Amitraz: Difference between revisions

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| ImageFile =Amitraz skeletal.svg

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| ImageFile1 = Amitraz molecule ball.png

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| ImageAlt1 = Ball-and-stick model of the amitraz molecule

| IUPACName =''N'',''N<nowiki>'</nowiki>''-[(Methylimino)dimethylidyne]di-2,4-xylidine

|Section1={{Chembox Identifiers

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| CASNo =33089-61-1

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEBI = 2665

| ChEMBL = 1365675

| PubChem =36324

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| Formula =C₁₉H₂₃N₃

| MolarMass =293.41 g/mol

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| MeltingPtC = 86 to 87

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| Solubility = Insoluble

| VaporPressure = 2.6 x 10⁻⁶ mmHg

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| ATCCode_prefix = P53

| ATCCode_suffix = AD01

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| ATCvet = yes

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'''Amitraz''' (development code '''BTS27419''') is a non-systemic [[acaricide]] and [[insecticide]]<ref name=Corta>Corta, E., Bakkali, A., Berrueta, L. A., Gallo, B., & Vicente, F. (1999). Kinetics and mechanism of amitraz hydrolysis in aqueous media by HPLC and GC-MS. Talanta, 48(1), 189-199</ref> and has also been described as a [[scabicide]]. It was first synthesized by the Boots Co. in England in 1969.<ref name=Harrison>Harrison, I. R., et al. (1973). 1,3,5-Triazapenta-1, 4-dienes: Chemical aspects of a new group of pesticides. Pestic. Sci. 4: 901</ref> Amitraz has been found to have an insect repellent effect, works as an [[insecticide]] and also as a pesticide [[Synergy#Biological_sciences|synergist]].<ref name=PubChem24868774>PubChem Substance. Amitraz – Substance Summary. retrieved from https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=24868774#x332</ref> Its effectiveness is traced back on [[Alpha-adrenergic agonist|alpha-adrenergic agonist activity]], interaction with [[octopamine]] receptors of the central nervous system and inhibition of [[monoamine oxidase]]s and [[prostaglandin]] synthesis.<ref name=Bonsall/> Therefore, it leads to overexcitation and consequently paralysis and death in insects. Because amitraz is less harmful to mammals, amitraz is among many other purposes best known as [[insecticide]] against mite- or tick-infestation of dogs.<ref name=Corta/> It is also widely used in the beekeeping industry as a control for the ''[[Varroa destructor]]'' mite, although there are recent reports of resistance (driven by overuse and off label use).{{citation needed|date=November 2020}}

== Use ==

Amitraz is particularly effective against [[acarids]],<ref name=Brown>Brown, P. M. (1977). Toxicological problems associated with the manufacture of triazapentadienes. Proceedings of the Royal Society of Medicine, 70(1), 41-43</ref> but it is used as a [[pesticide]] in many different fields. Therefore, amitraz is available in many different forms, such as a wettable powder, an emulsifiable concentrate, a soluble concentrate/liquid, and an impregnated collar (for dogs).<ref name=EPA1996>Environmental Protection Agency. (1996). R.E.D. Facts – Amitraz. Prevention, Pesticides And Toxic Substances (7508W), November 1996 retrieved from {{cite web|url=http://www.epa.gov/oppsrrd1/REDs/factsheets/0234fact.pdf |title=Archived copy |access-date=2012-04-05 |url-status=dead |archive-url=https://web.archive.org/web/20120518014513/http://www.epa.gov/oppsrrd1/REDs/factsheets/0234fact.pdf |archive-date=2012-05-18 }}</ref>

It is characterized as an insect repellent, [[insecticide]], and [[Synergy#Biological_sciences|pesticide synergist]]. These are the properties which make it especially useful as a [[pesticide]]:<ref name=Bonsall>Bonsall, J. L., & Turnbull, G. J. (1983). Extrapolation from safety data to management of poisoning with reference to amitraz (a formamidine pesticide) and xylene. Human Toxicology</ref>

* The repellent effect causes insects to turn away from their target as this is treated with amitraz.<ref name=Bonsall/>

