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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.

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.

Lee MG, Chiou WL. Mechanism of ascorbic acid enhancement of the bioavailability and diuretic effect of furosemide. Drug Metab Dispos 1998 May;26(5):401-407.
Abstract: : The following possible explanations for the significant increases in the oral bioavailability and the diuretic and natriuretic effects of orally administered furosemide observed when ascorbic acid was coadministered to dogs were investigated: ascorbic acid might enhance the gastrointestinal (GI) absorption of furosemide, might inhibit GI wall metabolism of furosemide, might enhance the reabsorption of furosemide from the renal tubules, and might increase the unionized fraction of furosemide at the receptor sites. The significant increase in the oral bioavailability with coadministration of ascorbic acid seemed to result from reduced gastric first-pass metabolism of furosemide and not enhanced GI absorption of furosemide. This might be supported by rat studies; the percentages of the oral doses of furosemide recovered from the GI tract at 8 hr after oral administration were similar (p < 0.583) without (39.5%) and with (44.7%) coadministration of ascorbic acid, and the amounts of furosemide remaining per gram of stomach after 30-min incubations of 50 micrograms of furosemide with 9000g supernatant fractions of stomach homogenates were increased significantly (48.5 vs. 42.4 micrograms) by the addition of 100 micrograms of ascorbic acid. The significant increases in the diuretic and natriuretic effects of furosemide with ascorbic acid could be the result of increases in the reabsorption of furosemide from renal tubules and increases in the unionized fraction of furosemide at the renal tubular receptor sites. This was supported by 1.5-4.2-fold increases in urine output and approximately 20% decreases in the time-averaged renal clearance of furosemide when the urine pH was decreased by 1.5-2.5 units by oral administration of ammonium chloride.

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]

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.

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.

Yue QY, Beermann B, Lindstrom B, Nyquist O. No difference in blood thiamine diphosphate levels between Swedish Caucasian patients with congestive heart failure treated with furosemide and patients without heart failure. J Intern Med 1997 Dec;242(6):491-495.
Abstract: OBJECTIVES: To determine whether furosemide treatment in congestive heart failure (CHF) patients is associated with thiamine deficiency. DESIGN: Patients without heart failure and without diuretic treatment were included to compare with patients with CHF belonging to New York Heart Association (NYHA) functional class II and III-IV, respectively, and receiving furosemide therapy. SETTING: All patients were recruited from the emergency ward of the cardiology section. Huddinge University Hospital, where they were admitted due to CHF or acute myocardial infarction. SUBJECTS: Ninety-nine patients were included from whom a blood sample was taken, as well as routine admission blood samples for the analysis of thiamine diphosphate (TPP) concentrations. Patients taking vitamin preparations were excluded. MAIN OUTCOME MEASURES: Blood TPP concentrations were measured by high performance liquid chromatography (HPLC) and compared between the patient groups by the use of ANOVA. RESULTS: No significant difference was found between the groups in blood TPP concentrations. CONCLUSIONS: Thiamine deficiency may not be a complication of furosemide treatment in the studied Swedish patient population.