Triamterene

Triamterene is an antihypertensive agent belonging to Potassium Sparing Diuretics.

Triamterene is a potassium-sparing diuretic used alone or in combination with other medicines to treat edema (swelling) and fluid retention associated with various conditions of heart, liver, and kidney.

Triamterene is rapidly absorbed in the gastrointestinal tract. Its onset of action achieved within 2 to 4 hours after oral ingestion and its duration of action is 12-16 hours. The mean peak plasma concentrations (Cmax) were 46.4 ng/mL reached at 1.1 hour after administration. The volumes of distribution of triamterene and its hydroxylated ester metabolite were 1.49 L/kg and 0.11 L/kg, respectively. Approximately

67% of Triamterene bound to proteins. Triamterene was found to cross the placental barrier and appear in the cord blood of animals. Triamterene undergoes phase I metabolism involving hydroxylation, via CYP1A2 activity, to form 4'-hydroxytriamterene. The half-life of the drug in plasma ranges from 1.5 to 2 hours. Triamterene and its metabolites are excreted by the kidney by filtration and tubular secretion. Upon oral ingestion, somewhat less than 50% of the oral dose reaches the urine. About 20% of an oral dose appears unchanged in the urine, 70% as the sulphate ester of hydroxy triamterene and 10% as free hydroxy triamterene and triamterene glucuronide.

Triamterene shows common side effects Dizziness, lightheadedness, tiredness, headache, stomach upset, or diarrhea, confusion, unusual dry mouth/thirst, fast/irregular heartbeat, severe or seizures, etc.

Triamterene is available in the form of Oral Capsule.

Triamterene is available in India, US, UK, Austria, Canada, and Germany.

Triamterene belonging to the Potassium Sparing Diuretics acts as an antihypertensive agent.

Triamterene blocks epithelial sodium channels in the late distal convoluted tubule (DCT) and collecting duct which inhibits sodium reabsorption from the lumen. This effectively reduces intracellular sodium, decreasing the function of Na+/K+ ATPase, leading to potassium retention and decreased calcium, magnesium, and hydrogen excretion. As sodium uptake capacity in the DCT/collecting duct is limited, the natriuretic, diuretic, and antihypertensive effects are generally considered weak.

The onset of action of Triamterene is about 2-4 hours.

The Duration of Action for Triamterene is about 12-16 hours.

The Tmax was found within approximately 3 hours

Triamterene is a potassium-sparing diuretic used alone or in combination with other medicines to treat edema (swelling) and fluid retention associated with various conditions of heart, liver, and kidney. This medicine is not recommended for use in children below 18 years of age.

Triamterene is approved for use in the following clinical indications

• Edema

Triamterene is indicated in the treatment of edema associated with congestive heart failure, cirrhosis of the liver and the nephrotic syndrome; steroid-induced edema, idiopathic edema and edema due to secondary hyperaldosteronism. Triamterene may be used alone or with other diuretics, either for its added diuretic effect or its potassium-sparing potential. It also promotes increased diuresis when patients prove resistant or only partially responsive to thiazides or other diuretics because of secondary hyperaldosteronism.

• Edema

Initial: 50 to 100 mg once daily; titrate as needed based on patient response. Maximum: 300 mg/day in divided doses.

Triamterene is available in various strengths as 50mg and 100mg.

Triamterene is available in the form of Oral Capsule.

• Avoid potassium-containing salt substitutes such as Bananas, oranges, potatoes, peas, mushrooms, cantaloupe, honeydew, apricots, grapefruit, raisins, and dates, while you are taking Triamterene.

Triamterene is contraindicated in patients with

● Hypersensitivity to triamterene or any component of the formulation

● Anuria

● Severe or progressive kidney disease or dysfunction with the possible exception of nephrosis

● Severe hepatic disease

● Hyperkalemia

● Coadministration with other potassium-sparing agents or other formulations containing triamterene.

• Fluid/electrolyte loss

Triamterene can lead to profound diuresis with fluid and electrolyte loss; close medical supervision and dose evaluation are required. Patients with heart failure, renal disease, or cirrhosis may be particularly susceptible to fluid and electrolyte abnormalities. Watch for and correct electrolyte disturbances; adjust dose to avoid dehydration.

