Thiazide Diuretics

Examples: Bendroflumethiazide (bendrofluazide), chlortalidone(chlorthalidone), cyclopenthiazide, indapamide, metolazone, xipamide.

Thiazides inhibit the sodium/chloride co-transport mechanism in the distal convoluted tubule of the kidney.

See individual drug monographs for full list.

• Hypertension - Low dose bendroflumethiazide (2.5 mg) is widely used as a first-line treatment for hypertension.^3,4 Higher doses are not more effective at lowering blood pressure (BP) and increase the risk of biochemical derangement. Indapamide is claimed to lower blood pressure with less provocation of diabetes mellitus.
  

  NICE Guidance4 is that thiazide diuretics and calcium channel blockers (CCBs) should be considered equal first-line choices for the treatment of hypertension for: Black patients (taken to mean those of Afro-Caribbean descent, not mixed race, Asian or Chinese) Patients aged 55 years or over The choice should be made by the clinician and patient based on: Risk of adverse effects Patient preference Cost

• Stroke prevention - PROGRESS⁵ looked at the use of perindopril and indapamide to prevent recurrent stroke in those with previous stroke or TIA in both normotensive and hypertensive patients. Therapy with both agents significantly reduced risk of further stroke (by 43%) with no significant reduction with the use of a single agent. This has been used to argue for the routine use of an ACEI and thiazide for secondary prevention in all patients irrespective of BP.
• Heart failure - where renal function is preserved, thiazides may be adequate to treat mild heart failure symptomatically but in general loop diuretics are preferred.
  • Chlortalidone has a longer duration of action compared to other thiazides and can be given on alternate days to control oedema and is useful where there is a risk of acute urinary retention through too rapid diuresis or where patients cannot tolerate faster acting diuretics.
  • In severe heart failure, they are often combined with loop diuretics to overcome oedema refractory to loop diuretics alone. Metolazone is particularly effective. Careful monitoring is required.⁶
• Treatment of calcium lithiasis - thiazides promote renal reabsorption of calcium, decreasing urinary calcium oxalate and calcium phosphate super-saturation, and this can be used to prevent recurrence of some types of renal stone.^7,8
• Osteoporosis - by reducing urinary excretion of calcium, thiazides may have a role to play in preventing the development of osteoporosis. Treatment with hydrochlorothiazide in post-menopausal women produces benefit to cortical bone density, sustained over at least the first four years of treatment.⁹ These effects are small, so this is unlikely to be useful monotherapy for the treatment of osteoporosis, but given many in this age-range also require treatment for hypertension, it may have a contribution to prevention.¹⁰
• Diabetes insipidus (DI) - thiazides are sometimes used in the treatment of DI where they paradoxically produce an anti-diuretic effect.
  The precise mechanism behind this is unknown.¹¹

See individual drug monographs for full list.

• Refractory electrolyte disturbances (hypokalaemia, hyponatraemia, hypercalcaemia)
• Severe renal and hepatic impairment
• Symptomatic hyperuricaemia
• Addisons disease

See individual drug monographs for full list.

• Pre-existing hyponatraemia and hypokalaemia or situations where the development of such electrolyte imbalances could be significant (be particularly alert in higher doses and with renal impairment)
• Diabetes, previous gout and hyperlipidaemia
• Porphyria
• SLE
• Pregnancy
• Breast-feeding

See individual drug monographs for full list.

• Electrolyte disturbances
  

  Depletions Hypokalaemia Hyponatraemia Hypovolaemia Hypocholoraemia causing metabolic alkalosis Hypomagnesaemia Retentions Hyperuricaemia Hypercalcaemia

• Metabolic disturbances: hyperglycaemia (due to increased insulin resistance) and hyperlipidaemia
• Hypersensitivity reactions - rash (usually mild), purpura, anaphylaxis
• Impotence (reversible on stopping treatment)
• Thrombocytopenia and neutropenia
• Pancreatitis (though no association has been found in some studies and the risk appears less than with other antihypertensive classes, for example, ACEIs and CCBs¹²)

Hyponatraemia

This occurs not uncommonly, usually in the first 4 weeks of treatment. Most at risk are elderly, thin women in the summer months who present with severe, symptomatic hyponatraemia (usually in the range 110-116 mmol/l), sometimes comatose. Unless recognised, it can be fatal. Treatment involves stopping the diuretic and correcting the hyponatraemia. Re-exposure is likely to produce similar consequences.¹³ In a UK primary-care based study, 20.6% of patients receiving a thiazide prescription were hyponatraemic and 8.5% hypokalaemic.¹⁴

Postural hypotension

Hypovolaemia causes consequent postural or orthostatic hypotension, which can be a risk factor for falling in the elderly. It has a high prevalence (65%) among US veterans, aged over 75 years, attending out patient clinic who are receiving hydrochlorothiazide,¹⁵ although thiazide use in another study did not increase women's risk of falling or experiencing non-spinal fractures.¹⁶

Gout¹⁷

Thiazides double the risk of being put on anti-gout therapy, effecting about 1% of those on such treatment. Higher doses are associated with increased risk.

