Thiazide Diuretics

Summary

drug class: Thiazide Diuretics

drugs and trade names:
• Chlorthiazide: Aldoril®, Diachlor®, Diuril®
• Hydrochlorothiazide: Esidrix®, Hydrodiuril®

type of drug: Potassium-depleting diuretic; antihypertensive.

Note: See the separate topic on Loop Diuretics or individual listings for potassium-sparing diuretics, such as Amiloride, Spironolactone (Aldactone), and Triamterene (Dyrenium), as they have different actions and precautions

used to treat: Edema associated with congestive heart failure; hepatic cirrhosis; in drug-induced edema (corticosteroid and estrogen therapy), nephrotic syndrome, acute glomerulonephritis, and chronic renal failure.

overview of interactions:
• nutrients affected by drug: Magnesium and Potassium and Potassium and Potassium

• nutrient affected by drug: Calcium

• nutrient affected by drug: Vitamin D

• nutrient affected by drug: Sodium Chloride (Salt)

• herb affected by drug: Glycyrrhiza glabra (Licorice)

• herb affected by drug: Ginkgo biloba (Ginkgo)

• herbal concerns: Hypertensive and Tachycardic Herbs

• herbal concerns: Hypotensive and Bradycardic Herbs

• herbal concerns: Vasoconstrictor Herbs

Interactions

nutrients affected by drug: Magnesium and Potassium

• mechanism: By definition potassium-depleting diuretics increase potassium excretion and, in practice, they also usually deplete blood levels of magnesium. In turn, the drug-induced magnesium deficiency can contribute to further potassium depletion. Ultimately the relationship between these two patterns of depletion can be difficult to determine.
(Kroenke K, et al. Arch Intern Med 1987;147:1553-1556; Martin BJ, et al. Arch Intern Med 1987 Oct;147(10):1768-1771.)

• adverse drug effects: A lack of magnesium interferes with healthy cardiac muscle function. This is especially important for patients on both thiazides and digitalis as they are more likely to develop arrythmias if not adequately supplemented with magnesium.

• testing: Serum levels of magnesium are not adequately sensitive to mild to moderate levels of depletion and thus are poor indicators of nutritional status.

• nutritional support: In practice, it is generally advisable for individuals taking any potassium-depleting diuretic, other than those with kidney failure, to supplement with both potassium and magnesium.

Slow-K® and Micro-K® are typical examples of the potassium supplementation suggested by most physicians. Potassium levels can be further enhanced by increasing the amount of fruit in the diet. However, increasing potassium intake by any means is usually contraindicated and often dangerous in patients with reduced kidney function, especially those on dialysis.

Supplementation of magnesium in the dosage range of 300-500 mg per day is usually appropriate but should be done in consultation with the prescribing doctor or a nutritionally-oriented physician. Magnesium supplementation can be risky in patients with kidney failure and usually contraindicated in such cases.
(Whang R, et al. Arch Intern Med 1992;152:40-45.)

nutrient affected by drug: Calcium


mechanism: Thiazide diuretics lower calcium excretion by the kidney, especially in contrast to loop diuretics which promote calcium excretion.
(Riis B, Christiansen C. Metabolism 1985 May;34(5):421-424; Rejnmark L, et al. Nord Med 1998 Feb;113(2):53-59)

nutritional concerns: Individuals taking thiazide diuretics may not need to supplement calcium at as high of levels as they might otherwise. Rather than trying to determine the appropriate level of calcium supplementation independently, individuals taking thiazide diuretics should consult with the prescribing physician and/or a nutritionally-oriented healthcare provider.

nutrient affected by drug: Vitamin D

• nutritional concerns: When thiazide diuretics decrease calcium excretion they, in turn, exert an influence on vitamin D metabolism. Given the uncertainty of such implications, individuals taking these drugs are advised to consult their prescribing physician and/or a nutritionally-trained healthcare provider before starting or increasing any Vitamin D supplementation.
(Seligmann H, et al. Am J Med 1991 Aug;91(2):151-155.)

nutrient affected by drug: Sodium Chloride (Salt)

• mechanism: The intended function of thiazide diuretics is to interfere with renal reabsorption of both sodium and chloride, with sodium excretion in particular being the fundamental purpose of the drug. The increased excretion of sodium leads to an increased excretion of water from the body and thereby cause a lowering of blood pressure and reduced load on the heart.

