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. The dose is 20 mg/kg IV ini- is 1.4 mL/kg body weight in cats and 4.4- bottles safely away from pets (and chil- tially, followed by 15 mg/kg IV, at 12 6.6 mL/kg in dogs with younger animals dren), and avoid leaving free fluids in the hour and 24 hour intervals then and 5 mg/ being more susceptible. This equates to a open by cleaning up spills ASAP. In a kg IV at 36 hr. In cats, 4-MP is ineffec- few tablespoons in a medium dog or a cat retail setting if a panicked owner comes tive at the canine dosage therefore the that has merely walked through a puddle in and requests an over-the-counter treat- recommended dose is 125 mg/kg initially, and then licked its paw! ment for their pet, be perceptive and ask followed by 31.3 mg/kg at 12, 24, and 36 further questions regarding symptoms and hours after the initial dose. Continue Prognosis risk of possible EG exposure. If EG ex- doses every 12 hours until ethylene glycol The outcome for the dog or cat that has posure is a risk, advise that they immedi- is no longer detected. If analysis of ethyl- ingested antifreeze varies inversely with ately seek the help of their veterinarian ene glycol is not available, treat with the amount of time that has elapsed be- and instill upon them how urgent the 31mg/kg every 12 hours through 60 tween ingestion and initiation of treat- situation is! If the situation occurs after hours. At the time of writing, Antizol® is ment as well as the amount ingested. In hours, as the pharmacist you are able to on backorder and must be compounded as dogs and cats with azotemia or in oliguric remain calm and offer to locate the clos- a 1 gram/ml sterile injection by com- acute renal failure, inhibition of alcohol est Emergency Vet and even call them so pounding pharmacists capable of provid- dehydrogenase is of little benefit because they are prepared in advance for the sick ing USP 797 compliant sterile com- almost all of the EG has already been animal’s arrival. pounds. metabolized. The prognosis for these animals is guarded to poor. Treatment Ethanol should include correction of fluid, elec- When fomepizole isn’t available, or if trolyte, and acid-base disorders and, if owners can’t afford it, the other choice is possible, establishment of diuresis. Usu- ethanol as it binds much more easily to ally, 12 to 24 hours post ingestion, drugs alcohol dehydrogenase than ethylene gly- are of little value because the EG has col. Because ethanol is the preferential already been metabolized in the body and substrate for alcohol dehydrogenase, the ethanol or fomepizole should not be used presence of ethanol should essentially in anuric patients because the un- block metabolism of ethylene glycol. metabolized EG will not be eliminated The canine dose for a 20% solution is and therefore it is a waste of financial References 5.5ml/kg IV every 4 hours for five treat- resources. 1. Up-To-Date: January 2012 ments then every 6 hours IV for four ad- 2. CDC.gov: January 2012 ditional treatments. For cats, 20% etha- Role of Veterinary Pharmacist 3. MerkVetManual.com nol is dosed 5 mL/kg IV and given as a With Antizole Vet® not currently avail- 4. Gfeller RW and Messonnier S. Hand- drip over 6 hours for five treatments, and able, pharmacists must be able to cor- book of Small Animal Toxicology & then over 8 hours for four more treat- rectly compound via USP 797 standards, Poisonings. St. Louis, MO: Mosby, Inc. ments. either 4-methylpyrazole 1gram/mL sterile 1998: 135-140. injection (fomepizole) or, the proper 20% 5. Khan SA, Schell MM, Trammel HL, et Sodium Bicarbonate IV ethanol dose for their animal patients. al. Ethylene Glycol Exposure Managed The metabolic acidosis associated with On the other hand, pharmacists can use by the ASPCA National Animal Poison Control Center from July 1995 to De- metabolism of ethylene glycol is cor- allegation to create 5% or 7% IV solu- rected by administration of sodium bicar- cember 1997. Vet Hum Toxicol. 1999: 41 tions depending on the strength of ethanol (6); 403-6. bonate. The formula to find the dose is: used (i.e. 40% is 80 proof) then diluting 6. Dial SM, Thrall MH, Hamar DQ. Effi- in appropriate IV solution such as LRS or cacy of 4-methylpyrazole for treatment Bicarb (mEq) = D5W. Pharmacists must also provide 0.3 − (0.5 × body weight kg ) x of ethylene glycol intoxication in dogs. instructions on how to safely administer Am J Vet Res. 1994: 55(12); 1771-82. (24 − plasma bicarbonate) this compound with the correct weight 7. Plumb DC. (2011). Plumb’s Veterinary based dosing over the correct CRI time as Drug Handbook (7th ed.)Stockholm, WI: One-half of this dose should be given mentioned above and include the use of Wiley-Blackwell IV slowly to prevent overdose, and an in-line filter. Pharmacists also have plasma bicarbonate concentrations should This article was written & submitted by: the unique ability to increase public be monitored every 4-6 hours. Additional awareness regarding ethylene glycol poi- Jessica Gaskins, PharmD doses of bicarbonate based on the above soning. Most owners do not realize the North Carolina State University formula are frequently necessary. Moni- life-threatening severity of anti-freeze College of Veterinary Medicine, toring urine pH may also be helpful with ingestion and recommending propylene Veterinary Pharmacy Resident a goal of maintaining the urine pH be- glycol-based antifreeze should be encour-