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Toxicology Flashcards

1
Q

Name 2 drugs that make EG cageside test false positive

A

IV diazepam (has propylene glycol)

oral AC (has glycerol)

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2
Q

Why can chocolate be decontaminated longer than most other toxins?

A

chocolate increases the pyloric sphincter tone - can be recovered by emesis up to 8 hours later

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3
Q

What proportion of stomach content is retrieved via emesis?

A

40-60%

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4
Q

List toxins that are not absorbed by AC

A
  • ethanol, methanol
  • fertilizer
  • fluoride
  • petroleum distillates
  • heavy metals
  • iodides
  • nitrates, nitrites
  • NaCl
  • chlorate
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5
Q

How does AC bind toxins?

A

weak Van der Waals forces

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6
Q

List differentials for methemoglobinemia

A
  • acetaminophen
  • onion/garlic tox
  • lidocaine/bezocaine
  • Chlorate
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7
Q

Why is hydrogen peroxide not recommended anymore for decontamination in cats?

A

causes severe hemorrhagic gastritis in 25% of cats

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8
Q

How soon after exposure to anticoagulant rodenticides will you see PT/aPTT elevations?

A

may be seen at 36 hours

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9
Q

What are the components of IV lipid emulsions?

A
  • medium-to long-chain triglycerides
  • phospholipid emulsifier
  • glycerin
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10
Q

How are IV lipids broken down?

A

cleared by skeletal muscle, splanchnic viscera, myocardial cells –> broken down to glycerol, FFA, choline –> energy source

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11
Q

why does a lower free phospholipid cc reduce risk of toxicity from intralipids?

A

interferes with lipoprotein lipase –> decreases clearance

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12
Q

What is the maximum lipid emulsion that can be given through a peripheral catheter?

A

20%

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13
Q

What can IV lipid emulsion cause in the face of hypoxia?

A
  • potentially results in negative myocardial inotropy –> decreased CO
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14
Q

How does Bupivacaine cause cardiotoxicity?

A

inhibits mitochondrial use of FFA by blockign carnitine acylcarnitine translocase –> prevents movement of FFA into the mitochondria

FFA prefered energy source of the heart

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15
Q

What are the 2 predominant theories for the MOA of IV lipid emulsions in toxicities?

A

Improved myocardial performance
* provides large volume FFA –> overcomes potential cardiotoxic effects of bupivacaine
* gives heart energy substrate
* influx of FFA also stimulates voltage-gated Ca channels –> increased IC CA++ –> increased contractility (particularly helpful for Ca++ channel blocker toxicity)

Lipid sink theory
* creates an expanded lipid phase within the plasma which sequesters lipophilic drugs (logP >1.0)
* may be strong enough to pull toxins out of the brain

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16
Q

What are potential complications from IV lipid emulsion?

A

note: more likely with prolonged lipid administration (i.e., parenteral nutrition)

  • bacterial contamination
  • lipemia interfering with laboratory tests
  • pancreatitis (theoretical, not reported in vet med)
  • if preexisting pulmonary inflammatory disease (e.g., ARDS) –> decreases PF ratio
  • pulmonary lipid emboli (only reported in human children)
  • “fat overload syndrome” - only reported in people
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17
Q

What is the ideal protein-binding percentage for TPE to be effective?

A

> 90%

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18
Q

What is the molecular size of toxins effectively removed by hemodialysis?

A

ideally < 500 Da (Emergency textbook)
< 2000 Da (Londono lecture IVECCS)

If hemofiltration used or added (hemodiafiltration) –> up to 50kDa (Emergency textbook) or 20kDa (Londono)

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19
Q

What is the difference between Hemodialysis, hemofiltration, and hemoperfusion?

A

Hemodialysis - filter lets small molecules move down its concentration gradient (i.e., diffusion)

Hemofiltration - negative pressure pulls water out of blood and can drag solutes with it (i.e., convection)

Hemoperfusion - blood is exposued to adsorbent (e.g., activated charcoal/carbon)

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20
Q

How does apomorphine induce vomiting?

A

dopamin receptor agonism within the chemoreceptor trigger zone

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21
Q

Where is the chemoreceptor trigger zone located?

A

area prostrema of the medulla

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22
Q

How does IV and SC administration of apomorphine compare?

A

same efficacy at inducing vomiting (80% SC versus 82% IV) but longer time to emesis with SC (median 2 versus 13.5 minutes)

no significant difference in number of adverse events

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23
Q

How can apomorphine also exert antiemetic properties?

