Hydrochlorothiazide

Description

Hydrochlorothiazide is a diuretic and antihypertensive agent, chemically identified as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. It is the 3,4-dihydro derivative of chlorothiazide, with a molecular formula of C₇H₈ClN₃O₄S₂ and a molecular weight of 297.74. Hydrochlorothiazide appears as a white or practically white crystalline powder, exhibiting slight solubility in water and free solubility in sodium hydroxide solution.

For oral administration, the tablets are available in strengths of 12.5 mg, 25 mg, and 50 mg of hydrochlorothiazide, USP. Each tablet also contains inactive ingredients, including corn starch, dibasic calcium phosphate, lactose monohydrate, magnesium stearate, pregelatinized starch, and sodium starch glycolate. The 12.5 mg and 25 mg tablet strengths additionally contain FD&C yellow #6.

Uses and Indications

Hydrochlorothiazide tablets are indicated as adjunctive therapy in the management of edema associated with various conditions, including congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. Additionally, these tablets have demonstrated utility in addressing edema resulting from renal dysfunction, such as nephrotic syndrome, acute glomerulonephritis, and chronic renal failure.

In the management of hypertension, hydrochlorothiazide tablets may be utilized either as a sole therapeutic agent or to enhance the effectiveness of other antihypertensive medications in patients with more severe forms of hypertension.

Limitations of use include the routine use of diuretics during normal pregnancy, which is deemed inappropriate and poses unnecessary risks to both the mother and fetus. Hydrochlorothiazide does not prevent the development of toxemia of pregnancy, nor is there satisfactory evidence supporting its efficacy in treating this condition. However, thiazides may be indicated in pregnancy when edema is attributable to pathological causes.

For dependent edema in pregnancy, which arises from venous return restriction due to the gravid uterus, appropriate management includes elevation of the lower extremities and the use of support stockings. The use of diuretics to reduce intravascular volume in such cases is considered illogical and unnecessary, as hypervolemia during normal pregnancy is not harmful in the absence of cardiovascular disease. In rare instances where edema during pregnancy causes significant discomfort unrelieved by rest, a short course of diuretic therapy may be warranted for symptomatic relief.

Dosage and Administration

The usual adult dosage for the treatment of edema is 25 to 100 mg daily, which may be administered as a single dose or divided into multiple doses. Many patients with edema may benefit from intermittent therapy, which involves administration on alternate days or on three to five days each week.

For the control of hypertension in adults, the recommended initial dose is 25 mg daily, administered as a single dose. This dose may be increased to 50 mg daily, which can be given as a single dose or divided into two doses.

In pediatric patients, the usual dosage for diuresis and control of hypertension is 0.5 to 1 mg per pound (1 to 2 mg/kg) per day, administered in either a single dose 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. For infants less than 6 months of age, doses may be increased to 1.5 mg per pound (3 mg/kg) per day, administered in two divided doses if necessary.

Contraindications

Use of this product is contraindicated in patients with anuria due to the inability to excrete the drug, which may lead to accumulation and toxicity. Additionally, hypersensitivity to this product or to other sulfonamide-derived drugs is a contraindication, as it may result in severe allergic reactions.

Warnings and Precautions

Use of thiazide diuretics requires careful consideration in patients with specific health conditions.

Renal Considerations Thiazides should be administered with caution in individuals with severe renal disease. In such patients, the use of thiazides may lead to the development of azotemia due to the drug's cumulative effects. Close monitoring of renal function is advised to mitigate potential risks.

Hepatic Function Patients with impaired hepatic function or progressive liver disease should also be treated with caution when prescribed thiazides. Minor alterations in fluid and electrolyte balance in these patients may precipitate hepatic coma, necessitating vigilant monitoring of liver function and electrolyte levels.

Drug Interactions and Sensitivity Reactions Thiazides may enhance the effects of other antihypertensive medications, which could lead to an increased risk of hypotension. Additionally, sensitivity reactions may occur in patients regardless of their allergy or bronchial asthma history. Healthcare professionals should remain alert to these potential interactions and adjust treatment regimens accordingly.

Autoimmune Considerations There have been reports of exacerbation or activation of systemic lupus erythematosus in patients taking thiazides. Clinicians should be aware of this risk and monitor for any signs of autoimmune activity.

Lithium Interaction The concomitant use of lithium with diuretics, including thiazides, is generally not recommended due to the potential for increased lithium levels and toxicity.

