Cholinesterases primary

DF and its precursor, DC are organophosphonic acids. They will react with alcohols to form crude lethal nerve agents, such as crude GB. High overexposure may cause inhibition of cholinesterase activity. Although much less toxic than GB, DF and DC are toxic and corrosive materials. Because DF and DC are relatively volatile compounds, the primary route of exposure is expected to be the respiratory system. However, ingestion also results from inhalation exposures in animals and could occur in humans. DF and DC vapors have a pungent odor and may cause severe and painful irritation of the eyes, nose, throat, and lungs. Data provided is for DF only, DC has similar properties. 

Fig. 11.2. Schematic representation of the primary structure of secreted AChE B of N. brasiliensis in comparison with that of Torpedo californica, for which the three-dimensional structure has been resolved. The residues in the catalytic triad (Ser-His-Glu) are depicted with an asterisk, and the position of cysteine residues and the predicted intramolecular disulphide bonding pattern common to cholinesterases is indicated. An insertion of 17 amino acids relative to the Torpedo sequence, which would predict a novel loop at the molecular surface, is marked with a black box. The 14 aromatic residues lining the active-site gorge of the Torpedo enzyme are illustrated. Identical residues in the nematode enzyme are indicated in plain text, conservative substitutions are boxed, and non-conservative substitutions are circled. The amino acid sequence of AChE C is 90% identical to AChE B, and differs only in the features illustrated in that Thr-70 is substituted by Ser.

Cholinesterases secreted by parasitic nematodes of (predominantly) the alimentary tract or other mucosal tissues are authentic AChEs when analysed by substrate specificity, inhibitor sensitivities and primary structure. In the first two respects, they resemble vertebrate AChEs, whereas somatic (and therefore presumably neuronal) enzymes of nematodes analysed to... 

ACh was first proposed as a mediator of cellular function by Hunt in 1907, and in 1914 Dale [2] pointed out that its action closely mimicked the response of parasympathetic nerve stimulation (see Ch. 10). Loewi, in 1921, provided clear evidence for ACh release by nerve stimulation. Separate receptors that explained the variety of actions of ACh became apparent in Dale s early experiments [2]. The nicotinic ACh receptor was the first transmitter receptor to be purified and to have its primary structure determined [3, 4]. The primary structures of most subtypes of both nicotinic and muscarinic receptors, the cholinesterases (ChE), choline acetyltransferase (ChAT), the choline and ACh transporters have been ascertained. Three-dimensional structures for several of these proteins or surrogates within the same protein family are also known. 

The primary and tertiary structures of the cholinesterases are known. The primary structures of the cholinesterases initially defined a large and functionally eclectic superfamily of proteins, the a,P hydrolase fold family, that function not only catalytically as hydrolases but also as surface adhesion molecules forming heterologous cell contacts, as seen in the structurally related proteins... 

While nerve agents vary in molecular structure, they all exert the same physiological effect on the body an increase in acetylcholine throughout the body caused by interference with a vital enzyme known as cholinesterase. The four primary nerve agents are tabun, sarin, soman, and VX. 

It will be shown below that D.F.P. is rapidly destroyed in vitro and in vivo.2 Therefore, the recovery of serum cholinesterase activity is not representative of a reversal of enzyme inhibition, but is indicative of synthesis of new enzyme proteins. Since the regeneration rate of serum cholinesterase in patients with liver damage is significantly depressed as contrasted with that in the normal patient, it is concluded that the ability of such patients to synthesize this particular enzyme protein is decreased. This constitutes evidence for the view that the fiver is a primary locus for the formation of serum cholinesterase. 

Mivacurium chloride (Mivacron) is a newer agent that is chemically related to atracurium. The primary mechanism of inactivation is hydrolysis by plasma cholinesterase. Although it is useful for patients with renal or hepatic disease, some caution is warranted, since these individuals may have reduced plasma cholinesterase as a result of the disease. Mivacurium has an onset of action (1.8 minutes) and duration of effect (20 minutes) only twice that of succinylcholine, and in this respect, it is the most similar to succinylcholine of all of the nondepolarizing agents. 