* It acts as an [[insecticide]], which means that it can be used to control insects that are directly or indirectly harmful to man.<ref name=Bonsall/>

* As a [[Synergy#Biological_sciences|pesticide synergist]] it also increases the effect of some other [[pesticide]]s if they are combined with amitraz.<ref name=Bonsall/>

These can be traced back to the mechanisms of action, which lead to a wide field of effects, including direct [[lethality]], excitant-repellant behavioral effects, and chemosterilization for the target species.<ref name=Hollingworth/> In addition, it generally causes low damage to nontarget species, which is one of the advantages of amitraz. Furthermore, amitraz is especially effective against insects such as [[spider mite]]s and [[tick]]s in their juvenile and resistant forms.<ref name=Hollingworth>Hollingworth, R. M. (1976). Chemistry, biological activity, and uses of formamidine pesticides. Environmental Health Perspectives, 14(April), 57-69</ref>

For agricultural purposes amitraz is primarily used to control the pear [[psylla]] (''Cacopsylla pyricola'') on Oregon pear crops and [[Whitefly|whiteflies]] and [[mite]]s on cotton or pear crops.<ref name=EPA1996/>

It's also applied to pome fruit, citrus fruit, cotton, stone fruit, bush fruit, strawberries, hops, cucurbits, aubergines, capsicums, tomatoes and ornamental plants to control all stages of tetranychid and eriophyid mites, pear suckers, scale insects, [[mealybug]]s, [[whitefly|whiteflies]], aphids and eggs and first instar larvae of [[lepidoptera]].<ref name=Corta/>

To apply amitraz, various techniques can be used such as an airblast and concentrate spray to pears or by ground boom and aircraft to cotton.<ref name=IPCS>IPCS INCHEM. (1984). Pesticide residues in food – 1984. retrieved from http://www.inchem.org/documents/jmpr/jmpmono/v84pr03.htm</ref>

Territorial differences in amitraz use depend on the species of mites that infest the crops/trees/etc., the local practice, and the number and size of the pear trees. An infestation e.g. by ''[[Tetranychus]]'' spp. requires higher rates of amitraz. Taking those factors into consideration the application volumes of amitraz have been standardized in terms of maximum spray concentration and in the rate of amitraz per hectare.<ref name=EPA1996/>

Besides its application as [[pesticide]] on plants, amitraz is also used as an animal [[ectoparasiticide]] on cattle, goats, sheep, pigs and dogs.<ref name=Corta/> In these applications, it is exclusively applied externally.<ref name=Peter /> It achieves special efficiency against [[mite]]s (first of all ''[[Demodex|Demodex canis]]''), but it also works against [[lice]], flies, and all development stages of [[tick]]s.<ref name=Corta/><ref name=Peter >Peter R., de Bruin C., Odendaal D., Thompson P.N. The use of a pour-on and spray dip containing Amitraz to control ticks (Acari: Ixodidae) on cattle. J S Afr Vet Assoc, 2006, 77(2), 66-9</ref><ref name=Tarallo >Tarallo V.D., Lia R.P., Sasanelli M., Cafarchia C., Otranto D. Efficacy of Amitraz plus Metaflumizone for the treatment of canine demodicosis associated with ''Malassezia pachydermatis''. Parasit Vectors, 2009, 2(1)</ref> In combination with additional agents it can be used against flea-infestation as well.<ref name=Peter/><ref name=Tarallo/>

For the treatment of dogs amitraz is available as a collar or as a spray- or wash-solution and has an immediate effect against tick infestation as well as a preventive effect.

