Sodium and hypertension. A review of the role of sodium in pathogenesis and the action of diuretic drugs

Pharmac,Ther,Vol. 9, pp 395 to 418

0163-7258/80/0601-0395505.00/0

© PergamonPress Ltd. Printed in Greal Britain

Specialist Subject Editor: AUSTIN DOYLE

SODIUM ROLE

AND

HYPERTENSION.

OF SODIUM ACTION

A REVIEW

IN PATHOGENESIS OF DIURETIC

OF THE

AND

THE

DRUGS

TREFOR MORGAN, SHANE CARNEY a n d JOHN MYERS

Faculty of Medicine, University of Newcastle N.S.W., Newcastle, Australia

1. INTRODUCTION Excess intake of salt or defective excretion of salt is associated in many circumstances with the development of hypertension. Evidence from epidemiological and anthropological studies support this concept and recent evidence indicates that modest as well as severe salt restriction reduces blood pressure. In specific diseases there is a clear cut relationship between blood pressure and salt balance. Diuretics reduce blood pressure primarily by changing salt balance. Specific diuretics have particular advantages related to their site of action and effects on other transport systems. Salt restriction and diuretics should be the mainstay of anti-hypertensive therapy. The evidence that excessive intake of salt is associated with hypertension will be reviewed together with the use of diuretics in the treatment of hypertension. The data reviewed will be that from human studies though data from animal studies may be used to illustrate specific points. 2. INTAKE OF SODIUM 2.1.

BETWEEN POPULATION COMPARISONS

The strongest evidence that salt intake and hypertension are related comes from studies of the blood pressure and salt intake of indigenous populations. (Kaminer and Leitz 1960, Cruz-Coke et al., 1964, Kean 1944, Maddocks 1967, Lowenstein 1961, Prior et al., 1968, Page et al., 1974, Shaper 1972, Sasaki 1964.) Most studies indicate that 'unacculturated' people have a low salt intake and a very low incidence of blood pressure. The increase in blood pressure observed with age in western society is not seen in such people. Most of these societies also have a high potassium intake and a high fiber intake. Studies of different communities have shown a correlation between the salt intake of different population groups and the mean blood pressure of the population or the percentage of people with diastolic blood pressure greater than 90 mmHg (Fig. 1). However, these comparisons are between people of different genetic makeup who live in different environments. Prior has attempted to correct for this genetic non homogeneity by studying genetically similar Polynesian populations who live in different situations (Prior et al., 1968). Prior has shown that the mean blood pressure and the incidence of hypertension varies and that the increased blood pressure on a population basis correlates with an increased salt intake and a decreased potassium intake. A large number of other variables are altered at the same time and the more urbanized people had the highest incidence of hypertension. Thus stresses of civilization, less fiber in the diet, more carbohydrates and many other factors may have contributed to the elevation of blood pressure. In South America, Lowenstein (1961) studied two different tribal groups, one of which, due to crop failure, had increased its salt intake while the other still used plant ash (KC1). 395

396

TREFOR MORGAN,SHANECARNEYand JOHN MYERS 40

Northern Japan~.

¢//

30-

,*-"Bantus • z'" South Japan /I • , / Australians

Q, >1

"r"

,.,//

/s"

10New

Guinea Highlanders

zf

if;

,z

• Americans

Eskimos 100 200

300

400

500

Sodium Intake m mol/day FIG. 1. A diagram illustrating relationships in different groups between salt excretion and the prevalence of hypertension. Many other points fall along this line but data for sodium intake (excretion) is incomplete.

The first group had more western influences but was hardly urbanized. The blood pressure was higher and this was correlated with increased salt intake. Maddocks (1967) showed that in New Guinea the blood pressure level was higher in people on a higher salt intake and that the blood pressure rose when salt intake increased. Shaper (1972) demonstrated that recruits from primitive tribes who joined the Army developed an increased blood pressure over the next 6 yr compared to those leading a nomadic existence. An interesting observation in a separate study was that initially blood pressure fell with age, but as salt intake increased it no longer fell with age and as salt intake increased further blood pressure rose with age as in western society. A study at the other extreme of salt intake comes from Japan (Sasaki 1964). In the northern island of Japan the salt intake may be greater than 600mmol/day. In this population the incidence of hypertension at the age of 45 yr is greater than 40 per cent and a large number of the population die of complications due to hypertension. All the studies reviewed have incomplete data. Many have not measured salt excretion and have relied on dietary observation. Repeat studies are few but may give the greatest information. These correlations do not prove that excessive salt intake causes hypertension, but when taken together they provide impressive evidence that increased salt intake does cause an increase in blood pressure and an increased incidence of hypertension. Observations similar to those recorded above for man have been confirmed and extended in animals. The usual laboratory strain of rats, if fed from birth on high salt diet, develop an increase in blood pressure (Meneely 1955). A similar effect has been seen in primates (Cherchovich et al., 1976). It has been possible selectively to breed rats which develop hypertension at lower levels of salt intake (Dahl et al., 1962). High potassium intake ameloriates the hypertension (Meneely et al., 1957). These salt sensitive rats do not have gross anomalies of the kidneys or of systems which control sodium excretion but may possess subtle anomalies that prevent salt being excreted as efficiently as normal. This may be a genetic disorder affecting the capacity of several systems and different strains have differing anomalies (Ikeda et al., 1978). In certain strains of rats, transplantation of kidneys from normal animals 'cures' the blood pressure implying that the defect is specific to the kidney (Bianchi et al., 1974). This does not apply to all rats with genetic hypertension. 2.2. WITHIN POPULATION COMPARISONS Although inter population studies have shown a correlation between salt intake and blood pressure levels similar results have not always been shown when individuals in the same population group have been studied. The discrepancies in intra population studies may relate to the pattern of analysis.

Sodium and hypertension

397

If the cause of hypertension were the relative failure of the kidneys and the control systems to excrete the salt load then it would prove difficult to show that hypertensive people had a higher salt intake than normotensive people. For example, if in a population at a given level of salt intake, 1 in 10 developed hypertension, all ten people would have the same salt intake but only one would have hypertension. Furthermore, salt appetite may be controlled by a system that responds to the total body content of salt or to its location in a specific compartment and a defect in the excretion of salt might cause hypertension and also inhibit salt appetite. Thus, patients with hypertension due to excess salt in their body could have a lower salt intake than normotensive people. Salt intake has been estimated by dietary history and in a few studies by 24 hr urine collections. Miall (1959) in a study of a Welsh mining village found no differences in the salt intake of normotensive and hypertensive people. Miall, who estimated salt intake by dietary history, found that the dietary history did not correlate with urinary sodium excretion which makes the results difficult to interpret. Simpson et al. (1978) in the town of Milton, New Zealand have recently completed a full study. Urinary sodium excretion was measured and the analysis was performed in an appropriate way. The study showed no correlation between salt intake and hypertension. In this study all patients with known or treated hypertension were excluded which may have invalidated the study. The classic and still the most complete study, was performed by Dahl and Love (1954, 1957). All members of a population were divided into a low, normal and high salt intake on dietary history which when studied, correlated with urinary salt excretion. People on a low salt diet had virtually no hypertension, while people ingesting a high salt intake had an incidence of 12 per cent. The medium group was in between (Table 1). TABLE 1. Incidence of Hypertension in a Population Correlated with Salt Intake

