the use of diuretics in modern antihypertensive therapy

79

From the Department of h4edicine 1, Salllgenska Hospital, University o f Gothenburg, S 4 1 3 45 Gothenburg, Sweden.

The use of diuretics in modern antihypertensive therapy

Ove Andersson

4 hstract 1 review is made to sum up the indications when

kriuretics may be the drug of choice in the treat- uicnt of hypertenTion. Advantages f rom the COITI-

1-incd treatment of thiazide diuretics and other .intihypcrtensive agents are also emphajized. Ad- "rse effects from diuretic t r ea tmen t , i. i'. hypoks- lt,mia. liyperuricemia, irnpaircd glucose tolerance a n d ri\ks associated \vith unfavourable serum lipoprotein patterns are discussed. It is concluded t?iat

from a heinodynarnic point of view thiazide diuretics can he it good therapeutic alternative for most patients, excepting those with hyperkinetic circulation. I t 15 rccommended to use lower doses of t hhz idc diuretics than previously and the monitoring of S-pota\siuni 15 necessary in all patients.

Kcdv war</.\: Hypertension. thiaxide diuretics, potas- ~ i u r n . ur-ic acicl. sertim l ipidv g!uccise to1er;tnce.

-1 tie hypotensive effect of thiazide diuretics and diuretic compounds is well known and this group of cardiovascular agents has constituted a i&)rnerstone in the treatment of hypertension t o r decades. Today. the diuretic agents have I I I S I their dominating role in the trealnient ot' 1i.ipertension and the thiazide diuretics 1iavc hcen substituted for B-adrenc,ceptorblocking ;Inrnts as the first drug of' choice to an litcreasing extent in unconiplicated as.wel1 as in rilore severe cases of Iiypertenzion (Andersson ti al. 1978). The reason f o r the gradual change u:' firsthand choice of drugs is probably the risk o!' developing metabolic side effects with diuretics rather than ;I superior hypotensive p t enc y wit 11 P-adrcnocc ptorhloc king drugs . T l i e considerable dose ireduction, Iiowevet. h.is probably changed the frequency a h well as tlie severity of side effects during t1ier;ipy with tl11a7ide diuretics. Furthermore. consideration o! effect and tolerance ofien necessitates d r u g i.IiAiiges during the course o f the therapy towards increasing individualization. With in$:reasing severity of the disease and increasing ;ige of the patients, more patients are treated w!th combinations of two or three drugs. ( 8 mequently, the dilemma regardir?g firsthand

drug when initiating therapy will be of less importance. since among middle-aged patients the m;ijority are treated both with thiazide diuretics a n d 0-adrenoceptorblocking drugs (Samuelsson e t al. 1982).

The aitn or the present review is to sum up the indications when diuretics may be the drug of choice in (lie treatment of hypertension, but advantages froin the combined treatment with diuretics arid other antihypertensive agents will be emphasized

WHAT DIURETIC DRUG TO CHOOSE?

,\mong thiazide diuretics" there are more than ten differen1 compounds. Tile maximal natriuretic potency for each compound is considered comparable (Goth 1966). Long-term clinical studies to compare antihypertensive potency when using doses equipotent with regard to the natriuretic effect for different thiazides are lacking. There is n o empirical or scientific proof. however, that one compound used in optirnal dosage is superior to any other with regard to hypotensive effect. Minor differences becween the thiazide diuretics are

* In the following including chlorthalidone. ___

80

due to pharmacokinetics and effect duration (Goth 1966). The gcneral recommendation today is to use thiazide diuretics with relatively short natriuretic duration, since t h e duration of the Iiypotensive effect is sufficient to advocate ;I cone dose per day regimen and the urinary potassium loss would be minimized.

DIURETICS AS THE FIRSTHAND DRUG OF CHOICE

Primary hypertension From ;I heniodynamic point of view the dominating pathophysiological aberration in sustained essential hypertension is a n increased hlood flow resistance (Lmd-Johansen 1980). The increase i n peripheral resistance is probably caused by hypertrophy of tlie vascular wall of the arteriole (Sivertsson 1970), but i n the early phase of the development of sustaineu hypertension increased vasoconstrictor tone or increased sensitivity of the v muscle has also been suggested (Rlausteiri 1977). Hypersensitivity in the vascular smooth muscle response to the same vasoconstrictor stimulation niight be secondary to a deranged content of sodium and hence calcium i n the arteriolar srnooth niusculature, but cdenias (water-logging) may also cause increased peripheral resistance and increased blood pressure reactivity in hypertensive patients (Blaustein 1977. Tobian & Uinion 1957).

