Diabetes and Hypoglycemia: Latent diabetes mellitus may become manifest and diabetic patients given thiazides may require adjustment of their insulin dose.
Renal Disease: Cumulative effects of the thiazides may develop in patients with impaired renal function. In such patients, thiazides may precipitate
Electrolyte and Fluid Balance Status
In published studies, clinically significant hypokalemia has been consistently
less common in patients who received 12.5 mg of hydrochlorothiazide than in
patients who received higher doses. Nevertheless, periodic determination of
serum electrolytes should be performed in patients who may be at risk for the
development of hypokalemia. Patients should be observed for signs of fluid or
electrolyte disturbances, i.e. hyponatremia, hypochloremic alkalosis, and hypokalemia
Warning signs or symptoms of fluid and electrolyte imbalance include 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, especially with brisk diuresis when severe cirrhosis
is present, during concomitant use of corticosteroid or adrenocorticotropic
hormone (ACTH) or after prolonged therapy. Interference with adequate oral electrolyte
intake will also contribute to hypokalemia. Hypokalemia and hypomagnesemia can
provoke ventricular arrhythmias or sensitize or exaggerate the response of the
heart to the toxic effects of digitalis. Hypokalemia may be avoided or treated
by potassium supplementation or increased intake of potassium rich foods.
Dilutional hyponatremia is life-threatening and may occur in edematous patients
in hot weather; appropriate therapy is water restriction rather than salt administration,
except in rare instances when the hyponatremia is life-threatening. In actual
salt depletion, appropriate replacement is the therapy of choice.
Hyperuricemia or acute gout may be precipitated in certain patients receiving thiazide diuretics.
Impaired Hepatic Function
Thiazides should be used with caution in patients with impaired hepatic function. They can precipitate hepatic coma in patients with severe liver disease.
Calcium excretion is decreased by thiazides, and pathologic changes in the parathyroid glands, with hypercalcemia and hypophosphatemia, have been observed in a few patients on prolonged thiazide therapy.
Carcinogenesis, Mutagenesis, Impairment of Fertility
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 of up to approximately 600 mg/kg/
day) or in male and female rats (at doses of approximately 100 mg/kg/day). The
NTP, however, found equivocal evidence for hepatocarcinogenicity in male mice.
Hydrochlorothiazide was not genotoxic in vitro in the Ames mutagenicity assay of Salmonella typhimurium strains TA 98, TA 100, TA 1535, TA 1537,
and TA 1538 and in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations,
or in vivo in 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 to
1300 mcg/mL, and in the Aspergillus nidulans non-disjunction 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 and 4 mg/kg, respectively, prior to conception and throughout
Pregnancy Category B: Studies in which hydrochlorothiazide was
orally administered to pregnant mice and rats during their respective periods
of major organogenesis at doses up to 3000 and 1000 mg hydrochlorothiazide/kg,
respectively, provided no evidence of harm to the fetus.
There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.
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.
Thiazides are excreted in breast milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue hydrochlorothiazide, taking into account the importance of the drug to the mother.
Safety and effectiveness in pediatric patients have not been established.
A greater blood pressure reduction and an increase in side effects may be observed in the elderly (i.e. > 65 years) with hydrochlorothiazide. Starting treatment with the lowest available dose of hydrochlorothiazide (12.5 mg) is therefore recommended. If further titration is required, 12.5 mg increments should be utilized.