomit, ruminal fluids, and feed for the toxin
- mouse bioassay
Describe the treatment procedures for botulinum toxicosis.
- decontaminate
- emesis, gastric lavage, charcoal
- supportive and symptomatic care
- ventilation, physostigmine for muscle function with atropine for muscarinic signs, IV fluids, remove bad feed
- nutritional support - hand feeding and watering
- antitoxin if diagnosis made early
- polyvalent (anti-B and anti-C) and monovalent (anti-B) antitoxins available for adult horses and foals and should be given ASAP
- antibiotic - penicillin, metronidazole, amoxicillin
- debride wounds for animals suffering from wound botulism
Name two tick species associated with tick paralysis in North America.
- Dermacentor andersoni
- Dermacentor variables
Provide the mechanism of action of tick toxins. What is the general name of these toxins?
- holocyclotoxins block ACh release at neuromuscular junction and inhibit depolarization of lower motor neurons - leading to paralysis
How is tick paralysis treated?
- remove tick, tick dip solution, support respiration in severe cases
What is anatoxin-a? Provide the mechanism of action of anatoxin-a including clinical signs associated with its action.
- nicotinic agonist produced by blue-green algae
- rapid onset of muscle rigidity and tremors, cyanosis, convulsion
- paralysis and respiratory distress leading to death
Differentiate between anatoxin-a and anatoxin-a(s) toxicoses.
- anatoxin-a
- agonist of nicotinic ACh receptors at both neuromuscular junction and neurons
- stimulation at neuromuscular junction in weakness, respiratory paralysis, death
- anatoxin-a(s)
- irreversible acetylcholinesterase inhibitor in PNS
- build up of ACh results in ataxia, seizures, respiratory arrest, death
- ”s” - salivation
Describe the diagnostic procedures for anatoxin-a toxicosis.
- evidence of ingestion of blue-green algae and compatible clinical signs
- decreased cholinesterase activity in blood and plasma
- examine water for appropriate algae type
- mouse bioassay with suspect water
- identify toxin in water by HPLC or GC-MS
Why is it difficult to treat anatoxin-a toxicosis?
- there is no antidote
- onset is so rapid that treatment may not be possible
Give 3 examples of ionophores. Provide the mechanism of action of ionophores.
- sources - coccidiostats (parasite treatment), growth promotants
- monesin - rumesin, coban
- lasalocid - bovatec, avatec
- narasin - maxiban, monteban
- salinomycin - biocox, saccox
- laidlomycin propionate - cattlyst
- binds and preferentially transports cations across cell membranes
- net effect is ion imbalance (Na, K, Ca, H) and deficits in the function of excitable tissues (neurons and muscles)
- mitochondrial ion imbalance leads to decreased ATP
Name the body systems most affected during ionophore toxicosis.
- neurologic
- muscular
- GI
- cardiovascular
Describe the treatment of ionophore toxicosis.
- no specific antidote
- decontamination
- emesis in dogs and cats, charcoal, cathartic
- supportive therapy
- IV fluids, minimize stress
- antioxidants
- vitamin E, selenium
In which geographic region of the US does larkspur poisoning commonly occur?
- western US
What are the toxic agents in larkspur?
- diterpene alkaloids
- methyllcaconitine (MLA)
- 14-deacetylnudicauline (DAN)
- DAN is more toxic, but MLA occurs in greater quantities
Which domestic animal species is most susceptible to larkspur toxins? Why are sheep used for biological control of larkspur?
- cattle are most susceptible
- sheep used for biological control becase they can tolerate 4-5x the amount lethal to cattle
- can eat it without getting sick and trample stalks
Provide the mechanisms of toxicity of larkspur toxins?
- block nicotinic receptors of ACh at neuromuscular junctions and in CNS (MLA)
Describe the diagnostic procedures for larkspur toxicosis.
- evidence that animals have grazed it
- plant presence in ruminal contents
- presence of bloat and ruminal contents in bronchi
Describe the treatment of larkspur toxicosis.
- decontaminate - charcoal, cathartic
- move animals to new pasture
- give cholinesterase inhibitors (physostigmine)
- avoid stress and excitement
- relieve bloat by stomach tube or trocarisation
- antibiotics for inhalation pneumonia
In which geographic region of the US are locoweeds most commonly found?
- pacific northwest
Name the toxins present in locoweeds. Which of these toxins cause neuromuscular toxicity?
- nitroptopanol glycosides (miserotoxins)
- hydrolyzed to nitrotoxins by rumen microbes
- nitrotoxins - 3-NPOH, 3-NPA
- 3-NPOH is absorbed and metabolized in the liver to 3-NPA
- 3-NPA is responsible for toxicity
- if ingested as 3-NPA, most of it is biodegraded in the GI tract, so there is a lower toxicity
- 3-NPA causes axonal degeneration in the spinal cord
- indolizidine alkaloid (swainsonine) and selenium
- CNS and skin toxicity
What is nitrotoxicosis? Provide the clinical signs of this condition.
- nitrotoxicosis - the clinical signs associated with nitrotoxin ingestion and toxicosis
- acute
- constipation, ataxia, staggering gait, recumbency, death from cardiac-respiratory failure
- in most cases, signs are gradual
- dyspnea, salivation, weakness, muscular spasms, docile appearance, goose-stepping, cracker heels, fetlock knuckling, posterior paresis/paralysis
- loss of body condition as toxicosis progresses
Identify a locoweed toxin and provide its mechanism of action.
- 3-NPA inhibits the krebs cycle leading to decreased energy (ATP) production and loss of cellular homeostasis
- axonal degradation in spinal cord, hypotension via vasodilation and cardiodepression
Describe the diagnostic procedures for nitrotoxicosis.
- clinical signs, evidence of plant consumption
- gross and histo respiratory and neuro lesions
- identification of NPA and NPH in plasma and serum by HPLC
Describe the treatment of nitrotoxicosis.
- withdraw animals from source of plant
- cattle will avoid locoweed when other forage available
- toxin concentration decreases rapidly as plants mature and undergo senescence
Name two sources of tremorgenic mycotoxins.
- tremorgenic forages - bermuda grass, ryegrass, dallis grass
- moldy cheese, bread, walnuts, and pasta
- garbage
Identify the mycotoxins referred to as tremorgens and the fungi that produce them. Which of these mycotoxins affect dogs?
- dogs
- Penicillium crustosum produces penitrem A
- Penicillium roquefort produces roquefortine C
- livestock
- Acemonium lolii produces lilitrem B
- Claviceps paspali produces paspalitrem
Provide the mechanisms of action of tremorgens and the main clinical signs of toxicosis.
- tremorgens cause presynaptic release of ACh and prolong depolarization at the neuromuscular junction
- facilitate transmission at motor end plate
- reduce levels of GABA and glycine
- CNS stimulation
- cerebral vasoconstriction
- leads to anoxia and CNS signs
- opisthotonus
- spasm of muscles causing backward arching of head, neck, and spine
Describe the decontamination procedures for tremorgenic mycotoxicosis in dogs.
- asymptomatic animals
- emesis, activated charcoal, cathartic
- symptomatic animals
- sedate/anesthesia and perform gastric lavage, then give activated charcoal and cathartic
Describe the treatment of tremorgenic mycotoxicosis in dogs.
- decontaminate then symptomatic and supportive therapy
- diazepam to control agitation, seizures, muscle tremors
- in patients that do not repsond to diazepam use methocarbamol or barbiturate
- IV fluids
Describe the treatment of tremorgenic mycotoxicosis in livestock.
- replace contaminated forage and keep animals in a quiet place until recovery
