Hydrochlorothiazide

Description

Hydrochlorothiazide is a diuretic and antihypertensive agent, specifically the 3,4-dihydro derivative of chlorothiazide. It is chemically designated as 6-chloro-3,4-dihydro-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide. 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 the following inactive ingredients: 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 various conditions, including congestive heart failure, hepatic cirrhosis, and corticosteroid or estrogen therapy. Additionally, these tablets are beneficial in treating 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: Routine use of diuretics, including hydrochlorothiazide, during normal pregnancy is inappropriate and poses unnecessary risks to both the mother and fetus. Diuretics do not prevent or effectively treat toxemia of pregnancy, and their use for dependent edema resulting from venous return restriction by the gravid uterus is illogical and unnecessary. Instead, dependent edema in pregnancy should be managed through elevation of the lower extremities and the use of support stockings.

Thiazides may be indicated during pregnancy when edema is due to pathological causes. In cases where edema causes significant discomfort and is not alleviated by rest, a short course of diuretic therapy may be appropriate. However, it is important to note that hypervolemia during normal pregnancy is not harmful in the absence of cardiovascular disease, and increased recumbency can often provide relief from discomfort associated with edema.

Dosage and Administration

The usual adult dosage for 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 initial recommended dose is 25 mg daily, given as a single dose. This dose may be increased to 50 mg daily, which can be administered as a single dose or divided into two doses.

In pediatric patients, the usual dosage for diuresis and 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 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 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 specific health conditions and necessitates ongoing monitoring for potential adverse effects.

Warnings

Thiazides should be administered with caution in individuals with severe renal disease, as they may precipitate azotemia and lead to cumulative effects in patients with impaired renal function. In patients with compromised hepatic function or progressive liver disease, thiazides may disrupt fluid and electrolyte balance, potentially precipitating hepatic coma. Additionally, thiazides can enhance the effects of other antihypertensive medications, necessitating careful management of combined therapies.

Sensitivity reactions may 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 advised that lithium not be co-administered with diuretics due to potential interactions.

General Precautions

Patients undergoing diuretic therapy must be monitored for signs of fluid or electrolyte imbalance, including hyponatremia, hypochloremic alkalosis, and hypokalemia. Regular serum and urine electrolyte assessments are crucial, particularly in cases of excessive vomiting or when parenteral fluids are administered. 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 risk, especially during brisk diuresis, in patients with severe cirrhosis, or after prolonged therapy. Inadequate oral electrolyte intake may exacerbate hypokalemia, which can lead to cardiac arrhythmias and increase the heart's sensitivity to digitalis toxicity. The use of potassium-sparing diuretics or potassium-rich foods may help mitigate this risk. While chloride deficits are typically mild, they may require replacement in cases of metabolic alkalosis, particularly in patients with liver or renal disease.

Dilutional hyponatremia may occur in edematous patients during hot weather; water restriction is the preferred management strategy, with salt replacement reserved for rare, life-threatening cases of hyponatremia. 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 thiazides 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.

Laboratory Tests

Periodic monitoring of serum electrolytes is essential to detect potential electrolyte imbalances at appropriate intervals during thiazide therapy.

Get Emergency Medical Help

Hydrochlorothiazide, a sulfonamide, may cause an idiosyncratic reaction leading to acute transient myopia and acute angle-closure glaucoma. Symptoms, including a sudden decrease in visual acuity or ocular pain, can manifest within hours to weeks of initiating treatment. Untreated acute angle-closure glaucoma poses a risk of permanent vision loss. Immediate discontinuation of hydrochlorothiazide is critical, and prompt medical or surgical intervention may be necessary if intraocular pressure remains uncontrolled.

Stop Taking and Call Your Doctor

Patients should discontinue hydrochlorothiazide immediately if symptoms of acute angle-closure glaucoma occur and seek medical advice without delay.

Side Effects

Adverse reactions associated with the use of this medication have been observed across various body systems, with some reactions categorized by seriousness and frequency.

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

Common adverse reactions include weakness, hypotension (including orthostatic hypotension), and various digestive issues such as diarrhea, vomiting, nausea, and abdominal cramping. Patients may also experience metabolic disturbances, including electrolyte imbalance, hyperglycemia, glycosuria, and hyperuricemia. Neurological symptoms such as vertigo, dizziness, headache, and paresthesias have been noted, along with musculoskeletal complaints like muscle spasms. Urogenital effects, including impotence, have also been reported.

In clinical trials and postmarketing experiences, the risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC), has been associated with hydrochlorothiazide. The increased risk is predominantly observed in white patients receiving large cumulative doses, with an estimated incidence of approximately 1 additional case of SCC per 16,000 patients per year in the overall population, and 1 additional case for every 6,700 patients per year in those taking a cumulative dose of ≥50,000 mg.

