Triamterene

Brand Names: Dyrenium

Clinical Names: Triamterene

Summary

generic name: Triamterene

trade name: Dyrenium®

related drug: Triamterene/Hydrochlorothiazide

trade names: Maxzide®, Dyazide®

type of drug: Potassium-sparing diuretic.

used to treat: Congestive heart failure, high blood pressure, edema associated with some kidney and liver diseases.

adverse drug effects: Triamterene has been found to cause kidney stones (largely composed of the drug) and interstitial nephritis.

overview of interactions:
• nutrient affected by drug: Folic Acid

• nutrient affected by drug: Potassium

• nutrient affected by drug: Sodium

• diet affecting drug performance: Food



Interactions

nutrient affected by drug: Folic Acid

• mechanism: Triamterene impairs folate availability. Tetrahydrofolates, the biologically active folates, are produced from unreduced dietary folates by the enzyme dihydrofolate reductase. Triamterene acts as a folate antagonist and produces folate deficiency by inhibiting this enzyme. Animal research also found that triamterene acted as a competitive inhibitor of folate absorption in the rat intestine.
(Schalhorn A, et al. Eur J Clin Pharmacol. 1981;20(3):219-224; Tuckerman M, Turco S. 1983, 215-222; Jackson EK. 1996, 706; Zimmerman J, et al. J Lab Clin Med. 1986 Oct;108(4):272-276.)

• research: Research indicates that triamterene is a relatively weak folic acid antagonist. As a result, folic acid-deficiency anemia appears to occurs primarily among users of triamterene who are already demonstrating or at risk for folic acid deficiency.

Zimmerman et al investigated the effect of triamterene on folic acid absorption in the rat jejunum. They found that, in an in vivo intestinal loop method, triamterene inhibited the intestinal absorption of folic acid in a dose-dependent fashion, with 50% inhibition of systemic absorption occurring at a luminal concentration of 0.01 mmol/L of triamterene. Later, in a study of 272 elderly individuals, Mason et al found normal folic acid levels and no signs of folic acid deficiency among individuals who used triamterene on a long term basis but lacked additional risk for folic acid deficiency. Case reports can be found in the literature involving patients who developed megaloblastic anemia while being treated with triamterene.
(Tuckerman M, Turco S. 1983, 215-222; Zimmerman J, et al. J Lab Clin Med 1986 Oct;108(4):272-276; Mason JB, et al. J Lab Clin Med 1991 May;117(5):365-369; Joosten E, et al. Neth J Med. 1991 Jun;38(5-6):209-211.)

• nutritional concerns: While the relationship between triamterene and folic acid deficiency remains inconclusive nothing definitive can be said as to its clinical significance or the need for supplementation. However, folic acid deficiency can produce a number of metabolic disorders and health problems. most notably anemia, that can be prevented or treated quite easily through supplementation. While the research has thus far pointed to adverse effects from triamterene in individuals suffering from folate deficiency, it is important to note that most people's diets do not provide the recommended levels of folic acid. Furthermore, the emerging evidence of a strong association between heart disease and elevated blood levels of homocysteine raises the importance of this concern in light of folic acid's central role in countering this pattern. Even so, those using triamterene might find common folic acid supplements ineffective because of the drug's interference with the vitamin's activation. This problem can be avoided by using the vitamin's activated form, folinic acid (5-formyltetrahydrofolate). Consequently, individuals using triamterene who are concerned about potential folic acid deficiency and its implications should consult their prescribing physician and/or a nutritionally trained healthcare professional.

nutrient affected by drug: Calcium

• mechanism: Triamterene may increase calcium loss through the urine.
(D'Arcy PF, Griffin, JP. 1972; Werbach WR. 1997, 246.)

