Respiratory Toxicants

Question 1

describe acute bovine pulmonary edema and emphysema (ABPE) sources (3)

Answer 1

sources:
1. herbicide: paraquat
2. feed: lush pastures, moldy sweet potato (peanut vine hay, soybeans)
3. toxic plant: perilla mint plant

Question 2

describe acute bovine pulmonary edema and emphysema (ABPE) mechanism

Answer 2

1. toxicant or metabolite targets type I alveolar endothelial cells
2. ROS and reactive intermediates are produced, which continue to damage type I alveolar endothelial cells via oxidative stress

*paraquat (from herbicide) has a 10x affinity for alveolar cells

-this compound undergoes rapid reduction/oxidation cycling, producing hydrogen peroxide, superoxide anions, and hydroxyl radicals, resulting in cell death ESPECIALLY in alveolar cells

Question 3

describe the metabolism of the sources of ABPE

Answer 3

lush pastures: rumen converts L-tryptophan to 3-methyindole which goes to the lung and produces reactive intermediates

perilla mint:
-perilla ketones formed in the body, goes to the lung and produces reactive intermediates

moldy sweet potato:
-fusarium spp. converted to 4-ipomeanol, goes to the lung and produced reactive intermediates

Question 4

describe the clinical syndrome of ABPE

Answer 4

paraquat: initial GI distress

all

1. acute respiratory distress: cyanosis, severe dyspnea, frothing
2. lesions:
   -pulmonary edema, emphysema, fibrosis
   -paraquat: necrosis of proximal tubule cells

Question 5

describe treatment of ABPE

Answer 5

1. no specific antidote!
2. remove source and supportive fluid diuresis
3. activated charcoal has limited success
4. clay-based adsorbents for paraquat (Novasil Plus)
   -effective, but not widely adopted, can be used as an additive for prevention

Question 6

describe cyanogenic glycoside plants

Answer 6

1. black cherry, choke cherry (prunus spp.)
2. hydrangeas
3. flowering quince (chaenomales spp.)
4. crabapple (malus spp.)
5. Johnson grass and other sorghum spp.
6. common vetch (vicia sativa)

major cyanogenic glycosides:
-amygdalin
-prunasin
-dhurrin
-linamarin

Question 7

describe conditions favoring intoxication of cyanogenic glycosides

Answer 7

1. cyanogenic glycosides are found in all parts of the plant
   -but highest in seeds and young growing plants
2. enzymes (B-glucosidase) in the plant convert the glycosides to hydrogen cyanide (HCN) during chewing or stress (frost)
3. the conversion can also occur in the rumen, so ruminants are the most susceptible species!
4. CN- is absorbed across the gut and rapidly distributes in the blood

Question 8

describe the MOA of cyanogenic glycosides

Answer 8

1. CN- forms stable complex with Fe3+ of cytochrome oxidase (complex 4 of the electron transport chain)
2. prevents conversion of Fe3+ to Fe2+
3. inhibits electron transport, cellular respiration
4. blood is oxygenated (cherry red) but O2 cannot but utilized by tissues!

Question 9

describe clinical syndrome of cyanogenic glycosides

Answer 9

1. death within a few minutes or within 20-120 minute (dose-dependent)
   -animals surviving beyond 120 minutes will usually recover (short kinetics)
2. initial clinical signs: salivation (frothing at the mouth) and rapid breathing
3. progression:
   -marked dyspnea, weakness, muscle fasciculation, urination, defecation
   -staggering, tachycardia, mydriasis
4. terminal:
   -lateral recumbency, convulsions, cyanosis
   -death from respiratory paralysis

Question 10

describe treatment for cyanogenic glycosides (3)

Answer 10

1. remove from source
2. goal (mostly small animals): forming a decoy receptor
   -hydroxycobalamin (vit B12a, give IV) forms cyancobalamin, which is excreted in the urine
3. goal (large and small animals): split the CN-Fe3+ bond and excrete CN

-amyl and/or sodium nitrite (inhalation, IV): forms methemoglobin, which can then bind CN to form cyanomethemoglobin, cytochrome oxidase is reactivated

-then give sodium thiosulfate: thiol reacts with CN from cyanomethemoglobin to form hydrogen thiocyanate, which is excreted in the urine

treatments for within the 120 minute window!

Question 11

describe the one health perspective of respiratory toxicants

Answer 11

1. pets and humans share indoor and outdoor environments
2. wildlife habitat overlaps increasingly with humans too
   -ex. 2025 LA wildfires: contaminated air mix of particulate matter, CO, NOx, Pb, chlorine, PAHs, etc. has short and long term effects on humans and animals
   -PM 2.5 is a particular concern (very small molecules, can get deep into the lungs and stay there for a long time)

Question 12

why is the respiratory tract a major target of toxicants? (4)

Answer 12

1. highly perfused area (lungs)
2. toxicants don’t have to get into the blood for exposure! direct contact with tissue via inhalation is enough in many cases!
3. the respiratory tract is large!! lots of area to target
4. the lung has some ability to bioactivate certain toxicants

Question 13

describe anticoagulant rodenticides history

Answer 13

history:
-used in the 1920s
-was observed that large animals that consumed moldy sweet clover hay and silage ended up with hemorrhagic syndrome thanks to consumption of coumarin

-a metabolite of coumarin, 4-hyroxycourmarin/Dicumarol, was isolated and has has anticoagulant activity and was used

-a synthetic analog of dicumarol was made in wisconsin (Warfarin) in the 1940s

Question 14

describe the generations of anticoagulant rodenticides

Answer 14

1st generation:
-1940s
-low potency: needed multiple doses to be effective, aversion developed, rapid excretion
-products: warfarin (t1/2: 14.5 hrs), dicoumarol, pindone

