Postgrad Med J: first published as 10.1136/pgmj.38.440.338 on 1 June 1962. Downloaded from POSTGRAD. MED. J. (I962), 38, 338

GUANETHIDINE IN THE TREATMENT OF HYPERTENSION K. N. V. PALMER, M.A., M.D., M.R.C.P. G. A. MCDONALD, M.D. Senior Lecturer, Lecturer, Department of Medicine, University of Aberdeen, Foresterhill, Aberdeen

IN the last decade great advances have been made blood pressure in addition to the postural effect in the treatment of hypertension, so that it is now may be seen. Most patients taking the drug possible in most cases, by the use of drugs, singly become more hypotensive during exercise and this or in combination, to reduce raised blood pressure is especially likely in the early morning when the to normal or near normal levels during the 24-hour postural fall is greatest (Dollery, Emslie-Smith day. The benefit to be derived from treatment is and Milne, I960). often great, especially in cases of malignant is a cumulative drug, its action hypertension, and this is particularly so when being prolonged for at least three days after a treatment is started before there is extensive single oral dose. In the presence of impaired renal vascular damage (Harington, Kincaid-Smith and function and after long periods of treatment with McMichael, 1959). In less severe degrees of high doses, excretion is further delayed (Dollery hypertension, there is symptomatic relief, heart and others, I960), and because the effective dose failure is usually relieved, and improvement often varies, and some patients are sensitive to small occurs in the electrocardiogram (Dustan, Schneck- doses, great care must be taken in finding theby copyright. loth, Corcoran and Page, I959). Unfortunately correct dose for each patient. The drug is supplied when there is much impairment of renal function as tablets containing io mg. (white) and 25 mg. lowering of the blood pressure may result in (pink). Cost of treatment averages 3d. to is. 6d. progressive renal failure and a further rise of blood daily at basic N.H.S. prices. urea, and these cases are, therefore, not usually Benzthiadiazine diuretics, and, to a lesser suitable for treatment. extent, Rauwolfia alkaloids, potentiate the action Until recently, the most effective hypotensive of guanethidine, so that the addition of a benz- drugs blocked transmission of impulses at auto- thiadiazine diuretic often reduces the amount of nomic ganglia and postural blood pressure control guanethidine necessary to obtain a satisfactory http://pmj.bmj.com/ due to paresis of the sympathetic nervous system fall in blood pressure (Blanshard and Essigman, was often obtained only at the cost of serious 196I). side effects due to simultaneous blockage of the The commonest side-effect is diarrhcea, but parasympathetic ganglia. Great interest was muscle aching and weakness, fluid retention, shown, therefore, in new compounds which gave mental depression and failure of ejaculation may good postural control of the blood pressure by also occur. Side effects occur more frequently blocking only the sympathetic nervous system when large doses of the drug are given. Nasal without parasympathetic inhibition, first stuffiness and parotid pain which were frequent on September 28, 2021 by guest. Protected tosylate (Darenthin) (Boura, Green, McCoubrey, with bretylium tosylate occur very rarely with Lawrence, Moulton and Rosenheim, I959) and guanethidine. Moreover, there is no significant later guanethidine (Ismelin) (Maxwell, Mull and development of drug tolerance, which is a great Plummer, 1959). advantage over bretylium. Guanethidine sulphate was synthesized in 1959. When is present or sus- It is thought to lower blood pressure by interfering pected, guanethidine is contraindicated because it with the metabolism of chemical transmitter may increase the pressor response to substances in post-ganglionic sympathetic nerve and noradrenaline secreted by the tumour, and fibres only. There are, therefore, no side effects dangerously high blood pressure may result. from parasympathetic blockage such as blurred Recent coronary or cerebral thrombosis is also a vision, dryness of mouth, constipation and bladder contraindication to immediate treatment, but atony, as commonly occur with ganglionic blockage treatment may be started cautiously six weeks therapy. Its hypotensive action is predominantly later when especial care must be taken to avoid postural but not exclusively so, and some fall in episodes of . Where angina of less Postgrad Med J: first published as 10.1136/pgmj.38.440.338 on 1 June 1962. Downloaded from June I962 PALMER and McDONALD: Guanethidine in the Treatment of Hypertension 339 than one year's duration is present, hypotensive The initial dose of guanethidine was io mg. therapy may be combined with anticoagulants. daily for four days, and subsequent increments of We report here our experience of the use of not more than io mg. daily were made at four-day guanethidine (Ismelin, Ciba) in the treatment of intervals until the standing diastolic pressure was 20 patients with severe hypertension and evidence I00 mm. Hg. or less. When a satisfactory fall in of hypertensive disease as shown by symptoms and blood pressure had been obtained without side signs of cardiac, renal or retinal disease. effects, the patients were seen at monthly intervals in the outpatient department. The average dose of Subjects guanethidine necessary to obtain a satisfactory Twenty patients (i6 women and four men) have reduction in blood pressure was 50 mg. (range been treated for periods up to 20 months; the mean I0 to I00 mg.). If the patient complained of diar- duration of treatment being I 1.7 months. Their rhoea (more than three stools a day) the dose of average age was 49 years (range i8 to 65 years). guanethidine was reduced by I0 mg. per day and a The patients were admitted to hospital from the tablet of a benzthiadiazine diuretic with potassium outpatient department or directly as an emergency. chloride given in addition. Four patients were In hospital, in addition to a detailed history and given hydrochlorothiazide but more recently six clinical examination, daily blood pressure readings have been given cyclopenthiazide containing were taken after a period of bed rest to determine 6oo mg. potassium chloride (Navidrex K, Ciba) the basal blood pressure level. All patients had instead because it is longer-acting and cheaper. routine chest X-ray examination, electrocardio- If diarrhcea still persisted, a small dose of pempi- graphy, ophthalmoscopic inspection, urinanalysis dine, 2.5 mg. t.d.s., was given as well. Because the including microscopy and culture, estimation of incidence of toxic effects increases appreciably blood urea and intravenous pyelography. A with doses of guanethidine over 6o mg. daily, a test and examination for urinary benzthiadiazine diuretic containing potassium were undertaken to exclude pheo- chloride was given routinely even in the absence chromocytoma in all cases. The presenting of side effects if a satisfactory fall in blood pressure symptoms were headache (15), dyspncea (6), had not been obtained with 6o mg. guanethidine. by copyright. blurring of vision (2) and dizziness (2). In If diarrhcea developed as the dose of guanethidine addition, three had hypertensive cardiac failure, was increased further, or propantheline i6 had evidence of left ventricular hypertrophy was given in addition. and strain on electrocardiography, and in io there Patients may be stabilized as outpatients, but, was cardiac enlargement clinically. Three had as a few are particularly sensitive to guanethidine, Grade IV and four Grade III retinopathy, five the daily dosage should in these circumstances be had a raised blood urea (greater than 5o mg. %) increased by not more than Io mg. at weekly and eight had persistent proteinuria presumably intervals until the stabilization dose is reached,

