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. The structural formula of hydrochlorothiazide is provided in the relevant documentation.

Hydrochlorothiazide, USP appears as a white or practically white crystalline powder. It exhibits slight solubility in water, is freely soluble in sodium hydroxide solution, n-butylamine, and dimethylformamide, and is sparingly soluble in methanol. The compound is insoluble in ether, chloroform, and dilute mineral acids.

For oral administration, hydrochlorothiazide is available in tablet form, with dosages of 25 mg and 50 mg. Each tablet contains inactive ingredients including FD&C Yellow #6 Lake, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and pregelatinized starch.

Uses and Indications

Hydrochlorothiazide tablets are indicated as adjunctive therapy in the management of edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid or estrogen therapy. Additionally, these tablets are beneficial in treating edema resulting from various forms of renal dysfunction, including 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 The routine use of diuretics, including hydrochlorothiazide, during normal pregnancy is not recommended due to potential risks to both the mother and fetus. Diuretics do not prevent the development of toxemia of pregnancy, nor is there satisfactory evidence supporting their efficacy in treating this condition.

Thiazides may be indicated during pregnancy when edema is due to pathologic causes. However, dependent edema resulting from the mechanical effects of pregnancy should be managed through non-pharmacological means, such as elevation of the lower extremities and the use of support stockings. The use of diuretics to lower intravascular volume in these cases is considered illogical and unnecessary, as hypervolemia during normal pregnancy is not harmful in the absence of cardiovascular disease. If edema causes significant discomfort, increased recumbency may provide relief, and in rare instances where discomfort persists, a short course of diuretic therapy may be appropriate.

Dosage and Administration

The usual adult dosage for the management of edema is 25 mg 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 3 to 5 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. It is important to note that doses exceeding 50 mg are frequently associated with significant reductions in serum potassium levels.

In pediatric patients, the usual dosage for diuresis and the control of hypertension is 0.5 mg to 1 mg per pound (1 to 2 mg/kg) per day, administered in either a single dose or two divided doses. The maximum daily dosage should not exceed 37.5 mg for infants up to 2 years of age or 100 mg 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 potential for exacerbating renal impairment. Additionally, individuals with hypersensitivity to this product or to other sulfonamide-derived drugs should not use it, as this may lead to severe allergic reactions.

Warnings and Precautions

Use of thiazide diuretics requires careful consideration in patients with severe renal disease, as these agents may precipitate azotemia and lead to cumulative effects in individuals with impaired renal function. Caution is also advised in patients with impaired hepatic function or progressive liver disease, as even minor alterations in fluid and electrolyte balance can trigger hepatic coma. Additionally, thiazides may enhance the effects of other antihypertensive medications, necessitating close monitoring of blood pressure and overall treatment response.

Sensitivity reactions can occur in patients regardless of prior allergy or bronchial asthma history. There is also a reported risk of exacerbation or activation of systemic lupus erythematosus. It is important to note that lithium should generally not be co-administered with diuretics due to potential interactions.

All patients undergoing diuretic therapy should be monitored for signs of fluid or electrolyte imbalance, including hyponatremia, hypochloremic alkalosis, and hypokalemia. Regular serum and urine electrolyte determinations are particularly critical in patients experiencing excessive vomiting or receiving parenteral fluids. Warning signs of fluid and electrolyte imbalance include dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle cramps, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.

Hypokalemia is a potential complication, especially during brisk diuresis, in patients with severe cirrhosis, or after prolonged therapy. Inadequate oral electrolyte intake can exacerbate hypokalemia, which may lead to cardiac arrhythmias and increase the heart's sensitivity to digitalis toxicity. To mitigate hypokalemia, potassium-sparing diuretics or potassium-rich foods may be beneficial. While chloride deficits are typically mild and may not require treatment, chloride replacement may be necessary in cases of metabolic alkalosis.

Dilutional hyponatremia can occur in edematous patients during hot weather; in such cases, water restriction is the preferred management strategy, with salt replacement reserved for rare, life-threatening situations. Hyperuricemia and acute gout may also be precipitated in certain patients receiving thiazides. In diabetic patients, dosage adjustments for insulin or oral hypoglycemic agents may be necessary, as thiazide therapy can induce hyperglycemia and unmask latent diabetes mellitus.

The antihypertensive effects of thiazides may be amplified in patients who have undergone sympathectomy. If progressive renal impairment is observed, it may be prudent to withhold or discontinue diuretic therapy. Thiazides can increase urinary magnesium excretion, potentially leading to hypomagnesemia, and may decrease urinary calcium excretion, resulting in intermittent elevations of serum calcium. Marked hypercalcemia could indicate hidden hyperparathyroidism, warranting discontinuation of thiazides prior to parathyroid function testing. Additionally, thiazide therapy may be associated with increases in cholesterol and triglyceride levels.

Periodic monitoring of serum electrolytes is essential to detect any potential imbalances during treatment.

