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A REVIEW OF VETERINARY ANTIDOTES
William Hare DVM, PhD, DABVT; USDA-ARS-ANRI, 177C BARC-East, 10300 Baltimore Ave. Beltsville, MD 20705
Lynn O Post DVM, PhD, DABVT; FDA, HFV-216, 7500 Standish Place, Rockville, MD 20855
Fred Oehme DVM, PhD, DABVT; Kansas State University, M213 Mosier Hall, 1800 Denison Ave., Manhattan, KS 66506
“Antidote” by definition is a remedy to counteract a poison. However, there is no consensus on where the term begins or ends. Classically speaking, an antidote acts specifically to prevent, counteract, reverse or relieve the action of a toxicant, i.e. the exact dose of poison counteracted by the same exact dose of antidote leads to no deleterious effect. But, contemporary usage of the term antidote usually refers to any substance that prevents or relieves the effects of a toxicant. Antidotes, like toxicants, are potentially harmful and should not be used indiscriminately; for as Paracelsus stated in the 18th century, “All substances are poisons; there is none which is not a poison. The right dose differentiates a poison from a remedy.” Since an antidote is a remedy for a poison, the pharmacologic-therapeutic effects of various antidotes, including their mechanism of action, opens the door to further classification and definition. An antidote, which would have therapeutic efficacy on all toxicants, would be referred to as a universal antidote. However, no such antidote exists. There are no antidotes which work on all toxicants. However, chemical antidotes bind chemically with the toxicant or its active site. Mechanical antidotes prevent the absorption of a specific toxicant. There are also physiologic antidotes that therapeutically produce systemic effects opposite to those produced by the toxicant. There are specific antidotes, such as antitoxins, which act specifically on toxins. Methods and protocols for toxicant decontamination of a suspected poisoned patient regardless of whether it is a food animal or companion animal should not be confused with the use of antidotes. Dilution, non-specific absorption, adjustments of pH, and other measures with natural or synthetic chemical substances, including some patent medicine preparations containing magnesium hydroxide, hydrogen peroxide and/or activated charcoal are often used in decontamination procedures. These substances, though still used, are usually applied after ingestion or exposure, but before absorption. Just as antidotes are a remedy, some medicinal substances if given to a patient poisoned by a specific toxicant are detrimental and would cause retrogression. This could happen by interfering with protein binding of the toxicant by administering a drug with greater protein binding affinity, thereby releasing more free-toxicant. It could also happen by adjusting pH and reducing the charge on a toxicant so that it is more easily absorbed. The potential for adverse drug-toxicant interaction is real and must be considered when treating all poisoning cases. In Table 1, we include most all of the antidotes presently available that could be beneficial in
veterinary clinical toxicology. In addition, readers will note that the vast majority of these antidotes are “not approved veterinary drugs,” and therefore not labeled for use in animals. Hence, it must be stated that the extra label use of most of these drugs as antidotes does not imply any recommendation or even encouragement by the authors for non-judicious use. Extra label use of drugs in veterinary medicine is a serious consideration, and the taking of such a responsibility by an attending veterinarian should always be done with all due care and concern. Published works referencing information on antidotes and their use are cited in Table 1 and listed in Table 2.
