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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    A fall in blood pressure can be obtained in almost every case if postural measures are also used, so that, even where the neurogenic element is slight, some reduction in blood pressure is possible. The second practical point in treatment, which is also of theoretical interest, is the development of tolerance to hexa- methonium. As treatment proceeds, a dose of hexamethonium which was previously effective gradually loses its action and has to be considerably increased in order to produce its original effect. This process seems to continue over a period of a few weeks, at the end of which time the dose may have increased as much as tenfold. The increased tolerance is lost fairly rapidly when treatment is suspended. It is uncer¬ tain whether the tolerance is restricted to the effect on the blood pressure or not; it may be that the other ganglionic systems also acquire some resistance to hexamethonium, but if so it is certainly less well developed than in the cardio¬ vascular system; for instance, constipation or paralysis of accommodation may become increasingly severe as a patient develops tolerance and has to be given larger doses. This accommodation by the organism to the hypotensive effects of hexamethonium may be compared on the one hand to the recovery of vascular tone after sympathectomy or, on the other, to restoration of the original hypertension by humoral compensatory mechanisms. The phenomenon deserves much closer investigation. The unreliability of oral absorption, the variation among individuals, and the development of tolerance, have made it necessary to develop a special method of administration, and the “ insulin regime ” described by Smirk has proved most satisfactory thus far. Papers by Smirk & Alstad (1951), Turner (1951), Freis (1951), and Rosenheim (1952) should be consulted for details of the induction and maintenance of treatment. As a rule it seems necessary for treatment with hexa¬ methonium to be continued more or less indefinitely. Some cases have been reported in which the benefits of treatment outlasted the treatment itself, and it was hoped that it might prove possible by a period of intensive therapy to break the hypertensive “ vicious circle ”, but the occurrence of occasional natural remissions in the disease means that there is no real evidence of this so far. a. Comparison of Hexamethonium with Other Drugs Tetraethylammonium was the first ganglion blocking agent used in hypertension and proved a useful and stimulating research tool, with which interest in the approach to therapy of hypertension through autonomic ganglia was awakened. Its transience, side-actions (paraesthesia, occasional “ curari- form ” action, and so on) and ability to provoke adrenaline secretion, have limited its clinical usefulness. Other ganglion blocking agents include tetra- and pentameth- onium, the dimethylethyl analogue of hexamethonium (M. &B. 1863) (N(CH3)2C2H5.(CH2)6N+(CH3)2C2H5) (Locket et al. 1951) and Pendiomide, an analogue of pentamethonium: these have been less closely studied, but seem to have pro¬ perties indistinguishable in man from those of hexamethonium save for being, respectively, much less, slightly less, slightly more and slightly less active (Barnett, 1951; Burt & Graham, 1950; Enderby, 1950; Enderby & Pelmore, 1951; Kay & Smith, 1951; Wien & Mason, 1951). A variety of other agents has received attention in recent years, particularly thiocyanate, sympatholytic agents, nitrites and the veratrum alkaloids. All of these have proved capable of producing a fairly sustained fall in blood pressure in normal and hypertensive subjects. But in each case the use of the drug is complicated by additional and diverse toxic effects which restrict treatment more or less severely. Hexamethonium provides an interesting contrast; the difficulties in its use do not spring from any additional toxic action of this kind, from which it is remarkably free, but principally from the danger of too intense an action of the kind used therapeutically, leading to too great a fall in blood pressure in an organism accommodated to the hypertensive state, or to the paralysis of other ganglia (including those concerned with ocular accommodation and with intestinal function). With the former drugs, a balance has to be struck between the therapeutic action and undesired action of quite a different sort. With hexamethonium, virtually all its effects are due to ganglionic blockade, and the problem is to adjust the intensity of this. Could this be done satisfactorily, the most serious difficulty of treatment would be removed. It need not be assumed that only one of these drugs should be used at one time. Patients on a low sodium diet are known to be more sensitive to hexamethonium. It may be, therefore, that a combination or alternation of hexamethonium with such a diet, or with one of the other drugs mentioned, or with less well-known compounds, may provide an effective and more easily controlled regime. 4. Other Peripheral Vascular Effects of Hexamethonium Hexamethonium has been used for other conditions affecting the cardiovascular system (Arnold et al. 1949; Burt & Graham, 1950; Finnerty & Freis, 1951). It has been as successful as paravertebral sympathetic block in increasing the blood flow to the lower limb in cases of occlusive arterial disease.2 Raynaud’s phenomenon can be checked by hexa¬ methonium. It has been used successfully in the treatment of causalgia (Rose & Wemple, 1951). Its use in these fields is limited by the fact that a general ganglionic paralysis is ob¬ tained where an action restricted to a particular limb or limbs is required. The reason for the effectiveness of hexamethonium in causalgia is obscure. It has itself no general or local anaesthetic activity and it acts presumably by increasing the blood flow either to the damaged nerve or to the adjacent tissues. It would be interesting to know more clearly the effects of hexamethonium in two other situations: the pulmonary vessels and the cerebral vessels. Evidence has accumulated that there is an effective vasomotor control of the pulmonary vessels and that tetraethylammonium can sometimes diminish the pulmonary vascular resistance. Certain anaesthetists have commented on the ease with which a patient may be kept oxygenated when hexamethonium is being used to diminish bleeding, and it seems possible that pulmonary vasodilatation by hexamethonium can contribute to this. There is also evidence that the cerebral vessels are under effective vaso¬ motor control and this is of interest in the pathogenesis of migraine. The therapeutics of this condition are distinctly confused, since ergotamine, first introduced as a sympatholytic, is now believed to act not by relieving sympathetic vaso¬ spasm but by causing vasoconstriction; and further, di- hydroergotamine appears to be equally effective in treatment 2 See articles elsewhere in this Bulletin by Learmonth & Slessor (p. 375) and Goodwin (p. 371).