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Sympatholytic Agents)* BRrrmsh 598 3 June 1967 MEDICAL JOURNAL Br Med J: first published as 10.1136/bmj.2.5552.598 on 3 June 1967. Downloaded from Double-blind Trial of Four Hypotensive Drugs (Methyldopa and Three Sympatholytic Agents)* V. VEJLSGAARD, M.D.; M. CHRISTENSEN, M.D.; E. CLAUSEN, M.D. Brit. med. 7., 1967, 2, 598-600 In general, drug treatment of hypertension is started with a Guanoclor is 2-(2,6-dichlorphenoxy) ethylamino-guanidine. diuretic. If such therapy is not successful another hypotensive In animal experiments and in experiments in vitro reduction of drug is added, either a specific sympatholytic agent or methyl- the concentration of catecholamine was found both in the hypo- dopa. thalamus and the adrenal medulla, and peripherally. Further- In order to be as objective as possible regarding which of these more, on administration of guanoclor a peripheral sympathetic methods of treatment is the best a double-blind trial was carried blockade has been demonstrated. out; this included two of the known hypotensive drugs, guan- In-vitro experiments have shown that guanoclor inhibits the ethidine (Ismelin) and methyldopa (Aldomet), and two new enzyme dopamine-beta-oxidase. Correspondingly, it was pos- drugs, guanoxan (Envacar) and guanoclor (Vatensol). sible to show a considerable reduction in the excretion of adrenaline both in experimental animals and in patients during hypotensive treatment with guanoclor (Brit. med. 7., 1964; Chemistry and Pharmacology Lawrie et al., 1964b). A similar reduced excretion was not observed in patients who were treated with guanoxan or guan- Guanethidine is a sympatholytic agent (Maxwell et al., 1959), ethidine. With oral administration of guanoclor the influence and its effect is predominantly a lowering of the blood pressure on the blood pressure becomes measurable after 24 hours and in the erect position, whereas only a slight reduction is obtained maximal effect is obtained after 48 hours. In the supine position (Page and Dustan, 1959). Guanethidine reduces the concentration of catecholamine both centrally and Since guanethidine and methyldopa were introduced for the peripherally, but not in the superior parts of the central nervous treatment of hypertension in the late 'fifties many reports have system. Intestinal absorption is constant, its elimination is been published on their clinical application and side-effects mainly renal and slow, and therefore the dose should be deter- (Cass et al., 1960; Dollery et al., 1960; Oates et al., 1960; mined cautiously in cases of impairment of renal function. Sannerstedt et al., 1961 ; Bayliss and Harvey-Smith, 1962; When the drug is administered intravenously the cardiac output Daley and Evans, 1962; Gillespie et al., 1962; Lauwers et al., and renal blood flow are distinctly reduced, and bradycardia 1963; Lowther and Turner, 1963). have is a characteristic finding. Only a few clinical trials of guanoxan and guanoclor http://www.bmj.com/ Methyldopa (alpha-methyl-3-4-dihydroxyphenyl-alanine) is been published. With respect to the former drug, two indepen- a decarboxylase inhibitor. Absorption takes place rapidly, but dent studies showed a good degree of control in 58% of 62 varies from patient to patient-a fact without positive correla- patients (Peart and MacMahon, 1964) and 48 patients (Mon- tion to the antihypertensive effect. The mechanism of the drug tuschi and Lovel, 1964). The side-effects reported were lack of has not yet been explained in detail. Its decarboxylase inhibi- energy, nausea, diarrhoea, and impotence, as well as failure of tory action is not alone responsible for the antihypertensive ejaculation. On guanoclor the blood pressure was well con- result; other decarboxylase inhibitors have no effect at all on trolled in 60% of 39 patients (Lawrie et al., 1964). Three patients stopped taking the drug because of dizziness and the raised blood pressure. Metabolites of methyldopa such as on 24 September 2021 by guest. Protected copyright. methylnoradrenaline could be the effective agents; a replace- muscular fatigue. ment of noradrenaline with this metabolite in tissue stores might act as a false transmitter on stimulation. Methylnoradrenaline has in itself some, though poor, pressor effect. This hypothesis Material could explain the poor orthostatic effect of methyldopa and the missing clinical sympatholytic action (Sannerstedt et al., 1962 Forty-two patients were selected from among our hyper- Onesti et al., 1964; Prescott et al., 1966). tensive outpatients. All had been admitted previously for Guanoxan is 2-guanidinomethylbenzo-1, 4-dioxan. Conse- assessment. All had normal urinary excretion of catecholamine. quently it is a guanethidine-ring with benzodioxane in the side Two patients were excluded from the study; one had moved chain. Guanoxan causes a reduction in the concentration of from the area, and the other did not want to continue after catecholamines in both the hypothalamus and the adrenal having been given the first