• nutritional concerns: Since decreased sodium levels are intentional, individuals who have been prescribed diuretics should not increase their salt intake without explicit directions from their prescribing physician to this effect. The corresponding drug-induced depletion of chloride is typically mild and usually not significant for individuals with normal liver and kidney function.

herb affected by drug: Glycyrrhiza glabra (Licorice)

• nutritional concerns: Potassium-depleting diuretics may potentiate the effects of glycyrrhizin, a saponin found in licorice, and thereby increase its toxic effects.
(Farese RV Jr, et al. N Engl J Med 1991 Oct 24;325(17):1223-1227; Shintani S, et al. Eur Neurol 1992;32(1):44-51; Bannister B, et al. Br Med J 1977 Sep 17;2(6089):738-739.)

• herbal alternatives: Most healthcare practitioners trained in botanical medicine now use deglycyrrhizinated licorice (DGL) in cases where there is significant risk of high blood pressure or other complications. DGL is safe to use with all diuretics. Nevertheless an individual with hypertension or taking any diuretic should only use licorice, in any form, within the context of appropriate medical supervision.

herb affected by drug: Ginkgo biloba (Ginkgo)

• interaction: One case has been reported in which an elderly patient developed elevated blood pressure while taking both a thiazide diuretic and Ginkgo biloba. This person's blood pressure returned to normal when both substances were discontinued. This reaction is paradoxical in light of the known pharmacological actions of the two agents which would more likely have been predicted to cause a hypotensive crisis.
(Shaw D, et al. Drug Saf 1997 Nov; 17 (5): 342-356.)

See also: Hypertensive and Tachycardic Herbs

See also: Hypotensive and Bradycardic Herbs...

See also: Vasoconstrictor Herbs...


Please read the disclaimer concerning the intent and limitations of the information provided here.
Do not rely solely on the information in this article.

The information presented in Interactions is for informational and educational purposes only. It is based on scientific studies (human, animal, or in vitro), clinical experience, case reports, and/or traditional usage with sources as cited in each topic. The results reported may not necessarily occur in all individuals and different individuals with the same medical conditions with the same symptoms will often require differing treatments. For many of the conditions discussed, treatment with conventional medical therapies, including prescription drugs or over-the-counter medications, is also available. Consult your physician, an appropriately trained healthcare practitioner, and/or pharmacist for any health concern or medical problem before using any herbal products or nutritional supplements or before making any changes in prescribed medications and/or before attempting to independently treat a medical condition using supplements, herbs, remedies, or other forms of self-care.



References

Bannister B, Ginsburg R, Shneerson J. Cardiac arrest due to liquorice induced hypokalaemia. Br Med J 1977 Sep 17;2(6089):738-739.

Brady JA, Rock CL, Homeffer MR. Thiamin status, diuretic medications, and the management of congestive heart failure. J Am Diet Assoc 1995 May;95(5):541-544.
Abstract: OBJECTIVE: To assess the prevalence of thiamin deficiency in patients with congestive heart failure who are treated with diuretics that inhibit sodium and chloride reabsorption in the thick ascending limb of the loop of Henle (loop diuretic therapy). DESIGN: A cross-sectional investigation of thiamin status of consecutive patients with congestive heart failure being treated with loop diuretic therapy. SETTING: Cardiology clinic of a midwestern tertiary-care medical center. SUBJECTS: Thirty-eight patients were recruited (mean age +/- standard deviation = 55 +/- 14 years). Validation of methodology was conducted with nine age-matched control subjects. MAIN OUTCOME MEASURES: Thiamin status was assessed biochemically by in vitro erythrocyte transketolase activity assay. Assessment of dietary intake of thiamin was accomplished with a semiquantitative food frequency questionnaire. STATISTICAL ANALYSES PERFORMED: Fisher's exact test and logistic regression were used to evaluate relationships between thiamin status and variables of interest. RESULTS: Biochemical evidence of thiamin deficiency was found in 8 of 38 (21%) patients. Evidence of risk for dietary thiamin inadequacy was found in 10 of 38 patients (25%). Seven of the 8 patients with biochemical evidence of thiamin deficiency met study criteria for dietary adequacy, although quantified data suggested that only 4 of the patients achieved two thirds of the Recommended Dietary Allowance. Biochemical evidence of thiamin deficiency tended to be more common among patients with poor left ventricular ejection fractions (P = .07). CONCLUSIONS: Thiamin deficiency may occur in a substantial proportion of patients with congestive heart failure, and dietary inadequacy may contribute to increased risk.

