Lecture 21 Cardiovascular Toxicology-II

Question 1

1. What plant is pictured below?
2. What does this plant do?
3. Where can this be sourced from?
4. Where is the toxin concentrated/located in the plant?

Answer 1

1. Gossypol (Bi-naphthyl-aldehyde)
2. Makes the cotton plant more insect-resistant
3. cotton plants (Gossypium spp.); Cotton seed, cottonseed meal, cottonseed cake
4. Toxin is concentrated in glands within the seeds

Question 2

What plant is pictured below?

Answer 2

Gossypol (Bi-naphthyl-aldehyde)

Question 3

Cottonseed is widely used in what industry?

Answer 3

Livestock Feed Industry

Question 4

Cottonseed is high in what?
How much does it cost to use?
What is cottonseed deficient in?

Answer 4

• 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)

Question 5

What species are susceptible to Gossypol (Bi-naphthyl-aldehyde)?

Answer 5

• 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

Question 6

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 ____

Answer 6

◦ 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

Question 7

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:?

Answer 7

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

Question 8

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

Answer 8

 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

Question 9

Sudden death in Gossypol toxicosis is misdiagnosed in what species?

Answer 9

Mis-Dx in lambs: over-eating

Question 10

Chronic labored breathing in Gossypol toxicosis is misdiagnosed as what?

Answer 10

Mis-Dx: pneumonia

Question 11

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

Answer 11

 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

Question 12

How do you Tx Gossypol (Bi-naphthyl-aldehyde) toxicosis?

Answer 12

 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)

Question 13

All toads produce _______, but venom potency
varies with ________ and __________ _________.

Answer 13

venom, species, geographic, locations

Question 14

The most toxic toads in North America are?

Answer 14

◦ Rhinella marina formerly Bufo marinus (cane or
marine toad)
◦ Bufo alvarius (Colorado River toad)

Question 15

Toxic toads are primarily found in ?

Answer 15

FL, TX, CO, AZ, HI

Question 16

Which species are susceptible to toxic toads?

Answer 16

Dogs and sometimes cats and ferrets

Question 17

Answer 17

Avoid “toad-licking” and “smoking toad”!
Sacrament for Church of the Toad of Light

Question 18

What are the toxic principles of Toxic toad toxicosis?

Answer 18

Christine Sucks Balls In Bed

 Bufadienolides (bufagenins and bufotoxins)
◦ Structurally similar to cardiac glycosides
 Bufotenine
 Catecholamines (dopamine, epinephrine,
norepinephrine)
 Serotonin
 Indolealkylamines

Question 19

Toxicity of toxic toads is variable, based on?

Answer 19

 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

Question 20

Describe the ADME of toxic toad toxicosis.

Answer 20

 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

Question 21

What are the main exposure periods of toxic toads?

Answer 21

Main exposure periods
* Summer
* Late summer/fall
* Periods of high humidity

Question 22

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

Answer 22

 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

Question 23

What are the clinical signs of toxic toad toxicosis?

Answer 23

 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

Question 24

How do you Dx toxic toad toxicosis?

Answer 24

History of witnessed exposure and clinical
signs

Question 25

What is the DDx of toxic toad toxicosis?

Answer 25

 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

Question 26

How do you treat toxic toad toxicosis? - Decontamination 1. _______ 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

Answer 26

1. 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

Question 27

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

Answer 27

◦ 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

Question 28

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

Answer 28

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

Question 29

List the sources of Ergot Alkaloids (Ergot, ergotism, ergot poisoning)

Answer 29

 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

Question 30

What species are susceptible to Ergot Alkaloids (Ergot, ergotism, ergot poisoning)?

Answer 30

cattle, sheep, swine, horses

Question 31

List the Examples of Grasses Associated With Ergotism.

Answer 31

1. Barley 2. Rye 3. Brome 4. Triticale

Question 32

Identify the plants below.

Answer 32

Question 33

Toxins in Ergot Alkaloids are concentrated in what part of the plant?

Answer 33

Toxins are Contained in Sclerotia/Ergot Bodies

Question 34

Label the image below.

Answer 34

Question 35

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 _____

Answer 35

 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

Question 36

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

Answer 36

 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

Question 37

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

Answer 37

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

Question 38

Answer 38

Gangrenous ergotism

Question 39

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

Answer 39

 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

Question 40

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

Answer 40

 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

Question 41

List the sources of Fescue.

Answer 41

Fescue Toxicosis (Festuca arundinacea - Tall Fescue)  Sources: Fescue, a major forage grass, grown on ~35 million acres in the USA

Question 42

Answer 42

Tall fescue

Question 43

Answer 43

Fescue toxicosis Fescue toxicosis costs US livestock industry $1 billion a year

Question 44

What are the toxic principles of Fescue toxicosis?

Answer 44

Toxic principles: ergot alkaloids (Ergoline and ergopeptine) produced by the endophytic fungus, Neotyphodium coenophialum

Question 45

_______ accounts for 90% of the alkaloid content

Answer 45

Ergovaline

Question 46

Answer 46

Fescue Corkscrew growth pattern along cells

Question 47

Answer 47

Fescue Neotyphodium coenophialum Corkscrew growth pattern along cells

Question 48

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

Question 49

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

Answer 49

 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

Question 50

What is the MOT of Ergot Alkaloid toxicosis? Stimulation of D2-dopamine receptors

Answer 50

◦ 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

Question 51

What are the clinical signs of Ergot Alkaloid toxicosis?  3? are the most sensitive species (____>____>___)  Four syndromes have been described: ?

Answer 51

 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

Question 52

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

Answer 52

 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

Question 53

Answer 53

Fescue foot, hoof loss

Question 54

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

Answer 54

 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

Question 55

Answer 55

Question 56

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

Answer 56

 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

Question 57

Answer 57

Fat necrosis

Question 58

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

Answer 58

 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

Question 59

Answer 59

Question 60

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 _______

Answer 60

 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

Question 61

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)

Answer 61

 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)

Question 62

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