Pro-Triazide

Uses

This drug is used to treat high blood pressure. Lowering high blood pressure helps prevent strokes, heart attacks, and kidney problems. This medication is a combination of two "water pills" (diuretics): triamterene and hydrochlorothiazide. This combination is used by people who have developed or are at risk for having low potassium levels on hydrochlorothiazide. It causes you to make more urine, which helps your body get rid of extra salt and water.

This medication also reduces extra fluid in the body (edema) caused by conditions such as heart failure, liver disease, or kidney disease. This can lessen symptoms such as shortness of breath or swelling in your ankles or feet.

Pro-Triazide is also used to associated treatment for these conditions: Acidosis, Renal Tubular, Calcium Nephrolithiasis, Cirrhosis of the Liver, Congestive Heart Failure (CHF), Diabetes Insipidus, Edema, High Blood Pressure (Hypertension), Hypertension,Essential, Hypokalemia caused by diuretics, Nephrotic Syndrome, Premenstrual tension with edema, Sodium retention, Stroke, Prophylaxis of preeclampsiaEdema, High Blood Pressure (Hypertension), Idiopathic Edema

How Pro-Triazide works

Hydrochlorothiazide is transported from the circulation into epithelial cells of the distal convoluted tubule by the organic anion transporters OAT1, OAT3, and OAT4. From these cells, hydrochlorothiazide is transported to the lumen of the tubule by multidrug resistance associated protein 4 (MRP4).

Normally, sodium is reabsorbed into epithelial cells of the distal convoluted tubule and pumped into the basolateral interstitium by a sodium-potassium ATPase, creating a concentration gradient between the epithelial cell and the distal convoluted tubule that promotes the reabsorption of water.

Hydrochlorothiazide acts on the proximal region of the distal convoluted tubule, inhibiting reabsorption by the sodium-chloride symporter, also known as Solute Carrier Family 12 Member 3 (SLC12A3). Inhibition of SLC12A3 reduces the magnitude of the concentration gradient between the epithelial cell and distal convoluted tubule, reducing the reabsorption of water.

Triamterene inhibits the epithelial sodium channels (ENaC) located on the lumenal side in the late distal convoluted tubule and collecting tubule , which are transmembrane channels that normally promotes sodium uptake and potassium secretion. In the late distal tubule to the collecting duct, sodium ions are actively reabsorbed via ENaC on the lumnial membrane and are extruded out of the cell into the peritubular medium by a sodium-potassium exchange pump, the Na-K-ATPase, with water following passively. Triamterene exerts a diuretic effect on the distal renal tubule to inhibit the reabsorption of sodium ions in exchange for potassium and hydrogen ions and its natriuretic activity is limited by the amount of sodium reaching its site of action. Its action is antagonistic to that of adrenal mineralocorticoids, such as aldosterone, but it is not an inhibitor or antagonist of aldosterone. Triamterene maintains or increases the sodium excretionm, thereby increasing the excretion of water, and reduces the excess loss of potassium, hydrogen and chloride ions by inhibiting the distal tubular exchange mechanism. Due to its diuretic effect, triamterene rapidly and reversibly reduces the lumen-negative transepithelial potential difference by almost complete abolition of Na+ conductance without altering K+ conductance. This reduces the driving force for potassium movement into the tubular lumen and thus decreases potassium excretion. Triamterene is similar in action to amiloride but, unlike amiloride, increases the urinary excretion of magnesium.

Dosage

Pro-Triazide dosage

Hypertension:Initially, 1 tablet (Hydrochlorothiazide 25 mg and Triamterene 50 mg) daily after the morning meal, adjust thereafter according to response. Max: 4 tab daily.

Oedema: Initially, 1 tablet (Hydrochlorothiazide 25 mg and Triamterene 50 mg) bid. Maintenance: 1 tab daily or 2 tab on alternate days. Max: 4 tab daily.

Take this medication by mouth as directed by your doctor, usually once daily in the morning with or without food. It is best to avoid taking this medication within 4 hours of your bedtime to prevent having to get up to urinate.

If you also take certain drugs to lower your cholesterol (bile acid-binding resins such as cholestyramine or colestipol), take this product at least 4 hours before or at least 4 to 6 hours after these medications.

