EFFECT OF PENTAMETHONIUM IODIDE ON NORMAL AND HYPERTENSIVE PERSONS

321

EFFECT OF PENTAMETHONIUM IODIDE ON NORMAL AND HYPERTENSIVE PERSONS P. ARNOLD M.D. Lond., M.R.C.P. ASSISTANT MEDICAL REGISTRAR

M. L. ROSENHEIM M.D. Camb., F.R.C.P. ASSISTANT

PHYSICIAN AND

DEPUTY DIRECTOR OF MEDICAL UNIT

UNIVERSITY COLLEGE

HOSPITAL,

LONDON

IN their investigation of the pharmacological properties of the homologous series of polymethylene bistrimethylammonium compounds Paton and Zaimis (1948a and b, 1949) found that both the pentamethylene and hexamethylene members paralysed transmission through the autonomic ganglia. Pentamethylene bistrimethylammonium di-iodide (now known as pentamethonium iodide) has the following formula :

CH,

CHa

CH3-N+-CH2-CH2-CH2-CH2-CH2-N+-CH3: C,43

’

injection ; the blood-pressure, in the supine subject, did not fall, but postural hypotension was observed as late as 30 minutes after injection. We have been investigating, at the request of the Medical Research Council, the clinical effects and possible Its action has been uses of pentamethonium iodide. studied in normal people, in patients with hypertension, and in patients with peripheral vascular disease. Its effect on the peripheral circulation-is the subject of a separate paper (Arnold et al. 1949). Pentamethonium iodide was used in a solution containing 50 mg. to the millilitre, and was given intravenously in doses ranging from 25 to 100 mg. It was injected within a period of 30 seconds, and the subject remained supine while under observation, except when tested

21"

CHg

It is a white powder, freely soluble in water. The solution is stable and is sterilisable by autoclaving. Paton and Zaimis showed that, in cats, intravenous injection of pentamethonium iodide caused relaxation of the nictitating membrane, excited to contraction by preganglionic stimulation, but did not alter the effect of postganglionic stimulation. It also caused a fall of blood-pressure in cats anaesthetised with chloralose, an effect which was inhibited by the previous administration of nicotine. Pentamethonium iodide prevented the bradycardia normally produced by stimulation of the peripheral end of the cut vagus. From these and other results Paton -and Zaimis concluded that, in animals, the principal site of the drug’s action was at the ganglionic Pentamethonium iodide does not stimulate synapse. the autonomic ganglia and is almost devoid of the curarising properties of the higher members of the series. In fact, it antagonises the curare-like action of decamethonium iodide (Paton and Zaimis 1949, Organe et al. 1949). In a preliminary trial of its action in man, Organe et al. (1949) found that intravenous doses of 20-40 mg. were well tolerated. Vasodilatation occurred after the

-

MINUTES in a normal person before and after the intravenous injection of 60 mg. of pentamethonium iodide, the to immersion of the hand in cold water and showing response to change of posture.

Fig. 2-Blood-pressure

and

pulse-rate

for

postural hypotension. intramuscularly in doses up

It has also-,been to 100 mg.

given

PERSONS

NORMAL .

In normal persons in the recumbent position intrainjection of pentamethonium iodide produces A transient feeling no immediate subjective sensation. of warmth or fullness in the head, hands, or feet is occasionally noted within a few minutes of the injection ; this is never well marked, and the tingling and coldness felt after injection of tetraethylammonium salts have been notably absent. Accommodation may be slightly impaired but not so much or so constantly as with tetraethylammonium chloride. Objectively, suffusion of the conjunctivas is often seen, and slight cyanosis of the lips has been observed on two occasions. Within a minute of the injection the pulse-rate usually increases by some 20-30 beats a minute. Little, if any, change in the blood-pressure occurs unless the erect posture is assumed, when wellmarked hypotension results. Postural hypotension can be observed up to 1½ hours after injection (fig. 1). Vasodilatation, as measured by digital and pulse volumes, begins within 2 minutes and is still present 60 minutes after injection. Digital blood-flow and skin temperature also increase (Arnold et al. 1949). Doses up to 70 mg. modify but do not abolish the cold pressor response (fig. 2). The lack of change in blood-pressure after venous

Fig. 1—Systolic blood-pressure and pulse-rate in a normal person before and after the intravenous injection of SO mg. of pentamethonium iodide, showing the effect of posture. After the injection, the subject stood up at intervals, for periods shown in black, until he felt faint and had to lie down.