• nutritional concerns: The clinical implications of this potential interactions are unclear at this time. Individuals concerned about potential calcium deficiency due to using triamterene should consult their prescribing physician and/or a nutritionally trained healthcare professional.

nutrient affected by drug: Potassium

• mechanism: Triamterene intentionally reduces urinary excretion of potassium. As a result of its role as a potassium-sparing diuretic, triamterene can produce a state of hyperkalemia, i.e., inappropriately elevated potassium levels. When used in combination with a thiazide diuretic, hyperkalemia (>5.4 mEq/L) has been reported ranging from 4% in patients less than 60 years of age to 12% in patients 60 years and older, with an overall incidence of less than 8%. Hyperkalemia has been reported to be associated with cardiac irregularities. On the other hand, concern has been raised about potential risks of hypokalemia among some patients using triamterene even though hypokalemia is a less common occurrence with the use of triamterene than with non-potassium sparing diuretics.
(Dorph S, Oigaard A. Nord Med 1968 Apr 18;79(16):516-518; Stepan VM, et al. Eur J Gastroenterol Hepatol. 1997 Oct;9(10):1001-1004; Schnaper HW, et al. Arch Intern Med 1989 Dec;149(12):2677-2681; Sawyer N, Gabriel R. Postgrad Med J 1988 Jun;64(752):434-437.)

• nutritional concerns: Individuals using potassium-sparing such as triamterene should limit their dietary intake of potassium to avoid excessive levels. Potassium supplements and potassium-containing salt substitutes, such as Lite Salt®, Morton's Salt Substitute and No Salt®, are designed for individuals suffering from potassium depletion due to other types of diuretics and should be avoided when taking potassium-sparing diuretics such as triamterene. For some individuals, foods with high potassium content may need to be limited. Several pieces of fruit per day may provide adequate potassium to elevate serum levels. Individuals taking triamterene should work with their prescribing physician to monitor serum potassium determinations regularly during the course of therapy and modify their diet accordingly to avoid elevated potassium levels and associated problems. This is particularly important in the treatment of patients with suspected or confirmed renal insufficiency such as elderly or diabetic patients.

nutrient affected by drug: Sodium

• mechanism: The basic function of diuretics is to reduce the amount of water in the body. Therefore, by their very nature and intent diuretics, such as triamterene, increase the amount of sodium excreted in the urine.

• nutritional concerns: Since the reduction of sodium levels in the body is purposeful, supplementation to reduce lost sodium would be counterproductive. However, if dietary changes undertaken to restrict sodium intake are successful the dosage of diuretic medications will need to be reevaluated and possibly modified. Thus, individuals with hypertension who are using a diuretic such as triamterene while also strictly limiting their salt intake should work closely with their prescribing physician to monitor and revise their prescription based on changes in their blood pressure.
(Roe DA. 1989, 146.)

diet affecting drug performance: Food

• nutritional concerns: Triamterene is known to cause digestive distress if taken with foods. Physicians and pharmacists generally recommend that triamterene be taken after a meal.
(Threlkeld DS, ed. Jul 1993.)


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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

D'Arcy PF, Griffin, JP. Iatrogenic Diseases. London: Oxford U. Press, 1972.

Dorph S, Oigaard A. [Effect of triamterene on serum potassium and serum creatinine in long-term treatment with thiazides]. Nord Med 1968 Apr 18;79(16):516-518. [Article in Danish]

Ettinger B. Excretion of triamterene and its metabolite in triamterene stone patients. J Clin Pharmacol 1985 Jul-Aug;25(5):365-368.
Abstract: As triamterene users may form kidney stones containing deposits of triamterene and its metabolites, we studied urinary excretion to detect any altered metabolism of triamterene in these patients. We found no significant differences between patients and matched control subjects in total recovery, hourly excretion patterns, and concentrations of triamterene and its sulfate metabolite. Approximately half of all subjects tested revealed urine concentrations of the sulfate metabolite that exceeded the observed solubility limit.

Jackson EK. Diuretics. In: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 9th ed. New York: McGraw Hill, 1996: 706.

Joosten E, Pelemans W. Megaloblastic anaemia in an elderly patient treated with triamterene. Neth J Med 1991 Jun;38(5-6):209-211.
Abstract: The case is presented of an elderly woman in whom megaloblastic anaemia due to folate deficiency was diagnosed. It is speculated that this disorder was induced by treatment with triamterene.

