Curariform action

It has long been known that quaternary ammonium salts can exert a curare-like action, and in recent years much attention has been given to the synthesis and pharmacological testing of such products work on this subject up to 1936 has been reviewed by Ing, and more recently a theoretical discussion of the relationship between structure and action in drugs of this type has been provided by Holmes, Jenden and Taylor.Chase, Lehmann and Yonkmann have compared the action of quaternary salts of quinine with that of -erythroidine hydrochloride and of dihydro- -erythroidine hydrobromide. Quinine ethochloride shows marked curariform action of short duration. ... 

The curariform action of some robust chelates was discovered by Beccari... 

Cerium nitrate has a curariform action on frog striated muscle and the decreased muscle contractility depends on the particular rare earth being investigated (Haley, 1965). La has been shown to influence both the pre- and postjunctional membrane receptor processes of the frog sartorius muscle and... 

Although this story proved a little too complex to be widely appreciated, and few were inclined to generalize from the evidence, the topic acquired a new facet when Ing (1936) published his much-quoted review. In this he pointed out that the alkaloid tubocurarine (2.6), which blocks neuromuscular transmission (see Section 2.0), must do so by competing with acetylcholine for a receptor in voluntary muscle (both substances are quaternary amines). In addition, Ing postulated that the somewhat weaker curariform action of innumerable quaternary ammonium, phosphonium, arsonium, stibonium, and sulphonium salts arose from their competition with acetylcholine (Ing, 1936). (For further reading on the physiological... 

The beanlike seeds of the trees and shrubs of the genus Erythrina, a member of the legume family, contain substances that possess curare-like activity. The plants are widely distributed in the tropical and subtropical areas of the American continent, Asia, Africa, and Australia, but apparently they are not used by the natives in the preparation of arrow poisons. Of 105 known species, the seeds from more than 50 have been tested, and all were found to contain alkaloids with curariform properties. Erythroidine, from E. americana, was the first crystalline alkaloid of the group to be isolated. It consists of at least two isomeric alkaloids, a and P-erythroidine both are dextrorotatory. Most experimental and clinical study has centered on the b form because it is more readily obtainable in pure state. P-Erythroidine is a tertiary nitrogenous base. Several hydrogenated derivatives of p-erythroidine have been prepared of these, dihydro-P-erythroidine has been studied most carefully and subjected to clinical trial. Conversion of P-erythroidine into the quaternary metho salt (p-erythroidine methiodide) does not enhance, but rather almost entirely, abolishes its curariform activity this constitutes a notable exception to the rule that conversion of many alkaloids into quaternary metho salts results in the appearance of curare-like action. 

The therapeutic uses of neostigmine include the treatment of atony of the urinary bladder and postoperative abdominal distention. In addition, it antagonizes the action of rf-tubocurarine and curariform drugs. Edrophonium, neostigmine, or pyridostigmine may be used to diagnose myasthenia gravis. Because edrophonium has the shortest duration of action, it is most often used for this purpose. 

Musck Halothane causes some relaxation of skeletal muscle via its central depressant effects and potentiates the actions of nondepolarizing muscle relaxants (curariform drugs see Chapter 9), increasing both their duration of action and the magnitude of their effect. Halothane and the other halogenated inhalational anesthetics can trigger malignant hyperthermia this syndrome frequently is fatal and is treated by immediate discontinuation of the anesthetic and administration of dantrolene. 

Crum Brown and Fraser (6) in 1868 attributed curariform activity to the onium ion. Even at that early date, they suggested therapeutic possibilities of synthetic quaternary salts which could be prepared of constant purity and effectiveness. Boehm (7, 8) first showed that the active alkaloids of curare preparations are quaternary ammonium compounds. Since these discoveries, a great many quaternary compounds have been investigated, and even the simplest quaternary ammonium salts, as well as sul-fonium, phosphonium, arsonium, and stibonium salts, exhibit curare activity (9). Quaternary ammonium compounds widely varied in character have been found to exhibit curare activity. Hunt and Renshaw and collaborators (10, 11) have published a series of papers on onium compounds and their effects on the autonomic nervous system. In addition to curare action, they were shown to exhibit muscarinic and nicotinic actions in varying degrees. 

Quinine has long been known to exert a weak curare-hke action. Rosen-stein (102), applying the premise that onium ions are responsible for curariform activity, showed that quaternary derivatives of quinine and cinchonine have lissive activity. Harvey (103) examined quinine methochloride extensively and found it to be effective orally and to produce in cats a sequence of events similar to that produced by curare. A number of quaternary derivatives of the cinchona alkaloids have been evaluated as curarizing agents the results are summarized in Table 4. 

Of the three alkaloids d-tubocurarine chloride, bebeerine, and curine (74, 76, 78, 80) the first has the strongest curarizing action. d-Tubocura-rine chloride produces complete paralysis of the frog when doses of 0.5 mg. per kilogram are administered (76). It seems to cause typical respiratory paralysis in mammals. LTubocurarine chloride is many times weaker in curariform activity than its enantiomorph d-tubocurarine chloride (123). 

---