Physostigmine enzyme effects

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). 

Reversible cholinesterase inhibitors form a transition state complex with the enzyme, just as acetylcholine does. These compounds are in competition with acetylcholine in binding with the active sites of the enzyme. The chemical stracture of classic, reversible inhibitors physostigmine and neostigmine shows their similarity to acetylcholine. Edrophonium is also a reversible inhibitor. These compounds have a high affinity with the enzyme, and their inhibitory action is reversible. These inhibitors differ from acetylcholine in that they are not easily broken down by enzymes. Enzymes are reactivated much slower than it takes for subsequent hydrolysis of acetylcholine to happen. Therefore, the pharmacological effect caused by these compounds is reversible. 

Absorption of the quaternary carbamates from the conjunctiva, skin, and lungs is predictably poor, since their permanent charge renders them relatively insoluble in lipids. Thus, much larger doses are required for oral administration than for parenteral injection. Distribution into the central nervous system is negligible. Physostigmine, in contrast, is well absorbed from all sites and can be used topically in the eye (Table 7-4). It is distributed into the central nervous system and is more toxic than the more polar quaternary carbamates. The carbamates are relatively stable in aqueous solution but can be metabolized by nonspecific esterases in the body as well as by cholinesterase. However, the duration of their effect is determined chiefly by the stability of the inhibitor-enzyme complex (see Mechanism of Action, below), not by metabolism or excretion. 

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. 

Perhaps the most famous instance of enzyme inhibition explaining a gross effect of an alkaloid is the inhibition of cholinesterase by (-)-physostigmine (eserine). Since acetylcholine is such a widespread and essential neurotransmitter, an increase in its concentration at synapses has serious consequences and physostigmine by inhibiting the hydrolysis intensifies and prolongs the action of acetylcholine on its receptors [372]. 

Because physostigmine acts on the enzyme cholinesterase— which is present at all cholinergic synapses—this drug increases acetylcholine effects at the nicotinic junctions as well as muscarinic ones. Bethanechol, on the other hand, is a direct-acting agent that is selective for muscarinic receptors and has no effect on nicotinic junctions such as the skeletal muscle end plate. The answer is (B). 

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