Farese RV Jr, Biglieri EG, Shackleton CH, Irony I, Gomez-Fontes R. Licorice-induced hypermineralocorticoidism. N Engl J Med 1991 Oct 24;325(17):1223-1227.

Folkersen L, Knudsen NA, Teglbjaerg PS. [Licorice. A basis for precautions one more time]! Ugeskr Laeger 1996 Dec 16;158(51):7420-7421. [Article in Danish]
Abstract: A 38 year-old male was admitted to hospital with somnolence, flaccid paralysis of the extremities, arterial hypertension, oedema, severe hypokalemia and rabdomyolysis. The course was complicated with respiratory and kidney failure. It became apparent that the symptoms were caused by the ingestion of 200 g of licorice daily for ten weeks together with a thiazide diuretic for two weeks.

Gomez-Sanchez EP, Gomez-Sanchez CE. Central hypertensinogenic effects of glycyrrhizic acid and carbenoxolone. Am J Physiol 1992 Dec;263(6 Pt 1):E1125-E1130.
Abstract: The apparent mineralocorticoid excess syndrome of patients ingesting large amounts of licorice or its derivatives is thought to be caused by the antagonism by these compounds of the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD). 11 beta-HSD inactivates cortisol and corticosterone, allowing the more abundantly produced glucocorticoids access to the mineralocorticoid receptor (MR) in the kidney, where they act as mineralocorticoids. We have found that the infusion of both glycyrrhizic acid, an active principle of licorice, and carbenoxolone, a synthetic analogue, into a lateral ventricle of the brain [intracerebroventricular (icv)] of a rat, at a dose less than that which has an effect when infused subcutaneously, produces hypertension. Furthermore, the hypertension produced by the oral administration of carbenoxolone or glycyrrhizic acid is blocked by the icv administration of RU 28318, an MR antagonist, at a dose below that which has an effect on blood pressure when infused subcutaneously. While the oral administration caused saline polydipsia and polyuria typical of chronic systemic mineralocorticoid excess, the icv licorice derivatives produced hypertension without affecting saline appetite. Sensitizing the rats to mineralocorticoid hypertension by renal mass reduction and increasing salt consumption was not necessary for the production of hypertension. These findings provide additional evidence for a central role in blood pressure control by mineralocorticoids that is distinct from their renal effects. They also suggest that more is involved in licorice-induced hypertension than only inhibition of 11 beta-HSD.

Heidemann HT, Kreuzfelder E. Hypokalemic rhabdomyolysis with myoglobinuria due to licorice ingestion and diuretic treatment. Klin Wochenschr 1983 Mar 15;61(6):303-305.
Abstract: A 54-year-old man was admitted to hospital with acute rhabdomyolysis and myoglobinuria due to hypokalemia. The hypokalemia was due to chronic licorice ingestion and diuretic treatment. The myoglobinemia led to a glomerulopathy and tubulopathy. There was, however, no clinical evidence of acute renal failure (ARF). We propose that the volume expansion caused by the steroid-like actions of licorice might have prevented the development of an ARF.

Kroenke K, Wood DR, Hanley JF. The value of serum magnesium determination in hypertensive patients receiving diuretics. Arch Intern Med 1987;147:1553-1556.

Martin BJ, Milligan K. Diuretic-associated hypomagnesemia in the elderly. Arch Intern Med 1987 Oct;147(10):1768-1771.
Abstract: Serum magnesium concentration was measured in 320 consecutive elderly patients (mean age, 81 years) receiving diuretic therapy at the time of hospital admission. When compared with serum concentrations of 250 elderly patients who were not taking diuretics at the time of hospital admission, only the group taking thiazide diuretics had a significantly reduced mean serum level. The 24-hour urine sampling from representative subgroups demonstrated impaired magnesium-conserving ability in hypomagnesemic subjects receiving loop and thiazide diuretic therapy. Patients taking therapy that included a potassium-sparing diuretic had no significant evidence of reduced magnesium-conserving ability. Dietary assessments of the study population revealed suboptimal magnesium intake in the diet.

