Toxicology Flashcards
Baclofen - MOA, toxic effects, tx?
Centrally acting γ-aminobutryic acid agonist, skeletal muscle relaxant - historically used to reduce urethral resistance in dogs with spinal injuries.
Narrow safety margin.
CSx - CNS depression, V+, ataxia. Less common - resp depression, cardiac arrhythmias, seizures.
Tx - decontamination (induce emesis), gastric lavage, activated charcoal (single dose), IVLE (lipophilic). Hemodialysis
Carprofen toxicity - MOA, CSx, Tx?
CSx reported in dogs >4mg/kg
>20mg/kg –> dose-related GI ulceration, hepatocellular injury.
>40mg/kg –> diuresis recc to prevent renal damage.
>200mg/kg –> neuro signs (seizures, stupor, coma)
Tx
Acute OD - decontaminate (not always effective due to high PO bioavailability & rapid GI absorption). Induce emesis, AC (single dose).
Onion toxicity - MOA, CSx?
Oxidative damage to RBCs due to presence
of aliphatic sulfides in onions –> interfere with glucose-6-phosphate dehydrogenase (G6PD) enzyme –> decrease production of reduced glutathione in RBCs –> RBC Hb become susceptible to oxidative degeneration and subsequent Heinz
body formation.
RBC with Heinz body inclusions often are
removed or lysed in the spleen, decreased lifespan if persist in circulation.
CSx/events –> hemoglobinemia, hemoglobinuria, and/or anemia. +/- metHb.
Cats - Hb has increased susceptibility to oxidative damage and Heinz body formation due to 8 reactive sulfhydryl groups on each globin tetramer.
Acetaminophen toxicosis in cats
- Explain why drug is toxic in this spp
- Clinical manifestations?
- Pathogenesis?
CSx: hematologic predominates over hepatotoxicosis.
- Methemoglobinemia - cyanosis, muddy MM. SQ oedema of face & paws.
- Heinz body formation from Hb denaturation & precipitation on RBC surface»_space; increased osmotic fragility of RBCs & hemolysis.
Pathogenesis:
- ATM is primarily biotransformed to nontoxic products in the liver via conjugation with glucuronic acid (> sulfate)»_space; renal elimination.
- Cats have absent expression of UGT1A6 = specific high affinity glucuronoyl transferase enzyme that glucuronidates ATM»_space; so more drug is conjugated to sulfates instead, But sulfation pathway has a finite capacity (lower in cats), so when reached capacity»_space; ATM accumulates in blood & metabolized by P-450 enzymes to NAPQI (toxic & reactive metabolite).
- Cats also have decr expression of ABCG2 transporter = enzyme that exports ATM.
- High circulating ATM suppresses glutathione synthesis.
- 2 sites in RBCs that are most susceptible to oxidative injury: iron in heme & sulfhydryl groups of globulin chains (cat Hb has 8 grps instead of 4) **
- Being electrophilic, NAPQI causes the oxidation of ferrous iron (Fe2+) to ferric iron (Fe3+) –> **converts Hb to metHb.
- Hb oxidation > denaturation & precipitation > Heinz bodies
- Cats also lack metHb reductase in RBCs
Name 5 (non-drug) hepatotoxins, disease forms/clinical manifesations, antidote (if any)
- **Cycad (cyasin): **GI, neuro signs. HyperBIL & hypoalb neg px. No antidote.
- Blue-green algae (microcystins): disrupt hepatocyte cytoskeleton > hepatic necrosis. No antidote.
- Amanita mushrooms/death cap (amatoxin esp a-amanitin): 4 phases: latency 24hrs, GI signs, false recovery, fulminant hepatic/renal/multiorgan failure. Tx silymarin, pen G, liver transplant (people)
- Aflatoxin (Aspergillus sp): alfatoxin B1 (only detectable in urine 1st 48h). Dose-dpt. Depletes I/C glutathione. Icterus, ascites etc. Acute form rapidly fatal, chronic form > immunodeficiency & hepati neoplasia. No antidote. Granular casts neg px.
- Xylitol: hypoglycemia (insulin surge), hypoK, hypophos. 2 forms - dose-dpt self-limiting incr LE, idiosyncratic ALF. No antidote
- Manganese OD (joint supp): hepatic accumulation > acute hepatic necrosis.
- Alpha lipoic acid: normal function is antioxidant, high doses promotes oxidation
List drugs that cause dose-dependent vs idiosyncratic hepatotoxicity.
Dose-dependent:
Oxidative stress
- Acetaminophen (dogs: high doses > acute centrilobular hepatic necrosis)
- Phenazopyridine (parent drug of acetaminophen) - rhabdomyolysis > hepatotox (dog case report)
- Azathioprine
- Azoles (keto & itra > toxic cf fluc)
p450 induction
- Phenytoin
- Phenobarb
Mitochondrial dysfunction
- Amiodarone (45% dogs)
- Tetracyclines (doxy) 36-39% dogs
Misc
- CCNU (29% dogs)
- Stanazol (cats)
- Primidone
- Glipizide (cats) > cholestatic jaundice 8%
Idiosyncratic
- Carprofen
- TMPS
- Sulfonamides
- Zonisamide, felbamate (AED)
- PO BZD - Diazepam, zolazepam (cats)
- Mitotane
- Methimazole
List 3 toxins that can cause systemic hypertension.