• Hyperkalemia

[US Boxed Warning]: Hyperkalemia can occur; patients at risk include those with renal impairment, diabetes, the elderly, and the severely ill. Serum potassium levels must be monitored at frequent intervals especially when dosages are changed or with any illness that may cause renal dysfunction. In patients who develop hyperkalemia or if hyperkalemia is suspected, obtain an electrocardiogram to rule out hyperkalemia induced QRS prolongation or other cardiac arrhythmias. Discontinue triamterene and any potassium supplementation in patients who develop hyperkalemia; treat cardiac arrhythmias as clinically indicated.

• Hypersensitivity reactions

Isolated occurrences have been reported. Observe for blood dyscrasias, liver damage or idiosyncratic reactions

• Photosensitivity

Can cause photosensitivity.

• Adrenal insufficiency

Avoid use of diuretics for treatment of elevated blood pressure in patients with primary adrenal insufficiency (Addison disease). Adjustment of glucocorticoid/mineralocorticoid therapy and/or use of other antihypertensive agents is preferred to treat hypertension (Bornstein 2016; Inder 2015).

• Diabetes

Use with caution in patients with prediabetes or diabetes mellitus; may increase blood glucose concentrations and necessitate dosage adjustment of hypoglycemic agents.

• Gout

May cause elevation in uric acid.

• Hepatic impairment

Use with caution in patients with severe hepatic dysfunction; in cirrhosis, avoid electrolyte and acid/base imbalances that might lead to hepatic encephalopathy.

• Kidney stones

Use with caution in patients with kidney stones.

• Abrupt discontinuation

In patients who have received triamterene for prolonged periods of time, a hypothetical risk of rebound kaliuresis may occur when abruptly discontinued; withdraw triamterene gradually in these patients.

Consumption of alcohol is not recommended during treatment with Triamterene due to the increased risk of side effects such as dizziness, lightheadedness, and fainting.

Triamterene has not been studied in nursing mothers. Triamterene appears in animal milk and is likely present in human milk. If use of the drug product is deemed essential, the patient should stop nursing.

Triamterene crosses the placenta and is found in cord blood. Use of triamterene to treat edema during normal pregnancies is not appropriate; use may be considered when edema is due to pathologic causes.

Avoid potassium-containing salt substitutes such as Bananas, oranges, potatoes, peas, mushrooms, cantaloupe, honeydew, apricots, grapefruit, raisins, and dates, while you are taking Triamterene.

• Common Adverse effects

Anaphylaxis, rash, photosensitivity, hyperkalemia, hypokalemia, azotemia, elevated Blood Urine Nitrigen (BUN) and creatinine, renal stones, acute renal failure, jaundice and/or liver enzyme abnormalities, nausea and vomiting, diarrhea, thrombocytopenia, megaloblastic anemia, weakness, fatigue, dizziness, headache, dry mouth.

• Rare Adverse effects

Acute interstitial nephritis, Inability to achieve or maintain an rection, agranulocytosis, thrombocytopenia.

• Lithium

Caution should be used when lithium and diuretics are used concomitantly because diuretic-induced sodium loss may reduce the renal clearance of lithium and increase serum lithium levels with risk of lithium toxicity. Patients receiving such combined therapy should have serum lithium levels monitored closely and the lithium dosage adjusted if necessary.

• Nonsteroidal anti-inflammatory agent

A possible interaction resulting in acute renal failure has been reported in a few subjects when indomethacin, a nonsteroidal anti-inflammatory agent, was given with triamterene. Caution is advised in administering nonsteroidal anti-inflammatory agents with triamterene.

• Combination therapy

The effects of the following drugs may be potentiated when given together with triamterene: antihypertensive medication, other diuretics, preanesthetic and anesthetic agents, skeletal muscle relaxants (non-depolarizing).

• Angiotensin-converting enzyme (ACE) inhibitors

Potassium-sparing agents should be used with caution in conjunction with angiotensin-converting enzyme (ACE) inhibitors due to an increased risk of hyperkalemia.