In some countries amitraz emulsions are also applied to treat [[demodicosis]] of cats or dogs, an exceeding infestation of mites of the family Demodicidae.<ref name=Peter/><ref name=Tarallo/>

For the treatment of cattle, sheep, goats and pigs amitraz is available as spray- or wash-solution, to treat or prevent infestations by mites, lice, flies and ticks. Thereby pigs and cattle should be sprayed and sheep and goats bathed.<ref name=Tarallo/>

Other animal species &mdash; horses or Chihuahuas, for example &mdash; should not be treated with amitraz because adverse effects may occur.<ref name=Peter/><ref name=Tarallo/>

== Adverse effects ==

Adverse effects in mammals are caused by amitraz' alpha-adrenergic agonist activity. Symptoms can include low blood pressure and pulse, hypothermia, lethargy, absence of appetite, vomiting, increased blood sugar and digestive problems.<ref name=Peter /><ref name=Tarallo /><ref name=Grossman >Grossman M.R. Amitraz toxicosis associated with ingestion of an acaricide collar in a dog. J Am Vet Med Assoc, 1993, 203(1), 55-7</ref> Furthermore, skin- or [[mucosa]]-irritations may occur in dogs as a response to an amitraz containing collar. This can lead to itching, eczema, [[alopecia]] or [[conjunctivitis]].<ref name=Peter/><ref name=Grossman/>

== Toxicity ==

=== Human toxicity ===

In 2006 the United States Environmental Protection Agency ([[USEPA]]) re-assessed the classification for amitraz to a non-quantifiable "Suggestive Evidence of [[Carcinogen]]icity" descriptor, and in 2013 determined that quantification of risk using a non-linear approach for amitraz will adequately account for all chronic toxicity, including carcinogenicity, that could result from exposure to amitraz and its metabolites.<ref>Federal Register Volume 78, Number 54 (Wednesday, March 20, 2013) Rules and Regulations Pages 17123-17130 [FR Doc No: 2013-06191].</ref> Accidental exposure of men to greater amounts of amitraz can lead to death due to respiratory failure, mainly after oral uptake or inhalation. In Turkey during 1989, 41 cases of deadly amitraz intoxications have been detected.<ref name=Ellenhorn/> The observed toxic dose in about 50% of these patients has been 0.3&nbsp;g to 1.25&nbsp;g of 12.5% amitraz formulations and 0.5 to 2&nbsp;g of 20% formulations. The remaining patients took doses up to 10&nbsp;g.<ref name=PubChem24868774/> Other frequently occurring symptoms after massive amitraz intoxication are [[CNS depression]], [[respiratory depression]], [[miosis]], [[hypothermia]], [[hyperglycemia]], loss of consciousness, vomiting and [[bradycardia]].<ref name=PubChem24868774/>

=== Treatment ===

In case of an amitraz overdose in humans [[atipamezole]] or [[yohimbine]], which act as α2-antagonists, can be used as antidote.<ref name=PubChem24868774/><ref name=Gifte>Gifte.de. (2007) Amitraz. retrieved from http://www.gifte.de/Chemikalien/amitraz.htm</ref> Initially it is important to remove the patient from the amitraz contaminated area. When amitraz has been inhaled the patient should first get respiratory protection. Additionally the patient should be supplied with 4&nbsp;L oxygen per minute.<ref name=PubChem24868774/><ref name= Gifte/> In case of an intoxication via skin-contact, contaminated clothes should be removed first. Affected areas need to be washed with water. If eyes have been exposed to amitraz, anesthesia should be administered and the eyes carefully washed.<ref name=PubChem24868774/><ref name= Gifte/> After the oral intake of amitraz it is important to make the patient drink ca. 0.3&nbsp;L water to reduce amitraz' irritating effect on the gullet.<ref name= Gifte/> Furthermore, it is important to prevent the patient as much as possible from vomiting, to reduce the risk of further aspiration of amitraz.<ref name= Gifte/> Subsequently, the patient need to be observed for at least 24 hours to ensure that the symptoms do not recur.<ref name=PubChem24868774/>

