Thiazide Diuretics No Longer First Line Antihypertensive Agents? A number of side effects may enhance atherosclerosis

With the increasing use of thiazide diuretics, metabolic and other complications have been increasingly recognised. In addition, a number of prospective studies have highlighted the potential of thiazide drugs for causing adverse effects. For example, a 1980 study revealed that elderly hypertensive men on diuretics had a higher mortality rate from myocardial infarction and sudden death than those on no treatment or other regimens.

Hypovolaemia is an occasional side effect in elderly patients whose renal function is normal. Resulting orthostatic hypotension may aggravate coronary artery disease. Intermittant day use or gradual introduction of the diuretic usually avoids this problem. Hyponatraemia is quite commonly encountered with thiazide therapy but even moderate degrees are relatively well tolerated, except among some predisposed elderly patients. A dosage reduction or water restriction is appropriate for hyponatraemia and other electrolyte disturbances should be corrected since these may exacerbate the problem.Hypokalaemia is common with thiazide therapy. More than 50% of patients develop serum potassium levels of < 3.5 mmoljL and 17% have levels that drop below 3 mmoljL.

The clinical significance of low serum potassium levels is the subject of controversy. Serum levels of potassium may be misleading since diuretic-induced metabolic alkalosis causes redistribution of potassium from extracellular to intracellular stores and in most the true potassium loss is < 200 mmol. The decision as to whether to treat hypokaleamia depends on the individual; most patients with mild hypertension taking thiazide diuretics, whose serum potassium levels are> 3 mmoljL, do not require therapy. However, patients susceptible to potassium loss should have serum levels maintained in the normal range (eg patients with oedema, those on corticosteroids or digitalis, patients with ECG evidence of heart disease).

Magnesium loss occurs with long term thiazide use but the clinical significance of hypomagnesaemia is unclear. However, several studies have indicated that magnesium may determine cardiac consequences of diuretic induced electrolyte depletion, possibly through its influence on potassium metabolism. Thus, it appears important to maintain adequate magnesium levels by using supplements or potassium sparing diuretics. Another reason for maintaining normal electrolyte values is that hypokalaemia and hypomagnesaemia increase blood pressure possibly by vasoconstriction. This is obviously undesirable in hypertensive patients.

Thiazide diuretics also enhance calcium reabsorption which may be hazardous in those predisposed to hypercalcaemia. Similarly, they increase reabsorption which is usually symptomatic but gout does occur in 10-20% of predisposed men. Thiazide agents may also promote diabetes mellitus in those with borderline blood sugar levels. Glucose intolerance can be prevented by maintaining normal body potaSSium levels. Triglyceride and cholesterol levels are adversely affected by thiazide diuretics; respective mean rises are 15 and 7%. The long term effects of these changes on coronary morbidity are not known.

Other miscellaneous side effects of thiazides include interstitial nephritis, purpura, dermatitis with photosensitivity, necrotizing vasculitis. hepatitis, pancreatitis and cholecystitis.

It is possible that the inability to demonstrate a reduction in coronary heart disease in trials of mild hypertension relates to side effects of thiazide therapy. including hyperlipidaemia, hyperglycaemia and hyperurinaemia. Equally. hypokalaemia. alkalosis and magnesium depletion may be contributing to sudden cardiac death in thiazide users. It may be that this array of adverse effects will ' .. • Iead to the displacement of thiazide drugs as pre-eminent first-line agents for the treatment of mild or moderate hypertension'. F,eld MJ LaMence JR Med,cal Journal of AustralIa 144 641·644 9 Jun 1986

2 INPHARMA® 26 July 1986 0156-2703/86/0726-0002/0$01.00/0 IS> ADIS Press