Hydrochlorothiazide

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Hydrochlorothiazide
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi

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Overview

Hydrochlorothiazide is a thiazide diuretic that is FDA approved for the {{{indicationType}}} of hypertension either as the sole therapeutic agent, or in combination with other antihypertensives. Common adverse reactions include hypotension, phototoxicity, and vertigo.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Hypertension
  • Dosing Information
  • 12.5 mg once daily whether given alone or in combination with other antihypertensives.
  • Total daily doses greater than 50 mg are not recommended.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Hydrochlorothiazide in adult patients.

Non–Guideline-Supported Use

Hypercalciuria
  • Dosing Information
Osteoporosis
  • Dosing Information

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding FDA-Labeled Use of Hydrochlorothiazide in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Hydrochlorothiazide in pediatric patients.

Non–Guideline-Supported Use

Hypercalciuria
  • Dosing Information
  • 0.5–2 mg/kg/day[8]
Bronchopulmonary Dysplasia of Newborn
  • Dosing Information

Contraindications

Warnings

  • Acute Myopia and Secondary Angle-Closure Glaucoma
  • Hydrochlorothiazide, a sulfonamide, can cause an idiosyncratic reaction, resulting in acute transient myopia and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue hydrochlorothiazide as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
  • Diabetes and Hypoglycemia
  • Renal Disease

Precautions

  • Electrolyte and Fluid Balance Status
  • Hyperuricemia
  • 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.
  • Parathyroid Disease

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Clinical Trial Experience of Hydrochlorothiazide in the drug label.

Postmarketing Experience

  • Whenever adverse reactions are moderate or severe, thiazide dosage should be reduced or therapy withdrawn.
  • The adverse reactions associated with hydrochlorothiazide have been shown to be dose related. In controlled clinical trials, the adverse events reported with doses of 12.5 mg hydrochlorothiazide once daily were comparable to placebo. The following adverse reactions have been reported for doses of hydrochlorothiazide 25 mg and greater and, within each category, are listed in the order of decreasing severity.
Body as a Whole

Weakness.

Cardiovascular

Hypotension including orthostatic hypotension (may be aggravated by alcohol, barbiturates, narcotics or antihypertensive drugs).

Neurologic

Vertigo, paresthesia, dizziness, headache, restlessness.

Hematologic

Aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, thrombocytopenia.

Gastrointestinal

Pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, anorexia.

Hypersensitivity

Anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress including pneumonitis and pulmonary edema, photosensitivity, fever, urticaria, rash, purpura.

Metabolic

Electrolyte imbalance, hyperglycemia, glycosuria, hyperuricemia.

Musculoskeletal

Muscle spasm.

Renal

Renal failure, renal dysfunction, interstitial nephritis.

Skin

Erythema multiforme including Stevens-Johnson syndrome, exfoliative dermatitis including toxic epidermal necrolysis, alopecia.

Special Senses

Transient blurred vision, xanthopsia.

Urogenital

Impotence.

Drug Interactions

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

  • Pregnancy Category B
  • Teratogenic Effects
  • 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.
  • Nonteratogenic Effects


Pregnancy Category (AUS):

  • Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Hydrochlorothiazide in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Hydrochlorothiazide during labor and delivery.

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.

Geriatic 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.

Gender

There is no FDA guidance on the use of Hydrochlorothiazide with respect to specific gender populations.

Race

There is no FDA guidance on the use of Hydrochlorothiazide with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Hydrochlorothiazide in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Hydrochlorothiazide in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Hydrochlorothiazide in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Hydrochlorothiazide in patients who are immunocompromised.

Administration and Monitoring

Administration

  • Oral

Monitoring

There is limited information regarding Monitoring of Hydrochlorothiazide in the drug label.

IV Compatibility

There is limited information regarding IV Compatibility of Hydrochlorothiazide in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

Management

Chronic Overdose

There is limited information regarding Chronic Overdose of Hydrochlorothiazide in the drug label.

Pharmacology

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Hydrochlorothiazide
Systematic (IUPAC) name
6-chloro-1,1-dioxo-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide
Identifiers
CAS number 58-93-5
ATC code C03AA03
PubChem 3639
DrugBank DB00999
Chemical data
Formula C7H8ClN3O4S2 
Mol. mass 297.74
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability Variably absorbed from GI tract. Bioavailability ~ 70%
Metabolism does not undergo significant metabolism (>95% excreted unchanged in urine)[10]
Half life 5.6–14.8 h
Excretion Primarily excreted unchanged in urine
Therapeutic considerations
Pregnancy cat.

B (D if used to treat pregnancy-induced hypertension)

Legal status

Prescription only

Routes Oral (capsules, tablets, oral solution)

Mechanism of Action

  • Hydrochlorothiazide blocks the reabsorption of sodium and chloride ions, and it thereby increases the quantity of sodium traversing the distal tubule and the volume of water excreted. A portion of the additional sodium presented to the distal tubule is exchanged there for potassium and hydrogen ions. With continued use of hydrochlorothiazide and depletion of sodium, compensatory mechanisms tend to increase this exchange and may produce excessive loss of potassium, hydrogen and chloride ions. Hydrochlorothiazide also decreases the excretion of calcium and uric acid, may increase the excretion of iodide and may reduce glomerular filtration rate. Metabolic toxicities associated with excessive electrolyte changes caused by hydrochlorothiazide have been shown to be dose-related.

