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Acta Med Scand 1986; 219: 381-6 Antihypertensive and Biochemical Effects of Different Doses of Hydrochlorothiazide Alone or in Combination with Triamterene ANIT1 KOHVAKKA. HANNU SALO, ARlEL GORDIN and ANTTI ElSALO From the First Department of Medicine, Helsinki University Central Hospital, Helsinki, and Research Laboratories, Orion Pharmaceutical Company, Espoo, Finland ABSTRACT. Kohvakka A, Salo H, Gordin A, Eisalo A. (First Department of Medicine, Helsinki University Central Hospital, Helsinki, and Research Laboratories, Orion Pharma- ceutical Company, Espoo, Finland.) Antihypertensive and biochemical effects of different doses of hydrochlorothiazide alone or in combination with triamterene. Acta Med Scand 1986; 219: 381-6. The antihypertensive and biochemical effects of 25 mg hydrochlorothiazide alone or 50 mg hydrochlorothiazide alone or in combination with triamterene (either 37.5 or 75 mg) once daily were studied in 26 patients with essential hypertension. After a 5-week run-in period the patients were randomized to receive active therapy in a cross-over manner. Each treat- ment period lasted 3 months. All drugs significantly (p<O.OI) lowered both systolic and dias- tolic blood pressure. There were no differences in blood pressure between the medication periods. Serum potassium concentration was slightly lower during all medication periods than during the run-in period. This change was statistically significant (pCO.01) only on 50 mg hydrochlorothiazide daily. There were no significant changes in serum magnesium during any of the periods compared to the run-in period. The lowest values were recorded on 50 mg hydrochlorothiazide alone and the highest on 50 mg hydrochlorothiazide plus 75 mg triam- terene daily. A slight increase in serum urate was recorded in all medication periods com- pared to the run-in period. No significant changes were observed in serum total cholesterol, HDL cholesterol or triglycerides between any of the periods. It can be concluded that 25 mg of hydrochlorothiazide is as effective in lowering blood pressure as higher doses of the diure- tic. Higher doses of thiazides will in some patients cause adverse metabolic reactions of which the fall in serum potassium and magnesium is effectively hindered by triamterene. Key words: hypertension, diuretics, hydrochlorothiazide, triamterene, serum potassium, serum magnesium, serum urate, serum lipids. Thiazide diuretics are often the drugs of first choice in the treatment of mild to moderate hypertension. Hydrochlorothiazide is probably the most widely used drug in this group. It is usually used on this indication in a dose of 50-100 mg daily. Several studies have shown that lower doses of diuretics than those traditionally used in the treatment of hypertension give a satisfactory blood pressure response but cause less subjective and biochemical side- effects (1, 2, 3). Hypokalemia is the most common biochemical side-effect of thiazide diuretics. Thiazide diuretics also increase urinary excretion of magnesium which may lead to hypomagnesemia (4). To avoid these electrolyte disturbances and their clinical consequences, e.g. cardiac ar- rhythmias (5, 6), triamterene and amiloride, which reduce urinary potassium and mag- nesium loss, are often combined with thiazides (7). The purpose of this study was to compare the antihypertensive as well as biochemical ef- fects of low-dose hydrochlorothiazide (25 mg daily) with those of the traditional dose of hydrochlorothiazide (50 mg daily) alone or in combination with triamterene (either 37.5 or 75 mg daily) in hypertensive patients.

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Page 1: Antihypertensive and Biochemical Effects of Different Doses of Hydrochlorothiazide Alone or in Combination with Triamterene

Acta Med Scand 1986; 219: 381-6

Antihypertensive and Biochemical Effects of Different Doses of Hydrochlorothiazide Alone or in Combination with Triamterene

ANIT1 KOHVAKKA. HANNU SALO, A R l E L GORDIN and ANTTI ElSALO From the First Department of Medicine, Helsinki University Central Hospital, Helsinki, and Research Laboratories, Orion Pharmaceutical Company, Espoo, Finland

ABSTRACT. Kohvakka A, Salo H, Gordin A, Eisalo A. (First Department of Medicine, Helsinki University Central Hospital, Helsinki, and Research Laboratories, Orion Pharma- ceutical Company, Espoo, Finland.) Antihypertensive and biochemical effects of different doses of hydrochlorothiazide alone or in combination with triamterene. Acta Med Scand 1986; 219: 381-6.

