Lecture 11 - CNS Toxicants Flashcards
(96 cards)
1
Q
Neurons are the _______ cell type in the nervous system and are responsible for _______ of impulses. They are adapted for _____ signal transmission which predispose CNS to _________.
A
primary, propagation, rapid, xenobiotics
2
Q
The CNS depends on what form of metabolism to function?
What supports this high metabolism?
A
High dependence on aerobic metabolism for function (e.g., maintenance of ion gradients; membrane depolarization).
20-25% of cardiac output goes to the brain to support the high metabolism
3
Q
Why does the CNS have extended axons?
A
Extended length of axons: maintenance of large volumes, transport of material
over long distances
4
Q
Can neurons regenerate after injury?
What is the exception?
A
Neurons do not regenerate upon injury (except granule cells of the
hippocampus).
5
Q
How does the CNS compensate for being so vulnerable?
A
Brain has specialized barriers; BBB and blood-cerebrospinal fluid barrier.
These barriers are effective for many compounds except those that are
nonpolar or actively transported.
6
Q
What does the BBB consist of? Describe how it maintains its structural integrity.
A
BBB consists of structural and biochemical barriers that restricts passage of solutes between blood and brain and therefore protects the brain from potentially harmful substances. The structural/ morphological component consists of tight junctions between adjacent capillary endothelial cells, astrocyte end-feet, and pericytes in the capillary basement membrane.
7
Q
Where is the BBB mainly loocalized?
A
The barrier is mainly localized in the endothelium.
8
Q
Where are the primary and secondary components of the anatomical barrier located?
A
However the main component of the barrier is within the capillary
endothelium. The second component of the anatomical barrier is the tight junctions between
the epithelial cells of the choroid plexus
9
Q
What molecules can pass through the BBB?
A
Large molecules (proteins and large peptides) do not usually pass through and polar molecules are generally physically restricted because the BBB is highly lipophilic. It is selectively permeable to some small molecules and there are specialized transport systems for ions and metabolites such as glucose and amino acids that are essential for the function of nerve cells.
10
Q
What are the biochemical components of the BBB?
A
Biochemical component:
P-glycoproteins and enzyme metabolism
The biochemical component comprises of P-glycoproteins that eject toxicants as they try to enter the cells and enzymes that metabolize toxicants before they enter the nerve
cells
11
Q
The transport system in the brain can be hijacked by?
A
These transport systems can be hijacked by toxicants and facilitate their entrance into
the brain and toxicants may disrupt the BBB
12
Q
The BBB is weaker in?
A
neonates and embryonic organisms
13
Q
Define functional toxicosis.
A
Impairment of neurotransmission
E.g.: NT synthesis, Storage,
Release, Binding, Degradation/reuptake,
Axonal propagation, etc
14
Q
What is structural toxicosis?
A
neuronopathies, myelinopathies
and axanopathies
15
Q
How do CNS toxicants/toxins act on NT?
A
CNS toxicants/toxins stimulate or inhibit the release of these
neurotransmitters.
16
Q
What are some examples of indirect CNS toxicosis?
A
Impaired metabolism, ion homeostasis, blood supply
17
Q
Which NT are commonly affected by Toxicants/Toxins?
A
The main neurotransmitters that are affected by toxicants and toxins of the
CNS are small molecules belonging to all the three classes, I to III.
– Class I: acetylcholine
– Class II (the amines): norepinephrine, epinephrine,
dopamine, serotonin (5-HT), histamine
– Class III (amino acids): GABA, glycine, glutamate, aspartate
– Class IV (gases): nitric oxide
Others:
* Neuropeptides: opioid peptides, tachykinins, etc.
* Purine-based: adenosine, ATP, AMP, ADP
18
Q
There is one major group of toxins, the ___________ (found in chocolate,
coffee, and tea), that affect _____-based neurotransmitters, specifically _______.
A
methylxanthines, purine, adenosine
19
Q
What do NT mediate?
A
Neurotransmitters mediate excitatory or
inhibitory responses when they are released after exposure to relevant
toxicants/toxins
20
Q
How are CNS toxicants classified?
