Pyrethroids

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=Piperonyl butoxide

Pyrethroids• Derived from pyrethrins; natural

compounds produced by chrysanthemum flowers (C. cinerariaefolium and C. cineum

• Pyrethrins will paralyze insect; animal will recover (enzyme detoxification)

• Pyrethroids are synthetic esters derived from pyrethrins; engineered for insect death, “knockdown” effect

• Synthetic modifications (addition of synergists) make these compounds more toxic to organisms, less degradable in environment

Pyrethroid Structures

• Pyrethrins are esters of chrysanthemic (I) or pyrethric (II) acid; have been synthetically modified into complex mixture of isomers

• Type 1 and 2 pyrethroids• Very lipophillic, low water

solubility• Structure of compound (I

or II) has different effects and associated poisoning symptoms

• Isomerism around the cyclopropane ring greatly influences toxicity

All pyrethroids have an acid moiety, acentral ester bond, and an alcohol moiety

Permethrin

• Pyrethroids are synthetic analogs of pyrethrins, made to last longer and be more toxic to insects.– Type I – shorter duration of

effects– Type II – longer acting,

enhanced by addition of cyano group

• Type I - pesticidesPyrethrins,bioallethrin,cismethrin

Type I - poisonings

•Severe fine tremor

• Marked reflex hyperexcitability

• Sympathetic activation

• Paresthesia (dermal exposure)

• Type II (cyano) - pesticides• fenvalerate• cyhalothrin• deltamethrin• cypermethrin

Type II - poisonings

• Profuse watery salivation

• Coarse tremor

• Sympathetic activation

• Choreoathetosis

• Seizures (dermal exposure)

Uses of pyrethroid• Domestic – e.g. bug bombs, mosquito nets,

insect sprays

• Medical - e.g. treatment of scabies and lice

• Commercial – e.g. insecticide for agriculture

• Veterinary – e.g. pet shampoos, fleas

Mode of entry into aquatic

environment

• Spray drift; pyrethroids often applied aerially and can contaminate nearby waters

• Runoff from fields, wastewater from manufacturing facilities

Mode of Entry into Organisms• Rapidly absorbed to particulate matter in water due to

high lipophillicity/low solubility• Half life for pyrethroids in aquatic medium has been

reported between 19 hours• Most pyrethroid half lives in water range from 1-2 days• Its speciation varies greatly with compound’s

structure, exposure to sunlight, and pH, temperature, and salinity of water medium

• Since pyrethroids are highly lipophillic, will readily be absorbed through the gills of aquatic animals

• In mammals, toxicity occurs when ingested, not readily absorbed through skin

• Absorption:– GI: moderate– Respiratory Tract: moderate– Dermal: poor

• Usually metabolized quickly by the liver • Excreted primarily in urine, less in feces• Half life – usually 5-20 hours, can be days• Often combined with synergist (e.g. piperonyl) to

enhance killing power & slow degradation• Lipophilic, may concentrate in fat tissues

Mechanism of Action

Acts primarily on voltage dependent sodium channels leading to hyperexcitable state, also affects chloride channels to increase excitability

• Increases adrenal activation – increasing adrenaline • Duration of effect is determined by the structure of the

offending pyrethroid

Mode of Toxic Interaction: Neurotoxicity

• Acute neurotoxicity is caused by binding to sodium channels--> slows down its activation and inactivation properties which leads to a hyperexcitable state

• A normal action potential is converted into double or continuous discharges in nerve and muscle

• Current duration dependant on pyrethroid structure; action stereospecific

• Insect sodium channels 100x more susceptible than mammals

Other Toxic Interactions• Most pyrethroids stimulate protein kinase C-

dependant protein phosphorylation (channel activity modulated by phosphorylation state)

• Antagonism of GABA-mediated inhibition (seizures)• Enhancement of noradrenalin release• Direct actions on calcium or chloride ion channels

(type II only)• Type II pyrethroids produce a more complex poisoning

syndrome and act on wider range of tissues

Metabolism and Breakdown• Biological activity destroyed by ester hydrolysis,

major route, creates oxidative metabolites• Oxidative reactions catalyzed by cytochrome P450

(CYP) enzymes in all animals (CYP6 family important for insects). Is thought that insecticidal properties of pyrethroids terminated by oxidative metabolism . Resistance to pyrethroids due to detoxification by CYP monooxygenases

• Resistance associated with elevated CYP activity.