Benzthiazide
Indications: Edema, secondary to corticosteroid therapy; Edema, secondary to estrogen therapy; Edema, secondary to heart failure; Edema, secondary to hepatic cirrhosis; Edema, secondary to renal dysfunction; Hypertension, essential
DESCRIPTION:
Benzthiazide is a diuretic for oral administration..
Benzthiazide is a white, crystalline powder with a characteristic odor, freely soluble in alkaline solution. The chemical structure is: 6-chloro-3[((phenylmethyl)thio)methyl]-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide
CLINICAL PHARMACOLOGY:
Benzthiazide is a diuretic and antihypertensive. It affects the renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage, all thiazides are approximately equal in their diuretic potency. The mechanism whereby thiazides function in the control of hypertension is unknown. Benzthiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate.
In humans, benzthiazide is excreted in the urine almost entirely unchanged. Following a single oral dose of benzthiazide tablets or benzthiazide solution, 1% and 4.3% of the respective doses were recovered in the urine in 24 hr. The relative bioavailability of benzthiazide tablets was determined to be about 25% in reference to benzthiazide solution.
INDICATIONS AND USAGE:
Benzthiazide is indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis and corticosteroid and estrogen therapy.
Benzthiazide has also been found useful in edema due to various forms of renal dysfunction as: nephrotic syndrome; acute glomerulonephritis; and chronic renal failure.
Benzthiazide is indicated in the management of hypertension either as the sole therapeutic agent or to enhance the effectiveness of other antihypertensive drugs in the more severe forms of hypertension.
Use in Pregnancy: The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of developed toxemia.
Edema during pregnancy may arise from pathological causes or from the physiologic and mechanical consequences of pregnancy. Thiazides are indicated in pregnancy when edema is due to pathologic causes, just as they are in the absence of pregnancy (however, see WARNINGS). Dependent edema in pregnancy, resulting from restriction of venous return by the expanded uterus, is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is illogical and unnecessary. There is hypervolemia during normal pregnancy which is harmful to neither the fetus nor the mother (in the absence of cardiovascular disease), but which is associated with edema, including generalized edema, in the majority of pregnant women. If this edema produces discomfort, increased recumbency will often provide relief. In rare instances, this edema may cause extreme discomfort which is not relieved by rest. In these cases, a short course of diuretics may provide relief and may be appropriate.
CONTRAINDICATIONS:
Anuria. Hypersensitivity to this or other sulfonamide-derived drugs.
WARNINGS:
Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.
Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Thiazides may add to or potentiate the action of other antihypertensive drugs. Potentiation occurs with ganglionic or peripheral adrenergic blocking drugs.
Sensitivity reactions may occur in patients with a history of allergy or bronchial asthma.
The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.
PRECAUTIONS:
General: All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance; namely, hyponatremia, hypochloremic alkalosis, and hypokalemia. Warning signs are dryness of mouth, thirst, or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbance such as nausea and vomiting.
Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt except in rare instances when hyponatremia is life threatening.
In actual salt depletion, appropriate replacement is the therapy of choice. Any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease).
Hypokalemia may develop with thiazides as with any other potent diuretic especially with brisk diuresis. Inadequate oral electrolyte intake will also contribute to hypokalemia.
Thiazide diuretics have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.
Calcium excretion is decreased by thiazide diuretics. Pathological changes in the parathyroid gland with hypercalcemia and hypophosphatemia have been observed in a few patients on thiazide therapy. The common complications few patients on thiazide therapy. The common complications of hyperparathyroidism such as renal lithiasis, bone resorption and peptic ulceration have not been seen.
If progressive renal failure becomes evident, a careful reappraisal of therapy is indicated with consideration given to withholding or discontinuing diuretic therapy.
Increases of cholesterol and triglyceride and triglyceride levels may be associated with thiazide diuretic therapy.
Latent diabetes mellitus may become manifest during thiazide administration: hyperuricemia or frank gout may also be precipitated in certain patients. The antihypertensive effect of the drug may be enhanced in the postsympathectomy patient.
This product contains FD&C yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who have aspirin hypersensitivity.
Information for the Patient: Warning signs of electrolyte imbalance are: dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.
Laboratory Tests: Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. When the patient is vomiting excessively or receiving parenteral fluids, serum and urine electrolyte determinations are particularly important.
In patients with renal impairment, nonprotein nitrogen or blood urea nitrogen level should be tested periodically; rising values would indicate progressive renal impairment and careful reappraisal of therapy is necessary with consideration given to withholding or discontinuing diuretic therapy.
