The Long-Term Treatment of Hypertension with Thiazide Diuretics D
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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 hypertension with thiazide diuretics 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 potassium supplements-but caused no symptoms. The incidence of diabetes and gout 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 Pregnancy 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 urea 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 diuretic alone-usually All underwent routine clinical examination, their hydroflumethiazide-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 uric acid 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 20 0 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 40 (a) 50 30 20 40 n~~~~~~~~~~10 7 30 e 0 40 20 @120 X:A~~~~~~~/ 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. Metabolic alkalosis 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.