HYDROFLUMETHIAZIDE
DESCRIPTION:
Hydroflumethiazide is an oral thiazide (benzothiadiazide) diuretic-
antihypertensive agent.
Chemical Name: 3,4-Dihydro- 6-(trifluoromethyl)-2H-1,2,4- benzothiadiazine-7-
sulfonamide 1,1-dioxide.
Hydroflumethiazide is an odorless white to cream- colored, finely divided,
crystalline powder. It has a melting point between 270 deg and 275 deg C.
Hydroflumethiazide is freely soluble in acetone, soluble in alcohol, and very
slightly soluble in water.
ACTIONS/CLINICAL PHARMACOLOGY:
Hydroflumethiazide is incompletely but fairly rapidly absorbed from the
gastrointestinal tract. It appears to have a biphasic biological half- life with
an estimated alpha-phase of about 2 hours and an estimated beta-phase of about
17 hours; it has a metabolite with a longer half- life, which is extensively
bound to the red blood cells. Hydroflumethiazide is excreted in the urine; its
metabolite has also been detected in the urine.
The mechanism of action 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. The mechanism
whereby thiazides function in the control of hypertension is unknown.
INDICATIONS AND USAGE:
HYDROFLUMETHIAZIDE is indicated as adjunctive therapy in edema associated with congestive
heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy.
HYDROFLUMETHIAZIDE has also been found useful in edema due to various forms of renal
dysfunction such as: nephrotic syndrome; acute glomerulonephritis; and chronic
renal failure.
HYDROFLUMETHIAZIDE is indicated in the management of hypertension either as the sole
therapeutic agent or to enhance the effect of other antihypertensive drugs in
the more severe forms of hypertension.
USAGE 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 "Precautions- -PREGNANCY" below).
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 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:
HYDROFLUMETHIAZIDE 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. Serum and urine electrolyte determinations are particularly
important when the patient is vomiting excessively or receiving parenteral
fluids. Medication such as digitalis may also influence serum electrolytes.
Warning signs, irrespective of cause, 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.
Hypokalemia may develop with thiazides as with any other potent diuretic,
especially with brisk diuresis, when severe cirrhosis is present, or during
concomitant use of corticosteroids or ACTH.
Interference with adequate oral electrolyte intake will also contribute to
hypokalemia. Digitalis therapy may exaggerate metabolic effects of hypokalemia,
especially, with reference to myocardial activity.
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.
Insulin requirements in diabetic patients may be increased, decreased, or
unchanged. Latent diabetes mellitus may become manifested during thiazide
administration.
The antihypertensive effects of the drug may be enhanced in the post-
sympathectomy patient.
If progressive renal impairment becomes evident, as indicated by a rising
creatinine or blood urea nitrogen, 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.
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 HYDROFLUMETHIAZIDE.
Thiazides have been shown to increase the urinary excretion of magnesium; this
may result in hypomagnesemia.
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.
LABORATORY TESTS
Periodic determination of serum electrolytes to detect possible electrolyte
imbalance should be performed at appropriate intervals.
DRUG INTERACTIONS
Anticoagulants, oral
(Effects may be decreased when used concurrently with thiazide diuretics; dosage
adjustments may be necessary).
Antigout medications
(Thiazide diuretics may raise the level of blood uric acid; dosage adjustment of
antigout medications may be necessary to control hyperuricemia and gout.)
Antihypertensive medications, other, especially diazoxide, or preanesthetic and
anesthetic agents used in surgery or skeletal-muscle relaxants, nondepolarizing,
used in surgery
(Effects may be potentiated when used concurrently with thiazide diuretics;
dosage adjustments may be necessary.)
Amphotericin B or Corticosteroids or Corticotropin (ACTH)
(Concurrent use with thiazide diuretics may intensify electrolyte imbalance,
particularly hypokalemia.)
Cardiac glycosides
(Concurrent use with thiazide diuretics may enhance the possibility of digitalis
toxicity associated with hypokalemia.)
Colestipol
(May inhibit gastrointestinal absorption of the thiazide diuretics;
administration 1 hour before or 4 hours after colestipol is recommended.)
Hypoglycemics
(Thiazide diuretics may raise blood glucose levels; for adult-onset diabetics,
dosage adjustment of hypoglycemic medications may be necessary during and after
thiazide diuretic therapy; insulin requirements may be increased, decreased, or
unchanged.)
Lithium salts
(Concurrent use with thiazide diuretics is not recommended, as they may provoke
lithium toxicity because of reduced renal clearance.)
Methenamine
(Effectiveness may be decreased when used concurrently with thiazide diuretics
because of alkalinization of the urine.)
Nonsteroidal anti-inflammatory agents
(In some patients, the steroidal anti- inflammatory agent can reduce the
diuretic, natriuretic, and antihypertensive effects of loop, potassium sparing,
and thiazide diuretics. Therefore, when hydroflumethiazide 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.)
Norepinephrine
(Thiazides may decrease arterial responsiveness to norepinephrine. This
diminution is not sufficient to preclude effectiveness of the pressor agent for
therapeutic use.)
Tubocurarine
(Thiazide drugs may increase the responsiveness to tubocurarine.)
