Pharmacology curarizing activity

Chapter 3 by Mary D. Menachery surveys the alkaloids of South American Menispermaceae (moonseed family). Many different structural types are included in this family. The alkaloidbearing plants are woody-vines, shrubs, or small trees. Several of these species possess potent curare activity. The chemistry as well as pharmacology of these alkaloids is summarized. 

Tubocurarine causes muscle relaxation by blocking nerve receptors at the motor muscle by competitive binding to the acetyl choline receptor. This mode of action is generally described in the field of pharmacology as the curarizing activity. 

In analysing a sample of curare, probably from the Amazon, King (306) found that the non-quaternary alkaloids made up 38% of the original curare and contained numerous phenolic bases. The two that he isolated and characterized were isomers of the isochondrodendrine series the pharmacologically inactive protocuridine (19b), also obtained by Boehm (189) from curare, and the optically inactive neoprotocuridine (19c) which had weak curarizing activity their stereochemistry has not yet been determined. Cf. also Section I.4.6.2. 

Canadine is bitter and in small doses causes drowsiness and depression. In large doses it gives rise to transient excitement succeeded by depression and paralysis of the central nervous system. Its injection is followed by violent peristalsis with diarrhoea. It is said to have no effect on the blood pressure. The pharmacological action of canadine a- and -meihochlorides was examined by Laidlaw, who found both to have the curare-like action common to ammonium bases, the -isomeride being the more active the relative activities of the four optically active forms are given as h da. ip dp = 1 Q 2 28. 

According to-Vellard, a Strychnos sp. similar to S. medeola is used by the Nambikwaras. Brasil, Campos and Kuhlmann have mentioned three S. American species of Strychnos, viz., S. diplinerva, S. off. albiflora Prog and S. brevifolia A.D.C., in which, using extracts of the roots in comparison with Tecuna curare, they have found curarising activity by pharmacological tests in rabbits. 

This view was supported by the observation that choline on treatment with nitric acid yielded a product having a pharmacological action similar to that of muscarine as known up to that time. Comparison of the natural and artificial products by Bohm showed that the former was much more active than the latter and that its action was antagonised by atropine, whilst the artificial muscarine had a curare-like action on the atropinised frog. Later, Nothnagel investigated the action of... 

The pharmacological properties of P-erythroidine and its dihydro derivative are very similar to those of d-tubocurarine and therefore need not be described in any detail. The two compounds differ from curare in three important respects, namely, less potent paralytic action on neuromuscular junctions, briefer duration of paralysis, and oral efficacy. Indeed, gastrointestinal absorption of the alkaloids is so rapid and complete that the difference between effective oral and subcutaneous doses is rather small. Dihydro-P-erythroidine is longer acting than P-erythroidine and about six times as active. Similar to curare, P-erythroidine and its dihydro derivative are antagonized at the neuromyal junction by anticholinesterases such as neostigmine. 

The bisbenzylisoquinolines have been the subject of many pharmacological studies, motivated originally by the knowledge that quaternary alkaloids of this type are the active constituents of tube curare. Certain nonquaternary bisbenzylisoquinolines, notably belonging to the curine group, are also smooth muscle re-laxants many bisbenzylisoquinolines are hypotensive, and a few possess anti-... 

Russian workers have prepared for pharmacological studies simple carbamates of trachelanthamidine (68) by treatment with the appropriate isocyanate. Some cholinesterase inhibitors based on the standard decamethonium model have been prepared. Decamethylene bistrachelanthamine dibromide (69) showed marked curare-like activity in cats and rabbits. New procedures for the iodometric determination of platyphylline bitartrate and for the colorimetric determination of trichodesmine and incanine in the organs of poisoned animals have been described. 

Such compounds often exhibit chemical and spectral behaviour which is specifically characteristic of the dimeric structure. Also of paramount interest are the specific pharmacological properties of certain of these alkaloids, such as the muscle relaxation action of the curare alkaloids and the anti-leukemia activity of the Vinca alkaloids leurocristine and vinblastine. Such aspects will be discussed in the last two sections of the review. 

Pharmacology of Calabash-curare.f —Paralytic Activity. A number of Strychnos alkaloids have considerably greater paralytic action than any previously known natural or synthetic neuromuscular blocking agent. Unfortunately, frogs are not suitable for the evaluation of curare effects because they show sea-... 

Table 5 Pharmacological activities of important curare alkaloids... 

A large number of alkaloids have been converted to quaternary salts and examined pharmacologically. The quaternary derivatives of certain bis-benzylisoquinoline alkaloids, which are closely related structurally to one class of curare alkaloids, are potent curarizing agents. Quaternary salts of cinchona alkaloids are effective and have been used in clinical investigations. Quaternary salts of many other alkaloids have been shown to exhibit curariform activity. 

Finally, it should be mentioned that the curare alkaloids - as is generally known - are quaternary salts and due to their strong hydrophilicity they have to be administered parenterally. In contrast, the Erythrina alkaloids are all tertiary amines and therefore they are able to develop their pharmacological activities upon oral administration. 

Pharmacological studies of curare were initiated in the middle of the nineteenth century by the French physiologist Claude Bernard (1813— 1878). The dominant pharmacological effect of curare is the paralysis of the whole skeletal muscle in both warm- and cold-blooded animals. The sequence of the paralytic effects of the skeletal muscle is well defined. At first, the eyes, ears, and toes are affected, and next the muscles of the arms and legs. Paralysis of the muscles of the neck then occurs, and finally the respiratory muscles are affected, resulting in suffocation in warm-blooded animals. The muscle relaxant activity of curare is strengthened by diethylether. Because curare can release stored histamine in the tissues, it may cause hypotension and excessive secretion in the trachea. 

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