Drug/Laboratory Tests Interactions: Thiazides may decrease serum PBI levels without signs of thyroid disturbance.
Thiazides should be discontinued before carrying out tests for parathyroid function (see PRECAUTIONS, General).
Carcinogenesis, Mutagenesis, and Impairment of Fertility: Studies to evaluate the carcinogenic or mutagenic potential of benzthiazide or the potential of the drug to affect fertility adversely have not been performed.
Pregnancy Category C: Teratogenic Effects: Benzthiazide has an embryocidal effect in rats when given in doses several hundred times the human dose. There are no adequate and well-controlled studies in pregnant women. Benzthiazide should be used during pregnancy only if clearly needed. Nonteratogenic Effects: Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions that have occurred in adults.
Nursing Mothers: It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Exna is administered to a nursing mother.
Pediatric Use: Safety and effectiveness in children have not been established.
DRUG INTERACTIONS:
When given concurrently the following drugs may interact with thiazide diuretics.
Alcohol, Barbiturates, Or Narcotics: Potentiation of orthostatic hypotension may occur.
Antidiabetic Drugs (Oral Agents and Insulin): Dosage adjustment of the antidiabetic drug may be required.
Other Antihypertensive Drugs: Additive effect or potentiation occurs with ganglionic or peripheral adrenergic-blocking drugs.
Digitalis: Medication such as digitalis may also influence serum electrolytes. Digitalis therapy may exaggerate metabolic effects of hypokalemia especially with reference to myocardial activity (e.g., increased ventricular irritability).
Pressor Amines (e.g., Norepinephrine): Possible decreased response to pressor amines. This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use.
Skeletal Muscle Relaxants, Nondepolarizing (e.g., Tubocurarine): possible increased responsiveness to the muscle relaxant.
Lithium: Generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with Exna.
Nonsteroidal Anti-Inflammatory Drugs: In some patients, the administration of a nonsteroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when Exna and nonsteroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.
Cholestyramine Resin And Colestipol HCl: May delay decrease absorption of thiazide diuretics.
Amphotericin B, Corticosteroids or Corticotropin: (ACTH): May intensify electrolyte imbalance, particularly hypokalemia.
ADVERSE REACTIONS:
The following adverse reactions have been observed, but there is not enough systematic collection of data to support an estimate of their frequency.
Gastrointestinal System: Jaundice (intrahepatic cholestatic jaundice); pancreatitis; gastric irritation; vomiting; cramping; nausea; anorexia; diarrhea; constipation.
Central Nervous System: Dizziness; restlessness; paresthesia; headache; xanthopsia.
Hematologic: Aplastic anemia; thrombocytopenia; agranulocytosis; leukopenia.
Dermatologic-Hypersensitivity: Necrotizing angiitis (vasculitis) (cutaneous vasculitis); purpura; urticaria; rash; photosensitivity.
Cardiovascular: Orthostatic hypotension may occur and may be aggravated by alcohol, barbiturates or narcotics.
Other: Hyperglycemia; glycosuria; hyperuricemia; weakness; muscle spasm.
Whenever adverse reactions are moderate or severe, thiazide dosage should be reduced or therapy withdrawn.
OVERDOSAGE:
Symptoms of overdosage include electrolyte imbalance and signs of potassium deficiency such as confusion, dizziness, muscular weakness, and gastrointestinal disturbances. General supportive measures including replacement of fluids and electrolytes may be indicated in treatment of overdosage.
DOSAGE AND ADMINISTRATION:
Therapy should be individualized according to patient response. This therapy should be titrated to gain maximal therapeutic response as well as the minimal dose possible to maintain that therapeutic response as shown in TABLE 1.
TABLE 1
Diuretic
Antihypertensive
Benzthiazide
50 to 200 mg
50 to 200 mg
Edema: Initiation of diuresis. 50 to 200 mg daily should be used for several days, or until dry weight is attained. With 100 mg or more daily, it is generally preferable to administer benzthiazide in two doses, following morning and evening meals. Maintenance of diuresis. 50 to 150 mg daily depending upon the patient's response. To maintain effectiveness, reduction to minimal effective dosage should be gradual.
Hypertension: Initiation of antihypertensive therapy. 50 to 100 mg daily is the average dose. It may be given in two doses of 25 mg or 50 mg each after breakfast and after lunch. This dosage may be continued until a therapeutic drop in blood pressure occurs. Maintenance of antihypertensive therapy. Dosage should be adjusted according to the patient response, either upward to as much as 50 mg q.i.d. or downward to the minimal effective dosage level.
Store at controlled room temperature, between 20Β°C and 25Β°C (68Β°F and 77Β°F).