Generic Name: hydrochlorothiazide

Brand Names: Diaqua, Hydro Par, Microzide, HydroDIURIL, Carozide, Oretic, Loqua, Ezide, Aquazide H, Esidrix

Uses

Hypertension

Used alone or in combination with other antihypertensive agents for all stages of hypertension.

Thiazides have well-established benefits, can be useful in achieving goal BP alone or combined with other antihypertensive drugs, enhance the antihypertensive efficacy of multidrug regimens, and are more affordable than other agents.

JNC 7 recommends that thiazides be used as initial therapy for the treatment of uncomplicated hypertension in most patients, either alone or combined with other classes of antihypertensive drugs with demonstrated benefit (e.g., ACE inhibitors, angiotensin II receptor antagonists, β-blockers, calcium-channel blockers).

Most hypertension outcome studies have involved thiazides, which generally have been unsurpassed in preventing cardiovascular complications of hypertension and are relatively inexpensive and well tolerated.

The principal goal of preventing and treating hypertension is to reduce the risk of cardiovascular and renal morbidity and mortality, including target organ damage. The higher the baseline BP, the more likely the development of MI, heart failure, stroke, and renal disease.

Effective antihypertensive therapy reduces the risk of stroke by about 34–40%, MI by about 20–25%, and heart failure by more than 50%.

Antihypertensive drug therapy is recommended for all patients with SBP/DBP ≥140/90 mm Hg who fail to respond to lifestyle/behavioral modifications.

Initial antihypertensive therapy with drugs generally is recommended for anyone with diabetes mellitus, chronic renal impairment, or heart failure having SBP ≥130 mm Hg or DBP≥80 mm Hg.

Black hypertensive patients generally tend to respond better to monotherapy with diuretics or calcium-channel blockers than to monotherapy with ACE inhibitors, angiotensin II receptor antagonists, or β-blockers.

Thiazides are preferred in hypertensive patients with osteoporosis. Secondary beneficial effect in hypertensive geriatric patients of reducing the risk of osteoporosis secondary to effect on calcium homeostasis and bone mineralization.

Thiazide diuretics (unlike potassium-sparing diuretics) may be used in patients who are at an increased risk for developing hyperkalemia (e.g., those receiving an ACE inhibitor).

Although hypertension during pregnancy responds well to thiazides, and the drugs had been used widely in the past for preeclampsia and eclampsia, such use no longer is recommended and other antihypertensives (e.g., methyldopa, hydralazine, labetalol) currently are preferred.

Although rarely induces acute gout, generally avoid or use with caution in hypertensive patients with a history of gout or elevated uric acid concentrations.

Edema (General)

Management of edema resulting from various causes; diagnose etiology before use.

Edema caused by renal disease or by corticosteroids or estrogens may be relatively resistant to treatment.

Ineffective in patients with S_cr or BUN concentrations greater than twice normal.

May be ineffective in patients with a GFR of <15–25 mL/minute; even when GFR is 25–50 mL/minute, more potent (e.g., loop) diuretics may be indicated.

No substantial difference in clinical effects or toxicity of comparable thiazide or thiazide-like diuretics, except metolazone may be more effective in edema with renal impairment.

Edema in CHF

Management of edema associated with CHF.

Used in conjunction with moderate sodium restriction (≤3 g of sodium daily), an ACE inhibitor, and usually a β-adrenergic blocking agent, with or without a cardiac glycoside.

Beneficial effects are additive with those of cardiac glycosides and/or ACE inhibitors.

Unless contraindicated or not tolerated, all patients with mild to severe CHF secondary to left ventricular systolic dysfunction (ejection fraction less than 35–40%) generally should receive therapy with a diuretic in conjunction with an ACE inhibitor with or without a cardiac glycoside or a β-adrenergic blocking agent.

Diuretic therapy and sodium restriction are not routinely necessary in patients with left ventricular systolic dysfunction and no or minimal overt signs or symptoms of heart failure (NYHA functional class I heart failure); diuretics should be added to ACE inhibitor therapy if volume overload develops or if symptoms of heart failure continue.

Concomitant diuretic therapy usually is indicated in patients with symptomatic heart failure (NYHA class II or greater) because of the likelihood of sodium and fluid retention.

Do not use diuretics as monotherapy in CHF even if symptoms (e.g., peripheral edema, pulmonary congestion) are well controlled; diuretics alone do not prevent progression of heart failure.

Diuretics produce rapid symptomatic benefits, relieving pulmonary and peripheral edema more rapidly (within hours or days) than cardiac glycosides, ACE inhibitors, or β-blockers (in weeks or months).

Once fluid retention has resolved in CHF, diuretic therapy should be maintained to prevent recurrence of fluid retention. Ideally, diuretic therapy should be adjusted according to changes in body weight (as an indicator of fluid retention) rather than maintained at a fixed dosage.

