Pharmacokinetics and Metabolism:

Hydrochlorothiazide is well absorbed (65% to 75%) fol­lowing oral administration. Absorption of hydrochlorothi­azide is reduced in patients with congestive heart failure.



Peak plasma concentrations are observed within 1 to 5 hours of dosing and range from 70 to 490 ng/mL follow­ing oral doses of 12.5 to 100 mg. Plasma concentra­tions are linearly related to the administered dose. Concen­trations of hydrochlorothiazide are 1.6 to 1.8 times higher in whole blood than in plasma. Binding to serum proteins has been reported to be approxi­mately 40% to 68%. The plas­ma elimination half-life has been reported to be 6 to 15 hours. Hydrochlorothiazide is eliminated primarily by renal pathways. Following oral doses of 12.5 to 100 mg, 55% to 77% of the administered dose appears in urine and greater than 95% of the absorbed dose is excreted in urine as unchanged drug. In patients with renal disease, plasma con­centrations of hydrochlorothi­azide are increased and the elimination half-life is pro­longed.



When hydrochloro­thiazide is adminis­tered with food, its bioavailabil­ity is reduced by 10%, the max­imum plasma concentration is reduced by 20%, and the time to maximum concentration increases from 1.6 to 2.9 hours.

Pharmacodynamics:

Acute antihypertensive effects of thi­azides are thought to result from a reduction in blood vol­ume and cardiac output, sec­ondary to a natriuretic effect, although a direct vasodilatory mechanism has also been pro­posed. With chronic adminis­tration, plasma volume returns toward normal, but peripheral vascular resistance is de­creased. The exact mechanism of the antihypertensive effect of hydrochlorothiazide is not known.



Thiazides do not affect normal blood pressure. Onset of action occurs within 2 hours of dos­ing, peak effect is observed at about 4 hours, and activity per­sists for up to 24 hours.

Clinical Studies:

In an 87 patient 4-week double-blind, placebo controlled, parallel group trial, patients who received hydrochloro­thiazide had reductions in seated systolic and diastolic blood pressure that were significantly greater than those seen in patients who received placebo. In published placebo-controlled trials com­paring 12.5 mg of hydrochlorothiazide to 25 mg, the 12.5 mg dose preserved most of the placebo-corrected blood pressure reduction seen with 25 mg.

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. Diuretics are indi­cated in pregnancy when edema is due to pathologic causes, just as they are in the absence of pregnancy. 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 the 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.

Information for Patients:

Non-melanoma Skin Cancer: Instruct patients taking hydrochlorothiazide to protect skin from the sun and undergo regular skin cancer screening.

Drug Interactions:

When given concurrently the following drugs may interact with thiazide diuretics:

Alcohol, barbiturates, or narcotics: potentiation of ortho­static hypotension may occur.

Antidiabetic drugs: (oral agents and insulin) dosage adjustment of the antidiabetic drug may be required.

Other antihypertensive drugs:  ­additive effect or potentiation.

Cholestyramine and colestipol resins: Cholestyramine and colestipol resins bind the hydrochlorothiazide and re­duce its absorption from the gastrointestinal tract by up to 85 and 43 percent, respectively.

Corticosteroid, ACTH: intensi­fied electrolyte depletion, particularly hypokalemia.

Pressor amines (e.g., norepinephrine): possible decreased response to pressor amines but not sufficient to preclude their use.

Skeletal muscle relaxants, nondepolarizing (e.g., tubocurarine): possible increased responsiveness to the muscle relaxant.

Lithium: generally should not be given with diuretics. Diuretic agents reduce the renal clear­ance of lithium and greatly increase the risk of lithium tox­icity. Refer to the package insert for lithium preparations before use of such preparations with hydrochloro­thiazide.

Non-steroidal anti-inflammatory drugs: In some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. When hydrochloro­thiazide and non-steroidal anti-inflammatory agents are used concomitantly, the patients should be observed closely to determine if the desired effect of the diuretic is obtained.

Drug/Laboratory Test Interactions: Thiazides should be discontinued before carrying out tests for parathyroid function (see PRECAUTIONS,General).

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 1,300 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 gestation.

Pregnancy:

Nursing Mothers: 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.

Pediatric Use:

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use:

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.

Postmarketing Experience:

The following adverse reaction has been identified during post-approval use of hydrochlorothiazide. Because the reaction is reported voluntarily from a population of uncertain size, it is not possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Non-melanoma Skin Cancer: Hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer. In a study conducted in the Sentinel System, increased risk was predominantly for squamous cell carcinoma (SCC) and in white patients taking large cumulative doses. The increased risk for SCC in the overall population was approximately 1 additional case per 16,000 patients per year, and for white patients taking a cumulative dose of ≥50,000 mg the risk increase was approximately 1 additional SCC case for every 6,700 patients per year.