Triamterene

Absorption

Triamterene is shown to be rapidly absorbed in the gastrointestinal tract Its onset of action achiveved within 2 to 4 hours after oral ingestion and its duration of action is 12-16 hours. It is reported that the diuretic effect of triamterene may not be observed for several days after administration. In a pharmacokinetic study, the oral bioavailability of triamterene was determined to be 52%. Following administration of a single oral dose to fasted healthy male volunteers, the mean AUC of triamterene was about 148.7 ng*hr/mL and the mean peak plasma concentrations (Cmax) were 46.4 ng/mL reached at 1.1 hour after administration. In a limited study, administration of triamterene in combination with hydrochlorothiazide resulted in an increased bioavailability of triamterene by about 67% and a delay of up to 2 hours in the absorption of the drug. It is advised that triamterene is administered after meals; in a limited study, combination use of triamterene and hydrochlorothiazide with the consumption of a high-fat meal resulted in an increase in the mean bioavailability and peak serum concentrations of triamterene and its active sulfate metabolite, as well as a delay of up to 2 hours in the absorption of the active constituents.

Toxicity

Acute oral LD50 of triamterene in rats is 400 mg/kg and 285-380 mg/kg in mice. There has been a case of reversible acute renal failure following ingestion of 50 combination pills containing 50 mg triamterene and 25 mg hydrochlorothiazide. Symptoms of overdose, such as nausea, vomiting, gastrointestinal disturbances, weakness, and hypotension, are related to electrolyte imbalances, such as hyperkalemia. As there is no specific antidote, emesis and gastric lavage should be use to induce immediate evacuation of the stomach and careful evaluation of the electrolyte pattern and fluid balance should be made. Dialysis may be somewhat effective in case of an overdosage.
In a carciongenicity study in male and female mice administered with triamterene at the highst dosage level, there was an increased incidence of hepatocellular neoplasia, primarily adenomas. However, this was not a dose-dependent phenomenon and there was no statistically significant difference from control incidence at any dose level. In bacterial assays, there was no demonstrated mutagenic potential of triamterene. In in vitro assay using Chinese hamster ovary (CHO) cells with or without metabolic activation, there were no chromosomal aberrations. Studies evaluating the effects of triamterene on reproductive system or fertility have not been conducted. It is advised that the use of triamterene is avoided during pregnancy. As triamterene has been detected in human breast milk, triamterene should be used when nursing is ceased.

Description

Triamterene is an inhibitor of the epithelial sodium channel (ENaC; IC₅₀ = 4.5 μM for the rat channel). In vivo, triamterene (0.5-32 mg/animal) enhances sodium secretion and decreases potassium secretion in adrenalectomized rats. Formulations containing triamterene have been used in the treatment of edema. This product is also available as an analytical reference standard .

Chemical properties

Yellow Solid

Originator

Jatropur,Rohm,W. Germany,1962

The Uses of Triamterene

Triamterene is a potassium-sparing diuretic ie, it inhibits the urinary excretion of potassium

The Uses of Triamterene

Triamterene is a weak diuretic with potassium sparing properties; blocks Na+ reuptake in the kidneys.

The Uses of Triamterene

This drug is recommended in combination with other diuretics for treating edema caused by usual reasons such as circulatory insufficiency, cirrhosis of the liver, and nephrotic syndrome.

What are the applications of Application

Triamterene is an Na+ channel blocker

Background

Triamterene (2,4,7-triamino-6-phenylpteridine) is a potassium-sparing diuretic that is used in the management of hypertension. It works by promoting the excretion of sodium ions and water while decreasing the potassium excretion in the distal part of the nephron in the kidneys by working on the lumenal side. Since it acts on the distal nephron where only a small fraction of sodium ion reabsorption occurs, triamterene is reported to have limited diuretic efficacy. Due to its effects on increased serum potassium levels, triamterene is associated with a risk of producing hyperkalemia. Triamterene is a weak antagonist of folic acid, and a photosensitizing drug.
Triamterene was approved by the Food and Drug Administration in the U.S. in 1964. Currently, triamterene is used in the treatment of edema associated with various conditions as monotherapy and is approved for use with other diuretics to enhance diuretic and potassium-sparing effects. It is also found in a combination product with hydrochlorothiazide that is used for the management of hypertension or treatment of edema in patients who develop hypokalemia on hydrochlorothiazide alone.

