Avermectin Poisoning Chen-Chang Yang, MD, MPH, DrPH Department of Environmental & Occupational Medicine, National Yang-Ming University; Division of Clinical.

Avermectin PoisoningAvermectin Poisoning

Chen-Chang Yang, MD, MPH, DrPHChen-Chang Yang, MD, MPH, DrPHDepartment of Environmental & Occupational Department of Environmental & Occupational

Medicine, National Yang-Ming University; Medicine, National Yang-Ming University; Division of Clinical Toxicology, Taipei VGH Division of Clinical Toxicology, Taipei VGH

Medical Center, Taipei, TaiwanMedical Center, Taipei, Taiwan EAPCCT, May 6-9, 2008EAPCCT, May 6-9, 2008

OutlineOutline

IntroductionIntroductionPharmacology/ToxicologyPharmacology/ToxicologyPharmacokinetics/ToxicokineticsPharmacokinetics/ToxicokineticsAnimal ToxicityAnimal ToxicityHuman ToxicityHuman ToxicityManagementManagementConclusionsConclusions

IntroductionIntroduction

A family of macrocyclic lactones with a novel A family of macrocyclic lactones with a novel mode of action against parasitesmode of action against parasites

Effective in as low as 10 Effective in as low as 10 g/kgg/kg First isolated from First isolated from Streptomyces avermitilisStreptomyces avermitilis at the at the

Kitasato Institute in JapanKitasato Institute in Japan 8 natural avermectin components, namely A8 natural avermectin components, namely A1a1a, A, A1b1b, ,

AA2a2a, A, A2b2b, B, B1a1a, B, B1b1b, B, B2a2a, and B, and B2b2b, were discovered. , were discovered. Compounds of the B series were found to be Compounds of the B series were found to be extremely effectiveextremely effective

Ivermectin (22, 23-dihydro-avermectin BIvermectin (22, 23-dihydro-avermectin B11) was ) was released for use in animals and humans in 1981 released for use in animals and humans in 1981

Vet Parasitol 1995;59:139-56.

IntroductionIntroduction

Ivermectin (MectizanIvermectin (Mectizan®®) has become a popular ) has become a popular drug in the treatment of many animal and human drug in the treatment of many animal and human parasite infestations, such as onchocerciasis parasite infestations, such as onchocerciasis (river blindness) because of its(river blindness) because of its

High tolerabilityHigh tolerability Prolonged post-treatment effectProlonged post-treatment effect Broad spectrum of anti-parasitic activityBroad spectrum of anti-parasitic activity Other avermectins, e.g. abamectin, doramectin, Other avermectins, e.g. abamectin, doramectin,

and emamectin, were subsequently used as and emamectin, were subsequently used as agricultural insecticides and miticides in animal agricultural insecticides and miticides in animal health and/or crop protection health and/or crop protection

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

Vet Parasitol 1995;59:139-56.

Pharmacology/ToxicologyPharmacology/Toxicology

Various avermectin components differ in their Various avermectin components differ in their potency and safetypotency and safety

All avermectins are believed to share common All avermectins are believed to share common pharmacologic/toxicologic mechanismspharmacologic/toxicologic mechanisms

Activation of glutamate-gated chloride channel Activation of glutamate-gated chloride channel present in the present in the invertebrateinvertebrate nerve and muscle nerve and muscle cells and/or through the effect on GABA cells and/or through the effect on GABA receptors receptors paralysis and death of parasites paralysis and death of parasites

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

Pharmacology/ToxicologyPharmacology/Toxicology In In vertebratesvertebrates, avermectins produce GABA-mimetic , avermectins produce GABA-mimetic

effects by acting as an agonist at GABAeffects by acting as an agonist at GABAAA receptor, receptor, stimulating the release of GABA, or through other stimulating the release of GABA, or through other mechanismsmechanisms

