Hydrochlorothiazide

Description

Hydrochlorothiazide is a diuretic and antihypertensive agent, specifically 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, with a molecular weight of 297.74. The chemical formula is C₇H₈ClN₃O₄S₂. Hydrochlorothiazide appears as a white or practically white crystalline powder, which is slightly soluble in water and freely soluble in sodium hydroxide solution.

Each tablet for oral administration contains either 25 mg or 50 mg of hydrochlorothiazide USP. The formulation includes several inactive ingredients: anhydrous lactose, calcium stearate, corn starch, dibasic calcium phosphate, FD&C Yellow No. 6, FD&C Yellow No. 10, and sodium starch glycolate.

Uses and Indications

Hydrochlorothiazide tablets are indicated as adjunctive therapy in the management of edema associated with congestive heart failure, hepatic cirrhosis, and corticosteroid and estrogen therapy. This medication is also effective 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 may be utilized either as a monotherapy or in combination with other antihypertensive agents to enhance their effectiveness, particularly in cases of more severe hypertension.

Limitations of Use: Routine use of diuretics, including hydrochlorothiazide, during normal pregnancy is not recommended, as it 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 efficacy in treating this condition. Thiazides may be indicated during pregnancy only when edema is due to pathological causes, similar to their use in non-pregnant patients.

Dependent edema during pregnancy, which arises from venous return restriction by the gravid uterus, should primarily be managed through non-pharmacological measures such as elevating the lower extremities and utilizing support stockings. The use of diuretics to reduce intravascular volume in cases of dependent edema during pregnancy is considered illogical and unnecessary. While hypervolemia is a normal physiological condition during pregnancy and is not harmful in the absence of cardiovascular disease, it may occasionally be associated with discomfort due to edema. In instances where edema causes significant discomfort that is not alleviated by rest, a short course of diuretic therapy may be appropriate.

Dosage and Administration

The usual adult dosage for the management 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, the initial recommended dose for adults is 25 mg daily, given as a single dose. This dose may be increased to 50 mg daily, which can be administered as either 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.

Administration should be performed as specified for each age group and condition, with the option for intermittent therapy for patients with edema.

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 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, where even minor alterations in fluid and electrolyte balance could trigger hepatic coma. Additionally, thiazides may enhance the effects of other antihypertensive medications, necessitating close monitoring of blood pressure and renal function.

Sensitivity reactions can occur in patients regardless of prior allergy or bronchial asthma history. There have been reports of exacerbation or activation of systemic lupus erythematosus associated with thiazide use. Furthermore, lithium should generally not be co-administered with diuretics due to the potential for adverse 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 crucial for 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 particular concern, especially during brisk diuresis, in cases of severe cirrhosis, or after prolonged therapy.

Interference with adequate 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, where water restriction is the preferred management strategy, except in rare life-threatening situations. In cases of actual salt depletion, appropriate replacement is essential.

Hyperuricemia and acute gout may 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 potentially 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, leading to hypomagnesemia, and may decrease urinary calcium excretion, resulting in intermittent elevations of serum calcium levels. Marked hypercalcemia could indicate underlying hyperparathyroidism, and thiazides should be discontinued prior to parathyroid function testing. Additionally, thiazide therapy may be associated with increases in cholesterol and triglyceride levels.

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

Side Effects

Adverse reactions associated with the use of this medication 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 occur, manifesting 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 reported in clinical trials and postmarketing experiences 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. Patients may also experience musculoskeletal symptoms like muscle spasms and nervous system/psychiatric effects including vertigo, paresthesias, dizziness, headache, and restlessness.

Metabolic disturbances such as electrolyte imbalances, hyperglycemia, glycosuria, and hyperuricemia have been noted. Urogenital effects, particularly impotence, and transient visual disturbances such as blurred vision and xanthopsia have also been reported.

In cases where adverse reactions are moderate or severe, it is recommended that the thiazide dosage be reduced or therapy withdrawn. Furthermore, in instances of overdose, the most common signs and symptoms are those resulting from electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration due to excessive diuresis. If digitalis has been administered concurrently, hypokalemia may exacerbate cardiac arrhythmias.

