Lecture 21 Cardiovascular Toxicology-II Flashcards
- What plant is pictured below?
- What does this plant do?
- Where can this be sourced from?
- Where is the toxin concentrated/located in the plant?
- Gossypol (Bi-naphthyl-aldehyde)
- Makes the cotton plant more insect-resistant
- cotton plants (Gossypium spp.); Cotton seed, cottonseed meal, cottonseed cake
- Toxin is concentrated in glands within the seeds
What plant is pictured below?
Gossypol (Bi-naphthyl-aldehyde)
Cottonseed is widely used in what industry?
Livestock Feed Industry
Cottonseed is high in what?
How much does it cost to use?
What is cottonseed deficient in?
- High protein (26-40%)
- High fiber (17-20%)
- High fat (23%)
- High energy content (91% total digestible
nutrients [TDN]) - Economical
- BUT it is deficient in essential amino acids
(lysine & tryptophan), vitamins (A & D)
and minerals (calcium)
What species are susceptible to Gossypol (Bi-naphthyl-aldehyde)?
- Monogastrics (but horses are relatively
resistant) - Ruminants are resistant (young cattle are not)
* Gossypol binds to soluble protein components in rumen liquor –> reduced toxicity - Sheep and poultry are of intermediate
sensitivity - Maximum gossypol allowed in swine and
poultry feed is 100 ppm –> Gossypol regulation in feed followed massive deaths of swine and poultry in 1900s
What is the ADME of Gossypol (Bi-naphthyl-aldehyde)?
◦ Gossypol occurs in _____ and _____ forms
◦ The _____ form is more bioavailable and toxic
◦ Exposure is always ____
◦ Gossypol accumulates in ? but not in ____
◦ Gossypol occurs in free and bound forms
◦ The free form is more bioavailable and toxic
◦ Exposure is always oral
◦ Gossypol accumulates in plasma, heart, liver,
muscle and testis but not in milk
What is the MOT of Gossypol (Bi-naphthyl-aldehyde)?
______ myocardial _______
- Destroys cardiac muscle and interferes with ________ by affecting ___ movement
Has anti-________ effects in males (Damages ________ epith., decreased sperm _______) and females (Suppresses ______ and _________)
Chelates _____ and causes lysis of RBCs –> ____
Binds ______ _____ in GI tract making them
unavailable for absorption
Inhibits ________ synthesis
Induces nutritional deficiencies:?
Focal myocardial necrosis
- Destroys cardiac muscle and interferes with conduction by affecting K+ movement
Has anti-fertility effects in males (Damages spermatogenic epith., sperm motility) and females (Suppresses estradiol and progesterone)
Chelates iron and causes lysis of RBCs anemia
Binds amino acids in GI tract making them
unavailable for absorption
Inhibits protein synthesis
Induces nutritional deficiencies: vit. A & E, Ca, and amino acids
What are the clinical signs of Gossypol (Bi-naphthyl-aldehyde) toxicosis?
May present as ________ death or ______ _______ breathing (‘_______’ in pig) unresponsive to _________ therapy
Gradual heart ______ (edema, _____ vein
distension, congestion)
Anorexia, weakness, rough hair-coat/poor-doer
and death
Cattle may display decreased heat tolerance and hemoglobinuria
Reproductive problems: decreased male & female fertility
May present as sudden death or chronic labored breathing (‘thumping’ in pig) unresponsive to antibiotic therapy
Gradual heart failure (edema, jugular vein
distension, congestion)
Anorexia, weakness, rough hair-coat/poor-doer
and death
Cattle may display decreased heat tolerance and hemoglobinuria
Reproductive problems: decreased male & female fertility
Sudden death in Gossypol toxicosis is misdiagnosed in what species?
Mis-Dx in lambs: over-eating
Chronic labored breathing in Gossypol toxicosis is misdiagnosed as what?
Mis-Dx: pneumonia
How do you Dx Gossypol (Bi-naphthyl-aldehyde) toxicosis?