Diuretics should be continued in CHF and comorbid conditions (e.g., hypertension) where ongoing therapy with the drugs is indicated.

Edema Secondary to Nephrotic Syndrome

May be useful if the patient fails to respond to corticosteroid therapy.

More likely to become refractory to thiazides than edema associated with CHF, and more potent diuretics may be required.

Edema in Pregnancy

Generally responds well to thiazides except when caused by renal disease.

Thiazides should not be used for routine therapy in pregnant women with mild edema who are otherwise healthy.

Diabetes Insipidus

Has been used widely in the treatment of diabetes insipidus†.

Effective in both the neurohypophyseal and nephrogenic forms of the disease, decreasing urine volume by up to 50%.

Particularly useful in nephrogenic diabetes insipidus, since this form of the disease is unresponsive to vasopressin or lypressin and chlorpropamide.

Useful in patients who are allergic or refractory to vasopressin or lypressin and has been used in combination with one of these hormones and a low-salt diet in patients who excrete an exceptionally large volume of urine.

Renal Tubular Acidosis

Has been used with success in the treatment of electrolyte disturbances associated with renal tubular acidosis†.

Renal Calculus Formation

Has been used with success in the prophylaxis of renal calculus formation associated with hypercalciuria†.

Dosage and Administration

Administration

Administer orally.

Dosage

Individualize according to requirements and response. Use lowest dosage necessary to produce desired clinical effect.

If added to potent hypotensive agent regimen, initially reduce hypotensive dosage to avoid the possibility of severe hypotension.

Pediatric Patients

Usual Dosage

Oral

Infants <6 months of age: Up to 3 mg/kg daily, in 2 divided doses; up to 37.5 mg daily.

Infants 6 months to 2 years of age: Usually, 1–2 mg/kg daily, in a single or 2 divided doses, up to 37.5 mg daily.

Children 2–12 years of age: 1–2 mg/kg daily, in a single or 2 divided doses, up to 100 mg daily.

Hypertension

Oral

Initially, 1 mg/kg once daily. Increase dosage as necessary up to a maximum of 3 mg/kg (up to 50 mg) once daily.

Adults

Hypertension

BP Monitoring and Treatment Goals

Carefully monitor BP during initial titration or subsequent upward adjustment in dosage.

Avoid large or abrupt reductions in BP.

Adjust dosage at approximately monthly intervals (more aggressively in high-risk patients [stage 2 hypertension, comorbid conditions]) if BP control is inadequate at a given dosage; it may take months to control hypertension adequately while avoiding adverse effects of therapy.

SBP is the principal clinical end point, especially in middle-aged and geriatric patients. Once the goal SBP is attained, the goal DBP usually is achieved.

The goal is to achieve and maintain a lifelong SBP <140 mm Hg and a DBP <90 mm Hg if tolerated.

The goal in hypertensive patients with diabetes mellitus or renal impairment is to achieve and maintain a SBP <130 mm Hg and a DBP <80 mm Hg.

Monotherapy

Oral

Initially, 12.5–25 mg daily.

Gradually increase until the desired therapeutic response is achieved or adverse effects become intolerable, up to 50 mg daily.

If adequate response is not achieved at maximum dosage, add or substitute another hypotensive agent.

Maintenance

Usually, 12.5–50 mg once daily.

Combination Therapy

Oral

Initially, administer each drug separately to adjust dosage.

May use fixed combination if optimum maintenance dosage corresponds to drug ratio in combination preparation.

Administer each drug separately whenever dosage adjustment is necessary.

Alternatively, may initially use certain (low-dose hydrochlorothiazide/other antihypertensive) fixed combinations for potentiation of antihypertensive effect and minimization of potential dose-related adverse effects of each drug.

Edema

Oral

Usually, 25–100 mg daily in 1–3 divided doses.

Many patients also may respond to intermittent therapy (e.g., alternate days, 3–5 days weekly); decreased risk of excessive diuretic response and resulting electrolyte imbalance.

Prescribing Limits

Pediatric Patients

Usual Dosage

Oral

Infants <2 years of age: Maximum 37.5 mg daily.

Children 2–12 years of age: Maximum 100 daily.

Hypertension

Oral

Maximum 3 mg/kg (up to 50 mg) once daily.

Adults

Hypertension

Oral

Maximum before switching/adding alternative drug is 50 mg daily.

Higher dosages had been used in the past (up to 200 mg daily) but no longer are recommended because of the risk of adverse effects (e.g., markedly decreased serum potassium). Instead, switch to or add alternative drug.

Special Populations

Hepatic Impairment

No specific dosage recommendations for hepatic impairment; caution because of risk of precipitating hepatic coma.

