Ivermectin

If you have given your Collie this drug and your pet is starting to behave strangely please print out and take this information to your Vet to help him treat your dog.

General:

• Ivermectin toxicosis is more likely in dogs following overzealous treatment with an ivermectin containing product formulated for horses or cattle.
• The breeds of dogs most commonly affected are collies and collie-crosses.
• Small birds such as parakeets (due to their body weight and difficulty in delivering the appropriate dose) can easily be overdosed with ivermectin following treatment for scaly leg mites.
• Ivermectin has a broad spectrum of activity against many internal and external parasites.

Source:

• Ivermectin is a macrolide antibiotic produced from a fungus first isolated from a soil sample in Japan - Streptomyces avermitilis .
• The avermectins are a class of chemicals that have a novel mode of action against nematode and arthropod parasites.
• Ivermectin is a mixture of the 22, 23-dihydro derivative of avermectin B1.
• Ivermectin was licensed for use in the United States in 1983.
• Formulations of Ivermectin :
  • Ivomec (Merck) - injectable, 10 mg/ml for swine and cattle
  • Equvalan (Merck) - oral paste, 8.7 mg/ml for horses
  • Ivomec (Merck) - oral drench, 0.8 mg/ml for sheep
  • Heartguard (Merck) oral tabs, 68, 136, and 272 micrograms of ivermectin for dog for the prevention of Canine Heartworm disease

Conditions Surrounding Toxicoses:

• Dogs are usually intoxicated with ivermectin from the inappropriate, extra-labeled use of cattle, sheep or horse product.
• Well-intentioned, yet uninformed, owners may "worm" the dog with a large animal formulation.
• Any species may be affected if the dose is large enough to penetrate the Blood-Brain-Barrier

Toxicity:

The following doses of ivermectin are those reported in the literature that cause clinical signs (most commonly ataxia or depression).

• Cattle: 4 - 8 mg/kg (20 - 40 times the therapeutic dose)
• Horses: 2 mg/kg (10 times the therapeutic dose)
• Pigs: 30 mg/kg (100 times the therapeutic dose)
• Dogs
  • Collies: 0.1 - 0.2 mg/kg (15 - 30 times the therapeutic dose)
  • Beagles: 2.5 - 40 mg/kg (greater than 200 times the therapeutic dose)
• Cats: there is a report of a kitten exhibiting toxicosis following administration of 0.3 mg/kg of body weight, subcutaneously. Adult cats seem to be less sensitive.
• Chelonians (red-footed and leopard tortoises): 0.1 - 0.4 mg/kg
• Leopard frogs: 2.0 mg/kg intramuscular resulted in death while 20 mg/kg cutaneous had no effect

Clinical Signs:

• mydriasis
• depression
• coma
• tremors
• ataxia
• stupor
• emesis
• drooling
• death

Mode of Action:

• Ivermectin is an agonist for the neurotransmitter gamma-aminobutyric acid (GABA).
• GABA is a major inhibitory neurotransmitter.
• In mammals, GABA-containing neurons and receptors are found in the Central Nervous System; while in arthropods and nematodes GABA is found primarily in the Peripheral Nervous System (neuromuscular junction).
  • This difference in location of GABA receptor may be the reason for the large margin of safety of ivermectin-containing products in mammals.
• The binding of ivermectin to a neuronal membrane increases the release of GABA.
• GABA binds to the GABA receptor-chloride channel complex of postsynaptic neuronal membranes causing an influx of chloride ions.
• The influx of chloride ions hyperpolarize the neuronal membrane making them less excitatory and decreasing nerve transmission.
• The hyperpolarization of neuronal membranes (at the NMJ) mediate a flaccid paralysis in arthropods and nematodes.

Diagnosis:

• Clinical Signs
• History of exposure to ivermectin-containing products
• Chemical analysis for ivermectin (generally not needed)
  • Methods used:
    • high-pressure liquid chromatography (HPLC)
    • enzyme-linked immunoassay (ELISA)
  • Samples:
    • liver
    • body fat
    • gastrointestinal contents (low GI absorption)
    • feces

    Ivermectin is metabolized only slightly by the liver. The majority of ivermectin is excreted in the feces. In cattle, sheep and horses significant amounts of ivermectin can remain in fecal 'pats' leading to reduced numbers of dung beetles.