History of extended feeding of _________ meal
or ___________ products
Clinical signs, especially _____ death or chronic _____
Lack of response to _________ therapy
Postmortem lesions: signs of _________
are the most important
Analytical detection of significant concentrations of ____ gossypol in feed
◦ Must be correlated with history, clinical signs, and PM findings
History of extended feeding of cottonseed meal
or cottonseed products
Clinical signs, especially sudden death or chronic
dyspnea
Lack of response to antibiotic therapy
Postmortem lesions: signs of cardiomyopathy
are the most important
Analytical detection of significant
concentrations of free gossypol in feed
◦ Must be correlated with history, clinical signs, and PM findings
How do you Tx Gossypol (Bi-naphthyl-aldehyde) toxicosis?
There is no effective Tx
Remove source (withdraw cottonseed
products from diet)
Activated charcoal and saline cathartics are
of little value
◦ Gossypol toxicosis entails chronic exposure and is cumulative in nature
Treat heart failure and pulmonary edema
Give nutritional supplements (vitamin A, Fe,
lysine and protein)
All toads produce _______, but venom potency
varies with ________ and __________ _________.
venom, species, geographic, locations
The most toxic toads in North America are?
◦ Rhinella marina formerly Bufo marinus (cane or
marine toad)
◦ Bufo alvarius (Colorado River toad)
Toxic toads are primarily found in ?
FL, TX, CO, AZ, HI
Which species are susceptible to toxic toads?
Dogs and sometimes cats and ferrets
Avoid “toad-licking” and “smoking toad”!
Sacrament for Church of the Toad of Light
What are the toxic principles of Toxic toad toxicosis?
Christine Sucks Balls In Bed
Bufadienolides (bufagenins and bufotoxins)
◦ Structurally similar to cardiac glycosides
Bufotenine
Catecholamines (dopamine, epinephrine,
norepinephrine)
Serotonin
Indolealkylamines
Toxicity of toxic toads is variable, based on?
Variable depending on size of toad and dog
◦ Severe toxicoses result when small dogs
encounter large toads (larger parotid glands
= more secretions = more toxins)
◦ 1mg secretion per kg bw results in clinical
signs of intoxication
Describe the ADME of toxic toad toxicosis.
Exposure is usually in the summer and during
periods of high humidity
Toxins are produced and stored in the parotid
glands which are along the neck and
parascapular region of the toad
When mouthed/bitten by a dog/cat, toads
release toxins in a thick milky-white substance
via pores on the parotid glands
The toxins are rapidly absorbed via the buccal
mucous membranes. They can be absorbed via
GI tract mucosa, broken skin and conjunctiva
Elimination is via urine
What are the main exposure periods of toxic toads?
Main exposure periods
* Summer
* Late summer/fall
* Periods of high humidity
What is the MOT of toxic toad toxicosis?
Bufadienolides are ________ ________-like
substances that inhibit ____/____/______
◦ Also affect voltage-gated ____, _____, and _____ channels → disruption of excitable cells
Bufotoxins cause ___________
Bufotenine has systemic ______ activity and
is a __________
Indolealkylamines are ______________
Catecholamines are ____________
__________ and ___________ act
synergistically to produce greater cardio-
respiratory effects
Bufadienolides are cardiac glycosides-like
substances that inhibit Na+,K+-ATPase
◦ Also affect voltage-gated Na+, K+, and Ca2+
channels → disruption of excitable cells
Bufotoxins cause vasoconstriction
Bufotenine has systemic pressor activity and
is a hallucinogen
Indolealkylamines are hallucinogenic
Catecholamines are arrhythmogenic
Catecholamines and bufadienolides act
synergistically to produce greater cardio-
respiratory effects
What are the clinical signs of toxic toad toxicosis?
