20. Detailed MoA/IRAC Group insecticides

Explain the Nerve Process - Acetylcholine

• Electrical Nerve impulse (action potential) reaches the Presynaptic Nerve terminal

• Voltage-gated Ca²⁺ channels open → Ca²⁺ enters the presynaptic terminal.

• The calcium influx triggers the synaptic vesicles to release acetylcholine into the synaptic cleft.

• Acetylcholine diffuses through the synaptic cleft and binds to Nicotinic Acetylcholine Receptor found on the postsynaptic membrane.

• The receptor channels open → positive ions, mainly Na⁺, enter → the postsynaptic membrane depolarises

• If threshold is reached, a new action potential is generated and the nerve signal continues

• Acetylcholinesterase (AChE) rapidly breaks ACh down into acetate + choline → stopping the signal.

• Choline is transported back into the presynaptic terminal and reused to synthesise new acetylcholine

Explain the MODe of action for IRAC group 1A and 1B

• Target site: Acetylcholinesterase (AChE)

• 1a – Carbamates

• 1b – Organophosphates

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• Active constituents: Bendiocarb (1A) and Chlorpyrifos(1B)

• Carbamates and organophosphates inhibit Acetylcholinesterase, preventing acetylcholine from being broken down.

• Acetylcholine Builds up in the Synaptic Cleft

• Acetylcholine keeps activating nicotinic acetylcholine receptors

• Continued never stimulation/overexcitation

• Tremors/twitching → paralysis → Death

Explain the Normal GABA Process

Normal GABA Proces

GABA is released from the presynaptic neuron.

GABA binds to GABA-gated chloride channels on the postsynaptic neuron.

The chloride channel opens → Cl⁻ enters the neuron.

This hyperpolarises/inhibits the neuron, making it less likely to fire.

Explain the MODE of action for IRAC group 1A and 1B

IRAC Group 2B

• Target site: GABA-gated chloride channels

• Class: Phenylpyrazoles (fiproles)

• Active constituent: Fipronil

• Fipronil blocks GABA-gated chloride channels.

• Cl⁻ cannot enter normally.

• GABA cannot properly inhibit/hyperpolarise the neuron.

• The neuron remains overexcited.

• Tremors → paralysis → death

• IRAC Group 30

• Target site: GABA-gated chloride channels — different binding site from 2B

• Class: Meta-diamides / Isoxazolines

• Active constituent: Broflanilide

• Broflanilide inhibits GABA-gated chloride

• Cl⁻ cannot enter normally.

• GABA cannot properly inhibit/hyperpolarise the neuron.

• The neuron remains overexcited.

• Tremors → paralysis → death

Explain the MODE of action for IRAC group 3A and 22A

IRAC Group 3A

Target site: Voltage-gated sodium channels on axons of neurons

Class: Synthetic pyrethroids

Active constituent: Bifenthrin or Deltamethrin

• Synthetic pyrethroids bind to voltage-gated sodium channels.

• They cause the sodium channels to stay open longer than normal.

• More Na⁺ enters the neuron than normal.

• The neuron keeps firing repeatedly.

• This causes overexcitation.

• Tremors → paralysis → death

RAC Group 22A

Target site: Voltage-gated sodium channels on axons of neurons

Class: Oxadiazines

Active constituent: Indoxacarb

• Indoxacarb blocks voltage-gated sodium channels.

• The sodium channels cannot function/open normally.

• Little or no Na⁺ enters the neuron.

• The action potential cannot continue along the axon.

• The nerve stops firing.

• This causes flaccid paralysis.

• Paralysis → death

Explain the MODE of action for IRAC group 4A and 5

IRAC Group 4a

Target site: Nicotinic acetylcholine receptors (nAChRs) on postsynaptic neurons

Class: Neonicotinoids

Active constituent: Imidacloprid or Dinotefuran

• Neonicotinoids bind to the acetylcholine site on nicotinic acetylcholine receptors.

• The receptors become abnormally/continuously activated.

• More Na⁺/positive ions enter the neuron than normal.

