Clinical Experience with Bethanidine in Treatment of Hypertension*

Byrnsn 2 December 1967 MEDICAL JOURNAL 519 Br Med J: first published as 10.1136/bmj.4.5578.519 on 2 December 1967. Downloaded from Clinical Experience with Bethanidine in Treatment of Hypertension* JULIAN BATH, M.B., B.SC., M.R.C.P.ED.; DOUGLAS PICKERING, M.B., M.R.C.P.ED. RICHARD TURNER, M.D., F.R.C.P., F.R.C.P.ED. Brit. med.JY., 1967, 4, 519-521 At the present time probably most patients with high blood a period with other drugs the change-over was arranged on an pressure in this country are being treated with guanethidine or outpatient basis. The usual reason for change was difficulty methyldopa with or without the addition of an oral diuretic. in controlling the blood pressure, undue postural hypotension, Because of certain disadvantages of these two drugs in our or side-effects. experience (Lowther and Turner, 1963 ; Johnson et al., 1966) TABLE I.-Clinical Features we have largely confined our attention during the past three years to debrisoquine (Kitchin and Turner, 1966) and bethan- Severe Moderate Hypertension Hypertension Total idine. Experience with the latter drug is the subject of this I I~~~~~~~Toa paper. Patient age group: 30-40 4 7 11 41-50 11 8 19 Pharmacology 51-60 13 21 1 34 61-70 11 7 18 Bethanidine is a post-ganglionic adrenergic neurone-blocking Mode of presentation: Left ventricular failure 6 2 8 agent which exerts a marked postural hypotensive effect (Boura Cerebrovascular accident 13 6 19 et al., 1961 ; Boura and Green, 1963; Fewings et al., 1964). In Headache 2 6 8 Dizziness 4 7 11 man sympathetic blockade begins about two hours after a single Visual disturbance 2 0 2 dose, is maximal in four to five hours, and fades in 8 to 12 hours, Angina 1 7 8 Routine examination 11 15 26 but the duration of action depends on the dose administered (Smirk, Blood urea: 1963; Johnston et al., 1964; Wilson et al., 1965). The absorption <40 mg./100 ml. 28 35 63 > 40 mg./100 ml. 11 8 19 and excretion of `C bethanidine in man was studied by Doyle and E.C.G.: who showed that after oral administration L.V. hypertrophy present.. 34 8 42 Morley (1965), absorp- L.V. hypertrophy absent 5 35 40 tion was rapid and almost complete. Excretion is almost entirely Retinal changes: in the the rate on the filtration rate. Normal 0 11 11 urine, depending glomerular Grade I-II. 21 27 48 Other studies have shown the renal clearance of inulin and of para- Grade III. 15 20 acid to be reduced in bethan- Grade IV 3 5 3 aminohippuric slightly patients given Resting diastolic pressure idine (Esch and Krammer, 1965). before treatment: 105-129 (mm. Hg).. 15 22 37 The precise mechanism whereby bethanidine causes blockade of 130-149 ,. 18 14 32 adrenergic neurones is unknown (Boura and Green, 1965). An 150+ 6 7 13 initial sympathomimetic effect has been demonstrated in man and 7 animals, possibly due to release of catecholamines, for it is blocked The initial dose of bethanidine was usually 5 mg. twice daily. et by phenoxybenzamine (Fewings al., 1964), and increased sensi- were every Increments made third day in hospital patients and http://www.bmj.com/ tivity to noradrenaline after bethanidine further suggests peripheral every week in those being treated at home until an adequate release of catecholamines by this drug. Bethanidine resembles bretyliumtosylate and debrisoquine in that blockade is achieved response was obtained. Frequency of attendance at the clinic without early depletion of tissue catecholamines, in this respect depended on the degree of control or the presence of side-effects. differing from guanethidine and guanoclor. However, large doses The daily dose ranged from 10 to 120 mg., with an average of of bethanidine over long periods reduce catecholamines in some 32.5 mg. in the initial stages and 43 mg. later on. tissues (Boura et al., 1961). Unless administered in very high As in previous studies of antihypertensive drugs the aim of concentration bethanidine does not block or motor- cholinergic treatment was to reduce the standing diastolic pressure to as neurone and activity (Boura Green, 1963). near normal levels as could be achieved without undue side- on 23 September 2021 by guest. Protected copyright. effects. In patients with cerebral or coronary atherosclerosis or Material and Methods with a persistently raised blood urea the blood pressure was lowered more cautiously and reduction to a standing diastolic Between September 1964 and March 1967 70 patients were level of 100-105 mm. was as a treated with bethanidine for periods ranging from six to 24 Hg regarded satisfactory result. the fall in pressure achieved and maintained months: 23 were followed up for six to 12 months, 10 for 13 Only has been considered in the results of treatment. A " to 18 months, 22 for 19 