Electrolyte Monitoring Periodic determination of serum electrolytes is essential to detect possible imbalances that may arise during treatment. Regular monitoring should be conducted at appropriate intervals to ensure patient safety and effective management of electrolyte levels.

Side Effects

Adverse reactions associated with thiazide therapy have been observed across various systems in patients.

Serious adverse reactions include hematologic events such as aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia. Additionally, hypersensitivity reactions can manifest as anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), and respiratory distress, which may include pneumonitis and pulmonary edema. Renal complications such as renal failure, renal dysfunction, and interstitial nephritis have also been reported. Skin reactions can be severe, including erythema multiforme (such as Stevens-Johnson syndrome) and exfoliative dermatitis (including toxic epidermal necrolysis).

Common adverse reactions include weakness, hypotension (including orthostatic hypotension), and various digestive issues such as pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, and anorexia. Neurological effects such as vertigo, paresthesias, dizziness, headache, and restlessness have been noted, along with musculoskeletal symptoms like muscle spasm. Patients may also experience transient blurred vision and xanthopsia as part of the special senses reactions. Urogenital issues, including impotence, have been reported as well.

Metabolic disturbances such as electrolyte imbalance, hyperglycemia, glycosuria, and hyperuricemia are also associated with thiazide use. In diabetic patients, dosage adjustments of insulin or oral hypoglycemic agents may be necessary, as hyperglycemia can occur, potentially revealing latent diabetes mellitus during therapy.

It is important to note that whenever adverse reactions are moderate or severe, the thiazide dosage should be reduced or therapy withdrawn. Caution is advised in patients with severe renal disease, as thiazides may precipitate azotemia and cumulative effects can develop in those with impaired renal function. Similarly, thiazides should be used cautiously in patients with impaired hepatic function or progressive liver disease, as minor alterations in fluid and electrolyte balance may precipitate hepatic coma. There have also been reports of exacerbation or activation of systemic lupus erythematosus in some patients receiving thiazides, and hyperuricemia may occur or acute gout may be precipitated in certain individuals.

Drug Interactions

The concomitant use of certain medications with hydrochlorothiazide may lead to significant drug interactions, categorized primarily into pharmacodynamic and pharmacokinetic interactions.

Pharmacodynamic Interactions

• Alcohol, Barbiturates, or Narcotics: The combination of hydrochlorothiazide with these agents may potentiate orthostatic hypotension. Patients should be monitored for signs of increased hypotensive effects.

• Antidiabetic Drugs (Oral Agents and Insulin): The use of hydrochlorothiazide may necessitate dosage adjustments of antidiabetic medications to maintain glycemic control. Close monitoring of blood glucose levels is advised.

• Other Antihypertensive Drugs: The use of hydrochlorothiazide in conjunction with other antihypertensive agents may result in an additive effect or potentiation of blood pressure-lowering effects. Blood pressure should be monitored regularly.

• Corticosteroids and ACTH: Co-administration may lead to intensified electrolyte depletion, particularly hypokalemia. Electrolyte levels should be monitored frequently.

• Pressor Amines (e.g., Norepinephrine): There may be a decreased response to pressor amines; however, this does not preclude their use. Additionally, there may be an increased responsiveness to nondepolarizing skeletal muscle relaxants, such as tubocurarine.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The administration of NSAIDs may reduce the diuretic, natriuretic, and antihypertensive effects of hydrochlorothiazide. Patients should be closely observed to ensure the desired diuretic effect is achieved.

Pharmacokinetic Interactions

• Cholestyramine and Colestipol Resins: The absorption of hydrochlorothiazide is significantly impaired when administered with anionic exchange resins. Cholestyramine can reduce hydrochlorothiazide absorption by up to 85%, while colestipol can reduce it by up to 43%. It is advisable to separate the administration of hydrochlorothiazide and these resins by at least 2 hours.

• Lithium: The use of hydrochlorothiazide with lithium is generally contraindicated due to the potential for reduced renal clearance of lithium, which increases the risk of lithium toxicity. Consultation of the package insert for lithium preparations is recommended prior to co-administration.

Drug/Laboratory Test Interactions

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

Packaging & NDC

The table below lists all NDC Code configurations of Hydrochlorothiazide, the U.S. brand-name prescription product. Columns show Packaging, Formulation Type, and Active Ingredient Strength.

