General Monograph,

Diuretic – Antihypertensive

Pharmacology: Hydrochlorothiazide inhibits reabsorption of sodium and chloride in the distal tubule thus promoting water loss. The higher urine volume increases potassium loss; this loss can often be decreased by restricting sodium intake. Oral doses are well absorbed and reach peak effect in about 4 hours, with a 6 to 12 hour duration. It is excreted unchanged in the urine with a half-life of 3 to 5 hours.

The mild blood pressure reducing effects are initially due to volume reduction but the persisting effect includes other undetermined mechanisms that reduce peripheral resistance. A high salt intake reverses its antihypertensive effect.

Indications: Adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis with ascites, in drug induced edema (corticosteroid and estrogen therapy) and in edema of renal origin (i.e., nephrotic syndrome, acute glomerulonephritis, chronic renal disease).

In the management of hypertension, hydrochlorothiazide may be used alone or as an adjunct to other antihypertensive drugs. Since it enhances the action of these agents, the dosage of either or both agents must be reduced to avoid an excessive drop in blood pressure.

Contraindications: Anuria; discontinue if increasing azotemia and oliguria occur during treatment of severe progressive renal disease. Do not use in patients known to be sensitive to thiazides or other sulfonamide derived drugs.

Precautions: May precipitate or increase azotemia; cumulative effects may develop in presence of impaired renal function; discontinue if increasing azotemia and oliguria occur during treatment of severe progressive renal disease. Use with caution in impaired hepatic function or progressive liver disease since minor alterations of fluid and electrolyte balance or of serum ammonia may precipitate hepatic coma.

The possibility of sensitivity reactions should be considered in patients with or without a history of allergy or bronchial asthma.

The possibility that hydrochlorothiazide may exacerbation or activate systemic lupus erythematosus has been reported.

Patients should be carefully monitored for signs of fluid and electrolyte imbalance, namely hyponatremia, hypochloremic alkalosis and hypokalemia. Hypomagnesemia may also occur. Serum and urine electrolyte determinations are particularly important when the patient has other disorders that predispose to fluid and electrolyte imbalance such as vomiting, diarrhea, heart failure, liver or renal disease, is on a salt-restricted diet, or is receiving parenteral fluids. The elderly may be at greater risk for developing electrolyte abnormalities, including hypomagnesemia, due to age-related changes in renal function. Warning signs of fluid and electrolyte imbalance include: dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances (nausea, vomiting), seizures or confusion.

Hypokalemia may be prevented or treated with potassium-rich foods, a potassium-sparing diuretic or potassium supplements.

Dilutional hyponatremia most commonly occurs during hot weather in patients with chronic congestive heart failure or hepatic disease. It may also be aggravated during chronic thiazide therapy. Treatment includes withdrawal of the diuretic, fluid restriction, and potassium and/or magnesium supplementation. Administration of sodium chloride is usually not required except in rare instances when the hyponatremia is life-threatening.

Although any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic or hypochloremic alkalosis.

Because thiazides decrease calciuresis and increase serum calcium levels, use of thiazides may unmask subclinical hyperparathyroidism with hypercalcemia and hypophosphatemia. The common complications of hyperparathyroidism such as renal lithiasis, bone resorption, and peptic ulceration have not been reported. Thiazides should be discontinued before carrying out parathyroid function tests.

Caution is necessary in patients with hyperuricemia or a history of gout.

Low doses of thiazides for treatment of hypertension usually do not cause alterations in lipid levels; however, thiazides are not recommended in patients with severe hyperlipidemia which requires drug therapy.

The antihypertensive effect of the drug may be enhanced in the post sympathectomy patient.

Drug Interactions : Hypokalemia may develop (especially with brisk diuresis) in severe cirrhosis; with concomitant steroid or ACTH therapy; or with inadequate electrolyte intake. Principally hypokalemia, but also hypomagnesemia and hypercalcemia, can sensitize or exaggerate the response of the heart to toxic effects of digitalis.

Thiazides may cause prolonged neuromuscular blockade in patients receiving nondepolarizing neuromuscular blocking agents (e.g., tubocurarine).

The hyperglycemic effect of hydrochlorothiazide may exacerbate diabetes mellitus resulting in increased dosage requirements of insulin or sulfonylureas and may worsen glycemic control in some patients. This effect may occur after several days to many months of thiazide therapy.

