In veterinary medicine, the primary treatment for toxicant exposure should be decontamination and detoxification of the patient to inhibit or minimize further toxicant absorption and to promote excretion or elimination of the toxicant from the body. When treating the poisoned patient, the clinician should have an understanding of the underlying mechanism of action of the toxicant, the pharmacokinetics (including absorption, distribution, metabolism, and excretion [ADME]), and the toxic dose (if available). This will help determine appropriate decontamination and therapy for the patient. If an antidote is available, its use should be promptly initiated if available, safe, and financially feasible. An antidote is defined as “any compound that is used to counteract the effects of a toxicant.” The goal of an antidote is to interfere with the ADME of a toxicant and eliminate or reduce the adverse effects of the toxicant. Antidotes can be classified into several board categories, based on the mechanism by which they work or are protective. These include the following:

• Chemical antidotes
• Functional antidotes
• Pharmacological or physiological antidotes

Unfortunately, in veterinary medicine, there is “little economic incentive for pharmaceutical companies to seek approval for antidotal medications with only a small projected market;” hence, there is a paucity of antidotes available. The use of antidotes is generally considered extra-label in veterinary medicine (Animal Medicinal Drug Use Act [AMDUCA] of 1994), and pet owners should be made aware of this. As there are thousands of “antidotes” out there, this lecture will only focus on the most common or important 10–12 used in veterinary medicine. When in doubt, the ASPCA Animal Poison Control Center should be consulted as needed.

Chemical Antidotes

Chemical antidotes work directly on the toxicant; these specific antidotes bind to the toxicant to “yield an innocuous compound that is excreted from the body.” Chemical antidotes work by affecting how the toxicant works or interacts directly with the compound. Chemical antidotes can either “decrease the toxicity of the agent or increase its excretion” and work by binding with the toxicant to product a non-harmful compound that is then later excreted by the body. Examples of chemical antidotes include antivenins, chelating agents and immunologic agents such as F(ab’) fragments—e.g., digoxin-specific F(ab’) fragments.

Antivenins

Antivenins work by neutralizing venom antigens via passive immunization with venom antigen-specific immunoglobulins (from horse, sheep) that have been hyper-immunized with the venom(s) of a given species. The use of antidote therapy can be considered with venomous snake and black widow spider bites to help prevent or help treat coagulopathy, paralysis, and thrombocytopenia; however, they will not help with tissue necrosis. Depending on the type, certain antivenins may be difficult to secure or find. The National Animal Poison Control Center (888-426-4435) or any Regional Poison Control Center (800-222-1222) may have additional resources that can enable the location of an appropriate antivenom. There are three USDA-approved veterinary antivenins available against North American pit vipers including the following types:

• Antivenin (Crotalidae) Polyvalent (Equine origin) (ACP); lyophilized IgG preparation; (Antivenin™; Boehringer Ingelheim Vetmedica, Inc., St. Joseph, MO); canine indication
• Antivenin Crotalidae Polyvalent (Equine origin); liquid plasma preparation; (Rattler Antivenin™; Mg Biologics, Ames, IA); canine and equine indication
• Antivenin Polyvalent Crotalidae F(ab’)₂ (Equine origin); liquid injectable preparation; (VenomVet™; MT Venom, LLC, Canoga Park, CA); use indication species not specified

There are two FDA-approved human antivenin products:

• Antivenin (Crotalidae) Polyvalent Immune Fab (Ovine origin); lyophilized preparation; (CroFab®; BTG International, West Conshohocken, PA)
• Crotalidae Immune F(ab’)₂ (Equine origin); lyophilized preparation; (Anavip®; Rare Disease Therapeutics, Inc., Franklin, TN)

The benefit of using an antivenin that contains F(ab) components of the immunoglobulin molecule is that it has lower risk of allergic reaction and allows for faster reconstitution and has a greater volume of distribution. However, its use is off label since it is for humans, and it is expensive, and the risks of administration may outweigh the potential benefits. The use of IV antivenin should be considered early in the treatment of envenomation (ideally within 6 hours). Depending on the type of antivenin used, several vials may be necessary, which can be cost-prohibitive. The patient should be monitored carefully during administration of antivenins, as serum sickness, anaphylactic, or anaphylactoid reactions can occur, particularly if the patient has received antivenin previously.

Immunologic Agents/Fab (Digibind, DigiFab)

Digoxin immune Fab fragments can be used for life-threatening cardiac glycoside toxicosis (e.g., cardiac glycoside-containing plants, digoxin, Bufo toad); however, its use is typically limited to life-threatening cardiac arrhythmias where traditional antiarrhythmic therapy has failed. The ds-Fab moieties work by “binding free digitalis glycoside molecules in the extracellular fluid as well as those already bound to sodium-potassium ATPase.” It has been reported to successfully treat toxicosis and is commercially available as 2 ds-Fab products: DigiFab (Protherics, Inc., Nashville, TN, USA) and Digibind (GlaxoSmithKline, Parma, Italy]. Antidigitoxin Fab fragments have a higher affinity for digoxin. Each bottle of Digibind contains 38 mg of Fab, which will bind to 0.6 mg of digoxin or digitoxin. Each vial of DigiFab contains 40 mg of Fab, which will bind approximately 0.5 mg digoxin. The FDA information for DigiFab is available here: www.fda.gov/downloads/BiologicsBloodVaccines/BloodBloodProducts/ApprovedProducts/LicensedProductsBLAs/FractionatedPlasmaProducts/ucm117624.pdf. Digoxin immune Fab fragments may be cost prohibitive ($500/bottle) and can be obtained from a human hospital. Little evidence or animal studies have been used to establish the veterinary dose; however, published doses include:

• If the serum digoxin level is available, the number of vials should be based on the serum digoxin level (ng/mL) ´ body weight (in kilograms)/100.