It is advised that whenever adverse reactions are moderate or severe, the dosage of thiazides should be reduced or therapy withdrawn. Caution is warranted in patients with severe renal disease, as thiazides may precipitate azotemia and cumulative effects may develop in those with impaired renal function. Additionally, 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. Sensitivity reactions can occur in patients with or without a history of allergy or bronchial asthma, and there have been reports of exacerbation or activation of systemic lupus erythematosus. Furthermore, lithium should generally not be administered concurrently with diuretics.

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, and Narcotics: The combination may potentiate orthostatic hypotension, necessitating caution in patients receiving these agents concurrently.

• Antidiabetic Drugs (Oral Agents and Insulin): Dosage adjustments of the antidiabetic medication may be required to maintain glycemic control when used alongside hydrochlorothiazide.

• Other Antihypertensive Drugs: There is a potential for an additive effect or potentiation of antihypertensive effects when hydrochlorothiazide is used with other antihypertensive agents.

• Corticosteroids and ACTH: The use of these agents may lead to intensified electrolyte depletion, particularly hypokalemia, which should be monitored closely.

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

• Skeletal Muscle Relaxants (Nondepolarizing, e.g., Tubocurarine): Increased responsiveness to muscle relaxants may occur, warranting careful monitoring of neuromuscular function.

• 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 concurrent use.

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): The administration of NSAIDs may diminish the diuretic, natriuretic, and antihypertensive effects of hydrochlorothiazide. Patients should be closely monitored to ensure the desired diuretic effect is achieved when these agents are used together.

Pharmacokinetic Interactions:

• Cholestyramine and Colestipol Resins: The absorption of hydrochlorothiazide is significantly impaired in the presence of anionic exchange resins. Single doses of cholestyramine or colestipol can reduce the gastrointestinal absorption of hydrochlorothiazide by up to 85% and 43%, respectively.

Laboratory Test Interactions:

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

Careful consideration and monitoring are recommended when hydrochlorothiazide is prescribed alongside these medications or in the context of laboratory testing.

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 careful 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 renal impairment, it may be necessary to withhold or discontinue diuretic therapy if progressive renal impairment is observed.

Thiazides should also be used with caution in geriatric patients who have impaired hepatic function or progressive liver disease. Minor alterations in fluid and electrolyte balance in these patients may precipitate hepatic coma, necessitating close monitoring.

The potential for exacerbation or activation of systemic lupus erythematosus has been reported in elderly patients, which warrants careful assessment of any pre-existing conditions. Additionally, hypokalemia may develop, particularly in patients with severe cirrhosis or those undergoing prolonged therapy, highlighting the importance of periodic serum electrolyte determinations to detect possible imbalances.

In the context of antihypertensive therapy, the effects of thiazides may be enhanced in patients who have undergone sympathectomy. Generally, elderly patients do not require doses exceeding 50 mg of hydrochlorothiazide daily when used in conjunction with other antihypertensive agents, which should be taken into account when determining appropriate dosing.

Pregnancy

Routine use of diuretics during normal pregnancy is inappropriate and poses unnecessary risks to both the mother and fetus. Diuretics do not prevent the development of toxemia of pregnancy, and there is insufficient evidence to support their efficacy in treating this condition. Edema during pregnancy can result from either pathological causes or the physiological and mechanical changes associated with pregnancy.

Thiazide diuretics may be indicated in cases where edema is due to pathological causes, similar to their use in non-pregnant patients. However, dependent edema, which occurs due to venous return restriction by the gravid uterus, should be managed through non-pharmacological measures such as elevating the lower extremities and using support stockings. The use of diuretics to reduce intravascular volume in this context is illogical and unnecessary.

During normal pregnancy, hypervolemia is a common physiological adaptation that is not harmful to the mother or fetus in the absence of cardiovascular disease. While this condition may be associated with edema, it is typically localized and rarely leads to generalized edema. If edema causes discomfort, increased recumbency often alleviates symptoms. In rare cases where edema results in extreme discomfort that is unresponsive to 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 breastfeeding 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 for potential adverse effects.

Hepatic Impairment

Patients with hepatic impairment should use thiazides with caution due to the potential for minor alterations in fluid and electrolyte balance, which may precipitate hepatic coma. It is essential to monitor these patients closely for any signs of deterioration in liver function and to assess their fluid and electrolyte status regularly. Adjustments to dosage may be necessary based on the severity of hepatic impairment and the patient's overall clinical condition.

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

Teratogenic effects have not been reported in the available data. However, nonteratogenic effects associated with thiazides indicate that these compounds can cross the placental barrier and are detectable in cord blood. This raises concerns regarding potential risks of fetal or neonatal jaundice, thrombocytopenia, and other adverse reactions that may also occur in adults.

