Thiazides affect 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.
The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides do not affect normal blood pressure.
Hydrochlorothiazide is contraindicated in patients with anuria or hypersensitivity to this or other sulfonamide-derived drugs (see WARNINGS).
Thiazides should be used with caution in patients with 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 imbalance 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 are more likely to occur in patients with a history of allergy or bronchial asthma.
The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.
All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance, namely hyponatremia, hypochloremic alkalosis, and hypokalemia (see Laboratory Tests and Drug/Drug Interactions). Warning signs are dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbance, such as nausea or vomiting.
Hypokalemia may develop, especially in cases of brisk diuresis or severe cirrhosis.
Interference with adequate oral intake of electrolytes will also contribute to hypokalemia. Hypokalemia may be avoided or treated by the use of potassium supplements or foods with a high potassium content.
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 cases of 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 may become manifest during thiazide administration (see Drug/Drug Interactions).
The antihypertensive effects of the drug may be enhanced in the postsympathectomy patient.
If progressive renal impairment becomes evident, withholding or discontinuing diuretic therapy should be considered.
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.
Thiazide diuretics have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.
Initial and periodic determinations of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals.
Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids.
Hypokalemia can sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability).
Hypokalemia may develop during concomitant use of steroids or ACTH.
Insulin requirements in diabetic patients may be increased, decreased, or unchanged.
Thiazides may decrease arterial responsiveness to norepinephrine, but not enough to preclude effectiveness of the pressor agent for therapeutic use.
Thiazides may increase the responsiveness to tubocurarine.
Lithium renal clearance is reduced by thiazides, increasing the risk of lithium toxicity.
There have been rare reports in the literature of hemolytic anemia occurring with the concomitant use of hydrochlorothiazide and methyldopa.
Concurrent administration of some nonsteroidal anti-inflammatory agents may reduce the diuretic, natriuretic and antihypertensive effects of thiazide diuretics.
Thiazides may decrease serum levels of protein-bound iodine without signs of thyroid disturbance. Thiazides should be discontinued before tests for parathyroid function are made. (See PRECAUTIONS: General: Hydrochlorothiazide: Calcium excretion.)
Two-year feeding studies in mice and rats conducted under the auspices of the National Toxicology Program (NTP) uncovered no evidence of a carcinogenic potential of hydrochlorothiazide in female mice (at doses up to approximately 600 mg/kg/day) or in male and female rats (at doses up to approximately 100 mg/kg/day). The NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.
Hydrochlorothiazide was not genotoxic in in vitro assays using strains TA 98, TA 100, TA 1535, TA 1537, and TA 1538 of Salmonella typhimurium (Ames assay) and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations, or in in vivo assays using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive test results were obtained only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and in the Mouse Lymphoma Cell (mutagenicity) assays, using concentrations of hydrochlorothiazide from 43 mcg/mL to 1300 mcg/mL, and in the Aspergillus nidulans nondisjunction assay at an unspecified concentration.
Hydrochlorothiazide had no adverse effects on the fertility of mice and rats of either sex in studies wherein these species were exposed, via their diet, to doses of up to 100 mg/kg/day and 4 mg/kg/day, respectively, prior to mating and throughout gestation.
Studies in which hydrochlorothiazide was orally administered to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 mg/kg/day and 1000 mg/kg/day, respectively, provided no evidence of harm to the fetus.
Thiazides cross the placental barrier and appear in cord blood, and there is a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in adults.
The following adverse reactions have been observed, but there has not been enough systematic collection of data to support an estimate of their frequency. Consequently the reactions are categorized by organ systems and are listed in decreasing order of severity and not frequency.
Digestive: Pancreatitis, jaundice (intrahepatic cholestatic), sialadenitis, vomiting, diarrhea, cramping, nausea, gastric irritation, constipation, anorexia.
Cardiovascular: Orthostatic hypotension (may be potentiated by alcohol, barbiturates, or narcotics).
Neurologic: Vertigo, dizziness, transient blurred vision, headache, paresthesia, xanthopsia, weakness, restlessness.
Musculoskeletal: Muscle spasm.
Hematologic: Aplastic anemia, agranulocytosis, leukopenia, thrombocytopenia.
Metabolic: Hyperglycemia, glycosuria, hyperuricemia.
Hypersensitive Reactions: Necrotizing angiitis, Stevens-Johnson syndrome, respiratory distress including pneumonitis and pulmonary edema, purpura, urticaria, rash, photosensitivity.
The most prominent feature of poisoning is acute loss of fluid and electrolytes.
Cardiovascular: Tachycardia, hypotension, shock.
Neuromuscular: Weakness, confusion, dizziness, cramps of the calf muscles, paresthesia, fatigue, impairment of consciousness.
Digestive: Nausea, vomiting, thirst.
Renal: Polyuria, oliguria, or anuria (due to hemoconcentration).
Laboratory Findings: Hypokalemia, hyponatremia, hypochloremia, alkalosis; increased BUN (especially in patients with renal insufficiency).
Combined Poisoning: Signs and symptoms may be aggravated or modified by concomitant intake of antihypertensive medication, barbiturates, curare, digitalis (hypokalemia), corticosteroids, narcotics, or alcohol.