The antihypertensive and biochemical effects of 25 mg hydrochlorothiazide alone or 50 mg hydrochlorothiazide alone or in combination with triamterene (either 37.5 or 75 mg) once daily were studied in 26 patients with essential hypertension. After a 5-week run-in period the patients were randomized to receive active therapy in a cross-over manner. Each treat- ment period lasted 3 months. All drugs significantly (p<O.OI) lowered both systolic and dias- tolic blood pressure. There were no differences in blood pressure between the medication periods. Serum potassium concentration was slightly lower during all medication periods than during the run-in period. This change was statistically significant (pCO.01) only on 50 mg hydrochlorothiazide daily. There were no significant changes in serum magnesium during any of the periods compared to the run-in period. The lowest values were recorded on 50 mg hydrochlorothiazide alone and the highest on 50 mg hydrochlorothiazide plus 75 mg triam- terene daily. A slight increase in serum urate was recorded in all medication periods com- pared to the run-in period. No significant changes were observed in serum total cholesterol, HDL cholesterol or triglycerides between any of the periods. It can be concluded that 25 mg of hydrochlorothiazide is as effective in lowering blood pressure as higher doses of the diure- tic. Higher doses of thiazides will in some patients cause adverse metabolic reactions of which the fall in serum potassium and magnesium is effectively hindered by triamterene. Key words: hypertension, diuretics, hydrochlorothiazide, triamterene, serum potassium, serum magnesium, serum urate, serum lipids.

Thiazide diuretics are often the drugs of first choice in the treatment of mild to moderate hypertension. Hydrochlorothiazide is probably the most widely used drug in this group. It is usually used on this indication in a dose of 50-100 mg daily. Several studies have shown that lower doses of diuretics than those traditionally used in the treatment of hypertension give a satisfactory blood pressure response but cause less subjective and biochemical side- effects (1, 2, 3).

Hypokalemia is the most common biochemical side-effect of thiazide diuretics. Thiazide diuretics also increase urinary excretion of magnesium which may lead to hypomagnesemia (4). To avoid these electrolyte disturbances and their clinical consequences, e.g. cardiac ar- rhythmias (5, 6), triamterene and amiloride, which reduce urinary potassium and mag- nesium loss, are often combined with thiazides (7).

The purpose of this study was to compare the antihypertensive as well as biochemical ef- fects of low-dose hydrochlorothiazide (25 mg daily) with those of the traditional dose of hydrochlorothiazide (50 mg daily) alone or in combination with triamterene (either 37.5 or 75 mg daily) in hypertensive patients.

Page 2: Antihypertensive and Biochemical Effects of Different Doses of Hydrochlorothiazide Alone or in Combination with Triamterene

382 A . Kohvakka et al. Acra Med Scand 1986; 219

Run-in Placebo 1 x l

I RUN-IN PERIOD^ MEDICATION PERIODS 1

Treatment I Drugs A - D 1 x 1

I I I I I I Fig. 1. Design of the trial. 0 5 29 41 53 l7 Weeks

4 4 4 4 4 4 4 4 4

4 4 4 4 4 + 4 4

Weeks I 1 4 e l 17 V i s i t s I I II Ill I IV

Clinical examination Sitting BP Sitting HR Weight (kg) Serum potassium Laboratory investigations Drug concentrations Tablet count Side effect inquiry ECG Thorax x ray