Low salt Medium salt High salt

No of People

No. of People diastolic BP > 90 mmHg

~o

101 522 501

1 38 58

1 7 12

Jossens et al. (1973) and Doyle et al. (1976) and Morgan et al. (1975) have reported that people with mild elevation of blood pressure do have a higher salt intake than normotensive people. Twenty four hr urinary sodium excretion was estimated in people with normotension and mild hypertension detected in a community survey (Doyle et al., 1976). The mean sodium excretion was higher in the mild hypertensive group of people but more significantly, there was a marked skewing of the distribution (Fig. 2). In the normal population few people had a sodium excretion exceeding 200 mmol/day while in the mild hypertensive group this was frequently seen. It has been stated that in some surveys patients with hypertension had a lower sodium excretion than normotensive individuals though the differences were small. It has also been claimed that patients taking a diuretic drug increase their salt intake (Langford et al., 1977). These points illustrate the complexity of the problem, but also suggest a difference in salt intake between normotensive and hypertensive individuals. The relationship may depend on the mechanism that has made salt excretion inadequate without blood pressure elevation. A factor of importance in these studies may be the population age, as it is probable that the ability of the kidneys to excrete sodium decreases with age. The incidence of hypertension also rises with age. Thus, it is possible that in a young population no correlation may be seen between salt intake and hypertension while a strong correlation may be seen in the older age groups. However, in a study from Mexico a correlation has been shown in adolescents between blood pressure and salt intake (Moragrega et al., 1978).

398

TREFOR MORGAN, SHANE CARNEY and JOHN MYERS Distribution of Salt

Excretion in 3

populations

N°rT°tensive /

//

~//" NN~',,,Mi..... ld~,.Hypertensive

/ •

;0

//

/ / ~

.." ......

...-

\

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"...Hypertensive . ..

"

x

8'0

,to

Sodium

,;o

2;o

Excretion

2;0

..

2;0

31.

m mol.day"

FIG. 2. Sodium excretion of normotensive people and people with mild hypertension (diastolic BP 95-109). Note the tail for high intake of salt in the group with mild hypertension.

In an individual who appears to have normal renal function and normal control systems it has been difficult in short term studies to show a correlation between salt intake and blood pressure level. An individual may ingest between 10 and 700 mmol of salt a day and may show no change in blood pressure. Most of these studies have been done in young people over a short time interval and their capacity to handle salt may not be exceeded even with this load. In a study by Morgan et al. (unpublished Fig. 3) there was a rise in blood pressure seen with salt loading in young people and a preliminary study indicates that if the same procedure is repeated in older patients the rise in blood pressure with salt loading is more clearly observed. Presumably the capacity of these normals to excrete salt is exceeded and hypertension results. 2.3. IMPAIRED SALT EXCRETION The previous section has dealt with evidence that increased salt intake increases the mean blood pressure and the incidence of hypertension in a population. Certain evidence has been provided Perera and Blood (1947), Morgan (Fig. 3) that increased salt intake in individuals increased that person's blood pressure. This section considers situations in which due to malfunction of the kidney or the adrenal gland, there is impairment of salt excretion. In these circumstances it is possible in most individuals to show a close correlation between salt intake and hypertension.

lO

r-

1

A BP mm Hg

T

20 - 30 years

60 - 70

n=7

n=7

years

FIG. 3. Difference in mean lying arterial pressure of normal people given an intake of 20 mmol/ day and 300 mmol/day of sodium chloride.

Sodium and hypertension

399

2.4. ALDOSTERONE HYPERSECRETION A few people with hypertension have hypersecretion of aldosterone due to primary hyperactivity of the adrenal gland (Fishman et al., 1968). This may be due to an adenoma, a carcinoma or bilateral adrenal hyperplasia. The principal action of aldosterone is to increase transport in a variety of tissues and by an action on the distal nephron it causes sodium and water to be retained by the body. After an initial retention of sodium and water which tends to expand plasma volume, other physiological controls come into play which prevents the accumulation continuing and body composition is little altered (Kirkendall e t al., 1976). Effects on the proximal tubule (Brenner and Berliner, 1969), and an increase in blood pressure, cause sodium to be excreted (Selkurt, 1951) and sodium balance is restored, usually with an increased plasma volume and with a low circulating plasma renin. If the proximal tubule effect were adequate by itself hypertension would not develop.

Control 120

E E 11o

¢ o

L/ow(50mmol) T~iazidand e KCI Salt

Ioo

m

:E 9O

60 62 Weight in kilograms

FIG. 4. Mean lying arterial pressure in a 42 yr old man with hypertension due to hyperaldosteronism treated by various measures that reduce salt control of the body.

Perera and Blood (1947) demonstrated the importance of salt in the hypertension that followed DOCA administration. A low salt intake prevented the elevation of blood pressure and a high salt intake enhanced it. At the usual salt intake hypertension usually follows excessive aldosterone secretion but the hypertension is salt dependent and can be prevented if salt accumulation is prevented. This hypertension may be controlled by methods that alter the body's content of salt (Fig. 4) such as a reduced salt intake or by the use of diuretics. Most can be controlled by amiloride or spironolactone which cause loss of the excess salt without loss of potassium (Brown et al., 1972). With such drugs there is a weight loss of approximately 2 kg before blood pressure falls. In the onset of hypertension there is a weight gain of the same amount before hypertension results. Thus, there is good experimental and clinical evidence that hypertension from excess aldosterone depends on the retention of salt. 3. RENAL DISEASE Salt excretion from the body may be impaired if the kidney is damaged. In renal disease excretion is impaired and the kidney is unable to compensate for either severe salt restriction or excessive intake despite appropriate responses of the control systems. In patients on haemodialysis the blood pressure can be altered by changing the salt content of the body (Fig. 5). The correlation is not the same in all patients as there are other influences working as for example, if angiotensin is present in large excess in the blood (Davies et al., 1973). Under these circumstances the balance of forces that control blood pressure is shifted and almost no amount of salt depletion can cause the blood pressure to fall. Kornerup (1978) has demonstrated that patients with severe renal failure who show a marked rise in blood pressure with salt loading are those who do not

400

TREFOR MORGAN, SHANE CARNEY and JOHN MYERS

A

B

'1 i~+ 'I !

Mean B P

1,S]il.0

mmHg

lJ .... ~

1001

s;.

Loaded Restricted

s,b

Loaded Restricted

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Mean BP

'fli'°,

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/

pm°lA|'mflht / ....

