SPECIFIC ANTIDOTES administered after toxicant absobtion 1. Acetylcysteine GENERAL • N-acetylcysteine (NAC; Mucomyst) • Acetylcysteine is a source of sulfhydryl groups for metabolic reactions and a precursor to glutathione. • Acetylcysteine therapy increases intracellular stores of glutathione, increases glutathione conjugation, and decreases the concentration of reactive metabolites. • Some questions have been raised concerning concurrent use of activated charcoal and acetylcysteine in humans due to possible adsorption of N-acetylcysteine to the activated charcoal. • The consensus is that use of activated charcoal does not necessitate an increased dose of N- acetylcysteine. MECHANISM OF ACTION • Acetylcysteine is a donor of sulfhydryl (SH) groups during biotransformation of toxicants (acetaminophen); it maintains cellular glutathione concentration and prevents organ damage caused by reactive metabolites. Table 1. Antidotal Therapy in Veterinary Medicine Antidote Toxin N-Acetylcysteine (Mucomyst) Acetaminophen Antivenin polyvalent (Crotalidae) Envenomation by Crotalidae (rattlesnake family) Atropine sulfate Organophosphorus insecticides, cholinergic compounds, slaframine, pyrethrins, cardiac glycosides Calcitonin Cholecalciferol rodenticides, vitamin D overdose Calcium disodium edetate (Versenate) Lead, Cadmium Calcium (calcium gluconate, calcium chloride) Oxalate Deferoxamine (Desferal) Iron Digoxin immune Fab (Digibind) Digitalis overdose Dimercaprol (BAL) Arsenic, mercury Ethanol Ethylene glycol, methanol Fomepizole (4-methyl-1H-pyrazole) Ethylene glycol Methylene blue Nitrites, chlorates, methemoglobinemia D-Penicillamine (Cuprimine) Arsenic, copper, mercury Physostigmine salicylate (Antilirium) Atropine, belladonna alkaloids, ivermectin Phytonadione, vitamin K1 Warfarin and other anticoagulant rodenticides, (Aquamephyton, Mephyton) coumarin Pralidoxime chloride (2-PAM; Protopam) Organophosphorus insecticides Protamine sulfate Heparin overdose, bracken fern Sodium bicarbonate Tricyclic antidepressants Succimer (Chemet) Lead and arsenic 1 INDICATIONS • Poisoning caused by • acetaminophen (cats and dogs) • reversal of methemoglobinemia (cats) • carbon tetrachloride • chloroform CONTRAINDICATIONS • Known hypersensitivity to acetylcysteine • Generally no contraindications for use as an antidote TREATMENT • Dogs and cats • 140–150 mg/kg by mouth or IV as a loading dose • followed by 50–70 mg/kg every 4–6 hours • No acetylcysteine products are approved for veterinary use. • Human formulations approved for oral or intratracheal administration are supplied as 10% or 20% solution. • Acetylcysteine has a strong sulfhydryl odor and taste (rotten eggs) and may require administration through an oral or nasogastric tube. ADVERSE EFFECTS • Emesis with oral administration • Hypersensitivity (anaphylactic) reaction with intravenous administration 2. Atropine Sulfate GENERAL • Atropine is commonly used as a preanesthetic agent in dogs, cats, and swine. • Low doses of atropine sulfate block the muscarinic cholinergic receptor; higher doses block the nicotinic cholinergic receptor. • Atropinization of a poisoned patient varies among individuals. • The dose ranges provided are a guide. • Atropine is administered to control and reduce the symptoms of cholinergic activity (salivation, lacrimation, and dyspnea). MECHANISM OF ACTION • Atropine is a parasympatholytic agent that binds to and blocks the actions of acetylcholine at postsynaptic muscarinic receptors. • This prevents prolonged action of acetylcholine within the synaptic cleft. • Atropine has little, if any, effect at the neuromuscular junction of skeletal muscles. INDICATIONS • Poisoning caused by the following: • organophosphorus insecticides (all species) • carbamate insecticides (all species) • muscarinic mushrooms (more commonly dogs) TREATMENT • Dogs and cats • 0.2–2 mg/kg • Ruminants • 0.2–0.5 mg/kg • may repeat dose every 3–4 hours for 1–2 days • Horses • 1 mg/kg, may repeat the dosing every 1.5–2 hours as needed • Auscult the abdomen during administration to reduce the possibility of colic. 