agent. The material therefore com- medulla, and peripherally. It has been shown that cats treated prised 20 men, average age 50.4 (34-65) years, and 20 women, with guanoxan present reduced avoiding reactions and inhibited average age 48.1 (29-66) years. vasoconstrictive response in the skin on hypothalamic stimula- In all cases the diagnosis was essential hypertension, with the tion. In dogs treated with guanoxan a reduced effect of exception of a 55-year-old man with chronic glomerulo- injected adrenaline due to adrenergic blockade has been found nephritis. No patients with severe reduction in renal function (Brit med. 7., 1964a; Davey and Reinert, 1965); similar were included. The average serum creatinine value was 1.5 findings were made with benzodioxane alone. In animal mg./100 ml., and in only two patients was it above 2 mg./100 experiments guanoxan differs from guanethidine in that it ml. blocks the alpha-receptors and reduces the concentration of On the basis of the ophthalmological findings all the patients catecholamine in the hypothalamus. On oral administration were assessed as having a moderate to severe increase in blood of guanoxan the influence on the blood pressure becomes pressure. The findings, according to the Keith-Wagener scale, measurable after 24 hours and maximal after 48 hours. were: three in grade 0-I, 13 in grade II, 16 in grade III, and eight in grade IV. Blood pressure values recorded without * From the Department of Medicine, Diakonissestifitelsen, and the De- before the were not avail- partment of Medicine, Bispebjerg Hospital, Copenhagen, Denmark. treatment immediately present study 3 June 1967 Hypotensive Drugs-Vejlsgaard et al. MEDICALBRrnSHJOURNAL 599599 able, since many of the patients had been under treatment for had to be withdrawn because of side-effects-pronounced ortho- several years, and it was thought unjustifiable to stop the anti- static dizziness on and dizziness, exertion, pronounced discom- Br Med J: first published as 10.1136/bmj.2.5552.598 on 3 June 1967. Downloaded from hypertensive therapy completely. fort and fatigue. Subjective complaints were often made before In all the patients the hypertension was so severe that diuretic the postural change in blood pressure could be recorded at the therapy alone could not produce an acceptable level of blood follow-up examination. One patient did not want to continue pressure. At the time the study was started the diuretic in the trial. The drug concerned was excluded from the blind regimen in all patients consisted of 4 mg. of polythiazide trial. At the termination of the study it was found to be (Renese). Our own investigations show that this dose had a guanoclor. maximum effect on the blood pressure. Potassium was not The results with the other three drugs-guanethidine, methyl- given permanently, but if the serum potassium was below 3 dopa, and guanoxan-are given in Table I. It will be seen that a mEq/l. 2 g. of potassium chloride daily was added. Serum satisfactory result without side-effects or with slight side-effects potassium levels were estimated at least once a month. In was obtained in 34 patients with methyldopa, 25 with guanoxan, addition to the diuretic therapy three patients had received and 20 with guanethidine. The average doses required to reach hydrallazine (Apresoline) (100-400 mg. daily) over a long this result were 1,000 mg. of methyldopa, 30 mg. of guanoxan, period. This medication was maintained constantly through- and 33 mg. of guanethidine. It should be noted that the mean out the study. blood pressure in both the lying and the standing positions was fairly uniform in the three groups. Method In a few patients the blood pressure was satisfactory, accord- ing to definition, but there were severe side-effects. When The patients were examined on an outpatient basis at intervals sympatholytic agents were used the side-effects were mainly of one to three weeks. An assistant recorded the blood pressure postural troubles ; this is apparent from the mean blood pressure after the patient had rested for at least 10 minutes and imme- recorded in the lying and standing positions shown in Table I. diately afterwards in the standing position. The examiner- Some patients appeared to be extremely resistant to the drugs same the person during the whole investigation-then fixed the used, even when, as shown in Table I, the dose was increased TABLE I Guanoxan Methyldopa Guanethidine No. Mean B.P. B.P. No. Dose No. Mean Dose Mean B.P. Dose of of of i (mg.) (mg.) Cases Lying Standingj (mg-) Cases Lying Standing Gases Lying _ _ _I Sandingj _ Satisfactory control. Side-effects: none or mild . 25 115 104 30 34 114 108 1.000 20 115 107 33 Satisfactory control. Severe side-effects 5 110 92 30 2 121 120 5 118 98 44 or poor 1,750 No control in spite of increase in dose 3 136 122 104 4 Poor control because of pronounced 147 125 side-effects 7 136 116 66 0 14 135 113 49 dosage of tablets for all patients according to the recorded considerably.
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