Hydroflumethiazide

Usage

Hydroflumethiazide is primarily prescribed for the treatment of hypertension (high blood pressure) and edema (fluid retention) associated with various conditions, including congestive heart failure, hepatic cirrhosis, and corticosteroid or estrogen therapy. It belongs to the thiazide class of diuretics, meaning it increases urine production. Hydroflumethiazide inhibits sodium and chloride reabsorption in the distal convoluted tubule of the nephron, leading to increased excretion of water and these electrolytes.

Alternate Names

Hydroflumethiazide is also known by various brand names, including Saluron and Diucardin.

How It Works

Pharmacodynamics: Hydroflumethiazide primarily acts on the distal convoluted tubule in the kidneys, where it inhibits the sodium-chloride symporter (SLC12A3). This action reduces sodium reabsorption, leading to increased excretion of sodium, chloride, and water. It also increases renal excretion of potassium and magnesium, while enhancing calcium reabsorption. The resulting decrease in blood volume contributes to its antihypertensive effect.

Pharmacokinetics:

• Absorption: Hydroflumethiazide is rapidly but incompletely absorbed from the gastrointestinal tract. Peak plasma concentrations are achieved in approximately 1–4 hours.

• Metabolism: Limited information is available about hydroflumethiazide’s specific metabolism. It is primarily excreted unchanged.

• Elimination: Hydroflumethiazide is predominantly excreted via the kidneys (40-80% as unchanged drug). Elimination half-life ranges from 12.4 to 26.9 hours.

Dosage

Standard Dosage

Adults:

• Hypertension: Initial dose is typically 25-50 mg once daily. The maintenance dose can range from 25-100 mg daily. Doses exceeding 100 mg should be divided into two administrations. Maximum daily dose is 200 mg.
• Edema: The initial dose is usually 50-200 mg daily, often given in two divided doses. The maintenance dose can range from 25 to 100 mg per day or on alternate days, depending on the clinical response.

Children:

A suggested starting dose for children is 1 mg/kg/day, which can be lowered for maintenance therapy. Safety and effectiveness in children have not been conclusively established.

Special Cases:

• Elderly Patients: A lower starting dose and careful dose titration is advisable.
• Patients with Renal Impairment: Hydroflumethiazide is contraindicated in patients with anuria. In patients with severe renal impairment (CrCl < 25 mL/min), it is generally not recommended. Dose reduction may be necessary in mild to moderate renal insufficiency.
• Patients with Hepatic Dysfunction: Use with caution due to the risk of precipitating hepatic coma. Dose adjustment might be required.
• Patients with Comorbid Conditions: Close monitoring is essential in patients with diabetes mellitus, gout, or systemic lupus erythematosus (SLE), as hydroflumethiazide may exacerbate these conditions.

Clinical Use Cases

Hydroflumethiazide is not typically used in clinical settings such as intubation, surgical procedures, mechanical ventilation, or intensive care. It’s primarily indicated for chronic management of hypertension and edema rather than acute situations.

Side Effects

Common Side Effects:

Low blood pressure (hypotension), dizziness, lightheadedness, dehydration, electrolyte imbalances (hypokalemia, hyponatremia), elevated blood sugar levels, elevated uric acid levels, and gastrointestinal disturbances like nausea, vomiting, diarrhea, constipation.

Rare but Serious Side Effects:

Severe allergic reactions, pancreatitis, jaundice (cholestatic jaundice), blood disorders (leukopenia, agranulocytosis, thrombocytopenia, aplastic anemia), skin reactions (photosensitivity, rash, urticaria, necrotizing angiitis), and impaired glucose tolerance.

Long-Term Effects

Electrolyte disturbances, particularly hypokalemia and hyponatremia. Metabolic changes like increased blood glucose and uric acid levels may also be observed with chronic use.

Adverse Drug Reactions (ADR)

Severe hypersensitivity reactions, Stevens-Johnson syndrome, toxic epidermal necrolysis. Severe electrolyte disturbances such as marked hypokalemia, hyponatremia.

Contraindications

Anuria, hypersensitivity to hydroflumethiazide or other sulfonamide-derived drugs. Severe renal or hepatic impairment.

Drug Interactions

Other antihypertensive medications (additive hypotensive effect), NSAIDs (reduced diuretic and antihypertensive effect), corticosteroids (increased risk of hypokalemia), digoxin (increased risk of digoxin toxicity due to hypokalemia), lithium (increased risk of lithium toxicity), and diabetes medications (may necessitate dose adjustment).

