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PubMed1979

[On the mechanism of the positive inotropic effect of triamterene on the myocardium (author's transl)].

The influence of triamterene on the contractile force and the cellular electrolyte content and exchange was studied in isolated, electrically stimulated guinea-pig atria. 1. Triamterene (40 to 200 mumol/l) produces a positive inotropic effect which is most pronounced when the extracellular calcium concentration is reduced (1.2 to 0.6 mmol/l) or the contractile force is diminished by pentobarbital (400 mumol/l). The inotropic action of triamterene was shown to be independent of the rate of stimulation (1--2 Hz). 2. By pretreatment with the adrenergic beta-receptor blocking drugs bupranolol and pindolol or by reserpinization the positive inotropic effect of triamterene was not significantly altered. 3. After incubating the atrial preparations with 45calcium for 30 min the intracellularly exchangeable calcium fraction was significantly enhanced by triamterene (100 mumol/l). If triamterene was added to the bathing medium after the 45calcium exchange process had already reached a steady-state, no further increase in the extent of the intracellular calcium exchange was observed during an additional 30-min period of incubation. Since the cellular total calcium content shows remained unchanged it is postulated that the increase in calcium influx is balanced by a simultaneous elevation of calcium efflux. In addition, triamterene did not show any influence on the intracellular potassium, sodium and magnesium content as well as on the extracellular space volume.

Adrenergic beta-Antagonists↗
PubMed1977

[Mechanism of the cardioprotective effect of triamterene in the rat heart. Myocardial protection via elevation of extracellular K+ and Mg++ concentrations].

1. 2,4,7-Triamino-6-phenyl-pteridine (triamterene) protects the rat heart against isoproterenol-induced myocardial lesions: Whilst cardiotoxic doses of isoproterenol produce deleterious myocardial Ca overload, simultaneous admistration of triamterene diminishes myocardial Ca incorporation considerably. 2. As to the mechanism of action, triamterene increases the plasma contents of K and Mg by inhibiting renal excretion. Accordingly, oral administration of K and Mg salts, leading to a similar rise in the K and Mg concentrations of the plasma, also prevents abundant myocardial Ca incorporation. 3. Cardioprotection by triamterene can, in fact, be simply explained by its action on the plasma K and (particularly) Mg levels. This conclusion is drawn from a quantitative comparison of the inhibitory effects of triamterene (40 mg/kg s.c.) with those of KCl or MgCl2 (10 mMol/kg p.o.) on the isoproterenol-induced increase in myocardial 45Ca uptake and absolute Ca concentration. 4. Isoproterenol induced cardiomyopathy of the rat, an experimental model of non-coronarogenic myocardial lesions, has hitherto been successfully prevented with the use of Ca-antagonists (verapamil, D 600, prenylamine, fendiline). These compounds reduce Ca influx by restricting the Ca conductivity of the myocardial sarcolemma membrane ("slow channel"). The action of triamterene, on the other hand, is based on a totally different cardioprotective principle, namely competitive inhibition of intracellular myocardial Ca accumulation via an increase in K and Mg supply. In the future treatment of cardiomyopathy it seems rather promising to try a combination of both a Ca-antagonist and triamterene, thus applying two different therapeutic principles simultaneously.

Animals↗
PubMed1985

Effect of triamterene on 5-hydroxytryptamine biosynthesis in different brain areas.

Triamterene is structurally similar to the natural cofactor of tryptophan hydroxylase, (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin. The hydroxylation of tryptophan has been studied by measuring the accumulation of 5-hydroxytryptophan (5-HTP) and the concentrations of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in brainstem, frontal cortex and hypothalamus after inhibition of L-amino acid decarboxylase with benserazide hydrochloride and administration of either the vehicle or triamterene. Triamterene (30 mg/kg i.p.) decreased 5-HTP accumulation and 5-HT concentrations in brainstem and hypothalamus after 90 min; when the diuretic was given p.o. either acutely or chronically (triamterene 30 mg/kg twice daily during 4 days), no effect either on 5-HTP accumulation or on 5-HT and 5-HIAA concentrations was observed in the three brain areas studied. These results are in accordance with the 4 to 5 times higher concentrations of triamterene plus metabolites found in brainstem and hypothalamus after the acute i.p. administration of the drug than after an acute or chronic p.o. treatment. Hence, the effect of triamterene on 5-HT biosynthesis depends on the concentration it reaches in each brain area after i.p. or p.o. administration.

5-Hydroxytryptophan↗
PubMed1991

Irreversible renal failure associated with triamterene.

