Pyrethroid Insecticides Derived from natural product Pyrethrum Found in Chrysanthemum cinerarifolium Synthetic pyrethroids Variable in structure toxicity Generally benign environmentally ID: 318906
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Pyrethroid InsecticidesSlide2
Pyrethroid Insecticides
Derived from natural product --
Pyrethrum
Found in Chrysanthemum cinerarifoliumSynthetic pyrethroidsVariable in structure, toxicityGenerally benign environmentallymost are highly toxic to fishMajor uses in Home and gardenAgricultureMedical entomologySlide3
Natural Pyrethrum
Mixture of esters:
Chrysanthemic acid or pyrethric acid
+ pyrethrolone, cinerolone, and/or jasmololoneStructural features essential for insecticidal activity:3-C ringVariables:Enantiomers around asymmetric carbon atomsSlide4
General structure of pyrethroid insecticides
Mix-and-match substituents
acid
ester
Pyrethrin I: A+C = 10%
Pyrethrin II: B+C = 9%
Cinererin I: A+D = 2%
Cinererin II B+D = 3%
Jasmolin I: A+E = 1%
Jasmolin II: B+E = 1%Slide5
Structural considerations
Contact with receptor must occur at 3 points
Iso
butenyl moiety of acidDimethylcyclopentane tingUnsaturated side chain of keto-alcoholSlide6Slide7
Pyrethroids have several asymmetric carbon atoms.
Stereochemistry of these cabin atoms matters
Toxicity to insects varies with enantiomers
SteroisomersSlide8
Synthetic pyrethroids
Objectives
Increase persistence
by decreasing insect inactivationBy decreasing photodegradationBy using synergistsMaintain Level of insecticidal activityRange of insects killedStages1st generationVaried R, R
’ with alkyl and aryl substituents2nd generationUsed Cl, Br, FLast 4-7 days on foliage in sunlight3rd generationCyano group
Last up to 10 days
Applied at 0.01 to 0.05 lb/ASlide9
1st generation
2nd generation
3rd generationSlide10
Toxicity of various pyrethroids
*Registration cancelled 2004
**Registration cancelled 1992
*
**Slide11
Systemic toxicity: Type I
Pyrethroids without cyano group
Target
CNS, primarily brain stemCerebellum and cerebrum not primary targetsProgressive development of fine whole body tremorExaggerated startle reflexLarge increase in metabolic rateUncoordinated twitchingHyperexcitabilityHyperthermiaDeath results from metabolic exhaustion and hyperthermiaSlide12
Systemic toxicity: Type II
Pyrethroids with cyano group
Target:
CNSAll regions affectedSymptoms complexSalivationRolling gait - increased extensor tone in hind limbsSpasms due to sensory stimuliTonic seizuresApneadeathSlide13
Allergic Reactions
Of topical exposure
Contact dermatitis
Either natural or synthetic pyrethroidsIrritant effectNot inflammatory responseLasts up to 24 hoursMay include numbness or parasthesias“Annoying but not disabling”Apparently completely reversible
Systemic allergic responsesPyrethroids derive from chrysanthemum componentsAllergies are well known to occurRespiratoryMay be seriousRarely, fatalOccupational exposure ---> emphysema (rare?)Slide14
Cellular Toxicity
Insecticidal activity:
Prolong opening of voltage-gated sodium channels
Mammalian toxicitySodium channelsVariable, depending on isoformSome voltage-gated calcium channelsSome voltage-gated chloride channelsPeripheral-type benzodiazepene receptors
Contributing to convulsive effectsVariations of effects on ion channels:Pyrethroids have high affinity for active membrane Na
+
channels
Only affect open channels, blocking them
“
Open channel blockers
”
Pyrethroids without alpha-cyano group Cause nerve channels to close very slowlyPyrethroids with alpha-cyano group (4th generation)Cause delayed closure of Na channelsSlide15
Transmembrane channels
Formed by proteins
Hydrophilic channels through the lipid membrane
May be permanently openMay be gated: normally closed, open for causeGates respond toLigandsElectrical chargeGates may close rapidly after opening, even if signal is still being givenExample: neuromuscular junctionElectric nerve impulse reaches nerve terminalSlide16Slide17
Neuromuscular junction
Signal: electrical
Depolarization of nerve impulse
Decrease in membrane polarization opens voltage-gated Ca+ channels in presynaptic membrane Ca+ ions stream into cell, triggering release of AChACh receptors are ligand-gatedTransiently permeable to Na+ and K+ in presence of AChSlide18Slide19
Gated transmembrane channels: presynaptic terminal
At terminal of axon:
Depolarization opens voltage-gated Ca
+2 channelResponds to nerve impulseReleases Ca+2 into axon terminalCauses ACh release into synaptic cleftSlide20
Degradation of pyrethroids
Photolytic
Very rapid for pyrethrum, early pyrethroids
MetabolicExtremely rapid for pyrethrum, early pyrethroidsLess rapid for later generations of syntheticsMediated by P450sInhibited by synergistsPiperonyl butoxideSlide21
Piperonyl butoxide
LD
50
= > 7500 mg/kg, rats, po
Inhibits cytochromes P450Synergizes PyrethroidsSome OPs, carbamatesSlide22
Ecotoxicology of Pyrethroids
Extremely toxic to fish
Mammalian toxicity
Minimal for most pyrethroidsExceptionsDeltamethrin, 25-60 mg/kgFlucythrinate, 53-87 mg/kgNatural pyrethroidsBenign except for toxicity to fishSynthetic pyrethroidsIncreased persistence not of an order to raise concern about bioaccumulation
Movement into water from terrestrial applications is a danger with more persistent pyrethroidsLow application rates minimize this