PROTECTOR (Topical Solution)

Indications

• Insecticide for agricultural use
• Pest control in crops and livestock

Dosage

Children: Refer to BNF for Children for specific dosing guidance.

Adults: Refer to BNF for specific dosing guidance.

Mechanism of action

Chlorpyrifos is metabolically converted to its active form, chlorpyrifos-oxon, which inhibits cholinesterase enzymes, including acetylcholinesterase. This inhibition leads to the accumulation of acetylcholine at neuromuscular junctions, causing overstimulation of cholinergic receptors and resulting in symptoms of cholinergic crisis. The interaction of chlorpyrifos oxon with acetylcholinesterase is complex and varies with inhibitor concentration.

Pharmacodynamics

The pharmacodynamic effects of chlorpyrifos are primarily due to its potent inhibition of acetylcholinesterase, leading to increased levels of acetylcholine in the synaptic cleft. This results in prolonged stimulation of cholinergic receptors, causing symptoms such as muscle twitching, respiratory distress, and potentially fatal cholinergic crises. The degree of inhibition can vary based on individual susceptibility and exposure levels.

Pharmacokinetics

Chlorpyrifos is absorbed through the gastrointestinal tract, skin, and respiratory system. It undergoes extensive hepatic metabolism, primarily converting to chlorpyrifos-oxon, which is responsible for its toxic effects. The elimination half-life is variable and can be affected by factors such as age, health status, and genetic factors influencing enzyme activity. Excretion primarily occurs through urine as metabolites.

Adverse effects

• Cholinergic crisis
• Nausea
• Vomiting
• Diarrhea
• Miosis
• Salivation
• Lacrimation
• Urination
• Defecation
• Gastrointestinal distress
• Respiratory failure

Precautions

• Use with caution in patients with respiratory conditions
• Monitor for signs of cholinergic toxicity
• Avoid exposure during pregnancy
• Handle with care to prevent skin and eye contact

Pregnancy

Chlorpyrifos should be avoided during pregnancy due to potential risks to fetal development.

Breast-feeding

Caution is advised as chlorpyrifos may excrete in breast milk.

Storage

Store in a cool, dry place away from light and moisture. Keep out of reach of children.

Formulations

• Liquid formulation for agricultural use
• Granular formulation for soil application

Indications

• Control of agricultural pests
• Public health pest control
• Vector control for diseases transmitted by insects

Dosage

Children: Refer to specific guidelines based on the formulation and target pest, as dosages can vary widely. Consult the product label or BNF for precise dosing information.

Adults: Refer to specific guidelines based on the formulation and target pest, as dosages can vary widely. Consult the product label or BNF for precise dosing information.

Mechanism of action

Cypermethrin exerts its effects primarily at voltage-sensitive sodium channels in both insect and mammalian neurons. It enhances the binding of specific ligands to these channels, leading to prolonged depolarization of the neuron and disruption of normal nerve function. Additionally, cypermethrin may also act on the gamma-aminobutyric acid (GABA) receptor-chloride ionophore complex, further contributing to its neurotoxic effects.

Pharmacodynamics

As a pyrethroid, cypermethrin has a high affinity for sodium channels, which causes sustained activation and subsequent paralysis of the insect’s nervous system. This mechanism results in the inability of the insect to coordinate movement or respond to stimuli, ultimately leading to death. The insecticidal potency is influenced by the stereochemistry of the compound, with different isomers demonstrating varying levels of effectiveness.

Pharmacokinetics

Cypermethrin is absorbed through the exoskeleton of insects and can also be absorbed through the skin in mammals. Once in the system, it is metabolized in the liver, with metabolites excreted primarily in urine. The compound has a relatively low bioavailability in mammals and is rapidly eliminated. Environmental factors such as temperature and moisture can influence its degradation and persistence in the environment.

Adverse effects

• Skin irritation
• Respiratory issues
• Nausea
• Headache
• Dizziness

Precautions

• Use with caution in patients with known hypersensitivity to pyrethroids
• Avoid contact with eyes and mucous membranes
• Use personal protective equipment when handling

Pregnancy

Cypermethrin should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

Breast-feeding

It is not known whether cypermethrin is excreted in human milk; caution should be exercised when administering to breastfeeding women.

Storage

Store in a cool, dry place, away from direct sunlight and heat. Keep out of reach of children.

