Pyrethroid Insecticides. Derived from natural product -- –Pyrethrum –Found in Chrysanthemum cinerarifolium Synthetic pyrethroids –Variable in structure,

Pyrethroid Insecticides

Pyrethroid Insecticides

• Derived from natural product --– Pyrethrum– Found in Chrysanthemum cinerarifolium

• Synthetic pyrethroids– Variable in structure, toxicity– Generally benign environmentally

• most are highly toxic to fish

• Major uses in – Home and garden– Agriculture– Medical entomology

Natural Pyrethrum

• Mixture of esters:– Chrysanthemic acid or pyrethric acid– + pyrethrolone, cinerolone, and/or jasmololone

• Structural features essential for insecticidal activity:– 3-C ring

• Variables:– Enantiomers around asymmetric carbon atoms

General structure of pyrethroid insecticides

Mix-and-match substituents

acid

esterPyrethrin 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%

Structural considerations• Contact with receptor must occur at 3 points

• Isobutenyl moiety of acid• Dimethylcyclopentane ting• Unsaturated side chain of keto-alcohol

• Pyrethroids have several asymmetric carbon atoms.

• Stereochemistry of these cabin atoms matters– Toxicity to insects varies

with enantiomers

Steroisomers

Synthetic pyrethroids• Objectives

– Increase persistence • by decreasing insect inactivation• By decreasing photodegradation• By using synergists

– Maintain – Level of insecticidal activity– Range of insects killed

• Stages– 1st generation

• Varied R, R’ with alkyl and aryl substituents– 2nd generation

• Used Cl, Br, F• Last 4-7 days on foliage in sunlight

– 3rd generation• Cyano group• Last up to 10 days• Applied at 0.01 to 0.05 lb/A

1st generation

2nd generation

3rd generation

Toxicity of various pyrethroids

• *Registration cancelled 2004• **Registration cancelled 1992

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Systemic toxicity: Type I• Pyrethroids without cyano group• Target

– CNS, • primarily brain stem• Cerebellum and cerebrum not primary targets

– Progressive development of fine whole body tremor– Exaggerated startle reflex

• Large increase in metabolic rate• Uncoordinated twitching• Hyperexcitability• Hyperthermia• Death results from metabolic exhaustion and hyperthermia

Systemic toxicity: Type II

• Pyrethroids with cyano group• Target:

– CNS– All regions affected

• Symptoms complex– Salivation– Rolling gait - increased extensor tone in hind limbs– Spasms due to sensory stimuli– Tonic seizures– Apnea– death

Allergic Reactions

• Of topical exposure– Contact dermatitis

• Either natural or synthetic pyrethroids– Irritant effect

• Not inflammatory response• Lasts up to 24 hours• May include numbness or parasthesias

– “Annoying but not disabling”– Apparently completely reversible

• Systemic allergic responses– Pyrethroids derive from chrysanthemum components– Allergies are well known to occur

• Respiratory• May be serious• Rarely, fatal• Occupational exposure ---> emphysema (rare?)

Cellular Toxicity• Insecticidal activity:

– Prolong opening of voltage-gated sodium channels• Mammalian toxicity

– Sodium channels• Variable, depending on isoform

– Some voltage-gated calcium channels– Some voltage-gated chloride channels– Peripheral-type benzodiazepene receptors

• Contributing to convulsive effects• Variations 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 slowly– Pyrethroids with alpha-cyano group (4th generation)

• Cause delayed closure of Na channels

Transmembrane channels

• Formed by proteins• Hydrophilic channels through the lipid membrane• May be permanently open• May be gated: normally closed, open for cause• Gates respond to

• Ligands• Electrical charge

• Gates may close rapidly after opening, even if signal is still being given

• Example: neuromuscular junction– Electric nerve impulse reaches nerve terminal

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 ACh

• ACh receptors are ligand-gated– Transiently permeable to Na+ and K+ in presence of ACh

Gated transmembrane channels: presynaptic terminal

– At terminal of axon:• Depolarization opens voltage-gated Ca+2 channel• Responds to nerve impulse• Releases Ca+2 into axon terminal• Causes ACh release into synaptic cleft

Degradation of pyrethroids

• Photolytic– Very rapid for pyrethrum, early pyrethroids

• Metabolic– Extremely rapid for pyrethrum, early pyrethroids– Less rapid for later generations of synthetics– Mediated by P450s– Inhibited by synergists

• Piperonyl butoxide

Piperonyl butoxide

• LD50 = > 7500 mg/kg, rats, po

• Inhibits cytochromes P450• Synergizes

– Pyrethroids– Some OPs, carbamates

Ecotoxicology of Pyrethroids

• Extremely toxic to fish• Mammalian toxicity

– Minimal for most pyrethroids– Exceptions

• Deltamethrin, 25-60 mg/kg• Flucythrinate, 53-87 mg/kg

• Natural pyrethroids– Benign except for toxicity to fish

• Synthetic pyrethroids– Increased persistence not of an order to raise concern about

bioaccumulation– Movement into water from terrestrial applications is a danger

with more persistent pyrethroids• Low application rates minimize this