Rapid onset, death can occur in 15 min
Brick-red buccal cavity mucous membranes,
hypersalivation, vomiting, vocalization, pawing
at the mouth, and foaming at the mouth
Anxiety, disorientation, ataxia, falling, blank
stare, mydriasis, nystagmus, hyperactivity,
hyperesthesia, opisthotonus, convulsions/
seizures, recumbency, coma
Tachypnea, hyperthermia, acidosis (metabolic
and/or respiratory) and hyperkalemia
Cardiac glycoside-like effects
◦ Arrhythmias (bradycardia, sinus tachycardia,
atrioventricular block, supraventricular and
ventricular tachycardia, ventricular fibrillation)
◦ Sudden death
How do you Dx toxic toad toxicosis?
History of witnessed exposure and clinical
signs
What is the DDx of toxic toad toxicosis?
Toxicosis with acute onset of clinical signs
◦ Metaldehyde, methylxanthines, oleander,
foxglove, insoluble oxalate-containing plants,
pyrethrins/pyrethroids, anticholinesterase
insecticides
Ingestion of acids and alkalis
Heat stroke, trauma
Antidepressants, sympathomimetics, -
blockers and -agonists
How do you treat toxic toad toxicosis? - Decontamination
- _______ mouth with copious amounts of water
Flush ________ to avoid ingestion of the water. Repeat 2-3 times, 5-10 min at a time
Advise owners to perform this procedure at home _______ seeking veterinary care
If severe signs are present, oral _____ is done by a veterinarian after ________, ______, and insertion of a ______ endotracheal tube
? are advised
- Flush mouth with copious amounts of water
Flush rostrally to avoid ingestion of the water. Repeat 2-3 times, 5-10 min at a time
Advise owners to perform this procedure at home
before seeking veterinary care
If severe signs are present, oral lavage is done by a veterinarian after stabilization, anesthesia, and insertion of a cuffed endotracheal tube
Activated charcoal and a cathartic are advised
How do you treat toxic toad toxicosis? - Symptomatic and supportive therapy
◦ Administer ___________ for tachycardia and
monitor ECG
◦ Use _______ doses for patients with pre-existing heart disease
◦ _________ may be used for unresponsive
tachyarrhythmia. ________ or _______ ________can also be used
◦ Give ________ only to patients with marked
bradycardia. _______ can be considered
◦ Atropine is contraindicated for ________: may worsen ________ & decrease _______ of toxins
◦ Administer propranolol for tachycardia and
monitor ECG
◦ Use lower doses for patients with pre-existing heart disease
◦ Lidocaine may be used for unresponsive
tachyarrhythmia. Phenytoin or procainamide
hydrochloride can also be used
◦ Give atropine only to patients with marked
bradycardia. Dopamine can be considered
◦ Atropine is contraindicated for hypersalivation: may worsen tachycardia & decrease dilution of toxins
What drugs can be used to treat toxic toad toxicosis?
Give __________ or a __________ for seizures, tremors and agitation
Provide supplemental ________ for compromised respiration
Treat hyperkalemia with ______, _______ and
_______ _________
Correct metabolic acidosis with balanced
________ IV fluids or _______ ______ if blood pH <7.1
Correct respiratory acidosis with _______ pressure ventilation
Treat hyperthermia: IV fluids, tepid water
baths, alcohol placement on foot pads
________ (antidote) may be of value but has
not been clinically tested for toad toxicosis
IV lipid emulsion may be beneficial in
reducing _______ of the more _______
constituents of the toad secretion, e.g., the
bufadienolides
What drugs can be used to treat toxic toad toxicosis?