Indications

Triamterene is indicated for the treatment of edema associated with congestive heart failure, cirrhosis of the liver, and the nephrotic syndrome; also in steroid-induced edema, idiopathic edema, and edema due to secondary hyperaldosteronism.
Triamterene in combination with hydrochlorothiazide is indicated for the managment of hypertension or treatment of edema in patients who develop hypokalemia following hydrochlorothiazide monotherapy, and in patients who require thiazide diuretic and in whom the development of hypokalemia cannot be risked. Triamterene allows the maintenance of potassium balance when given in combination with loop diuretics and thiazides.

Definition

ChEBI: Triamterene is pteridine substituted at positions 2, 4 and 7 with amino groups and at position 6 with a phenyl group. A sodium channel blocker, it is used as a diuretic in the treatment of hypertension and oedema. It has a role as a diuretic and a sodium channel blocker.

Manufacturing Process

To a solution of 9 grams of 5-nitroso-2,4,6-triaminopyrimidine in 500 mi of refluxing dimethylformamide is added 9 grams of phenylacetonitrile and the refluxing is stopped. The 3 grams of anhydrous sodium methoxide is added and the mixture is refluxed for 15 minutes. The mixture is chilled and the solid is filtered and washed several times with warm water until the washings are neutral. Drying gives yellow crystals which are recrystallized with a Darco treatment from formamide-water heating the solution no hotter than 125°C.
This product is then suspended in filtered deionized water and warmed for 15 minutes. This yields the 2,4,7-triamino-6-phenylpteridine as yellow crystals with a MP of 314° to 317°C.

Therapeutic Function

Diuretic

Biological Functions

Triamterene (Dyrenium) results in changes in urinary electrolyte patterns that are qualitatively similar to those produced by spironolactone. The mechanism by which this agents bring about the alterations in electrolyte loss, however, is quite different. Triamterene produces this effects whether or not aldosterone or any other mineralocorticoid is present. The action of this drug is clearly unrelated to endogenous mineralocorticoid activity, and this drug is effective in adrenalectomized patients.

General Description

Odorless yellow powder or crystalline solid. Melting point 316°C. Almost tasteless at first and with a slightly bitter aftertaste. Acidified solutions give a blue fluorescence. Used as a diuretic drug.

Air & Water Reactions

Sensitive to light; slowly oxidized upon exposure to air. Insoluble in water.

Reactivity Profile

2,4,7-Triamino-6-phenylpteridine neutralizes acids in exothermic reactions to form salts plus water. May be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen may be generated in combination with strong reducing agents, such as hydrides.

Fire Hazard

Flash point data for 2,4,7-Triamino-6-phenylpteridine are not available; however, 2,4,7-Triamino-6-phenylpteridine is probably combustible.

Mechanism of action

Triamterene is a pyrazine derivative that inhibits reabsorption of sodium ions without increasing excretion of potassium ions. It exhibits the same approximate effect as spironolactone; however, it does not competitively bind with aldosterone receptors. Its action does not have an effect on secretion of aldosterone or its antagonists, which are a result of direct action on renal tubules.
This potassium sparing diuretic causes a moderate increase in excretion of sodium and bicarbonate ions in urine, and it raises excretion of potassium and ammonia ions. It has little effect on urine volume.

Pharmacokinetics

Triamterene, a relatively weak, potassium-sparing diuretic and antihypertensive, is used in the management of hypertension and edema. It primarily works on the distal nephron in the kidneys; it acts from the late distal tubule to the collecting duct to inhibit Na+ reabsorption and decreasing K+ excretion. As triamterene tends to conserve potassium more strongly than promoting Na+ excretion, it can cause an increase in serum potassium, which may result in hyperkalemia potentially associated with cardiac irregularities. In healthy volunteers administered with oral triamterene, there was an increase in the renal clearnace of sodium and magnesium, and a decrease in the clearance of uric acid and creatinine due to its effect of reducing glomerular filtration renal plasma flow. Triamterene does not affect calcium excretion. In clinical trials, the use of triamterene in combination with hydrochlorothiazide resulted an enhanced blood pressure-lowering effects of hydrochlorothiazide.