The Animal Medicinal Drug Clarification Act of 1994 allows veterinarians to legally administer or prescribe any human or veterinary drug for extra label purposes. However, any liability associated with their use becomes the responsibility of the administering veterinarian. This is a particularly critical issue when assuring that no drug or toxic residues remain in the animal tissues when intended as a human or animal food source. Likewise, the veterinarian has a responsibility to assure a safe and wholesome food-animal enters the food chain. Therefore, the veterinarian must take into consideration poison residues and institute appropriate pre- Clinical toxicology is ever changing due to the continually evolving array of potentially toxic substances, which in practice is frequently followed by the development of appropriate antidotal therapy. Because of this, safety precautions should always be taken, regardless of whether the patient is a food animal or a companion animal. Food safety and the quality assurance of animal-produced food products can not be jeopardized. Proper steps in determining a risk assessment of both the toxicant and the antidote must be carried out. The veterinarians and professional staff of the Food Animal Residue Avoidance Databank (FARAD) are readily available to assist veterinarians in determining appropriate withdrawal times for any extra label drugs used as antidotes. Some withdrawal times for commonly used extra label antidotes are well known and published; others are less so. Sodium nitrite and sodium thiosulfate administered to treat cyanide toxicosis have no withdrawal times; while methylene blue used for methemoglobin formation from nitrate, nitrite and chlorate poisoning does. Methylene blue currently has a withdrawal time of 180 days for meat and milk producing animals. However, withdrawal time can change as more relevant data is generated through controlled studies. Therefore, it is recommended that FARAD be contacted, either by telephone (888-873-2723) or by e-mail (farad~1Thcsu.edu or farad~ucdavis.edu), to determine the most current information on appropriate withdrawal times. As our clinical toxicology experiences increase and our knowledge broadens, so will the standards of therapy and the clinical choices for which antidote and detoxification procedure may be most appropriate in any given situation. One must remember that it is always the attending veterinarian’s responsibility to determine the most appropriate antidote for the situation, select its dose, and prescribe the treatment protocol. The veterinarian should always rely on his or her experience and knowledge with poisons and antidotes, as well as giving earnest consideration to the poisoned animal, the circumstances surrounding the exposure and The ease of availability of human and veterinary pharmaceutical products, as well as chemical products, creates a perpetual problem. The manufacturing and marketing of these products are usually driven by economics. When there is little or no profit to be made with a new drug, there is usually little effort made to identify and market an antidote. The Food and Drug Administration (FDA) Center for Veterinary Medicine may apply regulatory discretion in the use of unapproved antidotes, especially in life-threatening situations, and thereby can allow legitimate manufacturers to produce and market such needed products. However, use of unapproved antidotes can generate unwarranted risk, can become problematic, and is a high priority regulatory issue when illegal antidote residues are detected in food animals and their products. Therefore, antidotes must be used responsibly and in appropriate circumstances. In addition, the vast number of commercial company mergers, coupled with frequent changes in the names of pharmaceutical firms and their products, makes finding the best available source One may check on current availability of specific antidotes marketed as a pharmaceutical products by utilizing the vast resources of the interne, as well as the contact information in Table 3. Following are internet sites that may be helpful:
