Toxicology Flashcards
1
Q
Name 2 drugs that make EG cageside test false positive
A
IV diazepam (has propylene glycol)
oral AC (has glycerol)
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
3
Q
What proportion of stomach content is retrieved via emesis?
A
40-60%
4
Q
List toxins that are not absorbed by AC
A
- ethanol, methanol
- fertilizer
- fluoride
- petroleum distillates
- heavy metals
- iodides
- nitrates, nitrites
- NaCl
- chlorate
5
Q
How does AC bind toxins?
A
weak Van der Waals forces
6
Q
List differentials for methemoglobinemia
A
- acetaminophen
- onion/garlic tox
- lidocaine/bezocaine
- Chlorate
7
Q
Why is hydrogen peroxide not recommended anymore for decontamination in cats?
A
causes severe hemorrhagic gastritis in 25% of cats
8
Q
How soon after exposure to anticoagulant rodenticides will you see PT/aPTT elevations?
A
may be seen at 36 hours
9
Q
What are the components of IV lipid emulsions?
A
- medium-to long-chain triglycerides
- phospholipid emulsifier
- glycerin
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
11
Q
why does a lower free phospholipid cc reduce risk of toxicity from intralipids?
A
interferes with lipoprotein lipase –> decreases clearance
12
Q
What is the maximum lipid emulsion that can be given through a peripheral catheter?
A
20%
13
Q
What can IV lipid emulsion cause in the face of hypoxia?
A
- potentially results in negative myocardial inotropy –> decreased CO
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
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
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
17
Q
What is the ideal protein-binding percentage for TPE to be effective?
A
> 90%
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)
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)
20
Q
How does apomorphine induce vomiting?
A
dopamin receptor agonism within the chemoreceptor trigger zone
21
Q
Where is the chemoreceptor trigger zone located?
A
area prostrema of the medulla
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
23
Q
How can apomorphine also exert antiemetic properties?
A
crosses BBB –> binds mu-receptors –> antiemetic
takes longer than the CRTZ triggering
24
Q
How does Ropinirole induce emesis?
A
dopamine receptor agonist (D2-like receptors, not D1)
25
What is the antidote for Ropinirole?
Metoclopramide - binds and antagonizes same D2 receptors in the CRTZ
26
What are the emesis-inducing receptors in the emetic center versus the CRTZ?
Emetic center
* 5HT1
* alpha-2 receptors
* neurokinergic (NK1)
CRTZ
* D2
* H1
* alpha-2
* 5HT3
* cholinergic (M1)
* Enkephalinergic
* Neurokinergic (NK1)
27
How does Ropinirol compare to apomorphine administration?
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
28
How successful is emesis for decontamination of gastric FBs in cats?
was only effective in 50% of cats (n = 22)
86% received dexmed at 7 mcg/kg
29
What is the toxic dose for GI signs, gastric ulcers, AKI, CNS signs, or death in dogs versus cats
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
30
How does the cox-selectivity of meloxicam differ between dogs and cats?
Cox-2 selective in dogs but non-selective in cats
31
How are NSAIDs metabolized and excreted?
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
32
What is the suspected reason for the increaed GI toxicities of NSAIDs in dogs compared to people?
undergoes enterohepatic recirculation in dogs - reexcreted into intestines - not in people
33
What is the function of prostaglandin in the GI tract
* enhances bicarbonate and mucus secretion
* mediates blood flow, immunity, and epithelial cell turnover
* inhibits secretions of gastrin (PGE2) and hydrochloric acid (PGE2, PGI2)
## Footnote
remember gastrin stimulates gastric acid secretion from parietal cells
34
What is the active metabolite of aspirin?
salicylic acid
35
How is aspirin the only COX inhibitor that irreversibly inhibits COX?
because it is acetylated and other NSAIDs are not
36
What are the toxic doses for GI and renal injury from carprofen?
over 20 mg/kg GI
over 40 mg/kg renal
37
Where do COX 1 versus COX 2 have their highest cc?
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)
38
Which prostaglandins are responsible for renal perfusion regulation?
PGE2, PGI2
39
How do hemoperfusion+hemodialysis vs membrane-TPE vs manual centrifugal TPE compare in their efficiency to remove carprofen?
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
40
What were the findings of Steele at al retrospectively looking into outcomes in dogs with NSAID tox?
