Antidote to organophosphates

Pralidoxime (Fig. 11.60) represents one of the best examples of rational drug design. It is an antidote to organophosphate poisoning and was designed as such. 

The problem faced in designing an antidote to organophosphate poisoning is to find a drug which will displace the organophosphate molecule from serine. This requires hydrolysis of the phosphate-serine bond, but this is a strong bond and not easily broken. Therefore, a stronger nucleophile than water is required. 

Organophosphates inactivate acetylcholinesterase by binding covalently to it. Since acetylcholine is not broken down, nerve transmission continues, resulting in muscle spasm. Pyridine aldoxime methiodide (PAM) is an antidote to organophosphate poisoning because it displaces the organophosphate, thereby allowing acetycholinesterase to function. 

THERAP cat (vet) Anticholinergic. Mydriatic- Antispas-modic. Antidote to organophosphous insecticides,... 

The active center of A. has two parts, the anionic binding site for the quatemaiy nitrogen (which is responsible for the alcohol specificity) and the esterase center (where a catalytic serine and histidine lyse the ester bond). The enzyme is inactivated by blockage of either the serine hydroxyl (by organic phosphate esters, such as diisopropylfluorophosphate or diethyl p-nitrophenylphosphate), or the anionic center by tri-methylammonium derivatives. If the enzyme has been blocked by organophosphates, it can be reactivated by pralidoxime salti which are therefore used as antidotes to organophosphate poisoning. 

Uses mydriatic and anticholinergic agent in ophthalmic preparations and pre-anesthetic medications antidote to organophosphous insecticides A... 

PAM CL Pralidoxime, chloride, Protopam , is an antidote to organophosphate poisoning such as might result from exposure to nerve agents or some insecticides. The drug, which helps restore an enzyme called acetylcholinesterase, must be used in conjunction with atropine to be effective. Restores normal control of skeletal muscle contraction (relieves twitching and paralysis). 

Antidotes to organophosphate poisoning must be given immediately (see below). 

Still another experimental route to introducing otherwise excluded molecules into the brain is to chemically modify them so that they are lipophilic and therefore can passively diffuse. The brain, just as most other organs and tissues of the body, has enzymes to metabolize or biotransform metabolites in order to use and then get rid of them. Many of these pathways are oxidative. A reduced species or derivative which is lipophilic can enter the brain by simple passive diffusion there to be oxidatively transformed into an active state. Compounds which have been tested in animals include derivatives of 2-PAM (an antidote for organophosphate insecticide poisoning) and phenylethylamine (similar to amphetamine type molecules). Figure 5 illustrates the general concept behind this method. 

Atropine is an "antidote" to poisoning by excessive stimulation of cholinergic muscarinic receptors such as occurs in mucarine and organophosphate insecticide poisoning. 

It has been possible to devise antidotes for organophosphate poisoning because the underlying mechanism by which they cause acute toxicity is understood. These are very effective for the rapid treatment of acute poisoning episodes but are ineffective for peripheral neuropathy or if poisoning occurred some days previously. 

Pyridinium aldoximes N-llnked to C-1 or C-6 of hexoses or to a 3-carbon aglycone unit of a glycoside have been synthesized as potential antidotes of organophosphate poisoning thus the N -... 

Obidoxime is an antidote used to treat poisoning with insecticides of the organophosphate type (p. 102). Phosphorylation of acetylcholinesterase causes an irreversible inhibition of ace-Ltillmann, Color Atlas of Pharmacology 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. 

Functional interactions are those in which both of the two chemicals affect a bodily system perhaps by different mechanisms, and either increase or decrease the combined effect. For example, both atropine and pralidoxime decrease the toxic effects of organophosphate compounds by different means, a combination of the two antidotes leads to a large increase in effectiveness synergism). 

Depending on the specific organophosphate, some phosphorylated enzyme may be reactivated ("dephosphorylated") by certain oxime antidotes from one to two days after OP absorption. Thereafter a change in the nature of the enzyme-phosphoryl bond occurs, rendering the inactivation irreversible and necessitating the generation of new enzyme. 

---