Healthcare professionals should be vigilant for symptoms indicative of acute angle-closure glaucoma, such as a sudden decrease in visual acuity or ocular pain, which may arise within hours to weeks of initiating therapy. Untreated, this condition can lead to permanent vision loss; therefore, hydrochlorothiazide should be discontinued immediately, and prompt medical or surgical intervention may be required if intraocular pressure remains uncontrolled. If symptoms of acute angle-closure glaucoma occur, patients should be advised to stop taking hydrochlorothiazide and contact their healthcare provider without delay.

Side Effects

Adverse reactions observed in patients include a range of effects categorized by seriousness and frequency.

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

Common adverse reactions reported 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 also been noted. Musculoskeletal symptoms may include muscle spasms, while metabolic disturbances can lead to electrolyte imbalances, hyperglycemia, glycosuria, and hyperuricemia.

Patients may experience transient blurred vision and xanthopsia as part of the special senses adverse reactions. Urogenital effects, such as impotence, have also been reported.

In clinical trials and postmarketing experiences, it is advised that whenever adverse reactions are moderate or severe, the dosage of thiazide should be reduced or therapy withdrawn to mitigate risks.

Drug Interactions

Co-administration of hydrochlorothiazide with certain substances may lead to significant drug interactions, categorized into pharmacodynamic and pharmacokinetic interactions.

Pharmacodynamic Interactions

• Alcohol, Barbiturates, and Narcotics: The concomitant use of these agents may potentiate orthostatic hypotension. Monitoring of blood pressure is advised to manage potential hypotensive effects.

• Antidiabetic Drugs (Oral Agents and Insulin): Dosage adjustments of antidiabetic medications may be necessary when used in conjunction with hydrochlorothiazide. Regular monitoring of blood glucose levels is recommended to ensure effective glycemic control.

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

• Corticosteroids and ACTH: The combination may lead to intensified electrolyte depletion, particularly hypokalemia. Electrolyte levels should be monitored regularly.

• Pressor Amines (e.g., Norepinephrine): There may be a decreased response to pressor amines; however, this interaction is not sufficient to contraindicate their use. Clinical response should be assessed.

• Skeletal Muscle Relaxants (Nondepolarizing, e.g., Tubocurarine): Increased responsiveness to muscle relaxants may occur. Monitoring of neuromuscular function is recommended.

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

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

Pharmacokinetic Interactions

• Cholestyramine and Colestipol Resins: The absorption of hydrochlorothiazide is significantly impaired in the presence of these anionic exchange resins. Single doses of cholestyramine or colestipol can reduce hydrochlorothiazide absorption by up to 85% and 43%, respectively. It is advisable to separate the administration of hydrochlorothiazide and these resins by several hours to minimize interaction.

Drug & Laboratory Test Interactions

• Parathyroid Function Tests: Thiazides 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 primarily derived from empirical use and published literature concerning the treatment of hypertension in pediatric patients. Caution is advised when prescribing, as the safety and efficacy of the medication in children have not been established through rigorous clinical trials.

Geriatric Use

Elderly patients may exhibit increased sensitivity to side effects, necessitating cautious use of this medication in this population. Dosage adjustments should be considered for geriatric patients, especially those with diminished renal function, as they may be at a higher risk for cumulative effects of the drug.

It is essential to monitor elderly patients for signs of fluid or electrolyte imbalance, given their increased susceptibility to these conditions. Additionally, there is an elevated risk of hypotension, particularly orthostatic hypotension, which may be exacerbated by the concurrent use of alcohol, barbiturates, narcotics, or other antihypertensive medications. Careful assessment and monitoring are recommended to ensure the safety and efficacy of treatment in geriatric patients.

Pregnancy

Routine use of diuretics during normal pregnancy is inappropriate and exposes both the mother and fetus to unnecessary hazards. Diuretics do not prevent the development of toxemia of pregnancy, and there is no satisfactory evidence supporting their efficacy in treating this condition. Edema during pregnancy may arise from either pathologic causes or the physiologic and mechanical consequences of pregnancy itself.

Thiazide diuretics may be indicated in pregnancy when edema is due to pathologic causes, similar to their use in non-pregnant patients. However, dependent edema resulting from the restriction of venous return by the gravid uterus should be managed through non-pharmacological means, such as 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 occurs, which is not harmful to the mother or fetus in the absence of cardiovascular disease. While hypervolemia may be associated with edema, it is rarely generalized. If edema causes discomfort, increased recumbency often provides relief. In rare cases where edema leads to extreme discomfort that is not alleviated by rest, a short course of diuretic therapy may be appropriate to provide relief.

Lactation

Thiazides are excreted in breast milk. Due to the potential for serious adverse reactions in nursing infants, healthcare professionals should consider whether to discontinue nursing or to discontinue hydrochlorothiazide, weighing the importance of the medication to the lactating 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 consideration of dosing adjustments and close observation 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 is removed from the body 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

Hydrochlorothiazide crosses the placental barrier and is detectable in cord blood, which may pose a risk of fetal or neonatal jaundice, thrombocytopenia, and potentially other adverse reactions observed in adults.