=== Non-human toxicity ===

{| class="wikitable"

|-

! Species !! Method of administration !! Dose<ref>Hayes W.J. et al. (1991). Handbook of Pesticide Toxicology. Volume 3 Classes of Pesticides. pg.1487</ref><ref>Lewis, R. J. (1996). Sax's Dangerous Properties of Industrial Materials. 9th edition, Volume 1-3, pg. 2227</ref>

|-

| ROWSPAN ="3" | Rat || oral || 400&nbsp;mg/kg

|-

| dermal || >1600&nbsp;mg/kg

|-

| intraperitoneal || 800&nbsp;mg/kg

|-

| ROWSPAN ="2" | Mouse || oral || 1600&nbsp;mg/kg

|-

| intraperitoneal || >100&nbsp;mg/kg

|-

| ROWSPAN ="2" | Rabbit || oral || >100&nbsp;mg/kg

|-

| dermal || >200&nbsp;mg/kg

|-

| Baboon || oral || 150–250&nbsp;mg/kg

|-

| Dog || oral || 100&nbsp;mg/kg

|-

| Guinea pig || oral || 400–800&nbsp;mg/kg

|}

== Synthesis ==

Since its discovery by Boots Co. in 1969 three main synthesis routes for amitraz has been developed, which stand out in terms of facility and generality.<ref name=Hollingworth/>

'''Route 1:'''

'''[[2,4-Xylidine]] + [[triethyl orthoformate]] + [[methylamine]] (imine formation/amine formation):''' <ref>PubChem Substance. Amitraz – Substance Summary. Retrieved from https://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?sid=13178#x321</ref>

[[File:Amitraz Synthesis Route1.png|thumb|Figure 1; Amitraz Synthesis Route 1]]

One of the first amitraz-manufacturing plants used this reaction scheme (figure 1).<ref name=Brown/>

Therefore, the reactions has been carried out in an enclosed area, to recycle unused reagents.<ref name=Brown/>

The first step of this route is the reaction of an [[aniline]] with [[triethyl orthoformate]]. In the named manufacturing plant [[2,4-Xylidine]] has been used as the [[aniline]].<ref name=Hollingworth/> The reaction yields an intermediate formimidate ester.<ref name=Brown/><ref name=Hollingworth/> In the next step [[methylamine]] is added, which combines with the formimidate ester to yield the desired formamidine.<ref name=Brown/><ref name=Hollingworth/> As the formamidines forms, [[ethanol]] is set free from the chemical reaction and is recycled.<ref name=Brown/>

This is probably the most suitable method for the synthesis of amitraz, because this second step yields ''{{prime|N}}''-2,4-dimethyl-''N''-methylformamidine. The free -NH groups of these molecules react with each other to finally yield amitraz.<ref name=Brown/>

The last steps of the manufacturing process include crystalisation out from [[isopropyl alcohol]], filtering and drying. These last steps need to be carried out by instructed personnel, who wear full protective clothing with a positive-pressure breathing apparatus.<ref name=Brown/><ref name=Hollingworth/>

'''Route 2: Substituted [[formamide]] + [[aniline]]:'''

[[File:Amitraz synthesis.png|thumb|Figure 2; Amitraz Synthesis Route 2]]

The first step of this synthesis route to an N-arylformamidine as amitraz is the reaction of a substituted [[formamide]], usually a dialkylformamide, with an [[aniline]].<ref name=EPA1996/> To gain amitraz N-methyl formamide and 2,4 dimethyl [[aniline hydrochloride]] can be used (figure 2). This reaction is catalyzed by the presence of acid halides, such as POCl₃, SOCl₂, COCl₂, or an arylsulfonylhalide, as p-toluene sulfonyl chloride (figure 2).<ref name=Hollingworth/><ref name=Thomas >Thomas A. Unger, T.A.U. (1996). Pesticide synthesis handbook. New Jersey: Noyes Publications, pp. 836.</ref> This yields an intermediate, which reacts further as its catalyzed by p-toluene acid to N, N'-[(methylimino) dimethylidyne] di-2,4-xylidine (amitraz).<ref name=Thomas /> Alternatively, the [[aniline]] in the first step can be replaced by an arylformamide.

In addition the replacement of the dialkylformamide with an ''N''-alkylpyrrolidone can be used to obtain products of the clenpyrin group from this reaction.<ref name=Hollingworth/>

'''route 3: arylisocyanate + formamide:'''

To achieve this reaction a mixture a suitable arylisocyanate and [[formamide]] is heated and marked by the evolution of CO₂, to yield the desired formamidine.