A

crosses BBB –> binds mu-receptors –> antiemetic

takes longer than the CRTZ triggering

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24
Q

How does Ropinirole induce emesis?

A

dopamine receptor agonist (D2-like receptors, not D1)

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25
Q

What is the antidote for Ropinirole?

A

Metoclopramide - binds and antagonizes same D2 receptors in the CRTZ

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26
Q

What are the emesis-inducing receptors in the emetic center versus the CRTZ?

A

Emetic center
* 5HT1
* alpha-2 receptors
* neurokinergic (NK1)

CRTZ
* D2
* H1
* alpha-2
* 5HT3
* cholinergic (M1)
* Enkephalinergic
* Neurokinergic (NK1)

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27
Q

How does Ropinirol compare to apomorphine administration?

A

less effectivve but very small difference - unlikely to be clinically relevant

Ropinirol caues ocular side effects in a significant amount of dogs (conjunctival hyperemia, protrusion of the third eyelid, ocular discharge) - also caused sedtion

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28
Q

How successful is emesis for decontamination of gastric FBs in cats?

A

was only effective in 50% of cats (n = 22)

86% received dexmed at 7 mcg/kg

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29
Q

What is the toxic dose for GI signs, gastric ulcers, AKI, CNS signs, or death in dogs versus cats

A

GI - 25-125 mg/kg
ulcers > 50 mg/kg
AKI 100-175 mg/kg
CNS > 400 mg/kg
lethal > 600 mg/kg

cats twice as sensitive

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30
Q

How does the cox-selectivity of meloxicam differ between dogs and cats?

A

Cox-2 selective in dogs but non-selective in cats

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31
Q

How are NSAIDs metabolized and excreted?

A

Metabolized in 2 steps in the liver
1. catalization
2. conjugation with glucuronic acid, glutathione, or sulfate

–> makes it water-soluble and excretable by the kidneys

renal excretion faster in alkaline urine

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32
Q

What is the suspected reason for the increaed GI toxicities of NSAIDs in dogs compared to people?

A

undergoes enterohepatic recirculation in dogs - reexcreted into intestines - not in people

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33
Q

What is the function of prostaglandin in the GI tract

A
  • enhances bicarbonate and mucus secretion
  • mediates blood flow, immunity, and epithelial cell turnover
  • inhibits secretions of gastrin (PGE2) and hydrochloric acid (PGE2, PGI2)

remember gastrin stimulates gastric acid secretion from parietal cells

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34
Q

What is the active metabolite of aspirin?

A

salicylic acid

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35
Q

How is aspirin the only COX inhibitor that irreversibly inhibits COX?

A

because it is acetylated and other NSAIDs are not

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36
Q

What are the toxic doses for GI and renal injury from carprofen?

A

over 20 mg/kg GI
over 40 mg/kg renal

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37
Q

Where do COX 1 versus COX 2 have their highest cc?

A

COX 1
* stomach
* kidneys
* endothelium
* platelets

COX 2
* macrophages/monocytes
* fibroblasts
* chondrocytes
* also in gastric pyloric and duodenal mucosa (even COX 2 selective drugs can cause ulcerations)

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38
Q

Which prostaglandins are responsible for renal perfusion regulation?

A

PGE2, PGI2

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39
Q

How do hemoperfusion+hemodialysis vs membrane-TPE vs manual centrifugal TPE compare in their efficiency to remove carprofen?

A

hemoperfusion+hemodialys - 67% removed
membrane-based TPE - 51%
centrifugal - 57%

just case-reports

this is counterintuitive as high protein-binding should make dialysis less efficient

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40
Q

What were the findings of Steele at al retrospectively looking into outcomes in dogs with NSAID tox?

A
  • vomiting most common clinical signs
  • AKI in 13.6% and Gastric ulceration in 12.8%
  • human NSAID ingestion overrepresented 75% (ibuprofen most common, followed by carprofen)
  • no difference in outcome between human formula and vet formula ingestion
  • only association with risk of death - duration of anorexia pefore presentation
  • more than 1/3 with elevated ALT and ALP
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41
Q

How does albuterol toxicity cause tachycardia if beta2-selective?

A

at high doses –> beta-2 selectivity diminishes –> activates beta-1 receptors –> CV stimulation

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42
Q

why is propranolol prefered over atenolol for albuterol toxicity?

A

non beta-selective - inhibits both beta 1 and beta 2

atenolol beta 1 selective

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43
Q

Which beta receptor activates NaKATPase pumps?