Renal Impairment

No specific dosage recommendations for renal impairment; caution because of risk of precipitating azotemia.

Geriatric Patients

Initiate therapy at the lowest dosage (12.5 mg daily); may adjust dosage in increments of 12.5 mg if needed.

Cautions

Contraindications

• Anuria.
• Known hypersensitivity to hydrochlorothiazide, other thiazides, or any ingredient in the formulation.
• Although manufacturers state allergy to other sulfonamide derivatives is a contraindication, evidence to support cross-sensitivity is limited, and history of sensitivity to sulfonamide anti-infectives (“sulfa sensitivity”) should not be considered an absolute contraindication.

Warnings/Precautions

Warnings

Severe Renal Impairment

Use with caution; thiazides decrease GFR and may precipitate azotemia.

Effects may be cumulative in impaired renal function.

Hepatic Impairment

Use with caution in hepatic impairment or progressive liver disease (particularly with associated potassium deficiency); electrolyte imbalance may precipitate hepatic coma.

Discontinue immediately if signs of impending hepatic coma appear.

Hypotensive Agents

May potentiate effects of other hypotensive agents. Although additive or potentiated antihypertensive effects usually are used to therapeutic advantage, hypotension could occur. (See Interactions.)

Lupus Erythematosus

Possible exacerbation or activation of systemic lupus erythematosus.

Lithium

Generally, do not use with lithium salts. (See Interactions.)

Sensitivity Reactions

Hypersensitivity

May occur with or without history of allergy or bronchial asthma.

Sulfonamide cross-sensitivity unlikely. (See Contraindications under Cautions.)

General Precautions

Electrolyte Imbalance

Monitor for fluid or electrolyte imbalance (hyponatremia, hypochloremic alkalosis, hypokalemia).

Observe for signs of electrolyte imbalance (e.g., dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, oliguria, muscle pains, cramps, muscular fatigue, hypotension, tachycardia, nausea, vomiting).

Perform periodic serum electrolyte determinations (particularly of potassium, sodium, chloride, and bicarbonate); institute measures to maintain normal serum concentrations if necessary.

Serum and urinary electrolyte measurements are especially important with diabetes mellitus, vomiting, diarrhea, parenteral fluid therapy, or expectations of excessive diuresis.

Weekly (or more frequent) electrolyte measurement recommended early in treatment; possible to extend interval between measurements to ≥3 months when electrolyte response has stabilized.

Hypokalemia

May occur after brisk diuresis, when cirrhosis is present, or with prolonged therapy; inadequate oral electrolyte intake may contribute.

May cause cardiac arrhythmias, exaggerate cardiac response to cardiac glycoside toxicity (increase ventricular irritability).

Use potassium-sparing diuretics and/or potassium supplementation to avoid or treat hypokalemia.

Hypochloremia

Generally mild, usually does not require specific treatment except in renal or hepatic impairment.

Chloride replacement may be required for metabolic acidosis.

Hyponatremia

Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate treatment usually is water restriction rather than salt administration except when hyponatremia is life-threatening.

In actual salt depletion, appropriate replacement is treatment of choice.

Gout

Hyperuricemia or precipitation of gout may occur.

Hyperglycemia

In diabetic patients, dosage adjustment of insulin or oral hypoglycemics may be required; hyperglycemia may occur and latent diabetes mellitus may become evident.

Sympathectomy

Antihypertensive effect may be enhanced after sympathectomy.

Hypomagnesemia

May increase magnesium urinary excretion, resulting in hypomagnesemia.

Hypercalcemia

May decrease calcium urinary excretion, cause slight intermittent serum calcium increase in absence of known calcium metabolism disorder; marked hypercalcemia may indicate hyperparathyroidism.

Discontinue prior to performing parathyroid tests.

Hyperlipidemia

May increase cholesterol and triglyceride concentrations.

Clinical importance of these changes is unknown. Diet low in saturated fat and cholesterol usually compensates.

Hypotensive Effects

Orthostatic hypotension rarely occurs.

Specific Populations

Pregnancy

Category B.

Although hypertension during pregnancy responds well to thiazides, and the drugs had been used widely in the past for preeclampsia and eclampsia, such use no longer is recommended and other antihypertensives (e.g., methyldopa, hydralazine, labetalol) currently are preferred. Diuretics are not recommended for pregnancy-induced hypertension because of the maternal hypovolemia associated with this form of hypertension; decreased placental perfusion is possible. Diuretics are considered second-line agents for control of chronic hypertension in pregnant women.

Thiazides should not be used as routine therapy in pregnant women with mild edema who are otherwise healthy.

Edema associated with pregnancy generally responds well to thiazides except when caused by renal disease.

Lactation

Distributed into milk. Discontinue nursing or the drug.

Although hydrochlorothiazide use generally is considered compatible with breast-feeding, thiazides can reduce milk volume and thus suppress lactation.

