Triamterene – Hydrochlorothiazide
Diuretic – Antihypertensive
Action And Clinical Pharmacology: Dyazide is a combination of 2 diuretics with different but complementary modes of action.
Diuretic activity following a single dose is evident within the first hour, reaches a peak at 2 to 3 hours, and tapers off during the subsequent 7 to 9 hours.
Because of the potassium-conserving effect of its triamterene component, Dyazide reduces the risk of hypokalemia, seen sometimes with other diuretics. The need for potassium supplements is virtually eliminated with the use of Dyazide. Hypochloremic alkalosis, sometimes a problem with hydrochlorothiazide alone, has not been reported with Dyazide.
Hydrochlorothiazide: The hydrochlorothiazide component blocks reabsorption of sodium (and attendant chloride anions) and thereby increases the quantity of sodium traversing the distal tubule and the volume of water excreted. A portion of the additional sodium presented to the distal tubule is exchanged there for potassium and hydrogen ions. With continued use of hydrochlorothiazide and depletion of sodium, compensatory mechanisms tend to increase this exchange and may produce excessive loss of potassium, hydrogen and chloride ions.
Hydrochlorothiazide also decreases the excretion of calcium and uric acid; it may increase the excretion of iodide and may reduce glomerular filtration rate. The exact mechanism of the antihypertensive effect of hydrochlorothiazide is not known.
Triamterene: The triamterene component of Dyazide exerts its diuretic effect on the distal renal tubule to inhibit the reabsorption of sodium in exchange for potassium and hydrogen ions. This natriuretic activity is limited by the amount of sodium reaching its site of action.
Although triamterene blocks the increase in this exchange, which is stimulated by mineralocorticoids (chiefly aldosterone), its action takes place through a direct effect on the renal tubule and not by competitive antagonism of aldosterone activity. This action of triamterene is not directly related to the level of aldosterone secretion, since it can be demonstrated in adrenalectomized rats and in patients with Addison’s disease.
By inhibiting the distal tubular exchange mechanism, triamterene maintains or increases the sodium excretion and reduces the loss of potassium, hydrogen, and chloride ions induced by hydrochlorothiazide. As with hydrochlorothiazide, triamterene may reduce glomerular filtration and renal plasma flow. Via this mechanism it may reduce uric acid excretion although it has no tubular effect on uric acid reabsorption or secretion. Triamterene does not affect calcium secretion. No predictable antihypertensive effect has been demonstrated for triamterene.
Indications And Clinical Uses: The treatment of edema associated with congestive heart failure, hepatic cirrhosis and the nephrotic syndrome; in corticosteroid edema; and in idiopathic edema. May also be used in patients whose response to other diuretic therapy is inadequate.
The treatment of mild to moderate hypertension in patients who have developed hypokalemia while on thiazide and thiazide-like diuretics alone, and in patients in whom potassium depletion is considered especially dangerous (e.g. digitalized patients). Medical opinion is not unanimous regarding the incidence and/or clinical significance of hypokalemia occurring among hypertensive patients treated with thiazide and thiazide-like diuretics alone, and concerning the use of potassium-sparing combinations as routine therapy in hypertension.
Triamterene alone has little or no antihypertensive effect. The usefulness of Dyazide in hypertension derives from the antihypertensive effect of the hydrochlorothiazide component and the potassium-conserving effect of triamterene.
Contra-Indications: Combination therapy with other potassium-sparing agents such as spironolactone or amiloride. Severe or progressive renal dysfunction, including oliguria and progressively increasing azotemia, with the possible exception of nephrosis. Severe or progressive hepatic dysfunction. Hypersensitivity to either component or to sulfonamide-derived drugs. Patients who develop hyperkalemia while on the drug. Nursing mothers. Patients with pre-existing elevated serum potassium, as is sometimes seen in patients with impaired renal function or azotemia.