A

beta 2 (Gs protein –> cAMP mediated)

44
Q

What is the first-line treatment for albuterol-induced hypokalemia?

A

beta-blocker (preferentially beta-2 activity, i.e., propranolol over atenolol)

K supplementation is not first-line

45
Q

What were the findings of Couchley et al., looking into salbutamol/albuterol toxicity in 501 dogs?

A
  • tachycardia is common (80%) and happens fast (about 2.5h after exposure) but arrhythmias are rare (3.4%)
  • other signs: dullness, tachypnea/panting, hypokalemia, vomiting most common
46
Q

How does beta 2 activation cause vasodilation?

A

Gs coupled receptor –> adenylyl cyclase activation –> more cAMP –> phosphorylation of phospholamban –> increaes uptake of Ca++ by SERCA

47
Q

What were the main findings in Meroni et al.’s retrospective evaluation of albuterol toxicity in dogs?

A
  • tachycardia most common sign (90%)
  • hypokalemia (69%)
  • hyperlactatemia and hyperglycemia common
  • no arrhythmias noted
  • good outcome
48
Q

What is the toxic dose of acetaminophen?

A

dogs - signs typically seen > 100 mg/kg but according to Peterson TD50 600 mg/kg
generally >200 mg/kg for methemoglobinemia

**cats - 50-100 mg/kg **
reported signs at 10 mg/kg

49
Q

Besides central COX inhibition, what are alternative theories for acetaminophen’s analgesic effects?

A

NMDA antagonism –> blockade of substance P’s nociceptive actions

activation of central serotonergic nociception pathways

50
Q

How is acetaminophene metabolized?

A
  • glucuronidation or sulfation
  • cats do not have sufficient glucuronidation (diphishate-glucuronosyltransferase lower) - rely more on sulfation

when these pathways are depleted:
* Cytochrome P450 pathway –> produces N-acetyl-p-benzoquinone imine (NAPQI) TOXIC
* NAPQI conjugated by glutathione –> cysteine + mercapturic acid –> excreted

glutathione depletion –> toxicity

51
Q

describe the toxic effects of acetaminophen

A

via NAPQI and glutathione depletion

  • NAPQI electrophilic - covalently binds to proteins –> disrupts cell function and causes lipid peroxidation
  • NAPQI toxic to liver cells –> binds to hepatic cell membranes –> necrosis and hepatotoxicity
  • nephrotoxic
  • glutathione depletion renders cells susceptible to oxidative injuries –> methemoglobinemia
  • Heinzbody anemia in cats

Other metabolite: Para-aminophenol
* caused by deficiency of N-acetyltransferase in dog’s and cat’s RBC
* potentially causes methemoglobinemia

52
Q

Why are cat’s erythrocytes more susceptible to oxidative damage?

A

have more sulfydryl groups on RBCs (8 instead of the 4 in dogs)

53
Q

What type of liver necrosis is caused by acetaminophen toxicity?

A

centrilobular hepatic necrosis on histopathology

liver necrosis less common in cats

54
Q

Does acetaminophen undergo enterohepatic recirculation?

A

Yes - administer multiple doses of AC

55
Q

List all treatment options for Acetaminophen toxicity

A
  • NAC - glutathione precursor and can bind NAPQI, sulfur donor (can increase sulfate conjugation)
  • Ascorbic Acid - reduces methemoglobin to hemoglobin
  • Silymarin - free radical scavenger, membrane stabilizer from lipid peroxidation, reduced glutathione depletion
  • histamine receptor antagonists (ranitidine, cimetidine) - reduces CytP450 activity - reduces NAPQI production - controversial
  • SAMe - initiates metabolic pathways in the liver to reduce NAPQI production
  • methylene blue - reduces methemoglobin to hemoglobin - can actually oxidize heme at high doses and worsen methemoglobin - not currently recommended in cats
56
Q

What changes hemoglobin to methemoglobin?

A

Ferrous iron (Fe2+) oxidized to Ferric iron (Fe3+)

Renders that one Heme unable to bind more oxygen and makes other 3 heme have higher O2 affinity (left shift of oxygen dissociation curve)

57
Q

How long should vitamin K1 be supplemented for after anticoagulant rodenticed exposure?

A

30 days - recheck PT 48 hours after d/c

58
Q

What is the LD50 of bromethalin?

A

2.4 mg/kg dogs
0.3 mg/kg cats

59
Q

What is the MOA of bromethalin toxicity?

A

uncouples oxidative phosphorylation –> decresed ATP production

60
Q

How should you decontaminate bromethalin?

