Transcript Case-Control Study

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
 Pharmacokinetics/Toxicokinetics
 Animal Toxicity
 Human Toxicity
 Management
 Conclusions
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Introduction
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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
Vet Parasitol 1995;59:139-56.
Introduction
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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
http://www.vacunasaep.org/imagen/mapa_oncocerca.jpg
Vet Parasitol 1995;59:139-56.
Pharmacology/Toxicology
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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
J Pharmacol Exp Ther 2000;295:1051-60.
Pharmacology/Toxicology
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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
J Pharmacol Exp Ther 2000;295:1051-60.
Hum Exp Toxicol 2003;22:433-7.
Pharmacokinetics/Toxicokinetics
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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
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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
Regul Toxicol Pharmacol 2007;47:257-60.
Animal Toxicity
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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?
Filaria J 2003;2(S1):S8
Figure 1. CF-1 mouse insensitive to
abamectin (0.8 mg/kg) demonstrating
Figure 3. CF-1 mouse sensitive to
moderate p-glycoprotein expression in abamectin demonstrating no
capillary endothelial cells
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.
Toxicol Appl Pharmacol 1997;143:357-65.
Human Toxicity
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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 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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Management
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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
Management
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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
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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
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