Unfortunately, in the veterinary patient, it is rare to obtain a timely serum digoxin concentration. For this reason, the general recommendation is to administer 1–2 vials (slowly over 30 minutes, using a 0.22-micron filter if possible) and reassess the patient.

Enzyme Inhibitors

Fomepizole (also known as 4-MP) is a competitive inhibitor of alcohol dehydrogenase. It is preferred over ethanol for the treatment of ethylene glycol toxicity in dogs as it does not result in CNS depression, diuresis, and hyperosmolality. In cats, it is the antidote of choice if used within 3 hours, as the survival with ethanol is much worse in comparison to fomepizole. While expensive, it is lifesaving when administered to dogs within the first 8–12 hours of ingestion; some sources say that it can be effective as late as 36 hours post-exposure. In cats, the antidote must be administered within 3 hours of ingestion to be effective. Dosing for 4-MP is significantly different between dogs and cats:

• Dogs: 4-MP 20 mg/kg, IV, first dose (over 15–30 minutes); 15 mg/kg at 12 hours; 15 mg/kg at 24 hours; 5 mg/kg at 36 hours. 5 mg/kg IV can be given every 12 hours until the EG test is negative
• Cats: 4-MP 125 mg/kg, IV, first dose; 31.25 mg/kg IV at 12 hours; 31.25 mg/kg IV at 24 hours; 31.25 mg/kg at 36 hours

Pharmacological Antidotes

Pharmacological antidotes (often called physiological antidotes) work by directly antagonizing the toxicant. These types of antidotes work by directly working on the receptor site, by preventing formation of toxic metabolites, by restoring normal physiological function, or by assisting with more rapid elimination of the toxicant from the body. Examples include reversal agents (e.g., naloxone for opioids, atipamezole for alpha-adrenergic agonists, flumazenil for benzodiazepines), N-acetylcysteine (e.g., acetaminophen), pralidoxime for OP toxicosis, etc.

• Atipamezole is an alpha-adrenergic antagonist that reverses medetomidine and dexmedetomidine. It can also be used off-label to reverse other drugs such as xylazine, clonidine, brimonidine, tizanidine, and amitraz.⁶ It has a very short half-life (e.g., 2–3 hours) and may need to be re-dosed if necessary.
• Atropine is an anticholinergic that competes with acetylcholine at the post-ganglionic parasympathetic sites (and hence is called an antiparasympathetic or parasympatholytic drug). It is also called an antimuscarinic as it antagonizes the muscarine-like actions of AcH. It is used for the treatment of SLUDGE signs from organophosphate or carbamate toxicity. With OP toxicosis, atropine should be given despite the tachycardia; higher doses are often necessary.
• Ethanol can be used as an antidote for ethylene glycol toxicosis, if fomepizole is not available. Ethanol competes with alcohol dehydrogenase, thereby preventing metabolism of ethylene glycol into its more toxic metabolites. Only clear ethanol should be used (e.g., grain alcohol, vodka).
• 7% ethanol is made by removing 175 ml from a 1-L bag of saline and adding 175 ml of an 80-proof vodka. If 190-proof grain alcohol is available, a 7% solution can be made by removing 74 ml from a 1-L bag of saline and adding 74 ml of the grain alcohol.
• Dose: loading dose of 8.6 ml/kg (600 mg/kg) 7% ethanol slow IV then continue with a CRI of 1.43 ml/kg/h (100 mg/kg/h), IV as a CRI for 24–36 hours.
• Flumazenil (Romazicon™) is the reversal agent for benzodiazepine overdoses as it competitively antagonizes the benzodiazepine receptor site. It is an imidazobenzodiazepine derivative that rapidly displaces benzodiazepines from the receptor, reversing its effect within minutes. It is very short-acting (e.g., 1–2 hours) and can be expensive. The author generally only uses this for severe respiratory depression or marked CNS signs.
• N-acetylcysteine (NAC) is the primary antidote for the treatment of acetaminophen/paracetamol toxicosis. NAC provides an available source of intracellular glutathione, and also is thought to have additional hepatoprotective effects including anti-inflammatory activity, enhanced mitochondrial energy metabolism, and improved oxygen delivery with liver injury. Specifically with acetaminophen, toxicosis occurs when glucuronidation and sulfation pathways are depleted; this results in toxic metabolites building up and secondary oxidative injury occurring. With acetaminophen toxicosis, NAC is used to limit the formation of the toxic metabolite NAPQI by providing additional glutathione substrate. While NAC can be safely used as a hepatoprotectant with hepatotoxicants, there is a paucity of veterinary literature on the outcome with its use. That said, it is considered benign and safe. When dosing, the author recommends parenteral administration to allow for continued administration of activated charcoal (as some limited enterohepatic recirculation occurs with acetaminophen toxicosis). When administering NAC by any route, it must be diluted, as it is corrosive or irritating. If NAC is not available, S-adenosyl-methionine (SAMe) can be also given as a glutathione source with any hepatotoxicant.
• Naloxone is a pure opioid antagonist and can be used for the reversal of opioid overdose. It has a rapid onset of action (1–5 minutes) but short duration of action (1.5 hours). Repeated doses are often necessary. It will not reverse respiratory depression from buprenorphine; much higher doses are often necessary to reverse buprenorphine.