A

emesis +/- gastric lavage (absorbed within 1.5 hours)
repeated AC - enterohepatic recirculation

IVL - shown to reduce blood cc in one case report

61
Q

How is VitD rodenticied metabolized?

A

cholecalciferol in rodenticide –> metabolized to calcifediol –> hydroxylated to 1,25-Dihydrocholecalciferol

62
Q

Why do the effects of vitamin D toxicity last so long?

A
  • intermediate compound calcifediol has a functional half-life of 29 days
63
Q

What Ca-P product cc will lead to metastatic mineralization?

A

60 mg/dL

64
Q

What are the most affected organs from vitamin D toxicity?

A
  • renal - AKI
  • GI tract - irreversible GI tract mineralization
  • CNS
65
Q

What can you detect first, hyperphosphatemia or hypercalcemia in VitD tox?

A

hyperphosphatemia

66
Q

What is Cholestyramine resin?

A

enhances excretion of cholesterole as bile acids

can be fiven to decrease GI absorption of Vit D toxicant

67
Q

Why can phosphide rodenticides pose a threat to healthcare staff?

A

when ingested –> reacts with water and acid to release phosphine gas which is toxic

68
Q

When giving Vitamin K1 to redenticide toxicity cases, how long does it take for synthesis of new clotting factors?

A

6-12 hours

69
Q

What were the findings in Scotti at all (retrospective evaluation of bromethalin in dogs)?

A
  • CS uncommon if presented early - but low doses
  • paralytic syndrome - mild to moderate signs with good prognosis
  • dogs with convulsant syndrome - mostly euthanized
  • one dog with seizures survived to discharge
  • small portion of study (25/192) had CS - too small to gather prognosis from CS
70
Q

Is Ivermectin (Heartguard) safe in herding breeds?

A

Yes, even though MDR1 gene common (ABCB1) - labeled doses are low enough to be safe for these breeds

71
Q

What is the LD50 of ivermectin?

A

80 mg/kg in most dogs
0.1 mg/kg in herding breeds with MDR1 gene

72
Q

What is the MOA of macrolides?

A

bind to glutamate-gasted Cl channels - trigger influx of Cl ions –> hyperpolarization of the neuron –> prevents action potential initiation/propagation –> paralysis

73
Q

What is the role of P-glycoprotein in the CNS?

A

“gate-keeper” of the BBB
binds drugs such as macrolides and moves them back from the brain into the capillary lumen

less concentrated and functional in MDR1 mutation dogs

74
Q

What is the mechanism of action of pyrethroids?

A

prolongs the period of Na channel opening –> increases length of depolarization –> repetetive nerve firing

75
Q

what are the 2 phases of kidney disease from lily toxicity?

A

polyuric renal disease - with secondary dehydration - at 18-30hr

anuria - by 24-48 hours

76
Q

What is the MOA of amphetamines and methamphetamines?

A

excitatory - cerebral cortex mostly

peripherally - cause release of norepi, stimulate alpa and beta adrenergic receptors directly

dopamine agonists

inhibition of monoamine oxidase - enzyme breaking down norepi, dopamine, serotonine

77
Q

What anti seizure drug should not be given for amphetamine toxicities?

A

benzodiazepines - can paradoxically exacerbate seizures

this is controversial - human recommendations include benzodiazepines even just for sedation and definitely recommended for seizure treatment

78
Q

What is the mechanism of action of barbiturates?

A

GABA-agonism

79
Q

What is the MOA of cocaine?

A

norepinephrine, dopamine, and serotonine reuptake inhibitor –> excess neurotransmitters –> excitatory –> seizures, tachycardia, etc.

80
Q

Where is THC metabolized and excreted?

A

metabolized in the liver to 11-hydroxy-delta-9-THC

only 15% excreted in urine
most eliminated in feces and undergoes enterohepatic recirculation

81
Q

Which opioid receptor activity does naloxone mostly block?

A

mu - most affinity

needs large doses to block kappa or omega receptors

82
Q

What is the proposed toxic compound in grapes? Explain why this compound is toxic in dogs but not people.

A

Tartaric acid

excreted into urine via organic anion transporters
basolateral site - OAT-1 (present in dogs)
luminal site - OAT-4 (deficient in dogs)

–> leads to IC accumulation and tubular damage

83
Q
A
84
Q

What could be a potential future antidote for grape toxicity in dogs?

A

probenecid

OAT-1 inhibitor

85
Q

What were the findings in the retrospective observational study on grapes/raisin ingestion by dogs by Crost et al.?