due to renal damage. when they may be seen at monthly intervals as http://pmj.bmj.com/ Before starting treatment a persistent elevation before. of diastolic pressure was demonstrated (Table i) by daily blood pressure readings under basal Results conditions. Eighteen were considered to be Using this regimen it was possible to obtain a suffering from essential hypertension and in two satisfactory fall in blood pressure without side the hypertension was thought to be secondary to effects in all the cases (Table 2). Diuretic was chronic pyelonephritis. added to guanethidine in seven because more than 6o mg. of guanethidine was required to obtain a on September 28, 2021 by guest. Protected TABLE I satisfactory fall in standing diastolic pressure and SEVERITY OF HYPERTENSION IN TREATED PATIENTS in three because of diarrheea with a dose of 20 guanethidine of less than 6o mg. per day. Diastolic Blood Pressure Number of Patients Symptoms were relieved in all cases. Hyperten- mm. Hg. sive cardiac failure cleared in all three patients, 120/129 2 electrocardiographic evidence of left ventricular I 30/139 10 hypertrophy and strain was abolished in six and I40/149 5 improved in io, serious retinopathy healed in all 150/159 3 seven and proteinuria persisted in one patient only. At least six months' treatment at stabilized Details of Treatment dosage was usually necessary before clear objective All the patients were treated in hospital until a improvement occurred. Blood urea levels showed satisfactory reduction of blood pressure was little change although in one case the blood urea obtained. rose transiently at the beginning of treatment. 340 POSTGRADUATE MEDICAL JOURNAL June i962Postgrad Med J: first published as 10.1136/pgmj.38.440.338 on 1 June 1962. Downloaded from