The hem ody namic adapt ;it ion to chronic treatnient with diuretics is vcry suitable. when considering thc increased peripheral resistance in essential hypertension. The treatment wilh tliiazide diurctics does not reduce cardiac out- p u ~ ant1 liericc the blood pressure reduction is secondary lo ii normalization of the peripheral resistance ( Lund-Johansen 1970). Since the

abnormalities are the most common ( Berglund et al. 1976). In general, the treatment of renaj hypertension is not different from the treat. inent of primary forms. especially if the renal excretory function is well preserved. Howevcr, renal hypertension may have certain pathogenetic characteristics depending on whether ;I

renop2renchynial o r a reiiov hand. In hypertension secondary to renoparen- chymal disease there is often fluid retention and treatment with a diuretic drug is necessary. When renal excretory function is reduced the tliiazide diuretics should be substituted for loop diuretics. I n renovascular hypertension tht: renin secretion is often the dominating pathogenetic factor and the treatment sliould be ad- justed to that fact. Consequently. when the therapy is aimed at reducing renin secretion, r - adrenoceptorblocking drugs is the basic choice o f drug. A completely new group of compounds is introduced for the treatment of renovascular hypertension. The property of these drugs of converting enzyme inhibitors in order to selectively inhibit the formation of' angiotensin 11 and hence counteract the mechanism of action for renin-dependent hypertension makes them very suitable and effective i n the treatment of such forms of hypertension. However. thiazide diuretics also have a place in this con- text. The antihypertensive effect of captopril is clearly potentiated by adding a thiazide diuretic in the combined t reatment of renovascular hypertension (Atkinson e t al. 1980).

In eases of primary or secondary hyperaldo- stermism we use spironolactone as tlie sole agent or in combinations with other hypoten- sivc drugs. In patients with primary hypertension spironolactone will replace the tlliazicle diuretics when complications such ;IS type I I d i a he te s o r 11 y pe ru rice m ia occur .

group of patients in the WHO stage 2 3 is by far the most coninion. thiazide diuretics is a logical choice as the firsthand drug in most cases of hypertension. Thicrzides and Padreno cep t orb lo cking

drugs Secondary hypertension Experience indicates a potentiating effect of Among secondary forms of hypertension renal adding thiazide diuretics to 0-adrenoceptor-

THlAZIDE DIURETICS IN HYPO- TENSIVE COMBTNATlON THERAPY

81

blockers. The efficacy and tolerability of such a combined regimen is evident and thiazide diuretics together with P-adrenoceptorblocking drugs are widely used. Half the dosage of these two compounds in combination therapy provides ;I superior hypotensive effect compared with the nornial dose of each drug in single therapy (Angervall & Bystedt 1974).

The urinary potassiuni loss when using ii

thiazide diuretic will a t least in part be cornpen- sated by the weak potassium saving effect observed in patients treated with P-adrenoceptorblockers (Berglund & Andersson 1981). I n both groups of compounds, drugs can be chosen with suitable pharrnacokinetic to assure blood pressure control for 24 hours with only one dose intake per day.

Thiazides and drugs affecting adrenergic frtnction Old antihypertensive drugs such as bethanidine and guanethidine are rarely used today in Scandinavia. These drugs cause decreased sympathetic activity in the peripheral nerve endings and are considered as potent adrenergic blocking agents. Bethanidine and guanethidine should not be used as single drugs. In combined therapy with diuretics the dosage and hence the side effects can he reduced (Maroude e t al. 1 % 1 , Blanshard & Essigman 1961. Moser 1969). Furthermore, the liypotensive effect is increased for both agents since fluid retention is prevented (Blanshard & Essigman 196 1 ).

Centrally acting adrenergic inhibitors such as inethyldopa and clonidine are still widely used. t%oth compounds are step two drugs in the treatment of hypertension. However. patients rcceiving methyldopa alone may develop problems with fluid retention, weight gain and edemas (Smith et al. 1960, Uayliss Sr Harvey- Sinith 1963). Tolerance or actually pseudoto- lerance frequently develops after several weeks of methyldopa due to an expanded plasma volume (Johansson & Kitchin 1966, Dollery & llarrington 1962). To regain good blood pressure control or prevent fluid retention problems, methyldopa shou!d be used i n combination with a diuretic drug, preferable a

thiazide diuretic (Smith et al. 1966, Bayliss & Harvey-Smith 1962, Johansson & Kitchin 1966). Colwill and co-workers found that treatment with methyldopa and hydrochlorothiazide individually produced normotension in 26 %: and 37 %I of the patients respectively (Colwill e t al. 1964). When the drugs were combined, the blood pressure in 60 9, of the patients was under good control.

