Physostigmine, action

The miotic effect induced by physostigmine lends itself to investigation of the interrelation of chemical constitution and pharmacological action, and Stedman has devoted much attention to this subject. Eseroline is devoid of miotic activity, so that the latter action in physostigmine must be mainly due to the fact that it is a methylurethane, and, since activity only becomes evident in the urethanes of phenolic bases or phenols with a basic side-chain, a basic nucleus for the urethanes appears also to be essential. 

Pilocarpine is being less used in medicine as a diaphoretic in dropsy and similar diseases because of its depressant action on the heart. It has also been employed as a substitute for physostigmine to contract the pupil and reduce intraocular pressure. It has been used as an antidote to atropine, but it does not antagonise the action of atropine in the central nervous system. 

In a monograph on ephedrine Gaddum has reviewed the differences in the action of adrenaline and ephedrine and has suggested that the latter has the same relation to adrenaline as physostigmine has to acetylcholine, that is, ephedrine inhibits the action of an enzyme system, which normally destroys adrenaline, or the substance closely resembling it, produced by adrenergic nerves. 

Miotic action by physostigmine and its substitutes, 549 miotine, 550 Mitragyna spp., alkaloids, 756 Mitragynine, 756, 757... 

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... 

The reactions of AChE-biotests results in the red-brown product (Hettchet pigment). The reaction of AChE-biotests on inhibitors can be estimated visually. The residual activity of AChE in biotests after the action of different concentrations of eserine (physostigmine) and proserine (neostigmine) is seen in Fig. 3. 

Physostigmine is an interesting alkaloid because it is generally recognized that it acts by inhibiting a specific enzyme, cholinesterase. This enzyme has been found to be at characteristic levels in the corpuscles and blood plasma of different individuals (p. 79), and it would be expected that the action of the alkaloid in different individ-... 

Nurses gave physostigmine intermittently to the two most affected volunteers. Whenever they withheld the antidote for more than two hours, scores predictably fell to the untreated level. These observations furthered our knowledge about the effectiveness and duration of physostigmine s actions. We had reached all our goals for the first field test without a glitch and on Saturday, we could release both the volunteers and the medical staff for the weekend. But on Monday, we had to be ready try the test at a 1,000 yards test with a second group of volunteers. 

When George Aghajanian and Fred Sidell decided to investigate the usefulness of antidotes other than physostigmine, scopolamine became the belladonnoid of choice, since its duration of action was short and both nursing and volunteer time required to conduct treatment studies were limited to a single day of observations. 

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. 

Destruction or removal of transmitter from site of action Tolcapone (COMT inhibitor) Phenelzine (MAO inhibitor) Tricyclic antidepressants (inhibit neuronal transport) Physostigmine (cholinesterase inhibitor)... 

The pharmacological actions of physostigmine are similar to those of cholinergic drugs. Topical instillation into the eye produces miosis, spasm of accommodation and decrease in intraocular pressure. Physostigmine is well absorbed after oral as well as parenteral administration and also produces central cholinergic actions because of penetration into blood brain barrier. 

It is a synthetic quartemary ammonium compound, similar to physostigmine and rapid onset of action and can inhibit both true and pseudocholinesterases. 

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. 

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