A
Therefore,
CNS toxicants will be classified as:
I. Toxicants causing CNS stimulation and/or
seizures
II. Toxicants causing CNS depression
III. Toxicants causing mixed CNS signs
21
Q
What are the sources of Tetanus neurotoxin (TeNT)?
A
A neurotoxin, tetanospamin, produced by Clostridium tetani under anaerobic conditions
* C. tetani spores are commonly present in feces of domestic animals especially those of the horse. Spores are resistant to many standard disinfection processes and can survive in soil for many years
22
Q
How do you get exposed to the Tetanus neurotoxin (TeNT)?
A
deep puncture wounds
23
Q
List the risk factors of exposure to TeNT?
A
field surgery, castration, docking,
retained placenta, shearing, umbilical infections
24
Q
Which species are susceptible to TeNT?
A
all, most toxicoses
occur in horses and ruminants
25
Tetanus toxin is a ______ _________ and has _____ and ______ chain.
zinc metalloprotease, heavy, light
26
The ________ and the _______ of the TeNT are mediated by the heavy-
chain (HC), whereas the ______ activity is located in the light-chain (LC) of
the molecule.
targeting, translocation, catalytic
27
How does the light chain of the TeNT mediate catalytic activity?
Light chain cleave SNARE proteins (VAMP), thereby interfering with the
fusion of synaptic vesicles and the plasma membrane and ultimately blocking neurotransmitter release from pre-synaptic nerve cells.
– Blocks the release of the neurotransmitter glycine in CNS → loss of inhibitory input
* Minor effect: inhibition of release of
GABA as well as ACh at NMJs
28
What are the clinical signs of TeNT toxiccosis?
* Hyperesthesia, tetany, convulsions, severe rigidity of musculature *(sawhorse stance)*, protrusion of third eyelid, *sardonic grin*
* *Locked jaw*, elevated tail, flared nostrils
* Sympathetic effects: sweating, cardiac arrhythmias, vasoconstriction, diminished urination and defecation, colic
* Eventually rigidity of muscles of
respiration asphyxiation and death
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Tetanus
Sawhorse stance
The more classic presentation of tetanus includes saw horse stance and rictus sardonicus (“sardonic grin”).
Excessive contraction of the facial muscles causes wrinkled forehead and erect ears,
The ears are pulled tightly back, as are the lips. The eyes bulge, and the animal appears to be grinning.
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Tetanus
Fixed stare, sardonic grin
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How do you Dx TeNT toxicosis?
Identification of C. tetani in a culture of the
wounD.
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How do you treat TeNT toxicosis?
Wound debridement
* Antibiotic therapy (penicillin)
* Administer antitoxin
* Keep animal in a quiet, dark area to minimize
convulsions
* Tranquilizers may be used for convulsions
33
What is Strychnine?
Strychnine is Gopher bait. It is an a lkaloid derived from seeds/bark of Indian tree,
Strychnos nux vomica and ignatii
34
Which species are most at risk for Strychnine toxicosis?
All, especially dogs.
35
List the sources of Strychnine.
– Found in pesticides for control of gophers,
moles, rats, prairie dogs, squirrels, etc. For
below ground use. Bait dyed red or green
– Accidental and malicious poisonings
36
Describe the ADME of Strychnine toxicosis?
– Absorbed ______ in GI tract, _____ distribution
– Metabolized in ____ and excreted in ____
– Absorbed rapidly in GI tract, wide distribution
– Metabolized in liver and excreted in urine
37
What is the MOT for Strychnine?
* __________ and __________ __________ the inhibitory neurotransmitter glycine in the
_______ ______ and __________
− Leads to _________ reflex stimulation with extensor rigidity (powerful ________ muscle groups predominate)
* Competitively and reversibly antagonizes the inhibitory neurotransmitter glycine in the
spinal cord and medulla
− Leads to uncontrolled reflex stimulation with extensor rigidity (powerful extensor muscle groups predominate)
* Toxicity: Oral LD50 (mg/kg bw) = 0.5-1.2
(dogs); 2 (cats); 0.5-1 (pigs); 0.5 (horses); 0.5
(cows)
38
What are the clinical signs of Strychnine Toxicosis?