• PharminfoNet (http://oharminfo.com) of the Pharmlink-Pharmaceutical Information Network (http://pharminfo.com/pharmlink.htnil) may be helpful in tracking down the current manufacturing and commercial availability of pharmaceutical products. • Chemfinder (http://www.chemfinder.com) may locate chemical products used as • The Physicians Desk Reference (http://www.pdr.net), Medical Economics Inc., Montvale, • The Merck Index (http://www.rnerck.com), Merck & Co., Inc, Whitehouse Station, NJ. • Compendium of Veterinary Products, North American Compendium, Inc., Port Huron, Ml. The doses for antidotes listed in Table 1 are given as a guide. Many are derived from anecdotal experiences, some have been handed down through generations, and others are veterinary extrapolations of human manufacturer’s recommendations. Remarkably, only a few have been confirmed by scientific investigations. However, all have histories of being successful at one time or another. Table 4 provides literature sources for the use of such antidotes in veterinary
medicine. It is our hope that judicious use of these antidotes will be of benefit in saving animal life, relieving animal suffering and conserving animal resources. TABLE 1. VETERINARY ANTIDOTES, SOURCES, INDICATIONS AND
Antidote Formulation
Source/References
Indication Dosage
organophosphate or strychnine poisoning. sulfide, and opiate poisoning as well as poisoning with metallic salts; arsenic, selenium, tin, thallium, antimony. recycling. Not effective for minerals (elemental, acids, salts, alkalis), nor oils. USP standardization with strychnine sulfate. poisonings: flurazepam, midazolam, forazepam, of Bethlehem (Ornithogalum), Bufo Toads (Bufonidae), Monarch Butterfly (Danaus), Digitalis, Digitoxin, Digoxin. and repeated every 2-4 hours as indicated; Cattle, Horses, Sheep, Dogs 1,500-20,000 Units in 50-250 ml 0.9% normal saline by slow intravenous drip; Dogs, Cats Alternative dosage is 100-200 Units/kg slowly IV, administered in 250 ml of 0.9% normal saline. Smaller the victim, the larger the dose; Dogs, Cats, Cattle, Sheep/Goats, Horses Monitor for acute and delayed hypersensitivity. and repeated every 2 hours as indicated. Smaller the victim, the larger the dose; Dogs, Cats, Cattle, Sheep/Goats, Horses Monitor for acute and delayed hypersensitivity administered slowly IV over a 1 hour period; Dogs, Cats Monitor for acute and delayed hypersensitivity. over a 1 hour period; Dogs, Cats Monitor for acute and delayed hypersensitivity. Weed (Amaranthus), Johnson Grass (Sorghum), Various Weeds and Feed Grain plants that have been stressed with drought or herbicide and thereby accumulate nitrates. competitive reversal agent for alpha-2-adrenergic agonist. Used in the treatment of medetomidine, xylazine, amitraz, midodrine, and phenylepherine overdose and poisoning. (Gyromitra), Mower’s Mushroom (Panaeolus), Common Toadstool Mushroom (Gymnopilus), Azaleas (Rhododendron), Carbolic Acid, Phenol, Benzene, Physostigmine, Nitrobenzene, Cyanides, Opium, Morphine monitored for kidney function and zinc levels. Phenobarbital, Thyroid hormones, Iron salts, Fat soluble vitamins (Vitamins A,D,E,K), Ionophores. Fenfluramine, Fluoxetine, Hydroxytryptophan, Imipramine, Isocarboxazid, Lithium, Meperidine, Moclobemide, Paroxetine, Selegiline, Sertraline, Tranylcypromine, Tryptophan, Venlafaxine, Bladder Flower (Araujia), Bull Nettle (Cnidoscolus), St. John’s Wort (Hypericum), Stonecrop (Sedum), Skunk Cabbage (Symplocarpus), Nettles (Urticaceae). halogenated