bendroflumethiazide
DESCRIPTION
Bendroflumethiazide, a thiazide diuretic-antihypertensive.
Bendroflumethiazide
Bendroflumethiazide is a white crystalline powder. It is soluble in alcohol and in sodium hydroxide, and insoluble in hydrochloric acid, water, and chloroform.
Bendroflumethiazide is designated chemically as 3-benzyl-3,4-dihydro-6-(trifluoromethyl)-2 H -1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Structural formula:
CLINICAL PHARMACOLOGY
Bendroflumethiazide
The mechanism of action of bendroflumethiazide results in an interference with the renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage all thiazides are approximately equal in their diuretic potency.
Thiazides increase excretion of sodium and chloride in approximately equivalent amounts. Natriuresis causes a secondary loss of potassium and bicarbonate.
The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides do not affect normal blood pressure.
Onset of action of thiazides occurs in two hours and the peak effect at about four hours. Duration of action persists for approximately six to 12 hours. Thiazides are eliminated rapidly by the kidney.
INDICATIONS
Management of hypertension.
Fixed combination drug is not indicated for initial therapy of hypertension. If the fixed combination represents the dose titrated to the individual patient' needs, it may be more convenient than the separate components.
CONTRAINDICATIONS
Bendroflumethiazide is contraindicated in anuria. It is also contraindicated in patients who have previously demonstrated hypersensitivity to bendroflumethiazide 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.
Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma.
The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.
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 concomitant therapy.
PRECAUTIONS
General
Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.
All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance, namely: hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance may include: dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances, such as nausea or vomiting.
Hypokalemia may develop, especially with brisk diuresis or when severe cirrhosis is present.
Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Concurrent administration of a potassium-sparing diuretic or potassium supplements may be indicated in these patients.
Any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease). 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 the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice.
Hyperuricemia may occur or frank gout may be precipitated in certain patients receiving thiazide therapy.
Latent diabetes mellitus may become manifest during thiazide administration.
The antihypertensive effect of thiazide diuretics may be enhanced in the postsympathectomy patient.
If progressive renal impairment becomes evident, as indicated by a rising nonprotein nitrogen or blood urea nitrogen (BUN), a careful reappraisal of therapy is necessary with consideration given to withholding or discontinuing diuretic therapy.
Thiazides may decrease serum PBI levels without signs of thyroid disturbance.
Calcium excretion is decreased by thiazides. Pathological changes in the parathyroid gland with hypercalcemia and hypophosphatemia have been observed 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.
Thiazides have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.
Information for Patients
Patients, especially those with evidence of coronary artery insufficiency, should be warned against interruption or discontinuation of therapy without the physician' advice. Although cardiac failure rarely occurs in properly selected patients, patients being treated with beta-adrenergic blocking agents should be advised to consult the physician at the first sign or symptom of impending failure.
The patient should also be advised of a proper course in the event of an inadvertently missed dose.
The patient should be informed of symptoms that would suggest potential adverse effects and told to report them promptly.
Laboratory Tests
Serum electrolyte levels should be regularly monitored (see WARNINGS , Bendroflumethiazide , also PRECAUTIONS , General , Bendroflumethiazide ).
Drug Interactions
Bendroflumethiazide
When administered concurrently the following drugs may interact with thiazide diuretics:
Alcohol, barbiturates, or narcotics --potentiation of orthostatic hypotension may occur.
Amphotericin B, corticosteroids, or corticotropin (ACTH) --may intensify electrolyte imbalance, particularly hypokalemia. Monitor potassium levels; use potassium replacements if necessary.
Anticoagulants (oral) --dosage adjustments of anticoagulant medication may be necessary since bendroflumethiazide may decrease their effects.
Antigout medications --dosage adjustments of antigout medication may be necessary since bendroflumethiazide may raise the level of blood uric acid.
Other antihypertensive medications (e.g., ganglionic or peripheral adrenergic blocking agents) --dosage adjustments may be necessary since bendroflumethiazide may potentiate their effects.
Antidiabetic drugs (oral agents and insulin) --since thiazides may elevate blood glucose levels, dosage adjustments of antidiabetic agents may be necessary.
Calcium salts --increased serum calcium levels due to decreased excretion may occur. If calcium must be prescribed monitor serum calcium levels and adjust calcium dosage accordingly.
Cardiac glycosides --enhanced possibility of digitalis toxicity associated with hypokalemia. Monitor potassium levels; use potassium replacement if necessary.
Cholestyramine resin and colestipol HCL --may delay or decrease absorption of bendroflumethiazide. Sulfonamide diuretics should be taken at least one hour before or four to six hours after these medications.
Diazoxide --enhanced hyperglycemic, hyperuricemic, and antihypertensive effects. Be cognizant of possible interaction; monitor blood glucose and serum uric acid levels.
