Bendroflumethiazide

Bendroflumethiazide (also known as bendrofluazide) is a thiazide diuretic primarily used in the treatment of hypertension and fluid retention (edema) associated with congestive heart failure, liver cirrhosis, or nephrotic syndrome. It promotes renal excretion of sodium and water, thereby reducing blood pressure and volume overload. It is often preferred in low doses for blood pressure management due to its favorable effect on cardiovascular outcomes.

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Brand Names

Bendroflumethiazide is available under several brand names globally, including:

• Aprinox

• Aprinoxide

• Corzide (in combination with nadolol)

• Normoretic (in combination with potassium-sparing agents)

• Bendrofluazide (generic name used in UK and EU)

• Durigeric

• Bendroside

It is typically available in:

• 2.5 mg tablets (most common for hypertension)

• 5 mg tablets (used less frequently due to higher risk of side effects)

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Mechanism of Action

Bendroflumethiazide acts on the distal convoluted tubule of the nephron by:

• Inhibiting the sodium-chloride symporter (Na⁺/Cl⁻ cotransporter), leading to:

  • Increased excretion of sodium (natriuresis) and chloride

  • Secondary water loss (diuresis)

  • Mild potassium loss due to enhanced sodium delivery to the distal nephron (→ increased Na⁺/K⁺ exchange)

Additional vascular actions:

• Reduces peripheral vascular resistance through direct vasodilatory effects.

• Long-term antihypertensive effect is more associated with vasodilation than diuresis.

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Therapeutic Uses

Bendroflumethiazide is indicated for the following:

Primary Indications:

• Essential (primary) hypertension – often first-line or as add-on therapy

• Edema due to:

  • Congestive heart failure

  • Hepatic cirrhosis with ascites

  • Nephrotic syndrome

  • Premenstrual fluid retention

Off-label/Secondary Uses:

• Hypercalciuria: Reduces urinary calcium excretion

• Calcium-based kidney stones: Prevents recurrent nephrolithiasis

• Mild diabetes insipidus: Paradoxically reduces polyuria

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Dosage and Administration

For Hypertension:

• 2.5 mg orally once daily in the morning

• If no adequate response, other agents are preferred over increasing the dose (to avoid side effects)

For Edema:

• 2.5 mg to 10 mg once daily (short-term)

• Minimum effective dose should be used

• Often combined with loop diuretics for resistant edema

Administration Notes:

• Take in the morning to avoid nocturia

• Ensure adequate hydration

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Contraindications

• Severe renal failure (eGFR <30 mL/min/1.73m²)

• Refractory hypokalemia or hyponatremia

• Anuria

• Hypersensitivity to sulfonamides or thiazides

• Addison’s disease (risk of exacerbating hyponatremia and volume depletion)

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Precautions

Use with caution in:

• Diabetics: May worsen glycemic control

• Gout patients: Can increase serum uric acid levels

• Elderly: More susceptible to electrolyte disturbances and orthostatic hypotension

• Liver disease: Risk of hepatic encephalopathy due to hypokalemia

• Renal impairment: May reduce efficacy and increase toxicity

Monitor:

• Serum electrolytes (K⁺, Na⁺, Mg²⁺)

• Renal function (creatinine, eGFR)

• Uric acid

• Blood glucose

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Side Effects

Common:

• Hypokalemia

• Hyponatremia

• Hyperuricemia → gout

• Hypercalcemia

• Hyperglycemia

• Dizziness or postural hypotension

• Mild dehydration

• Polyuria initially

Less Common:

• Erectile dysfunction

• Photosensitivity

• Rash or urticaria

• Fatigue

Rare/Serious:

• Arrhythmias (due to electrolyte imbalances)

• Pancreatitis

• Thrombocytopenia, agranulocytosis

• Interstitial nephritis

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Drug Interactions

Drugs that Increase Toxicity:

• ACE inhibitors / ARBs: Additive risk of hyperkalemia or hypotension, especially in volume-depleted patients

• NSAIDs: May reduce antihypertensive effect and increase nephrotoxicity

• Lithium: Reduced clearance, risk of lithium toxicity

• Digoxin: Enhanced risk of digoxin toxicity if hypokalemia present

• Corticosteroids: Increased risk of hypokalemia

• Antidiabetics: Reduced efficacy due to hyperglycemic effect of thiazides

Drugs with Additive Hypotensive Effects:

• Beta-blockers, CCBs, alpha-blockers

• Alcohol

• Tricyclic antidepressants

Other interactions:

• Cholestyramine / colestipol: May reduce absorption of bendroflumethiazide; separate by 4–6 hours

• Amphotericin B: Additive nephrotoxic and electrolyte-wasting effect

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Use in Special Populations

Pregnancy:

• Not recommended for routine use

• May cause placental hypoperfusion and neonatal electrolyte disturbances

• Considered Category C (US)

Breastfeeding:

• Excreted in breast milk; may suppress lactation

• Generally not recommended

Pediatrics:

• Not routinely used; specialist guidance required

Geriatrics:

• Commonly prescribed; however, close monitoring of electrolytes and renal function essential

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Pharmacokinetics

• Absorption: Well absorbed orally

• Onset: Within 1–2 hours

• Peak effect: 4–6 hours

• Duration of action: 12–24 hours

• Plasma half-life: ~3–6 hours

• Protein binding: ~95%

• Metabolism: Minimal hepatic metabolism

• Excretion: Renal (primarily unchanged)

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Comparison with Other Diuretics

Feature	Bendroflumethiazide	Hydrochlorothiazide	Indapamide	Furosemide
Class	Thiazide	Thiazide	Thiazide-like	Loop
Duration of action	12–24 h	6–12 h	24–36 h	6–8 h
Main indication	Hypertension	Hypertension	Hypertension	Edema
Hypokalemia risk	Moderate	Moderate	Lower	High
Metabolic side effects	Yes	Yes	Less pronounced	Yes

Clinical Guidelines Support

NICE (UK) & ESC Guidelines:

• First-line or second-line antihypertensive in older adults (particularly >55 years or Black patients)

• Low-dose bendroflumethiazide (2.5 mg) is recommended; higher doses discouraged due to metabolic complications

JNC 8 / ACC/AHA (US):

• Thiazide-type diuretics are preferred initial therapy for hypertension in many patients, although hydrochlorothiazide or chlorthalidone is more commonly used in the US

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Patient Counseling Points

• Take in the morning to avoid nighttime urination

• Avoid alcohol initially, as it can worsen postural hypotension

• Hydrate adequately, especially during warm weather or illness

• May need potassium-rich diet (bananas, spinach) or potassium supplements

• Regular blood tests for electrolytes, renal function, and blood pressure monitoring are essential

• Inform your healthcare provider of any:

  • Muscle cramps

  • Palpitations

  • Persistent fatigue

  • Gout symptoms

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Storage

• Store at room temperature (15–25°C)

• Protect from light and moisture

• Keep out of reach of children