Structure

  • Microzide® (hydrochlorothiazide, USP) Capsules 12.5 mg is the 3,4-dihydro derivative of chlorothiazide. Its chemical name is 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. Its empirical formula is C7H8ClN3O4S2; its molecular weight is 297.74; and its structural formula is:
This image is provided by the National Library of Medicine.
  • It is a white, or practically white, crystalline powder which is slightly soluble in water, but freely soluble in sodium hydroxide solution.
  • Microzide is supplied as 12.5 mg capsules for oral use.
  • Inactive ingredients: colloidal silicon dioxide, corn starch, lactose monohydrate, magnesium stearate. Gelatin capsules contain D&C Red No. 28, D&C Yellow No. 10, FD&C Blue No. 1, gelatin, titanium dioxide. The capsules are printed with edible ink containing black iron oxide, D&C Yellow No. 10, FD&C Blue No. 1, FD&C Blue No. 2, FD&C Red No. 40.

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.

Pharmacokinetics

  • 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 Microzide 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.

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Hydrochlorothiazide in the drug label.

Clinical Studies

  • In an 87 patient 4-week double-blind, placebo controlled, parallel group trial, patients who received Microzide 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.

How Supplied

  • Microzide® (hydrochlorothiazide, USP) Capsules 12.5 mg are #4 Teal Opaque/Teal Opaque two piece hard gelatin capsules imprinted with Microzide and 12.5 mg in black ink. They are supplied in bottles of 100 with child resistant closures (NDC 52544-622-01).
  • Dispense in a tight, light-resistant container as defined in the USP.
  • Keep out of reach of children.
  • Store at 20°-25°C (68°-77°F). [See USP controlled room temperature.] Protect from light, moisture, freezing, -20°C (-4°F). Keep container tightly closed.

Storage

There is limited information regarding Hydrochlorothiazide Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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This image of the FDA label is provided by the National Library of Medicine.
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This image of the FDA label is provided by the National Library of Medicine.

Patient Counseling Information

There is limited information regarding Patient Counseling Information of Hydrochlorothiazide in the drug label.

Precautions with Alcohol

Brand Names

Look-Alike Drug Names

  • Microzide® — Maxzide®[12]
  • Microzide® — Micronase®[12]

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

  1. Scholz, D. (1982-11). "Double-blind study with thiazide in recurrent calcium lithiasis". The Journal of Urology. 128 (5): 903–907. ISSN 0022-5347. PMID 7176047. Unknown parameter |coauthors= ignored (help); Check date values in: |date= (help)
  2. Laerum, E. (1984). "Metabolic effects of thiazide versus placebo in patients under long-term treatment for recurrent urolithiasis". Scandinavian Journal of Urology and Nephrology. 18 (2): 143–149. ISSN 0036-5599. PMID 6463598.
  3. Laerum, E. (1984). "Thiazide prophylaxis of urolithiasis. A double-blind study in general practice". Acta Medica Scandinavica. 215 (4): 383–389. ISSN 0001-6101. PMID 6375276. Unknown parameter |coauthors= ignored (help)
  4. Bentur, L. (1987-03). "Hypercalciuria in chronically institutionalized bedridden children: frequency, predictive factors and response to treatment with thiazides". The International Journal of Pediatric Nephrology. 8 (1): 29–34. ISSN 0391-6510. PMID 3583554. Unknown parameter |coauthors= ignored (help); Check date values in: |date= (help)
  5. Wasnich, R. D. (1986-04). "Differential effects of thiazide and estrogen upon bone mineral content and fracture prevalence". Obstetrics and Gynecology. 67 (4): 457–462. ISSN 0029-7844. PMID 3960416. Unknown parameter |coauthors= ignored (help); Check date values in: |date= (help)
  6. Ray, W. A. (1989-04-01). "Long-term use of thiazide diuretics and risk of hip fracture". Lancet. 1 (8640): 687–690. ISSN 0140-6736. PMID 2564506. Unknown parameter |coauthors= ignored (help)
  7. LaCroix, A. Z. (2000-10-03). "Low-dose hydrochlorothiazide and preservation of bone mineral density in older adults. A randomized, double-blind, placebo-controlled trial". Annals of Internal Medicine. 133 (7): 516–526. ISSN 0003-4819. PMID 11015164. Unknown parameter |coauthors= ignored (help)
  8. Scholz, D. (1982-11). "Double-blind study with thiazide in recurrent calcium lithiasis". The Journal of Urology. 128 (5): 903–907. ISSN 0022-5347. PMID 7176047. Unknown parameter |coauthors= ignored (help); Check date values in: |date= (help)
  9. Albersheim, S. G. (1989-10). "Randomized, double-blind, controlled trial of long-term diuretic therapy for bronchopulmonary dysplasia". The Journal of Pediatrics. 115 (4): 615–620. ISSN 0022-3476. PMID 2677293. Unknown parameter |coauthors= ignored (help); Check date values in: |date= (help)
  10. Beermann B, Groschinsky-Grind M, Rosén A. (1976). "Absorption, metabolism, and excretion of hydrochlorothiazide". Clin Pharmacol Ther. 19 (5 (Pt 1)): 531–7.
  11. "Microzide (hydrochlorothiazide) capsule, gelatin coated".
  12. 12.0 12.1 "http://www.ismp.org". External link in |title= (help)

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