* Poisoning is common in _____ _________
* Onset of toxicosis is fast: ___-__ min After oral exposure, clinical signs may appear within ___-____ min. The Presence of food in the stomach can ____ onset.
* Early signs: apprehension, nervousness,
tenseness, stiffness and excessive salivation
* Severe tetanic seizures with _______ stance
– Seizures initiated by touch, sound or bright light
* Apnea, cyanosis, hyperthermia, mydriasis and strained facial expression
* No loss of consciousness
* Death from medullary _________ and ________ with rapid onset of rigor mortis
Clinical Signs
* Poisoning is common in Pacific Northwest
* Onset of toxicosis is fast: 10–60 min After oral exposure, clinical signs
may appear within 30-60 min. The Presence of food in the stomach can delay onset.
* Early signs: apprehension, nervousness,
tenseness, stiffness and excessive salivation
* Severe tetanic seizures with sawhorse stance
– Seizures initiated by touch, sound or bright light
* Apnea, cyanosis, hyperthermia, mydriasis and
strained facial expression
* No loss of consciousness
* Death from medullary paralysis and exhaustion
with rapid onset of rigor mortis
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Early signs, which may often be overlooked, consist of apprehension,
nervousness, tenseness, and stiffness. Vomiting usually does not occur.
Severe tetanic seizures may appear spontaneously or may be initiated by
stimuli such as touch, sound, or a sudden bright light. Seizures begin with
facial, neck and limbs and spread throughout the body. An extreme and
overpowering extensor rigidity causes the animal to assume a “sawhorse”
stance. Rigidity inhibits respiration Apnea
The mucous membranes become cyanotic, and the pupils dilated.
Frequency of the seizures increases, and death eventually occurs from
medullary paralysis, exhaustion or asphyxiation during seizures with rapid
onset of rigor mortis.
40
How do you Dx Strychnine Toxicosis?
Dx
* History of exposure
* Clinical signs
* Presence of red- or green-dyed grain in vomitus, lavage washings, or stomach contents
* Chemical analysis in stomach contents and
tissues (HPLC, GC-MS)
41
What are the DDx for Strychnine Toxicosis?
Metaldehyde, penitrem A (tremorgenic
mycotoxins), organophosphates/ carbamates,
pyrethrins/pyrethroids, chocolate, tetanus,
bromethalin
42
How do you treat Strychnine Toxicosis?
Decontamination: emesis or gastric lavage,
then give activated charcoal and cathartic
* Symptomatic Tx: barbiturates or diazepam
for convulsions; methocarbamol for muscle
relaxation
* Supportive: IV fluids to correct hypovolemia,
respiratory assistance, correct hyperthermia
43
List the sources of Metaldehyde.
Molluscicide in slug and snail baits
(2-5% metaldehyde). Also used as fuel in
camping stoves and lamps. Malicious
poisoning. Secondary poisoning can occur.
Formulations may contain arsenic, OPs and CMs
44
Baits are available in liquid, powder, pellet, and granular formulations.
The concentration of metaldehyde in these products ranges from 2% to 5%.
Generally formulated in corn-based pellets that animals mistake for kibble.
Baits appear like dog food and are flavored with molasses or bran to attract
snails
Currently there is an increase in number of cases attributed to accidental or
malicious use of metaldehyde
45
Which species are susceptible to Metaldehyde toxicity?
all species especially dogs and cats. Most cases occur in coastal US
46
Describe the ADME of Metaldehyde toxicosis?
After ingestion, metaldehyde is absorbed _____ or _________ in the acidic stomach pH to _______ which is subsequently oxidized to ______ ______
* The metabolic fate after absorption is largely ________
– Rapid metabolism by _______ is suspected
after ingestion, metaldehyde is absorbed intact or hydrolyzed in the acidic stomach pH to acetaldehyde which is subsequently oxidized to acetic acid
* The metabolic fate after absorption is largely unknown
– Rapid metabolism by CYP450 is suspected
47
What is the MOT of Metaldehyde toxicosis?
48
What are the clinical signs of Metaldehyde toxicosis?
49
How do you Dx Metaldehyde toxicosis?
50
How do you treat Metaldehyde toxicosis?
51
List the ways in which you would provide symptomatic and supportive Tx for Metaldehyde toxicosis?
