Cardiovascular and Hematopoietic Toxicity

Question 1

Anticoagulants and anticoagulant rodenticide

Answer 1

Widely used by homeowners and professionals for rodent control
1st and 2nd generation compounds

Question 2

1st generation rodenticide compounds

Answer 2

• ex: warfarin
• Short half life (15 hours)
• Low potency, required multiple feedings (LD50 = 10-50 mg/kg)

Question 3

2nd generation rodenticide compounds

Answer 3

• ex: brodifacoum
• Long half life (20 days)
• High potency, kills in single feeding (LD50 = 0.25 mg/kg)

Question 4

MOA of anticoagulants/rodenticides

Answer 4

• Inhibits vitamin K1 epoxide reductase
• Prevents formation of Vit K dependent clotting factors (2, 7, 9, 10)

Question 5

Clinical signs of anticoagulant/rodenticides

Answer 5

• Delayed onset of clinical signs (3-5 days) as clotting factors present in plasma are consumed
• Initial signs are often depression, anorexia, and anemia
• Dyspnea, nosebleeds, bleeding gums, and bloody feces
• Hemorrhage (most commonly in chest/abdomen) and hematoma
• In clinical setting, prolonged bleeding from injection sites is usually noted

Question 6

Diagnosis of anticoagulant/rodenticides

Answer 6

• *1. history of exposure
  2. evidence of a coagulopathy
  3. response to vitamin K1 therapy**

Specific hematological tests:

• increased PT (first18-48 hours)
• increased APTT or PTT >25% longer than normal with normal platelet counts

Question 7

Treatment of anticoagulant/rodenticides

Answer 7

• If ingestion has occurred within the last few hours:
  
  • emetic, adsorbent and cathartic therapy
• Vitamin K administration
  
  • 0.25-2.5 mg/kg for exposure to short-acting rodenticides
  • 2.5-5 mg/kg for long-acting rodenticides
• Therapy should be continued for 10-14 days for warfarin to 30 days for second generation compounds
• May need transfusion in severe cases

Question 8

nitrate toxicosis

Answer 8

• Found in fertilizers, many plants, contamination of water
• susceptibility: pigs>cattle>sheep>horses

Question 9

MOA of nitrate toxicosis

Answer 9

• Nitrate converted to nitrite
• Nitrite anion causes vasodilation and oxidized ferrous iron in hemoglobin to the ferric state forming methemoglobin
• Results in oxygen starvation of tissues

Question 10

clinical signs of toxicosis

Answer 10

• Depends on levels of metHb
• <10% asymptomatic, may see changes in MM color
• 15% cyanosis, blood and MM appear brown
• 50% serious toxicity - ataxia, seizures, coma
• >70% death

Question 11

diagnosis of nitrate toxicosis

Answer 11

• Diagnosis by nitrate levels in feed or water
• In suspected nitrate death, save eye for analysis of nitrate

Question 12

treatment of nitrate toxicosis

Answer 12

• IV methylene blue in a 1-2% aqueous solution at a rate of 1-2 mg/kg body weight
  
  • most effective in ruminants
  • urine will become dark green
• Use ascorbic acid in cats and horses
• Educate farmers and ranchers regarding nitrate accumulation in weeds and forages intended for feeding/grazing
• Can feed cattle corn to increase rate of nitrate reduction by rumen flora

Question 13

cardiac glycosides

Answer 13

• contain glycosides
• mostly ornamental plants

Question 14

MOA of cardiac glycosides

Answer 14

Inhibit the Na/K ATPase pump through competition with K for binding sites

Question 15

Clinical signs of cardiac glycosides

Answer 15

• Can occur anywhere from 1 hour to weeks after ingestion, depending on plant species
• trembling, staggering and dyspnea often present in grazing animals
• increase in Ca and intracellular Na
• racing HR and rhythm/arrhythmia, weak pulse
• hyperkalemia (K can double)

Question 16

diagnosis of cardiac glycosides

Answer 16

Based on history, access to plants, and clinical signs as well as analysis of vomit

Question 17

treatment of cardiac glycosides

Answer 17

• GI decontamination
• Treat arrhythmias with propranolol
• treat hyperkalemia if needed (diuretics)
• Use digoxin immune Fab fragments if propranolol ineffective
• Antidote for digoxin and similar glycosides
• Bind directly to glycosides
• Complete resolution of clinical signs within 4 hours

Question 18

cyanide toxicity

Answer 18

• Usually a problem with consumption of wilted leaves and seeds of wild cherry, white clover, or fresh Sorghum spp.
• Also found in fertilizers, pesticides/rodenticides, fumigants, combustion
• Non-toxic when dry, as hydrogen cyanide is volatile

Question 19

MOA of cyanide

Answer 19

• Inhibition of cytochrome C oxidase
• Blocks mitochondrial function and cellular respiration