• The neuron is continuously stimulated.

• This causes overexcitation.

• Tremors → paralysis → death

IRAC Group 5

Target site: Nicotinic acetylcholine receptors (nAChRs) — different binding site from Group 4A

Class: Spinosyns

Active constituent: Spinosad

• Spinosad bind to the acetylcholine site on nicotinic acetylcholine receptors.

• The receptors become abnormally/continuously activated.

• More Na⁺/positive ions enter the neuron than normal.

• The neuron is continuously stimulated.

• This causes overexcitation.

• Tremors → paralysis → death

Explain the Normal GABA Process

Normal Glutamate Process

• Glutamate is released from the presynaptic neuron.

• Glutamate binds to glutamate-gated chloride channels on the postsynaptic neuron.

• The chloride channel opens → Cl⁻ enters the neuron.

• The neuron becomes more negative (hyperpolarised).

• The neuron is inhibited/relaxed and less likely to fire.

Explain the MODE of action for IRAC group 6

IRAC Group 6

Target site: Glutamate-gated chloride channels

Class: Avermectins / Milbemycins

Active constituent: Abamectin

• Abamectin allosterically activates glutamate-gated chloride channels.

• The chloride channels remain excessively activated/open.

• Cl⁻ continues entering the neuron.

• The neuron becomes excessively hyperpolarised/inhibited.

• The neuron cannot fire normally.

• Flaccid paralysis → death

Explain the Normal Mitochondrial ATP Production

Normal Mitochondrial ATP Production

• The electron transport chain uses energy to pump H⁺ from the mitochondrial matrix into the intermembrane space.

• H⁺ builds up in the intermembrane space.

• This creates a proton (H⁺) gradient across the inner mitochondrial membrane.

• H⁺ flows back into the matrix through ATP synthase.

• ATP synthase uses this flow to produce ATP (energy).

Explain the MODE of action for IRAC group 13 and 20A

IRAC Group 13

Target site: Mitochondrial oxidative phosphorylation / proton gradient

Class: Pyrroles

Active constituent: Chlorfenapyr

• Chlorfenapyr ultimately causes H⁺ to leak back across the inner mitochondrial membrane without passing through ATP synthase.

• The proton gradient collapses.

• ATP synthase loses the H⁺ gradient it needs to produce ATP effectively.

• ATP production fails → energy failure → death

IRAC Group 20A

Target site: Mitochondrial Complex III — Qo site

Class: Hydramethylnon

Active constituent: Hydramethylnon

• Hydramethylnon blocks electron transport at mitochondrial Complex III.

• The electron transport chain cannot function normally.

• H⁺ pumping is reduced/disrupted.

• The proton gradient cannot be maintained properly.

• ATP production fails → energy failure → death

Explain the Normal moulting/metamorphosis process

Normal process

• Before moulting, the insect begins forming a new cuticle/exoskeleton beneath the old one.

• Chitin synthase produces chitin, an important structural component of the new cuticle.

• The old exoskeleton is shed.

• The new cuticle expands and hardens

Explain the MODE of action for IRAC group 15

IRAC Group 15

Target site: Chitin synthase 1 (CHS1) / chitin synthesis

Class: Benzoylureas

Active constituent: Diflubenzuron

Diflubenzuron inhibits chitin synthesis by affecting CHS1.

The new cuticle/exoskeleton cannot form properly.

When the insect attempts to moult, the new cuticle is weak or defective.

The insect cannot complete moulting normally.

Moulting failure → death

Explain the MODE of action for IRAC group 28

IRAC Group 28

Target site: Ryanodine receptor (RyR) on the sarcoplasmic reticulum of muscle cells

Class: Diamides

Active constituent: Chlorantraniliprole

• Diamides bind to the RyR and hold it open.

• Ca²⁺ continuously leaks from the sarcoplasmic reticulum into the sarcoplasm/cytoplasm.

• This causes uncontrolled muscle contraction.

• Calcium stores in the sarcoplasmic reticulum become depleted.

• The muscle can no longer contract properly.

• Flaccid Paralysis → death