Hydrochlorothiazide

Uses and Indications

Hydrochlorothiazide tablets and capsules are indicated for the management of hypertension, either as the sole therapeutic agent or in combination with other antihypertensive medications. This drug is also indicated as adjunctive therapy in the treatment of edema associated with:

• Congestive heart failure

• Hepatic cirrhosis

• Corticosteroid and estrogen therapy

• Various forms of renal dysfunction, including nephrotic syndrome, acute glomerulonephritis, and chronic renal failure

In patients at risk for hyperkalemia, such as those taking ACE inhibitors, hydrochlorothiazide may be used with caution.

Limitations of Use

Routine use of diuretics during normal pregnancy is inappropriate and exposes both the mother and fetus to unnecessary risks. Hydrochlorothiazide does not prevent the development of toxemia of pregnancy, and there is no satisfactory evidence supporting its efficacy in treating this condition.

Use in Pregnancy

Hydrochlorothiazide is indicated in pregnancy only when edema is due to pathologic causes. Dependent edema resulting from restriction of venous return by the gravid uterus should be managed through elevation of the lower extremities and the use of support stockings. The use of diuretics to lower intravascular volume in this context is illogical and unnecessary.

During normal pregnancy, hypervolemia is not harmful to the mother or fetus in the absence of cardiovascular disease. If edema causes discomfort, increased recumbency may provide relief. In rare cases where edema leads to extreme discomfort not relieved by rest, a short course of diuretic therapy may be appropriate.

Dosage and Administration

Therapy with hydrochlorothiazide should be individualized according to patient response, utilizing the smallest effective dosage necessary to achieve the desired therapeutic effect.

Adults:

For Edema, the usual dosage ranges from 25 mg to 100 mg daily, administered as a single or divided dose. Many patients may benefit from intermittent therapy, which involves administration on alternate days or three to five days each week.

For Control of Hypertension, the recommended initial dose is 25 mg daily, given as a single dose. This may be increased to 50 mg daily, either as a single dose or in two divided doses. Doses exceeding 50 mg are generally not recommended, particularly when used in conjunction with other antihypertensive agents, as they may lead to significant reductions in serum potassium.

Infants and Children:

For Diuresis and Control of Hypertension, the typical pediatric dosage is 0.5 mg to 1 mg per pound (1 to 2 mg/kg) per day, administered in single or two divided doses. The maximum dosage should not exceed 37.5 mg per day for infants up to 2 years of age or 100 mg per day for children aged 2 to 12 years. In infants less than 6 months of age, doses may be increased to 1.5 mg per pound (3 mg/kg) per day, given in two divided doses.

Hydrochlorothiazide is available in tablet and capsule forms. The adult initial dose for the capsule formulation is one capsule taken once daily, whether used alone or in combination with other antihypertensives. Total daily doses greater than 50 mg are not recommended for any formulation.

Contraindications

Hydrochlorothiazide is contraindicated in patients with anuria. Additionally, it should not be used in individuals with hypersensitivity to this product or to other sulfonamide-derived drugs.

Warnings and Precautions

Use with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia, and cumulative effects of the drug may develop in patients with impaired renal function. Thiazides should also be used with caution in patients with impaired hepatic function or progressive liver disease, as minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

Serious Warnings

• Thiazides may add to or potentiate the action of other antihypertensive drugs.

• Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma.

• The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.

• Lithium generally should not be given with diuretics.

• 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.

General Precautions

• All patients receiving diuretic therapy should be observed for evidence of fluid or electrolyte imbalance, including hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively or receiving parenteral fluids. Warning signs or symptoms of fluid and electrolyte imbalance, irrespective of cause, include dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, 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 or after prolonged therapy. Interference with adequate oral electrolyte intake will also contribute to hypokalemia. Hypokalemia may cause cardiac arrhythmia and may also sensitize or exaggerate the response of the heart to the toxic effects of digitalis (e.g., increased ventricular irritability). Hypokalemia may be avoided or treated by use of potassium-sparing diuretics or potassium supplements such as foods with a high potassium content.

• Although any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease), chloride replacement may be required in the treatment of metabolic alkalosis.

• Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction rather than administration of salt, except in rare instances when the hyponatremia is life-threatening. In actual salt depletion, appropriate replacement is the therapy of choice.

