Main trends in the search for new neuromuscular blocking agents

Abstract

218 Main trends in the search for new neuromuscular blocking agents D. A. Kharkevich Department of Pharmacology, Fint Medica/Institute, .W'oscow, U.S.S.R. It is generally known that the neuromuscu­lar blocking agents are used in practically every field of surgery. Furthermore, they are applied for treatment of various neurological diseases which are accom­panied by an increased tonus of skeletal muscles and tetanus. The various demands of clinicians for neuromuscular blocking agents have made it necessary to create a set of such drugs with precise indications for the use of each drug. Defined in terms of the mode administration and the duration of action the required neuromuscular blocking drugs can be classified in the following groups: I. Drugs for parenteral (intravenous) administration 1. Of short duration of action ( 5-15 min) 2. Of moderate duration of action (20-60 min) (a) rapidly evoking apnea (b) weakly inhibiting respiration 3. Of long duration of action (more than 60 min) (a) rapidly evoking apnea (b) weakly inhibiting respiration II. Drugs for oral administration (of long duration of action, weakly inhibiting respiration). pharmacological antagonists. This may cause some difficulties cases when the inactivation succinylcholine is disturbed and the effect (myorelaxation, apnea) lasts for several hours. Such a situation may occur with genetically conditioned insuffi­ciency of pseudocholinesterase. Besides, succinylcholine, belonging to the depolariz­ing agents, increases the permeability of the endplate membrane, which is accompanied by release an excessive amount of Diadonium HO t:::O CH.OH HOH,C OH t:::02CI tH~CHr-0-o-Q-CH;_tH, Diplacinum Tercuronium TIPS-August 1981 potassium ions into the extracellular space. Their content increases in plasma and decreases in skeletal muscles. The altera­tion in the distribution of potassium ions may have an undesirable effect on the activity of various organs (heart, for ex­ample). Muscle soreness, which may be observed during the postanesthetic period is probably also caused by the potassium imbalance. Also the use of succinylcholine is contraindicated in galucoma. Thus, it is quite natural, that phar­macologists and chemists should aim at creating short acting neuromuscular block­ing agents with non-depolarizing mode of action. The general trends of their search are as follows. One lies in synthesis of agents, which are rapidly inactivated (for example, in the series of esters related to succinylcholine). Also, short duration of action can be based on the unstable fixation of the agent on acetylcholine receptor. In the series of his-quaternary ammonium compounds this may be achieved by chang­ing the character of radicals attached to quaternary nitrogen atoms. Proceeding a H.--'71 .#·rcHo ~ ~ ·2CI ·4H,Q --ICH·I·---N·-Qualidilum The drugs of short duration action are used for short manipulations- intubation, setting of dislocations, reposition of bone fragments, etc. The myorelaxation induced by the neuromuscular blocking agents of this group should not exceed 5-15 min. At the same time short acting agents can be useful for prolonged dripfeed or multi­ple intravenous administration. The drip infusion facilitates control of the degree of muscle relaxation. It is important that, after the discontinuance of the infusion the drug, initial tonus of skeletal mus­cles should be rapidly restored. Dioxonium Succinylcholine (lysthenon), a well known drug of depolarizing mode action, is a short acting neuromuscular blocking agent. However, it has a number of disadvantages. First all, it has no £; El~e\ler/~orlh-Holland B10medical Pre'' 1 Y~ I 0\65-fll47/81/0000- 0000/$02.50 H.c. oc~~N-CH, H,C,Nf'\N \__/ 'CH, H~C \___/ -2ar-H.C-OCO Arduan OCO-C.H.--N-CO--CH(CH,}-CH..-CO Fig. 1. Chemical structures o [some neuromuscular blocking agents. H,C,~ ~ Condelphinum