Manufacturers’ Warnings In Clinical States: Hyperkalemia: Abnormal elevation of serum potassium, though uncommon, is potentially the most severe electrolyte disturbance with Dyazide therapy. Hyperkalemia (>5.4 mEq/L) has been reported ranging in incidence from 4% in patients less than 60 years of age to 12% in patients 60 years and older, with an overall incidence of less than 8%. Hyperkalemia has been reported to be associated with cardiac irregularities. Accordingly, serum potassium determinations should be performed regularly during the course of therapy. This is particularly important in the treatment of patients with suspected or confirmed renal insufficiency such as elderly or diabetic patients. In those patients who develop hyperkalemia, Dyazide should be withdrawn and a thiazide alone substituted.
Potassium supplementation, either in the form of medication or as a potassium-rich diet, should not be used in conjunction with Dyazide since hyperkalemia may result.
Use of Dyazide in patients receiving an angiotensin converting enzyme inhibitor may lead to significant increases in serum potassium. Therefore, such combination of drugs should be given only to patients with documented hypokalemia, and with caution and frequent monitoring of serum potassium.
Hypokalemia: Because of the potassium-conserving effect of triamterene, hypokalemia is a less common occurrence with the use of Dyazide than with thiazides alone but may occur in some cases when the triamterene component is unable to completely compensate for the potassium-wasting effect of the hydrochlorothiazide component or the disease.
Should hypokalemia develop, corrective measures should be taken such as potassium supplementation or increased dietary intake of potassium-rich foods. Institute such measures cautiously with frequent determinations of serum potassium levels. If laboratory determinations reveal an abnormal elevation of serum potassium, discontinue corrective measures immediately, discontinue Dyazide and substitute a thiazide diuretic alone until potassium levels return to normal.
The myocardial effects of digitalis may be exaggerated in patients with hypokalemia. In these patients, signs of digitalis intoxication may be produced by previously tolerated doses of digitalis.
Renal Stones: The triamterene component of Dyazide has been found in renal stones in association with the other usual calculus components. This should be taken into consideration especially in those patients with histories of renal stones.
Precautions: Pertinent laboratory data such as serum potassium, BUN and ECGs should be checked periodically when using Dyazide, especially in elderly patients, in persons with suspected or confirmed renal insufficiency, in diabetics, and in those patients who have developed hyperkalemia during a previous course of therapy with the drug. (Blood samples require careful handling to prevent hemolysis on standing, and resulting false serum potassium readings.)
Patients should be observed regularly for the possible occurrence of electrolyte imbalance, blood dyscrasias, liver damage, or other idiosyncratic reactions. Appropriate laboratory studies should be done as required.
Electrolyte imbalance: Since Dyazide is a combination of 2 potent diuretics, the possibility of electrolyte imbalance should be kept in mind when using high doses for prolonged periods or in patients on a salt-restricted diet.
Electrolyte imbalance, often encountered in such diseases as heart failure, renal disease or cirrhosis of the liver, may be aggravated or caused independently by any diuretic agent, including Dyazide. Signs and symptoms include dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscular fatigue, hypotension, oliguria, tachycardia and gastrointestinal symptoms.
The triamterene component of Dyazide may cause a decrease in alkali reserve, with the possibility of metabolic acidosis.
Blood Dyscrasias: Rare cases of blood dycrasias (agranulocytosis, aplastic anemia, leukopenia, thrombocytopenia) have been reported with both triamterene and the thiazides. Cirrhotics with splenomegaly, by the nature of their illness, may have marked variations in their blood pictures – including thrombocyte and leukocyte levels – which are not related to drug therapy; therefore periodic blood studies are recommended in these patients.
The triamterene component of Dyazide is a weak folic acid antagonist; it may contribute to the appearance of megaloblastosis in cases where folic acid stores are depleted.
