Hydrochlorothiazide

Description

Hydrochlorothiazide is a diuretic and antihypertensive agent, chemically designated 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 compound has a structural formula that reflects its unique chemical properties.

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 and 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 monotherapy or in conjunction 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 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. 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 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 considered illogical and unnecessary. It is important to note that hypervolemia during normal pregnancy is not harmful to the mother or fetus in the absence of cardiovascular disease. If edema during pregnancy leads to significant discomfort, increased recumbency may provide relief; however, in rare cases where discomfort is extreme and unrelieved 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 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.

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.

Renal and Hepatic Considerations Thiazides should be administered with caution in individuals with severe renal disease, as they may precipitate azotemia and lead to cumulative effects due to impaired renal function. Similarly, caution is warranted in patients with impaired hepatic function or progressive liver disease, as even minor alterations in fluid and electrolyte balance can trigger hepatic coma.

Drug Interactions and Sensitivity Reactions Thiazides may enhance the effects of other antihypertensive medications, necessitating careful monitoring of blood pressure and overall treatment response. Sensitivity reactions can occur in patients regardless of prior allergy or bronchial asthma history. Additionally, there have been reports of exacerbation or activation of systemic lupus erythematosus in some patients. It is also advised that lithium not be co-administered with diuretics due to potential interactions.

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

Hypokalemia and Other Electrolyte Concerns Hypokalemia may develop, especially during brisk diuresis, in patients with severe cirrhosis, or after prolonged therapy. Inadequate oral electrolyte intake can exacerbate this condition, which may lead to cardiac arrhythmias and increased sensitivity to digitalis toxicity. To mitigate hypokalemia, potassium-sparing diuretics or potassium-rich foods may be beneficial. While chloride deficits are typically mild, they may require replacement in cases of metabolic alkalosis, particularly in patients with liver or renal disease.

Hyponatremia and Hyperuricemia Dilutional hyponatremia can occur in edematous patients, particularly in hot weather; water restriction is the preferred management strategy, except in rare cases of life-threatening hyponatremia. Hyperuricemia and acute gout may also be precipitated in certain patients receiving thiazides.

Diabetes Management In diabetic patients, dosage adjustments of insulin or oral hypoglycemic agents may be necessary, as thiazides can induce hyperglycemia and potentially unmask latent diabetes mellitus.

Renal Function Monitoring If progressive renal impairment is observed, it may be necessary 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. Marked hypercalcemia could indicate hidden hyperparathyroidism, and thiazides should be discontinued prior to parathyroid function testing.

Lipid Levels Patients on thiazide therapy may experience increases in cholesterol and triglyceride levels, which should be monitored as part of routine care.

Laboratory Tests Periodic determination of serum electrolytes is recommended to detect potential imbalances at appropriate intervals.

Emergency Medical Attention Hydrochlorothiazide, a sulfonamide, can cause idiosyncratic reactions, including acute transient myopia and acute angle-closure glaucoma. Symptoms such as sudden decreased visual acuity or ocular pain may arise within hours to weeks of initiating therapy. Untreated acute angle-closure glaucoma can result in permanent vision loss; therefore, discontinuation of hydrochlorothiazide should occur immediately, and prompt medical or surgical intervention may be necessary if intraocular pressure remains uncontrolled.

Discontinuation of Therapy Patients should be advised to discontinue hydrochlorothiazide promptly and contact their healthcare provider if symptoms of acute angle-closure glaucoma develop.

Side Effects

Adverse reactions observed in patients receiving the treatment include a range of serious and common effects, categorized by system involvement.

Serious Adverse Reactions:

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

Common Adverse Reactions:

Among the more frequently reported adverse reactions, patients have experienced weakness, hypotension (including orthostatic hypotension), and various digestive issues such as diarrhea, vomiting, nausea, and abdominal cramping. Other gastrointestinal effects include sialadenitis, constipation, gastric irritation, and anorexia. Neurologically, participants have reported symptoms such as vertigo, paresthesias, dizziness, headache, and restlessness. Musculoskeletal complaints, including muscle spasms, have also been observed.

Metabolic and Endocrine Effects:

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

Urogenital and Special Senses:

Impotence has been reported among urogenital adverse reactions. Patients may also experience transient blurred vision and xanthopsia as part of the special senses reactions.

Management of Adverse Reactions:

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

Patients should be monitored closely for these adverse reactions, and appropriate measures should be taken to address any serious or concerning symptoms.

Drug Interactions

The following drug interactions have been identified for hydrochlorothiazide, categorized by interaction type and clinical significance.

Pharmacodynamic Interactions:

• Alcohol, Barbiturates, and Narcotics: Concurrent use 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. Close monitoring of blood glucose levels is recommended.

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

• Corticosteroids and ACTH: There is a risk of intensified electrolyte depletion, particularly hypokalemia. Electrolyte levels should be monitored, and supplementation may be required.