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Loaded Restricted

Loaded Restricted

F1G. 5. These figures illustrate the effect of altering salt balance in patients on chronic haemodialysis. A, shows the effect of altering salt balance on a group of six patients who had a previous nephrectomy. B is the effect in one patient who had severe uncontrollable hypertension with very high renin values. This patient had a nephrectomy and then behaved as a patient in A, C and D are in patients on dialysis with kidneys in situ. These were subdivided into two groups. C (five patients) had a change of less than 40 per cent in P.R.A. after salt loading and D (seven patients) had a change of 40 per cent or more in P.R.A. after salt loading. Note that the steepest changes in blood pressure took place in patients who failed to suppress renin on a high salt intake. Note also that the mean blood pressure in patients with no circulating renin was lower than in the other groups.

suppress renin, whereas those who suppress renin secretion have a flatter response. Williams et al. (1978) and Tuck et al. (1976) demonstrated that the feedback of angiotensin on renin release may be impaired in hypertension, suggesting that this may be yet another mechanism which could affect the normal interrelationship that exists between salt, angiotensin, and blood pressure. At the other extreme are patients who have had bilateral nephrectomy in whom the pressor response to salt loading may be flat. A similar flat response is seen in patients with poor myocardial function. These patients presumably are not able to increase cardiac output in response to the increased volume stimulus and hence develop cardiac failure rather than hypertension. As renal impairment occurs the kidney loses its ability to handle a salt load so that in patients with renal impairment a correlation can be shown between salt intake and hypertension. The more salt ingested the higher the blood pressure (Fig. 6). However, the 120

'~110

[ ~ 100

t00

200

300

400

Urinary Na ÷ (mmol/day) FIG. 6. Effect of altering salt intake on patients with various degrees of renal impairment. Creatinine clearance 10-50 ml/min.

Sodium and hypertension

401

resultant blood pressure results from a complex interaction between plasma volume, cardiac output and vascular tone and disorders of one may alter this relationship. Thus, paradoxically, certain patients with renal failure may have a salt losing state, be volume depleted and be profoundly hypertensive (Davies et al., 1973, Kincaid Smith et al., 1971). Such patients have a high renin and angiotensin level. The stimulus to renin secretion in these patients is such that the vasoconstrictor limb elevating blood pressure is more effective than the volume depletion reducing blood pressure and thus the patients become hypertensive. (Paradoxically, saline infusion may reduce blood pressure in these people.) The two previous situations refer to specific causes of hypertension and not to the large number of people with essential hypertension. As discussed before, in populations that have a high salt intake blood pressure rises with age, while in populations with a low salt, high potassium intake the blood pressure falls slightly with age (Shaper 1972, Maddocks 1967). Since glomerular filtration rate declines with age (Wesson 1969) and the ability to excrete (or conserve) sodium probably declines more rapidly it is likely that in many older people on a moderate to high salt diet the renal capacity to excrete salt at a given blood pressure level is exceeded and blood pressure rises. This could explain the increased level of blood pressure and the increased incidence of hypertension as the population ages. A similar argument can be extended to younger people with elevated blood pressure. The defect in a person with 'normal' renal function may be the presence of suboptimal control systems to excrete salt or an intrinsic defect in the kidney, reducing salt excretory capacity. Such a situation might be analogous to that in rats with inherited hypertension in which there appears to be a defect in the kidney that causes hypertension (Bianchi et al., 1974). This hypothesis is not yet proven and needs to be evaluated in the children of humans with a strong family history of hypertension; preliminary evidence appears to show an anomaly of this type. A major problem is the nature of the mechanism which causes hypertension to develop and to persist with excessive salt ingestion. The development could be due to increased cardiac output but abnormalities have recently been shown in white cell and red cell sodium concentrations (Patrick and Jones 1974, Garay and Meyer 1979) and cellular electrolyte changes may be of major importance. The intracellular composition of arteriolar muscle cells might be altered (Pammani et al., 1978) leading to an increased responsiveness to nervous and humoral factors that normally act on arteriolar tone. This would cause an increased peripheral resistance and hypertension. These electrolyte changes could result from the presence of a circulating humoral factor which is increased in amount when the salt content of the body is elevated. This may be the 'natriuretic' factor described and studied by de Wardener which altered sodium content of isolated proximal tubule cells (Clarkson et al., 1970). 3.1. EVIDENCE FROM THERAPEUTIC STUDIES IN PATIENTS WITH ESSENTIAL HYPERTENSION The earliest effective form of therapy for hypertension was a very low salt diet (Grollman et al., 1945, Kempner 1948, Watkin et al., 1950, Corcoran et al., 1951). Patients with severe hypertension were controlled by a diet containing 10 mmol of salt or less each day. Because these diets were poorly tolerated, the development of diuretics and other antihypertensive agents led to the abandonment of severe salt restriction (Kincaid Smith et al., 1975). However, the fact remains that a very low salt diet can reduce blood pressure. Few studies have investigated the effect of modest salt restriction on blood pressure in patients with mild hypertension. In 1947 Perera and Blood showed that hypertension varied with salt intake and that the blood pressure on 70 mmol/day was 12 mmHg less than on 200 mmol/day, a not uncommon intake in western society (Morgan et al., 1978, Simpson et al., 1978). Parijs et al. (1973) in a well designed cross over study showed that

402

TREFOR MORGAN, SHANE CARNEYand JotlN MYERS ~ Cardiac_ _ Output ~) Proximal Tubule

Effects reabsorption

(~ Urea

) ~ reabsorption

(~ ~Aldosterone¢

] [~raic acid ~ etc. (~-

(~GFR

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m

4-~(~ FRUSEMIDE

--

ater

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FIG. 7. A figure illustrating the changes that take place when a diuretic is given. Follow the arrows around to observe the sequence of events. If you come to the end of a sequence of numbers go back to volume alteration and continue along the next tract from that site. blood pressure fell with salt restriction. Morgan et al. (1978) have treated a large number of male patients with mild hypertension and have shown that reduction of salt intake reduced blood pressure. The fall in blood pressure was similar to that achieved by a diuretic and might have been greater if patients had reduced their salt intake to the desired amount (70-100 mmol/day). The men studied were over 50 yr of age and results could differ in younger patients. However, certain young people with hypertension do respond to salt restriction. These patients are ones who also have a good response to thiazide diuretics. Hunt (1977) has reported even larger falls in blood pressure with a low salt diet and weight reduction. Other studies in smaller groups of patients have confirmed this effect of salt restriction on blood pressure (Owens and Brachett 1978). If the salt hypothesis were correct, it might be expected that reduced salt intake should reduce blood pressure in all people with hypertension. This ignores the fact that salt balance also controls the other effector arm that controls blood pressure (Vaughan et al., 1978). Weber et al. (1977) have shown that in people who fail to respond to thiazide diuretics there was a greater rise in aldosterone levels. Some important conclusions can be drawn from studies using angiotensin blocking drugs. Some inferential conclusions can also be made from the interaction that occurs between propranolol and diuretics, but the more important conclusions relate to captopril. Captopril, an oral converting enzyme inhibitor, blocks the formation of angiotensin II (Ferguson et al., 1977). Some people have a fall in blood pressure when it is administered by itself. If combined with a diuretic (or salt restriction) the blood pressure is controlled in most patients (Brunner et al., 1978). Some patients are not controlled by this mechanism including patients with pheochromocytoma or with excessive activity of the sympathetic nervous system. Similar results have been obtained using intravenous saralasin (Fagard et al., 1977, Johnson et al., 1975) in association with salt depletion. Salt depletion by itself induced a hypotensive effect that correlated with a low initial plasma renin. Patients who did not respond to salt restriction had an elevation of plasma renin. Infusion of saralasin when the people were depleted of salt, caused the blood pressure to fall in all patients. Infusion of saralasin alone produced no fall in blood pressure when patients were on their normal salt diet of 130 retool/day or greater. This study and others strongly support the concept that most cases of blood pressure result from a defective handling of an excessive salt intake.