Drug Interactions

Concomitant use of thiazide diuretics with certain medications may lead to significant drug interactions, categorized primarily into pharmacodynamic and pharmacokinetic interactions.

Pharmacodynamic Interactions

• Alcohol, Barbiturates, or Narcotics: The combination may potentiate orthostatic hypotension. Patients should be monitored for signs of hypotension and advised to use caution when standing up.

• Antidiabetic Drugs (oral agents and insulin): Dosage adjustments of the antidiabetic medication may be necessary to maintain glycemic control. Regular monitoring of blood glucose levels is recommended.

• 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, ACTH: Concurrent use 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 observed.

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

• Lithium: Thiazide diuretics can reduce the renal clearance of lithium, increasing the risk of lithium toxicity. Co-administration is generally not recommended, and careful monitoring of lithium levels is essential if used together.

• Nonsteroidal Anti-inflammatory Drugs (NSAIDs): The effectiveness of thiazide diuretics may be reduced in some patients when NSAIDs are administered concurrently. Patients should be observed closely to ensure the desired diuretic effect is achieved.

Pharmacokinetic Interactions

• Cholestyramine and Colestipol Resins: The absorption of hydrochlorothiazide is significantly impaired when these anionic exchange resins are present. Single doses can reduce hydrochlorothiazide absorption by up to 85% and 43%, respectively. It is advisable to separate the administration of these agents to minimize interaction.

Laboratory Test Interactions

Thiazide diuretics 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 require special consideration when using thiazide diuretics, particularly those aged 65 and older. Caution is advised in this population, especially in individuals with severe renal disease, as thiazides can precipitate azotemia and lead to cumulative effects due to impaired renal function.

In patients with impaired hepatic function or progressive liver disease, thiazides should also be used with caution. Minor alterations in fluid and electrolyte balance in these patients may precipitate hepatic coma, necessitating careful monitoring.

All patients receiving diuretic therapy, including geriatric patients, should be closely observed for signs of fluid or electrolyte imbalance, such as hyponatremia, hypochloremic alkalosis, and hypokalemia. Hypokalemia is particularly concerning in elderly patients, especially those experiencing brisk diuresis, severe cirrhosis, or prolonged therapy.

If there is evidence of progressive renal impairment in elderly patients, it may be necessary to withhold or discontinue diuretic therapy. Additionally, the antihypertensive effects of thiazides may be enhanced in patients who have undergone sympathectomy, which should be taken into account when managing blood pressure in this demographic.

For diabetic elderly patients, dosage adjustments of insulin or oral hypoglycemic agents may be required to maintain glycemic control. Regular monitoring of serum electrolytes is recommended to detect potential imbalances, and this should be performed at appropriate intervals to ensure patient safety.

Pregnancy

Hydrochlorothiazide is classified as Pregnancy Category B. 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 any evidence of fetal harm. However, there are no adequate and well-controlled studies in pregnant women. Due to the limitations of animal reproduction studies in predicting human outcomes, hydrochlorothiazide should be used during pregnancy only if clearly needed.

It is important to note that thiazides, including hydrochlorothiazide, cross the placental barrier and can be detected in cord blood. This raises concerns regarding potential 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 weigh the benefits against the risks when considering the use of hydrochlorothiazide in pregnant patients.

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 breastfeeding or to discontinue hydrochlorothiazide, weighing the importance of the medication to the lactating mother.

Renal Impairment

Patients with renal impairment should be treated with caution, particularly those with severe renal disease. In this population, 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, which underscores the importance of dose adjustments and vigilant observation.

Thiazides should also be used with caution in patients with impaired hepatic function or progressive liver disease, as even minor alterations in fluid and electrolyte balance may precipitate hepatic coma. Therefore, healthcare professionals are advised to closely monitor these patients to mitigate potential risks.

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 prevent potential complications. No specific dosage adjustments are provided; however, clinicians should assess the risks and benefits of thiazide therapy in patients with compromised liver function.