Pediatric Use

There are no well-controlled clinical trials conducted in pediatric patients. Dosing information for this age group is derived from empirical use and published literature concerning the treatment of hypertension in pediatric patients. Healthcare professionals should refer to the Dosage and Administration section for specific guidance on dosing in infants and children.

Geriatric Use

Elderly patients may require special consideration when using thiazide diuretics, particularly those aged 65 and older. Caution is advised in patients with severe renal disease, as thiazides can precipitate azotemia and lead to cumulative effects due to impaired renal function. In cases of progressive renal impairment, it may be necessary to withhold or discontinue diuretic therapy.

Thiazides should also be used with caution in geriatric patients who have impaired hepatic function or progressive liver disease, as even minor alterations in fluid and electrolyte balance can precipitate hepatic coma. Additionally, there is a reported possibility of exacerbation or activation of systemic lupus erythematosus in this population.

Elderly patients are at risk for developing hypokalemia, particularly with brisk diuresis, severe cirrhosis, or prolonged therapy. Therefore, periodic determination of serum electrolytes is recommended to monitor for potential electrolyte imbalances at appropriate intervals.

In diabetic elderly patients, dosage adjustments of insulin or oral hypoglycemic agents may be necessary due to the effects of thiazides on glucose metabolism. Furthermore, the antihypertensive effects of thiazides may be enhanced in patients who have undergone sympathectomy.

When thiazides are used in conjunction with other antihypertensive agents, doses typically do not exceed 50 mg of hydrochlorothiazide daily in geriatric patients. Careful monitoring and dose modifications are essential to ensure safety and efficacy in this population.

Pregnancy

Hydrochlorothiazide is classified as a Pregnancy Category B medication. Animal studies involving the oral administration of hydrochlorothiazide to pregnant mice and rats during critical periods of organogenesis, at doses up to 3000 mg/kg and 1000 mg/kg respectively, have not demonstrated teratogenic effects or harm to the fetus. However, there are no adequate and well-controlled studies in pregnant women. Therefore, the use of hydrochlorothiazide during pregnancy should be considered only if the potential benefits justify the potential risks to the fetus, as animal reproduction studies may not reliably predict human outcomes.

It is important to note that thiazides, including hydrochlorothiazide, cross the placental barrier and can be detected in cord blood. This raises concerns regarding nonteratogenic effects, including the risk of fetal or neonatal jaundice and thrombocytopenia, as well as other adverse reactions that may occur in adults. Healthcare professionals should carefully evaluate the necessity of hydrochlorothiazide in pregnant patients and monitor for potential adverse effects in both the mother and the fetus.

Lactation

Thiazides are excreted in breast milk. Due to the potential for serious adverse reactions in nursing infants, lactating mothers should make a decision regarding whether to discontinue breastfeeding or to discontinue hydrochlorothiazide. This decision should take into account the importance of the medication to the mother.

Renal Impairment

Patients with renal impairment should use this medication with caution, particularly in cases of severe renal disease. In individuals with renal disease, thiazides may precipitate azotemia, necessitating careful monitoring of renal function. Additionally, the cumulative effects of the drug may develop in patients with impaired renal function, warranting dose adjustments and vigilant oversight to mitigate potential adverse effects.

Hepatic Impairment

Patients with hepatic impairment should use thiazides with caution. In individuals with impaired hepatic function or progressive liver disease, minor alterations in fluid and electrolyte balance may precipitate hepatic coma. Therefore, careful monitoring of liver function and electrolyte levels is recommended in this population to mitigate potential risks. Adjustments to dosage may be necessary based on the severity of hepatic impairment and the patient's overall clinical status.

Overdosage

In cases of overdosage, the most frequently observed signs and symptoms are primarily attributed to electrolyte depletion, including hypokalemia, hypochloremia, and hyponatremia, as well as dehydration resulting from excessive diuresis. It is important to note that if digitalis has been concurrently administered, hypokalemia may exacerbate the risk of cardiac arrhythmias.

Management of overdosage should involve the implementation of symptomatic and supportive measures. Induction of emesis or performance of gastric lavage is recommended to mitigate the effects of the overdose. Additionally, it is crucial to correct any dehydration and electrolyte imbalances, as well as to address hepatic coma and hypotension using established medical procedures. In cases of respiratory impairment, the administration of oxygen or the provision of artificial respiration may be necessary.

The extent to which hydrochlorothiazide can be removed through hemodialysis has not been definitively established. Furthermore, it is noteworthy that the oral LD50 of hydrochlorothiazide exceeds 10 g/kg in both mouse and rat models, indicating a significant margin of safety in these species.