Pregnancy and Breastfeeding

Pregnancy Category C. Hydroflumethiazide crosses the placenta and may pose risks to the fetus, including electrolyte imbalances and thrombocytopenia. Its use during pregnancy should be limited to situations where the potential benefits outweigh the risks. Hydroflumethiazide passes into breast milk; other diuretics are generally preferred during breastfeeding.

Drug Profile Summary

• Mechanism of Action: Inhibits sodium-chloride symporter in the distal convoluted tubule, leading to increased excretion of sodium, chloride, and water, reducing blood volume and blood pressure.

• Side Effects: Hypotension, electrolyte imbalances, elevated blood sugar, gastrointestinal upset. Rarely: blood disorders, pancreatitis, allergic reactions.

• Contraindications: Anuria, hypersensitivity to sulfonamides, severe renal or hepatic impairment.

• Drug Interactions: Other antihypertensives, NSAIDs, corticosteroids, digoxin, lithium, diabetes medications.

• Pregnancy & Breastfeeding: Category C; use with caution. Not recommended during breastfeeding.

• Dosage: Hypertension: 25-100 mg/day. Edema: 25-200 mg/day.

• Monitoring Parameters: Blood pressure, electrolytes (sodium, potassium, chloride, calcium, magnesium), blood glucose, uric acid, renal function tests.

Popular Combinations

Hydroflumethiazide is often combined with other antihypertensive agents, such as ACE inhibitors, angiotensin receptor blockers, or beta-blockers, to achieve better blood pressure control.

Precautions

Assess renal function and electrolyte status before initiating therapy. Monitor blood pressure, blood glucose, and uric acid levels regularly. Caution in patients with liver disease, diabetes, gout, or SLE. Avoid excessive sun exposure.

FAQs

Q1: What is the recommended dosage for Hydroflumethiazide?

A: For hypertension in adults, the usual initial dose is 25-50 mg once daily, with a maintenance dose of 25-100 mg/day. For edema, the initial dose is 50-200 mg daily, adjustable to 25-100 mg/day for maintenance. Pediatric dosage starts at 1 mg/kg/day.

Q2: What are the primary side effects of Hydroflumethiazide?

A: Common side effects include low blood pressure, electrolyte imbalances (especially low potassium), increased blood sugar, increased uric acid levels, and gastrointestinal disturbances (nausea, vomiting, diarrhea).

Q3: What are the contraindications to Hydroflumethiazide use?

A: Anuria (lack of urine output), known hypersensitivity to hydroflumethiazide or sulfonamide-derived drugs, and severe renal or hepatic impairment.

Q4: How does Hydroflumethiazide interact with other medications?

A: It interacts with other antihypertensives (additive effects), NSAIDs (reduced efficacy), corticosteroids, digoxin, lithium, and antidiabetic agents. These interactions necessitate close monitoring.

Q5: Can Hydroflumethiazide be used during pregnancy or breastfeeding?

A: It’s classified as Pregnancy Category C, indicating potential fetal risk. Use only if benefits clearly outweigh risks. It is excreted in breast milk; alternate diuretics are preferred for breastfeeding mothers.

Q6: What monitoring parameters should be checked during Hydroflumethiazide therapy?

A: Monitor blood pressure, serum electrolytes (potassium, sodium, chloride), blood glucose, uric acid levels, and renal function tests.

Q7: What are the signs of Hydroflumethiazide overdose?

A: Excessive diuresis, lethargy, coma, gastrointestinal disturbances, and electrolyte imbalances.

Q8: What are the long-term effects of Hydroflumethiazide?

A: Potential long-term effects include persistent electrolyte imbalances, elevated blood glucose, and increased uric acid levels. Regular monitoring can help mitigate these risks.

Q9: Is Hydroflumethiazide safe for patients with diabetes?

A: It should be used with caution in diabetics as it may increase blood glucose levels. Careful monitoring and possible adjustments to antidiabetic medications are essential.

Q10: How does Hydroflumethiazide affect patients with renal impairment?

A: Dose adjustments are crucial for patients with renal impairment, as the drug is primarily excreted through the kidneys. It is contraindicated in anuria and generally avoided in severe renal impairment.