Chapter 24 Antidotes for Specific Poisons*
Specific antidotes exist for relatively few poisons. Antidotes react with the poison or its receptor or interfere with its metabolic or specific toxic pathway. For example, chelators react directly with metals, and atropine competes with organophosphates for muscarinic receptors. Fomepizole is an example of an enzyme inhibitor, which blocks the metabolic pathway that activates the poison. Another way to block a metabolic pathway is to provide an alternative substrate for the enzymes involved; examples include giving ethanol for ethylene glycol toxicosis or acetates for sodium fluoroacetate (1080) poisoning. Pamidronate disodium is an example of an antidote that reverses the specific toxic effect of the poison, cholecalciferol.
The use of an antidote does not lessen the importance of thorough detoxification or of supportive therapy. Many antidotes are potentially toxic and should be used with care and only when the diagnosis has been confirmed. Excluding venoms, which are covered later in this chapter, significant small animal poisons for which specific antidotes exist are listed in Table 24-1. These antidotes are discussed in alphabetical order below. Antidotes that work by preventing absorption are dealt with in a separate section.
|Acetaminophen||Acetylcysteine or sodium sulfate|
|Amitraz||Tolazine or yohimbine|
|Anticoagulant rodenticides||Vitamin K1 (= phytonadione)|
|Antifreeze (see Ethylene glycol)|
|Arsenic||Dimercaprol (= BAL, British antilewisite)|
|Cadmium||Calcium disodium EDTA or D-Penicillamine|
|Copper (inherited storage, dogs)||D-Penicillamine or zinc acetate|
|Crimidine||Pyridoxine (vitamin B6)|
|Digitalis (digoxin)||Digoxin immune Fab|
|Ethylene glycol||4-Methylpyrazole (not cats) or ethanol|
|Lead||Calcium disodium EDTA, with or without dimercaprol or D-Penicillamine or DMSA, Succimer, dogs|
|Mercury (inorganic)||Calcium disodium EDTA or D-Penicillamine, or DMSA|
|Mercury (organic)||Dimercaptosuccinic acid? (experimental)|
|Organophosphates (and carbamates)||Atropine (or glycopyrrolate) and 2-PAM|
|Sodium fluoroacetate (1080) or sodium fluoroacetamide (1081)||Monoacetin (acetin, glyceryl mono-acetate), acetic acid, and ethanol|
|Zinc||Calcium disodium EDTA or D-Penicillamine|
The suppliers named are suggestions only and may be relevant only to the United States. Some antidotes must be used “off-label” because they are licensed only for human use or only for large animal use. Certain older drugs, such as atropine and apomorphine, on which there is no patent, are sometimes unavailable because it is not commercially worthwhile for manufacturers to maintain continuous production of these drugs. Similarly, some antidotes are made by only one company and may be made in intermittent batches. In an emergency, human prescription drugs (e.g., Digibind, Desferal, Narcan) may be obtained from a hospital emergency room. Various compounding pharmacies across the country supply many of these antidote products. Compounding pharmacies may be found by contacting The International Academy of Compounding Pharmacists (281-933-8400; www.iacprx.org) or Professional Compounding Centers of America, Inc. (800-331-2498; www.pccarx.com). For local sources of antidotes, call the nearest poison control center at the number listed in the front of the telephone directory or a pharmacy (national toll-free number: 800-222-1222).
ANTIDOTES (LISTED ALPHABETICALLY)
Abbreviations: IV, intravenous or intravenously; IM, intramuscular or intramuscularly; SC, subcutaneous or subcutaneously; PO, oral or orally. Dosages may vary with product throughout the literature; refer to a drug formulary or product insert and label for more detailed information if necessary. Except where otherwise indicated, dose rates are for dogs and cats.
Acetamide, 10% in 5% dextrose, at 7 to 10 mL/kg body weight over a 30-minute period, then continued at 5 mL/kg every 4 hours for 24 to 48 hours, for sodium fluoroacetate and sodium fluoroacetamide toxicoses.