• Hyperuricemia may occur or acute gout may be precipitated in certain patients receiving thiazides.

• In diabetic patients, dosage adjustments of insulin or oral hypoglycemic agents may be required. Hyperglycemia may occur with thiazide diuretics, thus latent diabetes mellitus may become manifest during thiazide therapy.

• The antihypertensive effects of the drug may be enhanced in the post-sympathectomy patient.

• If progressive renal impairment becomes evident, consider withholding or discontinuing diuretic therapy.

• Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesemia.

• Thiazides may decrease urinary calcium excretion. They may cause intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Marked hypercalcemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function.

• Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

Laboratory Tests

Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be done at appropriate intervals.

Get Emergency Medical Help

Symptoms of acute angle-closure glaucoma include acute onset of decreased visual acuity or ocular pain, typically occurring 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.

Stop Taking and Call Your Doctor

Discontinue hydrochlorothiazide as rapidly as possible if acute angle-closure glaucoma symptoms occur.

Side Effects

• Weakness is a common adverse reaction reported in patients taking hydrochlorothiazide.

• Cardiovascular:

  • Hypotension, including orthostatic hypotension, may occur and can be aggravated by alcohol, barbiturates, narcotics, or other antihypertensive drugs.

• Digestive:

  • Adverse reactions may include pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, and anorexia.

• Hematologic:

  • Serious hematologic reactions include aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia.

• Hypersensitivity:

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

• Metabolic:

  • Electrolyte imbalances, hyperglycemia, glycosuria, and hyperuricemia are potential metabolic adverse reactions.

• Musculoskeletal:

  • Muscle spasms may occur in some patients.

• Nervous System/Psychiatric:

  • Patients may experience vertigo, paresthesias, dizziness, headache, and restlessness.

• Renal:

  • Renal failure, renal dysfunction, and interstitial nephritis are serious renal adverse reactions.

• Skin:

  • Skin reactions may include erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis (including toxic epidermal necrolysis), and alopecia.

• Special Senses:

  • Transient blurred vision and xanthopsia have been reported.

• Urogenital:

  • Impotence may occur in some patients.

Non-melanoma Skin Cancer

Hydrochlorothiazide is associated with an increased risk of non-melanoma skin cancer, predominantly for squamous cell carcinoma (SCC) in white patients taking large cumulative doses. The increased risk for SCC in the overall population is 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 is approximately 1 additional SCC case for every 6,700 patients per year.

Warnings

• Use with caution in severe renal disease, as thiazides may precipitate azotemia and cumulative effects may develop in patients with impaired renal function.

• Caution is advised in patients with impaired hepatic function or progressive liver disease, as minor alterations of fluid and electrolyte balance may precipitate hepatic coma.

• Sensitivity reactions may occur in patients with or without a history of allergy or bronchial asthma.

• The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.

• Hydrochlorothiazide can cause acute myopia and secondary angle-closure glaucoma, which may lead to permanent vision loss if untreated. Symptoms typically occur within hours to weeks of drug initiation.

Additional Notes

Whenever adverse reactions are moderate or severe, thiazide dosage should be reduced or therapy withdrawn. The most common signs and symptoms observed in overdosage are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration resulting from excessive diuresis. If digitalis has also been administered, hypokalemia may accentuate cardiac arrhythmias.

Drug Interactions

When hydrochlorothiazide is administered concurrently with other medications, several interactions may occur, categorized primarily into pharmacodynamic and pharmacokinetic interactions.

Pharmacodynamic Interactions

• Alcohol, Barbiturates, or Narcotics: The combination may lead to potentiation of orthostatic hypotension.

• Antidiabetic Drugs (Oral Agents and Insulin): Dosage adjustments of the antidiabetic medication may be necessary to maintain glycemic control.

• Other Antihypertensive Drugs: There may be an additive effect or potentiation of antihypertensive effects when used with other antihypertensive agents.

• Corticosteroids and ACTH: These agents can intensify electrolyte depletion, particularly hypokalemia, when used with hydrochlorothiazide.

• Pressor Amines (e.g., Norepinephrine): There is a potential for decreased response to pressor amines, although this does not preclude their use.