Nielsen H, Landbo K. [Hypokalemia, myopathy with myoglobinuria after prolonged ingestion of licorice]. Ugeskr Laeger 1970 Sep 17;132(38):1778-1780. [Article in Danish]

Riis B, Christiansen C. Actions of thiazide on vitamin D metabolism: A controlled therapeutic trial in normal women early in the postmenopause. Metabolism 1985 May;34(5):421-424.
Abstract: The effect of thiazide on vitamin D metabolism in normal postmenopausal women was studied during a twelve-month placebo-controlled clinical study. Nineteen healthy women in their early menopause were randomized for treatment with bendroflumethiazide (5 mg/d) (n = 11) or placebo (n = 8) for twelve months. All participants were given a calcium supplement of 0.5 g/d throughout the study. A significant increase (p less than 0.01) in the serum concentration of 24,25-dihydroxycholecalciferol was observed in the thiazide group. Moreover, this group showed a tendency toward decreased serum 1,25-dihydroxycholecalciferol, whereas the mean serum 25-hydroxycholecalciferol was unchanged. Except for a highly significant decrease in urinary calcium in the thiazide group (P less than 0.01) all other biochemical indices of calcium metabolism were unchanged. The present data indicate that thiazide given to early postmenopausal women has a primary effect on the renal tubules followed by a secondary change in vitamin D metabolism leading to an increase in serum 24,25-dihydroxycholecalciferol.

Rejnmark L, Mosekilde L, Andreasen F. [Diuretics and osteoporosis].  Nord Med 1998 Feb;113(2):53-59. [Article in Danish]
Abstract: Thiazide diuretics lower while loop diuretics promote calcium excretion by the kidney. Several studies have found thiazide use to be associated with higher bone mineral density and some have found that thiazides reduce the risk of hip fracture. The mechanisms by which thiazides favour preservation of the bones are uncertain. Thiazide use results in decreased renal calcium excretion and thiazide users have been shown to have lower levels of S-PTH and S-1,25-dihydroxy-vitamin D. The beneficial bone effects may result from a decrease in PTH-stimulated bone resorption and an associated reduction in the bone turn-over rate. Whether loop diuretics increases the bone turn-over by augmenting the urinary calcium excretion is more controversial as only few studies have been carried out on loop diuretics. However, in these studies the use of loop diuretics have been associated with decreased bone mineral density and increased risk of fractures. Future research should determine the minimal dose of thiazide therapy necessary to produce a sustained hypocalciuric effect and in addition the influence of diuretic dose on bone turn-over. Equally important is the need to evaluate potential unwanted effects of loop diuretics. In the mean time, thiazide diuretics may be used safely while some caution is necessary in the long term use of loop diuretics in patients who are prone to osteoporosis.

Seligmann H, Halkin H, Rauchfleisch S, Kaufmann N, Motro M, Vered Z, Ezra D. Thiamine deficiency in patients with congestive heart failure receiving long-term furosemide therapy: a pilot study. Am J Med 1991 Aug;91(2):151-155.
Abstract: PURPOSE: To test the hypothesis that long-term furosemide therapy in patients with congestive heart failure (CHF) is associated with clinically significant thiamine deficiency via urinary loss. DESIGN: (1) Biochemical evaluation of thiamine status in hospitalized patients with CHF treated with long-term furosemide and in age-matched control patients. (2) Uncontrolled trial of the effect of intravenous thiamine on cardiac performance in a subset of six patients with CHF. SETTING: General medical ward of a teaching community hospital. PATIENTS: Twenty-three patients with chronic CHF receiving furosemide, and 16 age-matched control patients without heart failure and not taking diuretics. Daily furosemide doses were 80 to 240 mg, and duration of furosemide therapy was 3 to 14 months. Patients with identifiable causes of inadequate thiamine intake, absorption, or utilization or increased metabolic requirements were excluded. INTERVENTION: A 7-day course of intravenous thiamine, 100 mg twice daily, in six consenting patients with CHF. RESULTS: A high thiamine pyrophosphate effect (TPPE), indicating thiamine deficiency, was found in 21 of 23 furosemide-treated patients and in two of 16 controls (p less than 0.001). The mean (+/- SE) TPPE (normal: 0% to 15%) in furosemide-treated and control patients was 27.7 +/- 2.5% and 7.1 +/- 1.6%, respectively (p less than 0.001). Despite the high TPPE, the mean (+/- SE) urinary thiamine excretion in the furosemide-treated patients (n = 18) was inappropriately high (defined as greater than 130 micrograms/g creatinine), 410 +/- 95 micrograms/g creatinine, even in comparison with that in the controls (n = 14): 236 +/- 69 micrograms/g creatinine. In six patients treated with intravenous thiamine, the elevated TPPE decreased to normal, from a mean (+/- SE) of 27.0 +/- 3.8% to 4.5 +/- 1.3% (p less than 0.001), indicating normal thiamine utilization capacity. Left ventricular ejection fraction increased in four of five of these patients studied by echocardiography. CONCLUSIONS: These preliminary findings suggest that long-term furosemide therapy may be associated with clinically significant thiamine deficiency due to urinary loss and contribute to impaired cardiac performance in patients with CHF. This deficit may be prevented or corrected by appropriate thiamine supplements.