Clonidine is considered when thiazides given alone fail to produce the desired blood pressure reduction (Joint International Commit tee on Detection, Evaluation and Treatment of High Blood Pressure 1977). When a thiazide diuretic is given in conjunction with clonidine, not only is a smaller dose of clonidine required but the effect is synergistic and the side effects are generally fewer with the combination (Yeh et al. 1971, Mroczek et al. 1972).

Thiazides and vasodilating drugs Among vasodilating drugs hydraluine is the oldest one and the drug was initially associated with numerous side effects and discomforts, probably because of the large oral doses necessary to induce blood pressure control. Today, hydralazine is regaining therapeutic use as part of the "standard triple" combination. When given together with a 0-adrenoceptorblocking agent and ;I thiazide diuretic, hydralazine shows good patient tolerability. The doses used should rarely exceed 200 mg/day. In a population- based series of patients followed for five years the frequency of such a triple combination was used i n 38 2 of the cases (Andersson et al. 1978). When given without diuretics, hydralazine may produce sodium retention (Finnerty 1971) and another study points to the fact that the combination of 0-adrenoceptorblockers and hydralazine will gain further effectiveness when adding a thiazide diuretic (Veterans Administra- tion Multi-Clinic Cooperative Study Group on Antihypertensive Agents 1977).

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THIAZIDE DIURETICS OR

Hypotenshie potency and effecl duration There is good agreement about the opinion that thiazide diuretics and 0-adrenoccptorblockers are comparable with regard to their hypotensive effect. When subgrouping the patients it is obvious that the thiazidcs cxert a superior effect in paticnts with expanded fluid volume and suppressed renin activity (Vaughan et al. 1973). Such patients are often characterized clinically by a tendency to develop edemas and show reduced cardiac left ventricular pcr- formarice.

p-adrenoceplorblockiiig drugs are most effective in patients with increascd sympathetic nervous system activity (Bulder et al. 1975). In a patient series of more than a hundred patients randomized to citlier propranolol or bendro- flumethiazide there was equally good blood pressure control in both groups during the six-year follow-u? (Rerglund Sr Andersson I98 1 ). The relatively cardioselective P-adrenoceptorblockers and /3-adrcnoceptorblockers with intrinsic syrnpathicomirnetic activity d o not show a hypotensive effect superior to the old ones. The effect duration with regard t o blood pressure control for thiazides as well as for /3-adrenoceptorblockng drugs is long enough to permit once daily dose regimens.

/3-ADRENERGIC BLOCKERS?

Potassium Due to a mild secondary aldosteronism a reduction of S-potassium will be induced with the use of thiazide diuretics (Morgan & Davidson 1980). The potassium loss is dose-dependent in relation to the natriuresis and the use of long-acting thiazide diuretics increases tlic risk of hypokaleniia. Different authors report a varying decrease in serum potassium and some have found the incidence of hypokalemia (K’ i 3.5 nimol/l) to be close to SO ‘1) (Louis & Doyle 1973, Kochar & ltskov 1973). The frequency of hypokalemia varies depending on the patients selected, the daily thiazide dose. the compound chosen and probably also on the

duration of the treatment. Good ~IiniciiI control implies repeated control on S-potassium and supplementation wlien hypokalernia is present. Special careful monitoring of potassium is advocated in aatients on digitalis and in patients with ischemic heart diseases. Supple- mentation is most effective using potassium- sparing drugs such as amilorid or spironolactone, but various potassium salts may be used in mild cases. A normal content of S-tnagnc- siuni has recently been recognized as important to normalize intracellular potassium (Wester Sr Dyckner 1981).

If a discrete reduction of cxtraccllular potas- s i w i probably is not harmful to the average hypertensive patient, the question is whcthcr the deficit will cause intracellular electrolyte imbalance. Total body loss of potassium is expressed as the change in endogenous 40 K nieasurcd in a whole body counter. Several studies on potassium balance in hypertensive patients using the common diuretic compounds indicate clearly that in t r acellular pot assiu rn (total body potassium) is normal (Healy et al. 1970, Andersson et al. 197 I , Edriionds 81 Jasini 1972, Wilkinson et ai. 1975). In a recent long-term study we found normal and un- changed total body potassium contents after six years of treatment with bendroflumethiazitle (Bcrglund & Andersson 1981 ). Obviousl,y, otherwise healthy patients with normal dietary habits obtain sufficient potassium from their diet and do not require potassium-sparing drugs.