Acetylcysteine, PO or IV, is given in a loading dose of 140 mg/kg followed by 70 mg/kg every 6 hours for up to seven treatments for acetaminophen toxicosis. Acetylcysteine is incompatible with oxidizing agents, including hydrogen peroxide, which is sometimes used as an emetic in poisonings. Acetylcysteine tastes bad, may cause vomiting, and may be adsorbed by activated charcoal. Suppliers include Bristol Myers Squibb, Mead Johnson, Cumberland Pharmaceuticals, Roxane, and others.
Atipamezole, at 50 μg/kg IM, has been shown to be an effective treatment of amitraz poisoning.
Atropine sulfate, at 0.2 to 0.5 mg/kg, is given in cases of acetylcholinesterase-inhibiting organophosphate and carbamate poisonings. The calculated dose may be given IV slowly to effect, or the practitioner may give one quarter of the dose IV, wait 15 minutes to observe effects, and then give the rest IM or SC. This agent should not be used in cyanotic cats. To minimize the toxic effects of atropine itself, the lowest dose should be used initially and increased only if the response is unsatisfactory. Heart rate and regularity should be monitored after IV administration and if high doses are used. Diphenhydramine, sometimes used to treat delayed nicotinic signs of organophosphate and carbamate toxicoses, may potentiate the effects of atropine, so concurrent use is not recommended. Atropine delays the actions of activated charcoal and cathartics by decreasing gastrointestinal motility. Suppliers include Vedco, Butler, Phoenix Pharmaceuticals, Western Veterinary Supply, and RX Veterinary Products.
Calcium disodium ethylenediaminetetraacetic acid (EDTA) is given at 110 mg/kg/day SC in four divided doses (27.5 mg/kg/dose) to a maximum of 2 g/day, diluted to 10 mg/mL in D5W, to chelate lead, zinc, inorganic mercury, and cadmium. IM injection is painful. The course of therapy should not exceed a maximum of 5 days because of the risk of nephrotoxicity. Allow 5 days before commencing a second course, if required. D-Penicillamine can be used between courses of calcium disodium EDTA. Make sure no lead is present in the gastrointestinal tract before using this antidote. Other side effects, which may be ameliorated by zinc supplements, include vomiting, diarrhea, and depression. In lead toxicosis, mobilization of lead may cause a transient increase in the severity of clinical signs. In human medicine dimercaprol is given beforehand to help alleviate acute neurological signs and to accelerate the excretion of lead. There are preparations of pharmaceutical grade calcium disodium EDTA for human use, or it may be obtained from chemical supply companies and compounded. Specify calcium disodium EDTA; do not attempt to use other salts of EDTA or the free acid. Calcium disodium EDTA is also known as calcium disodium edetate or calcium disodium versenate.
D-Penicillamine is given for acute lead, zinc, cadmium, or inorganic mercury poisoning and as a chelator of copper in inherited copper storage disorders in dogs. For dogs with lead poisoning, give up to 110 mg/kg PO on an empty stomach for 1 to 2 weeks. For cats, give 125 mg twice daily PO on an empty stomach for 5 days. For dogs with inherited copper storage disorders, give 10 to 15 mg/kg/day orally. D-Penicillamine may cause vomiting, in which case give smaller doses at more frequent intervals (same total daily dose) or reduce the dose to 33 to 55 mg/kg/day divided into three or four doses. For inherited hepatic copper storage disorder in dogs, D-penicillamine can also be given at 10 to 15 mg/kg PO twice daily on an empty stomach with concurrent ascorbic acid therapy (500 to 1000 mg PO per day). Suppliers include Merck & Co. and Wallace.
Deferoxamine (desferrioxamine, Desferal) is given for iron toxicosis. Emergency treatment consists of continuous IV infusion to 15 mg/kg/hr with close monitoring of cardiac function and blood pressure. If monitoring is not practical or if the animal is not in shock, a safer dose regimen is 40 mg/kg IM at 4- to 8-hour intervals to a total dose not exceeding 6 g/day. These dose rates have been established for dogs. There is a lack of information on appropriate doses for cats. Treatment should be continued until serum iron levels fall to within the normal range. Oral ascorbic acid can be used concurrently to accelerate excretion. It is normal for the urine to turn reddish brown during deferoxamine therapy. The color is caused by excretion of the chelated iron. Deferoxamine has a number of adverse effects, the most clinically significant of which is pulmonary toxicity following continuous infusion. Deferoxamine is supplied by Novartis.
