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Avermectin Poisoning

Avermectin Poisoning. Chen-Chang Yang, MD, MPH, DrPH Department of Environmental & Occupational Medicine, National Yang-Ming University; Division of Clinical Toxicology, Taipei VGH Medical Center, Taipei, Taiwan EAPCCT, May 6-9, 2008. Outline. Introduction Pharmacology/Toxicology

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Avermectin Poisoning

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  1. Avermectin Poisoning Chen-Chang Yang, MD, MPH, DrPH Department of Environmental & Occupational Medicine, National Yang-Ming University; Division of Clinical Toxicology, Taipei VGH Medical Center, Taipei, Taiwan EAPCCT, May 6-9, 2008

  2. Outline • Introduction • Pharmacology/Toxicology • Pharmacokinetics/Toxicokinetics • Animal Toxicity • Human Toxicity • Management • Conclusions

  3. Introduction • A family of macrocyclic lactones with a novel mode of action against parasites • Effective in as low as 10 mg/kg • First isolated from Streptomyces avermitilis at the Kitasato Institute in Japan • 8 natural avermectin components, namely A1a, A1b, A2a, A2b, B1a, B1b, B2a, and B2b, were discovered. Compounds of the B series were found to be extremely effective • Ivermectin (22, 23-dihydro-avermectin B1) was released for use in animals and humans in 1981

  4. Vet Parasitol 1995;59:139-56.

  5. Introduction • Ivermectin (Mectizan®) has become a popular drug in the treatment of many animal and human parasite infestations, such as onchocerciasis (river blindness) because of its High tolerability Prolonged post-treatment effect Broad spectrum of anti-parasitic activity • Other avermectins, e.g. abamectin, doramectin, and emamectin, were subsequently used as agricultural insecticides and miticides in animal health and/or crop protection

  6. http://www.vacunasaep.org/imagen/mapa_oncocerca.jpg

  7. Vet Parasitol 1995;59:139-56.

  8. Pharmacology/Toxicology • Various avermectin components differ in their potency and safety • All avermectins are believed to share common pharmacologic/toxicologic mechanisms • Activation of glutamate-gated chloride channel present in the invertebrate nerve and muscle cells and/or through the effect on GABA receptors  paralysis and death of parasites

  9. J Pharmacol Exp Ther 2000;295:1051-60.

  10. Pharmacology/Toxicology • In vertebrates, avermectins produce GABA-mimetic effects by acting as an agonist at GABAA receptor, stimulating the release of GABA, or through other mechanisms • Mammals are less susceptible to the toxic effects of avermectins because GABA-mediated nerves occur only in the CNS and avermectins do not readily cross the BBB  wide margin of safety • May induce hypotension through an increase in serum NO levels • Potential toxicity of solvents/additives (e.g. hexanol, butylated hydroxytoluene, propylene glycol) in pesticides

  11. J Pharmacol Exp Ther 2000;295:1051-60.

  12. Hum Exp Toxicol 2003;22:433-7.

  13. Pharmacokinetics/Toxicokinetics • Absorbed orally, parenterally, and dermally • Maximum serum concentrations (ivermectin) appeared 2.7 to 5h after oral dosing, and elimination half-life was 2810h among healthy volunteers and treated subjects • Largely excreted into the bile and feces • Urinary excretion: 0.5-2.0% • No relevant information in poisoned subjects

  14. Animal Toxicity • High doses of avermectins do cause neurotoxicity • Manifestations: mydriasis, emesis, anorexia, diarrhea, drooling, depression, ataxia, stupor, coma, tremors, blindness, and death • Cattle injected s.c. with 30X the recommended dose of ivermectin (i.e. 6 mg/kg): no signs of toxicity • Higher (40X) dose: toxicity and death • Dogs (beagles) showed no toxic effects at 2 mg/kg • Mydriasis and tremors were seen at 5 mg/kg (> 200X the therapeutic dose) of ivermectin; and more pronounced toxic signs at 10 mg/kg • Dose-related toxicity was also found in chickens

  15. Regul Toxicol Pharmacol 2007;47:257-60.

  16. Animal Toxicity • Young animals are more sensitive. For example, a kitten exhibited toxicosis after receiving s.c. administration of 0.3 mg/kg of ivermectin • Animals deficient in p-glycoprotein, a component of the BBB, are also more sensitive (>50X) than animals with normal p-glycoprotein levels Findings in abamectin-sensitive CF-1 mice Collies allow more avermectins into the CNS because of mdr1 gene mutation Ivermectin: a potent inhibitor of p-glycoprotein? Possible drug (toxin)-drug (toxin) interactions?

  17. Filaria J 2003;2(S1):S8

  18. Figure 1. CF-1 mouse insensitive to abamectin (0.8 mg/kg) demonstrating moderate p-glycoprotein expression in capillary endothelial cells Figure 3. CF-1 mouse sensitive to abamectin demonstrating no p-glycoprotein expression Figure 2. CD-1 mouse insensitive to abamectin demonstrating slight to moderate p-glycoprotein expression Toxicol Appl Pharmacol 1997;143:357-65.

  19. Toxicol Appl Pharmacol 1997;143:357-65.

  20. Human Toxicity • Adverse effects of ivermectin therapy are not uncommon and most of them appear within 48h of initiating therapy  myalgia, pruritus, painful skin edema, hypotension, and dyspnea (Mazzotti-type reaction) • Little data concerning human avermectin poisoning • Two children had vomiting, somnolence, tachycardia, hypotension, and mydriasis after ivermectin overdose • A 46-year-old man developed marked drowsiness, unconsciousness, weakness, ataxia, and visual changes after iatrogenic overdose by 200 mg of ivermectin

  21. Human Toxicity • Chung et al (1999) reported 19 patients with agricultural avermectin poisoning. Most patients had certain CNS and GI effects after mild poisoning; and showed hypotension and coma following severe poisoning • Sriapha et al (2006) reported 49 cases with abamectin poisoning. Most patients were asymptomatic or had mild symptoms 16 cases (34%) had serious symptoms, manifesting coma, hypotension, and metabolic acidosis; 5 died • Emamectin poisoning in a 67-year-old man: GI upset, mild CNS depression, and aspiration

  22. Management • Prompt GI decontamination followed by activated charcoal therapy may be helpful • Picrotoxin, a GABA antagonist, has been proposed as an antidote in treating ivermectin toxicosis in animals. However, its use is not recommended because of its seizure activity and narrow margin of safety • Neostigmine in a dose of 25-150 mg showed some effects in the treatment of ivermectin toxicosis in cats

  23. Management • Physostigmine in a dose of 1-2 mg was shown to temporarily reverse CNS depression and reduce seizure-like behaviors in the management of comatose animals (collies) • Avermectins do not regulate cholinergic nerve transmissions and both neostigmine and physostigmine are unlikely to be effective • Flumazenil: probably ineffective • Conclusions: no effective antidote

  24. Conclusions • Avermectins are newer pesticides with a wide margin of safety • Human avermectin poisonings are uncommon • Avermectins can produce dose-related toxicity primarily through their effects on GABAergic neurons • Severely poisoned patients may develop coma, hypotension, metabolic acidosis, and even death • The prognosis of avermectin poisoned patients is generally favorable unless complicated with severe hypotension or aspiration

  25. Welcome to Taipei in 2009!

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