2 • In most instances, 25% of the dose is given intravenously and the rest intramuscularly or subcutaneously. • Atropine is given to effect (reduction of salivation). ADVERSE EFFECTS • All species • tachycardia • hypertension • hyperthermia • xerostomia • dysphagia • reduced gastrointestinal motility • constipation • urinary retention • drowsiness • Species-specific adverse reactions • cattle and sheep: ruminal stasis • horses: colic 3. Calcium Disodium Edetate (CaEDTA, Versenate, Edetate Calcium Disodium, Calcium Edetate) GENERAL • CaEDTA is an effective chelating agent for several heavy metal intoxications; however, this agent is not widely available. • Veterinary formulations of CaEDTA have been withdrawn. • Veterinarians may have to use the product approved for humans or enlist the services of a compounding pharmacist to use this antidote. MECHANISM OF ACTION • CaEDTA is a complex of edetate with calcium and sodium ions. • The calcium ions can be replaced by lead and zinc to form a watersoluble heavy metal carrier eliminated in the urine. • Other metals that can replace calcium in the CaEDTA complex but are not excreted in large amounts are cadmium, copper, iron, and manganese. INDICATIONS • Lead and cadmium intoxication CONTRAINDICATIONS • Anuria • Use of other nephrotoxic drugs TREATMENT • Dogs and cats • 100 mg/kg subcutaneously every 6 hours • Horses • 75 mg/kg IV by means of slow infusion for 4–5 days • Stop for 2 days. • Repeat dosing regimen for another 4–5 days. • Cattle • 67–73 mg/kg per day divided into two or three doses by means of IV slow infusion for 2–5 days • Withhold dose for 2 days and repeat the treatment cycle if necessary. • General treatment recommendation is to remove the animal from the source of lead or remove the lead objects from the animal before chelation therapy. 3 • The product used by humans usually is diluted in 5% dextrose in water or saline solution before intravenous administration. • Intramuscular injection can cause pain that can be dampened by diluting the CaEDTA with procaine. ADVERSE EFFECTS • All species: renal tubular necrosis • Dogs: depression and vomiting or diarrhea • Oral administration of CaEDTA may increase intestinal absorption of lead. 4. Deferoxamine Mesylate (Desferal) GENERAL • Poorly absorbed by the oral route, must be given intramuscularly or intravenously • Deferoxamine and iron produce a characteristic reddish color of urine (vin rose). • Supplied as a lyophilized powder in 500-mg or 2-g vials. MECHANISM OF ACTION • Deferoxamine chelates iron and aluminum. • The chelator forms complexes with iron to form ferrioxamine. • This chelate is inert and cannot interact with cellular macromolecules. • The chelated iron complex is water soluble. • The complex is excreted in the urine. INDICATIONS • Iron toxicosis • Aluminum intoxication CONTRAINDICATIONS • Known hypersensitivity to deferoxamine TREATMENT • Dogs • 10 mg/kg IM or IV every 8 hours for 24 hours • Monitor urinary iron excretion and serum iron concentration. ADVERSE EFFECTS • Uncommon 5. Dimercaprol (British Anti-lewisite, BAL) GENERAL • Dimercaprol (DMP) is an oily preparation and must be administered by means of deep intramuscular injection. MECHANISM OF ACTION • The sulfhydryl groups of dimercaprol are bound by arsenic or other metals that prevent binding to sulfhydryl-containing enzymes. INDICATIONS • Chelation of arsenic intoxication—more effective with inorganic arsenic • Also used to chelate lead and mercury CONTRAINDICATIONS • Chelation of iron, selenium, or cadmium—the chelated complex is more toxic than the metal itself. TREATMENT • Dogs and cats • 2.5–5.0 mg/kg IM every 4 hours for the first 48 hours every 8 hours on the third day every 12 hours for the next 10 days 4 • Closely monitor renal and hepatic function. • Maintain renal function and urine flow during therapy. ADVERSE EFFECTS • Nephrotoxicity; use with caution when treating patients with decreased renal function. • Urinary alkalization may prevent renal damage. 6. Ethanol (Grain Alcohol, Alcohol) GENERAL • Ethanol is readily available and an economical antidote. • Ethanol is much more effective if administered in the first 8–12 hours after antifreeze ingestion. • A recently approved antidote, fomepizole (4-MP, Antizol-Vet), has greater affinity for the target and a more favorable pharmacokinetic profile with less central nervous system depression but is not used widely in veterinary medicine primarily because of the cost. MECHANISM OF ACTION • Ethanol inhibits cellular alcohol dehydrogenase and prevents production of toxic metabolites from agents metabolized through this pathway. INDICATIONS • Acute ethylene glycol (antifreeze) intoxication among dogs and cats • Methanol intoxication from windshield washer fluid, antifreeze, or paint remover CONTRAINDICATIONS • No absolute contraindications as an antidote TREATMENT • Dogs and cats • 5.5 mL/kg of 20% ethanol solution IV every 4 hours for five treatments • followed by same dose every 6 hours (dogs) or 8 hours (cats) for four treatments • Intravenous therapy is more reliable than oral administration because of the risk of gastric irritation and vomiting. • This concentration of ethanol is hyperosmotic and must be diluted in fluid. • Ethanol must be filtered before intravenous administration. • Careful monitoring of fluid and electrolyte status is necessary during therapy because ethanol and ethylene glycol inhibit antidiuretic hormone and induce diuresis.