Hydrochlorothiazide

[Section Outline]

Administration
Dosage

Administration

Hydrochlorothiazide is administered orally.

Extemporaneously Compounded Oral Liquid

Extemporaneously compounded oral liquid formulations of hydrochlorothiazide containing 5 mg/mL have been prepared.113,114,115

Standardize 4 Safety

Standardized concentrations for an extemporaneously prepared oral liquid formulation of hydrochlorothiazide have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 252Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 252 For additional information on S4S (including updates that may be available), see [Web].252

Table 1: Standardize 4 Safety Compounded Oral Liquid Standards for Hydrochlorothiazide252

Concentration Standards
5 mg/mL

Dosage

Dosage of hydrochlorothiazide should be individualized according to the patient's requirements and response. The lowest dosage necessary to produce the desired clinical effect should be used.109 If hydrochlorothiazide is added to the regimen of a patient stabilized on a potent hypotensive agent, dosage of the hypotensive agent should initially be reduced to avoid the possibility of severe hypotension.

Edema

For the management of edema, the usual adult dosage of hydrochlorothiazide is 25-100 mg daily in 1-3 divided doses.109 Many patients also may respond to intermittent therapy (e.g., on alternate days or on 3-5 days weekly).109 Excessive diuretic response and the resulting undesirable electrolyte imbalance are less likely to occur with such intermittent administration of the drug.109

For the management of fluid retention (e.g., edema) associated with heart failure, some experts recommend initiating hydrochlorothiazide at a low dosage (e.g., 25 mg once or twice daily) and increasing the dosage (maximum of 200 mg daily) until urine output increases and weight decreases, generally by 0.5-1 kg daily.524 When hydrochlorothiazide is used for sequential nephron blockade in the management of fluid retention in heart failure, some experts recommend an initial dosage of 25-100 mg once or twice daily in combination with a loop diuretic.524 Experts state that diuretics should be administered at a dosage sufficient to achieve optimal volume status and relieve congestion without inducing an excessively rapid reduction in intravascular volume, which could result in hypotension, renal dysfunction, or both.524

Hypertension

Usual Dosage

For the management of hypertension in adults, the manufacturers recommend an initial hydrochlorothiazide dosage of 12.5-25 mg once daily600,601 and a usual maximum dosage of 50 mg daily (in 1 or 2 divided doses).109,112,600,601 Dosages of 25-100 mg daily (in 1 or 2 divided doses) have been used in randomized controlled studies; experts recommend a dosage of 25-50 mg daily for optimal balance between efficacy and safety in the management of hypertension in adults.501,1200 Dosages exceeding 50 mg daily usually are associated with marked hypokalemia;600 some manufacturers state that such dosages are not recommended.601

Fixed-combination Therapy

When combination therapy is required in the management of hypertension, dosage can first be adjusted by administering each drug separately. If it is determined that the optimum maintenance dosage corresponds to the ratio in the commercial combination preparation, the fixed combination may be used. Alternatively, therapy can be initiated with a fixed combination of 2 antihypertensive agents.502,1200 Use of fixed-combination preparations may increase patient compliance.502,1200

For information on commercially available preparations containing hydrochlorothiazide in fixed combination with a potassium-sparing diuretic, see the individual monographs in 40:28.10.

Monitoring and Blood Pressure Treatment Goals

The patient's renal function and electrolytes should be assessed 2-4 weeks after initiation of diuretic therapy.1200 Blood pressure should be monitored regularly (i.e., monthly) during therapy and dosage of the antihypertensive drug adjusted until blood pressure is controlled.1200 If an adequate blood pressure response is not achieved with hydrochlorothiazide monotherapy, another antihypertensive agent with demonstrated benefit and preferably with a complementary mechanism of action (e.g., angiotensin-converting enzyme [ACE] inhibitor, angiotensin II receptor antagonist, calcium-channel blocker) may be added; if goal blood pressure is still not achieved, a third drug may be added.1200,1216 (See Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.) In patients who develop unacceptable adverse effects with hydrochlorothiazide, the drug should be discontinued and another antihypertensive agent from a different pharmacologic class should be initiated.1200,1216

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure.1200 However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.501,503,504,505,506,507,508,515,523,526,530,1200,1201,1207,1209,1222,1223,1229 A 2017 multidisciplinary hypertension guideline from the American College of Cardiology (ACC), American Heart Association (AHA), and a number of other professional organizations generally recommends a blood pressure goal of less than 130/80 mm Hg in all adults regardless of comorbidities or level of atherosclerotic cardiovascular disease (ASCVD) risk.1200,1207 Many patients will require at least 2 drugs from different pharmacologic classes to achieve this blood pressure goal; the potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs also should be considered when deciding a patient's blood pressure treatment goal.1200,1220

For additional information on target levels of blood pressure and on monitoring therapy in the management of hypertension, see Blood Pressure Monitoring and Treatment Goals under Dosage: Hypertension, in Dosage and Administration in the Thiazides General Statement 40:28.20.

