Paralysis of autonomic ganglia by methonium salts / by W.D.M. Paton and E.J. Zaimis.

  • William Paton
Date:
[1951?]
Catalogue details

Licence: In copyright

Credit: Paralysis of autonomic ganglia by methonium salts / by W.D.M. Paton and E.J. Zaimis. Source: Wellcome Collection.

    15/18 (page 167)
    Relation of activity to chemical structure It is still premature to attempt to relate the chemical structure of known ganglion¬ blocking drugs to their pharmacological activity. For instance, among salts containing methylated quaternary nitrogen are several highly effective compounds (e.g., pentamethonium, hexamethonium, ^/-tubocurarine); but ganglion-blocking activity occurs also among ethylated quaternary salts (e.g., tetraethylammonium, bistriethylammonium decane, 2512F). Again, although a five or six carbon atom methylene chain produces the highest potency in the bistrimethylammonium series, it causes almost the lowest activity in the bistriethylammonium series (Chou and de Elio, 1947). It seems likely that order will not be achieved among such flagrant inconsistencies until there has been further analysis of the details of the action of the various compounds concerned. In a discussion (Paton and Zaimis, 1949a) of the fact that decamethonium is the most active member of the methonium series in producing neuromuscular block, it was argued that the evidence indicated that the drug acted by forming a link at each end of its molecule with receptor groups spaced the corresponding distance apart. On such a theory, the ten carbon atom chain is a measure of the inter-receptor dis¬ tance. Similar arguments may be invoked here, for, as with decamethonium, there appears to be no other physical property of the molecule competent to change its activity by a factor of 40 when a single carbon atom is removed from the poly¬ methylene chain. We suggest, then, that we are again measuring an inter-receptor distance, but it is quite different from that at the motor endplate. Despite the profound analogies between transmission processes at the myoneural and at the ganglionic synapses, there are evidently significant and fundamental differences between them. Summary 1. The shorter chain members of the polymethylene bistrimethylammoni um series cause ganglionic block. The pentane and hexane derivatives, pentamethonium and hexamethonium, are particularly effective. 2. Pentamethonium and hexamethonium do not affect the response of the nictitat¬ ing membrane to adrenaline or to stimulation of the postganglionic trunk of the superior cervical ganglion. Injected into the perfused ganglion, they do not affect the release of acetylcholine produced by stimulating the preganglionic trunk. They do not cause any initial excitation of the ganglion. They paralyse ganglionic transmission solely by raising the threshold of the ganglion cell to the acetylcholine released at preganglionic nerve endings. 3. Intravenous injections of pentamethonium or hexamethonium cause a fall of cat’s blood-pressure which is greater the higher the initial level of pressure; they also cause vasodilatation of the rabbit’s ear. They abolish or reduce the pressor action of nicotine and of tetramethylammonium, and reduce the pressor response to asphyxia. The action of acetylcholine on the blood-pressure is not reduced by large doses of hexamethonium, but is slightly prolonged; that of adrenaline is considerably enhanced and prolonged. The vascular actions of pentamethonium and hexamethonium are entirely attributable to removal by these drugs of autonomic vascular control. 4. Slowing of the heart and fall in blood-pressure produced by peripheral vagal stimulation are abolished by pentamethonium and by hexamethonium, without any reduction of the effects of an initially equiactive dose of acetylcholine.