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 dehydration and any electrolyte imbalances, as well as to address hepatic coma and hypotension through 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 from the body via hemodialysis has not been definitively established. For reference, the oral LD50 of hydrochlorothiazide is greater than 10 g/kg in both mouse and rat models, indicating a relatively high threshold for acute toxicity in these species.

Nonclinical Toxicology

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, demonstrated no evidence of teratogenic effects on the fetus. However, it is important to note that there are no adequate and well-controlled studies in pregnant women. Given that animal reproduction studies may not reliably predict human outcomes, the use of this drug during pregnancy should be considered only when clearly necessary.

Hydrochlorothiazide is known to cross the placental barrier and can be detected in cord blood. This raises concerns regarding potential risks such as fetal or neonatal jaundice, thrombocytopenia, and other adverse reactions that have been observed in adults.

Two-year feeding studies conducted by the National Toxicology Program (NTP) in mice and rats revealed no evidence of carcinogenic potential for hydrochlorothiazide 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 of 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 genotoxicity 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 observed only in the in vitro CHO Sister Chromatid Exchange assay and the 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 male or female mice and rats in studies where these animals were 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 the postmarketing experience include a range of events. Weakness and hypotension, including orthostatic hypotension, have been noted, with potential exacerbation by alcohol, barbiturates, narcotics, or antihypertensive medications. Gastrointestinal disturbances such as pancreatitis, intrahepatic cholestatic jaundice, diarrhea, vomiting, sialadenitis, cramping, constipation, gastric irritation, nausea, and anorexia have also been documented.

Hematological events including aplastic anemia, agranulocytosis, leukopenia, hemolytic anemia, and thrombocytopenia have been reported. Additionally, anaphylactic reactions, necrotizing angiitis (vasculitis and cutaneous vasculitis), respiratory distress (including pneumonitis and pulmonary edema), photosensitivity, fever, urticaria, rash, and purpura have been observed.

Electrolyte imbalances, hyperglycemia, glycosuria, and hyperuricemia have been noted, along with muscle spasms. Neurological symptoms such as vertigo, paresthesias, dizziness, headache, and restlessness have also been reported. Renal complications, including renal failure, renal dysfunction, and interstitial nephritis, have been documented.

Dermatological reactions such as erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis (including toxic epidermal necrolysis), and alopecia have been observed. Transient blurred vision and xanthopsia have been reported, as well as impotence.

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 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 the warning signs and symptoms associated with 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 sensitize or exacerbate the heart's response 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 metabolic alkalosis, chloride replacement may be necessary. Patients should be informed that dilutional hyponatremia can occur in edematous individuals during hot weather, and that the appropriate management is typically water restriction, rather than salt administration, unless the hyponatremia is life-threatening. Conversely, in instances of actual salt depletion, appropriate replacement therapy is essential.

Healthcare providers should also discuss the potential for hyperuricemia or the precipitation of acute gout in certain patients receiving thiazide diuretics. For diabetic patients, it may be necessary to adjust the dosage of insulin or oral hypoglycemic agents, as hyperglycemia can occur with thiazide use, potentially revealing latent diabetes mellitus.

If progressive renal impairment is observed, healthcare providers should consider withholding or discontinuing diuretic therapy. Thiazides are known to increase urinary excretion of magnesium, which may lead to hypomagnesemia, and they may decrease urinary calcium excretion, potentially causing intermittent and slight elevations in serum calcium levels in the absence of known calcium metabolism disorders. Marked hypercalcemia may indicate hidden hyperparathyroidism, and thiazides should be discontinued prior to conducting tests for parathyroid function.

Patients should be informed that thiazide diuretics may be associated with increases in cholesterol and triglyceride levels. Regular monitoring of serum electrolytes is recommended to detect any possible imbalances, and patients should be observed closely when hydrochlorothiazide is used in conjunction with nonsteroidal anti-inflammatory agents to ensure the desired diuretic effect is achieved.

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 should be stored at a temperature range of 20 to 25°C (68 to 77°F), in accordance with USP Controlled Room Temperature guidelines. Additionally, it is essential to protect the product from light and moisture to maintain its integrity and efficacy.

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 Contract Pharmacy Services-PA. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)