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
ester
Pyrethrin I: A+C = 10%
Pyrethrin II: B+C = 9%
Cinererin I: A+D = 2%
acid
Mix-and-match substituents
Cinererin II B+D = 3%
Jasmolin I: A+E = 1%
Jasmolin II: B+E = 1%
General structure of
pyrethroid insecticides
Structural considerations
• Contact with receptor must occur at 3 points
• Isobutenyl moiety of acid
• Dimethylcyclopentane ting
• Unsaturated side chain of keto-alcohol
Steroisomers
•Pyrethroids have several
asymmetric carbon atoms.
•Stereochemistry of these
cabin atoms matters
–Toxicity to insects varies
with enantiomers
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
PYRETHROID LD50 (mg/kg)
(po, rats)
Pyrethrum
1,500
Barthrin (1)
> 20,000
Phenothrin (2) > 5,000
Permethrin (3) 1,500
Cypermethrin(4) 247
Deltamethrin (4) 128
Resmethrin (2) 2,000
Fenvalerate (3) 450
Flucythrinate (4) 53-67
Fluvalinate (4) > 3,000
• *Registration cancelled 2004
•**Registration cancelled 1992
CHARACTERISTICS USES
Rapidly degraded
Rapidly degraded
Persistent (1973)
Sufficiently persistent
Very safe
1972
Home and garden
No longer marketed
No longer marketed
Agriculture: corn, cotton
Agriculture; roach control
Most persistent
Household, greenhouse
Field crops, vegs, fruits*
Broad spectrum
General use **
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
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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
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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
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Respiratory
May be serious
Rarely, fatal
Occupational exposure ---> emphysema (rare?)
Cellular Toxicity
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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
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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
Concentration gradient
high
ATP
low
Diffusion of
lipid-soluble
substances
Passive transport
of water-soluble
substances
Active transport
through ATPase
Figur
Pag
Slid
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
neurotransmitter molecule
ions
receptor for
neurotransmitter
gated channel protein
Figure 34.7c
Page 584
Slide 18
Gated transmembrane channels:
presynaptic terminal
– At terminal of axon:
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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
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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