Diuretics, thiazide and thiazide-like

Key examples

• Bendroflumethiazide
• Indapamide
• Chlorthalidone

 

Common indications

1. Thiazides are an alternative first-line treatment for hypertension where a calcium channel blocker would otherwise be used, but is either unsuitable (e.g. due to oedema) or there are features of heart failure.
2. Thiazides are also an add-on treatment for hypertension in patients whose blood pressure is not adequately controlled by a calcium channel blocker plus an ACE inhibitor or angiotensin receptor blocker (ARB).

 

Mechanisms of action

• Thiazide diuretics (e.g. bendroflumethiazide) and thiazide-like diuretics (e.g. indapamide, chlortalidone) differ chemically but have similar effects and uses; we refer to them collectively as ‘thiazides.’ Thiazides inhibit the Na+/Cl− co-transporter in the distal convoluted tubule of the nephron. This prevents reabsorption of sodium and its osmotically associated water. The resulting diuresis causes an initial fall in extracellular fluid volume. Over time, compensatory changes (e.g. activation of the renin–angiotensin system) tend to reverse this, at least in part. The long-term antihypertensive effect is probably mediated by vasodilatation, the mechanism of which is incompletely understood.

 

Important adverse effects

• Preventing sodium ion reabsorption from the nephron can cause hyponatraemia, although this is not usually problematic. The increased delivery of sodium to the distal tubule, where it can be exchanged for potassium, increases urinary potassium losses and may therefore cause hypokalaemia. This, in turn, may cause cardiac arrhythmias. Thiazides may increase plasma concentrations of glucose (which may unmask type 2 diabetes), LDL-cholesterol and triglycerides. 
• However, their net effect on cardiovascular risk is protective. They may cause impotence in men.

 

Warnings

• Thiazides should be avoided in patients with hypokalaemia and hyponatraemia. 
• As they reduce uric acid excretion, they may precipitate acute attacks in patients with gout.

 

Important interactions

• The effectiveness of thiazides may be reduced by non-steroidal anti-inflammatory drugs (although low-dose aspirin is not a concern). 
• The combination of thiazides with other drugs that lower the serum potassium concentration (e.g. loop diuretics) is best avoided. 
• If combination is essential, it should prompt intensive electrolyte monitoring.