VETTALK Volume 15, Number 02 American College of Veterinary Pharmacists ‘Tis the Season for Antifreeze…and its Toxicities! Introduction outcomes. As with ethanol and methanol, resembles ethanol (alcohol) intoxication. Antifreeze is known to most as the EG is also metabolized by ADH to form Dogs and cats exhibit vomiting due to GI neon green liquid that goes into our cars glycoaldehyde which is then oxidized to irritation, polydipsia, polyuria, and neu- to lower the freezing point and prevent glycolate, glyoxalate, and oxalate. Gly- rologic signs such as CNS depression, our radiators from locking up in cold colate and oxalate are responsible for stupor, ataxia, knuckling, decreased with- weather. However, to veterinarians and metabolic acidosis and renal damage. drawal or righting reflexes. Polydipsia veterinary pharmacists, it is ethylene gly- This is because ethylene glycol metabo- occurs due to osmotic stimulation of the col, a source of tens of thousands of ani- lites target the kidney and lead to oliguric thirst center, and polyuria occurs due to mal poisonings each year, the majority of or anuric acute renal injury, which in turn an osmotic diuresis. As CNS depression which occur in late fall, winter, and early slows elimination of ethylene glycol mak- increases in severity, dogs and cats drink spring which is why the timing appeared ing toxicity worst. The process of renal less, however the osmotic diuresis contin- suitable for this newsletter. The other failure is primarily due to glycolate- ues and results in severe dehydration. reason for publishing this article now is induced direct damage to tubules, al- Dogs may appear to transiently recover that the antidote for antifreeze poisoning, though tubule obstruction from precipi- from these CNS signs approximately 12 Antizol-Vet®(fomepizole), is on indefi- tated oxalate crystals may contribute as hours after ingestion. nite backorder. However, before there well. Hypocalcemia in ethylene glycol Phase II: The onset here is approxi- was an official antidote, there was com- overdose results from calcium oxalate mately 12-24 hours post ingestion and pounded fomepizole (4-methylpyrazole) formation. When EG is ingested, a pro- includes symptoms of tachycardia and and ethanol as solutions for this common found anion gap metabolic acidosis de- tachypnea which insidiously tie into the toxicity most often seen in our pet dogs, velops, which directly correlates with the last phase. though occasionally noted in cats. accumulation of toxic acid metabolites. Phase III: This develops between 12 and 24 hours in cats and between 36 and Pathophysiology/Etiology of Ethylene 72 hours in dogs. Patients will present Glycol (EG) Toxicity with signs and symptoms of oliguric This chemical is water-soluble and is acute renal failure including swollen and rapidly and completely absorbed and dis- painful kidneys on abdominal physical tributed within the body. In dogs, peak exam, lethargy, anorexia, vomiting, diar- blood concentrations occur within 3 hours rhea, oral ulcers, salivation, tachypnea, of ingestion. Although the parent com- pound EG, C2H6O2, may cause some alteration of mental status, it is a rela- tively nontoxic compound before it is metabolized for it is the metabolites which cause the distinct toxicity associ- ated with this compound. In order to un- derstand how EG becomes toxic, one must first examine the ethanol metabolic Clinical Signs and Symptoms of an pathway. Ethanol is metabolized by the Overdose alcohol dehydrogenase (ADH) enzyme Clinical signs are dose- and time- pathway located in the liver and gastric dependent and can be divided into those mucosa, and by the cytochrome P-450 caused by un-metabolized ethylene glycol (CYP) mixed function oxidase system in and those caused by its toxic metabolites the liver. The CYP-450’s are subject to representing the 3 phases of overdose. greater inducibility than alcohol dehydro- Phase I: Acute onset (30min-12 hours) genase which can alter patient specific of clinical signs is almost immediate and 2. Rule out other causes for symptoms used as a reliable emetic in cats at a a. Household toxins, plants, mush- dose of 0.4-0.5mg/kg IV. seizures, coma, and even death. rooms, owner’s prescription 3. Syrup of Ipecac: Not currently recom- drugs mended, though it was once histori- LaBoratory ABnormalities b. Confirm if there is any chance of cally. It contains emetine, a toxic Within 3 hours of ingestion, as previ- EG exposure alkaloid that produces vomiting by ously mentioned, a distinct anion gap 3. Preliminary Lab Results (will vary acting as a stomach irritant. It usually metabolic acidosis develops. Serum os- depending on stage of poisoning) produces vomiting in 15-30 min. molality can be increased by as much as a. Chemistry Profile However, if repeated use fails to in- 100 mOsm/kg above the normal (280- i. Metabolic acidosis duce emesis, then gastric lavage is 310 mOsm/kg) range. The difference with anion gap necessary to remove