Mammals are less susceptible to the toxic effects of Mammals are less susceptible to the toxic effects of avermectins because GABA-mediated nerves occur only avermectins because GABA-mediated nerves occur only in the CNS and avermectins do not readily cross the BBB in the CNS and avermectins do not readily cross the BBB wwide margin of safetyide margin of safety

May induce hypotension through an increase in serum May induce hypotension through an increase in serum NO levelsNO levels

Potential toxicity of solvents/additivesPotential toxicity of solvents/additives (e.g. hexanol, (e.g. hexanol, butylated hydroxytoluene, propylene glycol) in pesticidesbutylated hydroxytoluene, propylene glycol) in pesticides

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

Hum Exp Toxicol 2003;22:433-7.

Pharmacokinetics/ToxicokineticsPharmacokinetics/Toxicokinetics

Absorbed orally, parenterally, and dermallyAbsorbed orally, parenterally, and dermally Maximum serum concentrations (ivermectin) Maximum serum concentrations (ivermectin)

appeared 2.7 to 5h after oral dosing, and appeared 2.7 to 5h after oral dosing, and elimination half-life was 28elimination half-life was 2810h among healthy 10h among healthy volunteers and treated subjectsvolunteers and treated subjects

Largely excreted into the bile and fecesLargely excreted into the bile and feces Urinary excretion: 0.5-2.0%Urinary excretion: 0.5-2.0% No relevant information in poisoned subjectsNo relevant information in poisoned subjects

Animal ToxicityAnimal Toxicity

High doses of avermectins do cause neurotoxicityHigh doses of avermectins do cause neurotoxicity Manifestations: mydriasis, emesis, anorexia, diarrhea, Manifestations: mydriasis, emesis, anorexia, diarrhea,

drooling, depression, ataxia, stupor, coma, tremors, drooling, depression, ataxia, stupor, coma, tremors, blindness, and deathblindness, and death

Cattle injected s.c. with 30X the recommended dose of Cattle injected s.c. with 30X the recommended dose of ivermectin (i.e. 6 mg/kg): no signs of toxicityivermectin (i.e. 6 mg/kg): no signs of toxicity

Higher (40X) dose: toxicity and deathHigher (40X) dose: toxicity and death Dogs (beagles) showed no toxic effects at 2 mg/kgDogs (beagles) showed no toxic effects at 2 mg/kg Mydriasis and tremors were seen at 5 mg/kg (> 200X Mydriasis and tremors were seen at 5 mg/kg (> 200X

the therapeutic dose) of ivermectin; and more the therapeutic dose) of ivermectin; and more pronounced toxic signs at 10 mg/kgpronounced toxic signs at 10 mg/kg

Dose-related toxicityDose-related toxicity was also found in chickens was also found in chickens

Regul Toxicol Pharmacol 2007;47:257-60.

Animal ToxicityAnimal Toxicity

Young animals are more sensitive. For example, a Young animals are more sensitive. For example, a kitten exhibited toxicosis after receiving s.c. kitten exhibited toxicosis after receiving s.c. administration of 0.3 mg/kg of ivermectinadministration of 0.3 mg/kg of ivermectin

Animals deficient in p-glycoprotein, a component of Animals deficient in p-glycoprotein, a component of the BBB, are also more sensitive (>50X) than the BBB, are also more sensitive (>50X) than animals with normal p-glycoprotein levelsanimals with normal p-glycoprotein levels

Findings in abamectin-sensitive CF-1 miceFindings in abamectin-sensitive CF-1 mice Collies allow more avermectins into the CNS Collies allow more avermectins into the CNS

because of mdr1 gene mutationbecause of mdr1 gene mutation Ivermectin: a potent inhibitor of p-glycoprotein?Ivermectin: a potent inhibitor of p-glycoprotein? Possible drug (toxin)-drug (toxin) interactions? Possible drug (toxin)-drug (toxin) interactions?

Filaria J 2003;2(S1):S8

Figure 2. CD-1 mouse insensitive to abamectin demonstrating slight to moderate p-glycoprotein expression

Toxicol Appl Pharmacol 1997;143:357-65.