2nd generation:
-1970s
-higher potency: single dose, retained longer, relay toxicosis
-products: brodifacoum (t1/2:120d!!), bromidiolone, diphacinome

affects all mammals and birds, dogs and cats most commonly

Question 15

describe anticoagulant rodenticides MOA

Answer 15

1. vitamin K like
   -lipid soluble vitamin, required for activation of clotting factors but the toxicants ANTAGONIZE vitamin K!
2. vitamin K dependent clotting factors: 2, 7, 9, 10 (both intrinsic and extrinsic pathways)
   -no conversion of prothrombin to thrombin, no conversion of fibrinogen to fibrin

Question 16

describe the toxicokinetics of anticoagulant rodenticides

Answer 16

1. absorption:
   -slow but complete, 90%
   -peak plasma levels in 12 hours
2. distribution:
   -plasma, protein bound to albumin
   -crosses placenta
   -accumulate in liver
3. elimination:
   -cytoP450 oxidases
   -excreted in the urine
   –brodifacoum: bile, enterohepatic recycling

Question 17

describe toxicosis caused by anticoagulant rodenticides

Answer 17

1. delayed onset!!
   -clinical signs not evident until activated factors used up (2-3d)
2. death: cerebral, thoracic, and pericardial hemorrhage
   -2nd generation: more toxic, so even lower dose will cause death!
3. early signs:
   -subcutaneous hematomas, epistaxis, bleeding gums, dark tarry stools, bloody vomit
4. late signs:
   -dyspnea, pale MM, exercise intolerance
   -anorexia, weakness, ataxia
   -widespread spontaneous hemorrhage: swelling of joints, SUBMANDIBULAR EDEMA
5. common clinical signs at admission:
   -dyspnea
   -prolonged ACT
   -prolonged PT
   -prolonged PTT
   -anemia

Question 18

describe hematology of anticoagulant rodenticides

Answer 18

1. PT 2-6x longer; early indicator
   -factor VII, extrinsic pathway affected first
   -may be useful in aymptomatic animals
2. activated PTT: 2-4x longer
3. activated coagulation time: 2-10x longer
   -least sensitive, 3 days post ingestion when animal is already symptomatic
4. PIVKA (proteins induced in vitamin K absence/antagonism)
   -potentially more specific for anticoagulants
5. anemia, possibly thrombocytopenia

Question 19

describe treatment for anticoagulant rodenticide toxicosis

Answer 19

for known exposure, asymptomatic animal:
1. GI decontamination
2. PT time baseline
3. antidote!! vitamin K1!!
-oral form
-send home with oral form, give daily with food
-repeat PT in 2-3 days
-IV admin could cause anaphylaxis, hemolysis, Heinz body anemia
-IM admin could cause hematoma

for symptomatic animal:
1. stabilize: whole blood or plasma transfusion
-if dyspneic: thoracocentesis
2. GI decontamination limited value
3. blood draw for baseline clotting times
4. vitamin K1 SQ

5. in 12 hours: repeat PT, give oral vitamin K and a fatty meal
6. handle carefully, keep warm and stress free, limit physical activity
7. daily PT times

Question 20

describe chronic treatment for anticoagulant rodenticide toxicity

Answer 20

1. once stabilized, send home on oral vitamin K1
2. duration depends on agent
   -warfarin: 14d
   -brodifacoum diphacinone: 30d
   -weekly PT values
   -after treatment ends: 5-7 days later, follow up PT
3. contraindicated:
   -broad spectrum abx: decrease vit K absorption
   -sulfonamides, corticosteroids: displace toxicant from plasma proteins

Question 21

describe aspirin

Answer 21

1. salicyclate
   -81, 325, and 500 mg tabs
   -in alka-seltzer, arthritis creas
   -in pepto0bismol and kaopectate
   -canine formulations in pet stores of 100 and 325 mg
2. therapeutic dose:
   cats: 10-25mg/kg/day to every other day
   -dog: 25-35mg/kg/day TID
3. toxic:
   -cat: 80-120mg/kg daily 10-12 days
   -dog (acute): 500 mg/kg BID
   -dog (chronic): 100-300mg/day for 1-4 weeks, 50 mg/kg for 8 weeks

Question 22

describe the toxicokinetics and mechanism of aspirin

Answer 22

1. absorption: weak acid
2. biotransformation:
   -glycine or gluuronic acid conjugation
   -cats: increased t1/2
3. renal excretion
4. MOA:
   -inhibit COX1 and COX2 enzymes
   -irreversibly acetylates platelet COC
   -blocks platelet aggregation
   -reduces gastric and renal blood flow
   -reduces gastric mucus
   -increases gastric H+ secretion

HIGH DOSES: uncouples oxidative phosophorylation

Question 23

describe toxicosis and labs of aspirin

Answer 23

lower doses:
-gastroenteritis: nausea, vomiting, GI bleeding

higher doses:
-elevated respiration
-depression, lethargy
-dehydration
-hyperthermia

labs:
-anemia
-cats: heinz body anemia
-prolonged clotting times
-decreased renal function

Question 24

describe treatment of aspirin toxicosis

Answer 24

1. stabilize:
   -blood transfusion
   -fluids (sodium bicarbonate)
2. decontamination:
   -emesis (recent exposure)
   -activated charcoal and cathartic
   -urine alkalinization
3. GI protectants:
   -misoprostol (cytotec): synthetic PG
   -sucralfate
   -H2 antagonists
4. monitor renal function and PCV!