Drugs and ionic channels: mechanisms and implications.

There is evidence that acetylcholine antagonists at the neuromuscular junction and elsewhere can act by blocking the ionic channels opened by acetylcholine as well as by competing with acetylcholine for receptor sites. This type of uncompetitive antagonism can be distinguished from competitive antagonism in various ways. (1) The degree of block increases rather than decreases if the agonist concentration is increased. (2) If the blocking agent is cationic, the degree of block increases markedly if the cell is hyperpolarized. (3) The kinetics of the channel opening and closing reactions are markedly affected. At the neuromuscular junction, antagonists such as tubocurarine and gallamine share both types of action. Recent studies on rat parasympathetic ganglion cells show that hexamethonium, decamethonium and tubocurarine act exclusively by the uncompetitive mechanism, whereas other blocking agents (e.g. trimetaphan, mecamylamine) appear to act competitively. The uncompetitive mode of action on synaptic ionic channels appears to resemble closely the effects of local anaesthetics and related drugs on voltage-sensitive ionic channels.