Administration Of Triamterene Research Articles

A role for ATP-sensitive potassium channels in the anticonvulsant effects of triamterene in mice

There are reports indicating that diuretics including chlorothiazide, furosemide, ethacrynic acid, amiloride and bumetanide can have anticonvulsant properties. Intracellular acidification appears to be a mechanism for the anticonvulsant action of some diuretics. This study was conducted to investigate whether or not triamterene, a K+-sparing diuretic, can generate protection against seizures induced by intravenous or intraperitoneal pentylenetetrazole (PTZ) models. And to see if, triamterene can withstand maximal electroshock seizure (MES) in mice. We also investigated to see if there is any connection between triamterene's anti-seizure effect and ATP-sensitive K+ (KATP) channels. Five days triamterene oral administration (10, 20 and 40mg/kg), significantly increased clonic seizure threshold which was induced by intravenous pentylenetetrazole. Triamterene (10, 20 and 40mg/kg) treatment also increased the latency of clonic seizure and decreased its frequency in intraperitoneal PTZ model. Administration of triamterene (20mg/kg) also decreased the incidence of tonic seizure in MES-induced seizure. Co-administration of a KATP sensitive channel blocker, glibenclamide, in the 6th day, 60min before intravenous PTZ blocked triamterene's anticonvulsant effect. A KATP sensitive channel opener, diazoxide, enhanced triamterene's anti-seizure effect in both intravenous PTZ or MES seizure models. At the end, triamterene exerts anticonvulsant effect in 3 seizure models of mice including intravenous PTZ, intraperitoneal PTZ and MES. The anti-seizure effect of triamterene probably is induced through KATP channels.

PP.40.20

Objective: The resistant hypertension (RHTN) is defined by blood pressure (BP) above 140 / 90mmHg, despite the use of 3 or more antihypertensive agents of different classes, including if possible a diuretic. Some hypertensive patients are falsely categorized as RHTN due to non-adherence to pharmacological therapy. Therefore, it is essential the evaluation of adherence with a reliable method in this group of patients. However, an ideal method for this purpose is unknown. The triamterene emerges as a potential biochemical marker of pharmacological adherence. The objective of this work is the assessment of the adherence to pharmacological treatment by direct method in RHTN subjects. Design and method: A pilot test was conducted with twelve volunteers: nine normotensives and three mild to moderate hypertensives. A serial collection of urine was performed before and after administration of triamterene, until the 12-hour period. The ROC curve was used to determine the fluorescence cutoff value of triamterene in the urine. In addition, the evaluation of adherence in the RHTN patients (n = 21) was performed in three home visits by collecting urine. The adherent patients should have the minimum fluorescence detected in all 3 visits. Results: The patients that administered triamterene showed a significant increase in the fluorescence values throughout the study period, as opposed to those who did not take the medication. A fluorescence peak was observed up to 6 hours, and therefore, this time was considered the ideal for analysis. In ROC curve analysis, patients were considered adherents when the fluorescence was above 0.44 x105. Among the 21 RHTN subjects evaluated, 9 patients were considered adherents and 12 non-adherents. Conclusions: The fluorescence analysis of triamterene in urine may be considered a potential method of evaluation of drug adherence in patients with resistant hypertension.

Liddle's syndrome associated with a point mutation in the extracellular domain of the epithelial sodium channel gamma subunit.

To characterize novel type of mutations of the epithelial sodium channel (ENaC) or subunits in patients with Liddle's syndrome, an autosomal dominant form of hypertension. DNA samples from two probands with early-onset, treatment-resistant hypertension and suppressed plasma renin activity were initially screened for mutations in the C-terminal exons of the ENaC or subunit genes, using amplification by polymerase chain reaction and direct DNA sequencing. Two novel mutations causing Liddle's syndrome were identified. One mutation due to a single nucleotide insertion in the exon 13 of ENaC results in a frameshift at codon 601 and abrogates the PY motif similar to all the previously described ENaC mutations causing Liddle's syndrome. The other mutation, substituting serine for asparagine at codon 530 (Asn530Ser) of the extracellular loop of ENaC subunit, was found in a 25-year-old man with hypertension, hypokalemia, low plasma renin activity and low serum aldosterone levels. Hypertension and hypokalemia favorably responded to amiloride or triamterene administration both in the proband and his affected mother. Expression of the mutant Asn530Ser ENaC subunit in oocytes demonstrated a two-fold increase in ENaC activity, compared with the wild-type, without a significant change in cell surface expression of ENaC. This suggests that the gammaENaC Asn530Ser mutation increases the channel open probability, and is consistent with an abnormally high sodium reabsorption in the distal nephron. This study describes the first mutation located in the extracellular domain of an ENaC subunit associated with an increased ENaC activity and Liddle's syndrome.