In nonclinical toxicology studies, two-year feeding trials 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. Nonetheless, the NTP did find equivocal evidence of hepatocarcinogenicity in male mice.

Hydrochlorothiazide was shown to be non-genotoxic in vitro in the Ames mutagenicity assay using various strains of Salmonella typhimurium (TA 98, TA 100, TA 1535, TA 1537, and TA 1538) and 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 (clastogenicity) and Mouse Lymphoma Cell (mutagenicity) assays at hydrochlorothiazide concentrations ranging from 43 to 1300 mcg/mL, as well as in the Aspergillus nidulans non-disjunction assay at an unspecified concentration.

Furthermore, hydrochlorothiazide did not adversely affect the fertility of either male or female mice and rats in studies where these animals were exposed to dietary doses of up to 100 mg/kg and 4 mg/kg, respectively, prior to conception and throughout gestation.

Postmarketing Experience

Postmarketing experience has identified several adverse events associated with hydrochlorothiazide, reported voluntarily or through surveillance programs.

Acute myopia and secondary angle-closure glaucoma have been noted as idiosyncratic reactions to hydrochlorothiazide. Symptoms typically manifest within hours to weeks of initiating treatment and may include a sudden decrease in visual acuity or ocular pain. If left untreated, acute angle-closure glaucoma can result in permanent vision loss. The primary intervention is the prompt discontinuation of hydrochlorothiazide, with further medical or surgical treatment considered if intraocular pressure remains uncontrolled. Risk factors for developing this condition may include a history of sulfonamide or penicillin allergy.

Additionally, hydrochlorothiazide has been associated with an increased risk of non-melanoma skin cancer, particularly squamous cell carcinoma (SCC). Data from a study conducted in the Sentinel System indicate that the risk is notably higher in white patients receiving large cumulative doses. The overall population shows an increased risk of approximately one additional case of SCC per 16,000 patients per year, while white patients with a cumulative dose of ≥50,000 mg exhibit an increased risk of about one additional SCC case for every 6,700 patients per year.

A range of adverse reactions has also been reported, categorized as follows:

Body as a Whole: Weakness.

Cardiovascular: Hypotension, including orthostatic hypotension, which may be exacerbated by alcohol, barbiturates, narcotics, or antihypertensive medications.

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

Hematologic: 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.

Metabolic: Electrolyte imbalance, hyperglycemia, glycosuria, and hyperuricemia.

Musculoskeletal: Muscle spasm.

Nervous System/Psychiatric: Vertigo, paresthesias, dizziness, headache, and restlessness.

Renal: Renal failure, renal dysfunction, and interstitial nephritis.

Skin: Erythema multiforme (including Stevens-Johnson syndrome), exfoliative dermatitis (including toxic epidermal necrolysis), and alopecia.

Special Senses: Transient blurred vision and xanthopsia.

Urogenital: Impotence.

Patient Counseling

Healthcare providers should instruct patients taking hydrochlorothiazide to take precautions to protect their skin from sun exposure and to undergo regular skin cancer screenings. It is important for patients to be monitored for signs of fluid or electrolyte imbalance, which may include conditions such as hyponatremia, hypochloremic alkalosis, and hypokalemia.

Patients should be made aware of warning signs or symptoms indicative of fluid and electrolyte imbalance, including 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. Hypokalemia, which may develop particularly with brisk diuresis, severe cirrhosis, or prolonged therapy, can lead to serious complications such as cardiac arrhythmias and may heighten the heart's sensitivity to the toxic effects of digitalis. To prevent or manage hypokalemia, patients may be advised to consider potassium-sparing diuretics or to incorporate potassium-rich foods into their diet.

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

Patients should be informed that hyperuricemia may occur, and acute gout may be precipitated in some individuals receiving thiazides. For diabetic patients, it may be necessary to adjust the dosage of insulin or oral hypoglycemic agents, as thiazide diuretics can lead to hyperglycemia and potentially unmask latent diabetes mellitus.

If there are signs of progressive renal impairment, healthcare providers should consider withholding or discontinuing diuretic therapy. Thiazides can increase urinary excretion of magnesium, potentially resulting in hypomagnesemia, and may decrease urinary calcium excretion, leading to intermittent slight elevations of serum calcium 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 also be advised to report any symptoms of acute myopia or acute angle-closure glaucoma, such as a sudden decrease in visual acuity or ocular pain. In the event of acute angle-closure glaucoma symptoms, patients should be instructed to discontinue hydrochlorothiazide immediately and seek prompt medical or surgical intervention if intraocular pressure remains uncontrolled.

Storage and Handling

The product is supplied in a tight, light-resistant container that complies with the specifications outlined in the United States Pharmacopeia (USP) 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. Proper adherence to these storage conditions ensures 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 Solco Healthcare U. S. , LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)