Kohvakka A, Salo H, Gordin A, Eisalo A. Antihypertensive and biochemical effects of different doses of hydrochlorothiazide alone or in combination with triamterene. Acta Med Scand 1986;219(4):381-386.
Abstract: The antihypertensive and biochemical effects of 25 mg hydrochlorothiazide alone or 50 mg hydrochlorothiazide alone or in combination with triamterene (either 37.5 or 75 mg) once daily were studied in 26 patients with essential hypertension. After a 5-week run-in period the patients were randomized to receive active therapy in a cross-over manner. Each treatment period lasted 3 months. All drugs significantly (p less than 0.01) lowered both systolic and diastolic blood pressure. There were no differences in blood pressure between the medication periods. Serum potassium concentration was slightly lower during all medication periods than during the run-in period. This change was statistically significant (p less than 0.01) only on 50 mg hydrochlorothiazide daily. There were no significant changes in serum magnesium during any of the periods compared to the run-in period. The lowest values were recorded on 50 mg hydrochlorothiazide alone and the highest on 50 mg hydrochlorothiazide plus 75 mg triamterene daily. A slight increase in serum urate was recorded in all medication periods compared to the run-in period. No significant changes were observed in serum total cholesterol, HDL cholesterol or triglycerides between any of the periods. It can be concluded that 25 mg of hydrochlorothiazide is as effective in lowering blood pressure as higher doses of the diuretic. Higher doses of thiazides will in some patients cause adverse metabolic reactions of which the fall in serum potassium and magnesium is effectively hindered by triamterene.

Mason JB, Zimmerman J, Otradovec CL, Selhub J, Rosenberg IH. Chronic diuretic therapy with moderate doses of triamterene is not associated with folate deficiency. J Lab Clin Med 1991 May;117(5):365-369.
Abstract: The diuretic drug triamterene has previously been shown to be a competitive inhibitor of folate absorption in the rat intestine (J Lab Clin Med 1986;108:272-6). We therefore investigated whether human subjects who are taking the drug on a long-term basis are at increased risk of folate deficiency. In each of two free-living populations, a study was performed to compare the folate status of triamterene users with those not taking the drug. The first population consisted of 272 elderly individuals not living in institutions who were participants in a nutrition status survey and who were taking a variety of antihypertensive medications; 32 of these individuals were daily users of triamterene. The hemoglobin concentration, red blood cell (RBC) count, and mean corpuscular volume (MCV) values were not significantly different between the triamterene users and nonusers. The female triamterene users had a slightly higher serum folate level than the female nonusers (p less than 0.04); a similar pattern was observed among the men, although the difference was not statistically significant. The second population consisted of 27 individuals attending a hypertension clinic; 18 subjects were taking 50 to 150 mg of triamterene per day and nine were taking antihypertensive drugs other than triamterene. The hemoglobin concentration, RBC count, MCV, serum folate values, and RBC folate values were found to not differ significantly between the triamterene users and the hypertensive controls (p greater than 0.05). These data suggest that chronic triamterene administration in individuals not living in institutions, at the doses examined in this study, is not associated with indications of folate deficiency.

Priewer H, Ullrich F. Potassium and magnesium retaining triamterene derivatives.Pharmazie 1997 Mar;52(3):179-181. (Review)

Roe DA. Diet and Drug Interactions. New York: Van Nostrand Reinhold, 1989: 146.

Sawyer N, Gabriel R. Progressive hypokalaemia in elderly patients taking three thiazide potassium-sparing diuretic combinations for thirty-six months. Postgrad Med J 1988 Jun;64(752):434-437.
Abstract: Three different thiazide potassium-sparing diuretic combinations were given to elderly patients for heart failure. Eighty patients received their allocated combinations for 3 years and had 6-monthly measurements of plasma potassium. A further 84 were recruited for study but 29 died within 6 months and 55 had to be withdrawn from the trial. The triamterene-containing preparation was discontinued most frequently (6/44) because of hypokalaemia (plasma potassium less than 3.0 mmol/l); amiloride (5/44) and spironolactone (1/47). The median fall in plasma potassium over 3 years in those patients not withdrawn because of hypokalaemia was similar in each case (P greater than 0.05) and possibly failed to reach significance because of the withdrawal rate (9%). The trend was for a greater fall in those patients taking triamterene. The spironolactone-containing preparation may be the least unsatisfactory of the three.