Two-year feeding studies conducted by the National Toxicology Program (NTP) in mice and rats revealed no evidence of carcinogenic potential in female mice at doses up to approximately 600 mg/kg/day or in male and female rats at doses up to approximately 100 mg/kg/day. However, the NTP did find equivocal evidence for hepatocarcinogenicity in male mice.

In terms of mutagenicity, hydrochlorothiazide was not found to be genotoxic in vitro in the Ames mutagenicity assay using various strains of Salmonella typhimurium, nor in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. Additionally, it did not exhibit genotoxic effects in vivo in assays involving mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene. Positive results were noted only in the in vitro CHO Sister Chromatid Exchange (clastogenicity) and Mouse Lymphoma Cell (mutagenicity) assays at concentrations ranging from 43 to 1300 mcg/mL, as well as in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.

Hydrochlorothiazide did not adversely affect the fertility of either sex in mice and rats exposed to doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to conception and throughout gestation.

Postmarketing Experience

Adverse reactions reported in postmarketing experience include a range of effects across various systems.

Body as a Whole: Weakness has been noted.

Cardiovascular: Instances of hypotension, including orthostatic hypotension, have been reported, with potential aggravation by alcohol, barbiturates, narcotics, or antihypertensive drugs.

Digestive: Reactions such as pancreatitis, intrahepatic cholestatic jaundice, diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, and anorexia have been documented.

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

Hypersensitivity: Reports include anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress (including pneumonitis and pulmonary edema), photosensitivity, fever, urticaria, rash, and purpura.

Metabolic: Electrolyte imbalances, hyperglycemia, glycosuria, and hyperuricemia have been identified.

Musculoskeletal: Muscle spasms have been reported.

Nervous System/Psychiatric: Symptoms such as vertigo, paresthesias, dizziness, headache, and restlessness have been noted.

Renal: Adverse events including renal failure, renal dysfunction, and interstitial nephritis have been documented.

Skin: Reactions such as erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis (including toxic epidermal necrolysis), and alopecia have been reported.

Special Senses: Transient blurred vision and xanthopsia have been observed.

Urogenital: Impotence has been noted.

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

Patient Counseling

Patients should be observed for evidence of fluid or electrolyte imbalance. Healthcare providers should discuss with patients the importance of recognizing signs such as dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances, including nausea and vomiting.

It is essential to inform patients that hypokalemia may develop, particularly with brisk diuresis, in cases of severe cirrhosis, or after prolonged therapy. Patients should be made aware that hypokalemia can lead to cardiac arrhythmia and may sensitize or exaggerate the heart's response to the toxic effects of digitalis. Healthcare providers should advise patients on strategies to avoid or treat hypokalemia, such as the use of potassium-sparing diuretics or potassium supplements, including foods rich in potassium.

Warning signs or symptoms of fluid and electrolyte imbalance should be monitored closely. Patients should also be informed that thiazides may cause an idiosyncratic reaction, which can result in acute transient myopia and acute angle-closure glaucoma. Symptoms to watch for include an acute onset of decreased visual acuity or ocular pain. If such symptoms occur, patients should be instructed to discontinue hydrochlorothiazide as rapidly as possible and seek prompt medical or surgical treatment if intraocular pressure remains uncontrolled.

Patients should be made aware that hydrochlorothiazide crosses the placental barrier and can appear in cord blood, posing a risk of fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions. Nursing mothers should be advised that thiazides are excreted in breast milk, and a decision should be made regarding whether to discontinue nursing or to discontinue hydrochlorothiazide, taking into account the importance of the drug to the mother.

Additionally, patients should be informed that the antihypertensive effects of hydrochlorothiazide may be enhanced in post-sympathectomy patients. They should be advised to report any signs of hypersensitivity reactions, such as rash, fever, or respiratory distress. Finally, healthcare providers should instruct patients to maintain adequate oral electrolyte intake to prevent electrolyte imbalances.

Storage and Handling

The product is supplied in a tight, light-resistant container that complies with USP standards and features a child-resistant closure. It is essential to store the product at a temperature range of 20° to 25°C (68° to 77°F), in accordance with USP Controlled Room Temperature guidelines.

To ensure the integrity of the product, it must be protected from moisture, freezing, and excessive heat. After each use, the cap should be securely tightened to maintain child-resistance. Additionally, the product should not be used if the bottle seal is not intact, as this indicates potential tampering.

Additional Clinical Information

Clinicians should conduct periodic determinations of serum electrolytes in patients to monitor for potential electrolyte imbalances. This assessment should be performed at appropriate intervals to ensure patient safety and effective management.

FDA Insert (PDF)

This document is the official FDA-approved prescribing information for Hydrochlorothiazide as submitted by Legacy Pharmaceutical Packaging. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)