Usage
Hydroflumethiazide + Spironolactone is prescribed for the treatment of edema (fluid retention) associated with congestive heart failure, hepatic cirrhosis, and nephrotic syndrome. It is also used to treat essential hypertension (high blood pressure) and hypokalemia (low potassium levels in the blood) induced by diuretic therapy. It is classified as a combination diuretic. More specifically, it combines a thiazide diuretic (hydroflumethiazide) with a potassium-sparing diuretic (spironolactone).
The combined mechanism of action involves increasing the excretion of sodium and water while conserving potassium. Hydroflumethiazide inhibits sodium reabsorption in the distal convoluted tubule of the nephron, while spironolactone antagonizes the effects of aldosterone in the distal convoluted tubule and collecting duct, promoting sodium excretion and potassium retention.
Alternate Names
This combination is often referred to as a spironolactone/hydrochlorothiazide combination. It’s marketed under various brand names, including Aldactazide and Aldactide.
How It Works
Pharmacodynamics: Hydroflumethiazide increases the excretion of sodium, chloride, potassium, and water by inhibiting sodium reabsorption in the distal convoluted tubule. Spironolactone is a competitive aldosterone receptor antagonist in the distal convoluted tubule and collecting duct, increasing sodium and water excretion while minimizing potassium loss. The combination provides synergistic diuresis and antihypertensive effects while maintaining potassium balance.
Pharmacokinetics: Hydroflumethiazide is well-absorbed orally. Peak plasma concentrations occur within 1 to 2.5 hours. It is excreted primarily unchanged in the urine with a half-life of approximately 6-15 hours. Spironolactone undergoes extensive hepatic metabolism, with canrenone being the primary active metabolite. It exhibits a longer half-life than hydroflumethiazide, ranging from 1.2 to 1.6 hours for the parent compound and up to 16.5 hours for canrenone.
Mode of Action: Hydroflumethiazide inhibits sodium-chloride cotransporter in the distal tubule, decreasing sodium reabsorption. Spironolactone acts as a competitive inhibitor of aldosterone, binding to mineralocorticoid receptors and blocking aldosterone-mediated sodium retention and potassium excretion.
Elimination Pathways: Hydroflumethiazide is primarily excreted unchanged by the kidneys. Spironolactone is extensively metabolized by the liver, and its metabolites, including canrenone, are excreted in urine and bile.
Dosage
Standard Dosage
Adults:
The initial dose is typically 25/25 mg (spironolactone/hydroflumethiazide) once daily. The dose can be increased to 50/50 mg once daily, or up to a maximum of 200 mg/day of each component, as directed by the physician. For some conditions, a higher starting dose (e.g., 100/100 mg) might be prescribed.
Children:
Dosage in children must be determined by a doctor.
Special Cases:
- Elderly Patients: Initial dose is generally lower, at 25/25 mg daily, given potential for age-related decline in renal function.
- Patients with Renal Impairment: The medication may be contraindicated in patients with anuria, acute renal insufficiency, or significant impairment of renal function. Dosage needs careful monitoring, with adjustment for creatinine clearance (CrCl), or avoidance in severe renal disease.
- Patients with Hepatic Dysfunction: Contraindicated in acute or severe hepatic failure. Use with caution in mild to moderate hepatic impairment with careful monitoring of potassium levels.
- Patients with Comorbid Conditions: Patients with gout, diabetes, lupus, or sulfa allergies should be monitored closely. Those with hypercalcemia or hyperkalemia should not use this medication.
Clinical Use Cases
Dosage adjustments in clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, and emergency situations should be based on individual patient assessment, hemodynamic status, and electrolyte balance, prioritizing patient safety and clinical stability.
Dosage Adjustments
Dosage adjustments are based on factors like renal and hepatic function, electrolyte balance, and response to therapy. Genetic polymorphisms affecting drug metabolism should also be considered when available.
Side Effects
Common Side Effects:
Dizziness, lightheadedness, headache, nausea, vomiting, diarrhea, stomach cramps, loss of appetite, fatigue, erectile dysfunction, menstrual irregularities, breast tenderness or enlargement, and rash.