Sodium and hypertension

403

4. DIURETICS Diuretics are the drugs most frequently used in the treatment of hypertension but even after their widespread use for more than 20 yr there is still debate concerning their long term effects and their mechanism of action (Fig. 7). Experimentally, thiazide diuretics can reduce blood pressure independent of any demonstratable effect on overall salt or volume status, whereas loop diuretics have not been shown to have such an action. This effect is probably of trivial clinical significance because regardless of their chemical composition or site of action in the renal tubule, equivalent pharmacological doses of diuretics have a similar antihypertensive effect (Freis 1961, Conway and Leonetti 1965, Davidson et al., 1966, Freis et al., 1958). Furthermore, the antihypertensive effect of diuretics is prevented by giving a patient extra salt to ingest (Winer 1961). It must be emphasized that salt depletion beyond a certain degree may not produce further falls in blood pressure so that diuretic drugs and severe salt restriction do not cause additive effects (Van Brummelen et al., 1978). Diuretics probably produce the initial fall in blood pressure by reducing cardiac output but within 2-3 weeks cardiac output returns to pretreatment levels and the fall in blood pressure is maintained by a fall in peripheral resistance (Crosley et al., 1960, Conway and Lauwers, 1960). The adjustments and changes that take place with thiazide diuretics are slow and prolonged. Thus, plasma renin initially rises but returns to pretreatment levels over the next 6-12 weeks. In most patients plasma potassium reaches its lowest value at week 4 and then returns by week 12 to near its pretreatment level (Gillies et al., 1975). However, the diuretic still exerts a significant effect on the kidney because when it is ceased weight increases by 1-2 kg, plasma renin falls and blood pressure rises (Tarazi et al., 1970, Leth, 1970). The mechanism of antihypertensive action is obscure but seems to relate to loss of salt and water. The long term effects are probably caused by some subtle interaction at the vessel wall related to this initial alteration in salt balance. This may be a change in electrolyte and water content which either directly reduces vascular resistance, or indirectly, may alter the response of the arteriolar muscle to vasoconstriction initiated by the sympathetic nervous system or circulating vasoconstrictor substances (Tobian and Binion, 1952; Winer, 1961; Friedman et al., 1960; Feisel et al., 1961). Diuretics exert most of their antihypertensive effect within two weeks but there appears to be a slow further fall in blood pressure that may take 3 months or longer to be fully expressed (Finnerty et al., 1977; Soghikian and Bartenbach, 1977). A similar effect was seen with salt restriction (Morgan et al., 1978). Diuretics are usually classified according to their site of action in the nephron. However, in their use in hypertension a suitable classification is as follows: 1. 2. 3. 4.

Loop Diuretics Diluting segment Diuretics Potassium sparing Diuretics Diuretics with specific other effects

The diuretics in the first and second group have a similar effect in hypertension and the side effects due to their natriuretic action are similar. Side effects related to their chemical class do differ. While diuretics can be grouped together in the above fashion, it should be emphasized that within the group there are specific differences in their effects. These relate to the half-life, duration of action and natriuretic potency (Table 2). Diuretics in the first 2 groups have a group of clinical and biochemical side effects which are similar and are due to the natriuresis and volume depletion produced. These changes are physiological responses that are a natural corollary of their action (Fig. 7). A brief summary of these follows; further detail about the mechanism is contained in reviews by Morgan (1974) and by Davis and Wilson (1975). J.P.r. 9/3--i

404

TREFOR MORGAN, SHANE CARNEY and JOHN MYERS

The first group of side effects is common to all diuretics (Table 3). (a) Weight loss. A weight loss of 1-2 kg usually results in the first week. The patient gradually regains weight back towards the initial value. (b) Lethargy, Tiredness, Weakness. These side effects are common in the first 4 weeks of therapy but usually resolve as physiological compensations take place. However, particularly with the short acting more potent diuretics, they may persist and are associated with the onset of diuresis. (c) Cramps. Cramps are common in the first 4-8 weeks after starting therapy and persist in some people. Their cause is unknown. A low serum potassium may be the cause in some people but they most likely result from changes in electrolyte composition of cells. Cramps may also develop in some people on a low salt diet. A second large group of side effects which includes many biochemical anomalies result from intrarenal compensations secondary to the natriuretic action of the drug. Two of these, hypokalaemia and alkalosis, are secondary to increased delivery of fluid to the distal nephron. Most of the others result from increased reabsorption of salt and water at other nephron sites consequent to the reduction in plasma volume induced by the diuretic (Fig. 7). 4.1. HYPOKALAEM1C ALKALOSIS Diuretics lead to increased delivery of salt and water to the distal tubule and diuretics which inhibit carbonic anhydrase also cause more bicarbonate to be delivered to this site. As plasma volume is reduced aldosterone secretion may rise. The potential difference across the distal nephron becomes more negative due to the presence of a less permeable anion (HCO£) and of increased sodium transport (aldosterone). Potassium can therefore, reach a higher concentration in the distal nephron. The greater flow rate coupled with the higher concentration causes increased potassium loss. This loss is self limiting because as serum potassium falls, less potassium is excreted; as serum potassium falls aldosterone secretion is reduced; and as volume reduction takes place there is increased proximal tubule reabsorption; this reduces the volume of fluid delivered to the distal nephron and reduces the bicarbonate concentration. Thus, in most circumstances K + loss ceases and the body comes back into balance with a serum K + slightly below the initial value. A similar argument applies to H + and thus a mild hypokalaemic alkalosis results. This becomes severe if aldosterone levels were initially high, or if large doses of a diuretic are used. 4.2. OTHER METABOLIC CHANGES

Diuretics reduce plasma volume, and by an ill defined mechanism also lead to increased reabsorption of sodium and water from the proximal tubule. A large number of compounds are absorbed from the proximal tubule, some probably 'linked' to the reabsorption of salt and water, others by diffusion, and others by active transport. As more

2

H2NSO2~ ' ~ ~ ' ~

S~ N

O2 CHLOROTHIAZIDE FIG. 8. C]orothiazide.