to 24 months, and 15 for 25 to 30 classifying " good result a fall in diastolic mm. months. In addition 12 patients stopped treatment earlier for signifies pressure to below 100 Hg. A " fair " result a fall of diastolic pressure to between reasons discussed below. Ages ranged from 21 to 66 years. signifies 100 and 110 mm. Hg. A "poor" result denotes failure to Of the 82 patients 41 were made and 41 female. Table I maintain a diastolic below mm. includes the age distribution related to severity of the disease. pressure 110 Hg. It will be appreciated that a precise classification is not possible because Indications for selection of of treatment, patients, methods in some patients the deliberate aim has been to achieve a fair blood criteria of and classifica- pressure measurement, severity, result as defined by reduction in blood pressure. tion of results were similar to those we have already described in relation to the other drugs except that this series includes The results have been tabulated for each patient at intervals more relatively young patients without evidence of secondary of six months. changes in the heart or fundi. Results Half the patients had previously received treatment with other antihypertensive drugs. Most new patients were admitted Of the original 82 patients, four died, seven discontinued to hospital for assessment of the severity and type of their bethanidine because of side-effects, and one defaulted before hypertension and the initiation of appropriate treatment. In the end of six months. The remaining 70 all completed at some who had been fully assessed previously and treated for least six months of treatment (Table II). After six months one * University Department of Medicine and the Cardiac Department of the patient discontinued the drug because Western General Hospital, Edinburgh 4. of side-effects, two defaulted, and seven died. At the end of 520 2 December 1967 Hypertension-Bath et al. MEDICAL JOURNAL TABLE II.-Results The incidence of side-effects bore no obvious relation to the Br Med J: first published as 10.1136/bmj.4.5578.519 on 2 December 1967. Downloaded from initial severity of hypertensive disease, the presenting symptoms, Patients Total Control associated atherosclerosis, the degree of blood pressure control, Moderate | Severe No - % or subsequent death. As with other antihypertensive drugs the Good 15 15 30 43 At 6 months .. Fair 13 8 21 30 incidence between individuals was most variable. Poor 9 10 19 27 Good 12 12 24 52 At 12 months .. { Fair 10 3 13 28 Poor 3 7 10 20 Oral Diuretic Supplements Good 13 8 21 56 At 18 months .. { Fair 5 3 8 22 In order to facilitate comparison with other drugs it had Poor 2 6 8 22 been intended, if possible, to treat all patients with bethanidine Good 4 5 9 60 At 24 months .. { Fair 3 1 4 27 alone. However, it became necessary to add an oral diuretic Poor 1 1 2 13 in 28 cases on account of difficulty in controlling the pressure, side-effects, or fluid retention. six months 73 % of patients had good or fair control of their As can be seen from Table III the mean daily dose of blood pressure. Results improved with continued treatment bethanidine was gradually increased for most patients. In 19 and adjustment of dosage with or without the addition of an cases the dose was increased to improve control and in seven oral diuretic, the or proportion having good fair control rising to regain control on account of tolerance. An oral diuretic to 80% after 12 months and to 87% in the 15 patients who was added to improve control in six and to regain control in had been treated for two years. Most of the poor results were two patients. The fact that supplementary oral diuretics were in patients with severe hypertension. used in 34% of all patients reflects the difficulty experienced Of the 19 patients in whom initial control was unsatisfactory in achieving satisfactory control with freedom from excessive 13 continued treatment for 12 months or more. Good or fair postural hypotension when using bethanidine alone. In a few control was achieved in five by increasing the dose and in three cases a diuretic was used from the start because rapid control more by the addition of an oral diuretic. Of the five patients of the blood pressure or a diuresis was required. Diuretics in whom control was persistently poor two had severe cerebral were used in a proportionately larger number of patients the atherosclerosis, one uraemia, one asthma requiring corticosteroid longer treatment continued, because of an increased tendency therapy, and one cor pulmonale. Temporary failure of control to make this addition whenever difficulty with control or side- was attributed to tolerance in two patients and to side-effects effects was experienced.

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