Treatment:

• There is no safe specific antidote for ivermectin toxicosis
• Initially following an oral exposure the focus should be on ivermectin removal:
  • activated charcoal
  • saline cathartic
• Symptomatic and Supportive care can help the majority of intoxicated animals
  • treatment could be prolonged (days to weeks)
  • intravenous fluids
  • pads
  • turning affected animals to prevent pressure sores
  • treat possible bradycardia
• Picrotoxin has been proposed as a specific antidote. There are some reports of using picrotoxin to treat ivermectin toxicosis. It is generally titrated to effect. Picrotoxin is a potent GABA antagonist that causes an increase in the excitability of neurons in the CNS which leads to convulsions. Seizures caused by picrotoxin administration may be treated with barbituates. Picrotoxin has a narrow margin of safety and is not the best treatment for ivermectin toxicosis.
• Physostigmine - is an uncharged, reversible inhibitor of acetylcholinesterase that can penetrated the Blood-Brain-Barrier.Physostigmine has been shown to have some effect in the comatose animal. This may be due to an increased concentration of acetylcholine in affected neurons. The comatose animal may exhibit a transient increase in metal alertness. This may be beneficial to the veterinarian by: confirming the diagnosis of ivermectin toxicosis, possibly treating the more severe cases and giving the owners hope for their comatose dog.

References:

• Button C, Barton R, Honey P, Rickford P; Avermectin toxicity in calves and an evaluation of picrotoxin as an antidote. Aust Vet J 1988 May;65(5):157-158, 1988.
• Godber LM, Derksen FJ, Williams JF, Mahmoud B; Ivermectin toxicosis in a neonatal foal. Aust Vet J 72(5):191-192, 1995.
• Hadrick MK, Bunch SE, Kornegay JN; Ivermectin toxicosis in two Australian shepherds. J Am Vet Med Assoc 206(8):1147-1150, 1995.
• Hopkins KD, Marcella KL, Strecker AE; Ivermectin toxicosis in a dog. J Am Vet Med Assoc 197(1):93-94, 1990.
• Houston DM, Parent J, Matushek KJ; Ivermectin toxicosis in a dog. J Am Vet Med Assoc 191(1):78-80, 1987.
• Jongen,MJ; Engel,R; Leenheers,LH: High-performance liquid chromatographic method for the determination of occupational exposure to the pesticide abamectin. Am. Ind. Hyg. Assoc. J. 52(10), 433-437, 1991.
• Letcher J, Glade M. Efficacy of ivermectin as an anthelmintic in leopard frogs. J Am Vet Med Assoc 200(4):537-538, 1992.
• Lewis DT, Merchant SR, Neer TM; Ivermectin toxicosis in a kitten. J Am Vet Med Assoc 205(4):584-586, 1994.
• Li,J; Qian,C: Determination of avermectin B1 in biological samples by immunoaffinity column cleanup and liquid chromatography with UV detection. J. AOAC. Int. 79(5): 1062-1067, 1996.
• Lovell RA; Ivermectin and piperazine toxicoses in dogs and cats. Vet Clin North Am Small Anim Pract 20(2):453-468, 1990.
• Mitsui,Y; Tanimori,H; Kitagawa,T; Fujimaki,Y; Aoki,Y : Simple and sensitive enzyme-linked immunosorbent assay for ivermectin. Am. J. Trop. Med. Hyg. 54(3): 243-248, 1996.
• Paul AJ, Tranquilli WJ, Seward RL, Todd KS Jr, DiPietro JA; Clinical observations in collies given ivermectin orally. Am J Vet Res 48(4):684-685, 1987.
• Ristic Z, Medleau L, Paradis M, White-Weithers NE; Ivermectin for treatment of generalized demodicosis in dogs. J Am Vet Med Assoc 207(10):1308-1310, 1995.
• Sams,R: Chemical assay of avermectins by high performance liquid chromatography with fluorescence detection. Vet. Parasitol. 48:59-66, 1993.
• Skopets B, Wilson RP, Griffith JW, Lang CM; Ivermectin toxicity in young mice. Lab Anim Sci 46(1):111-112, 1996.
• Teare JA, Bush M; Toxicity and efficacy of ivermectin in chelonians. J Am Vet Med Assoc 183(11):1195-1197, 1983.
• Tranquilli WJ, Paul AJ, Seward RL, Todd KS, Dipietro JA; Response to physostigmine administration in collie dogs exhibiting ivermectin toxicosis. J Vet Pharmacol Ther 10(1):96-100, 1987.
• Tranquilli WJ, Paul AJ, Seward RL; Ivermectin plasma concentrations in collies sensitive to ivermectin-induced toxicosis. Am J Vet Res 50(5):769-770, 1989.
• Yamazaki J, Matsumoto K, Ono H, Fukuda H; Macrolide compounds, ivermectin and milbemycin D, stimulate chloride channels sensitive to GABAergic drugs in cultured chick spinal neurons. Comp Biochem Physiol C 93(1):97-104, 1989.

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