FRUSEMIDE FIG. 9. Frusemide.

Sodium and hypertension

405

salt and water is reabsorbed, so more urea, uric acid, calcium, phosphate, glucose, amino acids are absorbed. Depending on the magnitude of this reabsorption, changes may develop in urine and plasma levels of these compounds. This compensation of increased reabsorption of salt and water leads to 'diuretic resistance' and is an important mechanism returning the body to a balance state. If the compensation is prevented by increasing the dose of a drug volume depletion, reduced cardiac output and alterations in renal blood flow may develop which may cause a fall in glomerular filtration rate. This is an unusual event but it is important to prevent its occurrence.

4.3. HYPERURICAEMIAAND GOUT All diuretics, except those with specific uricosuric effects, cause a rise in serum uric acid levels (Demartini et al., 1972) which also rise with reduced salt intake (Carney et al., 1975). The rise is due to changes in the site of reabsorption of salt and water consequent to the initial volume depletion (Morgan, 1974). Certain diuretics also specifically inhibit uric acid secretion and with these retention of uric acid is greater. Three to ten percent of hypertensive patients may develop gout (Breckenridge, 1966). The incidence depending on the population at risk and the dose of diuretic used.

4.4. ELEVATEDUREA LEVELS

Blood urea rises with all diuretics due to the change in site of salt and water reabsorption, but is rarely of any significance. Serum creatinine usually does not rise because as renal blood flow falls glomerular filtration rate remains unaltered so filtration fraction rises. The combination of diuretics acting at the distal tubule with those affecting the loop or diluting segment gives greater elevation of blood urea and in some circumstances causes serum creatinine to rise (Gillies et al., 1975). The mechanism may be by interference with the local feedback signal at the macula densa, thereby reducing G.F.R. (Thurau, 1974) although recent studies have shown no major fall in G.F.R. and only a slight decrease in renal blood flow (Myers and Morgan, 1979).

4.5. HYPERCALCAEMIA-HYPOCALCURIA

Increased reabsorption of calcium in the proximal tubule occurs with most diuretics but is most common with the thiazide diuretics. In a few patients serum calcium may become elevated outside the normal range. Paradoxically, frusemide in large doses with adequate saline infusion may be used to treat hypercalcaemia by increasing calcium loss in the urine.

4.6. OTHER ELECTROLYTECHANGES Changes in magnesium and in trace metals may occur (Wester, 1973). Their significance is in most cases not known and their blood levels are usually not measured.

4.7. HYPONATRAEMIA

A small fall in serum sodium occurs with most diuretics but is rarely of significance. It is more usual when combinations of diuretics acting at different sites are used, particularly if associated with severe salt restriction.

406

TREFOR MORGAN,SHANECARNEYand JOHNMYERS

4.8. HYPERRENINAEMIA

Renin frequently rises transiently following administration of a diuretic. The level later tends to return towards but probably does not usually reach normal levels. Brunner et al (1972) have postulated that high renin levels cause vascular injury, a finding not confirmed by others (Doyle et al., 1973). However, it is possible that mild elevation of renin may have long term effects. 4.9. IMPAIRED GLUCOSE TOLERANCE The thiazide and the high ceiling diuretics have both been stated to have this effect (Breckenridge et al., 1967). It has not been seen with the potassium sparing diuretics. Usually it produces no clinical problems, but diabetes needing treatment may be occasionally induced. There is some evidence that thiazides do cause alterations in serum lipids and this together with impaired glucose tolerance might hasten the development of atherosclerosis (Ames and Hill, 1978). 4.10. LIPIDS AND CHOLESTEROL In recent years attention has focused on changes in serum levels of lipids and cholesterol. Alterations have been shown (Ames and Hill, 1978) but it is difficult to know if these are direct drug effects or a response to alterations in blood pressure. Morgan et al. (1980), Jones et al. (1978) have provided preliminary evidence that suggests that myocardial infarction may be more common in people treated with thiazide diuretics. This proposition needs careful evaluation. 5. DOSE OF DIURETIC IN HYPERTENSION The aim when a diuretic is used in hypertension is not to induce salt depletion or a reduction in plasma volume but to facilitate salt excretion so that, together with the normal controls, there is sufficient capacity to excrete dietary salt without the need to raise blood pressure. Many studies have now shown that with a thiazide diuretic or chlorthalidone, small doses have most of the antihypertensive activity of much larger doses and exert this antihypertensive action without significant biochemical side effects (Carney et al., 1976; Materson et al., 1978). Although there may be a small increase in antihypertensive effect, volume depletion and weight loss also increases and the net gain to the patient appears to be greatly outweighed by the increased number of side effects (Louis et al., 1973). There are some specific situations where there is a more direct correlation between volume expansion and hypertension. One such situation is in people with renal damage. In these circumstances the thiazide type diuretics may not possess sufficient natriuretic effect and a loop diuretic may be required. As renal function deteriorates the dose of the loop diuretic may need to be increased, or salt intake reduced. In a recent study Myers et al. (1979) compared the duration of effect of 3 diuretics: Frusemide, Chlorothiazide and Chlorthalidone. Each diuretic had a similar hypotensive effect. The antihypertensive effect of frusemide lasted between 24-36 hr, that of chlorothiazide between 36-48 hr and that of chlorthalidone persisted for about 7 days. Sanchez Tortes et al. (1978) reported the mean duration of antihypertensive effect of chlorthalidone was 9.6 + 3.7 days. In both studies the effect correlated with changes in weight and suggested that long acting diuretics may have certain advantages. Frusemide caused a noticeable diuresis which was not as well tolerated by the patient. 6. THIAZIDE DIURETICS AND RELATED DERIVATIVES The compounds in this class are analogues of 1,2,4-benzothiodiazine 1-1 dioxide. Chlorthalidone, Quinethazone and Metolazone have a different heterocyclic ring but are

Sodium and hypertension CI

407

CI

/o-c. coo. ETHACRYNIC ACiD

FIG. 10. Ethacrynic acid.