== Metabolism ==

Since amitraz most common use is as a [[pesticide]], it is important to consider that between animals and plants often different pathways for [[biotransformation]] occur.

Most animal species, including humans can metabolize amitraz rapidly to form six metabolites during [[biotransformation]], ''N''-methyl-''{{prime|N}}''-(2,4-xylyl)formamide, Form- 2'4'xylidine, 4-N-Methyl-formidoyl) amino-meta-toluix acid, 4-Formamido-meta-toluic acid, 4- Acetamido- meta-toluic acid and 4- Amino- meta- toluic acid.<ref name=Chou>Chou, C.-P. et al. (2004). Solid-Phase Extraction and GC-MSD Determination of Amitraz and Metabolites in Urine. Journal of Food and Drug Analysis. Vol. 12, No. 3, 2004, 212-216</ref><ref name=IPCSINCHEM>IPCS INCHEM. (2012). Amitraz. retrieved from http://www.inchem.org/documents/jmpr/jmpmono/v098pr02.htm</ref><ref name=Roberts>Terence Robert Roberts, T.R.R. (1999). Metabolic pathways of agrochemicals. Cambridge: The Royal Society of Chemistry, pp 729 – 733</ref>

[[File:Amitraz Metabolism in Animals.jpg|thumb|Figure 3; Amitraz Metabolism in Animals]]

In rats the metabolic pathway (figure 3) has been examined after oral administration of {{sup|14}}C-labelled amitraz, which was found to be effectively metabolized, degraded and excreted to four of the metabolites in urine and six in faeces.<ref name=IPCSINCHEM/>

The metabolic pathway or rate did not differ between the sexes.

Hornish and Nappier (1983){{full|date=August 2014}} detected that the metabolic pathway after dermal administration follows the same route of degradation as after oral uptake, because the parent compound, N-methyl- N'-(2,4-xylyl)formamidine and form-2',4'-xylidide were found in urine and blood also after dermal administration.<ref name=IPCSINCHEM/>

In humans, ''N''-methyl-''N''-(2,4-xylyl)formamidine, form-2',4'-xylidide, 4-amino- meta-toluic acid, 4-acetamido- meta-toluic and 4-formamido- meta-toluic acids were recognized in the urine as well which indicates for the same or a similar metabolic pathway.<ref name=Roberts/>

As illustrated in figure 3 the first step is a hydrolysis reaction to N-methyl-N'-(2,4-xylyl)-formamidine, which already can be excreted in the urine but is still pharmacological active.<ref name=IPCSINCHEM/><ref name=Roberts/> Depending on the dose, the quantity of this metabolite in the urine can vary from 4% at low doses to 23%-38% at high doses (e.g. in case of rats: 1–100&nbsp;mg per kg body weight).<ref name=IPCSINCHEM/>

As it isn't excreted it also can be oxidized to 4-N-Methyl-formidoyl)amino-meta-toluic acid, which can be further oxidized to 4-formamido-meta-toluic acid.<ref name=IPCSINCHEM/>

Form-2,4-xylidine is formed directly by [[hydrolysis]] from amitraz or arises from N-methyl- N'-(2,4-xylyl)formamidine.<ref name=Roberts/> During this early stage of [[biotransformation]] N-methyl- N'-(2,4-xylyl) formamidine and Form-2,4-xylidine may already form conjugates.<ref name=IPCSINCHEM/>

But the major route followed after the formation of Form-2,4-xylidine is the oxidation to 4-formamido-meta-toluic acid, which is further metabolized to its acetyl conjugate, 4-acetamido-meta-toluic acid or 4-amino- meta-toluic acid.<ref name=IPCSINCHEM/><ref name=Roberts/>

4-formamido- meta-toluic acid and 4-acetamido- meta-toluic acid make 32% of the [[metabolites]] found in urine and are detected at any administered dose. Therefore, they are considered as two of the major metabolites in the amitraz pathway.<ref name=IPCSINCHEM/> Form-2',4'-xylidide and 4-amino- meta-toluic acid account only for 2% of the total excretion.<ref name=IPCSINCHEM/>