Formulations

• Liquid concentrate
• Aerosol spray
• Emulsifiable concentrate

Mechanism of action

The toxicity of chlorpyrifos is probably the result of metabolic conversion to its oxygen analog, chlorpyrifos-oxon, and its subsequent inhibition of various enzymes (eg, cholinesterases, carboxylases, acetylcholinesterases, and mitochondrial oxidative phosphorylases). The organophosphorus insecticides have been known for many years to cause cholinergic crisis in humans as a result of the inhibition of the critical enzyme acetylcholinesterase. The interactions of the activated, toxic insecticide metabolites (termed oxons) with acetylcholinesterase have been studied extensively for decades. However, more recent studies have suggested that the interactions of certain anticholinesterase organophosphates with acetylcholinesterase are more complex than previously thought since their inhibitory capacity has been noted to change as a function of inhibitor concentration. In the present report, chlorpyrifos oxon (O,O-diethyl O-(3,5,6-trichloro-2-pyridyl) phosphate) was incubated with human recombinant acetylcholinesterase in the presence of p-nitrophenyl acetate in order to better characterize kinetically the interactions of this oxon with enzyme. Determination of the dissociation constant, K(d), and the phophorylation rate constant, k(2), for chlorpyrifos oxon with a range of oxon and p-nitrophenyl acetate concentrations revealed that K(d), but not k(2), changed as a function of oxon concentration. Changes in p-nitrophenyl acetate concentrations did not alter these same kinetic parameters. The inhibitory capacity of chlorpyrifos oxon, as measured by k(i) (k(2)/K(d)), was also affected as a result of the concentration-dependent alterations in binding affinity. These results suggest that the concentration-dependent interactions of chlorpyrifos oxon with acetylcholinesterase resulted from a different mechanism than the concentration-dependent interactions of acetylthiocholine. In the latter case, substrate bound to the peripheral anionic site of acetylcholinesterase has been shown to reduce enzyme activity by blocking the release of the product thiocholine from the active site gorge. With chlorpyrifos oxon, the rate of release of 3,5,6-trichloro-2-pyridinol is irrelevant since the active site is not available to interact with other oxon molecules after phosphorylation of Ser-203 has occurred. ... Mechanisms contributing to the adverse effects of chlorpyrifos (CPF) on DNA synthesis, cell number and size, and cell signaling mediated by adenylyl cyclase (AC) in PC12 cells, a neuronotypic cell line that recapitulates the essential features of developing mammalian neurons /were concluded/ . ... In undifferentiated cells, cholinergic receptor antagonists had little or no protective effect against the antimitotic actions of CPF; however, when nerve growth factor was used to evoke differentiation, the antagonists showed partial protection against deficits in cell loss and alteration in cell size elicited by CPF, but were ineffective in preventing the deterioration of AC signaling. Nicotine, which stimulates nicotinic acetylcholine receptors but also possesses a mixture of prooxidant/antioxidant activity, had adverse effects by itself but also protected undifferentiated cells from the actions of CPF and had mixed additive/protective effects on cell number in differentiating cells. The antioxidant vitamin E also protected both undifferentiated and differentiating cells from many of the adverse effects of CPF but worsened the impact on AC signaling. Theophylline, which prevents the breakdown of cyclic AMP, was the only agent that restored AC signaling to normal or supranormal levels but did so at further cost to cell replication. ... /It was concluded that the/ results show definitive contributions of cholinergic hyperstimulation, oxidative stress, and interference with AC signaling in the developmental neurotoxicity of CPF and point to the potential use of this information to design treatments to ameliorate these adverse effects. Organophosphorus

Mechanism of action

Pyrethroid insecticides are synthetic neurotoxins patterned after the naturally occurring pyrethrins. Their mechanism of action is thought to involve effects primarily at the voltage-sensitive sodium channel of both insect & mammalian neurons, although recent studies have raised the possibility that these cmpds may also act at the gamma-aminobutyric acid receptor-chloride ionophore complex. Here we show that active pyrethroids of the alpha-cyano-3-phenoxybenzyl class allosterically enhance the binding of (3)H-batrachotoxinin-A 20-alpha-benzoate to voltage-sensitive sodium channels of rat brain in a dose-dependent & stereospecific manner. Comparison of the rank order of potency for enhancement of (3)H-batrachotoxinin-A 20-alpha-benzoate binding & insecticidal activity in a series of toxic steroisomers of cypermethrin, representative of the class, reveals a correlation between the two measures. These results support a sodium channel site model for pyrethroid action & suggest a useful & practical method to help evaluate the relationship between the sodium channel & insecticidal potency for members of this class of cmpds. Following absorption through the chitinous exoskeleton of arthropods, pyrethrins stimulate the nervous system, apparently by competitively interfering with cationic conductances in the lipid layer of nerve cells, thereby blocking nerve impulse transmissions. Paralysis and death follow. /Pyrethrins/ The efforts of this study were directed at defining the importance of esterases, mixed function oxidases and mitochondrial respiratory chain enzymes in in vitro covalent binding of cismethrin and the two cyanopyrethroids, cypermethrin and deltamethrin to phenobarbital induced rat liver homogenate and microsomes. Each enzyme system was selectively inhibited to elucidate the activation mechanism involved. Piperonyl-butoxide and carbon-monoxide were used to inhibit mixed function oxidases. Tetraethylpyrophosphate inhibited esterase and trichloropropene-oxide inhibited epoxide-hydrolase. Potassium cyanide or rotenone was used to block the mitochondrial electron transport. The study demonstrated that covalent binding of cismethrin, cypermethrin, and deltamethrin was dependent on pyrethroid concentration. Inhibition of esterases and mitochondrial respiration only slightly altered the covalent binding level. Inhibition of cytochrome p450 and mixed function oxidases reduced the covalent binding, making it almost nonexistent. The covalent binding was decreased by 50% through an 80% inhibition of epoxide-hydrolase. In vitro, the comparison of data between alcohol and acid labeling of the same pyrethroid suggested that the whole molecule was bound to proteins in an activation process, perhaps epoxidation, and that hydrolysis could only occur afterwards. The role of cytochrome p450 dependent monooxygenases in the covalent binding process was stressed. Interaction with sodium channels is not the only mechanism of action proposed for the pyrethroids. Their effects on the CNS have led various workers to suggest actions via antagonism of gamma-aminobutyric acid (GABA)-mediated inhibition, modulation of nicotinic cholinergic transmission, enhancement of noradrenaline release, or actions on calcium ions. Since neurotransmitter specific pharmacological agents offer only poor or partial protection against poisoning, it is unlikely that one of these effects represents the primary mechanism of action of the pyrethroids, & most neurotransmitter release is secondary to incr sodium entry. /Pyrethroids/ For more Mechanism of Action (Complete) data for CYPERMETHRIN (12 total), please visit the HSDB record page.