52
What are the DDx of Metaldehyde toxicosis?
* Organophosphates/carbamates
* Pyrethrins/pyrethroids
* Sodium fluoroacetate
* Strychnine
* Zinc phosphide
* Xylitol
* Salt (sodium ion toxicosis)
* Tremorgenic mycotoxins
* Chocolate
* Bromethalin
53
List the sources of Fluoroacetate
– Plants (Dichapentalum, Acacia) in Australia,
Brazil, South Africa. Not found in US/Canada
– Pesticide used for control of rodents, coyotes,
wolves, and ground squirrel
– Current use restricted to livestock protection
collars for sheep and goats in some states (MT,
NM, SD, TX, WY)
– The anticancer drug fluorouracil is metabolized
to fluoroacetate
54
1080 refers to the catalog number of the poison which became its brand name.
Occurs naturally in plants
Use discontinued in 1990. Still in use as a widely available rodenticide in
some Latin American and other countries of the world.
USEPA strictly limits the use of FA to livestock protection collars for sheep
and goats in some states (Montana, New Mexico, south dakota, texas,
wyoming).
Chemotherapeutic anticancer agent
Main exposure is thru pesticides
55
Describe how Fluoroacetate spreads between species in the environment
56
Describe the ADME of Fluoroacetate toxicosis?
* Readily absorbed from ___ and ______
tracts, as well as _________ _____
* Undergoes hydrolysis to ______ --> enters a series of reactions leading to inhibition of ___ cycle
* Eliminated in _____, does not _________
* Readily absorbed from GI and respiratory
tracts, as well as abraded skin
* Undergoes hydrolysis to monofluoroacetic
acid (MFAA)
* MFAA enters a series of reactions leading to
inhibition of TCA cycle
* Eliminated in urine, does not accumulate
57
What is the MOA of Fluoroacetate toxicosis?
58
What are the Consequences of Aconitase Inhibition?
59
Which species are susceptible to Fluoroacetate toxicosis?
All, mainly carnivores.
60
What are the clinical signs of Fluoroacetate toxicosis in dogs?
CNS excitation and GI hyperactivity
– Anxiety, frenzied behavior (e.g., **running fits**, howling), seizures, hyperesthesia, tonic and clonic convulsions, hyperthermia
– Anoxia --> respiratory failure
– Salivation, vomiting, urination, tenesmus,
defecation
– Weakness, coma and death
61
What are the clinical signs of Fluoroacetate toxicosis in Cats?
CNS and cardiac signs
– Excitation or depression, vocalization,
hyperesthesia, cardiac arrhythmiasS
62
What are the clinical signs of Fluoroacetate toxicosis in horses?
Hyperesthesia and cardiac signs
63
What are the clinical signs of Fluoroacetate toxicosis in ruminants?
Lethargy, salivation,
tachycardia, tachypnea, dyspnea,
staggering, trembling, collapse, teeth
grinding, seizures, coma, death
64
What are the clinical signs of Fluoroacetate toxicosis in swine?
cardiac and nervous signs +
vomiting
65
How do you Dx Fluoroacetate toxicosis?
* History of exposure and clinical signs
* Chemical analysis in stomach contents, vomitus,
liver, kidney, and suspected bait
66
How do you treat Fluoroacetate toxicosis?
* Tx is difficult due to rapid onset of toxicosis
– Often animals die before getting veterinary attention
* Decontamination with activated charcoal and
cathartic
*See image for further details
67
List some examples of Organochlorines that are banned in the US and canada.
DDT, Aryl hydrocarbons, Cyclodiene
Limited use of lindane & methoxyclor
68
In 2006 the World Health Organisation (WHO) approved ____ for use indoors to fight malari
DDT
69
Why are Organochlorines banned in the US and Canada?
They persist in the environment, bioaccumulate in
food chains and are carcinogenic
70
Which species are susceptible to Organochlorine toxicosis?
All animals can be exposed to old stores of these pesticides. Cats are very sensitive
71
Describe the ADME of Organochlorines.
highly _____ soluble, absorbed through ___ tract and ____, slowly metabolized in ____, excreted in ____ and _____.
highly lipid soluble, absorbed through GI tract and skin, slowly metabolized in liver, excreted in bile and urine
72
What is the MOT of a DDT-type Organochlorine?