4 4 4 4 4 4 4 4 4 4 4

4 4

4 4 4 4

V 1 VI

Treatment IV Drugs A-D 1 x l

53 VI I

4 4 4 4 4 4 4 4 4 4 4

PATIENTS AND METHODS Patients with newly diagnosed or long-standing essential hypertension were entered into the study. The exclusion criteria were arterial hypertension classified as WHO grade 111, decompensated cardiac fail- ure, severe coronary artery disease, insulin-dependent diabetes mellitus, liver or renal failure, manifest gout, hypokalemia (S-K <3.5 mmol/l), hyperkalemia (S-K >5.5 mmol/l) and pregnancy. Initially, 30 patients were accepted. Four patients discontinued the study-one due to poor compliance, two due to causes independent of the trial and one because of side-effects (vide infra). Thus, 26 patients (21 women and 5 men), aged 29-65 years (mean 5 5 ) . were included in the statistical evaluation. Hyperten- sion had been diagnosed 1-23 years (mean 9) before onset of this study. Six patients had not previously received antihypertensive treatment, and the others had been on diuretic andor other antihypertensive medication, which was withdrawn at the beginning of the run-in period. In order to bring about differ- ences in blood pressure responses, only patients with at least moderately elevated blood pressure were accepted. Patient consent was obtained.

The trial was divided into five periods (Fig. l ) , starting with a five-week run-in period during which the patients received a placebo tablet once daily. For inclusion in the proper trial the diastolic blood pressure had to be at least 95 mmHg in weeks 4 and 5 . The patients were thereafter randomized to re- ceive either 25 mg hydrochlorothiazide (Hyrex-Semi), 50 mg hydrochlorothiazide (Hydrex), a combi- nation preparation of 25 mg hydrochlorothiazide and 37.5 mg triamterene (Triamtex semi) or a com- bination preparation of 50 ing hydrochlorothiazide and 75 mg triamterene (Triamtex). All the drugs were made identical in appearance. The study followed a cross-over design, the treatment periods with no wash-out periods in-between lasting 3 months each. All drugs were taken once daily, at 7-9 a.m.

Blood pressure (Korotkoff 1 and V) was measured by two trained nurses with the same sphyg- momanometer throughout the study from the right arm supported horizontally in the sitting position after 10 min of rest. Five measurements were performed at one-minute intervals, and the mean of the last three was recorded. All measurements were performed at the same time of the day, and heart rate was also measured on the same occasion.

The patients were asked about any untoward effects of the treatment at the time of blood pressure recording. No systematic questionnaire was used.

An ECG was recorded and a chest X-ray was taken before the start of the active trial medication and at the end of the whole study. Venous blood samples were taken for Hb, Hct, S-K, S-Na, S-CI, S-Mg,

Page 3: Antihypertensive and Biochemical Effects of Different Doses of Hydrochlorothiazide Alone or in Combination with Triamterene

Acta Med Scand 1986; 219 Hydrochlorothiazide and triamterene in hypertension 383

220

200

180

160

m 140-

E

I SYSTOLIC PRESSURE i

-

-

-

- -

1201.

DIASTOLIC PRESSURE

120

8ot t 1 2 3 4 5

Fig. 2. Systolic and diastolic blood pressure in the different medication periods (I = rum-in, 2=25 mg hydrochloro- thiazide, 3=25 mg hydrochlorothiazide plus 37.5 mg triam- terene, 4=50 mg hydrochlorothiazide, 5=50 mg hydro- chlorothiazide plus 75 mg triamterene) (mean f SD). Both the systolic and diastolic blood pressure were statistically signifi- cantly lower @<0.01) during each medication period than dur- ing the run-in period. There were no significant differences be- tween the medication periods.

S-urate, fasting B-glucose, S-total cholesterol, S-HDL cholesterol and S-triglycerides before onset of the active trial medication and at the end of each treatment period. Hb, Hct, serum electrolytes, serum urate and glucose were determined by routine methods. Serum total cholesterol and triglycerides were measured enzymatically (Boehringer-Mannheim). HDL cholesterol was determined after precipitation of VLDL and LDL with dextran sulphate, and HDL cholesterol was determined enzymatically in the supernatant (8). Reference values are given in Tables I and 11. Plasma hydrochlorothiazide concentra- tion was determined by gas chromatography (9). Patient compliance was followed by tablet count and hydrochlorothiazide serum concentration determinations after each period.