• Chlorpropamide

Triamterene may raise blood glucose levels; for adult-onset diabetes, dosage adjustments of hypoglycemic agents may be necessary during and/or after therapy; concurrent use with chlorpropamide may increase the risk of severe hyponatremia

The common side effects of Triamterene includes the following

• Common

Dizziness, lightheadedness, tiredness, headache, stomach upset, or diarrhea, confusion, unusual dry mouth/thirst, fast/irregular heartbeat, severe or seizures.

• Rare

Nausea/vomiting, stomach/abdominal pain, yellowing eyes/skin, dark urine, signs of infection (such as sore throat that doesn't go away, fever, chills, cough), signs of kidney problems (such as pain in the side/back/abdomen, painful urination, blood in the urine, change in the amount of urine), joint pain (such as big toe pain), easy bruising/bleeding.

• Pregnancy

Pregnancy Category C

Teratogenic Effects

Reproduction studies have been performed in rats at doses as high as 20 times the Maximum Recommended Human Dose (MRHD) on the basis of body weight, and 6 times the MRHD on the basis of body-surface area, without evidence of harm to the fetus due to triamterene. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

• Nursing Mothers

Triamterene has not been studied in nursing mothers. Triamterene appears in animal milk and is likely present in human milk. If use of the drug product is deemed essential, the patient should stop nursing.

• Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

• Geriatric Use

Safety and effectiveness in geriatric patients have not been established.

• In the event of overdosage, it can be theorized that electrolyte imbalance would be the major concern, with particular attention to possible hyperkalemia. Other symptoms that might be seen would be nausea and vomiting, other G.I. disturbances and weakness. It is conceivable that some hypotension could occur. As with an overdose of any drug, immediate evacuation of the stomach should be induced through emesis and gastric lavage. Careful evaluation of the electrolyte pattern and fluid balance should be made. There is no specific antidote.

• Reversible acute renal failure following ingestion of 50 tablets of a product containing a combination of 50 mg triamterene and 25 mg hydrochlorothiazide has been reported.

• The oral LD50 in mice is 380 mg/kg. The amount of drug in a single dose ordinarily associated with symptoms of overdose or likely to be life-threatening is not known. Although triamterene is 67% protein bound, there may be some benefit to dialysis in cases of overdosage.

Pharmacodynamic

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 clearance 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.

Pharmacokinetics

• Absorption

Triamterene is shown to be rapidly absorbed in the gastrointestinal tract. Its onset of action achieved within 2 to 4 hours after oral ingestion and its duration of action is 12-16 hours. 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.

• Distribution

In a pharmacokinetic study involving healthy volunteers receiving triamterene intravenously, the volumes of distribution of the central compartment of triamterene and its hydroxylated ester metabolite were 1.49 L/kg and 0.11 L/kg, respectively. Approximately

67% of Triamterene bound to proteins. Triamterene was found to cross the placental barrier and appear in the cord blood of animals.

• Metabolism and Excretion

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 sulfates, which retains a diuretic activity. The half-life of the drug in plasma ranges from 1.5 to 2 hours. Triamterene and its metabolites are excreted by the kidney by filtration and tubular secretion. Upon oral ingestion, somewhat less than 50% of the oral dose reaches the urine. About 20% of an oral dose appears unchanged in the urine, 70% as the sulphate ester of hydroxy triamterene and 10% as free hydroxy triamterene and triamterene glucuronide.

There are some clinical studies of the drug Triamterene mentioned below:

1. Fairley KF, Woo KT, Birch DF, Leaker BR, Ratnaike S. Triamterene-induced crystalluria and cylinduria: clinical and experimental studies. Clinical nephrology. 1986 Oct 1;26(4):169-73.

2. Muirhead MR, Somogyi AA, Rolan PE, Bochner F. Effect of cimetidine on renal and hepatic drug elimination: studies with triamterene. Clinical Pharmacology & Therapeutics. 1986 Oct;40(4):400-7.

3. Ginsberg DJ, Saad A, Gabuzda GJ. Metabolic studies with the diuretic triamterene in patients with cirrhosis and ascites. New England Journal of Medicine. 1964 Dec 10;271(24):1229-35.