H2

322

injection, the occurrence of tachycardia, the presence of postural hypotension, and the modification of the cold pressor response are shown in figs. 1 and 2. HYPERTENSIVE PATIENTS

Pentamethonium iodide was given to fifteen patients with various forms of hypertension in the medical wards and, by Mr. J. G. Dumoulin, to patients with toxæmia of pregnancy. In hypertensive patients a sharp fall of blood-pressure usually follows intravenous injection. This begins within a minute and reaches The fall lasts much a maximum within 2-5 minutes. longer than with tetraethylammonium chloride, and a steady base-line is usually obtained (fig. 3). In a few patients the fall has been observed to persist for several hours (fig. 4). Tachycardia of about the same degree as in normal people usually occurs, and postural hypotension can be demonstrated. The subjective sensations in these hypertensive patients are again far less than with an injection of tetraethylammonium chloride. In the accompanying table the lowest pressures obtained in six hypertensive patients given various doses of pentamethonium iodide, tetraethylammonium chloride, and ’Seconal’ (a rapidly acting barbiturate) are compared. Those patients in whom tetraethylammonium

HOURS

Fig. 4-Protracted effect of an intravenous injection of 50 mg. of pentamethonium iodide on the blood-pressure of a woman, aged 56, with benign essential hypertension.

et al.

drugs

1947), and this aspect of the action of the two is under investigation. TOXIC EFFECTS

In one patient, with toxaemia of pregnancy, a dramatic fall in blood-pressure was accompanied by syncope. This reaction is similar to that occasionally encountered with tetraethylammonium chloride, but such a reaction may be more serious with pentamethonium iodide. responded well to adrenaline, Though the the lasting action of pentamethonium iodide led to a further fall of pressure requiring repeated injections 01 adrenaline (fig. 5). The reaction in this patient followed a large initial dose (75 mg.), and it is now our custom to start, in any patient, with a dose not exceeding 40 mg. In one other patient, however, an old man with peripheral and coronary vascular disease, an initial dose of 25 mg. led to a fall.in systolic pressure from 134 to 72 mm. Hg, though the patient complained of no symptoms, and the blood-pressure rose spontaneously. In three patients, after repeated injections, a maculopapular erythematous rash developed. This cleared rapidly, there were no other symptoms suggesting iodism, and one of these patients was subsequently given iodides without reaction. No other toxic effects have been observed.

blood-pressure

Fig. 3-Effect of

an intravenous injection of 50 mg. of pentamethonium iodide on the blood-pressure and pulse-rate of a woman, aged 57, with benign essential hypertension.

chloride and seconal produce a large fall in blood-pressure also experience a large fall with pentamethonium iodide. A small fall is usually obtained in those whose pressure only falls slightly with the other two drugs. Discrepancies, however, occur, and the effect obtained with pentamethonium iodide is occasionally surprisingly great (cf. case 2). The table also shows the effect of varying the dose of the drugs, and from these and other results it seems that a dose of pentamethonium iodide will produce a fall of blood-pressure similar to that obtained with about ten times the weight of tetraethylammonium chloride. In addition, this response lasts longer (figs. 3 and 4). Intramuscular injections of pentamethonium iodide have been used in only two cases and produced no local pain and no disturbance of -bladder or bowel function. In a patient with chronic nephritis who had a sudden rise in blood-pressure, associated with headache, vomiting, and papillcedema, intramuscular doses, ranging from 20 to 75 mg., lowered the blood-pressure for periods up to 8 hours and relieved the headache. In one other hypertensive patient, with raised intracranial tension, an intravenous injection of 60 mg. produced an immediate fall in cerebrospinal-fluid pressure. Similar results have been reported ’with tetraethylammonium salts (Lyons

DISCUSSION

The results so far obtained, in man, with pentamethonium iodide confirm that its action is similar to that of the tetraethylammonium salts but is more potent and lasts longer. It is probably more selective

MINUTES

Fig. S-Effect of an initial intravenous dose of 7S mg. of pentamethonium iodide in a recumbent patient, aged 27, with pre-eclamptic toxemia The patient collapsed and became semi-conscious as the bloodpressure reached its minimum. The figure shows the effect of adrenaline (intramuscular or subcutaneous) on the blood-pressure. Note the transitory effect of the first injection of adrenaline.