A 66-year-old man was admitted with acute oliguric renal failure. The patient was known to have chronic heart failure (ejection fraction 13%) and his medication included furosemide, digoxin and triamterene. Physical examination was unremarkable, and blood pressure was 170/80 mm Hg. Serum creatinine was 1,173 mumol/l. Renal ultrasound, CT scan and angiogram were normal. Despite correction of potential reversible factors and discontinuation of triamterene, renal function did not improve. Renal biopsy showed tubular obstruction with deposition of birefringent crystals and interstitial lymphocytic infiltration; the crystals emitted a blue autofluorescence at 425 nm, typical of triamterene. Renal tissue contained large amounts of triamterene (6.44 mg/g kidney at the initial biopsy and 400 micrograms/g kidney 5 months later). Triamterene has been previously reported to cause acute reversible renal failure, but to our knowledge, this is the first case of irreversible renal failure due to intratubular obstruction by triamterene crystal deposition.

Acute Kidney Injury↗
PubMed1976

[Inhibition of the exchange of Na+ for K+ and and H+ by triamterene (in epithelia)(author's transl)].

The salivary duct epithelium, which actively transports Na+, K+ and H+/HCO3/- similarly to renal distal tubules, was used as a model tissue to study the mechanism of action of triamterene (Jatropus, Dyrenium) on electrolyte transport. Triamterene was only effective when administered from the luminal side of the duct, not from the interstitial side. 10-4 M triamterene completely blocked Na+-reabsorption. At the same time K+ secretion dropped to half of control, whereas HCO-/3 accumulated in the duct lumen following reduced H+ secretion. These changes in electrolyte transport are caused by an inhibition of Na+-entry by triamterene as suggested by measurements of ion permeability of the cell membrane. Triamterene has no specific effect on the membrane-bound ATPase. Since Na+-entry is functionally coupled with exit of K+ and H+ from cell to lumen, impairment of Na+-entry by triamterene necessarily causes reduction of K+ and H+ secretion into lumen.

Adenosine Triphosphatases↗
PubMed1991

Antiarrhythmic properties of benzyl-triamterene derivatives in the coronary artery ligated and reperfused rat.

Triamterene (CAS 396-01-0) and a series of benzyl-triamterene derivatives were evaluated for their antiarrhythmic properties in the coronary artery ligated and reperfused (CAL-R) rat. The effects were compared with the antiarrhythmic activity of the potassium sparing diuretic amiloride and drugs out of the class-I (lidocaine) and class-III (amiodarone and sotalol). Triamterene and sotalol revealed at high doses antifibrillator activity, while the benzyl-triamterenes 2, 3, 5 and 6 could also depress ventricular extrasystoles (VES) and ventricular tachycardia (VT). At low doses the most benzyltriamterenes protected significantly against ventricular fibrillation (VF) and so they were equieffective or more effective than amiodarone or lidocaine. Amiloride showed in the CAL-R rat no antiarrhythmic activity, so that we conclude different mechanisms responsible for antikaliuretic and antiarrhythmic properties of amiloride and triamterenes. Taking into account the results of recently reported in vitro studies, where we could demonstrate antiarrhythmic activity combined with positive inotropic properties for triamterenes, the antiarrhythmic profile of these compounds may offer new possibilities for the treatment of ventricular arrhythmias.

Animals↗
PubMedDate not supplied

Transfer characteristics of triamterene and its analogs. Central nervous system, placenta, and kidney.

Earlier in vivo studies revealed a low concentration of triamterene in the brain of guinea pigs and baboons, and a transfer of the drug from the fetus to the mother. Additional investigations have been performed to characterize further the transport system(s) for triamterene in the central nervous system (CNS), placenta, and kidney. In guinea pigs a very low brain to free plasma concentration ratio (0.1) was achieved 3.5 min after drug administration and was maintained during 180 min of drug infusion. The cerebrospinal fluid (CSF) concentration was similar to the concentration of the drug in the brain. A higher brain to free plasma concentration ratio was gradually reached in dogs studied with nanogram per ml and microgram per ml concentrations of triamterene in CSF. Administration of triamterene to fetal and maternal sheep revealed a placental extraction (E) from fetal plasma to placenta 20 times greater than that from maternal plasma to placenta. The E from fetal plasma to placenta was unaffected by a triamterene concentration in the maternal circulation 10 times that in the fetus. These findings and studies of renal clearance support an active transfer of triamterene by the CNS, placenta, and kidney; the physiologic substrate for these systems is unknown.

Amiloride↗
PubMed1987

Interaction of phosphodiesterase inhibitors triamterene, papaverine, theophylline, IBMX and amrinone with other positive inotropic acting substances on isolated guinea-pig atria.