Schalhorn A, Siegert W, Sauer HJ. Antifolate effect of triamterene on human leucocytes and on a human lymphoma cell line. Eur J Clin Pharmacol 1981;20(3):219-224.
Abstract: The inhibitory effect of triamterene and its metabolites on human leucocyte dihydrofolate reductase has been studied. Under test conditions with dihydrofolic acid 0.5 X 10(-5) M, triamterene 7 X 10(-5) M produced total enzyme inhibition, whereas the metabolites hydroxytriamterene and the sulphate ester of hydroxytriamterene were less effective inhibitors; at their maximum attainable concentration of 5 X 10(-5) M, dihydrofolate reductase was inhibited by 80% and 50%, respectively. Cultures of the BJAB-B95-8 human lymphoma cell line were incubated with various concentrations of triamterene. Because of their increased specific activity of dihydrofolate reductase, the cells were able to maintain normal DNA metabolism, as measured by the ratio of the incorporation rates of 3H-deoxyuridine and 3H-thymidine, as well as normal cell growth at 1 X 10(-6) M, and in some cases at 1 X 10(-5) M triamterene. At 8 X 10(-5) M triamterene, the strong inhibitory effect caused severe impairment of DNA metabolism and subsequently dissolution of the cell culture. The results are discussed in relation to the possible toxic side effects of long-term triamterene treatment in patients suffering from alcoholic cirrhosis, who may have impaired metabolism of triamterene and a concomitant severe folate deficiency.

Schnaper HW, Freis ED, Friedman RG, Garland WT, Hall WD, Hollifield J, Jain AK, Jenkins P, Marks A, McMahon FG, et al. Potassium restoration in hypertensive patients made hypokalemic by hydrochlorothiazide. Arch Intern Med 1989 Dec;149(12):2677-2681.
Abstract: Among 447 hypertensive patients, most with a history of diuretic-induced hypokalemia, 252 developed diuretic-induced hypokalemia while receiving hydrochlorothiazide, 50 mg/d. In a randomized study we evaluated the efficacy of three drug regimens in restoring potassium levels while maintaining blood pressure control: hydrochlorothiazide (50 mg/d) plus potassium supplement (20 mmol/d); hydrochlorothiazide (50 mg/d) plus potassium supplement (40 mmol/d); or hydrochlorothiazide (50 mg/d) with triamterene (75 mg/d) in one combination tablet. In all groups, mean serum levels of potassium rose within 1 week and showed no further change thereafter. However, the hydrochlorothiazide/triamterene and hydrochlorothiazide plus 40 mmol of potassium regimens were significantly more effective in restoring serum potassium levels than was the hydrochlorothiazide plus 20 mmol of potassium regimen. A significant increase in magnesium levels was observed only in the group treated with the hydrochlorothiazide/triamterene combination. Each regimen provided continued control of mild to moderate hypertension.

Spence JD, Wong DG, Lindsay RM. Effects of triamterene and amiloride on urinary sediment in hypertensive patients taking hydrochlorothiazide. Lancet 1985 Jul 13;2(8446):73-75.
Abstract: In a crossover study of 26 hypertensive patients, the effects of triamterene (50 mg/day) and amiloride (5 mg/day) on urinary sediment were compared. Each drug was given for one month and all patients also received hydrochlorothiazide (50 mg/day). An abnormal urinary sediment--evident grossly as a reddish-brown precipitate after routine staining procedures and microscopically as characteristic reddish-brown crystals and casts, as previously described--was identified in 14 of 26 (54%) triamterene urine samples but in none of the amiloride samples. Results of renal function tests were similar for both drugs. In a clinic population of more than 1000 hypertensive patients over 4 years, interstitial nephritis was diagnosed in 4, all of whom were taking a triamterene-containing combination diuretic. It is possible that triamterene is a factor in the aetiology of interstitial nephritis.