New Therapy Update

Dyrenium® (triamterene, GlaxoSmithKline) is a potassium-sparing diuretic used in the treatment of edema associated with congestive heart failure, liver cirrhosis, nephrotic syndrome, and use of steroids or secondary hyperaldosteronism. The drug is also used in combination with other diuretics in the treatment of hypokalemia and hypertension. Triamterene inhibits the reabsorption of sodium in exchange for potassium and hydrogen in the distal tubule. The action of the drug is under the control of mineralocorticoid (aldosterone) activity. The more sodium reaching the distal tubule, the stronger the diuretic effect and potassium conservation. After oral administration, the drug is rapidly absorbed. The onset of action is in 2–4 hours, and peak effect occurs after several days of therapy. The duration of action is 7–9 hours. 80% of the drug is metabolized in the liver and 50% is excreted in the urine. The plasma half-life is 1.5–2.5 hours. The drug is contraindicated in patients with anuria or severe, progressive renal disease and diabetic nephropathy. It should not be given to patients with severe hepatic dysfunction. It should not be used in patients with elevated potassium levels or patients already taking another potassium-sparing diuretic. During triamterene administration, blood pressure, urine output, weight, and serum electrolytes should be monitored. Arrhythmias, orthostatic hypotension, and angina are the most common adverse cardiac reactions. Dehydration, fatigue, muscle cramps, nausea, and diarrhea are other reported adverse effects. The drug should not be used with other potassium-sparing diuretics, such as spironolactone and amiloride. Care must be taken when the drug is administered with other potassium-sparing agents, such as angiotensin-converting enzyme inhibitors and angiotensin II receptor-blocking agents. Drug interactions have been reported with lithium, nonsteroidal anti-inflammatory agents, and cardiac glycosides. Triamterene can raise blood glucose levels in patients with adult-onset diabetes mellitus. Concomitant use of the drug with chlorpropamide can increase the risk of hyponatremia. The drug can be used in pregnancy if clearly indicated; it is not recommended during breast feeding. The usual starting dose is 100 mg/b.i.d. after meals. The daily dosage should not exceed 300 mg. Once symptoms of edema are controlled, the dosage can be reduced to administration every other day or to 50 mg/day. When triamterene is used in combination with other kaluretic diuretics, the initial dosage is 25 mg/day, with increases as needed to a maximum dose of 100 mg/day. Dyrenium® is a familiar potassium-sparing diuretic used in the treatment of symptomatic edema of various etiologies. The drug can also be used in combination with other diuretics in the treatment of hypertension. Monitoring of electrolytes is important to ensure its safe use.

Triamterene Increases Lithium Excretion in Healthy Subjects: Evidence for Lithium Transport in the Cortical Collecting Tubule

The possible presence of lithium transport beyond the proximal tubule was examined by measuring lithium excretion after administration of triamterene, a potassium-sparing diuretic, exclusively acting in the cortical collecting tubule. Eight young and healthy volunteers were studied on two occasions during maximal water diuresis. After obtaining baseline values triamterene (100 mg orally) or placebo was administered, and measurements continued for 4 hours. Creatinine clearance was used as a marker of glomerular filtration rate, and phosphate excretion was used as an additional marker of proximal sodium transport. Compared to placebo (P), triamterene (T) caused a significant increase in fractional excretion of sodium (P, 0.74 +/- 0.08%; T, 1.73 +/- 0.24%, mean +/- SEM; P less than 0.01), and lithium (P, 21.2 +/- 1.3%; T, 27.5 +/- 1.5%; P less than 0.01), whereas fractional excretion of phosphate remained unchanged (P, 9.8 +/- 1.3%; T, 9.4 +/- 1.5%; P = NS). These results indicate that lithium is transported in the cortical collecting tubule, and provide further evidence that the use of lithium as a marker of purely proximal tubular sodium transport is of limited value.

Effect of Triamterene on the Mammalian Distal Tubule <i>in vivo</i>

Using the recollection micropuncture technique it was demonstrated that the intragastric administration of triamterene significantly reduced the fraction of filtered potassium remaining (from 27 to 17%) and enhanced the fraction of filtered sodium remaining (from 3.6 to 7.9%) at the end of the accessible distal tubule in 7 rats. Fractional delivery of water, sodium and potassium to the distal tubule was not significantly altered. Urinary potassium excretion was reduced (from 17 to 7%). Similar experiments in 6 control rats disclosed no significant changes in the foregoing variables. In these experiments the principal effect of triamterene <i>in vivo </i>was an inhibition of potassium secretion in the distal tubule. An ostensible inhibitory effect on sodium reabsorption in the distal tubule was not unequivocally established.

Trimethoprim-induced elevation of dihydrofolate reductase activity in human leukocytes.