Pediatric Use

No controlled studies in children; use is supported by experience and published literature about hypertension treatment in children.

Geriatric Use

Elderly may be at increased risk of dilutional hyponatremia, especially underweight females with poor oral fluid and electrolyte intake or excessive low-sodium nutritional supplement intake. (See Hyponatremia under Warnings/Precautions.)

Increased incidence of adverse effects and excessive reduction in BP in those >65 years of age. (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Use caution. (See Hepatic Impairment under Warnings.)

Renal Impairment

Use caution. (See Severe Renal Impairment under Warnings.)

Consider interruption or discontinuance if progressive renal impairment (rising nonprotein nitrogen, BUN, or serum creatinine) occurs.

Common Adverse Effects

Potassium depletion, hyperuricemia (usually asymptomatic rarely leading to gout). Hypochloremic alkalosis in patients at risk (e.g., hypokalemic patients). Hyperglycemia and glycosuria in diabetics.

Interactions

Specific Drugs and Laboratory Tests

Pharmacokinetics

Absorption

Bioavailability

Variable absorption from GI tract.

Onset

Diuretic effect: Within 2 hours; peak effect in 3–6 hours.

Hypotensive effect: Generally 3–4 days.

Duration

Diuretic effect: 6–12 hours.

Food

Food decreases rate and extent of absorption of Microzide^® capsules.

Distribution

Extent

Distributed in the extracellular space.

Does not cross blood-brain barrier.

Readily crosses the placenta.

Distributed into breast milk.

Elimination

Metabolism

Not metabolized.

Elimination Route

Excreted unchanged in urine; ≥61% eliminated in 24 hours.

Half-life

5.6–15 hours.

Special Populations

In patients with uncompensated CHF or impaired renal function, excretion may be delayed. Effect of hemodialysis on elimination of the drug has not been determined.

Stability

Storage

Oral

Capsules

Tight containers at <40°C, preferably at 15–30°C; protect from light, moisture, and freezing.

Oral Solution

Tight containers at <40°C, preferably at 15–30°C. Avoid freezing.

Tablets

Tight containers at <40°C, preferably at 15–30°C; protect from light, moisture, and freezing.

Actions

• Exact mechanism of diuretic action is unclear; may act by altering metabolism of the tubular cells.
• Enhances excretion of sodium, chloride, and water by interfering with the transport of sodium ions across the renal tubular epithelium.
• Primary site of diuretic action appears to be the cortical diluting segment of the nephron.
• GFR decreases, but unclear whether secondary to a direct effect on renal vasculature or to the decrease in intravascular fluid volume or an increase in tubular pressure caused by the inhibition of sodium and water reabsorption. The fall in GFR is not important in the mechanism of action.
• Enhances urinary excretion of potassium secondary to increased amount of sodium at distal tubular site of sodium-potassium exchange.
• Increases urinary bicarbonate excretion (although to a lesser extent than chloride excretion) but change in urinary pH is usually minimal; diuretic efficacy is not affected by the acid-base balance of the patient.
• Hypocalciuric effect is thought to result from a decrease in extracellular fluid (ECF) volume, although calcium reabsorption in the nephron may be increased; also, slight or intermittent elevations in serum calcium concentration.
• Rate of uric acid excretion is decreased, probably because of competitive inhibition of uric acid secretion or a decrease in ECF volume and a secondary increase in uric acid reabsorption.
• Hypotensive activity in hypertensive patients; also augments the action of other hypotensive agents. Precise mechanism of hypotensive action has not been determined, but postulated that part of this effect is caused by direct arteriolar dilation.

Advice to Patients

• Advise patient of signs of electrolyte imbalance (e.g., dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, oliguria, muscle pains or cramps, muscular fatigue, hypotension, tachycardia, GI disturbances such as nausea and vomiting).
• Advise patients of importance of compliance with scheduled determinations of serum electrolyte concentrations (particularly potassium, sodium, chloride, and bicarbonate).

• Advise hypertensive patients of importance of continuing lifestyle/behavioral modifications that include weight reduction (for those who are overweight or obese), dietary changes to include foods that are rich in potassium and calcium and moderately restricted in sodium (adoption of the Dietary Approaches to Stop Hypertension [DASH] eating plan), increased physical activity, smoking cessation, and moderation of alcohol intake.

  Advise that lifestyle/behavioral modifications reduce BP, enhance antihypertensive drug efficacy, and decrease cardiovascular risk and remain an indispensable part of the management of hypertension.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs as well as any concomitant illnesses.
• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.
• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

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

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 09/2009. For the most current and up-to-date pricing information, please visit www.drugstore.com. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

AHFS Drug Information. © Copyright, 1959-2009, Selected Revisions June 2006. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.