pharmacologically similar. The substitution of a different group alters the metabolism and excretion of the drug thereby increasing the half life and duration of action. The substitution probably also alters the affinity for the site at which drugs act as different concentrations (mmol/1) have the same net effect. The maximum saluretic effect is similar and the dose response curves are parallel. The properties that alter the drug's effect are primarily related to protein binding and lipid solubilities. These diuretics are absorbed rapidly from the gastrointestinal tract and exert their effect within one hour. The binding to plasma protein varies and the longer acting drugs are more fully bound. Some of the drug is filtered but the principal route of excretion is secretion in the proximal tubule by the weak acid secretory system (Brettell et al., 1960; Beyer and Baer, 1961). The clearance of the short acting drugs which are only partially bound to plasma protein is greater than the glomerular filtration rate. In addition to filtration and secretion, some of the longer acting drugs are lipid soluble and are reabsorbed from the distal nephron after they have passed their site of action. Thus, if a drug was sufficiently lipid soluble it would be secreted and reach a high concentration in the tubule, exert its action and be almost all reabsorbed to repeat this sequence of events allowing a marked prolongation of action. The secretion of thiazide is by the weak acid secretory system and thus certain drugs, e.g. probenecid, can interfere with their secretion into the proximal tubule (Garcia and Yendt 1970). Thiazides also interfere with the secretion of weak acids, either drugs or natural compounds, and these may accumulate in the body. This is part of the explanation for the elevation of serum uric acid. However, in the dose used in hypertension, interference with the excretion of other drugs is uncommon. Thiazide diuretics are secreted and become concentrated in tubular fluid and exert their effect from the luminal side of the nephron. The site of action differs from that of frusemide and amiloride as the saluretic effects of these 3 drugs are additive. They interfere with the dilution of urine but not the concentration process and thus they are said to act on the cortical diluting segment; a segment that has no direct anatomical representation. It is unknown what enzymatic process they inhibit; they may act on many enzyme systems. Certain of the thiazides also have an effect inhibiting carbonic anhydrase (Maren and Wiley, 1964) but this is not the major site of action. On theoretical grounds such drugs would cause the excretion of more potassium/mol of sodium in the urine. Effects on calcium and uric acid are largely a resultant of the natriuretic action and volume reduction. However, it is possible that they may specifically inhibit the secretion of these substances as well. All thiazide diuretics have been used in hypertension and the question is not so much which drug to use but rather what is the correct dose, The dosages that were initially recommended were higher than is ideal (Louis et al., 1973; Carney et al., 1976). The dose schedule was based on that needed for treatment of oedematous states or for treatment of severe hypertension. In these situations side effects are acceptable. The dose required to obtain 70 per cent or more of the antihypertensive effect is listed in Table 2. In long term management of mild hypertension a dose should be chosen that exerts most of the effects with absence of side effects. Studies by Carney et al., (1976) showed that chlorthalidone 25 mg/day had most of the antihypertensive effect of chlorthalidone 100 mg/day but caused minimal changes in uric acid or serum potassium levels. In most patients serum potassium stays in the normal range and potassium supplements are not indicated (but see under K sparing diuretics).

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TREFOR MORGAN, SHANECARNEYand JOHN MYERS

TABLE2. Diuretic Doses and Half Life

Agent

Trade name

Dose range (rag)

Dose usually needed in Hypertension

ThiazideType

Chlorothiazide Hydrochlorothiazide Flumethiazide Cyclopenthiazide Hydroflumethiazide Bendroflumethiazide Bendrofluazide Methylchlothiazide Polythiazide Cyclothiazide Quinethazone Chlorthalidone Mefuside

Chlotride Diuvet Dichlotride Esidrex

500-2000

500

25-100

25

Navidex Diademit

0.25-2 25-100

0.5 25

Aprinox

0.25-10

5

Aquamox Hygroton Baycaron

50-100 25-100 25-50

50 25 25

Lasix Frusid Edicril

40-1000

40

50-100

Rarely used

Dytac Midimor Aldactone

100-400 5-~20 100~,00

200 5 10 200

Moduretic

1 2 tabs

1 tab

Dyazide

1~4 tabs

1-2 tabs

Loop Type

Frusernide Ethacrynic Acid Distal Tubule Diuretics

Triarnterene Amiloride Spironolactone Combination Diuretics

Amiloride (5 mg) Hydrochlorothiazide (25 mg) Triamterene (50 mg) Hydrochlorothiazide (25 mg)

There is no objective evidence that long acting thiazide diuretics are preferable to short acting. However, studies have shown that long acting thiazide type diuretics may have a hypotensive action that persists for 1 week or longer while the hypotensive action of the short acting disappears much sooner (Myers et al., 1979). The author's view is that rapid and short acting diuretics should be avoided and drugs used that act over the 24 hr. To achieve, with once/day dosage (which should be an aim) comparable weights loss and hypotensive effect at 24 hr with a short acting diuretic means that at some stage of the day the weight loss is greater. This produces symptoms related to volume shifts and is an increased stimulus for salt retaining systems. The extreme examples of this are seen in idopathic oedema states that are usually due to taking of short acting diuretics (MacGregor et al., 1979). Thiazide diuretics have similar side effects and hypersensitivity reactions do occur. The last are independent of dose and there is cross sensitivity with frusemide. 6.1. HIGH CEILING DIURETICS 6.1.1. Loop o f Henle These drugs are a pharmacological and not a chemical class. Most are carboxylic acids and have many similar features in their metabolism and action. The most commonly used drug is furosemide. The role of these drugs routinely in hypertension is debated. Usually the potency of their action is not required and the short duration of effect is a

Sodium and hypertension

409

handicap. These drugs are secreted by the proximal tubule at the weak acid secreting site and in high dosages interact and inhibit the secretion of other drugs. They exert their effect from the luminal surface of the ascending limb of the loop of Henle and inhibit chloride reabsorption (Morgan et al., 1970: Burg et al., 1973). The effect takes place as soon as the drug is in contact with the luminal surface and disappears as soon as it is removed (Morgan et al., 1970). It would appear that it acts on the membrane preventing chloride entering the transport process or alternatively, on an energy producing system. 6.1.2. F u r o s e m i d e Furosemide is a sulphonamide derivative and has a structure similar to the thiazide diuretics. Derivatives of furosemide are available, most of which have a similar pharmacological action, but some act on the cortical diluting segment and are more like thiazide diuretics. TABLE 3. Side Effects of Diuretics 1. Related to diuresis --tiredness --weakness --lethargy --cramps --hyperkalaemia alkalosis

weakness (not distal tubule agents)

--hyperuricaemia ~ gout

--hypercalcaemia --other electrolyteproblems --hyperglycaemia --other electrolyteproblems --hyperglycaemia (not with distal tubule agents) 2, Related to hypersensitivityreactions --rashes May occur with most diuretics. --photosensitivity Rare with spironolactone. Fruse--blood dyscrasias mide, thiazides may have cross --purpura sensitivity.

Furosemide is rapidly and completely absorbed into the blood stream where it is strongly bound to plasma protein. It is secreted by the proximal tubule and exerts its effects within minutes of its entry into the blood stream. It is rapidly secreted and the effect of a 40 mg dose is over within 4 hr. The diuresis obtained is dose dependent and with normal doses can reach 10 per cent of glomerular filtration. In higher doses proximal tubule reabsorption of salt and water is also inhibited and the diuresis may, given the right circumstances, reach 50-70 per cent of the glomerular filtrate. Furosemide acts on other sodium chloride transport systems and in high doses depresses sodium chloride transport in the cochlear and causes deafness (Cannon and Kilcoyne 1969, Brusilow and Gondes 1973). The role of furosemide in hypertension should be in those circumstances in which a greater excretion of salt and water is needed. This effect may be achieved by combining salt restriction with a thiazide, but when there is renal impairment (serum creatinine >0.25 mmol/l) furosemide may be the more logical therapy. Likewise, some people on vasodilating drugs may become resistant to therapy due to salt retention and furosemide may be used in these circumstances (Wilson et al., 1977). It should be emphasized that furosemide can be used in hypertensive patients (Araoye et al., 1978; Finnerty et al., 1977; Valmin and Hansen, 1975) but its short duration of action, its rapid effect and production of symptoms make other drugs preferred. An alternative would be to use a slow release furosemide tablet or give it in smaller doses twice/day.