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

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

• Non-Steroidal Anti-Inflammatory Drugs (NSAIDs): NSAIDs may diminish 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 absorption by up to 85%, while colestipol can reduce it by 43%. It is advisable to separate the administration of hydrochlorothiazide and these resins by at least 2 hours.

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

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, to mitigate potential adverse effects.

Monitoring for signs of electrolyte imbalance is critical, as elderly patients are more susceptible to conditions such as hyponatremia and hypokalemia. The cumulative effects of hydrochlorothiazide may also develop in elderly patients with impaired renal function, warranting careful observation.

Additionally, there is an increased risk of orthostatic hypotension in elderly patients, particularly when the medication is used concurrently with other antihypertensive agents, alcohol, barbiturates, or narcotics. Therefore, periodic determination of serum electrolytes is essential in this demographic to detect and address possible electrolyte imbalances promptly.

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 pathologic causes or the physiological and mechanical changes associated with pregnancy.

Thiazide diuretics may be indicated in cases where edema is due to pathologic causes, similar to their use in non-pregnant patients. However, dependent edema, which occurs due to restricted venous return from 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 considered illogical and unnecessary.

During normal pregnancy, hypervolemia is a common physiological adaptation that is not harmful to the mother or fetus, provided there are no underlying cardiovascular issues. While hypervolemia may be associated with edema, it is typically localized and rarely leads to generalized edema. If edema causes discomfort, increased recumbency is often effective in providing relief. In rare cases where edema results in extreme discomfort that is unresponsive to rest, a short course of diuretic therapy may be appropriate.

Lactation

Thiazides are excreted in breast milk. Due to the potential for serious adverse reactions in nursing infants, lactating mothers should consider whether to discontinue breastfeeding or to discontinue hydrochlorothiazide, weighing the importance of the medication to the mother against the risks to the breastfed infant.

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, warranting dose adjustments and vigilant oversight to mitigate 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 important to monitor these patients closely for any signs of deterioration in liver function or fluid status. Adjustments to dosage may be necessary based on the severity of hepatic impairment and the patient's overall clinical condition. Regular assessment of liver function tests is recommended to ensure safe and effective use of thiazides in this population.

Overdosage

In cases of overdosage, the most frequently observed signs and symptoms are primarily associated with 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 two-year feeding studies conducted by the National Toxicology Program (NTP) in mice and rats, hydrochlorothiazide demonstrated 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. Nonetheless, the NTP did find equivocal evidence for hepatocarcinogenicity in male mice.

Hydrochlorothiazide was evaluated for genotoxicity and showed no genotoxic effects in vitro in the Ames mutagenicity assay using various strains of Salmonella typhimurium, nor in the Chinese Hamster Ovary (CHO) test for chromosomal aberrations. In vivo assessments using mouse germinal cell chromosomes, Chinese hamster bone marrow chromosomes, and the Drosophila sex-linked recessive lethal trait gene also yielded negative results. Positive results were observed 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.

Studies assessing the impact of hydrochlorothiazide on fertility indicated no adverse effects in mice and rats of either sex. These studies involved dietary exposure to doses of up to 100 mg/kg for mice and 4 mg/kg for rats, administered prior to conception and throughout gestation.

Postmarketing Experience

Adverse reactions reported in postmarketing experience include a range of events across multiple 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: Reports include pancreatitis, 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 documented.

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

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

Musculoskeletal: Muscle spasms have been noted.

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

Renal: Instances of renal failure, renal dysfunction, and interstitial nephritis have been documented.

Skin: Adverse skin reactions 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 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 arrhythmias 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.

Patients should be informed that thiazides may cause acute myopia and acute angle-closure glaucoma, with symptoms that include an acute onset of decreased visual acuity or ocular pain. If these symptoms occur, hydrochlorothiazide should be discontinued as rapidly as possible.

It is important to communicate to patients that thiazides cross the placental barrier and can appear in cord blood, posing a risk of fetal or neonatal jaundice, thrombocytopenia, and potentially 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, considering the importance of the medication to the mother.

Patients should be monitored for signs of electrolyte imbalance, especially during hot weather, and healthcare providers should initiate appropriate therapy as necessary. Additionally, patients should be informed that the antihypertensive effects of hydrochlorothiazide may be enhanced in post-sympathectomy patients.

Finally, patients should be advised to report any signs of hypersensitivity reactions, such as rash, fever, or respiratory distress, to their healthcare provider immediately.

Storage and Handling

The product is supplied in a tight, light-resistant container that complies with the United States Pharmacopeia (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. Proper storage conditions are essential to maintain the integrity and efficacy of the product.

Additional Clinical Information

Clinicians should conduct periodic determinations of serum electrolytes in patients to identify any potential electrolyte imbalances. This monitoring should occur 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 Aidarex Pharmaceuticals LLC. It includes detailed information about indications, dosage, contraindications, warnings, and clinical pharmacology.

View full prescribing information (PDF)