Cholinesterase inhibitors organophosphates

The UK Pesticide Safety Directorate (PSD) has decided to use the TEF approach for assessment of combined risk from exposure to mixtures of acetyl cholinesterase inhibitors (organophosphate (OP) compounds and carbamates) (PSD 1999). Despite clear differences in the action of carbamates and OP compounds, the index compounds selected for all acetyl cholinesterase inhibitors were either aldicarb (carbamate) or chlorpyrifos (OP). The POD for determining relative potency was predetermined as the dose level that produced 20% inhibition of red blood cell cholinesterase in a 90-day dietary study in rats. 

Cholinesterase inhibitor (anti-cholinesterase, ChEI) is a chemical that prevents cholinesterases (ChEs) from breaking down. ACh, which consequently increases the level and duration of action of this neurotransmitter. ChEIs such as organophosphates (esters of phosphoric acid) and carbamates (esters of carbamic acid) - serve as insecticides, pesticides, warfare agents and drugs. 

The mechanism of OPIDN is poorly understood, but, since all organophosphate esters that produce OPIDN are either direct cholinesterase inhibitors or are metabolically converted to cholinesterase inhibitors, inhibition of an esterase of some kind has generally been thought to be involved (Baron 1981). Certain... 

Although bicyclophosphates do not inhibit acetylcholinesterase, they exhibit a synergistic toxic effect with materials that do. Individuals who have had previous exposure to cholinesterase inhibitors such as nerve agents and commercial organophosphate or carbamate pesticides may be at a greater risk from exposure to bicyclophosphates. 

Two important classes of cholinesterase inhibitors are the organophosphates and the carbamates, a few of which are widely used insecticides. Two such insecticides are chloropyrifos and carbaryl (structures shown). They are highly effective insecticides and, if used properly, appear to be without significant risk to humans (although the use of chloropyrifos and some other members of the class is somewhat controversial). 

The Committee examined five organophosphate pesticides (acephate, chlorpyrifos, dimethoate, disulfoton, and ethion), which are all cholinesterase inhibitors and may be present as residues in fruits and vegetables. Chlorpyrifos was used as the index compound. The TEF was defined as the ratio of the NOAEL or LOAEL for each pesticide to the NOAEL or LOAEL for chlorpyrifos. TEFs based on LOAELs were used when a NOAEL could mot be established for two of the compounds. 

Organophosphates The second class of cholinesterase inhibitors is made up of organophosphorous compounds with the general formula ... 

Malathion is an organophosphate cholinesterase inhibitor. Up to 8% of the topically applied dose may be absorbed. Malathion is used as a treatment for head lice, body lice and scabies. It effectively kills both the eggs and the adult lice. Malathion is an insecticide of relatively low human toxicity. However if malathion is used in an indoor environment, as it breaks down into malaoxon, it can be seriously and chronically poisonous. The safety of malathion in pregnancy and in lactating women and in children has not been established. 

Structures of some organophosphate cholinesterase inhibitors. The dashed lines indicate the bond that is hydrolyzed in binding to the enzyme. The shaded ester bonds in malathion represent the points of detoxification of the molecule in mammals and birds. 

The organophosphate inhibitors are sometimes referred to as "irreversible" cholinesterase inhibitors, and edrophonium and the carbamates are considered "reversible" inhibitors because of the marked differences in duration of action. However, the molecular mechanisms of action of the three groups do not support this simplistic description. 

Pralidoxime (2-PAM) Organophosphate cholinesterase inhibitors Adult dose is 1 g IV, which should be repeated every 3-4 hours as needed or preferably as a constant infusion of 250-400 mg/h. Pediatric dose is approximately 250 mg. No proved benefit in carbamate poisoning. 

Organophosphate and carbamate cholinesterase inhibitors (see Chapter 7) are widely used to kill insects and other pests. Most cases of serious organophosphate or carbamate poisoning result from intentional ingestion by a suicidal person, but poisoning has also occurred at work (pesticide application or packaging) or, rarely, as a result of food contamination or terrorist attack (eg, release of the chemical warfare nerve agent sarin in the Tokyo subway system in 1995). 

Malathion is an organophosphate cholinesterase inhibitor that is hydrolyzed and inactivated by plasma carboxylesterases much faster in humans than in insects, thereby providing a therapeutic advantage in treating pediculosis (see Chapter 7). Malathion is available as a 0.5% lotion (Ovide) that should be applied to the hair when dry 4-6 hours later, the hair is combed to remove nits and lice. 

Excessive muscular blockade may be caused by compounds such as the cholinesterase inhibitors. Such inhibitors, exemplified by the organophosphate insecticides such as malathion (chap. 5, Fig. 12) (see also chap. 7) and nerve gases (e.g., isopropylmethylphosphonofluor-idate), cause death by blockade of respiratory muscles as a result of excess acetylcholine accumulation. This is due to inhibition of the enzymes normally responsible for the inactivation of the acetylcholine (see chap. 7). Respiratory failure may also result from the inhibition of cellular respiration by cyanide, for example, or central effects caused by drugs such as dextropropoxyphene. 

Muscarinic cholinomimetics mediate contraction of the circular pupillary constrictor muscle and of the ciliary muscle. Contraction of the pupillary constrictor muscle causes miosis, a reduction in pupil size. Miosis is usually present in patients exposed to large systemic or small topical doses of cholinomimetics, especially organophosphate cholinesterase inhibitors. Ciliary muscle contraction causes accommodation of focus for near vision. Marked contraction of the ciliary muscle, which often occurs with cholinesterase inhibitor intoxication, is called cyclospasm. Ciliary muscle contraction also puts tension on the trabecular meshwork, opening its pores and facilitating outflow of the aqueous humor into the canal of Schlemm. Increased outflow reduces intraocular pressure, a very useful result in patients with glaucoma. All of these effects are prevented or reversed by muscarinic blocking drugs such as atropine. 

The acute toxic effects of the cholinesterase inhibitors, like those of the direct-acting agents, are direct extensions of their pharmacologic actions. The major source of such intoxications is pesticide use in agriculture and in the home. Approximately 100 organophosphate and 20 carbamate cholinesterase inhibitors are available in pesticides and veterinary vermifuges used in the USA. 

Chronic exposure to certain organophosphate compounds, including some organophosphate cholinesterase inhibitors, causes neuropathy associated with demyelination of axons. 

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