In insects different metabolites are formed. N-methyl- N'-(2,4-xylyl)formamidine, Form-2,4-xylidine and 4-Amino-meta-toluic acid occur, but in addition several unidentified metabolites were detected, too.<ref name=Roberts/>

[[File:Amitraz Metabolism in Plants.jpg|thumb|Figure 4; Amitraz Metabolism in Plants]]

In plants the [[biotransformation]] of amitraz proceeds very rapidly. The predominant [[metabolites]] detected are N-(2,4-dimethylphenyl)-N'-methylformamidine (BST 27 271) and 2,4-dimethylformanilide (BST 27 919).<ref name=IPCS/>

N-(2,4-dimethylphenyl)-N'-methylformamidine (BST 27 271), 2,4-dimethylformanilide (BST 27 919) and N,N'-bis-dimethylphenylformamidine (BTS 28 037) result from [[hydrolysis]] of amitraz.

Thereby N-(2,4-dimethylphenyl)-N'-methylformamidine (BST 27 271) occurs in higher amounts than 2,4-dimethylformanilide (BST 27 919). N-(2,4-dimethylphenyl)-N'-methylformamidine (BST 27 271) can be further metabolized to 2,4-dimethylformanilide (BST 27 919) or [[2,4-Xylidine|2,4-dimethylaniline]] (BTS 24 868).<ref name=IPCS/>

N,N'-bis-dimethylphenylformamidine (BTS 28 037) can be transformed to 2,4-dimethylformanilide (BST 27 919) or directly react to 2,4-dimethylaniline (BTS 24 868), but the exact mechanisms of these biotransformations are not known yet.<ref name=IPCS/>

However, of 2,4-dimethylaniline (BTS 24 868) and N,N'-bis-dimethylphenylformamidine (BTS 28 037) less than 1% has been accounted, which makes them minor [[metabolites]] compared to N-(2,4-dimethylphenyl)-N'-methylformamidine (BST 27 271) and 2,4-dimethylformanilide (BST 27 919).<ref name=IPCS/> Figure 4 shows the suggested amitraz' metabolic pathway in plants.<ref name=IPCS/>

=== Kinetics ===

The [[hydrolysis]] reactions of amitraz strongly depend on the environmental pH. Even though amitraz undergoes [[hydrolysis]] reactions at any pH, [[spectrophotometry]], [[HPLC]], and [[GC-MS]] studies revealed that pH-depending differences occur, affecting both the sort of reaction-products and the reaction rate.<ref name=Corta/><ref name=Pierpoint>Pierpoint, A. C. Et al (1997). Kinetics and Mechanism of Amitraz Hydrolysis. Journal of Agricultural and Food Chemistry. 45 (5), pp 1937–1939</ref> Under basic conditions (pH>6) amitraz is metabolized to 2,4-dimethylphenylformamide. Followed by [[hydrolysis]] to 2,4-dimethylaniline, which also benefits from a basic pH.<ref name=Corta/><ref name=Pierpoint/> At very acidic pH (pH<3) 2,4-dimethylaniline has been observed as the main degradation product. Under less acidic conditions (pH 3–6) mainly N-(2,4-dimethylphenyl)-{{prime|N}}-methylformamidine and already amounts of 2,4-dimethylphenylformamide occur.<ref name=Corta/>

== Mechanism of action ==

Amitraz is used as a [[pesticide]]. Therefore, amitraz exposure to humans occurs mainly through inhalation or dermal contact with the compound during its use or production.<ref name=Ellenhorn>Ellenhorn, M.J., S. Schonwald, G. Ordog, J. Wasserberger. Ellenhorn's Medical Toxicology: Diagnosis and Treatment of Human Poisoning. 2nd ed. Baltimore, MD: Williams and Wilkins, 1997., p. 1730</ref>

The toxic effects to humans following on amitraz-uptake include loss of consciousness, vomiting, respiratory failure, [[miosis]], [[hypothermia]], [[bradycardia]], [[hyperglycemia]] and [[central nervous system depression]].<ref name=Bonsall/>

The pharmacological activity of amitraz includes different mechanisms of action leading to toxic effects in humans as well as in animals.