– Slow down _____ of Na+ channel and inhibit ___ efflux in CNS and peripheral nerves
* Diminish the threshold for stimulation of nerves --> _________ firing
– Chronic exposure causes (3)?
This results in _______ intracellular K+ in the neuron, which partially ________ the cell. The threshold for action potential is ______ resulting in increased firing of the neuron.
– Slow down closing of Na+ channel and inhibit K+ efflux in CNS and peripheral nerves
* Diminish the threshold for stimulation of nerves --> increased firing
– Chronic exposure causes endocrine disruption, estrogenic effects and eggshell thinning in birds
This results in excess intracellular K+ in the neuron, which partially depolarizes the cell. The threshold for action potential is decreased resulting in increased firing of the neuron.
73
What is the MOT of a Cyclodienes (aldrin, chlordane, etc)?
Cyclodienes are GABA _________: _______ ______ of the binding of GABA to its receptor
– GABA antagonists: competitive inhibition of the binding of GABA to its receptor
74
What are the EARLY clinical signs of Organochlorine toxicosis?
* Agitation, tremors, hyperexcitability, nervousness, ataxia, aggressiveness
75
What are the ADVANCED clinical signs of Organochlorine toxicosis?
* Clonic-tonic seizures, opisthotonus, paddling, clamping of the jaws, hyperthermia, muscle fasciculations, abnormal posture, walking
backward, paresthesia, excessive licking and chewing, coma and death
76
What are some other clinical signs of Organochlorine toxicosis?
* Other signs: vomiting, weakness, resp. depression
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How do you Dx Organochlorine toxicosis?
* Clinical signs
* Detection of OC in blood, liver, brain, milk
fat or adipose tissue
78
How do you treat Organochlorine toxicosis?
* No antidote. Perform decontamination:
– GI exposure: Emesis for recent exposure (if signs are not present); gastric lavage if signs are present. Then give multiple-doses of activated charcoal and a cathartic.
* Decontamination-Dermal exposure
– Wash patient with warm soapy water. Clip hair of long-haired animals
* Wear PPE (rubber gloves and apron) when bathing patient to avoid self-exposure
* Symptomatic and supportive therapy
– Lightly sedate animal (barbiturate) or give muscle relaxant (methocarbamol) for convulsions
– Maintain airway patency and give supplemental oxygen
79
Which species are susceptible to Sodium Ion Toxicosis?
all but most
commonly swine, cattle and poultry
80
List the DIRECT sources of Sodium Ion Toxicosis.
– Direct Na+ toxicity: excess salt intake in water or feed, high salt milk substitutes, whey, inappropriate use of Na+-containing IV fluids
81
List the INDIRECT sources of Sodium Ion Toxicosis.
water deprivation (especially
in swine and poultry)
INDIRECT: Due to frozen water sources, unpalatable water, mechanical
failure, naïve animal, overcrowding or neglect
82
What is the most common type of sodium toxicosis?
Indirect toxicity
83
How long until the onset of clinical signs in a case of DIRECT Na+ toxicity?
Acute, signs in 24-48 hrs
84
How long until the onset of clinical signs in a case of INDIRECT Na+ toxicity?
Chronic, 4-7 days
85
When does hypernatremia occur?
– Na+ content of ECF __________ relative to the free water content
– Free water in ECF is ____ without compensatory ________ in Na+ concentration
* Restricted water intake
* Third spacing (accumulation of water in transcellular space (body cavities: pleural and peritoneal), joints, and GI tract
1st space = intravascular
2nd space = interstitial and intracellular
– Na+ content of ECF increases relative to the free water content
– Free water in ECF is lost without compensatory decrease in Na+ concentration
* Restricted water intake
* Third spacing (accumulation of water in transcellular space (body cavities: pleural and peritoneal), joints, and GI tract
1st space = intravascular
2nd space = interstitial and intracellular
86
What is the third space?
The third space is space in the body where fluid does not normally collect in larger amounts, or where any significant fluid collection is physiologically nonfunctional. Major third spaces include the peritoneal cavity and pleural cavity
87
What is the MOT of sodium toxicosis?
