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Thiazide Diuretics

Chloride; Sodium

Thiazides increase urinary excretion of sodium and chloride. Patients should be observed for clinical signs of hyponatremia or hypochloremic alkalosis (Hines Burnham et al. 2000).

Significance of Depletion

Because of the wide availability of sodium in dietary sources, deficiency is uncommon (National Research Council 1989). Sodium deficiency is associated with nausea, headache, lethargy, confusion, stupor, seizures, and possibly coma (Singer and Brenner 1998; National Research Council 1989). Severe deficiency may increase the potential for harmful hormone and lipid effects, myocardial infarctions, cardiovascular mortality (Kaplan 2000). Development of symptoms depends in large part on the rate of the loss of sodium (Singer and Brenner 1998). Clinical problems with depletion are more common in elderly and debilitated patients.

Replacement Therapy

The US dietary guideline for sodium is 2.4 g/day, the equivalent of 6 g/day sodium chloride (Kaplan 2000). Since these are general recommendations for health maintenance, doses for replacement therapy should be adjusted on an individual basis, depending on the patient's age, gender, clinical presentation, serum levels, dietary habits, and medication regimen.

Coenzyme Q10

Thiazide diuretics inhibit CoQ10-NADH-oxidase in heart tissue; this enzyme is important for cardiac function (Kishi et al. 1975). More research is needed to determine if chronic thiazide treatment could lead to a CoQ10 deficiency. However, beta-adrenergic blockers also inhibit CoQ10-NADH-oxidase as well as CoQ10-succinoxidase. The potential for CoQ10 depletion is greater in patients managed on combination therapy consisting of both a beta-blocker and a thiazide diuretic.

Significance of Depletion

Although CoQ10 is manufactured by the body, deficiencies occur in some physiological and pathological conditions (Artuch et al. 1999). CoQ10 deficiency may be related to certain conditions such as gingivitis (Nakamura et al. 1974); breast cancer (Jolliet et al. 1998); congestive heart failure (Munkholm et al. 1999); angina pectoris (Kamikawa et al. 1985); acute myocardial infarction (Singh et al. 1998); mitochondrial encephalomyopathies (Chan et al. 1998); hypertension, and cardiac function (Singh et al. 1999). In addition, CoQ10 depletion may contribute to aging and photoaging (Hoppe et al. 1999). Low levels of CoQ10 may also compromise immune function (Folkers et al. 1993) and play a role in male infertility (Overvad et al. 1999).

Replacement Therapy

Daily doses of coenzyme Q10 as high as 200 mg for periods of 6 to 12 months or 100 mg for up to 6 years have not been associated with reports of serious adverse effects in clinical studies (Overvad et al. 1999). There are no known studies showing clinical benefits of CoQ10 replacement in the presence of thiazide diuretics specifically.

Magnesium; Potassium

Hypomagnesemia and hypokalemia occur in a high percentage of patients receiving thiazide monotherapy (Dyckner and Wester 1987). Hypokalemia reduces magnesium transport in the distal tubule, increasing urinary magnesium excretion (Dai et al. 1997). Other clinical studies have demonstrated that hydrochlorothiazide also decreases concentrations of magnesium and potassium in mononuclear cells (Abraham et al. 1991).

When HCTZ is combined with triamterene, a potassium-sparing diuretic, there is a reduction in potassium and hydrogen loss (PDR 1998). However, triamterene does not compensate entirely for the kaliuretic effect of HCTZ; some patients may remain hypokalemic while taking this combination therapy. Hyperkalemia may actually develop in some individuals, particularly elderly or severely ill patients, and those with diabetes (with or without renal impairment) (Hollenberg and Mickiewicz 1989). Patients receiving HCTZ with triamterene should be monitored carefully for signs of hypo- or hyperkalemia (PDR 1998).

When HCTZ is combined with losartan, an angiotensin II receptor antagonist, the hypokalemic response to HCTZ decreases as the dose of losartan increases (PDR 1998).

Combining HCTZ with lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, may attenuate the thiazide-induced potassium loss because lisinopril reduces the production of aldosterone (PDR 1998). As a result, magnesium-wasting may not occur with the combination of lisinopril and HCTZ. Nevertheless, patients should be observed for fluid or electrolyte imbalances while taking this drug combination.