Clinical Use

Triamterene can be used in the treatment of congestive heart failure, cirrhosis, and the edema caused by secondary hyperaldosteronism. It is frequently used in combination with other diuretics except spironolactone. Amiloride, but not triamterene, possesses antihypertensive effects that can add to those of the thiazides. These K⁺-sparing diuretics have low efficacy when used alone, since only a small amount of total Na reabsorption occurs at more distal sites of the nephron.
These compounds are used primarily in combination with other diuretics, such as the thiazides and loop diuretics, to prevent or correct hypokalemia. The availability of fixed-dose mixtures of thiazides with nonsteroidal K⁺-sparing compounds has proved a rational form of drug therapy. Both triamterene and amiloride are available alone or in combination with hydrochlorothiazide.

Side Effects

Because the actions of triamterene and amiloride are independent of plasma aldosterone levels, their prolonged administration is likely to result in hyperkalemia. Both amiloride and triamterene are contraindicated in patients with hyperkalemia.Triamterene should not be given to patients with impaired renal function. Potassium intake must be reduced, especially in outpatients.A folic acid deficiency has been reported to occur occasionally following the use of triamterene.

Synthesis

Triamterene, 2,4,7-triamino-6-phenylpteridine (21.5.13), is synthesized in by the following scheme. Reacting guanidine with malonodinitrile gives 2,4,6-triaminopyrimidine (21.5.11). This undergoes nitrosation by reacting it with nitric acid, which results in the formation of 5-nitroso-2,4,6-triaminopyrimidine (21.5.12), which upon condensation with benzyl cyanide in the presence of sodium methoxide cyclizes into triamterene (21.5.13).

Veterinary Drugs and Treatments

Triamterene is a potassium-sparing diuretic that potentially could be used as an alternative to spironolactone for the adjunctive treatment of congestive heart failure in dogs, however, there is little experience associated with its use in dogs or cats.

Drug interactions

Potentially hazardous interactions with other drugs
ACE inhibitors and angiotensin-II antagonists: enhanced hypotensive effect (risk of severe hyperkalaemia).
Analgesics: increased risk of nephrotoxicity with NSAIDs; increased risk of hyperkalaemia, especially with indometacin; antagonism of hypotensive effect.
Antibacterials: avoid concomitant use with lymecycline.
Antidepressants: enhanced hypotensive effect with MAOIs; increased risk of postural hypotension with tricyclics.
Antipsychotics: enhanced hypotensive effect with phenothiazines.
Antihypertensives: enhanced hypotensive effect; increased risk of first dose hypotensive effect of postsynaptic alpha-blockers, e.g. prazosin.
Ciclosporin: increased risk of hyperkalaemia.
Cytotoxics: increased risk of nephrotoxicity and ototoxicity with platinum compounds.
Lithium: reduced excretion of lithium (risk of lithium toxicity).
Potassium salts: increased risk of hyperkalaemia.
Tacrolimus: increased risk of hyperkalaemia.

Metabolism

Triamterene undergoes phase I metabolism involving hydroxylation, via CYP1A2 activity, to form 4'-hydroxytriamterene. 4'-Hydroxytriamterene is further transformed in phase II metabolism mediated by cytosolic sulfotransferases to form the major metabolite, 4′-hydroxytriamterene sulfate, which retains a diuretic activity. Both the plasma and urine levels of this metabolite greatly exceed triamterene levels while the renal clearance of the sulfate conjugate was les than that of triamterene; this low renal clearance of the sulfate conjugate as compared with triamterene may be explained by the low unbound fraction of the metabolite in plasma.

Metabolism

Triamterene is extensively metabolised apparently via the cytochrome P450 isoenzyme CYP1A2. It is mainly excreted in the urine in the form of metabolites with some unchanged triamterene; variable amounts are also excreted in the bile.