The pharmacology of ganglion blocking agents / by W.D.M. Paton.

  • William Paton
Date:
[1959?]
Catalogue details

Licence: In copyright

Credit: The pharmacology of ganglion blocking agents / by W.D.M. Paton. Source: Wellcome Collection.

    4/12 (page 368)
    sociation speeds is high, then the action of the drug is prolonged, since that amount combined takes a long time to get away; if the ratio is low, then the reverse. But there is another, less obvious prediction: If dissociation is rela¬ tively very slow, then the time taken to reach maximum action is also pro¬ longed. Perhaps a domestic example may serve to illustrate this; suppose you turn on the taps (faucets) of a bath, and the drain-away is closed, then the bath will go on filling indefinitely. In other words, if dissociation doesn’t occur at all, association will continue indefinitely (until limited by satura¬ tion). On the other hand, if the drain-away is both open and very large, equilibrium (with a virtually empty bath) is rapidly reached; here dissocia¬ tion is rapid compared to association. Between these limits, the faster the rate of filling (association) of the bath (receptor area) compared to the rate of draining (dissociation), the longer it will take to reach any given approxi¬ mation to the equilibrium state. I have found this a generalization of rather wide application, when one studies, for instance, muscle relaxants, atropinic substances, antihistamines, and so on. For ganglion blocking agents, too, it seems enlightening. Take the series of drugs, TEA, hexamethonium, pentolinium, pempidine and mecamyl- amine, with durations of action ranging roughly from 30 minutes to 24 hours. As far as I can judge from the published data, the shapes of the time action curves are all alike, differing only in scale; and, roughly speaking, the time of maximum action is about one-sixth of the total duration. This is just what one would expect if the action of these drugs were dictated simply by the constants of association and dissociation. One may notice, too, that if, say, the difference in time course between mecamylamine and pentolinium makes one propose a different mode of action between the two, then the greater proportionate difference between pentolinium and TEA requires the same conclusion; and we multiply modes of action to an extent that one cannot accept. One last point in this connection: If what I have argued is correct then, although there may be widely varying differences in time of peak effect, all the blocking agents should show some effect quite early. This indeed seems to be the case. There is no hint of any irreducible delay, with any of these agents, such as might point to the intervention, say, of a biochemical con¬ version, or to the poisoning of an enzyme to some critical level. One may say, therefore, that the varying durations of action of ganglion blocking agents need point to nothing more than varying affinities for the receptor groups. But, surely, uptake into the tissues must influence time course somehow? My own guess is that this is true, but that the effect is different from that normally supposed; and that if you could prevent the tissue uptake (other factors remaining the same), duration of action and potency would be increased. At this point, it could be retorted that pempi¬ dine is taken up less than mecamylamine by the tissues, yet its duration of action is shorter, not longer. One can answer, besides referring to the long- acting quaternary agents, by another pharmacodynamic suggestion: It may well be that, among compounds able to penetrate cells, those that can do it best may also tend to be bound to the receptor area best. In that case, the association, with nonquaternary salts, of prolonged action and tissue take-up may be a coincidence of the type which might lead one to suggest, for in¬ stance, that poliomyelitis is caused by the internal combustion engine. The association between the latter rests, of course, on the common connection