Digoxin immune Fab (Digibind) is used for toxicosis following ingestion of digoxin tablets and also in humans for ingestion of plants including Digitalis purpurea (foxglove), Convallaria majalis (lily of the valley), Kalanchoe blossfeldiana (Christmas kalanchoe) and Nerium oleander (oleander). Doses for animals have not been established, but as a guideline in humans the emergency dose is 400 mg of Digibind. Ideally, 1.7 mL of Digibind should be administered per mg of digoxin ingested. Ideally, Digibind should be administered IV over 30 minutes through a 0.22-μ filter, but it can be given as a bolus if cardiac arrest is imminent. The patient must be monitored for hypokalemia and anaphylaxis. A large dose of Digibind may cause a febrile reaction. To reconstitute Digibind, add 4 mL of distilled water to the vial and mix gently; then dilute to a convenient volume with normal saline. Do not save reconstituted Digibind. The patient should show improvement within 30 minutes and should recover within 4 hours. In veterinary cases, digoxin levels may not be readily available; it is sometimes recommended to administer 1 to 2 vials initially and then observe the effects. Digibind is manufactured by GlaxoSmithKline.
Dimercaprol (BAL [British Anti-Lewisite]) is given for acute arsenic and lead toxicosis and may also be used for copper chelation in dogs with inherited copper storage disease. In clinical arsenic toxicosis, a dose of 6 mg/kg IM is given every 8 hours for 3 to 5 days. For preclinical exposure to arsenic, 3 mg/kg IM is given every 8 hours. In clinical lead toxicosis, 2.5 to 5.0 mg/kg IM as a 10% solution is given every 4 hours for 2 days and then every 6 hours on the third day, followed by twice a day (b.i.d.) for 10 days. Because dimercaprol is nephrotoxic, renal function should be monitored during therapy, and the course should not be too long. Because dimercaprol is carried in a peanut oil vehicle, the injection is painful, and it should not be given SC or IV. Once arsenic is bound, the resulting compound is water soluble and is excreted in the urine. Dimercaprol is manufactured by Becton Dickinson and by Hynson, Westcott and Dunning, Inc.
Dimercaptosuccinic acid (DMSA or Succimer) is a suggested chelation therapy for dogs with lead or zinc toxicosis because it is less toxic than calcium disodium EDTA and can be given orally. Suggested dose regimens include 10 mg/kg PO given every 8 hours for 10 days or 10 mg/kg PO every 8 hours for 5 days followed by 10 mg/kg PO every 12 hours for 2 weeks. Recent experimental evidence suggests that DMSA may also be effective in removing organic mercury from the central nervous system (CNS) of mammals. DMSA is supplied as a human drug by Ovation Pharmaceuticals, Inc.
Diphenylthiocarbazone (dithizone) is used for thallium toxicosis. The dose is 70 mg/kg PO three times daily. Dithizone should be used within 24 hours of exposure to thallium. It is known to cause cataracts in dogs. If the animal is seen more than 24 hours after exposure, Prussian blue should be used rather than dithizone. Suppliers of dithizone include Sigma, Acros, and other chemical suppliers.
Ethanol (20%) is given for ethylene glycol (antifreeze) toxicosis. Guidelines are: dogs, 5.5 mL/kg IV every 4 hours for five treatments and then every 6 hours for four treatments; for cats, 5 mL/kg IV every 6 hours for five treatments and then every 8 hours for four treatments. In practice the dose is titrated to the desired effect, which is profound stupor (near coma) for up to 72 hours. Ethanol provides an alternative substrate for alcohol dehydrogenase and therefore inhibits the metabolism of ethylene glycol to its much more toxic metabolites. If metabolism is prevented, ethylene glycol will be excreted as the parent compound. Do not give a dog ethanol concurrently with or following 4-methylpyrazole (4-MP) because ethanol poisoning and fatal respiratory depression could result.