TABLE 2 drug for lowering elevated blood pressure when EFFECT OF GUANETHIDINE ON STANDING BLOOD PRESSURE given as a single morning dose. It is well tolerated and although diarrhfiea is a fairly frequent side Case No. Before Treatment After Treatment effect this can usually be readily controlled without I 240/145 155/85 an increase in blood pressure readings by reducing 2 270/155 125/85 the dose of guanethidine by io mg. and adding a 3 240/140 I6o/80 benzthiadiazine diuretic. If the dose of guan- 4 260/150 170/70 5 230/135 190/100 ethidine required for blood pressure control is 6 230/120 140/95 greater than 6o mg. daily, a benzthiadiazine 7 230//135 120/70 diuretic should be given in addition as the amount 8 230/130 150/90 of guanethidine required, and, therefore, the 9 200/135 145/95 10I80/140 110/75 incidence of side effects is thereby reduced, and it I I 240/130 I80/95 seems likely that diarrhea would have been a 12 230/130 I65/105 greater problem had we not adopted this policy. I3 230/130 I 50/90 There is complete freedom from side effects due I4 230/130 155/95 15 250/155 105/70 to parasympathetic paresis which often made i6 220/130 1I90/95 treatment with ganglionic blockage agents difficult, 17 250/140 145/85 and in contrast to the earlier sympathetic-blocking i8 270I55 I60/90 agent, bretylium tosylate, drug tolerance has not I9 240/130 135/80 20 150/90 been a problem. The drug has a slow effect and 230/125 some weeks are often necessary to obtain satisfac- tory control of the blood pressure. It is not, Side Effects therefore, suitable for control of acute hypertensive Diarrhaea, worse in the morning and associated crises such as acute left ventricular failure with with urgency, occurred in four patients. In three pulmonary cedema or encephalopathy and for the dose of guanethidine was less than 6o mg. a these cases parenteral pempidine is to be preferred. day but the diarrhaea did not persist in two when That careful treatment with hypotensive agentsby copyright. is the dose was reduced by IO mg. and cyclopen- worth while is shown by this series, because, in added, although one required pempidine addition to relief of symptoms and fall in blood as well. One patient having 8o mg. guanethidine pressure to normal or near-normal levels, such and a diuretic developed diarrheea which was serious manifestations as left ventricular strain, controlled by a small dose of propantheline. Three retinopathy and proteinuria were reduced or patients complained of muscle aching and easy abolished in the great majority of the patients fatigue but these symptoms were transient and did treated. not persist when the stabilization dose had been

reached. Severe postural hypotension was not Summary http://pmj.bmj.com/ troublesome, and, although six patients complained Guanethidine lowered blood pressure satisfac- of a feeling of light-headedness on rising from bed torily in 2o hypertensive patients and subjective in the morning, lasting five minutes or less, this and objective benefit resulted. A combination of tended to wear off as treatment continued. None guanethidine and a benzthiadiazine diuretic re- of the patients complained of depression. No duces the amount of guanethidine necessary to evidence of drug tolerance was found, and once the control the elevated blood pressure, and this correct dose had been arrived at it did not have to combination enables side effects of the drug to be be changed. controlled. If more than 6o mg. of guanethidine on September 28, 2021 by guest. Protected are necessary for satisfactory control of blood Discussion pressure, we recommend that a benzthiadiazine We have found guanethidine to be an effective diuretic should always be given simultaneously. REFERENCES BLANSHARD, G., and ESSIGMAN, W. (I96I): Guanethidine and Hydrochlorothiazide in the Treatment of Hypertension, Lancet, ii, 334. BoURA, A. L. A., GREEN, A. F., MCCOUBREY, A., LAWRENCE, D. R., MOULTON, R., and ROSENHEIM, M. L. (1959): Darenthin. Hypotensive Agent of New Type, Ibid, ii, I7. DOLLERY, C. T., EMSLIE-SMITH, D., and MILNE, M. D. (I960): Clinical and Pharmacological Studies with Guan- ethidine in the Treatment of Hypertension, Ibid, ii, 38I. DUSTAN, H. P., SCHNECKLOTH, R. E., CORCORAN, A. C., and PAGE, I. H. (1958): The Effectivene3s of Long-Term Treatment of Malignant Hypertension, Circulation, I8, 644. HARINGTON, M., KINCAID-SMITH, P., and MCMICHAEL, J. (1959): Results of Treatment in Malignant Hypertension. A Seven Year Experience in 94 Cases, Brit. med. J., ii, 969. MAXWELL, R. A., MULL, R. P., and PLUMMER, A. J. (1959): A New Synthetic Antihypertensive Agent (Ciba 5864-SU) Expeiientia (Basel), 15, 267.