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TREFOR MORGAN,SHANECARNEYand JOHN MYERS

6.1.3. Bumetanide This drug has structural and pharmacological resemblances to furosemide and is a 3-amino benzoic acid derivative. It is more potent than furosemide (i mg is equivalent to 40 mg furosemide) and has similar effects on urine composition. It is stated that it does not cause magnesium loss in the urine. Whether this has any clinical implications is unknown. It should not be the first diuretic to be used in hypertension.

6.1.4. Ethacrynic Acid This drug has little role in the management of hypertension. It is however, a phenoxyacetic acid derivative and does not have cross sensitivity with the thiazide diuretics or with furosemide (Table 4). It has a unique property of an additional action on hydrogen ion excretion, an effect that may be useful in certain patients with renal disease. 6.1.5. Piretamide (Merkel et at., 1976) This drug is at present under study, it appears to have similar effects to furosemide but may have a more prolonged effect. It does not seem to reduce serum potassium as much as chlorothiazide and this could be important. However, in the dose of diuretics usually used in hypertension this is not a problem. 6.2. DISTAL TUBULE DIURETICS

The salt and water loss produced by these drugs is relatively small and it has usually been regarded as not being sufficient to be used alone. However, studies with both spironolactone and amiloride have shown that these drugs have an antihypertensive effect similar to that of a thiazide diuretic (Kremer et al., 1978; Waiters et al., 1978; Bevegoard et al., 1977; Ogilvie et al., 1978). In short term studies there were stated to be fewer side effects. These drugs have three potential advantages-They inhibit sodium reabsorption in the distal nephron and thereby prevent potassium excretion. Thus, hypokalaemia does not occur. There have been no reports of abnormal glucose tolerance developing with these drugs, and thirdly, elevated uric acid levels are not so common because these drugs do not interfere with uric acid secretion and they produce a lesser degree of volume contraction. However, they may be associated with elevation of serum potassium and/or acidosis. This may be marked in people with renal impairment and becomes a major problem if high doses are used. Thus, their usual use in hypertension has been in association with other diuretics. This allows the use of a small dose of the drug and corrects the hypokalaemic alkalosis usually produced by other diuretics (Carney et al., 1975). 6.2.1. Spironolactone This drug is a steroid derivative and is a competitive inhibitor of aldosterone (Kagawa et al., 1959). Spironolactone is absorbed from the gut and is transported bound to protein. It exerts its effect on the distal nephron cells of the kidney from the blood side. It is metabolised in the liver and produces compounds that have steroid and progesterone like effects. Long term studies indicate a large number of side effects associated with its use, (gynaecomastia, gastrointestinal irritations, nausea and vomiting) and these are greater as the dose is increased (Ogilvie et al., 1978). In short term studies it is well tolerated. Spironolactone competitively binds with cytoplasmic receptors for aldosterone and thereby prevents the aldosterone induced synthesis of a protein important in sodium

Sodium and hypertension

411

transport (Feldman et al., 1972). This aldosterone induced distal nephron transport system is not the only mechanism for sodium reabsorption in the distal tubule and thus a basal level proceeds even if aldosterone exerts no effect. The dose of spironolactone is not predictable clinically as it depends on the circulating aldosterone level. Its onset of action is slow and may take 24-48 hr to exert its effect. The drug was thought to be very effective in low renin hypertension however, it is no more effective than a thiazide diuretic (Ferguson et al., 1977). The drug can be used in hypertension, but if a distal tubule drug is required the following drugs are probably superior. 6.2.2. Triamterene This drug is a pteridine derivative which has been available for many years but has never been widely used. It is irregularly absorbed from the gastrointestinal tract, it is bound to plasma protein and is excreted by filtration and secretion. It is excreted rapidly and has a short duration of action. It has a similar effect to amiloride. 6.2.3. Amiloride (Bull and Laragh, 1968) Amiloride is an organic base which is poorly absorbed (15-25 per cent) from the gastrointestinal tract. It is excreted in the urine, probably by filtration and secretion, and exerts its action from the luminal side of the collecting tubules and collecting ducts (Stoner et al., 1974). After an oral dose it has its peak effect at about 4 hr and an effect lasts for about 12 hr. It is not metabolised and is excreted unchanged in the urine. Amiloride and Triamterene inhibit sodium reabsorption in the distal nephron. They probably retard the entry of sodium to the transport site. The basal and the aldosterone stimulated sodium transport systems are both inhibited and their action is independent of the presence of aldosterone (Baba et al., 1962; Bull and Laragh, 1968). The major side effects are hyperkalaemia and acidosis. In usual dosage this is not a major problem but if higher doses of the drug are used, if the patient has impaired renal function, if the patient is on potassium supplements, or if the patient has a high potassium intake (e.g. a vegetarian) this may become a potentially fatal problem. The role of these drugs in hypertension is not certain. They do have an effect by themselves but the magnitude has not been adequately studied. The recommended role is to use them in hypertension if hypokalaemia and alkalosis develop. Usually they would be used in association with another diuretic (Kremer et al., 1978). 6.2.4. Combination of Thiazide diuretics with potassium sparing diuretics Moduretic-Dyazide-These combinations are an example of successful use of a combination tablet. In states where hypokalaemia, total body potassium depletion and alkalosis are likely to occur these drugs are most valuable ((e.g. cardiac failure) Whight et al., 1974). Their role in hypertension is however, debatable and depends on the desirability of keeping serum potassium in the high normal range. The most common cause of vascular related deaths from hypertension is myocardial infarction and it is believed that the incidence of associated fatal arrhythmias is higher if the serum potassium is low. Therefore, all steps should TABLE 4. Pharmacological Cross Sensitivity Group I Thiazides Chlorthalidone Frusemide Mefruside

Group II

Group III

Group IV

Group V

Ethacrynic Acid Indanone

Amiloride

Triamterene

Spironolactone

412

TREFOR MORGAN, SHANE CARNEY and JOHN MYERS

be taken to maintain serum potassium at a high level. In a recent study of the treatment of hypertension in the elderly there was an increased number of fatal myocardial infarcts in patients treated with thiazide diuretics (Morgan et al., 1978). These patients were not supplemented with potassium chloride unless serum K + fell below 3.4. Whether the mortality was related to the thiazide diuretic or to potassium effects is unknown, but it does support the argument to keep serum potassium close to normal. If these drugs are used it is important not to exceed 2 tablets/day as hypokalaemia can result. Potassium supplements and potassium rich foods should be avoided.