On isolated electrically stimulated left and spontaneously beating right guinea-pig atria the interaction between PDE-inhibitors and the positive inotropic and chronotropic action of orciprenaline, forskolin and histamine in dose-response curve was examined. The experiments led to the following results: triamterene (20-120 mumol/l) and papaverine (10-100 mumol/l) inhibit the positive inotropic and chronotropic action of orciprenaline, whereas theophylline (10-100 mumol/l) and isobutyl-methyl-xanthine (0.1-10 mumol/l) only inhibit the inotropic action of orciprenaline. Amrinone (100-316 mumol/l) increases the positive inotropic and chronotropic action of orciprenaline; the positive inotropic and chronotropic action of forskolin is inhibited by triamterene but not by theophylline and IBMX. The positive chronotropic action of forskolin and histamine is inhibited by triamterene, whereas the positive inotropic action of histamine is not influenced; our experimental results suggest that triamterene and papaverine antagonize orciprenaline action by inhibition of adenylate cyclase. For this there is further evidence in the antagonism between triamterene and the inotropic action of forskolin and the tachycardic action of histamine. As theophylline and IBMX inhibit only the inotropic action of orciprenaline, there might be a different mechanism for their interaction regarding the chronotropic action of orciprenaline compared to triamterene and papaverine. The amrinone mechanism differs from that of the other PDE-inhibitors as it increases the positive inotropic and chronotropic action of orciprenaline.

1-Methyl-3-isobutylxanthine↗
PubMed1982

[Triamterene induced nephrolithiasis (author's transl)].

Various studies have demonstrated a relationship between nephrolithiasis and the ingestion of certain drugs. We are particularly interested in the effects of triamterene. Five published case studies on patients of both sexes between 43 and 60 years of age have proven that a regular consumption of normal doses of triamterene has a direct effect upon the formation of renal stones. The stones analysed by infra-red spectrophotometry during the above observations contained from 20 to 100% of triamterene and it's metabolite hydroxytriamterene, following a daily consumption of 150 to 350 mg during a period of 6 to 38 months. It has been confirmed that triamterene and it's metabolite hydroxytriamterene are very poorly soluble and super-saturate the urine for a brief period following the ingestion of the drug. Triamterene might also intervene in the initial phenomena of nucleation. It is therefore recommended that triamterene be used with caution in those patients presenting a history of nephrolithiasis. The existence of drug induced nephrolithiasis reinforces the importance of the technique of renal stone analysis, and the necessity of a systematic study of all renal stones found. This will allow us to develop the study of the correlations between the different episodes of renal stone disease, the nature of the treatment undertaken and the systematic analysis, layer by layer, of the stone.

Adult↗
PubMed1980

Triamterene nephrolithiasis.

We identified triamterence in 181 renal calculi (o.4% of 50.000 calculi submitted for analysis). Triamterene formed the nucleus of the stone or was deposited with calcium oxalate or uric acid. One third of these stones were mainly or entirely triamterene, though a similar proportion had only minor amounts. A recommended dose of triamterene-hydrochlorothiazide sufficed to produce triamterene deposition in renal calculi. We estimate the annual incidence of the complication to be one per 1,500 users of triamterene-hydrochlorothiazide. Triamterene lithiasis develops particularly in persons who have had a renal stone, and they should not receive this drug.

Calcium Oxalate↗
PubMed1993

[The effect of triamterene on the ERG of Long-Evans rats].

Dopamine is an important mediator of the neuronal adaptation mechanism of the retina. Tetrahydrobiopterin (BH4) is cofactor of the rate-limiting enzymatic tyrosine-hydroxylase step in the biosynthetic pathway of dopamine. This enzymatic step causes an oxidation of BH4 to dihydrobiopterin (BH2), which is reduced again to BH4 by action of dihydropterin-reductase (DHPR) and dihydrofolate-reductase (DHFR). Triamterene, a pterin derivate, is known to induce DHFR after initial inhibition. Concomitant elevation of retinal BH4 will result in a higher dopamine concentration. ERG changes of Long-Evans rats mediated by this triamterene effect on dopamine concentration were examined after the rats received triamterene with tap water in two experimental series for 5 and 11 days. After 5 days of triamterene administration a significant decrease of scotopic a- and b-wave ERG amplitudes were registered. After 11 days of triamterene application the decrease could be shown to be even more substantial. This effect was completely reversible: 10 weeks after cessation of triamterene supply ERG amplitudes increased to previous levels. The observed transient ERG changes support the concept of biopterin as an mediator of neuronal adaptation mechanisms of the retina.