323 in its action, since subjective sensations, paralysis of accommodation, and bowel and bladder disturbances The dosage required to produce are far less prominent. an equivalent effect seems to be only a tenth of that of tetraethylammonium chloride. It is recommended that the initial intravenous dose should not exceed 40 mg., though doses up to 100 mg. have been well tolerated. This recommendation is made because signs of collapse may occasionally accompany a sudden fall in bloodpressure. This has been observed in one of our cases and has been reported (Hewer et al. 1949) in three anæsthetised patients in whom pentamethonium iodide This was given as an antidote to decamethonium iodide. effect can be counteracted with adrenaline, which we suggest should always be at hand. Repeated injections may be necessary. Though pentamethonium iodide is of value in the investigation of hypertension, postural hypotension will probably limit its use in routine treatment. It may, OF OF EFFECTS COMPARISON PENTAMETHONIUM IODIDE, TETRAETHYLAMMONIUM CHLORIDE, AND SECONAL IN SIX HYPERTENSIVE PATIENTS

(Blood-pressures in

mm.

Hg)

ACQUIRED RESISTANCE TO PROGUANIL IN PLASMODIUM FALCIPARUM D. R. SEATON

A. R. D. ADAMS

M.D. Lpool, F.R.C.P. M.B. Camb., M.R.C.P. From the Clinical Department, Liverpool School of Tropical Medicine

AFTER it had been shown that Plasmodium gallinaceum, maintained by serial blood inoculation in chicks, could readily be made resistant to proguanil (’Paludrine’) by repeatedly giving subeffective doses of this substance ’(Bishop and Birkett 1947, Williamson et al. 1947) it became desirable to find out whether proguanil-resistance could similarly be induced in the human malarial parasites. This was shown to be the case with P. vivax (Seaton and Lourie 1949) ; in this paper it is shown that the same is true of P. falciparum. A strain of P. falciparum was isolated in November, 1947, from a patient who had contracted malaria in West Africa. This patient had been taking proguanil intermittently during his infection, but without apparently increasing the resistance of his parasites to the level of ordinary therapeutic doses, since after he had come under our care a single dose of 300 mg. was sufficient to clear his peripheral blood of demonstrable parasites within twenty-four hours. Blood was taken from this man and inoculated into a neurosyphilitic patient and the strain has since been maintained by intravenous blood inoculation in a series of such patients. As a rule, proguanil treatment was started in -the subinoculated cases as soon as parasites were found in thick blood-films, though in 2 cases (2c and 6) the drug was given for some days before the patients were inoculated. Our aim was to adjust the initial treatment so that the doses given were insufficient to abolish the fever and parasitæmia but sufficient to prevent the development of cerebral malaria. This treatment was usually followed by a ten-day course of daily doses of proguanil, based on the observation by Fairley (1946) DEVELOPMENT OF RESISTANCE TO PROGUANIL

prove of value in the control of hypertensive Pentamethonium iodide is a powerful vasodilator, and it is in the field of peripheral vascular disease that it is most likely to be of clinical use.

however, crises.

SUMMARY

Pentamethonium iodide has an action similar to that of tetraethylammonium chloride, but is effective in smaller doses. Judged by the presence of postural hypotension and vasodilatation and the persistence of a lowered blood-pressure in hypertensive patients, its action, after intravenous injection, lasts for at least an hour. An excessive fall of blood-pressure has been the only serious toxic effect so far observed, and it has been shown that this can be counteracted by repeated injections of adrenaline. Our thanks are due to Dr. W. D. M. Paton for his advice and for a supply of pentamethonium iodide. Much of the drug used in this investigation was kindly supplied by the Wellcome Foundation. REFERENCES

Arnold, P., Goetz, R. H., Rosenheim, M. L. (1949) Lancet (in the press). Hewer, A. J. H., Lucas, B. G. B., Prescott, F., Rowbotham, E. S. (1949) Lancet, i, 817. Lyons, R. H., Moe, G. K., Neligh, R. B., Hoobler, S. W., Campbell, K. N., Berry, R. L., Rennick, B. R. (1947) Amer. J. med. Sci. 213, 315. Organe, G., Paton, W. D. M., Zaimis, E. J. (1949). Lancet, i, 21. Paton, W. D. M., Zaimis, E. J. (1948a) Nature, Lond. 161, 718. (1948b) Ibid, 162, 810. (1949) J. Physiol. 108, p 55. —

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