Friedman’s two-way analysis of variance was used for statistical analysis of the values between the treatment periods. A two-sided probability p<0.05 was considered statistically significant.

RESULTS The average systolic and diastolic blood pressures in the sitting position are shown in Fig. 2. Both the systolic and the diastolic blood pressure were significantly lower (pCO.01) dur-

Table I. Serum electrolyte concentrations (mmolll during the medication periods (mean k SD)

Run-in

Potassium 4.08f0.27 Magnesium 0.89f0.05 Sodium 145.3f2.4 Calcium 2.36f0.06 Chloride 106.4f2.7

Hydrochloro- thiazide 25 mg

Hydrochloro- Hydrochloro- + triamterene thiazide 25 mg thiazide 50 mg 37.5 mg

3.92f0.41 3.7 1 f0.39” 4.00f0.51 0.88f0.10 0.85+0.08’ 0.91f0.W 143.4f2.2 142.5 f 2.6 142.7f2.5 2.39 f 0.07 2.39f0.08 2.4120.09 103.6f 2.6 101.7f 1.8 103.2f2.6

Hydrochloro- thiazide 50 mg + triamterene Reference 75 mg range

3.94f0.49 3.5-5.1

142.9f2.1 136146 2.43f0.07 2.0-2.65 102.1 k 1.8 96-110

0.93 f 0.08 0.7-1.0

pCO.01 compared to the run-in period, p<0.05 compared to the hydrochlorothiazide 50 mg plus triamterene 75 mg period.

Page 4: Antihypertensive and Biochemical Effects of Different Doses of Hydrochlorothiazide Alone or in Combination with Triamterene

384 A. Kohvakka et al. Acta Med Scand 1986; 219

ing each medication period than during the run-in period. There were no differences be- tween the respective medication periods. No statistically significant changes were recorded in heart rate or body weight between any of the periods.

Serum potassium concentration was slightly lower during all medication periods than dur- ing the run-in period. This change was statistically significant @<0.01) only between the Hydrex and run-in period (Table I). Slightly decreased S-K values (<3.5 mmoVI) were re- corded in all periods; in 3 patients on Hydrex-semi, in 2 on Triamtex-semi, in 5 on Hydrex and 3 on Triamtex. Serum magnesium values were quite stable throughout the study. There were no significant differences between the run-in period and any of the medication periods (Table I). The lowest values were observed in the Hydrex period and the highest in the Triamtex periods. The only statistically significant difference was recorded between the Hydrex and Triamtex periods @<0.05).

No statistically significant differences were recorded in serum calcium, serum sodium or serum chloride between any of the periods (Table I).

A slight increase in serum urate concentration was seen in all medication periods com- pared to the run-in period. However, the difference was statistically significant (pt0.01) only between the Triamtex period and the run-in period (Table 11). There was a statistically significant increase in serum creatinine during the Triamtex period compared to the run-in period (p<O.Ol). although all individual values were within the normal range (Table 11). No statistically significant changes were observed in blood glucose between any of the periods (Table 11).

No statistically significant changes were observed in serum total cholesterol, HDL choles- terol or triglycerides between any of the periods.

One patient discontinued the trial due to urticaria while on Triamtex semi, which was the last medication period. When earlier on Triamtex, this patient did not exhibit urticaria.

Compliance was good in all patients except one, who was excluded from the study, as evaluated by tablet count and serum hydrochlorothiazide concentrations. At the end of the

Table 11. Serum concentrations of urate, creatinine, cholesterol, H D L cholesterol and triglyceride and blood glucose during the medication periods (mean k SD)

Hydrochloro- Hydrochloro- thiazide 25 mg thiazide 50 mg

Hydrochloro- Hydrochloro- + triamterene + triamterene Reference Run-in thiazide 25 mg thiazide 50 mg 37.5 mg 75 mg range