The dosage is based on your medical condition and response to treatment. Use this medication regularly to get the most benefit from it. To help you remember, take it at the same time each day. It is important to continue taking this medication even if you feel well. Most people with high blood pressure do not feel sick.

Side Effects

Nausea, vomiting, diarrhoea, dizziness, weakness, hypotension, headache, muscle cramps, dry mouth, thirst, anaphylaxis, rash, metabolic acidosis, pancreatitis. Rarely, SLE and photosensitivity.

Toxicity

The oral LD₅₀ of hydrochlorothiazide is >10g/kg in mice and rats.

Patients experiencing an overdose may present with hypokalemia, hypochloremia, and hyponatremia. Treat patients with symptomatic and supportive treatment including fluids and electrolytes. Vasopressors may be administered to treat hypotension and oxygen may be given for respiratory impairment.

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.

Precaution

Patients with prediabetes or DM, diabetic nephropathy, predisposition to gout, history of renal lithiasis. Hepatic or renal impairment. Pregnancy and lactation.

Interaction

May reduce the renal clearance of lithium. May antagonise diuretic effect with NSAIDs, corticosteroids, oestrogens, combined OCs. Enhanced effect with other hypotensive agents, baclofen, tizanidine. May decrease arterial responsiveness to norepinephrine. Increases responsiveness to tubocurarine. Risk of acute renal failure with indometacin. Increased risk of hyperkalaemia with reboxetine, tacrolimus. Increased risk of ototoxicity and nephrotoxicity with platinum compounds (e.g. cisplatin).

Volume of Distribution

The volume of distribution varies widely from one study to another with values of 0.83-4.19L/kg.

In a pharmacolinetic 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. Triamterene was found to cross the placental barrier and appear in the cord blood of animals.

Elimination Route

An oral dose of hydrochlorothiazide is 65-75% bioavailable, with a T_max of 1-5 hours, and a C_max of 70-490ng/mL following doses of 12.5-100mg. When taken with a meal, bioavailability is 10% lower, C_max is 20% lower, and T_max increases from 1.6 to 2.9 hours.

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.

Half Life

The plasma half life of hydrochlorothiazide is 5.6-14.8h.

The half-life of the drug in plasma ranges from 1.5 to 2 hours. In a pharmacokinetic study involving healthy volunteers, the terminal half-lives for triamterene and 4′-hydroxytriamterene sulfate were 255 ± 42 and 188 ± 70 minutes, respectively, after intravenous infusion of the parent drug.

Clearance

The renal clearance of hydrochlorothiazide in patients with normal renal function is 285mL/min. Patients with a creatinine clearance of 31-80mL/min have an average hydroxychlorothiazide renal clearance of 75mL/min, and patients with a creatinine clearance of ≤30mL/min have an average hydroxychlorothiazide renal clearance of 17mL/min.

The total plasma clearance was 4.5 l/min and renal plasma clearance was 0.22 l/kg following intravenous administration of triamterene in healthy volunteers.

Elimination Route

Hydrochlorothiazide is eliminated in the urine as unchanged hydrochlorothiazide.

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 hydroxytriamterene and 10% as free hydroxytriamterene and triamterene glucuronide.

Pregnancy & Breastfeeding use

Category C: Either studies in animals have revealed adverse effects on the foetus (teratogenic or embryocidal or other) and there are no controlled studies in women or studies in women and animals are not available. Drugs should be given only if the potential benefit justifies the potential risk to the foetus.

Contraindication

Hyperkalaemia (≥5.5 mEq/L), hypercalcaemia, diabetic ketoacidosis, Addison’s disease, progressive renal failure, increasing hepatic dysfunction. Concomitant use with K supplements, other K-conserving drugs, including ACE inhibitors.

Special Warning

Elderly: in some patients specially the elderly an initial dose of 12.5 mg daily may be sufficient.

Children: An initial dose for children has been 1 to 2 mg per kg body-weight in 2 divided doses. Infants under 6 months may need doses upto 3 mg per kg daily.

Acute Overdose

Symptoms: Electrolyte imbalance, nausea, vomiting, weakness, polyuria, lassitude, fever, flushed face, hyperactive deep tendon reflexes, hypotension, cardiac arrhythmias.

Management: Induce immediate evacuation through emesis or gastric lavage. Pressor agents e.g. norepinephrine may be given in case of hypotension.

Storage Condition

Store between 20-25°C. Protect from light.

Innovators Monograph

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