Postgraduate Medical Journal (October 1971) 47, 639-643. Postgrad Med J: first published as 10.1136/pgmj.47.552.639 on 1 October 1971. Downloaded from

The long-term treatment of with thiazide D. G. BEEVERS M. HAMILTON M.B., M.R.C.P. M.D., F.R.C.P. Medical Registrar Physician J. E. HARPUR M.B., B.S Research Registrar Chelmsford Group ofHospitals

Summary TABLE 1. Aetiology of hypertension Two hundred and twenty-seven cases of moderate to Essential hypertension 198 severe hypertension were treated with thiazide Chronic pyelonephritis 23 diuretics alone for periods of up to 12 years. In 80%. Polycystic kidneys 2 the Disseminated lupus 1 hypertension was adequately controlled without Parathyroid adenoma 1 additional antihypertensive agents. Renal artery stenosis 2 Hypokalaemic alkalosis was common despite Total 227 supplements-but caused no symptoms. The incidence of and was low. TABLE 2. Mode of presentation Protected by copyright. It is concluded that thiazide diuretics provide Headache 70 excellent control of hypertension with very few side Routine medical examination 40 effects. Breathlessness 38 Dizziness 20 Introduction Angina pectoris 17 19 Thiazide diuretics have been used in the treatment Strokes 12 of hypertension since the introduction of chloro- Coronary thrombosis 8 thiazide in 1957. The mode of action is obscure, but Grade III retinopathy 19 is probably unrelated to the natriuretic effect Grade IV retinopathy 3 Left ventricular enlargement 67 (Maronde, Milgrom & Dickey, 1969; Dollery et aL, Cardiac failure 1962) and may 33 be due to relaxation of arteriolar Blood at beginning of study: smooth muscle. Whilst thiazides have few clinically 40-60 mg/100 ml 33 evident side-effects, it is commonly held that hypo- Over 60 mg/100 ml 1 kalaemic alkalosis, carbohydrate intolerance and hyperuricaemia are frequent unwanted effects. The of those presenting in the accelerated phase is http://pmj.bmj.com/ thiazides are most frequently used as an adjunct to naturally low as such patients usually require more potent antihypertensive drugs. immediate and more potent therapy (Hamilton, 1966). Patients and methods Patients were generally treated on an out-patient Two hundred and twenty-seven patients with basis and seen within 6-weekly intervals until moderate to severe hypertension (eighty-nine males, adequate blood pressure control was achieved, average age 52 6, 138 females, average age 52-3) thereafter they were seen at 4-6-monthly intervals. on October 2, 2021 by guest. were treated with a thiazide alone-usually All underwent routine clinical examination, their -and followed for periods of up urine was tested and they had regular checks of their to 12 years. This number does not include those blood urea and electrolytes. Ninety-six cases had hypertensives who required additional antihyper- their serum checked on several occasions. tensive agents within a few months of starting The duration of follow-up is shown in Fig. 1. thiazide therapy. The patients underwent conven- Eleven cases were referred to us whilst on other tional investigations in order to determine the anti-hypertensive agents which had failed to control aetiology of their hypertension (Table 1). their hypertension. In these cases an untreated blood The mode of presentation and complications at pressure level was not available. presentation (Table 2) were the same as commonly The majority (71%Y) of patients were treated with found in any group of hypertensives, the proportion 200 mg of hydroflumethiazide (Hydrenox, Boots). J. E. 640 D. G. Beevers, M. Hamilton and Harpur Postgrad Med J: first published as 10.1136/pgmj.47.552.639 on 1 October 1971. Downloaded from

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0-11 12-2324-35 36-4748-59 60-71 72-8384-9596-107108-120 120+ Months FIG. 1. Duration of treatment with thiazides alone (227 patients).

The remainder received smaller doses, and a few had TABLE 3. Thiazides in hypertension other thiazide diuretics in equivalent doses. Potas- Standard 95°/ sium supplements were recommended as a routine- Mean error confidence usually slow K (Ciba) in a dose of 1-2 tablets daily BP of mean interval (for (600-1200 g daily), but 22%Y were given increasing (SEM) mean BP) doses if their serum potassium fell to very low Pre-treatment levels. In eight cases the thiazide was given on 5 days Systolic 203 4 1-8 199 9-206 9 in 7 in an attempt to lessen the hypokalaemic effect. Diastolic 120-6 1-0 118-7-1225 Protected by copyright. On thiazides Systolic 161-6 1-3 1590-164-2 Results Diastolic 96-8 07 954- 98-2 Bloodpressure control The mean and standard error, and 95°/ confidence interval for the mean blood pressure before and Complications ofhypertension when receiving treatment are shown in Fig. 2 and Those patients in whom the blood pressure Table 3. Good control (diastolic blood pressure less became uncontrolled were given additional anti- than 100 mmHg) was maintained in 50%/, fair con- hypertensive therapy and it is in this group that trol (diastolic blood pressure less than 110 mmHg) in complications of hypertension are most likely to 35%/ and poor control (diastolic blood pressure more develop. The incidence of complications developing than 110 mmHg) in only 15%. In all fifty-six of the whilst on thiazides alone is shown in Table 4. 227 cases (20 2%) eventually required the addition of At the start of treatment thirty-four patients had a more potent agent, and the time when this became a raised blood urea, but the majority did not show a rise. Six patients developed significant renal necessary is shown in Fig. 5. http://pmj.bmj.com/ failure, but all had underlying renal disease.