A

low rate of acute kidney injury if dogs receiving supportive care and hosp. (1/33 AKI I)

86
Q

What is the minimum lethal dose for undiluted EG in dogs and cats?

A

6.6 mL/kg dogs
1.5 mL/kg cats

87
Q

Describe the metabolism of EG

A
88
Q

Which EG metabolite is primarily responsible for CNS dysfunction?

A

glycoaldehyde

89
Q

Which EG metabolite is mostly responsible for metabolic acidosis. Why does this metabolite accumulate?

A

Glycolic acid

accumulates becasue lactic dehydrogenase gets saturated –> should convert glycolic acid to glyoxylic acid

90
Q

What causes the renal damage from EG toxicity?

A

calcium oxalate monohydrate crystal formation in renal tubules

adhere to renal tubular cell membranes –> internalize –> alter cell membrane structure, increase ROS, cause mitochondrial dysfunction –> necrosis

91
Q

What crystals are these, which one causes renal disease?

A

left: Ca-oxalate monohydrate
right: Ca-oxalate dihydrate

left one causes nephrotoxicity
right: seen in health and normal urine

92
Q

What are the phaes of EG toxicity?

A

within 30 to hours - vomiting and CNS signs, PU/PD (osmotic diuresis)
after 12 hours - dogs transiently improve, cats done

12-24 hours after ingestion - cardiopulmonary signs possible (tachypnea, tachycardia - presumambly from severe metabolic acidosis)

36-72 hours (dogs) 12-24 hours (cats) oliguric AKI

anuria 72-96 hours after ingestion

93
Q

How early after EG ingestion can you see an increased AG?

A

increases by 3 hours and peaks at 6 hours - stays elevated for 2 days

94
Q

For how long after ingestion can you detect EG in urine or serum?

A

48-72 hours

95
Q

Besides EG tests for urine or serum, what are diagnostics that can help increase the index of suspicion of toxicity?

A
  • high AG
  • high measured osmolality with high osmolar gap
  • hypocalcemia (later, 50% of cases)
  • hyperglycemia (aldehyde metabolites inhibit glucose metabolism)
  • hyperphosphatemia (early if compound has phosphate, which is common)
  • woodlamp exam of mouth and face, urine
  • Ca-oxalate crystals (within 3-6 hours after ingestion)
96
Q

What are the 2 laboratory methods for measuring osmolality?

What is the normal osmolal gap?

A

freezing point osmometry
vapor pressure osmometry

< 10 mOsm/L

97
Q

Why do EG toxicity patients show an erroneously high POC lactate?

A

glycolate read as lactate

98
Q

What is the suspected mechanism of action of amitraz toxicity?

A

alpha-2 agonism

causes bradycardia, sedation, hyperglycemia

newly found: metabolic alkalosis and respiratory acidosis

99
Q

With a logP of 5.5 is IV lipid therapy indicated in amitraz toxicity?

A

likely not beneficial as shown in previous case report of 3 dogs - prioritize alpha-2 antagnoist over IVLE

100
Q

What are the toxins in blue-green algae

A

Cyanotoxins from Cyanobacteria

Hepatotoxins:
* Microcystins
* Nodularins

Neurotoxins:
* Anatoxin-A
* Homoanatoxin-A
* Anatoxin-A(s)

101
Q

What is the MOA of blue-green algae hepatotoxicity?

A

inhibit serine-threonine protein phosphatases 1 and 2A –> disrupts cytoskeletal components –> liver necrosis, hepatic hemorrhage, shock

102
Q

What is the MOA of blue-green algae neurotoxicity?

A
  • nicotinic cholineric receptor agonist –> repeated stimulation and then nerve block –> paralysis (respiratory) death
  • opening of L-type Ca channels
  • acetylcholinesterase inhibitor
103
Q

What is the MOA of Lead toxicity?

A

competes with Ca for many cellular mechanisms

disrupts transmembrane flux of Ca

104
Q

What is the MOA of Methaldehyde toxicity?

A

disrupts the GABA-ergic system - decreased gaba concentrations –> tremors, seizures, hyperthermia

105
Q

What is the mechanism of action of methylxanthine toxicities?

A

inhibits cyclic nucleotide phosphodiesterases

antagonizes receptor-mediated actions of adenosine

106
Q

What is the main proposed MOA for hemolysis caused by zinc toxicity?

A

oxidative damage via inhibition of glutathione reductase pathway

inhibition of enzymes involved in the hexose monophosphate shunt pathway (needed for NADPH production)

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