Lithium salts --may enhance lithium toxicity due to reduced renal clearance. Avoid concurrent use; if lithium must be prescribed monitor serum lithium levels and adjust lithium dosage accordingly. (See WARNINGS )
MAO inhibitors --dosage adjustments of one or both agents may be necessary since hypotensive effects are enhanced.
Nondepolarizing muscle relaxants, preanesthetics and anesthetics used in surgery (e.g., tubocurarine chloride and gallamine triethiodide) --effects of these agents may be potentiated; dosage adjustments may be required. Monitor and correct any fluid and electrolyte imbalances prior to surgery if feasible.
Nonsteroidal anti-inflammatory agents --in some patients, the administration of a nonsteroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effect of loop, potassium-sparing or thiazide diuretics. Therefore, when bendroflumethiazide 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.
Methenamine --possible decreased effectiveness due to alkalinization of the urine.
Pressor amines (e.g., norepinephrine) --decreased arterial responsiveness, but not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Use caution in patients taking both medications who undergo surgery. Administer preanesthetic and anesthetic agents in reduced dosage, and if possible, discontinue bendroflumethiazide one week prior to surgery.
Probenecid or sulfinpyrazone --increased dosage of these agents may be necessary since bendroflumethiazide may have hyperuricemic effects.
Drug/Laboratory Test Interactions
Bendroflumethiazide may produce false-negative results with the phentolamine and tyramine tests; may interfere with the phenosulfonphthalein test due to decrease excretion; and it may cause diagnostic interference of serum electrolyte levels, blood and urine glucose levels, and a decrease in serum PBI levels without signs of thyroid disturbance.
Carcinogenesis, Mutagenesis, Impairment of Fertility
Bendroflumethiazide
Studies have not been performed to evaluate carcinogenic potential, mutagenesis, or whether this drug adversely affects fertility in males or females.
Pregnancy--Teratogenic Effects
Bendroflumethiazide
Category C. Animal reproduction studies have not been conducted with bendroflumethiazide. It is also not known whether this drug can cause fetal harm when administered to a pregnant woman or can affect reproduction capacity. Bendroflumethiazide should be given to a pregnant woman only if clearly needed.
Pregnancy--Nonteratogenic Effects
Thiazides cross the placental barrier and appear in cord blood. The use of thiazides in pregnant women requires that the anticipated benefit be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions which have occurred in the adult.
Nursing Mothers
Bendroflumethiazide are excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from both drugs, a decision should be made whether to discontinue nursing or to discontinue therapy taking into account the importance of Bendroflumethiazide Tablets to the mother.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established.
ADVERSE REACTIONS
Bendroflumethiazide
Gastrointestinal --Nausea, vomiting, cramping and anorexia are not uncommon; diarrhea, constipation, gastric irritation, abdominal bleeding, jaundice (intrahepatic cholestatic jaundice), hepatitis, and sialadenitis occasionally occur; and pancreatitis has been reported.
Central Nervous System --Dizziness, vertigo, paresthesia, headache, and xanthopsia occasionally occur.
Hematologic --Leukopenia, agranulocytosis, thrombocytopenia, hemolytic anemia, and aplastic anemia have been reported.
Dermatologic-Hypersensitivity --Purpura, exfoliative dermatitis, pruritus, ecchymosis, urticaria, necrotizing angiitis (vasculitis, cutaneous vasculitis), respiratory distress including penumonitis, fever, and anaphylactic reactions occasionally occur; photosensitivity and rash have been reported.
Cardiovascular --Orthostatic hypotension may occur and may be potentiated by coadministration with certain other drugs (e.g., alcohol, barbiturates, narcotics, other antihypertensive medications, etc.; see PRECAUTIONS , Drug Interactions ).
Other --Muscle spasm, weakness, or restlessness is not uncommon; hyperglycemia, glycosuria, metabolic acidosis in diabetic patients, hyperuricemia, allergic glomerulonephritis, and transient blurred vision occassionally occur.
Whenever adverse reactions are moderate or severe, thiazide dosage should be reduced or therapy withdrawn.
OVERDOSAGE
In addition to the expected diuresis, overdosage of bendroflumethiazide may produce varying degrees of lethargy which may progress to coma with minimal depression of respiration and cardiovascular function and without significant serum elecrolyte changes or dehydration. The mechanism of thiazide-induced CNS depression is unknown. Gastrointestinal irritation may occur. Transitory increase in BUN has been reported, and serum electrolyte changes may occur, especially in patients with impaired renal function.
DOSAGE AND ADMINISTRATION
DOSAGE MUST BE INDIVIDUALIZED WITHOUT REGARD TO MEALS.
Bendroflumethiazide is usually given at a dose of 5 mg daily.