Thiazide diuretics + Calcium and/or Vitamin D - Drug Interactions

Hypercalcaemia and possibly metabolic alkalosis can develop inpatients who are given high doses of vitamin D and/or largeamounts of calcium if they are also given diuretics such as thiazides, which can reduce urinary excretion of calcium.One case of hypercalcaemia has been reported in a patient usinga high-strength topical tacalcitol with a thiazide diuretic.

An elderly woman taking hydrochlorothiazide 25mg and triamterene 50mg daily became confused,disorientated and dehydrated 6 months after starting to take vitamin D2 50 000 units and calcium 1.5 g daily (as calcium carbonate) for osteoporosis. Her serum calcium level had risen to about 3.5 mmol/L (normal range about 2 to 2.6 mmol/L) (See reference number 1).

A 47-year-old man was admitted to hospital complaining of dizziness and general weakness,which had begun 2 months previously. He was taking chlorothiazide 500mg daily for hypertension,thyroid 120mg daily for hypothyroidism and calcium carbonate 7.5 to 10 g daily for heartburn. On examination he was found to have metabolic alkalosis with respiratory compensation,a total serum calcium concentration of 3.4 mmol/L (range given as 2.15 to 2.6 mmol/L) and an abnormal ECG. He was diagnosed as having milk-alkali syndrome. Recovery was rapid when thiazide and calcium carbonate were withdrawn and a sodium chloride infusion, furosemide and oral phosphates were given (See reference number 3).

In both cases thiazide diuretic was thought to be implicated as levels of calcium ingestion were in region of normally recommended doses

In a group of 12 patients treated for hypoparathyroidism with vitamin D (dihydrotachysterol or ergocalciferol),5 patients became hypercalcaemic when they took bendroflumethiazide or methyclothiazide (See reference number 5). A significant rise in plasma calcium levels occurred in 7 patients given vitamin D and methyclothiazide or chlorothiazide,and hypercalcaemia developed in 3 of them (See reference number 6). A study in 12 children taking calcitriol (31 nanograms/kg daily) found that addition of hydrochlorothiazide (1 to 2 micrograms/kg daily) reduced urinary excretion of calcium caused by calcitriol (See reference number 7). Another study in 7 patients with vitamin D-induced calciuria found that addition of hydrochlorothiazide and amiloride reduced urinary excretion of calcium due to calcitriol to a greater extent than hydrochlorothiazide alone. Moreover, addition of amiloride helped to prevent adverse effects associated with use of hydrochlorothiazide, such as hypokalaemia and alkalosis (See reference number 8).

55 mmol/L 28 days after starting tacalcitol ointment and it fell back to within normal range within 7 days of stopping ointment (See reference number 9)

The thiazide diuretics (and triamterene) can cause calcium retention by reducing its urinary excretion. This, added to increased intake of calcium, resulted in excessive calcium levels. Alkalosis (the milk-alkali syndrome, associated with hypercalcaemia, alkalosis, and renal impairment) may also occur in some individuals because thiazide limits excretion of bicarbonate.

The incidence is unknown but reports cited(See reference number 5,6) suggest that it can be considerable if intake of vitamin D and calcium are high. Concurrent use need not be avoided; thiazides have been used clinically to reduce vitamin-D induced hypercalciuria,(See reference number 7,8) but serum calcium levels should be regularly monitored to ensure that they do not become excessive. Patients should be warned about ingestion of very large amounts of calcium carbonate (readily available without prescription) if they are taking thiazide diuretics

The case of hypercalcaemia with use of a topical vitamin D analogue is rare and strength of preparation of tacalcitol used was fivefold higher than current licensed preparation of 4 micrograms/g (Curatoderm). However,bear this case in mind should a patient taking thiazides with a topical vitamin D analogue develop hypercalcaemia.

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