Liver: Thiazides should be used with caution in patients with impaired hepatic function. They can precipitate hepatic coma in patients with severe liver disease. Potassium depletion induced by the thiazide may be important in this connection. Administer Dyazide cautiously and be alert for early signs of impending coma such as confusion, drowsiness and tremor; if mental confusion appears discontinue Dyazide for a few days. Attention must be given to other factors that may precipitate hepatic coma, such as blood in the gastrointestinal tract or preexisting potassium depletion.
Blood Chemistry: Dyazide may produce an elevated blood urea nitrogen level, creatinine level, or both. This apparently is secondary to a reversible reduction of glomerular filtration rate or a depletion of intravascular fluid volume (prerenal azotemia) rather than renal toxicity; levels return to normal when Dyazide is discontinued. Elevated levels are seldom seen with every-other-day therapy. If azotemia increases, discontinue Dyazide.
Slight elevations in serum transaminase (AST, ALT), levels sometimes accompany the administration of Dyazide.
Endocrine: Dyazide, because of its hydrochlorothiazide component, may cause hyperglycemia and glycosuria and may alter insulin requirements in diabetes.
Diabetes mellitus which has been latent may become manifest during thiazide administration.
Hyperuricemia may be observed with possible occurrence of gout. Caution is necessary in treating patients with hyperuricemia or a history of gout.
Thiazides may decrease serum PBI levels without signs of thyroid disturbance.
Calcium excretion is decreased by thiazides. Pathological changes in the parathyroid glands with hypercalcemia and hypophosphatemia have been reported in a few patients on prolonged thiazide therapy. The common complications of hyperparathyroidism such as renal lithiasis, bone resorption and peptic ulceration have not been seen. Thiazides should be discontinued before carrying out tests for parathyroid function.
Other Conditions: Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma.
Sulfonamide derivatives, including thiazides, have been reported to exacerbate or activate systemic lupus erythematosus.
The antihypertensive effects of Dyazide may be enhanced in the post-sympathectomy patient.
Drug Interactions: Dyazide may add to or potentiate the action of other antihypertensive agents. The use of Dyazide with another antihypertensive drug requires reduced dosage of the latter agent. When Dyazide is added to another antihypertensive already being used, the dose of the other antihypertensive drug should be reduced at least by half, particularly if it is a ganglionic blocking agent. Subsequent adjustment of dosage should be made as required.
Thiazides have been shown to decrease arterial responsiveness to norepinephrine (an effect attributed to loss of sodium). This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use.
Thiazides have also been shown to increase the paralyzing effect of non-depolarizing muscle relaxants such as tubocurarine (an effect attributed to loss of potassium); consequently caution should be observed in patients undergoing surgery.
Lithium generally should not be given with diuretics because they reduce its renal clearance and increase the risk of lithium toxicity. Read circulars for lithium preparations before use of such concomitant therapy with Dyazide.
Concurrent use of amphotericin B or corticosteroids or corticotropin (ACTH) with thiazides may intensify electrolyte imbalance, particularly hypokalemia, although the presence of triamterene minimizes the hypokalemic effects.
The effects of oral anticoagulants may be decreased when used concurrently with thiazides; dosage adjustments may be necessary.
Caution is advised in administering nonsteroidal anti-inflammatory agents with Dyazide. A possible interaction resulting in acute renal failure has been reported in a few patients on Dyazide when treated with indomethacin, a nonsteroidal anti-inflammatory agent.
The triamterene component of Dyazide and quinidine have similar fluorescence spectra; thus, Dyazide will interfere with the fluorescent measurement of quinidine.
Concurrent use with chlorpropamide may increase the risk of severe hyponatremia.
Pregnancy: Reproduction studies in animals and clinical use in pregnant patients have produced no evidence of fetal abnormalities due to Dyazide. However, thiazides have been reported to cross the placental barrier and to appear in cord blood. This may result in fetal or neonatal hyperbilirubinemia, thrombocytopenia, altered carbohydrate metabolism and possible other adverse reactions that have occurred in the adult. Therefore, Dyazide should be used in pregnant patients only when, in the judgement of the physician, its use is deemed necessary for the welfare of the patient.