The most prominent pharmacologic effects of cholinesterase inhibitors are on the cardiovascular and gastrointestinal systems, the eye, and the skeletal muscle neuromuscular junction (as described in the Case Study). Because the primary action is to amplify the actions of endogenous acetylcholine, the effects are similar (but not always identical) to the effects of the direct-acting cholinomimetic agonists. 

The extremely short duration of action of succinylcholine (5-10 minutes) is due to its rapid hydrolysis by butyrylcholinesterase and pseudocholinesterase in the liver and plasma, respectively. Plasma cholinesterase metabolism is the predominant pathway for succinylcholine elimination. Since succinylcholine is more rapidly metabolized than mivacurium, its duration of action is shorter than that of mivacurium (Table 27-1). The primary metabolite of succinylcholine, succinylmonocholine, is rapidly broken down to succinic acid and choline. Because plasma cholinesterase has an enormous capacity to hydrolyze succinylcholine, only a small percentage of the original intravenous dose ever reaches the neuromuscular junction. In addition, as there is little if any plasma cholinesterase at the motor end plate, a succinylcholine-induced blockade is terminated by its diffusion away from the end plate into extracellular fluid. Therefore, the circulating levels of plasma cholinesterase influence the duration of action of succinylcholine by determining the amount of the drug that reaches the motor end plate. 

Organophosphates are characterized by their similar mechanism of toxic action in insects and mammals, resulting in the irreversible inhibition of the enzyme cholinesterase, and the accumulation of acetylcholine at nerve endings (synapses). The primary mechanism is phosphorylation of the enzyme critical to normal transmission of nerve impulses from fibers to innervated tissues. A critical fraction of tissue enzyme must be inactivated before the symptoms of toxicity appear. At sufficient dose, the loss of enzyme function results in... 

A method to set REIs would account for the rate of dermal absorption, the rate of foliar contact and the rate of change in cholinesterase. These factors were used in the Popendorf and Leffingwell (1982) Unified Field Model for determining REIs. This model also accounts for the relative rate of DFR dissipation, and differences in potency based on the dermal LD50 of the pesticide. The Unified Field Model is an elegant technique that takes into account many variables affecting exposure and cholinesterase inhibition as a response. Ultimately, the rate of cholinesterase inhibition, and not a fixed level of inhibition, is the primary... 

Cholinesterases (ChE) are well-known targets for organophosphates (OPs), and RVX is no exception. Much less information is available about other enzymes that could be primary targets upon exposure to low doses of OP, and on biochemical markers of possible delayed effects of OP intoxication when the level of ChE activities is the same as the control. However, this problem is very important due to various reasons, among which is fulfillment of chemical weapon agents (CWAs) nonproliferation conventional programs and inherent possibility of accidental exposure of... 

Enzymatic hydrolysis is a primary route for elimination of nerve agents. Specifically, treatment for OP intoxication includes atropine, a muscarinic receptor antagonist, an anticonvulsant such as diazepam, and a cholinesterase reactivator, an oxime. It has been found that drag-induced inhibition of ACh release and accumulation in the synaptic cleft, such as adenosine receptor antagonist early in the OP intoxication, improves the chances of survival. Some AChE reactivators, such as bispyridinum oximes, HI 6 and HLo 7 with atropine, are quite effective. 

Once touted as the medication of choice to treat lethal tricyclic antidepressant overdoses, physostigmine (antilirium ) has very limited uses today in overdose management. Physostigmine is a cholinesterase inhibitor and finds its primary application in the treatment of severe anticholinergic poisoning. When indicated, physostigmine is administered preferably in small incremental doses of 2 mg mixed in 10 cc of saline by slow intravenous infusion over 10 min. 

---