Many of these effects and most of the effects on humans are caused by its [[alpha-adrenergic agonist]] activity.<ref name=Bonsall/> Furthermore, amitraz inhibits [[prostaglandin]] synthesis, interacts with the [[octopamine]] receptors of the central nervous system and inhibits [[monoamine oxidase]]s.<ref name=Bonsall/>

Animal studies revealed that damages due to amitraz poisoning can be recovered even after exposure to a potentially [[lethal dose]]. This could mean that amitraz' effects are reversible or at least are recoverable.<ref name=Agin>Agin, H., Calkavur, S., Uzun, H., & Bak, M. (2004). Amitraz poisoning: clinical and laboratory findings. Indian Pediatrics, 41(5), 482-486</ref>

When an amitraz poisoning is lethal, death results from respiratory depression.<ref name=Agin/>

=== Alpha-adrenergic agonist activity ===

Amitraz is a central alpha-adrenoreceptor agonist.<ref name=Ellenhorn /> That means that it selectively stimulates [[alpha adrenergic receptor]]s, which are metabotropic G-protein-coupled receptors, that are usually targeted by [[catecholamines]]. Stimulating these receptors is in great extent the reason for the neurotoxic and preconvulsant effects of amitraz.<ref name=Chen>Chen-Izu, Y., Xiao, R. P., Izu, L. T., Cheng, H., Kuschel, M., Spurgeon, H., & Lakatta, E. G. (2000). G(i)-dependent localization of beta(2)-adrenergic receptor signaling to L-type Ca(2+) channels. Biophysical Journal, 79(5), 2547–2556</ref> Xylene present in amitraz formulations additionally induces [[central nervous system depression]].<ref name=Bonsall/>

[[Adrenergic receptor|Adrenergic Receptors]] can be divided into two subclasses, alpha1- and alpha2-adrenergic receptors. To determine whether amitraz interacts with subclass 1 oder subclass 2, subcutaneous injections of amitraz (0.3–3.0&nbsp;mg/kg) were given to mice.<ref name=Hsu>Hsu, W. H. and Lu, Z.-X. (1984). Amitraz' induced delay of gastrointestinal transit in mice: Mediated by α2 adrenergic receptors. Drug Development Research, Volume 4 (6), 655- 680.</ref> Consequently, a dose-dependent delay of [[gastrointestinal]] transit in conscious mice occurs. This effect could be [[Antagonist|antagonized]] by alpha2-adrenergic blocking agents, but administration of other [[Receptor antagonist|antagonist]]s did not reduce the depressant effect on the [[gastrointestinal]] transit.<ref name=Hsu/> So it is suggested that amitraz-induced delay of [[gastrointestinal]] transit is mediated by postjunctional alpha2-adrenergic receptors and appears not to involve the activation of β-adrenergic, [[dopaminergic]], [[Serotonin|serotonergic]], [[histaminergic]], [[cholinergic]], [[GABAergic]], or [[opioid receptors]].<ref name=Hsu/>

Besides the neurotoxic effects other clinical effects observed in amitraz poisoning are related to alpha2-adrenergic agonistic activity.<ref name=PubChem24868774/> [[Adrenergic receptors]] are present in many different cells. The activation of these receptors by an [[agonist]] as amitraz generally induces a [[sympathetic response]]. This leads to an increased heart rate, dilation of the pupils, elevation of blood pressure and blood and energy supply focus on skeletal muscles.<ref name=Ellenhorn />

=== Interaction with the octopamine receptor ===

It's thought that the mode of action of amitraz involves the interaction with the neuromodulator [[octopamine]].<ref name=Chen2>Chen, A. C., He, H., & Davey, R. B. (2007). Mutations in a putative octopamine receptor gene in amitraz-resistant cattle ticks. Veterinary Parasitology, 148(3-4), 379-383.</ref> This interaction is probably the reason for increased nervous activity of [[ticks]] as a response on amitraz.<ref name=Chen2/><ref name=Li>Li, A. Y., Davey, R. B., Miller, R. J., & George, J. E. (2004). Detection and characterization of amitraz resistance in the southern cattle tick, Boophilus microplus (Acari: Ixodidae). Journal of Medical Entomology, 41(2), 193-200</ref>

