CV - Diuretics, thiazide and thiazide-like

Question 1

Diuretics, thiazide and thiazide-like: bendroflumethiazide, indapamide, chlortalidone

Clinical pharmacology

Common indications

Answer 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.
• 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).

Question 2

Mechanisms of action?

Answer 2

• 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.

Question 3

Important adverse effects?

Answer 3

• 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.

Question 4

Warnings?

Answer 4

• 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.

Question 5

Important interactions?

Answer 5

• 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.

Question 6

Practical prescribing

Prescription?

Answer 6

• Thiazides are taken orally as part of the patient’s regular medication. Indapamide (e.g. 2.5 mg daily) and chlortalidone (12.5–25 mg daily) are recommended for hypertension.
• Historically in UK practice, bendroflumethiazide 2.5 mg daily has been widely used, but this is less desirable as there are no supporting clinical trials to confirm its benefit.
• There is little to be gained from higher dose treatment, as this tends just to increase side effects without significantly improving the antihypertensive effect

Question 7

Clinical tip?

Answer 7

• One of the main adverse effects of thiazides is hypokalaemia, while one of the main adverse effects of ACE inhibitors and ARBs is hyperkalaemia.
• Moreover, these drug classes have a synergistic blood pressure lowering effect: thiazides tend to activate the renin–angiotensin system, while ACE inhibitors/ARBs block it.
• Consequently, the combination of a thiazide and an ACE inhibitor/ARB is very useful in practice, both to improve blood pressure control and to maintain neutral potassium balance.