hydrocarbons, atropine, dinitrophenol, metaldehyde, cocaine, amphetamines, spent Hops (Lumulus), Ergot alkaloids (Claviceps), Tall Fescue (Festuca), Jimson Weed (Datura), Ryegrass (Lolium) Web Spiders in general (Dipluidae). paraquat, aminoglycoside and acetaminophen poisonings. Buckeye (Aesculus), False Morel (Gyromitra). Bismuth, Chromium, Nickle, Tungsten, Zinc, and methyl bromide poisoning. Nightshade Atropa), Jimson Weed (Datura), Henbane (Hyoscyamus), Mandrake (mandragora), Jasmine (Cestrum), Bittersweet (Solanum), Ground Cherry (Chinese Lantern) (Physalis). Cleaners and Detergents and most other Corrosive Chemical poisonings. Monitor electrolytes acid/base balance. Rodenticides, Vitamin D, and Calcipotriene Poisonings. Monitor for efficacy and seizure induction. 125 mg/kg PO; Dogs, Cats Loading dose, followed by 35 mg/kg q12h PRN for 4 treatments. Must be initiated within 3 hours of ingestion. Monitor renal function. chemical poisoning; aqueous cleaners, bases and alkalis. (Canavalia), Bird’s-foot Trefoil and Nevada Deer Vetch (Lotus), Clovers (Trifolium), Hydrangea (Hydrangea), Rushes (Juncus), Bamboo (Nandina), Stargrass/Bermudagrass (Cynodon), Mannagrass (Glyceria), Switchgrass, Kleingrass, and Millet (Panicum), Canarygrass (Phalaris), Indiangrass (Sorghastrum), Sorghum and Sudangrass(Sorghum), Buttercup (Ranunculus), Serviceberry, Shadebush, and Juneberry (Amelanchier), Mountain Mahogany (Cercocarpus), Cotoneaster (Contoneaster), Christmas Berry (California Holly) (Heteromeles), Apricot, Cherry and Chokecherry, Almond, Peach, and Mock Orange (Prunus), Firethorn (Pyracantha), Jetbead (Rhodotypos), Spirea (Bridal Wreath) (Spirea), Yew Taxus), Arrowgrass (Triglochin) lead foil, lead weights, lead paint and sinker poisonings especially of cattle, swine. (Acetanilide), Benzocaine, Chloates, Hydrazine, Dapsone, Nitrates, Nitrites, Nitrobenzenes, Cresol, Duron, Gluthetimide, Cetacaine, Mercaptan, Napthalene, Nitric Oxide, Nitroglycerin, Propylene glycol dinitrate, Nitrofurantoin, Nitrotolulenes, Promiquine, Quinine, Pigweed (Amaranthus), Galenia groundcover (Galenia), Ragweeds (Ambrosia), Canada thistle (Cirsium), Cudweeds (Gnaphalium), Sunflower (Helianthus), Milk thistle (Silybum), Golden eyes (Viguiera), Sorghum (Poaceae), Sage (Salvia), Lambsquarter and Goosefoot (Chenopodium) Gelsamine, Gelsemicine, Butterfly Bush (Buddleja), Yellow Jessamine (Gelsemium), poisonings. Tremorgenic Mycotoxin (Acremonium), Ergot Alkaloids (Claviceps), and Penicillium Molds as calcium caseinate (phosphoprotein) denatures and coagulates in acids, soluble in water, non-polar solvents and especially aqueous alkali solutions. Used in the treatment of poisonings: Bleaches, Soaps, Detergents, Ammonia Compounds, General Corrosives, Organic Solvents, Essential Oils, Volatile organics, Oxalates, Dumb Cane (Dieffenbachia), Philodendron (Monstera and Philodendron), Rhubarb (Rheum), Goosefoot Family (Chenopodiaceae), Sugar Beet (Beta), Jack-in-the-Pulpit (Araceae), Skunk Cabbage (Symplocarpus), Elephant-ear (Colocasia), Halogeton (Halogeton), Sorrel (Oxalis and Rumex), Purslane (Portulaca and Trianthema), Tumbleweed (Salsola), Greasewood (Sarcobatus), Soda Bush (Threlkeldia). Codine, Heroin, Dextromethorphan, Atropine, Diphenoxylate, Fentanyl Citrate, GHBA, Guanfacine, Hydrocodone, Homatropine, Hydromorphone, Ketobemidone, Levomethadyl, Acetate, Levophanol Tartrate, Lisinopril, Loperamide, Meperidine, Methadone, Morphine, Nalbuphine, Nitrous Oxide, Opium Alkaloids, Opium Tincture, Oxycodone, Oxymorphone, Paregoric, Propoxyphene, Sulfentanil, Tramadol, Valproic Acid, Zipeprol, Jimsonweed (Datura), Belladonna (Atropus), Jessamine (Cestrum), Henbane (Hyoscyamus), Poppy (Papaver). Vecuronium, Botulism (Cl. Botulinum), and as a secondary agent in the treatment of Coral (Micrurus) and Cobra (Naja) snake bite and Tetrodotoxin