200 Hypokalaemia There was a marked fall in the plasma potassium in most cases as shown in Fig. 3 which compares the 180 _ pre-treatment plasma potassium with the average of TABLE 4. Complications of hyper- X 160 on October 2, 2021 by guest. E_ tension developing whilst on treat- ment with thiazides ma- 140- No. of patients 0 Cardiac infarct 15 E12 Before Angina 32 treatment Cardiac failure 9 I00 Stroke 10 On Renal failure 5 thiazides Blood urea at end of study FIG. 2. Pre-treatment and treatment mean systolic and 40-60 mg/100 ml 44 diastolic blood pressures. Over 60 mg/I00 ml 10 641 Treatment of hypertension with diuretics Postgrad Med J: first published as 10.1136/pgmj.47.552.639 on 1 October 1971. Downloaded from

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0 Protected by copyright. 2-0-2 42-5-2-9 3-0-3-43-5-3-94-0-4-44-5-4-95-0-5.4 '5-5 15-19 20-24 25-29 30-34 35-39 Serum pot4ssium (mEq/ ) Plasma total C02 (mEq/L) FIG. 3. (a) Serum potassium pre-treatment (143 patients). Mean, 4 30; SD, 0-61. (b) Serum potassium on treat- FIG. 4. Final plasma total CO2 on treatment (157 ment (180 patients). Mean, 3 S4; SD, 0-47. patients). the plasmia potassium on treatment. Patients who Hyperuricaemia and gout developed a very low plasma potassium were given Four patients (1 7%) developed clinical gout with increasing doses of potassium supplement. How- hyperuricaemia and one other developed an arthro- ever, no cases at any time developed subjective to Some pathy with a normal serum uric acid. Those patients symptomLs attributable hypokalaemia. with gout were effectively treated with allopruinol or patients developed suspicious symptoms, but these probenecid. patients had their uric were the dose of Ninety-six serum not altered by increasing potassium acid estimated and eighteen of these were greater supplements and elevating the plasma potassium. than 7 0 mg/100 ml giving an incidence of hyper- uricaemia of 18% of estimations. http://pmj.bmj.com/ During the period of observation there was a In no cases was it necessary to discontinue therapy change in the method of estimation, and laboratory on account of side-effects of thiazide diuretics. normals, of the plasma total C02 so only the most recent value is submitted-otherwise the com- Discussion parison would not be real. However, Fig. 4 demon- In the majority of the 227 patients who were strates that analkalosis developed in a largenumber of maintained on thiazide diuretics for up to 12 years, cases: the present normal level for this laboratory is it was possible to achieve good control of the blood 24-32mEq/1. The plasma total CO2 was over 30 mEq/1 pressure with no symptoms attributable to the on October 2, 2021 by guest. in ninety-six out of 157 patients examined (62%). administration of the drugs except a low incidence of diabetes and gout. The patients in this report all had Carbohydrate intolerance a severe manometric hypertension with mean pre- Two patients had hyperglycaermia and glycosuria treatment levels of blood pressure of 203-4 mmHg before starting thiazides and there wvas one case of systolic and 1206 mmHg diastolic, and many had renal glycosuria. After starting thiazides the two either symptoms or objective complications of raised hyperglycaemic patients did not require hypogly- arterial pressure (Table 2). In spite of this the caenmic agents, but were controlled by diet alone. majority were adequately controlled, without re- Five other patients (2 2%) developed hyperglycaemia course to more potent anti-hypertensive agents. The after starting thiazides-of which three required incidence of complications of hypertension whilst on antidiabetic drugs. treatment is low (Table 4), although this is partly 642 D. G. Beevers, M. Hamilton and J. E. Harpur Postgrad Med J: first published as 10.1136/pgmj.47.552.639 on 1 October 1971. Downloaded from because those patients in whom the blood pressure Hypokalaemia occurs almost invariably, may be became uncontrolled were given additional drugs profound, and is persistent, often despite large doses and are no longer considered. However, it is interest- of potassium supplement. In view of the absence of ing to note that, as during therapy with other drugs, symptoms attributable to hypokalaemia here and the blood pressure may go out of control even after elsewhere (Maronde etal., 1969) it has been suggested years on thiazides (Fig. 5). The incidence of side- that potassium supplements are unnecessary (Healy effects of thiazide drugs, e.g. diabetes and gout, was et al., 1970). We have used potassium supplements low, and no patient required to discontinue therapy. as a routine because many patients may subsequently These results compare well with other trials from require digitalis therapy or develop an acute potas- this clinic with (Hamilton, 1968) and sium-losing condition (e.g. gastro-enteritis) which (Kellett & Hamilton, 1969), in which there might precipitate a serious hypokalaemia. Large were a higher incidence of side-effects and an quantities of potassium supplements are incon- appreciable number of treatment failures. venient and may in themselves give rise to side-effects Direct comparison of the adequacy of control of and trials are being performed on potassium- blood pressure is not possible, as in the other trials retaining agents. There is no doubt that a marked there was a larger proportion of patients with more metabolic alkalosis also occurs, sometimes even severe hypertension including some who had failed to when the plasma potassium is within the lower range respond to thiazides initially. of accepted normal: when potassium supplements We have used high doses of thiazides in most cases are increased the alkalosis is usually reversed, and it as it was found at the beginning of the period of is possible that the degree of alkalosis is a better observation that patients who showed a poor measure of the total body content of potassium than response to small doses initially, often responded to is a simple measure of the plasma potassium, especi- a higher dose. This is contrary to the findings of ally as potassium is mainly an intracellular . other workers who demonstrated a flat dose- The incidence of thiazide-induced diabetes wasProtected by copyright. response curve in a short term investigation (Crans- lower than commonly reported, although a similar ton et al., 1963). However, the antihypertensive incidence has been found elsewhere (Kohler et al., effect of the majority of drugs is augmented by an 1970). Furthermore, the two patients who were increased dose. diabetic before starting treatment did not require