Hydrochlorothiazide may add to or potentiate the action of other antihypertensive drugs, and decrease responsiveness to norepinephrine.

Hydrochlorothiazide may enhance the cardiotoxic (e.g., ECG changes) and neurotoxic (e.g., ataxia, confusion and mental disorientation) effects of lithium. If possible, an alternative agent should be used. In those rare instances when these drugs must be given together, dosage should be reduced, and patients should be observed closely for signs and symptoms of lithium toxicity. Close monitoring of serum electrolytes and lithium concentrations and maintenance of adequate fluid, potassium and sodium intake also are recommended.

NSAIDs: Concomitant use may increase the risk of renal failure and reverse the antihypertensive effect. This combination should be avoided if possible. If these drugs must be given together, close monitoring of serum creatinine, potassium concentrations and patient’s weight is recommended.

Pregnancy: The routine use of thiazide diuretics in an otherwise healthy pregnant woman with or without edema is not appropriate. Edema in pregnancy, resulting from restriction of venous return by the expanded uterus, is treated through elevation of the lower extremities and use of support hose. A short course of diuretics may be appropriate in patients with severe hypervolemia not relieved by rest or these measures. Pathological edema such as cardiac, nephrotic or hepatic edema may be an indication for use of thiazide diuretics. Thiazides do not prevent toxemia of pregnancy, nor are they useful in its treatment.

Thiazides cross the placental barrier. Possible risks include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in the adult.

Lactation: Thiazides are excreted into the milk of nursing women, although apparently not in significant amounts. The potential for idiosyncratic or allergic reactions in the infant should be considered. It should be noted that thiazides may partially suppress lactation.

Adverse Effects: Cardiovascular: Orthostatic hypotension may occur, especially in elderly patients with reduced plasma volume and may be potentiated by alcohol, barbiturates or narcotics.

CNS: dizziness, vertigo, paresthesias, headache, xanthopsia.

Gastrointestinal: anorexia, gastric irritation, nausea, vomiting, cramping, diarrhea, constipation, jaundice (intrahepatic cholestatic), pancreatitis, sialadenitis.

Hematologic: leukopenia, thrombocytopenia, agranulocytosis, aplastic anemia, hemolytic anemia.

Hypersensitivity: purpura, photosensitivity, rash, urticaria, necrotizing angiitis, fever, respiratory distress including pneumonitis, anaphylactic reactions.

Miscellaneous: muscle spasm, weakness, restlessness, hyperglycemia, glycosuria, transient hyperlipidemia, hyperuricemia, transient blurred vision.

Whenever adverse reactions are moderate or severe, thiazide dosage should be reduced or therapy withdrawn.

Overdose: Symptoms: Overdosage may lead to excessive diuresis with electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration. If digitalis has also been administered, hypokalemia may accentuate myocardial abnormalities (e.g., cardiac arrhythmias).

Signs are dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, gastrointestinal disturbances, mental confusion, delirium, convulsions, shock, coma.

Treatment: There is no specific antidote. If ingestion is recent, gastric lavage or emesis may reduce absorption; activated charcoal may be given. Otherwise, management includes symptomatic treatment with special attention to cardiac rate and output, blood volume, electrolyte balance, dehydration, paralytic ileus, urinary function, hepatic coma, and cerebral activity. Administration of sympathomimetic drugs (e.g., dopamine) may be indicated. Administer oxygen or artificial respiration for respiratory impairment.

Dosage: Diuresis: the usual adult dose is 25 to 100 mg per day, depending on patient response. Some patients may respond to intermittent therapy (alternate days or 3 to 5 days per week). The usual oral dosage for children is 2 mg/kg per day, given in 2 divided doses. Infants under 6 months of age may require up to 3 mg/kg per day, in 2 divided doses.

Hypertension: Doses as low as 12.5 mg daily may be effective, especially in the elderly. Some clinicians advocate the use of 6.25 mg as a starting dose. Usual adult dose is 25 to 50 mg daily, adjusted as necessary every 2 to 4 weeks. Doses above this level may offer only a limited increase in effectiveness while increasing the severity of side effects. In hypertension associated with volume overload in renal failure, more potent agents such as loop diuretics may be required.

HYDROCHLOROTHIAZIDE General Monograph,Diuretic – Antihypertensive

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