Pediatric Dosage

In children 6 months to 12 years of age, the usual dosage of hydrochlorothiazide for the management of hypertension or for diuresis is 1-2 mg/kg daily given as a single dose or in 2 divided doses.600,1150 Infants younger than 6 months of age may require up to 3 mg/kg daily in 2 divided doses.600 The total daily dosage should not exceed 37.5 mg for children up to 2 years of age or 100 mg for children 2-12 years of age.600 Experts recommend initiation of the drug at the low end of the dosage ran the dosage may be increased every 2-4 weeks until blood pressure is controlled, the maximum dosage is reached, or adverse effects occur.1150 For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

Geriatric Dosage

Because an increased incidence of adverse effects to hydrochlorothiazide and excessive reduction in blood pressure may occur in geriatric patients (older than 65 years of age), hydrochlorothiazide should be initiated at the lowest dosage (12.5 mg daily); dosage may be adjusted in increments of 12.5 mg if needed.112

Cautions ⬆ ⬇

Hydrochlorothiazide shares the pharmacologic actions, uses, and toxic potentials of the thiazides, and the usual precautions of thiazide administration should be observed. (See Cautions in the Thiazides General Statement 40:28.20)

When hydrochlorothiazide is used in fixed combination with other drugs, the cautions, precautions, contraindications, and interactions associated with the concomitant agent(s) should be considered in addition to those associated with hydrochlorothiazide.

Some commercially available formulations of hydrochlorothiazide contain sulfites that may cause allergic-type reactions, including anaphylaxis and life-threatening or less severe asthmatic episodes, in certain susceptible individuals. The overall prevalence of sulfite sensitivity in the general population is unknown but probably low; such sensitivity appears to occur more frequently in asthmatic than in nonasthmatic individuals.

Other Information ⬆ ⬇

[Section Outline]

Chemistry
Stability

Pharmacokinetics

Hydrochlorothiazide is well absorbed from the GI tract, with an oral bioavailability of approximately 65-75%.112 Although the rate and extent of absorption have been reported to vary depending on the formulation administered, no studies have been performed to determine the clinical importance (if any) of variations in absorption in patients receiving chronic hydrochlorothiazide therapy. Following oral administration of hydrochlorothiazide at doses of 12.5-100 mg, peak plasma concentrations of 70-490 ng/mL are observed within 1-5 hours of dosing.112 Food decreases the rate and extent of absorption of hydrochlorothiazide capsules (Microzide^®).112 Bioavailability and peak plasma concentrations of the drug were decreased by about 10 and 20%, respectively, when hydrochlorothiazide capsules (Microzide^®) were administered with food.112 Times to peak plasma concentration for such capsules were delayed by 1.3 hours (from 1.6 to 2.9 hours).112 Absorption of hydrochlorothiazide is reduced in patients with heart failure.112

Approximately 40-68% of the drug is bound to plasma proteins.112

Hydrochlorothiazide exhibits linear pharmacokinetics.112 Based on determination of plasma drug concentrations over a period of at least 24 hours, the plasma half-life of hydrochlorothiazide reportedly ranges from 5.6-15 hours. Hydrochlorothiazide apparently is not metabolized and is excreted unchanged in urine. At least 61% of the drug is reportedly eliminated from the body within 24 hours. Increased hydrochlorothiazide plasma concentrations and a prolonged elimination half-life have been reported in patients with renal impairment.112 The effect of hemodialysis on the elimination of the drug has not been determined.112

Chemistry and Stability

Chemistry

Hydrochlorothiazide is a thiazide diuretic. Hydrochlorothiazide occurs as a white or practically white, practically odorless, crystalline powder and has a slightly bitter taste. The drug is slightly soluble in water and soluble in alcohol and has pK_as of 7.9 and 9.2.

Stability

Hydrochlorothiazide tablets and capsules should be stored in tightly closed containers at a controlled room temperature of 15-30°C and protected from light, moisture, and freezing.109,112 Hydrochlorothiazide oral solution should be stored in well-closed containers at a temperature less than 40°C, preferably at 15-30°C. Freezing of the oral solution should be avoided. Commercially available hydrochlorothiazide tablets have an expiration date of 3 or 5 years following the date of manufacture depending on the packaging.

For further information on chemistry and stability, pharmacology, pharmacokinetics, uses, cautions, acute toxicity, drug interactions, laboratory test interferences, and dosage and administration of hydrochlorothiazide, see the Thiazides General Statement 40:28.20.

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations ⬆ ⬇

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.