Anticholinesterases reversible

Since mivacurium is metabolized by plasma cholinesterase, the interaction with the anticholinesterase reversal drugs is less... 

In summary, ANTX-A(S) uses the two-site attachment mechanism analogous to substrate and does not inhibit AChE in the manner of the reversible anticholinesterases. 

In contrast to the nicotinic antagonists and indeed both nicotinic and muscarinic agonists, there are a number of muscarinic antagonists, like atropine, hyoscine (scopolamine) and benztropine, that readily cross the blood-brain barrier to produce central effects. Somewhat surprisingly, atropine is a central stimulant while hyoscine is sedative, as least in reasonable doses. This would be the expected effect of a drug that is blocking the excitatory effects of ACh on neurons but since the stimulant action of atropine can be reversed by an anticholinesterase it is still presumed to involve ACh in some way. Generally these compounds are effective in the control of motion but not other forms of sickness (especially hyoscine), tend to impair memory (Chapter 18) and reduce some of the symptoms of Parkinsonism (Chapter 15). 

ACh is metabolised extraneuronally by the enzyme acetylcholinesterase, to reform precursor choline and acetate. Blocking its activity with various anticholinesterases has been widely investigated and some improvement in memory noted. Such studies have invariably used reversible inhibition because of the toxicity associated with long-term irreversible inhibition of the enzyme. Physostigmine was the pilot drug. It is known to improve memory in animals and some small effects have been seen in humans (reduces number of mistakes in word-recall tests rather than number of words recalled), but it really needs to be given intravenously and has a very short half-life (30 min). 

The failure of physostigmine to reverse BZ effects during the first 8 hours (Fig. 8) is interesting and unexplained. It reminds one of the Berry and Davies findings (in 1970 at the British labs in Porton Down) which showed that the reversible anticholinesterase pyridostigmine was paradoxically effective as a prophylactic agent in the event of nerve gas exposure (see ref. ). 

Toxicology. Carbaryl is a short-acting anticholinesterase agent with the important characteristic of rapid reversibility of inhibition of the enzyme. 

Holmes, R., Robins, E.L. 1955. The reversal by oximes of neuromuscular block produced by anticholinesterases. Brit. J. Pharmacol. 10 490-495. 

Rapid advances in chemistry during the nineteenth and twentieth centuries, coupled with the success of mustard gas as a toxic weapon in World War I, attracted attention to the warfare potential of chemical agents. This led to support for research on lethal nerve agents during and immediately after World War II. The research was followed by the development of treatment methods, and prominent among these was the use of cholinesterase reactivators to reverse the lethal effects of anticholinesterase nerve gases. 

It soon became evident that no available antidotes could block the pharmacologic activity of these chemicals, alleviate the signs and symptoms of toxicity, or restore normal bodily functions after exposure. Atropine readily antagonized the muscarinic actions, including those in the central nervous system (CNS), but elicited no reversal of the nicotinic effects. Better forms of therapy were sought, particularly to alleviate the nicotinic effects of anticholinesterase agents. 

As given in classification, these agents are of two type e.g. reversible and irreversible. The reversible anticholinesterases have a structural resemblance to acetylcholine, are capable of combining with anionic and esteratic sites of cholinesterase as well as with acetylcholine receptor. The complex formed with the esteratic site of cholinesterase is less readily hydrolyzed than the acetyl esteratic site complex formed with acetylcholine. Edrophonium forms reversible complex with the anionic site and has shorter duration of action. Also, neostigmine and edrophonium have a direct stimulating action at cholinergic sites. 

Satisfactory neuromuscular block can be maintained with an atracurium bolus of 0.5-0.6 mg-kg-1 followed by an infusion at a rate of about 0.5 mg-kg-l-h-1. The unique metabolism of atracurium makes it suitable for use in critically ill patients with organ dysfunction, in whom it can be used for even longer periods of time as long as hypothermia is not present. The reversal of an atracurium block can be easily accomplished with anticholinesterase agents. 

Pralidoxime is administered by intravenous infusion, 1-2 g given over 15-30 minutes. In spite of the likelihood of aging of the phosphate-enzyme complex, recent reports suggest that administration of multiple doses of pralidoxime over several days may be useful in severe poisoning. In excessive doses, pralidoxime can induce neuromuscular weakness and other adverse effects. Pralidoxime is not recommended for the reversal of inhibition of acetylcholinesterase by carbamate inhibitors. Further details of treatment of anticholinesterase toxicity are given in Chapter 58. 

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