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Chen-Chang Yang, MD, MPH, DrPH

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1 Chen-Chang Yang, MD, MPH, DrPH
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

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5 Vet Parasitol 1995;59:

6 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

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8 Vet Parasitol 1995;59:

9 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

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

11 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

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

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

14 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: % No relevant information in poisoned subjects

15 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

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

17 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?

18 Filaria J 2003;2(S1):S8

19 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:

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

21 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

22 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

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24 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 mg showed some effects in the treatment of ivermectin toxicosis in cats

25 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

26 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

27 Welcome to Taipei in 2009!


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