Animals↗
PubMed1997

Pharmacokinetics and pharmacodynamics of triamterene and hydrochlorothiazide and their combination in healthy volunteers.

Although triamterene has been in clinical use for over 30 years, the linearity of triamterene kinetics was not systematically tested. Moreover, although triamterene is mostly applied concomitantly with thiazide-type diuretics the interaction of triamterene (TA) with hydrochlorothiazide (HCT) is subject to a controversial discussion. Therefore, the aim of this study was to examine the dose linearity of TA and the pharmacokinetic and pharmacodynamic interaction of triamterene and hydrochlorothiazide. In the first study 10 healthy volunteers received 0, 12.5, 25, 50, and 100 mg triamterene orally in a balanced crossover design. In the second study 0, 25, and 50 mg TA with 12.5, and 25 mg HCT, respectively, were administered to 12 healthy volunteers. Urine volume and concentration of sodium, TA, hydroxytriamterene sulfate (OH-TA ester), and HCT were measured by flame photometry and thin-layer chromatography, respectively. The observation period for each treatment was 3 days and the drug was given on the second day. Sodium excretion was increased by both drugs. Renal excretion of both TA and OH-TA ester seemed to be reduced at higher doses. However, statistical evaluation revealed no significant (p = 0.37, and p = 0.20, respectively) deviation from linearity. Renal excretion of HCT was not affected by TA and vice versa. However, renal excretion of OH-TA ester is significantly reduced when HCT is administered concomitantly. The renal excretion rate of sodium can be described by a common Emax model when the effects of the excretion rates of both TA and HCT are additive. It is concluded that the pharmacokinetics of TA is linear within the tested dose range and that pharmacodynamic additivity of HCT and TA is not due to a pharmacokinetic interaction. The results support the hypothesis of a sequential nephron blockade for both drugs acting on different tubular segments.

Adult↗
PubMed1977

Distribution and pharmacokinetics of triamterene in rats.

The tissue distribution of 14C-triamterene was examined in the fact. After intravenous administration of 14C-triamterene, high concentration ratios between tissues and blood were found in most tissues except the brain, fat, and testes. The maximal concentration of the drug was in the kidneys, liver, heart, lungs, and skeletal muscle within the first 20 min, when the maximal natriuresis was observed. No metabolite of triamterene was detected in these tissues. The pharmacokinetics of 14C-triamterene also were investigated. The volume of distribution of the drug was greater in the central compartment (60% of the dose) than in the peripheral compartment (40%). The binding of the drug to skeletal muscle is responsible for the fraction of the dose in the peripheral compartment. Rate constants indicate that slow elimination of triamterene is related to its binding to tissue in the central compartment.

Animals↗
PubMed1984

Absence of a significant pharmacokinetic interaction between hydrochlorothiazide and triamterene when coadministered.

Hydrochlorothiazide, triamterene, and hydroxytriamterene sulfate were monitored in the plasma and urine of 24 healthy young men taking single doses of a liquid preparation containing both hydrochlorothiazide and triamterene, liquid preparations containing either of these drugs alone, and a combination tablet recently formulated with a dose ratio of hydrochlorothiazide : triamterene (1 : 1.5) found to give optimal potassium-sparing effect. In contradiction to a recent publication, no interaction between the drugs affecting the bioavailability or renal clearance of either could be demonstrated. The previous report of drug-drug interaction probably arose from formulation-related problems with bioavailability from the two capsule and two tablet products which had been studied. A well-formulated hydrochlorothiazide-triamterene combination tablet promotes plasma concentrations and urinary excretion of hydrochlorothiazide, triamterene, and hydroxytriamterene sulfate which are virtually identical to those seen after either a combination liquid dosage form or simple liquid forms containing only one of the two drugs.

Adult↗
PubMed1986

Lack of in vivo mutagenicity and testicular toxicity of triamterene in mice.

Triamterene (2,4,7-triamino-6-phenylpteridine), a widely used diuretic/antihypertensive agent with weak antifolate activity, has been found to be positive in several in vitro assays for mutagenicity. The present studies were undertaken to characterize the potential mutagenic and antifolate activity of triamterene in the bone marrow and testes of mice with in vivo treatment. Triamterene had no clastogenic effects on the bone marrow at 6, 16, or 24 hr after a single oral dose of 25, 125, or 250 mg/kg. No alterations in hematopoietic cell maturation characteristic of antifolate action were observed in a dose-range study in which triamterene was orally administered to mice at 5-300 mg/kg/day for 5 days. Triamterene had no adverse effects on mating or fertility and did not induce dominant lethal mutations in the germ cells of male mice when given for 5 days at 5-100 mg/kg/day. Oral exposure to mice under identical conditions had no effect on testicular weight, DNA content, or activity of the de novo pathway for thymidine synthesis from deoxy [6-3H]uridine. The present findings are consistent with an absence of mutagenic effect and antifolate action on the bone marrow and testes with in vivo administration.