Serum urate (WmoUI) 321.7f99.2 336.0f92.4

Serum creatinine (WOW 78.9f8.5 72.4210.2

Blood glucose

Serum cholesterol

Serum HDL cholesterol

(mmoUI) 5.03f0.62 5.04f1.04

(mmoUI) 6.54k0.96 6.52+1.01

(mmolll) 1.28k0.43 1.39f0.49

Serum triglycerides (mmoUI) 1.83k1.43 1.70k1.36

357.5f105.9 348.7k102.2 404.6+97.6* P 120-340 d 150450

76.429.7 80.6211.3 85.5k13.1* P <loo, d <125

5.08f0.94 4.94k0.89 5.03k0.86 3 . 3 4 . 5

6.47+1.07 6.45f1.35 6.68f1.02 3.S7.5

1.39f0.40 1.44f0.51 1.3920.46 P >0.95, d >0.85

1.64f1.07 2.10+2.05 1.8721.41 0.5-1.70

* p<O.Ol compared to the run-in period.

Page 5: Antihypertensive and Biochemical Effects of Different Doses of Hydrochlorothiazide Alone or in Combination with Triamterene

Acta Med Scand 1986; 219 Hydrochlorothiazide and triamterene in hypertension 385

treatment periods, median hydrochlorothiazide concentration varied from 20.5 to 33.0 ng /d in the different treatment groups.

DISCUSSION

This study shows that hydrochlorothiazide once daily alone or combined with a potassium- sparing agent, triamterene, is effective in lowering blood pressure in mild to moderate es- sential hypertension. The fall in blood pressure was of the same magnitude whether 25 mg or 50 mg hydrochlorothiazide was used alone or whether these dosages were used in com- bination, respectively, with 37.5 mg or 75 mg of triamterene. This kind of a flat dose re- sponse to a thiazide diuretic has been shown in some previous studies with diuretics alone (2, 10) or in combination with other antihypertensive agents (3).

The flat dose response of blood pressure to increased doses of diuretics is at least partly due to the compensatory rise in renin release and angiotensin I1 and aldosterone concent- rations (10). The increased activity of the renin-aldosterone system during diuretic therapy also potentiates the deleterious metabolic consequences of the therapy, e.g. hypokalemia

Of the drugs studied, only the higher dose of hydrochlorothiazide alone significantly de- creased the serum potassium concentration, while there were no changes during the other treatment periods. However, it must be remembered that some patients-usually those with initially low serum potassium levels-are prone to develop hypokalemia even on low doses of thiazides. The fall in serum potassium induced in this study by 50 mg of hyd- rochlorothiazide was not encountered when triamterene was added to the medication. This is in agreement with previous knowledge of triamterene being a potent potassium-sparing agent (11, 12).

Plasma magnesium values did not change during any of the drug regimens. While serum potassium often decreases within a few days after initiative diuretic therapy, magnesium de- ficiency develops slowly during diuretic therapy and is often not apparent in serum determi- nations (6, 13). Thus, longer treatment periods would probably be necessary to show more clear-cut differences in serum magnesium or intracellular magnesium concentrations. Our results do, however, give some evidence for the magnesium-sparing effect of triamterene, which conforms with earlier studies (11, 14, 15).

As expected, hydrochlorothiazide slightly increased the serum urate concentrations. This parameter was further slightly increased when triamterene was added to the medication.

Although diuretics are generally considered to increase total lipid concentrations (16, 17), this has not been the case in all studies (18, 19). In accordance with the latter studies, no sig- nificant changes were found in total serum cholesterol or triglycendes in the present study; nor were any significant changes observed in the serum HDL cholesterol fraction between any of the treatment periods, which is also in agreement with previous studies (16, 20).

Our results suggest that a hydrochlorothiazide dose of 25 mg is effective in the treatment of hypertension. The higher dose of thiazide involves adverse metabolic effects without further lowering blood pressure.

(2, 10).

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Page 6: Antihypertensive and Biochemical Effects of Different Doses of Hydrochlorothiazide Alone or in Combination with Triamterene

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668): 102-9.

Received Aug. 31, 1984.

Correspondence: Dr A. Gordin, M.D., Orion Pharmaceuticals, Box 65, SF-02101 Espoo, Finland.