For sodium fluoroacetate (1080) and sodium fluoroacetamide (1081) toxicoses, 8 mL of 50% ethanol per kg PO is indicated in conjunction with 5% acetic acid (also 8 mL/kg PO). The purpose is to supply an alternative source of acetate to minimize conversion of fluoroacetate to fluorocitrate, which blocks the citric acid cycle by inhibiting aconitase. Clear spirits, such as gin, vodka, “white” rum (e.g., Bacardi) or Everclear, can be used as antidotes. To convert “proof” to percentage, divide by two. For example, a spirit labeled 100 proof is 50% ethanol. Alternatively, laboratory ethanol can be purchased from chemical companies, such as Aldrich. It may be listed as ethyl alcohol. Laboratory ethanol may be contaminated with benzene, so one should ensure that it is absolute ethanol (99.5+%) and deal only with reputable companies.
Glycopyrrolate may be used as an alternative to atropine in acetylcholinesterase-inhibiting organophosphate and carbamate poisonings. The dose rate for dogs is 0.05 μg/kg. A dose rate for cats has not been established. Glycopyrrolate takes somewhat longer than atropine to show an effect, but the effect lasts longer. It is supplied by Fort Dodge Animal Health and by various manufacturers of generic pharmaceuticals for human use.
4-Methylpyrazole (4-MP, fomepizole) is used for ethylene glycol (antifreeze) toxicosis in dogs. It is given IV in a 5% solution; the initial dose is 20 mg/kg, followed by 15 mg/kg at 12 and 24 hours and 5 mg/kg at 36 hours. Dosages used in cats are much higher (see Chapter 45). A specific inhibitor of alcohol dehydrogenase, 4-MP prevents the enzymatic metabolism of ethylene glycol to its more toxic metabolites. Do not use 4-MP concurrently with ethanol in dogs because fatal ethanol toxicosis may result. 4-MP can be purchased as the concentrated compound from chemical companies, such as Sigma-Aldrich; this compound should be refrigerated. A kit (Antizol-Vet) containing 4-MP and diluent, which is stored at room temperature, is marketed by Orphan Medical Inc., which also markets Antizol to the medical profession for use in methanol toxicosis.
Monoacetin (acetin, glyceryl monoacetate) is used for sodium fluoroacetate (1080) and sodium fluoroacetamide (1081) toxicoses. It provides an alternative source of acetate to minimize conversion of fluoroacetate to fluorocitrate, which blocks the citric acid cycle. The dose is 0.55 g/kg IM given every hour to a total dose of 2 to 4 g/kg. Monoacetin is not widely available, but can be purchased from suppliers of fine chemicals, such as Acros. Because of the various names for this chemical, it may be most productive to search for it by CAS number, which is 26446-35-5.
Naloxone (Narcan) reverses a number of opioids including meperidine (pethidine), fentanyl, and oxymorphone. A dose of 0.4 mg naloxone HCl reverses 1.5 mg of oxymorphone hydrochloride, 15 mg of morphine sulfate, 100 mg of meperidine, or 0.4 mg of fentanyl. If the amount of narcotic is unknown, titrate naloxone to effect, using an initial dose of 0.04 mg/kg IV (for the most rapid response), SC, or IM. Naloxone has a wide margin of safety and virtually no agonist action. However, small doses are recommended for severe narcotic overdose because of the risk of producing acute withdrawal syndrome. Patients should be monitored for relapse because the narcotic may have a longer duration of action than naloxone; repeat doses of naloxone can be given as needed. Naloxone is supplied by Endo Pharmaceuticals Inc.
Nicotinamide (niacinamide), given at a dose of 50 to 100 mg IM, replaces nicotinamide antagonized by pyriminil (Vacor), an old avicide that has been deregistered in the United States. There are various vitamin B complex injectables that include niacinamide available to veterinarians. These injections usually also contain thiamine, which can cause an anaphylactic reaction.
Pamidronate disodium (Aredia, Novartis) is one of a class of pharmaceuticals, bisphosphonates, developed to inhibit bone resorption in human beings. Pamidronate disodium has been identified relatively recently as a useful antidote for cholecalciferol and calcipotriene poisoning of dogs. The treatment regimen is 1.3 to 2 mg/kg diluted in saline for IV infusion over 2 to 4 hours. A second infusion 4 to 7 days later may be required. Calcitonin, the antidote previously recommended for cholecalciferol poisoning, is of doubtful effectiveness, more likely to have undesirable side effects, and more tedious to administer than pamidronate sodium. It is not advisable to use both antidotes together, since limited experimental evidence suggests that the outcome is worse than if only one antidote is used.