Usual activation of the receptors may lead to changes in the concentration of intracellular second messengers such as cyclic nucleotides [[cyclic AMP]] (cAMP) and [[cyclic GMP]], [[inositol trisphosphate|inositol-1,4,5-trisphosphate]] and Ca²⁺.<ref name=Grohmann>Grohmann, L., Blenau, W., Erber, J., Ebert, P. R., Strünker, T., & Baumann, A. (2003). Molecular and functional characterization of an octopamine receptor from honeybee (Apis mellifera) brain. Journal of Neurochemistry, 86(3), 725-735</ref> Influencing this signal transduction system can lead to various events depending on the celltype.<ref name=Grohmann/>

Since it has been discovered that the [[octopamine]] receptor coding gene is expressed on very high rates in the [[somata]] of the honeybee brain, it is suggested that it is involved in the processing of sensory inputs, antennal motor outputs and higher-order brain functions.

The amitraz-[[octopamine]] receptor interaction restrains these normal functions of the [[octopamine]] receptor. Therefore, it is efficient as an insect-pesticide.<ref name=Chen2/><ref name=Grohmann/>

Still, resistance against amitraz can occur. A mutation can lead to a working version of the [[octopamine]] receptor but with an altered pesticide target side.<ref name=Chen2/> This is probably the case for a very resistant Brazilian and Mexican tick strain, which have two [[nucleotide]] substitutions on the [[octopamine]] receptor coding gene compared with the Australian strains.<ref name=Chen2/>

A closer understanding of these resistance meachnisms would help to develop more rapid and accurate diagnostic tools for detecting resistance and steer development of alternative [[acaricides]].<ref name=Chen2/>

=== Inhibition of monoamine oxidases ===

In vitro a [[Monoamine oxidase inhibitor|monoamine oxidase-inhibiting]] effect of amitraz has been found.<ref name=Ellenhorn /> Monoamine oxidases catalyze the oxidative deamination of [[monoamines]] and thereby form [[flavoproteins]] and inactivate [[neurotransmitters]].<ref name=Tipton >Tipton KF, Boyce S, O'Sullivan J, Davey GP, Healy J (August 2004). "Monoamine oxidases: certainties and uncertainties". Curr. Med. Chem. 11 (15): 1965–82</ref>

However, ''in vivo'' it has been observed that only at high doses of amitraz or its main metabolite ''N''-2,4-dimethylphenyl-''N''-methyl-formamide monoamine oxidase inhibition occurs.<ref name=Ellenhorn /> In dogs it has been observed that after administration of such a dose an increase in plasma [[glucose]] and suppression of [[insulin]] occurs.<ref name=Ellenhorn />

=== Inhibition of prostaglandin synthesis ===

Like other formamidines amitraz inhibits the synthesis of [[prostaglandin E2]] from [[arachidonic acid]] by bovine seminal vesicle microsomes.<ref name=Yim>Yim, G. K., Holsapple, M. P., Pfister, W. R., & Hollingworth, R. M. (1978). Prostaglandin synthesis inhibited by formamidine pesticides. Life Sciences, 23(25), 2509–2515</ref> In a dose of 5 to 80&nbsp;mg/kg body weight, given intraperitoneally to rats, amitraz reduces yeast-induced fever and antagonizes the carrageenin-induced swelling of the hind paw.<ref name=Yim/> Some of the physiological effects of amitraz probably go back to this aspirin-like activity and occur due to inhibition of prostaglandin synthesis.<ref name=Agin />

==See also==

* [[Mitaban]]

==References ==

{{Reflist}}

== External links==

* {{PPDB|30}}

{{Insecticides}}

{{Adrenergic receptor modulators}}

[[Category:Acaricides]]

[[Category:Alpha-2 adrenergic receptor agonists]]

[[Category:Amidines]]

[[Category:Insecticides]]