Diabetes¹⁸

In ALLHAT,¹⁹ a diuretic (chlortalidone) had similar efficacy to a calcium channel blocker (amlodipine) and a ACEI (lisinopril) in reducing the risk of major CV events but was associated with the more frequent development of diabetes mellitus (DM). The ASCOT study^20,21 revealed a 34% relative risk reduction for the development of DM with the use of amlodipine+/-perinodopril combination compared to atenolol+/-thiazide. NICE guidance has subsequently advised the avoidance of diuretic/beta-blocker combinations because of the increased risk of DM.⁴

It has been argued that the diabetic state induced by thiazides appears to be more benign, possibly with the raised fasting glucose produced by alternative mechanisms compared to naturally occurring DM, and thus should not deter us from their first-line use, given the positive overall risk-benefit ratio and their cheap cost. Many feel uncomfortable given the short time of follow-up (although findings from the 14 year follow-up of the SHEP study were in keeping²²) and lack of prospective data.

Erectile dysfunction

Hypertension and erectile dysfunction (ED) are closely associated. The incidence of ED amongst hypertensive men is very common - more than 60% were thought to suffer some degree of ED in a recent American study.²³ Antihypertensives can also contribute to ED, particularly thiazides and beta-blockers,²⁴ so alternatives may be tried where this is already a problem. However, use of thiazides does not alter the efficacy of a phosphodiesterase inhibitor such as tadalafil,²⁵ nor does it offer potential risk in combination as with alpha-blockers.

See individual drug monographs for full list.

• NSAIDs interfere with the anti-hypertensive action of thiazides and increase the risk of nephrotoxicity.
• Prior treatment with diuretics increases the risk of first-dose hypotension when commencing ACEIs. Suspend the diuretic for 2 days prior to starting ACEI and give the first dose in bed prior to sleep if possible.
• Lithium excretion is reduced by thiazides, causing potentially toxic levels. Consider reducing dose of lithium and monitor serum lithium concentrations over introduction of thiazides. Loop diuretics are safer with lithium.
• Corticosteroids and theophyllines increase the risk of hypokalaemia.

• Check electrolytes prior to starting treatment and correct any pre-existing hypokalaemia.^1,2,6,26
• Check BP and fluid status - avoid diuresis where evidence of hypovolaemia.
• Check blood glucose and lipids - pre-existing glucose intolerance or hyperlipidaemia may be worsened by thiazides.

• Low dose thiazides (such as used to treat hypertension) do not usually cause major electrolyte disturbance. However, BP and electrolytes should be checked within 4-6 weeks of commencing therapy.²⁶ If BP is not adequately controlled by a low dose of thiazide, an additional anti-hypertensive agent should be considered rather than increasing the dose. If BP is stable and electrolytes are normal, annual monitoring (BP, U&Es, lipids and fasting blood sugar) should suffice unless the patient's clinical condition changes or interacting drugs are added.²⁶
• Compliance - many patients find that diuresis interferes with their daily activity. Discuss with the patient to find the most convenient time to take their diuretic (not necessarily first thing in the morning). Also antihypertensive drugs that have a once-daily regimen are more likely to be taken than others needing more frequent dosing.²⁷
• Thiazides have a high rate of patient-initiated discontinuation due to side-effects, median time to discontinuation is 1.5 years and it is important to be alert to the possibility of discontinuation since many patients do not seek medical advice to switch to an alternative class and consequently suffer untreated hypertension.

• Explain indication for use of diuretic (or “water tablet”).
• Explain frequency of initial monitoring and how blood tests/reviews will be arranged and followed-up.
• Diuretics usually make people need to pass urine more frequently. Please tell the doctor/nurse if you experience difficulty getting to the toilet in time or if your sleep or day-time activities are being upset.
• Side-effects such as impotence should be mentioned since patients may not volunteer these themselves.
• Advise that some OTC medications such as NSAIDs may interact with their diuretic and patients should check with pharmacists/their doctor before taking additional medicines.