Stepan VM, Hammer HF, Krejs GJ. Hyperkalaemia and diarrhoea in a patient with surreptitious ingestion of potassium sparing diuretics. Eur J Gastroenterol Hepatol 1997 Oct;9(10):1001-1004.
Abstract: We report a patient who presented with the unusual combination of chronic diarrhoea and hyperkalaemia. The patient was admitted to our hospital after repeated negative evaluations elsewhere including exploratory laparotomy. The patient had a long history of diarrhoea with hypokalaemia which was documented on several occasions in the past. Several months before admission to our hospital for evaluation of diarrhoea the patient developed hyperkalaemia. Her daily stool output reached 1200 g and her serum potassium was as high as 6.0 mmol/l. Extensive evaluation revealed surreptitious ingestion of the diuretics triamterene, hydrochlorothiazide and spironolactone as the cause of hyperkalaemia and diarrhoea. In addition, she had melanosis coli which was interpreted to be the consequence of surreptitious ingestion of anthraquinone-containing laxatives in the past although no current laxative intake could be proven. We postulate that diarrhoea in our patient was mainly due to the decreased sodium absorption in the small intestine and colon caused by diuretics. Serum aldosterone levels were more than eight times the upper limit of normal. Increased aldosterone levels presumably arose secondary to volume contraction and sodium chloride depletion, but presumably were not able to affect renal and colonic electrolyte transport because of blockage of mineralocorticoid receptors by spironolactone. Thus, the unusual combination of diarrhoea and hyperkalaemia resulted.

Threlkeld DS, ed. Diuretics and Cardiovasculars, Potassium-Sparing Diuretics, Triamterene. In: Facts and Comparisons Drug Information. St. Louis, MO: Facts and Comparisons, Jul 1993.

Trenkwalder P, Plaschke M, Aulehner R, Lydtin H. Felodipine or hydrochlorothiazide/triamterene for treatment of hypertension in the elderly: effects on blood pressure, hypertensive heart disease, metabolic and hormonal parameters. Blood Press 1996 May;5(3):154-163.
Abstract: The aim of the study was to compare the antihypertensive efficacy of either felodipine or the diuretic combination hydrochlorothiazide/triamterene in a group (n = 65) of elderly (> or = 70 years) hypertensives (office blood pressure > or = 160/95 mmHg) with special regard to ambulatory blood pressure monitoring, hypertensive heart disease and metabolic parameters. This was a randomized, double-blind study with a treatment period of 6 months. Reduction of office and 24-hr ambulatory blood pressure was comparable with both treatment regimens; after 6 months. 18 of 29 patients in the felodipine group (62%) and 20 of 27 patients in the diuretic group (74%; p = 0.4) were controlled. While episodes of ischemic type ST-segment depression were significantly reduced in the felodipine group (from 49 to 9 episodes), there was no significant change in the diuretic group (from 24 to 21 episodes). Both regimens decreased left ventricular wall thickness, but the decline in left ventricular muscle mass index was significant only for felodipine. Felodipine did not induce any change in metabolic or hormonal parameters; the diuretic combination significantly increased serum creatinine, uric acid, plasma renin activity, and plasma prorenin. Thus, the antihypertensive efficacy of felodipine and the diuretic combination was comparable in elderly hypertensives; only felodipine, however, improved parameters of hypertensive heart disease and showed a neutral metabolic and hormonal profile.

Tuckerman M, Turco S. Human Nutrition. Philadelphia: Lea and Febiger, 1983: 215-222.

Werbach WR. Foundations of Nutritional Medicine. Tarzana, CA: Third Line Press, 1997: 246. (Review)

Zimmerman J, Selhub J, Rosenberg IH. Competitive inhibition of folic acid absorption in rat jejunum by triamterene. J Lab Clin Med 1986 Oct;108(4):272-276.
Abstract: Triamterene, a diuretic agent, has been reported to cause megaloblastic anemia in some patients. Because this drug is a pteridine derivative, we investigated its effect on folic acid absorption in the rat jejunum. In an in vivo intestinal loop method, triamterene inhibited the intestinal absorption of folic acid in a dose-dependent fashion, with 50% inhibition of systemic absorption occurring at a luminal concentration of 0.01 mmol/L of triamterene. Kinetic analysis using the influx chamber method demonstrated that triamterene is a competitive inhibitor of intestinal folate transport, with a Ki of 0.125 mmol/L. Because therapeutic doses can result in luminal concentration of the drug approximating or exceeding the Ki, the interaction between triamterene and folate absorption is potentially of clinical interest.