poisoning from Porcupine Fish (Diodon), Deadly Nightshade Atropa), Jimson Weed (Datura), Henbane (Hyoscyamus), Mandrake (Mandragora), Jasmine (Cestrum), Bittersweet (Solanum), Ground Cherry (Chinese Lantern) (Physalis) Copper, Ergot alkaloids (Ergotamine, Ethchlorvynol), Amanita (Amanitia), Yew (Taxus), Quinine sulfate, Parazosin HCL, Lilly-of-the-valley (Convallaria), Periwinkle (Vinca), Tricyclic antidepressants, Phenoxybenzamine, Phentolamine, Terazosin treatment of poisoning: Acrylonitrile, Carbon Monoxide, Carbon Tetrachloride, Cyanide, Hydrocarbon Products, Hydrogen Sulfide, Methylene Chloride, Chloroform, Rosaceae sub-family of plants including Stone-Fruits, Chokecherry, Elderberry, Laurel, Hawthorn, Mountain Ash, etc., Mushrooms (Lepiota, Amanita, and Galerina), Arachnid Bite-Systemic Manifestation (Loxosceles, Agelenopsis, Phiddipus, Lycosa). poisonings: Vitamin D, Cholecalciferol Rodenticides, Calcipotriene, Jessamine (Cestrum), Leadwort (Plumbago), Sacahuista-Bunchgrass (Nolina) Iron, Lead, Mercury, Bismuth, Gold, Arsenic and possibly other heavy metals. Monamine Oxidase Inhibitors, 4-aminopyridine, Metaldehyde, Isoniazid, Strychnine, Tetanus Toxin, Hemlock (Cicuta and Aethusa), Horse Chestnut and Buckeye (Aesculus), Camphor (Cinnamomum). stimuli. It also is a marked inducer of microsomal enzymes. Used to control seizures associated with drug overdose and poisoning, as well as stimulating detoxification of pesticides: Organochlorines and Chlorinated hydrocarbons, Cocaine, Monamine oxidase inhibitors (MAO), 4-aminopyridine, Metaldehyde, Isonazid. blocks alpha-adrenergic receptors, in a transient way, by action on vascular smooth muscle. Produces a positive inotropic and chronotropic cardiac effect, increasing cardiac output, through action on beta-adrenergic receptors. Used to control hypertensive episodes related to poisoning and drug overdose. Used in the treatment of poisoning by direct acting alpha-adrenergic agents like Epinepherine, Phenylepherine, and Ergotamine, as well as indirect acting agents like Cocaine, Amphetamines, Tricyclic antidepressants, Monamine oxidase inhibitors and plants Acacia and Guajillo (Acacia), and Sassafras (Sassafras) . (Lycopersicon), Belladonna (Atropa), Jimsonweed (Datura), Nightshade (Solanum), Boxthorn (Lycium), various Mushrooms; Amanita (Amanita), Boletus (Boletus), Clytocybe (Clytocybe), Inocybe (Inocybe), as well as reversing the effects of imipramine and other tricyclic antidepressants. plant poisonings: Coumarin, Indandione, Quinidine, Quinine, Salicylates, Sulfonamides, Brodifacoum, Bromadiolone, Chlorphacinone, Hydroxycoumarin, Indanedione, Phytonadione, Pindone, Pivaldione, Dicumarol, Warfarin, Difethialone, Sweet Clover (Melilotus), Vernalgrass (Anthoxanthum). Used in the treatment of poisonings causing severe respiratory depression: Petobarbital, Phenobarbital, Secobarbital, Hexobarbital, Methexital, Thiopental, Thiamyal, Thialbarbitone. and drug overdose: Atropine, Hyoscyamine, Scopolamin, Henbane (Hyoscyamus), Mandrake (Mandragora), Tomato (Lycopersicon), Belladonna (Atropa), Jimsonweed (Datura), Nightshade (Solanum), Boxthorn (Lycium), various Mushrooms; Amanita (Amanita), Boletus (Boletus), Clytocybe (Clytocybe), Inocybe (Inocybe). central nervous system respiratory centers than neuromuscular sites. Used in the treatment of poisoning by organophosphate pesticides and drug overdose: Bromophos, Chlorfenvinphos, Chlopyrifos, Diazinon, Dicrotophos, Dioxathion, Disulfoton, Endrophonium, Fensulfothion, Fenthion, Malathion, Methidathion, Sarin, Soman, Tabun, Parathion, Profenfos, Tacrine, Terbufos, Tetraethyl Pyrophosphate, Echothiophate. neutralizing their action. Used in the treatment of anticoagulant poisoning and drug overdose: Heparin, Dalteparin, Enoxaparin Iron Ferrocyanide Pyridostigmine Bromide anticholinesterase activity. 