2-Pralidoxime (pralidoxime chloride, 2-PAM) is useful to reactivate acetylcholinesterase in organophosphate toxicosis, but may not be effective in carbamate toxicosis. If it is uncertain whether the toxicant is an organophosphate or a carbamate, 2-PAM should be used unless it is likely that the toxicant is carbaryl, in which case there is evidence that 2-PAM may be harmful. The first dose of 2-PAM should be given as early as possible, since it is not effective once “aging” has occurred. Treatment may be repeated once or twice at 12-hour intervals. The dose rate is 20 mg/kg by IM, SC, or slow IV injection. 2-PAM is marketed under the trade name Protopam Chloride by Elkins Sinn.
Prussian blue (ferric ferrocyanide) is used in thallium toxicosis to bind thallium excreted in the bile and interrupt enterohepatic cycling. The treatment course in dogs is 3 g/day and given in three to six divided doses for 7 to 14 days. Studies have not been done in cats. Prussian blue can be obtained from chemicals suppliers, such as Acros Organics.
Pyridoxine (vitamin B6), given at 20 mg/kg IV, is used to replace pyridoxine antagonized by crimidine, an older rodenticide. There are numerous veterinary vitamin B complex preparations that contain pyridoxine, including IV preparations. Vitamin B complex injections usually also contain thiamine, which can cause an anaphylactic reaction.
Sodium sulfate is an effective antidote to acetaminophen poisoning and may be used instead of acetylcysteine. Sodium sulfate is given at a dose of 50 mg/kg IV every 4 hours as a 1.6% solution and is available from pharmacies or chemical companies.
Tolazine (tolazoline HCl), marketed as a reversal agent for xylazine, is also effective as an antidote for amitraz. The dose rate for both purposes is 4 mg/kg IV in dogs. Dose rates for cats have not been published. Side effects may include tachycardia and arrhythmia. Tolazine is supplied by Lloyd Laboratories.
Vitamin K1 (phytonadione) is used in anticoagulant rodenticide poisonings. Phytonadione is best administered PO, 2 to 5 mg/kg/day in divided doses with a fatty meal; it is given daily for 21 to 30 days. SC administration does not result in better or faster absorption than oral administration and may cause hemorrhage. Intravenous administration may cause an anaphylactic reaction and should only be used in emergencies and then by slow infusion over at least 15 minutes. Not all phytonadione preparations are suitable for IV use. It may not be necessary to give phytonadione for 21 to 30 days, particularly if gastrointestinal detoxification is prompt and thorough, or if warfarin is ingested. To test whether it is necessary, stop treatment after 10 days, wait 3 days, and then test clotting parameters. If they are normal, test again after another 3 days without phytonadione. If they are still normal, further phytonadione is not required. Testing clotting parameters 3 days after finishing a 21- or 30-day course of phytonadione is prudent if the toxicant is a second-generation anticoagulant. Oral and injectable forms of phytonadione are supplied by Merck and by veterinary pharmaceutical companies.
Yohimbine, marketed as a reversal agent for xylazine, is also effective as an antidote for amitraz. The dose rate for both purposes is 0.1 to 0.125 mg/kg IV in dogs. Dose rates for cats have not been published. Reported signs of overdose include tachycardia, agitation, and tremors. Yohimbine is marketed by Wildlife Pharmaceuticals.
Contact details for the pharmaceutical companies mentioned may be obtained from veterinary pharmaceutical wholesalers or their catalogues, the most recent edition of Veterinary Pharmaceuticals and Biologicals (Veterinary Medicine Publishing Group), or the Internet. The telephone numbers in the United States of some chemical supply companies mentioned are:
Acros (division of Fisher Scientific): 1-800-766-0000 or 1-800-766-7000
These companies require the purchaser to have an account with them before an order can be placed. All of them have a multinational presence. Outside the United States, contact details for these companies should be easy to obtain from the biochemistry or chemistry department of any university or from the Internet.