• Skeletal Muscle Relaxants (Nondepolarizing, e.g., Tubocurarine): Increased responsiveness to muscle relaxants may occur.

• Lithium: The use of diuretics, including hydrochlorothiazide, is generally contraindicated as they reduce renal clearance of lithium, significantly increasing the risk of lithium toxicity.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The administration of NSAIDs may reduce the diuretic, natriuretic, and antihypertensive effects of hydrochlorothiazide. Close monitoring is advised to ensure the desired diuretic effect is achieved.

Pharmacokinetic Interactions

• Cholestyramine and Colestipol Resins: These anionic exchange resins can impair the absorption of hydrochlorothiazide, reducing its gastrointestinal absorption by up to 85% (cholestyramine) and 43% (colestipol).

Drug & Laboratory Test Interactions

• Parathyroid Function Tests: Thiazides should be discontinued prior to conducting tests for parathyroid function to avoid interference with test results.

In summary, careful consideration and monitoring are required when hydrochlorothiazide is used in conjunction with the aforementioned drugs to mitigate potential adverse effects and ensure therapeutic efficacy.

Pediatric Use

There are no well-controlled clinical trials in pediatric patients for Hydrochlorothiazide. Information on dosing in this age group is supported by evidence from empiric use in pediatric patients and published literature regarding the treatment of hypertension in such patients.

Efficacy

Hydrochlorothiazide is indicated for the treatment of hypertension in pediatric patients. The usual pediatric dosage is 0.5 to 1 mg per pound (1 to 2 mg/kg) per day, administered in single or two divided doses. The maximum dosage should not exceed 37.5 mg per day in infants up to 2 years of age or 100 mg per day in children aged 2 to 12 years. In infants less than 6 months of age, doses up to 1.5 mg per pound (3 mg/kg) per day in two divided doses may be required.

Safety

Safety and effectiveness in pediatric patients have not been established for Hydrochlorothiazide in capsule forms. Caution is advised when prescribing this medication to pediatric patients due to the lack of established safety and efficacy data.

For further details on dosing, refer to the DOSAGE AND ADMINISTRATION section, specifically for Infants and Children.

Geriatric Use

Elderly patients (i.e., those aged > 65 years) may experience a greater reduction in blood pressure and an increased incidence of side effects when treated with hydrochlorothiazide. It is recommended to initiate therapy with the lowest available dose of hydrochlorothiazide (12.5 mg) to mitigate these risks. If further titration is necessary, increments of 12.5 mg should be utilized.

Caution is advised when prescribing hydrochlorothiazide to geriatric patients due to the potential for reduced kidney function and increased sensitivity to side effects. Regular monitoring of kidney function is essential, as elderly patients are at a higher risk for acute kidney injury. Additionally, careful observation for electrolyte imbalances, particularly hypokalemia, is crucial, as these imbalances may be more pronounced in this population. Periodic serum and urine electrolyte determinations are recommended to detect any imbalances early.

In cases of progressive renal impairment, consideration should be given to withholding or discontinuing diuretic therapy. Elderly patients may also be more susceptible to adverse reactions, including hypotension, which can be exacerbated by concurrent use of other medications such as alcohol, barbiturates, or narcotics. Therefore, close monitoring of blood pressure and renal function is necessary throughout the treatment course.

Pregnancy

Studies involving the administration of hydrochlorothiazide to pregnant mice and rats during their respective periods of major organogenesis at doses up to 3000 mg and 1000 mg hydrochlorothiazide/kg have shown no evidence of harm to the fetus. Hydrochlorothiazide is classified as Pregnancy Category B. However, there are no adequate and well-controlled studies in pregnant women, and animal reproduction studies are not always predictive of human response. Therefore, hydrochlorothiazide should be used during pregnancy only if clearly needed.

Thiazides, including hydrochlorothiazide, cross the placental barrier and can be detected in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia, and potentially other adverse reactions that have been observed in adults. Routine use of diuretics during normal pregnancy is inappropriate and may expose both the mother and fetus to unnecessary risks. Diuretics do not prevent the development of toxemia of pregnancy, and there is insufficient evidence to support their use in treating this condition.