Lactation: Thiazides appear and triamterene may appear in breast milk. If use of Dyazide is deemed essential, the patient should stop nursing (see Contraindications).
Children: Adequate information on the use of Dyazide in children is not available.
Adverse Reactions: The following adverse reactions have been associated with the use of thiazide diuretics or triamterene:
Gastrointestinal: dry mouth, anorexia, gastric irritation, nausea, vomiting, diarrhea, constipation, jaundice (intrahepatic cholestatic), pancreatitis, sialadenitis. Nausea can usually be prevented by giving the drug after meals. It should be noted that symptoms of nausea and vomiting can also be indicative of electrolyte imbalance (see Precautions).
CNS: dizziness, vertigo, paresthesias, headache, xanthopsia.
Dermatologic-Hypersensitivity: fever, purpura, anaphylaxis, photosensitivity, rash, urticaria, necrotizing angiitis (vasculitis).
Hematologic: agranulocytosis, aplastic anemia, leukopenia, thrombocytopenia.
Cardiovascular: orthostatic hypotension (which may be potentiated by alcohol, barbiturates, or narcotics), arrhythmia.
Renal: Triamterene has been reported in higher doses to increase the incidence of renal stones. Rare cases of interstitial nephritis have been reported with the use of Dyazide.
Electrolyte imbalance: (see Precautions).
Miscellaneous: glycosuria, hyperglycemia, hyperuricemia; muscle cramps, weakness; restlessness, transient blurred vision; allergic pneumonitis; rare cases of impotence (causal relationship not established).
In rare instances, newborns, whose mothers had received thiazides during pregnancy, have developed thrombocytopenia or pancreatitis.
Symptoms And Treatment Of Overdose: Electrolyte imbalance is the major concern, with particular attention to possible hyperkalemia.Symptoms: Symptoms reported include polyuria, nausea, vomiting, weakness, lassitude, hypotension, fever, flushed face and hyperactive deep tendon reflexes.
Treatment: There is no specific antidote. Treatment should be symptomatic and supportive. Induce immediate evacuation of the stomach through emesis and gastric lavage. Careful evaluation of the electrolyte pattern and fluid balance should be made. If profound hypotension occurs, pressor agents such as norepinephrine may be used with the usual measures to maintain blood pressure levels.
Dosage And Administration: Dyazide should be taken after an adequate meal.
Adults: Edema: The usual starting dosage is 1 tablet twice daily after meals. When dry weight is reached, maintenance dosage of 1 tablet daily will usually suffice. In some patients, 1 tablet every other day may be indicated.
Hypertension: The usual starting dosage is 1 tablet twice daily after meals. Subsequently, dosage may be increased or decreased according to patient’s need. If 2 or more tablets per day are needed they should be given in divided doses.
Maximum daily dosage should not exceed 4 tablets, and at this dosage the incidence of adverse effects may increase.
When changing from other diuretics or antihypertensives to Dyazide, stop the previous therapy and start Dyazide at the recommended dosage. Since Dyazide has an antihypertensive effect, its use with another antihypertensive drug requires reduced dosage of the latter agent. When Dyazide is added to another antihypertensive already being used, reduce the dose of the other antihypertensive drug at least by half particularly if it is a ganglionic blocking agent. Make subsequent dosage adjustment as required.
Children: Adequate information on Dyazide’s use in children is not available.
Availability And Storage: Each round, flat, bevel-edged, peach-colored, scored, compressed tablet, debossed SKF, contains: triamterene 50 mg and hydrochlorothiazide 25 mg. Nonmedicinal ingredients: FD&C yellow no. 6, magnesium stearate, povidone, sodium lauryl sulfate, sterotex powder and wheat starch. Plastic securitainers of 1 000. (Shown in Product Recognition Section)
DYAZIDE® SmithKline Beecham Triamterene – Hydrochlorothiazide Diuretic – Antihypertensive