Rare but Serious Side Effects:
Electrolyte imbalances (hyperkalemia, hyponatremia, hypokalemia), dehydration, hypotension, kidney dysfunction, liver dysfunction, pancreatitis, gynecomastia, allergic reactions, and blood disorders.
Long-Term Effects:
Gynecomastia in some men, and electrolyte imbalances with prolonged use.
Adverse Drug Reactions (ADR):
Severe hyperkalemia, anaphylactic shock, acute renal failure, hepatic coma, and blood dyscrasias are examples of ADRs requiring immediate attention.
Contraindications
Anuria, acute renal insufficiency, significant renal impairment, hyperkalemia, hypercalcemia, Addison’s disease, hypersensitivity to thiazides or sulfonamide-derived drugs, severe hepatic dysfunction, concomitant use of eplerenone, and pregnancy or breastfeeding.
Drug Interactions
This combination can interact with numerous medications, including: other diuretics, ACE inhibitors, ARBs, NSAIDs, potassium supplements, digoxin, lithium, corticosteroids, some antibiotics (e.g., aminoglycosides), and certain antihypertensive drugs. It may also interact with alcohol, barbiturates, and narcotics, potentially exacerbating orthostatic hypotension. CYP450 interactions are possible and should be evaluated. Grapefruit juice may also interact with this medication.
Pregnancy and Breastfeeding
Contraindicated in both pregnancy and breastfeeding due to potential fetal harm and excretion in breast milk.
Drug Profile Summary
- Mechanism of Action: Inhibits sodium reabsorption and antagonizes aldosterone.
- Side Effects: Dizziness, headache, nausea, hyperkalemia, gynecomastia.
- Contraindications: Anuria, hyperkalemia, Addison’s disease, pregnancy.
- Drug Interactions: ACE inhibitors, ARBs, potassium supplements, digoxin, lithium.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: Initial 25/25 mg daily, adjustable up to 200/200 mg.
- Monitoring Parameters: Serum electrolytes (especially potassium), renal function, blood pressure.
Popular Combinations
Often used with other antihypertensives, but requires careful monitoring for additive effects and potential for drug interactions.
Precautions
- General Precautions: Closely monitor potassium levels and renal function, especially in elderly patients or those with pre-existing conditions. Monitor for signs of dehydration.
- Specific Populations: Use with caution in the elderly and those with renal or hepatic impairment. Avoid use in pregnancy and breastfeeding.
- Lifestyle Considerations: Limit alcohol intake and be cautious when driving or operating machinery due to potential dizziness or hypotension.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Hydroflumethiazide + Spironolactone?
A: The initial recommended dose for adults is typically 25/25 mg once daily, adjustable according to clinical response and tolerability, up to a maximum of 200/200 mg daily. Pediatric dosages must be determined by a physician.
Q2: What are the primary uses of this combination medication?
A: Treatment of edema associated with heart failure, liver cirrhosis, or nephrotic syndrome, as well as essential hypertension and diuretic-induced hypokalemia.
Q3: What are the most common side effects?
A: Dizziness, lightheadedness, headache, gastrointestinal upset, and fatigue.
Q4: What are the serious side effects to watch for?
A: Hyperkalemia, hyponatremia, acute renal failure, hepatic coma, and hypersensitivity reactions.
Q5: When is this medication contraindicated?
A: In anuria, acute renal insufficiency, severe renal impairment, hyperkalemia, Addison’s disease, pregnancy, and hypersensitivity to thiazides or sulfonamides.
Q6: What are the key drug interactions?
A: ACE inhibitors, ARBs, potassium supplements, digoxin, lithium, NSAIDs, and certain antibiotics.
Q7: Can this medication be used during pregnancy or breastfeeding?
A: No, it is contraindicated.
Q8: What monitoring parameters are important?
A: Serum potassium, renal function tests, and blood pressure.
Q9: What precautions are necessary for elderly patients?
A: Initiate therapy at a low dose and monitor closely for electrolyte imbalances and renal function changes.
Q10: How does this combination medication affect potassium levels?
A: Hydroflumethiazide lowers potassium, whereas spironolactone conserves it, theoretically balancing the effect; however, hyperkalemia remains a risk and monitoring is crucial.