Shaw D, Leon C, Kolev S, et al. Traditional remedies and food supplements: a 5-year toxicological study (1991-1995). Drug Saf 1997 Nov; 17 (5): 342-356.

Shintani S, Murase H, Tsukagoshi H, Shiigai T. Glycyrrhizin (licorice)-induced hypokalemic myopathy. Report of 2 cases and review of the literature. Eur Neurol 1992;32(1):44-51.
Abstract: Fifty-nine cases of glycyrrhizin (licorice)-induced hypokalemic myopathy (GIHM), 2 females treated in our departments (85 and 73 years old) and 57 cases reported in the literature were studied, and conditions leading to the onset, factors, clinical manifestations, laboratory assessments, muscle biopsy findings, treatment and outcome were discussed. The 59 GIHM cases comprised 32 men, 25 women and 2 patients without record of sex; the average age was 55.2 years. In many cases, conditions leading to the onset of GIHM were habitual licorice ingestion, ingestion of antituberculosis agents containing licorice and long-term ingestion of licorice-containing agents for chronic gastritis, chronic hepatitis or chronic dermatitis. The combined use of hypotensive diuretic agents increased the risk of GIHM in an overwhelming number of cases. The main clinical symptom was flaccid quadriplegia in almost all cases, with muscle pain in 32.2% and peripheral dysesthesia in the extremities, manifested mainly by numbness (27.1%). Laboratory findings included a mean serum K+ value of 1.98 mEq/l (56 GIHM cases), a mean creatine kinase of 5,385.7 IU/l (n = 30), a mean blood aldosterone concentration of 2.92 ng/dl (n = 30; normal: 2.0-13.0 ng/dl) and a mean plasma renin activity of 0.17 ng/ml/h (n = 27; normal: 0.8-4.4 ng/ml/h). Muscle biopsy was performed in 17 of the 59 cases with resultant findings of myopathic changes consisting mainly of phagocytosis, necrotic fibers, vacuolar degeneration, together with sporadic neurogenic changes. Complete cure was attained in 57 of the 59 cases of GIHM by discontinued ingestion of glycyrrhizin (licorice) and potassium supplement.

Whang R, Whang DD, Ryan MP. Refractory potassium repletion-a consequence of magnesium deficiency. Arch Intern Med 1992;152:40-45.
Abstract: Experimental and clinical observations support the view that uncorrected magnesium (Mg) deficiency impairs repletion of cellular potassium (K). This is consistent with the observed close association between K and Mg depletion. Concomitant Mg deficiency in K-depleted patients ranges from 38% to 42%. Refractory K repletion due to unrecognized concurrent Mg deficiency can be clinically perplexing. Refractory K repletion as a consequence of Mg deficiency may be operative in patients with congestive failure, digitalis toxicity, cisplatin therapy, and in patients receiving potent loop diuretics. Therefore, we recommend that: (1) serum Mg be routinely assessed in any patients in whom serum electrolytes are necessary for clinical management and (2) until serum Mg is routinely performed consideration should be given to treating hypokalemic patients with both Mg as well as K to avoid the problem of refractory K repletion due to coexisting Mg deficiency.