Neuromyopharmacology as related to anticholinesterase action

Abstract

INTRODUCTION Skeletal neuromyal (NM) junction is one of the primary targets of either acute or chronic action of anticholinesterases (antiChE's) generally and of organophosphorus (OP) ChE inhibitors specifically (Karczmar, 1967a). In fact one of the first (Holmstedt, 1963; Karczmar, 1970) observations with respect to OP, acute or chronic administration, concerned the resulting muscle weakness. In the historical 1946 issue of the Journal of Pharmacology and Experimental Therapeutics where some of the results .obtained wi th OP agents at the US Army Chemical Center, Edgewood, MD, were published for the first time in open literatur~e, the neuromyal weakness was described as an overt symptom of systemic administration of OP antiChE's; also, it was emphasized that when it was attenuated wi th time in non-fatal cases upon discontinuation of the OP administration, the NM block reappeared, accompanied by fasciculations, upon stimulation of the.animal (Modell et aL, 1946; Modell and Krop, 1946; Koelle and Gilman, 1949). After the init iat ion of studies of isolated NM preparations this effect was related to non-substenance of tetanus or .to tetanic fade (Karczmar, 1967a; Hobbiger, 1976; Bowrn'an, 1979). As it wi l l be stressed here it appears today that still another factor may be involved in the antiChE induced muscle weakness, namely receptor desensitization. On the other hand, block of response to single indirect stimulation required very large in the neighborhood of 104M in the in vitro experiments concentrations of OP or non-OP antiChE's (Barstad and Lil leheil, 1968; Meer and Meeter, 1956; Fleisher et aL, 1960; Hobbiger, 1976). These as wel l as more recent data (Wills, 1970; Grob, 1963; Drachman, 1981 ) emphasize the significance of the NM junction in OP and, generally, antiChE poisoning. This presentation wi l l shift the focus of the NM action of antiChE's from its toxic to its basic aspects, as their synaptic effect on the NM transmission is of a particularly heuristic character. Some of the aspects of this action wi l l be reviewed as wi l l be the effect of antiChE's on desensitization and their interaction with drugs capable of antagonizing desensitization.