Give diazepam or a barbiturate for seizures,
tremors and agitation
Provide supplemental oxygen for compromised
respiration
Treat hyperkalemia with insulin, glucose and
sodium bicarbonate
Correct metabolic acidosis with balanced
crystalloid IV fluids or sodium bicarbonate if
blood pH <7.1
Correct respiratory acidosis with positive
pressure ventilation
Treat hyperthermia: IV fluids, tepid water
baths, alcohol placement on foot pads
Digibind (antidote) may be of value but has
not been clinically tested for toad toxicosis
IV lipid emulsion maybe beneficial in
reducing toxicity of the more lipophilic
constituents of the toad secretion, e.g., the
bufadienolides
List the sources of Ergot Alkaloids
(Ergot, ergotism, ergot poisoning)
Sources: ergot alkaloids produced by the
fungus Claviceps purpurea that invades grasses (rye,
oats, barley, canary, brome, triticale, etc.). The
alkaloids include:
◦ Ergopeptine alkaloids, e.g., ergotamine,
ergovaline, ergosine, ergocristine, ergocornine
◦ Ergoline alkaloids, e.g., lysergic acid, ergonovine,
lysergol
What species are susceptible to Ergot Alkaloids
(Ergot, ergotism, ergot poisoning)?
cattle, sheep, swine, horses
List the Examples of Grasses Associated With Ergotism.
- Barley
- Rye
- Brome
- Triticale
Identify the plants below.
Toxins in Ergot Alkaloids are concentrated in what part of the plant?
Toxins are Contained in Sclerotia/Ergot Bodies
Label the image below.
What is the ADME of Ergot Alkaloid?
_____ well-known
Metabolism of ergot alkaloids is assumed to
take place in the ______
Ergopeptine alkaloids are excreted via ____
and ergoline alkaloids via ____
Residues have not been detected in _____ or
_____
Not well-known
Metabolism of ergot alkaloids is assumed to
take place in the liver
Ergopeptine alkaloids are excreted via bile
and ergoline alkaloids via urine
Residues have not been detected in meat or
milk
What is the MOT of Ergot Alkalioid?
Ergot alkaloids interact with biogenic amines
(3?):
◦ Inhibition of D1 dopamine vasodilatory receptors, agonism of ___-adrenergic and serotonin receptors: –> ________ –> ischemia and _______ formation
◦ Stimulation of D2 dopamine receptors in anterior pituitary –> decreased ________ secretion
Ergot alkaloids interact with biogenic amines
(norepinephrine, serotonin and dopamine):
◦ Inhibition of D1 dopamine vasodilatory receptors, agonism of a1-adrenergic and serotonin receptors: –? vasoconstriction –> ischemia and gangrene formation
◦ Stimulation of D2 dopamine receptors in anterior pituitary –> decreased prolactin secretion
What are the clinical signs of Ergot Alkaloid toxicosis?
Attributable to _________ and decreased _________
1. Gangrenous/cutaneous ergotism
◦ Lameness, swelling and sloughing of feet below the fetlocks. The ears and tail may also slough off
Hyperthermia
2. Reproductive syndrome
◦ Agalactia, prolonged gestation, dystocia, abortions
3. Nervous syndrome (?): was thought to be more
common in carnivores, horses and sheep
◦ Possibly caused by tremorgenic mycotoxins
Attributable to vasoconstriction and decreased prolactin
Gangrenous/cutaneous ergotism
◦ Lameness, swelling and sloughing of feet below the fetlocks. The ears and tail may also slough off
Hyperthermia
Reproductive syndrome
◦ Agalactia, prolonged gestation, dystocia, abortions
Nervous syndrome (?): was thought to be more
common in carnivores, horses and sheep
◦ Possibly caused by tremorgenic mycotoxins
Gangrenous ergotism
How do you Dx Ergot Alkaloid toxicosis?
Detection of ______ _______ _______ in plant tissues and feeds
Determine ergot alkaloids concentrations in
____/____/________ feeds
Analysis of animal ______ for ergot alkaloids
may be of value
Clinical signs
Detection of C. purpurea sclerotia in plant
tissues and feeds
Determine ergot alkaloids concentrations in
forage/hay/processed feeds
Analysis of animal tissues for ergot alkaloids
may be of value
Clinical signs
How do you treat Ergot Alkaloid toxicosis?