Animals↗
PubMed1985

Blood pressure lowering and potassium conservation by triamterene-hydrochlorothiazide and amiloride-hydrochlorothiazide in hypertension.

Effects of once-daily doses of 50 mg triamterene with 25 mg hydrochlorothiazide and 5 mg amiloride with 50 mg hydrochlorothiazide were compared in a randomized, multicenter study of 84 adult subjects with mild to moderate hypertension (diastolic blood pressure 90 to 114 mm Hg). After a 3-wk placebo lead-in period, the subjects entered a 6-wk treatment period. The two drug regimens were compared with respect to antihypertensive effects and effects on serum potassium and magnesium levels during the final week of drug therapy, with the use of the last week of placebo therapy as a covariate. Both drug regimens substantially reduced mean supine systolic and diastolic blood pressures to well within normal limits; there was no significant difference the two groups. Twenty-four of the 41 subjects receiving triamterene-hydrochlorothiazide (59%) and 29 of the 43 patients receiving amiloride-hydrochlorothiazide (67%) had diastolic blood pressure less than 90 mm Hg at week 9. Five subjects receiving amiloride-hydrochlorothiazide (12%) and two subjects receiving triamterene-hydrochlorothiazide (5%) had hypokalemia (serum potassium level less than 3.5 mEq/l) at week 9. The average decrease in serum potassium levels during amiloride-hydrochlorothiazide therapy (-0.33 +/- 0.08 mEq/l) was greater than that after triamterene-hydrochlorothiazide (- 0.08 +/- 0.07 mEq/l). Serum magnesium levels were not changed by either regimen. Weight loss was greater in the amiloride-hydrochlorothiazide group than in the triamterene-hydrochlorothiazide group.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1986

Absorption and disposition of two combination formulations of hydrochlorothiazide and triamterene: influence of age and renal function.

In this study we compared the absorption and disposition of two commonly used combination formulations of hydrochlorothiazide and triamterene (Dyazide and Maxzide) in 48 patients with essential hypertension after dosing with each formulation to steady state. Interdose AUC and urinary recovery of hydrochlorothiazide, triamterene, and the major metabolite of triamterene, hydroxytriamterene sulfate (adjusted for dose), documented marked impairment in the absorption of hydrochlorothiazide (approximately two third as bioavailable) and triamterene (about half as bioavailable) from Dyazide in comparison to Maxzide. The study also demonstrated a reduction in the clearance of triamterene, hydrochlorothiazide, and hydroxytriamterene sulfate with increasing age. Linear correlation analyses suggested that this effect was a result of the reduction in renal function that occurs with increasing age.

Absorption↗
PubMed1994

Triamterene inhibits the delayed rectifier potassium current (IK) in guinea pig ventricular myocytes.

In humans, proarrhythmia during therapy with action potential-prolonging drugs can be associated with hypokalemia often provoked by concomitant administration of diuretic agents. Consequently, therapy with class III antiarrhythmics and K(+)-sparing diuretics, such as triamterene, may be indicated. Triamterene, along with its K(+)-sparing properties, exhibits other pharmacological effects. In the heart, it can increase action potential duration (guinea pig atria and papillary muscles), protect against reperfusion-induced arrhythmias (rat), and increase the QT interval (humans). Therefore, studies were undertaken to assess effects of triamterene on cardiac K+ repolarizing currents. Guinea pig ventricular myocytes were superfused at 30 degrees C with Cd(2+)-containing solution to block Isi and held at -40 mV to inactivate INa. Currents were measured in the whole-cell configuration of the patch-clamp technique. The delayed rectifier outward current (IK) was elicited by short (250-millisecond) and long (5000-millisecond) depolarizing pulses, and time-independent currents were assessed by a rapid ramp test protocol. After high-voltage long pulses (+50 mV; 5000 milliseconds), tail current amplitude of the slow component of IK (IKs) was decreased 36 +/- 6% (n = 6) and 51 +/- 8% (n = 6) by triamterene 10(-5) and 10(-4) mol/L, respectively. After low-voltage short pulses (-20 mV; 250 milliseconds), tail current amplitude corresponding essentially to the rapid component of IK (IKr) was decreased only 14 +/- 11% (n = 9) and 19 +/- 10% (n = 10) by triamterene 10(-5) and 10(-4) mol/L, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