Figure 1. CF-1 mouse insensitive to abamectin (0.8 mg/kg) demonstrating moderate p-glycoprotein expression incapillary endothelial cells

Figure 3. CF-1 mouse sensitive to abamectin demonstrating no p-glycoprotein expression

Toxicol Appl Pharmacol 1997;143:357-65.

Human ToxicityHuman Toxicity Adverse effects of ivermectin therapy are not Adverse effects of ivermectin therapy are not

uncommon and most of them appear within 48h of uncommon and most of them appear within 48h of initiating therapy initiating therapy

myalgia, pruritus, painful skin edema, hypotension, myalgia, pruritus, painful skin edema, hypotension, and dyspnea (and dyspnea (Mazzotti-type reactionMazzotti-type reaction))

Little data concerning human avermectin poisoningLittle data concerning human avermectin poisoning Two children had vomiting, somnolence, Two children had vomiting, somnolence,

tachycardia, hypotension, and mydriasis after tachycardia, hypotension, and mydriasis after ivermectin overdoseivermectin overdose

A 46-year-old man developed marked drowsiness, A 46-year-old man developed marked drowsiness, unconsciousness, weakness, ataxia, and visual unconsciousness, weakness, ataxia, and visual changes after iatrogenic overdose by 200 mg of changes after iatrogenic overdose by 200 mg of ivermectinivermectin

Human ToxicityHuman Toxicity

Chung et al (1999) reported 19 patients with Chung et al (1999) reported 19 patients with agricultural avermectin poisoning. Most patients had agricultural avermectin poisoning. Most patients had certain CNS and GI effects after mild poisoning; and certain CNS and GI effects after mild poisoning; and showed showed hypotension and coma following severe hypotension and coma following severe poisoningpoisoning

Sriapha et al (2006) reported 49 cases with Sriapha et al (2006) reported 49 cases with abamectin poisoning. Most patients were abamectin poisoning. Most patients were asymptomatic or had mild symptoms asymptomatic or had mild symptoms

16 cases (34%) had serious symptoms, manifesting 16 cases (34%) had serious symptoms, manifesting coma, hypotension, and metabolic acidosis; 5 diedcoma, hypotension, and metabolic acidosis; 5 died

Emamectin poisoning in a 67-year-old man: GI Emamectin poisoning in a 67-year-old man: GI upset, mild CNS depression, and aspirationupset, mild CNS depression, and aspiration

ManagementManagement

Prompt GI decontamination followed by Prompt GI decontamination followed by activated charcoal therapy may be helpfulactivated charcoal therapy may be helpful

Picrotoxin, a GABA antagonist, has been Picrotoxin, a GABA antagonist, has been proposed as an antidote in treating ivermectin proposed as an antidote in treating ivermectin toxicosis in animals. However, its use is not toxicosis in animals. However, its use is not recommended because of its seizure activity recommended because of its seizure activity and narrow margin of safetyand narrow margin of safety

Neostigmine in a dose of 25-150 mg showed Neostigmine in a dose of 25-150 mg showed some effects in the treatment of ivermectin some effects in the treatment of ivermectin toxicosis in cats toxicosis in cats

ManagementManagement

Physostigmine in a dose of 1-2 mg was shown Physostigmine in a dose of 1-2 mg was shown to temporarily reverse CNS depression and to temporarily reverse CNS depression and reduce seizure-like behaviors in the reduce seizure-like behaviors in the management of comatose animals (collies)management of comatose animals (collies)

Avermectins do not regulate cholinergic nerve Avermectins do not regulate cholinergic nerve transmissions and both neostigmine and transmissions and both neostigmine and physostigmine are unlikely to be effectivephysostigmine are unlikely to be effective

Flumazenil: probably ineffectiveFlumazenil: probably ineffective Conclusions: Conclusions: no effective antidoteno effective antidote

ConclusionsConclusions

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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