DIAGNOSTIC INTERFERENCE--With expected physiologic effects:
Blood and urine glucose levels (usually only in patients with a predisposition
for glucose intolerance) and
Serum bilirubin levels (by displacement from albumin binding) and
Serum calcium levels (thiazide diuretics should be discontinued before
parathyroid-function tests are carried out) and
Serum uric acid levels (may be increased)
Serum magnesium, potassium, and sodium levels (may be decreased; serum magnesium
levels may increase in uremic patients)
Serum protein-bound iodine (PBI) levels (may be decreased)
Thiazides should be discontinued before carrying out tests for parathyroid
function (see "Precautions--GENERAL, Calcium excretion").
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
No studies have been performed to evaluate carcinogenic or mutagenic potential
of HYDROFLUMETHIAZIDE or the potential of HYDROFLUMETHIAZIDE to impair fertility.
PREGNANCY
Teratogenic Effects--Pregnancy Category C
Animal reproduction studies have not been conducted with HYDROFLUMETHIAZIDE. It is also
not known whether HYDROFLUMETHIAZIDE can cause fetal harm when administered to a pregnant
woman or can affect reproduction capacity. HYDROFLUMETHIAZIDE should be given to a
pregnant woman only if clearly needed.
Nonteratogenic Effects
Fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse
reactions which have occurred in the adult.
NURSING MOTHERS
Thiazides appear in breast milk. If use of the drug is deemed essential, the
patient may consider stopping nursing.
PEDIATRIC USE
Safety and effectiveness in children have not been established.
DRUG INTERACTIONS:
Anticoagulants, oral
(Effects may be decreased when used concurrently with thiazide diuretics; dosage
adjustments may be necessary.)
Antigout medications
(Thiazide diuretics may raise the level of blood uric acid; dosage adjustment of
antigout medications may be necessary to control hyperuricemia and gout.)
Antihypertensive medications, other, especially diazoxide, or preanesthetic and
anesthetic agents used in surgery or skeletal-muscle relaxants, nondepolarizing,
used in surgery
(Effects may be potentiated when used concurrently with thiazide diuretics;
dosage adjustments may be necessary.)
Amphotericin B or Corticosteroids or Corticotropin (ACTH)
(Concurrent use with thiazide diuretics may intensify electrolyte imbalance,
particularly hypokalemia.)
Cardiac glycosides
(Concurrent use with thiazide diuretics may enhance the possibility of digitalis
toxicity associated with hypokalemia.)
Colestipol
(May inhibit gastrointestinal absorption of the thiazide diuretics;
administration 1 hour before or 4 hours after colestipol is recommended.)
Hypoglycemics
(Thiazide diuretics may raise blood glucose levels; for adult-onset diabetics,
dosage adjustment of hypoglycemic medications may be necessary during and after
thiazide diuretic therapy; insulin requirements may be increased, decreased, or
unchanged.)
Lithium salts
(Concurrent use with thiazide diuretics is not recommended, as they may provoke
lithium toxicity because of reduced renal clearance.)
Methenamine
(Effectiveness may be decreased when used concurrently with thiazide diuretics
because of alkalinization of the urine.)
Nonsteroidal anti-inflammatory agents
(In some patients, the steroidal anti- inflammatory agent can reduce the
diuretic, natriuretic, and antihypertensive effects of loop, potassium sparing,
and thiazide diuretics. Therefore, when hydroflumethiazide 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.)
Norepinephrine
(Thiazides may decrease arterial responsiveness to norepinephrine. This
diminution is not sufficient to preclude effectiveness of the pressor agent for
therapeutic use.)
Tubocurarine
(Thiazide drugs may increase the responsiveness to tubocurarine.)
(See Also PRECAUTIONS)
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 SYSTEMS
Anorexia, gastric irritation, nausea, vomiting, cramping, diarrhea,
constipation, jaundice (intrahepatic cholestatic jaundice), pancreatitis,
sialadenitis.
CENTRAL NERVOUS SYSTEM
Dizziness, vertigo, paresthesias, headache, xanthopsia.
HEMATOLOGIC
Leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic
anemia.
CARDIOVASCULAR
Orthostatic hypotension (may be aggravated by alcohol, barbiturates, or
narcotics).
DERMATOLOGIC-HYPERSENSITIVITY
Purpura, photosensitivity, rash, urticaria, necrotizing angiitis (vasculitis,
cutaneous vasculitis), fever, respiratory distress including pneumonitis,
anaphylactic reactions.
OTHER
Hyperglycemia, glycosuria, hyperuricemia, muscle spasm, weakness, restlessness,
transient blurred vision.
Whenever adverse reactions are moderate or severe, thiazide dosage should be
reduced or therapy withdrawn.
OVERDOSAGE:
SIGNS AND SYMPTOMS
Diuresis, lethargy progressing to coma, with minimal cardiorespiratory
depression and with or without significant serum electrolyte changes or
dehydration; GI irritation; hypermotility; transient elevation in BUN level.
TREATMENT
Empty stomach by gastric lavage, taking care to avoid aspiration. Monitor serum
electrolyte levels and renal function, and institute supportive measures, as
required to maintain hydration, electrolyte balance, respiration, and
cardiovascular and renal function. Treat GI effects symptomatically.
DOSAGE AND ADMINISTRATION:
The average adult diuretic dose is 25 to 200 mg per day. The average adult
antihypertensive dose is 50 to 100 mg per day.
Therapy should be individualized according to patient response. This therapy
should be titrated to gain maximal response as well as the minimal dose possible
to maintain that therapeutic response.
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