* GI mucosal irritation anorexia, vomiting, diarrhea, dehydration, electrolyte imbalance
* Na+ is rapidly absorbed from the GI tract and distributed throughout the body
– Plasma [Na+] increases above normal (>135- 155mEq/l) Na+ passively diffuses into CSF
but requires active transport to be removed.
See photo for more info
88
What is the basic tenet of fluid shifts?
The basic tenet of fluid shifts in the body is that water always follows sodium. Water diffuses across cell membranes from areas of low solute concentration to areas of high solute concentration. The purpose of this is to equalize osmolality across various body fluid compartments. Sodium is the major solute in the body that is water soluble and therefore has the greatest effect on water movement. The force that drives water movement across cell membranes (or between body compartments) is higher solute concentration on one side or in
one compartment relative to the other. When a solute like sodium is at
different concentrations in different body compartments it exerts a force
known as osmotic pressure that draws water to the compartment with higher sodium concentration. Therefore, because sodium concentration in the CSF is
higher than that in ECF during sodium ion toxicosis, water flows from the ECF into the CSF.
89
In summary, when there is high sodium intake or low water intake, the
concentration of sodium in the ECF increases. This results in the passive entry of sodium (down the concentration gradient) into the CSF/brain, but the removal of sodium from CSF requires active transport, that is, it requires energy in the form of ATP. The problem is that the high sodium concentration inhibits aerobic glycolysis which is the main mechanism of ATP synthesis in
the brain. Therefore, without sufficient ATP sodium cannot be removed and it accumulates in the brain where it can cause dehydration and rupture of blood vessels resulting in hemorrhage. This however is not the main problem. The main problem arises if this sodium accumulation is followed by rapid re-hydration which together with the loss of sodium in urine reduces the ECF sodium concentration to normal or below normal. When the sodium
concentration is lower in the ECF than in the CSF, the high sodium in the CSF
exerts osmotic pressure that draws water from the ECF resulting in cerebral edema and the clinical signs of sodium ion toxicosis.
90
What are the clinical signs of sodium toxicity in swine?
* Occur after 1-5 days of water deprivation
* Restlessness, thirst, colic, vomiting,
diarrhea, anorexia, pruritus, constipation,
polyuria, anuria
* Aimless wondering, circling, head pressing,
head jerking, pivoting around one foot
* Blindness, deafness and non-responsiveness,
tremors, dog-sitting, lateral recumbency
with paddling, clonic-tonic seizures,
opisthotonus and death
91
What are the clinical signs of sodium toxicity in cattle?
* Aggressiveness, sucking in air with water --> bloat
* Incoordination, bellowing, fasciculation of facial muscles, ear twitching, sticking the tongue out
* Fence walking and aimless wondering, blindness, convulsive seizures, partial paralysis, knuckling at
the fetlocks
* Salivation, increased thirst, vomiting, diarrhea, abdominal pain, constipation and dehydration
92
What are the clinical signs of sodium toxicity in poultry?
* Sudden death. Thirst, dyspnea, fluid discharge from beaks, ascites, wet droppings, weakness, paralysis of the legs, depression
93
What are the clinical signs of sodium toxicity in dogs?
* Poisoning is rare and usually not life threatening: GI tract signs (vomiting and diarrhea)
* In severe poisoning: polyuria, polydipsia, muscle tremors and seizures, depression, coma
94
How do you Dx Sodium toxicosis?
* History
* Clinical signs
* Measurement of serum and CSF/brain Na+
levels
* Assessment of hydration/dehydration
status, e.g., PCV, urine specific gravity
95
How do you treat sodium toxicosis?
* Hypertonic saline is recommended to reduce incidence of iatrogenic cerebral edema
– Na+ levels of parenteral and oral fluids should closely match serum Na+ levels
* Na+ levels in fluids should be gradually decreased as clinical signs subside
* Give furosemide (loop diuretic) to augment NaCl elimination
* Relieve cerebral edema and brain swelling
– Mannitol
– Glycerin (orally diluted 50/50 with water)
– Dexamethasone
– Dimethyl sulfoxide
* Administer diazepam for seizures
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