pyrethroid insecticides. derived from natural product -- –pyrethrum –found in chrysanthemum...
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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