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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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slide1

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
Outline
  • Introduction
  • Pharmacology/Toxicology
  • Pharmacokinetics/Toxicokinetics
  • Animal Toxicity
  • Human Toxicity
  • Management
  • Conclusions
introduction
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
introduction1
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
pharmacology toxicology
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
pharmacology toxicology1
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
pharmacokinetics toxicokinetics
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
animal toxicity
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
animal toxicity1
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?

slide19

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.

human toxicity
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
human toxicity1
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
management
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
management1
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
conclusions
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