Physostigmine, acetylcholinesterase

Released ACh is broken down by membrane-bound acetylcholinesterase, often called the true or specific cholinesterase to distinguish it from butyrylcholinesterase, a pseudo-or non-specific plasma cholinesterase. It is an extremely efficient enzyme with one molecule capable of dealing with something like 10000 molecules of ACh each second, which means a short life and rapid turnover (100 ps) for each molecule of ACh. It seems that about 50% of the choline freed by the hydrolysis of ACh is taken back into the nerve. There is a wide range of anticholinesterases which can be used to prolong and potentiate the action of ACh. Some of these, such as physostigmine, which can cross the blood-brain barrier to produce central effects and neostigmine, which does not readily... 

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). 

Analysis of ACh in blood and CSF poses two obstacles—low concentrations (<20 pmol/ml) and very fast hydrolysis by esterase (Tsai, 2000). An acetylcholinesterase inhibitor such as physostigmine maybe added to artificial CSF used for the collection of microdialysates to help overcome this problem (Kato et al., 1996). 

Acetylcholine is removed from the synapse through hydrolysis into acetylCoA and choline by the enzyme acetylcholinesterase (AChE). Removing ACh from the synapse can be blocked irreversibly by organophosphorous compounds and in a reversible fashion by drugs such as physostigmine. 

Another use for acetylcholinesterase inhibitors is in glaucoma, in which high intraocular pressure can lead to permanent damage to the optic disk, resulting in blindness. The local instillation of physostigmine (8.14) or echothiophate (8.19) solution in the eye results in a long-lasting decrease in the intraocular pressure as well as myosis (contraction of the pupil). 

Physostigmine, an acetylcholinesterase inhibitor widely used in treatment of glaucoma. Compare with other carbamate esters (Box 12-E)... 

One of the best-understood autoimmune diseases is myasthenia gravis, a condition associated with a decrease in the number of functional post-synaptic nicotinic acetylcholine receptors (Fig. 30-23) in neuromuscular junctions. e The resulting extreme muscular weakness can be fatal. Myasthenia gravis is not rare and affects about one in 10,000 peopled An interesting treatment consists of the administration of physostigmine, diisopropyl-phosphofluoridate (Chapter 12, Section C,l), or other acetylcholinesterase inhibitors (Box 12-E). These very toxic compounds, when administered in controlled amounts, permit accumulation of higher acetylcholine concentration with a resultant activation of muscular contraction. The same compounds... 

Physostigmine is one of the major alkaloids in calabar bean. It has been shown to inhibit acetylcholinesterase at low concentration and to reverse the toxic effects resulting from diazepam overdose. The phytostigmine skeleton is easily obtained in very good yields from an appropriate non-stabilized imidate methylide.162,292,465... 

Physostigmine [fi zoe STIG meen] is an alkaloid (a nitrogenous compound found in plants) and a tertiary amine. It is a substrate for acetylcholinesterase, and forms a relatively stable enzyme-substrate intermediate that reversibly inactivates acetylcholinesterase. The result is potentiation of cholinergic activity throughout the body. 

Adverse effects The effects of physostigmine on the CNS may lead to convulsions when high doses are used. Bradycardia may also occur. Inhibition of acetylcholinesterase at the skeletal neuromuscular junction causes the accumulation of acetylcholine and ultimately results in paralysis of skeletal muscle. However, these effects are rarely seen with therapeutic doses. 

Perola E, et al. Long-chain analogs of physostigmine as potential drugs for Alzheimer s disease new insights into the mechanism of action in the inhibition of acetylcholinesterase. Biochim. Biophys. Acta, 1997, 1343(1), 41-50. 

The main action of physostigmine is on the parasympathetic nervous system. It is now known (52, 53) that physostigmine produces its effect by inhibition of the enzyme acetylcholinesterase. The role played by acetylcholinesterase in the transmission of nerve impulses at nerve endings (54, 55) and in the conduction of impulses along nerve and muscle fibers (56, 55) has been described in detail elsewhere. 

The mechanism of the inhibition of acetylcholinesterase by physostigmine is related to the more general problem of the nature and mode of action of the active site (or sites) of the acetylcholinesterase molecule. 

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