the emetine to between measured and calculated osmo- ii. Hypocalcaemia prevent cardiovascular toxicosis and lality is referred to as the anion gap b. Urine Analysis therefore this method for emesis in- which is caused by the presence of un- i. Hypotonic urine duction is not recommended. measured osmotically active particles (ie. ii. Crystalluria 4. Hydrogen peroxide (3%): Stimulates ethylene glycol) in the serum. Minimally iii. Acidic urine pH vomiting via the ninth cranial nerve concentrated urine with an acidic pH as (normal 7-7.5 dogs, 6.3-6.6 when given in 5-10 mL doses (not well as calcium oxalate crystalluria is cats) more than 2 doses 15 minutes apart) commonly seen as early as 3 hours and 6 4. Ultrasound via oral syringe until emesis occurs. hours after ingestion in cats and dogs a. Potentially could get a baseline of However, use cautiously especially in respectively, with monohydrate calcium pet’s kidneys on arrival cats, because aspiration of hydrogen oxalate crystals more common than di- peroxide foam causes severe aspira- hydrate calcium oxalate crystals. EG tion pneumonia. Repeated doses concentrations in serum and urine are should be avoided as severe gastric detectable by 1 to 2 hours after ingestion. erosion can result. Commercial test kits can detect serum EG concentrations of ≥50 mg/dL. Some Activated Charcoal antifreeze preparations contain fluo- To further inhibit absorption of EG if it rescein, which appears bright yellow to has been ingested within 1-2 hours, ad- green when viewed under a Wood’s minister activated charcoal dosed at 1-4 lamp. Urine fluorescence has been used Treatment Algorithm mg/kg by mouth for granules or 6-12mL/ in EG ingestions in humans and may be Treatment of EG toxicity is aimed at kg by mouth if it’s a suspension product. useful in veterinary medicine. Acidemia decreasing absorption of ingested EG, Do NOT administer emetics after char- increases the ability of the toxic metabo- increasing excretion of un-metabolized coal has been given due to risk of char- lites to penetrate cells, further depressing chemical to prevent further metabolism coal aspiration. CNS function and causing a rapid down- of EG, and correcting the metabolic aci- ward spiral of hypoxia and acidemia. dosis that occurs with EG poisoning. Gastric Lavage If the product was ingested 2-4 hours Diagnosing Emesis previously, then a gastric lavage can be Diagnosing ethylene glycol toxicity Further absorption of EG can be pre- performed. can be difficult when done purely on the vented by induction of emesis if animal basis of a simple physical exam as it can presents within 1 hour of ingestion. ***Note, once absorption has occurred, these pre- mimic head trauma, encephalitis, or a There are a few way to induce vomiting. vious methods are futile and instead focus should be generalized drug overdose, so a very in- 1. Apomorphine: opiate that acts as a placed on increasing excretion of EG via increasing fluid therapy designed to correct dehydration and volved history needs to be taken as well potent central dopamine agonist and increase urine production. as conducting a chemistry panel and uri- can be administered 0.03-0.05mg/kg nalysis when a patient presents with such IV or 0.1 mg/kg SQ. It can also be Antizol-Vet® (fomepizole) symptoms as discussed above in addition applied directly to conjunctival and To prevent metabolism of EG, the ac- to a thorough physical exam giving spe- gingival membranes and is generally tivity of alcohol dehydrogenase must be cial attention to the kidneys as they are provided as a compounding kit result- decreased by direct inactivation or by the organs of primary concern. Make ing in a 2.5mg/ml concentration after competitive inhibition. The only FDA sure the physical exam tests for neu- reconstitution since Apomorphine is approved treatment that has this mecha- rologic components as well such as nor- no longer commercially available. nism of action is Antizol-Vet® also mal reflexes, righting response, and eye Vomiting usually occurs in 5-10 min- known as 4-methylpyrazole or fomepi- movements (i.e., nystagmus). utes. If the first dose does not induce zole. Fomepizole (4-MP) competitively emesis, additional doses are not help- inhibits the rate-determining step of eth- Diagnostic Algorithm ful. This medication is most useful in ylene glycol metabolism which is the 1. Assess history, physical exam, neu- dogs but should not be used in cats. enzyme alcohol dehydrogenase. 4-MP rology exam, and clinical signs 2. Xylazine: α-2-adrenergic agonist, is effectively inactivates alcohol dehydro tween 7.0 and 7.5 in dogs and 6.3 to 6.6 aged in areas with animals (or children) in cats. The average commercial anti- nearby. To reduce accidental pet inges- genase in dogs without the side effects of freeze solutions are about 95% EG and tions, owners should be encouraged to ethanol and is considered the treatment of the minimum lethal dose of undiluted EG use bottles with child proof lids, store choice.