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12-23 24-35 36-47 48-59 60-71 72-83 84-95 96-107 108-120 120+ Months Fio. 5. The time at which additional anti-hypertensive therapy became

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TABLE 5. Comparison of thiazides with other anti-hypertensive agents in trials done at this clinic No. of No. discontinuing drug Adequate Agent patients because of side effects BP control (Y.) (%Y) Thiazide 227 0 80 Methyldopa (Hamilton, 1968) 222 5 91 Methyldopa 44 7 80 (Kellett & Hamilton, 1969) Clonidine J 40 28 50 Treatment of hypertension with diuretics 643 Postgrad Med J: first published as 10.1136/pgmj.47.552.639 on 1 October 1971. Downloaded from any additional anti-diabetic drugs and none of the References patients in either group required insulin. Great BRECKENRIDGE, A. (1966) Hypertension and hyperuricaemia. emphasis is placed in weight reduction in obese Lancet, i, 15. CRANSTON, W.I., JUEL-JENSEN, B.E., SEMMENCE, A.M., hypertensives, which is also an effective means of HANDFIELD JONES, R.P.C., FORBES, J.A. & MUTCH, L.M.M. treating maturity-onset obese diabetics. (1963) Effects of oral diuretics on raised arterial pressure. We have found a lower incidence of hyperuricae- Lancet, ii, 966. mia than has been reported elsewhere. Breckenridge DOLLERY, C.T., PENTECOST, B.L. & SAMAAN, N.A. (1962) in of hyper- Drug-induced diabetes. Lancet, ii, 735. (1966) reported hyperuricaemia 58% HAMILTON, M. (1966) Symposium on Antihypertensive tensives on treatment and in 27% of untreated Therapy, pp. 196-206. Springer Verlag, Berlin. hypertensives, although he used slightly different HAMILTON, M. (1968) Some aspects of the long-term treat- criteria of normal, and also more patients had ment of severe hypertension with methyl dopa. Post- impaired renal function. Clinical gout was rare graduate Medical Journal, 44, 66. HEALY, J.J., MCKENNA, T.J., CANNING, B.ST.J., BRIEN, T.G., (1 7%) in this survey and provided the blood pressure DUFFY, G.J. & MULDOWNEY, F.P (1970) Body composi- is well controlled, it is desirable to treat the gout and tion changes in hypertensive subjects on long-term diuretic continue the thiazides. therapy. British Medical Journal, 1, 716. KELLETT, R.J. & HAMILTON, M. (1969) Catapres in Hyper- tension, p. 197. Butterworths, London. KOHNER, E.M., DOLLERY, C.T., Lowy, C., SCHUMER, B. & SAMUELS, C. (1970) Diabetogenic effect of long-term diuretic therapy. Symposium of the Seventh Congress of Acknowledgments International Diabetes Federation, 23 August, p. 107. We would like to thank The Chelmsford Medical Educa- MARONDE, R.F., MILGROM, M. & DICKEY, J.M. (1969) tion and Research Trust for the provision of the Research Potassium loss with thiazide therapy. American Heart Registrar's salary, and Mrs A. Oldfield for secretarial help. Journal, 16, 16. Protected by copyright. http://pmj.bmj.com/ on October 2, 2021 by guest.