Functional Antidotes

Functional antidotes lessen the severity of the clinical signs of the toxicant. Functional antidotes do not directly interact with the toxicant itself. An example of functional antidotes includes cyproheptadine (e.g., serotonin syndrome), calcitonin (e.g., hypercalcemia), bisphosphates (hypercalcemia), intravenous lipid emulsion (ILE) (e.g., fat-soluble toxicant exposure), and methocarbamol (e.g., toxicants resulting in tremors).

• Bisphosphates (e.g., pamidronate) are used as an antidote for hypercalcemia secondary to cholecalciferol toxicosis. It lowers calcium levels by binding to hydroxyapatite crystals within the bone. Bisphosphates impede osteoclast activity and induce osteoclast apoptosis. As it is now generic, it is much more cost-effective and readily available. Calcium levels should be monitored every 12 hours; if persistent hypercalcemia is evidence, additional dosing can be used 3–7 days after the initial dose. Calcitonin can also be considered. It is preferred by some toxicologists over the use of calcitonin as it has longer-lasting effects.
• Calcitonin can be used to treat hypercalcemia secondary to cholecalciferol toxicosis. It is an osteoclast inhibiting hormone that acts directly on bone by inhibiting osteoclastic bone resorption. Calcitonin also reduces tubular reabsorption of calcium (along with phosphate, potassium, sodium, magnesium, and chloride) and promotes renal excretion. It must be given parenterally, as it is destroyed in the gut after oral administration. Can be used when a bisphosphate is not readily available or in conjunction with treatment.
• Cyproheptadine (Periactin™) is a serotonin antagonist and antihistamine (H1 blocker). Cyproheptadine competes with histamine for sites on H1-receptor sites. Formerly used as an appetite stimulant in cats, it is now used to treat serotonin syndrome (e.g., agitation, hyperesthesia, tremors, seizures) secondary to SSRI antidepressant and amphetamine toxicosis.
• Intravenous lipid emulsion (ILE) For more information on ILE, please see the proceedings on “The use of ILE for the poisoned patient.”
• S-adenosyl-methionine (SAMe) acts as a methyl donor, while also donating an aminopropyl group to be a source of polyamines. SAMe also generates sulfur containing compounds necessary for conjugation reactions used in detoxification within the liver and as a precursor for glutathione. Exogenous SAMe increases liver and RBC glutathione levels and/or prevents its depletion. It is also an inhibitor of apoptosis within the hepatocyte. It should be given on an empty stomach, as the presence of food can significantly reduce the amount absorbed. It is commonly used as a benign, safe hepatoprotectant with toxicants such as Amanita spp. poisoning, blue-green algae, xylitol, acetaminophen, etc.

Limitations of Antidotes

There are several limitations to the use of antidotes in veterinary medicine. Unfortunately, some are cost-prohibitive, including 4-MP (e.g., fomepizole), which is currently several thousand per bottle (unless compounded). Likewise, F(ab’) crotalid antivenin therapy can cost close to $1000/bottle. Certain antidotes have limited to no availability; the antidote for botulism (antitoxin) is only available through the Centers for Disease Control and Prevention (CDC). Lastly, keep in mind that the cost versus benefit analysis must be considered for the patient. Adverse effects can rarely be seen with antidotes and can result in rare but potentially deadly complications. The pet owner should be made aware of the extra-label use—along with the rare complications—that can occur with the use of antidotes in the veterinary patient.

Conclusion

Knowledge of the underlying mechanism of action, the pharmacokinetics (including absorption, distribution, metabolism, and excretion), and the toxic dose of the toxicant are imperative in determining appropriate decontamination and therapy for the patient. Keep in mind that as very few toxicants have a readily available antidote, treatment should always be aimed at symptomatic supportive care. When in doubt, if the veterinary professional is unaware of how to treat a specific toxicant, the ASPCA Animal Poison Control Center should be consulted for life-saving care.

Note

When in doubt, all drug dosages should be confirmed and cross-referenced with a reference guide.

Footnotes

a. Personal communication, the ASPCA Animal Poison Control Center.
b. Loftin E. Toxicities in the ER. Available at: www.dovelewis.org/pdf/events/Erika_toxins.pdf. Accessed August 11, 2018.

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