6.3. DIURETICS WITH URICOSURIC PROPERTIES 6.3.1. Tienylic Acid (Ticrynafen) (Gillies and Morgan, 1978; Lemieux et al., 1978; Reese and Steele, 1976) This drug is dichloro-2; 3-(thier-2-kilo)-4-phenoxy acetic acid. The drug is readily absorbed from the gastrointestinal tract and is excreted in the urine probably by a combination of filtration and secretion. A dose of 250 mg has a diuretic action that lasts approximately 12 hr. The drug inhibits sodium reabsorption in the cortical diluting segment at the same site as thiazide diuretics. The drug also inhibits the reabsorption of both filtered and secreted urate and this effect may be at a site different to where it exerts is natriuretic effect. The drug is a very effective uricosuric agent and causes a marked fall in serum uric acid from 0.35 to 0.18 mmol/1 (Gillies and Morgan, 1978). In similar patients treated with a thiazide diuretic that gave the same control of blood pressure the serum uric acid rose from 0.33 to 0.45 mmol/1. The drug acts by inhibiting reabsorption of uric acid and at the start of its administration urinary uric acid levels increase and crystallisation and stone formation could result. Thus, at the start of therapy it is important to ensure a good fluid intake. Another possibility is that gout could be precipitated due to mobilization of uric acid from the tissue; this has not proved to be a problem. Most patients develop a very low serum uric acid and it is possible--though unlikely--that this could have long term effects on purine metabolism. This drug has been withdrawn from use due to the occurrence of liver damage.

6.3.2. Indanone (Watson et al., 1976) This drug has certain structural resemblances to ethacrynic acid but does not have the sulphamyl radicle common to chlorothiazide and frusemide. It is (6,7-dichloro-2-methyl-2 phenyl-l-oxo-5-indanyl) oxy acetic acid. The drug is rapidly absorbed from the gut and is metabolized extensively to a phenolic metabolite. The drug and its metabolite are excreted in the urine probably by a combination of filtration and secretion. The site of action of the drug is uncertain and its dose response curve differs from both frusemide and hydrochlorothiazide. In addition to it natriuretic and hypotensive effect, which is similar to that of other diuretics, it does increase uric acid excretion in the urine. The uricosuric effect is not as potent as with tienylic acid. The serum uric acid may fall but in many instances the final uric acid is similar to that before therapy. The uricosuric effect has prevented the rise in serum uric acid associated with the change in volume associated with a diuretic or with salt restriction. The role of indanone and tienylic acid in hypertension is being studied and they are being combined with amiloride to observe if this produces a useful combination. Whether it is desirable to reduce serum uric acid below normal, or control it at its previous level is unknown, but if long term studies prove these drugs to be safe they will become useful adjuvants to the diuretics used to treat hypertension.

Sodium and hypertension

413

So °

TRIAMTERENE

FIG. 11. Spironolactone.

FIG. 12. Triameterene.

NH2

SPIRONOLACTONE

~

C

~ ' ~ CI

O--CHz--COOH CI

FIG. 13. Tienylic acid.

6.4. OTHER DIURETICS 6.4.1. Indapamide Indapamide is a substituted 3-sulphamyl-4 chlorobenzamide derivative. The drug is rapidly absorbed from the gastrointestinal tract and is bound (80 per cent) to plasma protein. In addition, the drug is taken up into red cells to a concentration 4 times greater than that in plasma (Campbell et al., 1977). This leads to a bimodal pattern of metabolism and the drug has two half lives, one of 14 hr, the other 25 hr. The drug is extensively metabolized and less than 5 per cent is excreted in the urine. However, the drug is filtered and is probably secreted by the proximal tubule. Little appears in the final urine as the drug is very lipid soluble and is rapidly reabsorbed. It is reabsorbed to such an extent that it may not have very much diuretic effect. If 2.5 mg is given daily a constant blood level is achieved after 3 days and at this time 40 per cent of the drug is in the vascular compartment. This drug is bound to plasma protein and to carbonic anhydrase in the red cells and the large amount present allows it to act readily on vascular smooth muscle. The antihypertensive effect of most diuretics correlates with the saluretic action. This is not the case with this drug and the antihypertensive action is stated to be present with little diuretic effect. The drug is a diuretic but it may be all reabsorbed before reaching the site where it exerts its diuretic activity. It has been stated that the drug does not cause potassium loss but the evidence for this is doubtful, though if it is not having a diuretic action the statement would be correct. The drug does however, appear to have an antihypertensive effect at a dose that causes only a small diuresis. Whether this is by the same mechanism that thiazides can be shown to have a direct effect is unknown and awaits study (Isaac et al., 1977; Lenzi and di Perri, 1977; Hatt and Leblond, 1975; Milliez and Tcherdakoff, 1975; Witchitz et al., 1975).

7. C O N C L U S I O N In the treatment of hypertension there are now a large number of diuretics. Despite their widespread use it is surprising that so little is known about their mode of action and the long term metabolic effects that they may produce. In the treatment of mild hypertension for which diuretics are extensively used, it is important that drugs are used that have long term safety and minimal side effects. One way of ensuring this is to use the minimum amount of diuretic and this is an important

414

TREFOR MORGAN, SHANE CARNEY and JOHN MYERS

aspect of modern management. It has been realized that maximum diuretic effect is not required to achieve most of the antihypertensive effect. Diuretics reduce blood pressure predominantly by their effect on salt excretion and a significant blood pressure lowering effect can be obtained by reducing salt intake. Excessive salt depletion may not reduce blood pressure as the other side of the blood pressure arm may be extensively activated. Angiotensin may be produced and blood pressure remains high or even becomes elevated in normals. The use of angiotension inhibitors indicates that if both components are blocked then most hypertensive patients can be adequately controlled. It is possible that a combination of salt restriction (or diuretics) with inhibition of a reflex rise in renin angiotensin attacks the fundamental cause of hypertension in a more direct way than is achieved with most antihypertensive drugs. A wide variety of diuretics do exist and there appears little need for the development of newer and more potent diuretics. The aim is to develop diuretics that may have additional specific actions that prevent unwanted effects. The development of potassium sparing diuretics, and the development of uricosuric diuretics are examples of such development. Required still is a diuretic that causes water loss in excess of salt and a potent diuretic that does not cause abnormalities in carbohydrate metabolism. To treat mild hypertension a diuretic that reduces blood pressure and causes no metabolic upset is needed. Diuretics used in small doses and in combination, allow this ideal to be approached. Acknowledgements--A significant part of work reported herein was supported by the National Health and

Medical Research Council, the National Heart Foundation, the Life Insurance Medical Research Fund and the Department of Veteran's Affairs.

REFERENCES

t

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