______ recognition is key to successful
treatment
Remove animals from ______ of ergot
alkaloids
Move animals to a ____, ______ environment
Treat secondary _______ infections
May institute treatment similar to that for
______ toxicosis (next) for severe poisoning
Early recognition is key to successful
treatment
Remove animals from sources of ergot
alkaloids
Move animals to a dry, warm environment
Treat 2o bacterial infections
May institute treatment similar to that for
fescue toxicosis (next) for severe poisoning
List the sources of Fescue.
Fescue Toxicosis
(Festuca arundinacea - Tall Fescue)
Sources: Fescue, a major forage grass,
grown on ~35 million acres in the USA
Tall fescue
Fescue toxicosis
Fescue toxicosis costs US livestock industry $1 billion a year
What are the toxic principles of Fescue toxicosis?
Toxic principles: ergot alkaloids
(Ergoline and ergopeptine) produced by the
endophytic fungus, Neotyphodium coenophialum
_______ accounts for 90% of the alkaloid content
Ergovaline
Fescue
Corkscrew growth pattern along cells
Fescue
Neotyphodium coenophialum
Corkscrew growth pattern along cells
Mutualism
Fungus generates toxins that make the fescue
resistant to drought, insects, nematodes, fungi
and herbivores; fescue provides comforting
internal environment and nutrients to fungus
What is the MOT of Ergot Alkaloid toxicosis?
Interaction With Biogenic Amines
Interaction With Biogenic Amines
D1 dopamine receptor ______ and ________ of alpha1-adrenergic and serotonergic receptors. Overall effects are:
1. ___________
Impaired thermoregulation
Impaired circulation to placenta, extremities,
and abdominal and pelvic fat
2. ________ contraction (a1-adrenergic effect)
3. _______ feed intake
D1 dopamine receptor inhibition and
agonism of 1-adrenergic and serotonergic
receptors. Overall effects are:
◦ Vasoconstriction
Impaired thermoregulation
Impaired circulation to placenta, extremities,
and abdominal and pelvic fat
◦ Uterine contraction (1-adrenergic effect)
◦ Decreased feed intake
What is the MOT of Ergot Alkaloid toxicosis?
Stimulation of D2-dopamine receptors
◦ Decreased prolactin secretion in pituitary –>
impaired lactogenesis –> agalactia
◦ Impaired steroidogenesis (low progesterone and
high estradiol) –> reproductive problems
◦ Decreased feed intake and inability to shed
winter hair coat
◦ Impaired metabolism of lipids and carbohydrates
◦ Dysregulation of thermoregulatory center –>
hypothermia or hyperthermia
What are the clinical signs of Ergot Alkaloid toxicosis?
3? are the most sensitive species (____>____>___)
Four syndromes have been described: ?
Horses, cattle and sheep are the most
sensitive species (horse>cattle>sheep)
Four syndromes have been described:
◦ Fescue foot
◦ Summer slump
◦ Fat necrosis
◦ Reproductive and lactation problems
What is fescue foot?
Occurs in cattle in late ___ or ____ (_______ conditions)
Characterized by progressive ________
Initially: swelling and reddening of ______ _______, knuckling of pastern joints, arching of the
back and weight shifting among the limbs
_______ necrosis above the hoof and in other
extremities (e.g., ears and tail)
_____ limbs are more commonly affected
Occurs in cattle in late fall or winter
(hypothermic conditions)
Characterized by progressive lameness
Initially: swelling and reddening of coronary
band, knuckling of pastern joints, arching of the
back and weight shifting among the limbs
Ischemic necrosis above the hoof and in other
extremities (e.g., ears and tail)
Hind limbs are more commonly affected
Fescue foot, hoof loss
What is summer slump?