Edema during pregnancy may arise from pathological causes or from the physiological and mechanical effects of pregnancy. Thiazides may be indicated when edema is due to pathological causes, similar to their use in non-pregnant patients. Dependent edema resulting from venous return restriction by the gravid uterus should be managed through non-pharmacological measures such as elevation of the lower extremities and the use of support stockings. In cases where edema causes significant discomfort and is not relieved by rest, a short course of diuretic therapy may be appropriate.

It is essential to monitor pregnant patients with hypertension, as untreated hypertension can lead to adverse outcomes for both the mother and fetus, including increased risks for pre-eclampsia, gestational diabetes, and intrauterine growth restriction.

Lactation

Thiazides, including hydrochlorothiazide, are excreted in breast milk. Due to the potential for serious adverse reactions in breastfed infants, healthcare providers should carefully consider whether to discontinue breastfeeding or to discontinue hydrochlorothiazide, weighing the importance of the medication to the lactating mother.

While available data indicate that hydrochlorothiazide is present in human milk, there are no reports of adverse effects on breastfed infants exposed to the drug during lactation. However, doses associated with clinically significant diuresis may impair milk production.

A single study reported a peak concentration of hydrochlorothiazide at 275 mcg/L in breast milk three hours after a 50 mg dose, with no detectable levels in the infant's plasma at 2 and 11 hours post-dose. This suggests that while the drug does transfer into breast milk, the systemic exposure in the infant may be minimal.

In summary, the decision regarding the use of hydrochlorothiazide during lactation should involve a discussion of the developmental and health benefits of breastfeeding alongside the mother's clinical need for the medication and any potential risks to the breastfed infant.

Renal Impairment

Patients with renal impairment should use hydrochlorothiazide with caution, particularly in cases of severe renal disease. The use of thiazides in these patients may lead to the precipitation of azotemia, a condition characterized by elevated blood urea nitrogen and creatinine levels.

Cumulative effects of hydrochlorothiazide can develop in individuals with impaired renal function, necessitating careful monitoring of kidney function and serum electrolytes. It is essential to assess renal function periodically to avoid potential complications associated with the drug's accumulation.

Given these considerations, healthcare providers should exercise caution when prescribing hydrochlorothiazide to patients with renal impairment, ensuring that appropriate monitoring and adjustments are made to mitigate risks.

Hepatic Impairment

Patients with hepatic impairment should use thiazides, such as Hydrochlorothiazide, with caution. Minor alterations in fluid and electrolyte balance in these patients may precipitate hepatic coma. There is no specific information regarding dosage adjustments, special monitoring, or additional precautions for patients with liver problems provided in the product insert. Therefore, careful consideration and monitoring of these patients are advised when prescribing thiazides.

Overdosage

The most common signs and symptoms of hydrochlorothiazide overdose are primarily due to electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. In cases where digitalis has also been administered, hypokalemia may exacerbate cardiac arrhythmias.

In the event of overdosage, it is essential to employ symptomatic and supportive measures. Inducing emesis or performing gastric lavage is recommended. Additionally, it is crucial to correct dehydration and any electrolyte imbalances, as well as to manage hepatic coma and hypotension using established medical procedures. If respiratory impairment occurs, oxygen or artificial respiration should be provided as necessary.

The degree to which hydrochlorothiazide is removed by hemodialysis has not been established. The oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mice and rats.

Nonclinical Toxicology

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. However, there are 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.

Non-Teratogenic Effects

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.

Nonclinical Toxicology

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 gestation.

Animal Pharmacology and Toxicology

No specific details are provided regarding animal pharmacology and toxicology beyond the nonclinical toxicology section.

Storage and Handling

Hydrochlorothiazide is supplied in tablet and capsule forms. The tablets are dispensed in well-closed or tight, light-resistant containers as defined in the USP, utilizing child-resistant closures where required. The capsules are also dispensed in tight, light-resistant containers.

All forms of Hydrochlorothiazide should be stored at a controlled room temperature of 20° to 25°C (68° to 77°F), with permissible excursions between 15° to 30°C (59° to 86°F) as per USP guidelines. It is essential to protect the capsules from light, moisture, and freezing conditions, specifically avoiding temperatures below -20°C (-4°F).

Containers must be kept tightly closed to maintain product integrity. Additionally, it is crucial to keep this and all medications out of the reach of children.