Is there a place for thiazide diuretics in the management of hypertension?

Before the introduction of antihypertensive drugs in the 1940s, one of the few effective approaches to treating high blood pressure was severe restriction of dietary salt intake. Orally active diuretic drugs were a welcome alternative when they became available in the late 1950s. The first of these drugs were the thiazide and thiazide-like diuretics. They were effective and generally well tolerated and have remained in use ever since. Apart from the now uncommon situation of excessive drug-induced salt and water retention, thiazides are more effective and better tolerated as antihypertensives than the more potent loop diuretics.

As newer antihypertensive drugs have been introduced and heavily promoted for the treatment of hypertension, the continuing role of the thiazide diuretics has been questioned. This questioning is fuelled by a popular misconception that thiazides are not as potent as other antihypertensives, have unacceptable biochemical adverse effects and are associated with negative effects on cardiovascular risk factors such as increases in plasma cholesterol and impairment of glucose tolerance. The image of diuretics as antihypertensive drugs has not been helped by their lack of promotion by the pharmaceutical industry.

As monotherapy, diuretics are as efficacious as drugs from each of the other commonly used classes of antihypertensive drugs - alpha and beta blockers, ACE inhibitors, calcium channel antagonists and `centrally acting' drugs. Diuretics are probably more effective in older hypertensive patients, and therefore they have been used as first-line therapy in all except one of the major outcome studies of the treatment of hypertension in the elderly. In all of these studies, together with the earlier outcome studies in younger and middle-aged hypertensive patients, first-line therapy with diuretics has had beneficial outcomes. These are an approximately 40% reduction in the incidence of stroke and a 20% reduction in the incidence of coronary heart disease events. As diuretics have this established outcome benefit, they are being used as the comparator in a number of current studies including the Second Australian National Blood Pressure Study (ANBP2), to assess the outcomes of treatment with newer antihypertensives (ACE inhibitors, calcium channel antagonists, angiotensin II antagonists).

Evidence has accumulated that the commonly used doses of diuretics have been too large. The dose-response relationship for the antihypertensive effect of thiazide diuretics is quite flat and changes little across a range down to 25% or less of the originally recommended doses.¹ In contrast, the dose-response relationship for the biochemical effects of the diuretics across the same dose range is steeper. Lower doses of thiazides (see box) thus maintain their antihypertensive efficacy, but have a reduced tendency to cause biochemical adverse effects.

The effects of diuretics on plasma concentrations of electrolytes and urate have been well characterised. They are clearly dose-dependent and are minimised at the doses now currently recommended in the management of hypertension.^2,3 Adverse effects on glucose tolerance and plasma lipids are also minimal at the currently recommended doses. As there is a likelihood of enhancing any tendency to gout, it is best to avoid diuretics initially in patients known to suffer from gout. Despite the lower incidence of adverse biochemical effects with low doses of diuretics, the effect in any individual patient is unpredictable. It is therefore wise to check the relevant biochemistry depending on the patient's individual risk. At low doses potassium supplements are usually not necessary.

In the first Medical Research Council study⁴ of the treatment of mild hypertension, the incidence of adverse effects on male sexual function was significant. The dose of diuretic (bendrofluazide 10 mg daily) used in this study was much greater than the currently recommended doses. Later outcome studies using lower doses of diuretics have not confirmed any specific effect of diuretics on male sexual function.

To encourage the achievement of better outcomes, recently released guidelines for the management of hypertension^2,3 are now recommending lower targets for blood pressures e.g. <130/85 in young, middle-aged and diabetic patients and <140/90 in patients over 65 years of age. These recommendations have been made with greater confidence than previously, as reduction of blood pressure to the recommended targets was shown to be feasible and safe in a recently completed large international outcome trial (the HOT study).⁵

To attain such low target blood pressures in the HOT study more than 70% of the patients needed to use combination antihypertensive therapy.⁵ Diuretics are often a particularly effective component of such combination regimens. They have at least additive antihypertensive effects with drugs from each of the commonly used classes of antihypertensives except possibly the calcium channel antagonists in young and middle-aged patients. In contrast, the combination of diuretics and calcium channel antagonists may be the most effective in elderly hypertensive patients. Diuretics are also the cheapest therapy with the monthly cost under the Pharmaceutical Benefits Scheme being 10% or less of the cost of some of the newer antihypertensives.

Diuretics have an established place in the management of hypertension that has not been displaced by the successive introduction of newer classes of antihypertensives over the past 30 years. The recent WHO-ISH guidelines for the management of hypertension³ describe the diuretics as `one of the most valuable classes of antihypertensive drugs. They are inexpensive, effective, generally well tolerated in low doses ... and have clearly been shown to prevent major cardiovascular events ... in a variety of hypertensive patient groups'. Diuretics should be considered as first-line antihypertensive therapy in all hypertensive patients, particularly in the elderly, and as a component of any combination antihypertensive regimen.

Professor Wing has been involved with several pharmaceutical company-sponsored trials which included thiazide diuretics.