Usage
Metolazone, in combination with spironolactone, is primarily prescribed for the treatment of edema and ascites resistant to other diuretic therapies, particularly in patients with conditions like congestive heart failure, cirrhosis, and nephrotic syndrome. Metolazone is classified as a thiazide-like diuretic, while spironolactone is a potassium-sparing diuretic and an aldosterone antagonist. The combination works synergistically to enhance diuresis while mitigating the risk of hypokalemia often associated with metolazone.
Alternate Names
Metolazone: Zaroxolyn, Mykrox
Spironolactone: Aldactone, CaroSpir
How It Works
Metolazone: Primarily inhibits sodium reabsorption in the distal convoluted tubule of the nephron, increasing sodium and chloride excretion. It also has a weaker effect on sodium reabsorption in the proximal convoluted tubule. This leads to increased water excretion and a reduction in blood volume, ultimately lowering blood pressure.
Spironolactone: Acts as a competitive antagonist of aldosterone, a hormone that promotes sodium retention and potassium excretion. By blocking aldosterone’s effects in the distal nephron, spironolactone promotes sodium and water excretion while conserving potassium. It also has mild anti-androgenic properties.
Pharmacokinetics:
- Metolazone: Well-absorbed orally, with peak plasma concentrations reached in 1 to 2 hours. It is primarily excreted unchanged in the urine.
- Spironolactone: Rapidly and extensively metabolized in the liver to active metabolites, including canrenone, which contribute to its diuretic effect. These metabolites are primarily excreted in the urine, with some biliary excretion.
Drug Interactions: Both drugs can interact with numerous medications, including NSAIDs, ACE inhibitors, ARBs, digoxin, and other potassium-altering drugs. Concurrent use with potassium supplements or potassium-sparing diuretics can lead to hyperkalemia.
Dosage
Standard Dosage
Adults:
- Metolazone: Initial dose is typically 2.5 to 5 mg orally once daily for edema. For hypertension, the starting dose is 2.5-5 mg once daily, which can be increased to 20 mg once daily as needed.
- Spironolactone: Dosages vary depending on the indication, typically ranging from 25 mg to 200 mg per day, often in divided doses. For heart failure, the initial dose is usually 25 mg once daily, titrated up as needed. For ascites, the starting dose may be higher (100-400 mg/day).
Children: Metolazone is not recommended for use in children under 18. Spironolactone pediatric dosing should be determined based on the child’s weight and the specific condition being treated. Pediatric use should be under careful medical supervision due to the risk of electrolyte imbalances.
Special Cases:
- Elderly Patients: Dose adjustments, especially for metolazone, may be necessary due to age-related decline in renal function. Close monitoring of electrolytes is crucial.
- Patients with Renal Impairment: No dose adjustment is typically required for metolazone in patients with renal impairment. For spironolactone, dosage adjustments may be needed, particularly in severe renal impairment.
- Patients with Hepatic Dysfunction: No dose adjustment is typically necessary for metolazone in patients with hepatic impairment. For spironolactone, close monitoring is recommended, as its metabolism is primarily hepatic.
- Patients with Comorbid Conditions: Careful consideration is needed in patients with diabetes, gout, and systemic lupus erythematosus, as these conditions can be exacerbated by metolazone.
Clinical Use Cases
The combination is primarily used for resistant edema and ascites, typically in the context of heart failure, cirrhosis, or nephrotic syndrome. Dosing is adjusted based on the severity of fluid overload and the patient’s response to therapy. It is not typically used for intubation, surgical procedures, mechanical ventilation, or emergency situations. In the ICU, this combination might be employed for managing fluid overload refractory to other diuretics.
Dosage Adjustments
Dose adjustments are made based on patient-specific factors, including renal function, hepatic function, electrolyte levels, and concomitant medications. Close monitoring of potassium levels is essential, especially in patients with renal impairment or those taking other potassium-altering drugs.
Side Effects
Common Side Effects
- Metolazone: Dizziness, lightheadedness, headache, nausea, weakness, loss of appetite, constipation, and elevated uric acid levels.
- Spironolactone: Gynecomastia, menstrual irregularities, decreased libido, and hyperkalemia.
Rare but Serious Side Effects
- Metolazone: Severe allergic reactions, electrolyte imbalances (hypokalemia, hyponatremia), and liver dysfunction.
- Spironolactone: Severe hyperkalemia, which can be life-threatening.
