Ganglionic blocking agents : with special reference to the effect of hexamethonium on the cardiovascular system / by W.D.M. Paton.

  • Paton, William D. M.
Date:
[1952?]
Catalogue details

Licence: In copyright

Credit: Ganglionic blocking agents : with special reference to the effect of hexamethonium on the cardiovascular system / by W.D.M. Paton. Source: Wellcome Collection.

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    Reprinted from British Medical Bulletin, 1952, Vol. 8, No. 4, pages 310-315 HEXAMETHONIUM AND OTHER GANGLIONIC BLOCKING AGENTS W. D. M. Paton GANGLIONIC BLOCKING AGENTS With Special Reference to the Effect of Hexamethonium on the Cardiovascular System W. D. M. PATON M.A. B.M. Reader in Pharmacology and Therapeutics University College Hospital Medical School, London 1 The principles of ganglionic blockade a Distribution of hexamethonium in the body b Antagonists c Selectivity d Activity e Maximality 2 Cardiovascular effects of hexamethonium in the normal subject a Postural hypotension b Effects on other vascular reflexes c “ Controlled circulation ” 3 Hexamethonium in the treatment of hypertension a Comparison of hexamethonium with other drugs 4 Other peripheral vascular effects of hexamethonium 5 Conclusion References 1. The Principles of Ganglionic Blockade Drugs which paralyze transmission in autonomic ganglia fall into two groups. In the first are drugs like nicotine which depolarize the ganglion cells, so that before they paralyze transmission they actually stimulate the ganglion more or less vigorously. Although the foundations of our knowledge of the autonomic nervous system rest on work done with nicotine, this is not suitable for use clinically, partly because of this initial excitant action, partly because it can, in addition, excite the chemoreceptors of the carotid bodies, cause neuro¬ muscular block and produce certain central stimulant effects. The clinically useful ganglion blocking drugs belong to the second category and include such agents as tetraethyl- ammonium (N+(C2H5)4) and hexamethonium (N+CH3)3. (CH2)6N+ (CH3)3). These substances have a purely inhibitory effect on transmission through a ganglion. They act in a way which is usually termed competitive: that is, they compete with the acetylcholine released at the preganglionic nerve terminals for the specific receptors on the ganglion cell bodies. Their action is thus comparable to that of other competitive blocking agents, such as curare at the neuromuscular junction, atropine at a peripheral parasympathetic site, or mepyramine in antagonizing the effects of histamine. It is unfor¬ tunate that only rarely have the quantitative investigations necessary to prove such competition been made. But the general belief that these drugs act in this way agrees with all their known properties and provides a satisfactory working hypothesis of their mode of action. (For further details of the pharmacology of such drugs, see Paton, 1951; Paton & Perry, 1951a, 1951b; Paton & Zaimis, 1948, 1949, 1951 and Paton & Zaimis, 1952; Wien & Mason, 1951.) a. Distribution of Hexamethonium in the Body Hexamethonium owes its ability to compete with acetyl¬ choline to the fact that, like acetylcholine, it is a compound of quaternary nitrogen; almost all the other agents with similar actions are also quaternary salts. This fact is responsible for many of the characteristics of ganglion blocking agents. Drugs penetrate cell membranes much more rapidly in the unionized form than as ions; consequently quaternary salts, which in solution can exist only in the ionized form, penetrate the cellular structures of the body very slowly, and in fact have a predominantly extracellular distribution. To this may be attributed: (i) the slowness of absorption of hexamethonium from the intestine (Milne & Oleesky, 1951; Harington, unpublished); (ii) the slowness of penetration of hexa¬ methonium into the cerebrospinal fluid (Paton, unpublished); (iii) the distribution of hexamethonium in the extracellular fluid of the body (Morrison & Paton, unpublished); (iv) the excretion of hexamethonium, like inulin, without tubular reabsorption or secretion (Young, de Wardener & Miles, 1951). The slowness of absorption from the intestine makes oral administration difficult in clinical practice, not so much because the absorption is usually only about 5-10% of the dose given, but because the percentage of absorption is variable; it may be as little as 2% and yet occasionally as high as 30%. Harington (unpublished) has shown that absorption depends to some extent on the salt of hexame¬ thonium used, the bromide being appreciably better absorbed than the chloride, tartrate, or methosulphate. He has also shown that absorption is greater as well as somewhat slower when hexamethonium is taken on an empty stomach. Many of the difficulties of oral administration could be overcome if the absorption could be made regular even if it were not at the same time increased. b. Antagonists The interruption of autonomic activity at the ganglionic level by ganglion blocking drugs has the advantage that their effects can be antagonized when necessary by sympatho¬ mimetic or parasympathomimetic substances which act peripherally. Because of the fairly ready excretion of hexa¬ methonium, antidotes to its effects are not often needed, particularly as experience is gained in using the drug. If such antidotes are necessary, noradrenaline or sympathomimetic amines may be used when too great a fall in blood pressure has been produced; or carbachol, urecholine or neostigmine may be used if intestinal stasis or ileus has developed. The use of drugs which actually antagonize hexamethonium at the ganglion itself is still poorly understood. In general, anticholinesterases (the logical antidotes) have a much less dramatic action at the ganglionic synapse than at the neuro¬ muscular junction. Some successful antagonisms to the actions of ganglionic blocking agents by anticholinesterases have been described, but special conditions are usually necessary for this and a casual test for such action usually fails to reveal it. In man, Grob & Harvey (1950) have found that prostigmine could not prevent the postural hypotension caused by pentamethonium, and this result is entirely concordant with general experience with animals.