Question 20

clinical signs of cyanide

Answer 20

• Generally occur within 15-20 minutes to a few hours after animal consumes toxic forage
• Classic symptom is cherry red blood that is slow to clot
• May smell almonds in stomach contents
• Sudden death, dyspnea, weakness, tremors

Question 21

diagnosis of cyanide

Answer 21

• History of ingestion and unclotted red blood
• analysis of frozen stomach contents

Question 22

treatment of cyanide

Answer 22

1. induce methemoglobin formation with sodium nitrite to bind cyanide (cyanide likes ferric iron and preferentially binds to it)
2. Give sodium thiosulfate to increase formation of thiocyanate by rhodanese. Thiocyanate is non-toxic and eliminated
   - If necessary, treat metHb with methylene blue

Question 23

Methylxanthines

Answer 23

• Includes caffeine, theobromine, theophylline
• Found in chocolate, coffee, medications
• Most common around holidays associated with chocolate
• Unsweetened baking chocolate is especially toxic
  
  • ​as little as 0.2 oz/kg may kill a dog
• Other common problems are caffeine tablets and cocoa bean mulch for horses

Question 24

MOA of methylxanthines

Answer 24

• Competitive antagonist of adenosine receptors
  
  • ​causes CNS stimulation, vasoconstriction, and tachycardia
• Prevents Ca reuptake leading to increased skeletal and cardiac muscle contractility
• Inhibits phosphodiesterase
• Increases cAMP and GMP contractions

Question 25

clinical signs of methylxanthines

Answer 25

• Vomiting, diarrhea, diuresis
• Hyperactivity, “bounce”
• panting, tachycardia, hypertension, ataxia, tremors
• seizures, coma
• death from arrhythmias or respiratory failure

Question 26

diagnosis of methylxanthine overdose

Answer 26

• Chemical analysis of stomach contents, plasma, serum, urine, or liver
• Theobromine can be detected in serum for 3-4 days after ingestion (b/c of long half-life)

Question 27

treatment of methylxanthine overdose

Answer 27

• GI decontamination
  
  • induction of emesis
  • repeated administration (every 3 hours)
• Monitor EKG
  
  • Treat arrhythmias with lidocaine (not in cats)
  • if this fails use metoprolol
• Treat seizures with diazepam or barbiturates
• Maintain respiration
• Fluid diuresis may increase excretion

Question 28

gossypol

Answer 28

• found in pigment glands of cottonseed, provides insect resistance
• levels vary with preparation and type of cotton (inactivated with heating)
• high level of energy (fat), protein, and effective fiber
• lipophilic
• plasma gossypol increases with time

Question 29

MOA of gossypol

Answer 29

• chelates iron and causes anemia, reduces protein availability
• produces toxicity by inhibition of dehydrogenases leading to decreased energy and protein production
  
  • oxidative stress
• non-ruminants are more sensitive
  
  • ruminants tolerate higher levels than monogastrics, horses are resistant

Question 30

clinical signs of Gossypol toxicity

Answer 30

• Usually occurs with long term feeding, but can be acute onset
• At lower concentrations, produces weight loss, weakness, and dyspnea
• Moderate anemia may be present, edema secondary to heart failure
• Myocardial necrosis, CHF
• Dairy cows and lambs may die suddenly with minimal lesions

Question 31

diagnosis of Gossypol toxicity

Answer 31

• Diagnose by history of cottonseed ingestion
• Cardiac necrosis, edema, vacuolization
• Chemical analysis of gossypol

Question 32

treatment of Gossypol toxicity

Answer 32

• Feed high protein diet
• Add vitamin A, iron, and lysine
  
  • remove gossypol from the diet
• Symptomatic treatment

Question 33

Cantharidin

Answer 33

• toxin in the Blister Beetle
• eggs develop on grasshopper larvae, so beetle numbers are tied to grasshopper numbers
• Beetles found in alfalfa, esp. flowering alfalfa
  
  • crimped alfalfa typically the source
• May congregate in large groups, so difficult to inspect hay as large numbers in a single bale
• usually affects horses (6-250 can be lethal)

Question 34

MOA of Cantharidin

Answer 34

• Inhibits protein phosphatases
• mucosal irritant

Question 35

clinical signs of Cantharidin

Answer 35

• Colic, frequent urination, diaphragm contraction with heart beat, shock
• Causes severe irritation and ulceration of oral, GI, and bladder epithelia
• Causes cardiac toxicity

Question 36

diagnosis of Cantharidin

Answer 36

• Alfalfa hay consumption
• Beetles in hay or stomach
• Hypocalcemia, increased BUN
• Ulceration of MM
• Cardiac necrosis

Question 37

treatment of Cantharidin

Answer 37

• GI decontamination and protection (sucralfate)
• antibiotics