Typical complaint: Cattle ______
Most _______ and _______ significant
syndrome in cattle & sheep characterized by:
◦ Reduced _____ intake, _____ and ____ production
◦ Reduced _________ and _______- rates
◦ Impaired __________ ability with heat
intolerance, hyperthermia and tachypnea
Results in behavioral changes: cattle spend more time under _____ or at ______ holes/ponds
◦ ______ hair coat, lethargy, and diarrhea
Typical complaint: Cattle “ain’t doing right”
(ADR)
Most common and economically significant
syndrome in cattle & sheep characterized by:
◦ Reduced feed intake, growth and milk production
◦ Reduced conception and calving rates
◦ Impaired thermoregulatory ability with heat
intolerance, hyperthermia and tachypnea
Results in behavioral changes: cattle spend more time
under shades or at watering holes/ponds
◦ Rough hair coat, lethargy, and diarrhea
What is fat necrosis (lipmatosis)?
Observed in a variety of ruminants esp. ______ cattle following ______ exposure to the toxins
Associated with the presence of ____ _____
fat in abdominal and pelvic cavities
◦ Fat masses are palpable trans-______ but are
normally seen at ________
Result in _____ and _______ signs due to obstruction and/or constriction e.g.,
◦ Dystocia, bloat, nephrosis and uremia
Observed in a variety of ruminants esp. mature
cattle following prolonged exposure to the
toxins
Associated with the presence of hard necrotic
fat in abdominal and pelvic cavities
◦ Fat masses are palpable trans-rectally but are
normally seen at postmortem
Result in digestive and genitourinary signs due to
obstruction and/or constriction e.g.,
◦ Dystocia, bloat, nephrosis and uremia
Fat necrosis
What is reproductive lactation syndrome?
Occurs in ?
The primary problems are ?
Horses: ______ conception rate,
________ gestation with increased fetal ____, minimal signs of impeding ______, ___-bag presentation, dystocia, weak foals, edema of fetal membranes, and retained placenta
decreased Prolactin, decreased progesterone and decreased estradiol
minimal signs of impeding parturition: foal preceded by chorioallantois
red-bag presentation: foal preceded by chorioallantois
Occurs in cattle, sheep and horses
The primary problems are abortion,
stillbirth and agalactia
Horses: decreased conception rate,
prolonged gestation with increased fetal
size, minimal signs of impeding parturition,
red-bag presentation, dystocia, weak foals,
edema of fetal membranes, and retained
placenta
decreased Prolactin, decreased progesterone and decreased estradiol
minimal signs of impeding parturition: foal preceded by chorioallantois
red-bag presentation: foal preceded by chorioallantois
How do you Dx reproductive lactation syndrome?
Detection of ____ _________ in plant tissues
and seed
Clinical signs
Determine concentrations of _______ in
forage/hay
Analysis of ergot alkaloids in animal _______
Detection of N. coenophialum in plant tissues
and seed
Clinical signs
Determine concentrations of ergovaline in
forage/hay
Analysis of ergot alkaloids in animal tissues
How do you treat reproductive lactation syndrome?
D___ receptor ______ (__________), a___-
adrenergic ________ (_______), and a__-_____ and ________ receptor blocker (______) have beneficial effects but:
◦ Not approved for food animals: side effects, drug residue concerns and require individual
administration
For agalactia and prolonged gestation in mares:
________ (Equidone), ______, _____, ______ or ________ can be used
These antagonize D2 receptor or deplete dopamine (reserpine)
Early detection is key to successful Tx
◦ Rule out foot rot, frost bite and injuries
Remove animals from infected fescue
◦ This may be impractical because of lack of
alternative forages and sources of hay
D2 receptor antagonist (metoclopramide), 1-
adrenergic antagonist (prazosin), and 1-
adrenergic and serotonin receptor blocker
(phenoxybenzamine) have beneficial effects but:
◦ Not approved for food animals: side effects, drug residue concerns and require individual
administration
For agalactia and prolonged gestation in mares:
domperidone (Equidone), perphenazine,
sulpiride, acepromazine or reserpine can be used
These antagonize D2 receptor or deplete dopamine (reserpine)
Ergotism vs. Fescue Toxicosis
Different fungi
◦ C. purpurea vs. N. coenophialum
◦ Parasitism vs. mutualism
Ergotism is most prevalent in late summer
when the seed heads of grasses mature
Fescue toxicosis is most common in late fall
and winter