The administration of trimethoprim (TMP)--a diamino benzylpyrimidine compound which binds very tightly the bacterial dihydrofolate reductase--was accompanied by the appearance of measurable levels of dihydrofolate reductase in peripheral leukocytes from patients with nonhematological diseases. In all instances, enzyme activity rose rapidly between the fourth and eighth day after TMP. The time course of the rise and fall of dihydrofolate activity approaches cellular life span and is similar to that obtained after methotrexate or triamterene administration. Dihydrofolate reductases, partially purified from leukocytes of patients treated with TMP, bone marrow and leukemic leukocytes, had simila molecular weights, pH optima, Ki of inhibitor (methotrexate); they were stimulated to the same degree by KCl and urea. Electrophoresis of the enzyme on cellulose acetate strip resulted in the separation of two enzymatically active protein components. No differences in the electrophoretic behavior of the three blood cell enzymes were noted. The findings noted above are consistent with the suggestion that the observed rise in dihydrofolate reductase activity is a quantitative one. Moreover, the effect of TMP in vivo is discussed in comparison with the currently held hypothesis for methotrexate action (stabilization by the drug of a previously synthetized enzyme).

Hypomagnesemia due to renal disease of unknown etiology

A young man, investigated because of tetanic convulsions and arthritic pains, was shown to have hypomagnesemia, hypermagnesuria, hypokalemia, hypercalciuria, progressive nephrocalcinosis and chondrocalcinosis. In this syndrome, renal function was normal except for the abnormal excretion of electrolytes. Renal sodium conservation was normal. Light and electron microscopic studies of renal biopsy specimens showed the presence of several abnormal tubules. Immunofluorescent staining showed deposits of immunoglobulins in the glomeruli and tubules. Magnesium therapy was started under balance study conditions and resulted in decreased calcluria and complete remission of subjective symptoms. The progression of nephrocalcinosis was halted, and there was some decrease in the intra-articular calcium deposits after two years of continuous oral magnesium therapy. The administration of spironolactone decreased urinary magnesium but did not normalize it, whereas triamterene administration was without effect in this respect. The results of the morphologic and electrolyte balance studies are discussed. The patient was found to exhibit several features which have not been described before in connection with hypomagnesemia of unknown origin.

ON CHANGES IN BLOOD VESSEL WALL ELECTROLYTES AND THE ADRENAL CORTEX IN EXPERIMENTAL HYPERTENSION

Reactivity to pressor substances increases in hypertensive subjects, while it decreases in patients suffering from secondary aldosteronism with edema. It is generally recognized that the contraction of vascular smooth muscle is influenced by the concentration of electrolytes in extracellular and intracellular fluid. Comparisons were made of the electrolyte content of the various tissues in hypertensive rats and those in rats with edema. The adrenal cortices of hypertensive rats caused by the constriction of the unilateral renal artery were studied histologically. Discussions were made of the role that aldosterone plays in renal hypertension of vascular origin. Materials and Methods Male Wister rats were divided into eleven groups and received each treatment as follows. A) control, B) the clipping of the unilateral renal artery, C) administration of triamterene to the hypertensive rats caused by the clipping of the renal artery, D) administration of aldosterone, E) administration of corticosterone, F) administration of aldosterone and corticosterone, G) administration of DOCA, H) administration of DOCA and NaCl, I) administration of aminonucleoside, J) administration of aminonucleoside and triamterene, K) administration of carbon tetrachloride. Blood pressure was determined, and the sodium and potassium content of the aorta, psoas muscle and heart muscle were measured. The adrenal glands of the renal hypertensive rats were removed, stained with hematoxylin-eosin or scarlet-red and submitted to histological examination. Results 1) Blood pressure and sodium and potassium content of the aorta. Blood pressure became elevated one week after the clipping of the renal artery The sodium content of the aorta increased slightly, and the potassium content increased significantly in rats in which hypertension was noted two weeks after the clipping. Both sodium and Potassium content increased significantly ten weeks after the clipping. Blood pressure in renal hypertensive rats failed to fall and the sodium and potassium content remained elevated despite the administration of triamterene. The administration of DOCA and NaCl induced elevation of blood pressure. In this group, both sodium and potassium content of the aorta increased significantly. In other groups to which the steroids of the adrenal cortex were administered, blood pressure was not elevated. In some groups of these normotensive rats, the sodium content of the aorta increased but the potassium content did not increase. The sodium content increased, while the potassium content decreased in rats with nephrosis caused by aminonucleoside and in rats with cirrhosis of the liver caused by carbon tetrachloride.

A new enzyme test for gynaecological cancer: Bonham and Gibbs: p. 823

Baba, Tudhope, and Wilson: Triamterene, A New Diuretic Drug, II, p. 760. The individual and combined effects of triamterene, spironolactone, and hydroflumethiazide are compared in 42 patients with chronic salt and water retention. Triamterene, when administered alone, is a weak diuretic agent. Hydroflumethiazide produces a greater water and sodium excretion than does triamterene. When the two drugs are used simultaneously, potentiation of effects of each is evident in further increase in sodium and water excretion and decreased potassium excretion. Potassium retention is greatest with triamterene administration, and levels of serum potassium must be closely watched during its use. Triamterene also appears to potentiate the action of spironolactone and hydroflumethiazide when the 3 are administered together. This combination was the optimum for patients with refractory edema. Edward E. Wallach