Nonclinical Toxicology

Thiazides are known to cross the placental barrier and can be detected in cord blood. This transference raises concerns regarding potential risks to the fetus, including the possibility of fetal or neonatal jaundice and thrombocytopenia. Additionally, there may be other adverse reactions that have been observed in adult populations, which could also pose risks to the developing fetus or neonate.

Postmarketing Experience

Adverse reactions have been reported voluntarily or through surveillance programs, categorized by system and listed in order of decreasing severity.

Body as a Whole: Reports include weakness.

Cardiovascular: Hypotension, including orthostatic hypotension, has been noted, with potential aggravation by alcohol, barbiturates, narcotics, or antihypertensive drugs.

Digestive: Adverse events include pancreatitis, jaundice (intrahepatic cholestatic jaundice), diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, and anorexia.

Hematologic: Cases of aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia have been reported.

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

Metabolic: Reports of electrolyte imbalance, hyperglycemia, glycosuria, and hyperuricemia have been received.

Musculoskeletal: Muscle spasms have been reported.

Nervous System/Psychiatric: Adverse reactions include vertigo, paresthesias, dizziness, headache, and restlessness.

Renal: Cases of renal failure, renal dysfunction, and interstitial nephritis have been noted.

Skin: Reports 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 has been documented.

In instances where adverse reactions are moderate or severe, it is recommended that thiazide dosage be reduced or therapy withdrawn.

Patient Counseling

Patients should be closely monitored for signs of fluid or electrolyte imbalance, including conditions such as hyponatremia, hypochloremic alkalosis, and hypokalemia. Healthcare providers are advised to inform patients about warning signs or symptoms indicative of these imbalances, which may include dryness of the mouth, increased thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

It is important to note that hypokalemia may develop, particularly in patients experiencing brisk diuresis, those with severe cirrhosis, or after prolonged therapy. Patients should be made aware that hypokalemia can lead to cardiac arrhythmias and may heighten the heart's sensitivity to the toxic effects of digitalis. To mitigate the risk of hypokalemia, healthcare providers should discuss the potential use of potassium-sparing diuretics or potassium supplements, including dietary sources rich in potassium.

In cases of dilutional hyponatremia, particularly in edematous patients during hot weather, healthcare providers should recommend water restriction as the appropriate management strategy, rather than salt administration, unless the hyponatremia is life-threatening. For patients with actual salt depletion, appropriate replacement therapy should be emphasized.

Patients receiving thiazide diuretics should be informed about the potential for hyperuricemia and the possibility of acute gout being precipitated. Additionally, diabetic patients may require dosage adjustments of insulin or oral hypoglycemic agents, as thiazide therapy can lead to hyperglycemia and may unmask latent diabetes mellitus.

If there are signs of progressive renal impairment, healthcare providers should consider the need to withhold or discontinue diuretic therapy. It is also important to communicate that thiazides can increase urinary excretion of magnesium, potentially resulting in hypomagnesemia, while they may decrease urinary calcium excretion and cause slight elevations in serum calcium levels in the absence of known calcium metabolism disorders. Marked hypercalcemia may indicate hidden hyperparathyroidism, necessitating the discontinuation of thiazides prior to parathyroid function tests.

Patients should be advised that thiazide diuretics may be associated with increases in cholesterol and triglyceride levels, and periodic monitoring of serum electrolytes is recommended to detect any possible imbalances. When hydrochlorothiazide is used in conjunction with non-steroidal anti-inflammatory agents, close observation is warranted to ensure the desired diuretic effect is achieved. Lastly, thiazides should be discontinued before conducting tests for parathyroid function to ensure accurate results.

Storage and Handling

The product is supplied in a well-closed container, adhering to the specifications outlined in the United States Pharmacopeia (USP). It is essential to utilize a child-resistant closure as mandated.

For optimal storage, the product should be maintained at a temperature range of 20 to 25°C (68 to 77°F), in accordance with USP Controlled Room Temperature guidelines. Proper adherence to these storage conditions is crucial to ensure the integrity and efficacy of the product.

Additional Clinical Information

Clinicians should conduct periodic determinations of serum electrolytes in patients to detect any potential electrolyte imbalances. This monitoring should occur at appropriate intervals to ensure patient safety and effective management of treatment.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Hydrochlorothiazide as submitted by H. J. Harkins Company, Inc.. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)