Patients with more severe hypertensive cardiovascular diseases generally develop secondary hyperaldosteronism with hypokalemia. These patients often need large doses of oral potassium or potassium-saving drugs. Such patients should be extra carcfully monito- red with regard to potassium since they often will be in need of digitalis glycosides and often have arrhythmias. Malignant arrhythmias in association with acute myocardial infarction might be a possible cause of sudden death in these high risk patients.

+

83

metabolism is not affected to the same extent. Some studies, however, show equal influence on serum lipoprotein fractions irrespective of whether a cardioselective or a conventional p- adrenoceptorblocker is used (Shaw e t al. 1978, Day et al. 1979).

An increase in serum triglycerides from 25 62 54 when treating patients with 0-adrenoceptorblockers Is reported (Day et al. 1979, Waal-Manning & Simpson 1977). Those studies, however, were of short duration and long-term treatment may show a normalization of lipoprotein metabolism (Berglund & Andersson 1981). The long-term treatment with small to medium-large doses of hydrochlorothiazide did not affect lipoproteins negatively in the Oslo study (Helgeland e t al. 1978).

iJric acid I typeruricemia may occur spontaneously in I~ypei-tensive patients who arc generally over- weight and may also show impaired renal function. Treatment with thiazide diuretics will generally increase S-urate since the thiazides competitively inhibits the tubular secretion of iirate (Bryant et al. 1967). The hyperuricemia r,irely precipitates acute gouty arthritis tzquiring therapy. Hyperuricemia repeatedly ;Ihove 500 pmol/l calls for a reduction or wiLhdrawa1 of the diuretic dose and only during Lery specific circumstances is allopurinol used to prevent side effects from diuretic drug treat- nierr t .

P-adrenoceptorblocking drugs also induce an iitcrease in S-urate but the reason is not known. Certain studies indicate that the urate increase i\ only temporary, while other long-term studies show a lasting increment of urate following treatment with propranolol ( Bengts- s(in 1074, Berglund & Andersson 1981). The Aiithor has found indications suggesting that the S-urate increases to a lesser extent following therapy with /3-adrenoceptorblockers compared with thiazide diuretics but systematic observa- t i m s are lacking. The development of gouty arthritis does not necessarily imply that the ;3-adrenoceptorbiocking drug., should be withdrawn. Known hyperuricemia is a relative zuunter-indication to the use o f thiazides but not p-adrenoceptorblockers.

Srrurn lipids llvpercholesterolemia and ;I relative increase in the LDL fraction of lipoproteins are obvious risk factors for ischemic heart disease (Gordon et al. 1977, Castelli et al. 1977, Lewis 1978). Since the hypertension treatment often will span over decades i t is alarming that thiazide diuretics as well as /3-adrenoceptorblockers seem to increase serum levels of cholesterol and triglycerides and reduce HDL lipoproteins (Ames & Hill 1976. Fries 1978. Bauer e t al. 1979, Helgeland et al. 1978). It is possible that the use of the cardioselective 0-adrenoceptorblockers constitutes an exception since lipid

Thiazidt. diuretics and impuired glucose tolerance Patients with arterial hypertension have impaired glucose tolerance cornpared with normo- tensive controls even when body weight and body fat is similar (Berglund et al. 1976). An increased incidence of adult diabetes is consequently to be expected among hypertensive patients and the incidence of diabetes should increase with age. Considering these facts the problems of connecting the development of glucosuria and impaired glucose tolerance with any specific antihypertensive therapy become obvious. Prospective studies comparing antihypertensive compounds with regard to diabetogenic activity are very few so far.

Despite the difficulties of linking adverse effects with drugs, extensive clinical evidence suggest a diabetogenic effect from thiazide diuretics. Hypokalemia, with the return of the glucose tolerance test t o normal as serum potassium rises, has been shown to be a mechanism by which thiazides induce abnormalities in the glucose metabolism (Sagild e t a l . 1961). The hypothesis that small doses of a thiazide diuretic with medium-long acting natriuretic effect would provide safe blood pressure control, modest if any hypokaleinia, and an acceptably low incidence of adult diabetes initiated the follow-

84

ing prospective study (Berglund & Anderson 1981). Just over one hundred men with untreated mild hypertension were randomly allocated to treatment with bendroflumethia- zide 2.5-5 nig once daily or propranolol 80-160 mg daily. The groups were comparable with regard to initial blood pressure, age and body weight. The blood pressure control was equally good in the groups and only very modest hypokalemia in thiazide-treated patients but no change in total body potassium was observed in the groups. During six years of treatment only

family history of diabetes, body weight and severity of cardiovascular disease probably account for the diverging results. Thus, in our group we recommend that thiazide diuretics bz avoided in patients with diabetes rncllitus and borderline glucose tolerance tests. In patients with a family history of frequent diabetes mclli- tus we generally check for glucosc tolerance before the diuretic treatment is started.