Significance of Depletion

Magnesium: Severely depleted levels of magnesium affect calcium and vitamin D metabolism and are associated with hypocalcemia (Cashman and Flynn 1999). Clinically, neuromuscular hyperexcitability may be the first symptom manifested in patients with hypomagnesemia (reflected in a serum concentration of 17 mg/L or less). Recent evidence supports a possible connection between chronically low magnesium levels and various illnesses such as cardiovascular disease, hypertension, diabetes, and osteoporosis.

Potassium: Potassium depletion as a consequence of prolonged drug therapy is usually associated with chloride deficiency and manifests as hypokalemic, hypochloremic metabolic acidosis (Covington 1999). Signs and symptoms of deficiency include anorexia, apprehension, drowsiness, listlessness, fatigue, nausea, muscle cramps and weakness, tetany, excessive thirst, altered mental status, and irrational behavior. Severe hypokalemia could also result in clinical manifestations of cardiac arrythmia, including primarily palpitations, cardiac arrest, and death. A loss from total body stores of approximately 100 to 200 mEq of potassium is usually required to cause a decrease in serum potassium levels of 1 mEq/L.

Replacement Therapy

Magnesium: The current recommended dietary allowance (RDA) for magnesium ranges from 30 to 420 mg/day, depending upon age and gender (Cashman and Flynn 1999). For replacement therapy, doses should be tailored to the patient's clinical condition, taking into account serum magnesium levels, dietary habits, and medication regimen.

Potassium: The usual range of treatment is 20 to 100 mEq/day of potassium (PDR 1998). The appropriate doses for replacement therapy should be determined on an individual basis, considering the patient's age, gender, clinical presentation, serum potassium levels, dietary habits, and medication regimen. The chloride salt is appropriate treatment for cases of alkalosis (Covington 1999). In cases of acidosis, other potassium salts such as bicarbonate, citrate, acetate, or gluconate are preferred.

Note: Treatment with potassium hydrochloride (1 g bid) alone or with magnesium hydroxide (500 mg bid) suppressed ventricular ectopic activity in thiazide-treated hypertensive patients at risk for developing ventricular extrasystoles (Lumme and Jounela 1989).


Chronic treatment with thiazides increases urinary zinc excretion and could lead to zinc deficiency (Mountokalakis et al. 1984; Reyes et al. 1982; Wester 1980). The use of thiazide diuretics in conditions such as hepatic cirrhosis, diabetes mellitus, gastrointestinal disorders, renal insufficiency, alcoholism, and pregnancy may increase the likelihood of a zinc deficiency (Reyes et al. 1982; Reyes et al. 1983). Because ACE inhibitors also reduce serum zinc levels and increase urinary zinc excretion (Golik et al. 1998; Peczkowska 1996), zinc levels should be carefully monitored in patients receiving a combination of HCTZ and ACE inhibitors.

Significance of Depletion

Clinically, signs and symptoms of zinc deficiency include alopecia, dermatitis, diarrhea, growth retardation, increased susceptibility to infection, and loss of appetite or sense of taste (Ames 2000; Falchuk 1998). Severe zinc deficiency further impacts dermatologic, gastrointestinal, immune, nervous, reproductive, respiratory, and skeletal systems (Ames 2000; Hambidge 2000).

Replacement Therapy

Doses of zinc up to 50 mg/day may be recommended (Hambidge 2000). This upper limit includes an adult's total daily intake, which may be higher than anticipated because of the increasing trend to fortify foods with zinc. It is important to be mindful of this limit, even if decisions are deliberately made to temporarily exceed this level for anticipated pharmacological benefits.

Editorial Note

This information is intended to serve as a concise reference for healthcare professionals to identify substances that may be depleted by many commonly prescribed medications. Depletion of these substances depends upon a number of factors including medical history, lifestyle, dietary habits, and duration of treatment with a particular medication. The signs and symptoms associated with deficiency may be nonspecific and could be indicative of clinical conditions other than deficiency. The material presented in these monographs should not in any event be construed as specific instructions for individual patients.


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Copyright © 2000 Integrative Medicine Communications

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