* 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
41
How does albuterol toxicity cause tachycardia if beta2-selective?
at high doses --> beta-2 selectivity diminishes --> activates beta-1 receptors --> CV stimulation
42
why is propranolol prefered over atenolol for albuterol toxicity?
non beta-selective - inhibits both beta 1 and beta 2
atenolol beta 1 selective
43
Which beta receptor activates NaKATPase pumps?
beta 2 (Gs protein --> cAMP mediated)
44
What is the first-line treatment for albuterol-induced hypokalemia?
beta-blocker (preferentially beta-2 activity, i.e., propranolol over atenolol)
K supplementation is not first-line
45
What were the findings of Couchley et al., looking into salbutamol/albuterol toxicity in 501 dogs?
* 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
How does beta 2 activation cause vasodilation?
Gs coupled receptor --> adenylyl cyclase activation --> more cAMP --> phosphorylation of phospholamban --> increaes uptake of Ca++ by SERCA
47
What were the main findings in Meroni et al.'s retrospective evaluation of albuterol toxicity in dogs?
* tachycardia most common sign (90%)
* hypokalemia (69%)
* hyperlactatemia and hyperglycemia common
* no arrhythmias noted
* good outcome
48
What is the toxic dose of acetaminophen?
**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
Besides central COX inhibition, what are alternative theories for acetaminophen's analgesic effects?
NMDA antagonism --> blockade of substance P's nociceptive actions
activation of central serotonergic nociception pathways
50
How is acetaminophene metabolized?
* 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
describe the toxic effects of acetaminophen
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
Why are cat's erythrocytes more susceptible to oxidative damage?
have more sulfydryl groups on RBCs (8 instead of the 4 in dogs)
53
What type of liver necrosis is caused by acetaminophen toxicity?
centrilobular hepatic necrosis on histopathology
liver necrosis less common in cats
54
Does acetaminophen undergo enterohepatic recirculation?
Yes - administer multiple doses of AC
55
List all treatment options for Acetaminophen toxicity
* 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
What changes hemoglobin to methemoglobin?
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
How long should vitamin K1 be supplemented for after anticoagulant rodenticed exposure?
30 days - recheck PT 48 hours after d/c
58
What is the LD50 of bromethalin?
2.4 mg/kg dogs
0.3 mg/kg cats
59
What is the MOA of bromethalin toxicity?
uncouples oxidative phosphorylation --> decresed ATP production
60
How should you decontaminate bromethalin?
emesis +/- gastric lavage (absorbed within 1.5 hours)
repeated AC - enterohepatic recirculation
IVL - shown to reduce blood cc in one case report
61
How is VitD rodenticied metabolized?
cholecalciferol in rodenticide --> metabolized to calcifediol --> hydroxylated to 1,25-Dihydrocholecalciferol
62
Why do the effects of vitamin D toxicity last so long?
* intermediate compound calcifediol has a functional half-life of 29 days
63
What Ca-P product cc will lead to metastatic mineralization?
60 mg/dL
64
What are the most affected organs from vitamin D toxicity?
* renal - AKI
* GI tract - irreversible GI tract mineralization
* CNS
65
What can you detect first, hyperphosphatemia or hypercalcemia in VitD tox?
hyperphosphatemia
66
What is Cholestyramine resin?
enhances excretion of cholesterole as bile acids
can be fiven to decrease GI absorption of Vit D toxicant
67
Why can phosphide rodenticides pose a threat to healthcare staff?
when ingested --> reacts with water and acid to release phosphine gas which is toxic
68
When giving Vitamin K1 to redenticide toxicity cases, how long does it take for synthesis of new clotting factors?
6-12 hours
69
What were the findings in Scotti at all (retrospective evaluation of bromethalin in dogs)?
* 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
Is Ivermectin (Heartguard) safe in herding breeds?
Yes, even though MDR1 gene common (ABCB1) - labeled doses are low enough to be safe for these breeds
71
What is the LD50 of ivermectin?
80 mg/kg in most dogs
0.1 mg/kg in herding breeds with MDR1 gene
72
What is the MOA of macrolides?
bind to glutamate-gasted Cl channels - trigger influx of Cl ions --> hyperpolarization of the neuron --> prevents action potential initiation/propagation --> paralysis
73
What is the role of P-glycoprotein in the CNS?
"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
What is the mechanism of action of pyrethroids?
prolongs the period of Na channel opening --> increases length of depolarization --> repetetive nerve firing
75
what are the 2 phases of kidney disease from lily toxicity?
polyuric renal disease - with secondary dehydration - at 18-30hr
anuria - by 24-48 hours
76
What is the MOA of amphetamines and methamphetamines?