Long-Term Effects
Long-term use of either drug can lead to chronic electrolyte imbalances if not carefully monitored. Spironolactone’s anti-androgenic effects can cause sexual dysfunction in men with prolonged use.
Adverse Drug Reactions (ADR)
Clinically significant ADRs requiring immediate intervention include severe allergic reactions, severe electrolyte imbalances, and acute kidney injury.
Contraindications
- Metolazone: Anuria, hepatic coma, and hypersensitivity to metolazone or sulfonamides.
- Spironolactone: Anuria, acute renal insufficiency, significant hyperkalemia, Addison’s disease, and concomitant use of eplerenone.
Drug Interactions
Both metolazone and spironolactone interact with various medications, including NSAIDs, ACE inhibitors, ARBs, digoxin, lithium, and potassium supplements. Concurrent use with potassium-sparing diuretics can exacerbate the risk of hyperkalemia. Metolazone can potentiate the effects of other antihypertensives.
Pregnancy and Breastfeeding
- Metolazone: Category B; should only be used during pregnancy if the potential benefit outweighs the risk. Can be excreted in breast milk and may harm a nursing infant.
- Spironolactone: Category C; should be avoided during pregnancy due to potential anti-androgenic effects on the developing fetus. Metabolites can be excreted in breast milk.
Drug Profile Summary
- Mechanism of Action: Metolazone inhibits sodium reabsorption; spironolactone antagonizes aldosterone.
- Side Effects: Dizziness, headache, nausea, gynecomastia, hyperkalemia.
- Contraindications: Anuria, hyperkalemia, Addison’s disease.
- Drug Interactions: NSAIDs, ACE inhibitors, ARBs, digoxin, potassium supplements.
- Pregnancy & Breastfeeding: Use with caution if benefits outweigh risks.
- Dosage: Metolazone 2.5-20 mg/day; spironolactone 25-400 mg/day (varies by indication).
- Monitoring Parameters: Serum electrolytes (especially potassium), renal function, blood pressure.
Popular Combinations
Metolazone and spironolactone are often combined with loop diuretics like furosemide for enhanced diuresis in resistant edema.
Precautions
- General Precautions: Monitor electrolytes, renal function, and blood pressure.
- Specific Populations: Careful dosing and monitoring in elderly patients and those with hepatic or renal impairment.
- Pregnant Women: Avoid spironolactone. Metolazone only if benefit outweighs risk.
- Breastfeeding Mothers: Not recommended.
- Children & Elderly: Metolazone not recommended for children. Careful dosing in the elderly.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Metolazone + Spironolactone?
A: Dosages are individualized and based on indication, patient response, and renal/hepatic function. Usual starting doses: metolazone 2.5-5 mg/day; spironolactone 25-100 mg/day.
Q2: What are the key monitoring parameters for this combination?
A: Serum electrolytes (especially potassium), blood pressure, and renal function.
Q3: How does the combination of these drugs affect potassium levels?
A: Metolazone can cause hypokalemia, while spironolactone conserves potassium, mitigating this risk. Close monitoring is still necessary.
Q4: What are the contraindications for using this drug combination?
A: Anuria, severe hyperkalemia, Addison’s disease, and hypersensitivity to either drug.
Q5: Can this combination be used in patients with renal impairment?
A: Metolazone requires no dosage adjustment in renal impairment. Spironolactone dose may need to be reduced. Closely monitor potassium levels.
Q6: What are the potential drug interactions to be aware of?
A: NSAIDs, ACE inhibitors, ARBs, digoxin, potassium supplements, and other potassium-sparing diuretics.
Q7: Can this combination be used during pregnancy or breastfeeding?
A: Spironolactone should generally be avoided during pregnancy. Metolazone only if the potential benefit outweighs the risk. Both drugs are excreted in breast milk and generally not recommended during breastfeeding.
Q8: What are the common side effects patients should be aware of?
A: Dizziness, headache, nausea, gynecomastia (spironolactone), and potential electrolyte imbalances.
Q9: How does this combination work synergistically to treat edema?
A: Metolazone increases sodium and water excretion, while spironolactone prevents potassium loss and enhances diuresis by blocking aldosterone.
Q10: What are the long-term potential side effects of this combination?
A: Chronic electrolyte imbalances if not monitored carefully. Spironolactone may cause sexual dysfunction in men with prolonged use.