PREVENTION OF HYPERTENSIVE COMPLICATIONS

one case of diabetes in each treatment group has been detected and the glucose tolerance was not reduced in the two groups. No further cases o f adult diabetes has developed and the patients are now being followed for ten years.

In another study, obviously not prospective, focusing on thiazide-induced diabetes niellitus, glucose tolerance was tested before and after six years of therapy with thiazide diuretics or chlorthalidone (Lewis e t al. 1976). The glucose tolerance was impaired in patients on diuretic therapy compared with controls who unfortu- nately were part of the group initially started on thiazides I,,, had discontinued therapy for some reason. Furthermore, the control group was only a minority of the total group and if these patients had less severe hypertension they could obviously bias tlie comparison with regard t o glucose tolerance as well. The patients in the latter study were given larger doses of diuretics compared with those in the first one.

antihypertensive therapy in patients over the age of 65 at the start of the therapy is under way (Aniery et al. 1978). Initial results indicate impaired glucose tolerance correlated to the degree of hypokalemia in these patients. Apart from being older then the patients in the first study, these patients were also given larger doses of thiazidc diuretics.

It is quite possible that older patients with reduced dietary potassium intake are more susceptible to thiazidc treatment with regard lo glucose tolerance. Other differences in the composition of the patient groups, such as

Several well controlled studies clearly show reduced mortality and morbidity in diseases causally related t o hypertension, i.e. stroke, cardiac decompensation and renal insufficiency (Veterans Administration Cooperative Study on Antihypertensive Agents 1970, Hypertension Detection and Follow-up Program Cooperative Group 1979, Management Committee of the Australian Hypertension Trial 1981). Only in tlie diastolic blood pressure range between 90-95 m m Hg is the proof of benefit from pharmacological treatment inconclusive and contradictory (Management Committee of the Australian Hypertension Trial 1981, Kaplan 1982, Fries 1982). I n all intervention trials without exception the basic and firsthand treatment has been diuretic drugs. In one respect, however, the hypotensive intervention has not yielded a reduced number of end points. Myocardial infarction is as frequent in the treatment groups as in placebo-treated patients (Veterans Administration Cooperative

reason for this effect is debated, the suggestion has been made that hypotensive drugs, unfavourable for the prevention of coronary heart disease, have been used.

Secondary prevention of ischemic heart disease using different /3-adrenoceptorblocking drugs is repeatedly shown (Wilhelmsson et al. 1974. The Norwegian Multicenter Study Group 1981. Betablocker Heart Attack Study Group 1981). Acute injections of nietoprolol shortly after the ischemic pain in the development of a myocardial infarction will reduce total mortali-

Another study O n the effects Of Study on Antillypertensive Agents 1970). The

85

ty, reduce infarction size and prevent malignant arrhythmias during the course of the disease and during the recovery period (Hjalmarsson et a l . 198 I ) . The beneficial effect of 0-adrenoceptorblocking therapy during and after myocardial infarction is indisputable. However, 110

evidence exists to prove that the P-adrenoceptorblockers possess primary preventive properties superior to those demonstrated with thiazide diuretics. However. since the de- monstration of secondary prevention of sudden death and reinfarction is so convincing, it is lempting today to use fl-adrenoceptorblockers &is the sole therapy or part of the combined lherapy in patients considered at high risk of ileveloping myocardial infarct' Lions.

First choice - thiazidr diuretics or $adrenoceptorblockers? From a hemodynamic point of view thiazide Jiuretics are well suited as the firsthand drug of choice in antihypertensive therapy of all patients excepting those with hyperkinetic circulation, It is widely recommended to avoid diuretics in patients with diabetes mellitus, gouty arthritis and severe hyperuricemia. Furthermore ~ thiazide diuretics are effective as potentiating agents in almost all hypotensive drug combinations. The modern concept of using lower doses of thiaride diuretics produce t'ew and probably milder side effects and tu start a blood pressure lowering therapy with iiiese agents is generally good advice. Monitor- ing of S-potassium is necessary in all patients and supplementation of potassium is particular- ly important in patients treated with digitalis glucosides. Since P-adrenoceptorblocking drugs have a proven beneficial effect on infarction size, arrhythmias and mortality in acute ischemic disease, these agents should be part of tile therapy in patients running a great risk of' developing such a disease.

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