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
What anti seizure drug should not be given for amphetamine toxicities?
benzodiazepines - can paradoxically exacerbate seizures
this is controversial - human recommendations include benzodiazepines even just for sedation and definitely recommended for seizure treatment
78
What is the mechanism of action of barbiturates?
GABA-agonism
79
What is the MOA of cocaine?
norepinephrine, dopamine, and serotonine reuptake inhibitor --> excess neurotransmitters --> excitatory --> seizures, tachycardia, etc.
80
Where is THC metabolized and excreted?
metabolized in the liver to 11-hydroxy-delta-9-THC
only 15% excreted in urine
most eliminated in feces and undergoes enterohepatic recirculation
81
Which opioid receptor activity does naloxone mostly block?
mu - most affinity
needs large doses to block kappa or omega receptors
82
What is the proposed toxic compound in grapes? Explain why this compound is toxic in dogs but not people.
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
84
What could be a potential future antidote for grape toxicity in dogs?
probenecid
OAT-1 inhibitor
85
What were the findings in the retrospective observational study on grapes/raisin ingestion by dogs by Crost et al.?
low rate of acute kidney injury if dogs receiving supportive care and hosp. (1/33 AKI I)
86
What is the minimum lethal dose for undiluted EG in dogs and cats?
6.6 mL/kg dogs
1.5 mL/kg cats
87
Describe the metabolism of EG
88
Which EG metabolite is primarily responsible for CNS dysfunction?
glycoaldehyde
89
Which EG metabolite is mostly responsible for metabolic acidosis. Why does this metabolite accumulate?
Glycolic acid
accumulates becasue lactic dehydrogenase gets saturated --> should convert glycolic acid to glyoxylic acid
90
What causes the renal damage from EG toxicity?
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
What crystals are these, which one causes renal disease?
left: Ca-oxalate monohydrate
right: Ca-oxalate dihydrate
left one causes nephrotoxicity
right: seen in health and normal urine
92
What are the phaes of EG toxicity?
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
How early after EG ingestion can you see an increased AG?
increases by 3 hours and peaks at 6 hours - stays elevated for 2 days
94
For how long after ingestion can you detect EG in urine or serum?
48-72 hours
95
Besides EG tests for urine or serum, what are diagnostics that can help increase the index of suspicion of toxicity?
* 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
What are the 2 laboratory methods for measuring osmolality?
What is the normal osmolal gap?
freezing point osmometry
vapor pressure osmometry
< 10 mOsm/L
97
Why do EG toxicity patients show an erroneously high POC lactate?
glycolate read as lactate
98
What is the suspected mechanism of action of amitraz toxicity?
alpha-2 agonism
causes bradycardia, sedation, hyperglycemia
newly found: metabolic alkalosis and respiratory acidosis
99
With a logP of 5.5 is IV lipid therapy indicated in amitraz toxicity?
likely not beneficial as shown in previous case report of 3 dogs - prioritize alpha-2 antagnoist over IVLE
100
What are the toxins in blue-green algae
Cyanotoxins from Cyanobacteria
Hepatotoxins:
* Microcystins
* Nodularins
Neurotoxins:
* Anatoxin-A
* Homoanatoxin-A
* Anatoxin-A(s)
101
What is the MOA of blue-green algae hepatotoxicity?
inhibit serine-threonine protein phosphatases 1 and 2A --> disrupts cytoskeletal components --> liver necrosis, hepatic hemorrhage, shock
102
What is the MOA of blue-green algae neurotoxicity?
* nicotinic cholineric receptor agonist --> repeated stimulation and then nerve block --> paralysis (respiratory) death
* opening of L-type Ca channels
* acetylcholinesterase inhibitor
103
What is the MOA of Lead toxicity?
competes with Ca for many cellular mechanisms
disrupts transmembrane flux of Ca
104
What is the MOA of Methaldehyde toxicity?
disrupts the GABA-ergic system - decreased gaba concentrations --> tremors, seizures, hyperthermia
105
What is the mechanism of action of methylxanthine toxicities?
inhibits cyclic nucleotide phosphodiesterases
antagonizes receptor-mediated actions of adenosine
106
What is the main proposed MOA for hemolysis caused by zinc toxicity?
oxidative damage via inhibition of glutathione reductase pathway
inhibition of enzymes involved in the hexose monophosphate shunt pathway (needed for NADPH production)