ACVIM consensus
Cocaine, methamphetamine, 5-hydroxytryptophan
Ethylene glycol toxicity
- Mechanism
- Clinical manifestations
- Dx
EG produces toxic metabolites via enzyme alcohol dehydrogenase.
- Glycoaldehyde > glycolic acid > oxidized to glyoxylic acid (rate-limiting step) > accumulation of glycolic acid > acidosis & nephrotoxicosis.
- Glyoxylic acid > formic acid, CO2, glycine, serine, oxalate. Oxalate is not further metabolized and is cytotoxic to the renal tubular epithelium > exacerbates the metabolic acidosis. Glycolic acid & oxalate = metabolites most responsible for acute tubular necrosis
- EG and metabolites eliminated in urine, but oxalate combines with Ca2+ to form soluble complex > ** CaOx crystals** within the tubular lumen when H2O is reabsorbed & pH decreases.
CSx: 3 phases. Up to 12hrs: CNS signs, PUPD, hypothermia. 12-24hrs: signs of metabolic acidosis (Tachypnea, tachycardia, muscle fasciculations, pulm oedema). >24hrs: progressive dehydration & oligo-anuric renal failure. Hyperechoic kidneys on AUS, +/- CaOx monohydate crystalluria.
Dx: EG test kit (only tests parent compound - metabolized within 24hrs), false neg (cats can be sick below detection limit), false+ (AC - propanol glycol, formalin, metaldehyde, mannitol, sorbitol etc).
Aminoglycoside overdose
- MOA
- Tx
- Risk factors
MOA: ionize to cationic complexes that bind anionic sites on brush border of PT cells > endocytosed by megalin receptor. Intracellular lysosomes concentrate the drug, causing lysosomal rupture into the cytoplasm, cellular damage & necrosis.
Nephrotoxicity has positive correlation with # of ionizable groups on drug (neomycin >amikacin).
Tx: Ticarcillin, carbenicillin can complex AMG, prevent renal uptake, may be an early tx option after known excessive dosing.
Risk factors: pre-existing kidney dz, cumulative dose, hypovolemia, concurrent furosemide use, high trough levels, >5d admin, hypoK, hypoCa, metabolic acidosis
Anti-coagulant rodenticide toxicity
- MOA?
E.g. warfarin. Normally vit K converts to vit K epoxide > reduced by vitamin K epoxide reductase to be available for future carboxylation. Rodenticides inhibit vitamin K epoxide reductase –> thus inhibit activation of vit-K dependent clotting factors (FII, VII, IX, X) & Ca-binding. These factors have short half-lives (6-42hrs) so coagulopathy develops quickly within 2-5 days
(Also affects anti-coagulants (protein S, protein C))
Organophosphate intoxication
- MOA
- Clinical manifestations
- Treatment
Autonomic signs - SLUD.
Delayed (1-6wks, can be acute tox or chronic mild/mod exposure) - neurotoxicity, related to inhibition of neurotoxic esterase (enzyme necessary for nutrient transport within neurons). Spontaneous improvement in 3-12wks.
Tx pralidoxime (2-PAM), atropine (anti muscarinic)
What are the antidote(s) for ethylene glycol intoxication?
In what time frame after ethylene glycol ingestion are these antidotes effective? What is the recommended treatment after this time period?
Tx: ethanol (competes for alcohol dehydrogenase, higher affinity vs EG) or 4-methylpyrazole (inhibits alcohol dehydrogenase). DON’T use tgt. Effective when given within 6-8hrs of ingestion (as conversion begins mins after EG ingestion, ineffective if glycolic acid already metabolised).
Supportive care for AKI, RRT.
IVLE - suitable for which toxins?
Bupivacaine, lignocaine
Verapamil, diltiazem
Propranolol
Clomipramine
Moxidectin, ivermectin
Baclofen
Cholecalciferol
Amlodipine
Permethrin
Marijuana
Trazodone
Barbiturates
Bromethalin
- MOA of toxicity
- tx
Neurotoxic rodenticide
Uncouples OP in brain & liver mitochondria > decreased ATP production
> CNS oedema
Cats more sensitive
Enterohepatic recirculation
Calcium channel blocker toxicity
- clinical manifestations
- antidote?
Inhibits transmembrane influx of Ca via slow/L-type Ca channels
Hypotension, met acidosis (hypoperfusion), v+, CNS depression, hypothermia
Tx calcium IV supp, refractory - high dose insulin (increases myocardial glucose uptake, causes mild hypoK- decr RMP enhancing inotropy, PDEIII inhibition)
Glucagon not really used