0.05-0.15 mg/kg IM Has fewer side effects neostigmine. Used in the pre-emptive treatment of nerve gas poisoning and drug overdose of some non-depolarizing relaxants: Sarin, Soman, Tabun, Tubocurarine, Gallamine, Atracurium, Metocurine, Pancuronium Bromide, Vecuronium, Botulism (Cl. Botulinum), and as a secondary agent in the treatment of Coral (Micrurus) and Cobra (Naja) snake bite and Tetrodotoxin poisoning from Porcupine Fish (Diodon), Deadly Nightshade Atropa), Jimson Weed (Datura), Henbane (Hyoscyamus), Mandrake (Mandragora), Jasmine (Cestrum), Bittersweet (Solanum), Ground Cherry (Chinese Lantern) (Physalis) transamination and decarboxylation with generation of pyruvate, nicotinic acid (NAD), porphyrins, arachidonic acid and serotoin. Used most often in the treatment of poisonings and drug overdoses which generate seizures, coma and general neuropathy: Acrylamide, Altretamine, Chloamphenicol, Ethylene Glycol, Hydrazine, Isonazide, Crimidine, Oral Contraceptives, Cycloserine, Iron, Alcohol, False Morrel (Gyrometria). Nortriptyline, Potassium Chloride, Propylene Glycol, Quinidine, Strychnine, Trimipramine Maleate, Ethanol, Salicylates, Chlorphenoxy Herbicides, Cockerell and Rubberweed (Hymenoxys), Jimmyweed and Goldenrod (Isocoma), Sugar Beet (Beta) Acetonitrile, Chinese Taro (Alocasia), Elderberry (Sambucus), Poison Suckleya (Suckleya), Eucalyptus (Eucalyptus), Cassava (Manihot), Stillingia (Stillingia), Acacia (Acacia), Trefoil (Lotus), Clover (Trifolium), Rush (Juncus), Bamboo (Nandina), Cherry, Plum, Peach, etc. (Prunus), Mannagrass (Glyceria), Indiangrass (Sorghastrum), Sorghum and Johnsongrass (Sorghum), Serviceberry (Amelanchier), Christmas Holly (Heteromeles), Arrowgrass (Triglochin) 70% Sorbitol to help prevent constipation. 95-280 mg/kg as 6% solution PO; Sheep, Goats, Swine 45-50 mg/kg as 6% solution PO; Dogs 75-150 mg/kg as 6% solution PO; Cats (Acacia), Trefoil (Lotus), (Nandina), Cherry, Plum, Peach, etc. (Prunus), Mannagrass (Glyceria), Indiangrass (Sorghastrum), Sorghum and Johnsongrass (Sorghum), Serviceberry (Amelanchier), Christmas Holly (Heteromeles), Arrowgrass (Triglochin). Contraindicated for Hydrogen Sulfide. their renal elimination. Used in the treatment of various metal poisonings: Arsenic, Cobalt, Lead, Iron, Mercury, Zinc. nicotinamide. Used in the treatment of various poisonings: Ametryn, Amitrole, Atrazine, Bromacil, 4-Methylimidazole, 2,4-D Phenoxy Herbicides, Glyphosate, Imazapyr, Picloram, Prometon, MCPA, Triclorpyr, Lead, Sulfur, Horsetail (Equisetum), Fireweed and Red Sage (Kochia), Bracken Fern (Pteridium), Lip Ferns (Cheilanthes), Male Fern and Wood Fern (Dryopteris), Sensitive Fern (Onoclea) action which increases cardiac output and rate, additionally cholinergic effect increases GI motility and direct acting relaxant effect on vascular smooth muscle produces vasodilation. Used in the treatment of drug overdose and poisonings: Xylazine, Clonidine, Ergot (Claviceps), Canarygrass (Phalaris) the renal elimination of copper. The molecule is dissimilar to D-penicillamine. Used in the treatment of Copper poisoning. TABLE 2. 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Abbott Laboratories
Vet-A-Mix Division of Lloyd Inc. 604 West Thomas Ave. PO Box130 Shenandoah, IA 51601 1-800-831-0004 Vet-Tech Inc. 100 S.E. Magellan Dr. Blue Springs, MO 64014 1-800-821-5570 Vetus Animal Health c/o Burns Veterinary Supply 1900 Diplomat Dr. Farmers Branch, TX 75234 1-800-922-8767 Wallace Laboratories PC Box 100! Cranbury, NJ 08512 1-800-526-3840 Wildlife Pharmaceuticals 1401 Duff Drive Fort Collins, CO 80524 1-877-883-9283 Wyeth-Ayerst Pharmaceuticals Divison American Home Products PO Box 8299 Philadelphia, PA 19101 1-800-934-5556 TABLE 4. BIBLIOGRAPHY FOR VETERINARY ANTIDOTES
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