Usage
Metolazone is prescribed for the treatment of:
- Hypertension (High Blood Pressure): It helps lower blood pressure, reducing the risk of complications like stroke, heart attack, and kidney problems.
- Edema (Fluid Retention): It reduces fluid buildup in the body caused by conditions like congestive heart failure, kidney disease (including nephrotic syndrome), and liver cirrhosis. It aids in symptom relief, particularly breathing difficulties associated with fluid overload.
Pharmacological Classification: Metolazone is classified as a thiazide-like diuretic or “water pill.” It’s structurally different from thiazides but shares a similar mechanism.
Mechanism of Action: Metolazone inhibits sodium and chloride reabsorption in the distal convoluted tubule of the nephron in the kidneys. This leads to increased excretion of water and these electrolytes, reducing blood volume and, consequently, blood pressure. It also has a mild vasodilatory effect.
Alternate Names
- Generic Name: Metolazone
- Brand Name: Zaroxolyn, Mykrox (discontinued in the US)
How It Works
Pharmacodynamics: Metolazone’s primary effect is to reduce blood volume through diuresis. This lowers blood pressure and reduces edema. It also increases potassium excretion, potentially leading to hypokalemia.
Pharmacokinetics:
- Absorption: Metolazone is well-absorbed orally. Food may delay absorption but not the extent of absorption for the non-micronized form (Zaroxolyn). The micronized formulation (Mykrox, discontinued in the US) is absorbed much more rapidly. It’s important not to interchange different formulations due to differences in bioavailability.
- Distribution: It is highly protein-bound in plasma (approximately 95%).
- Metabolism: Undergoes enterohepatic recirculation. Affects the expression and activity of certain metabolic enzymes, specifically CYP3A4.
- Elimination: Primarily excreted unchanged in the urine with an elimination half-life of 6-8 hours.
Mode of Action: Metolazone acts on the sodium-chloride cotransporter (NCC) in the distal convoluted tubule, inhibiting its function. This prevents sodium and chloride from being reabsorbed back into the bloodstream, promoting their excretion along with water.
Receptor Binding, Enzyme Inhibition or Neurotransmitter Modulation: The main action is through NCC inhibition. There is also evidence it modulates CYP3A4 activity, influencing the metabolism of other drugs metabolized by this enzyme.
Elimination Pathways: Primarily eliminated through renal excretion with minimal hepatic metabolism.
Dosage
Standard Dosage
Adults:
- Edema: The usual initial dose is 5-20 mg once daily, adjusted as needed based on the patient’s response.
- Hypertension: Initial dose is 2.5-5 mg daily or 1.25mg once daily. Some sources recommend an initial 0.5mg dose for the rapidly bioavailable formulation that can be increased to 1mg if needed. Maintenance dose is 5mg on alternate days (every other day) according to one source or 2.5mg daily for geriatric patients. This can be increased up to 20 mg daily as per clinical response.
Children:
- Safety and efficacy have not been fully established. Off-label use has been reported for edema and hypertension. For edema, 0.2-0.4mg/kg/day given once or twice daily. Maximum dose: 10mg BID. For hypertension, 2.5-5mg PO qDay. Dosage must be determined by a physician and closely monitored.
Special Cases:
- Elderly Patients: Lower initial doses are recommended due to potential for decreased renal function. Close monitoring is essential. Start with 2.5 mg PO every day or every other day for edema.
- Patients with Renal Impairment: No dose adjustment is usually needed, even for those on dialysis, but careful monitoring of renal function is important.
- Patients with Hepatic Dysfunction: No specific dose adjustment is recommended, but caution is advised in advanced liver failure.
- Patients with Comorbid Conditions: Metolazone can exacerbate conditions like gout, diabetes, and systemic lupus erythematosus (SLE). Close monitoring is necessary. For patients with diabetes, monitor blood glucose closely as metolazone can cause hyperglycemia.
Clinical Use Cases
Metolazone’s clinical use is primarily focused on managing fluid overload (edema) and hypertension. Its use in acute settings like intubation, surgical procedures, mechanical ventilation, or the ICU would be rare and typically only for managing fluid status or resistant hypertension. It is not a first-line agent for emergency situations such as cardiac arrest or status epilepticus.
Dosage Adjustments
Dosage adjustments are based on patient response and the presence of renal or hepatic impairment, comorbid conditions, and potential drug interactions.
Side Effects
Common Side Effects:
- Dizziness, lightheadedness
- Dry mouth
- Constipation, diarrhea
- Headache
- Blurred vision
- Nausea
Rare but Serious Side Effects:
- Electrolyte imbalances (hypokalemia, hyponatremia, hypochloremia, hypomagnesemia, hypercalcemia)
- Severe allergic reactions (rash, hives, swelling, difficulty breathing)
- Liver problems (jaundice, abdominal pain, fatigue)
- Pancreatitis
- Blood disorders (thrombocytopenia, agranulocytosis)
Long-Term Effects:
- Gout exacerbation
- Hyperglycemia
- Worsening of SLE
Adverse Drug Reactions (ADR):
Any severe manifestation of the above-listed side effects necessitates immediate medical intervention.
Contraindications
- Anuria (inability to produce urine)
- Hepatic coma or pre-coma
- Hypersensitivity to metolazone or sulfonamides
Drug Interactions
Metolazone interacts with numerous medications, including:
- Other antihypertensives (additive effects)
- Digoxin (increased risk of digoxin toxicity)
- Lithium (increased lithium levels)
- NSAIDs (reduced diuretic effect, increased risk of renal impairment)
- Corticosteroids (increased risk of hypokalemia)
- Diabetes medications (altered blood sugar control)
- Warfarin (altered anticoagulant effect)
- CYP3A4 inhibitors or inducers (affect metolazone metabolism)
- Alcohol (additive hypotensive effect)
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Formerly Category B; current FDA classification is unclear. Use during pregnancy should be avoided unless the potential benefit justifies the risk to the fetus. Metolazone can cross the placenta and may cause fetal harm.
- Breastfeeding: Metolazone is excreted in breast milk and may cause side effects in the nursing infant. Breastfeeding is not recommended while taking this drug.
Drug Profile Summary
- Mechanism of Action: Inhibits sodium and chloride reabsorption in the distal convoluted tubule, leading to increased excretion of water and electrolytes.
- Side Effects: Dizziness, dry mouth, constipation, electrolyte imbalances, allergic reactions.
- Contraindications: Anuria, hepatic coma, sulfonamide hypersensitivity.
- Drug Interactions: Numerous interactions, including other antihypertensives, digoxin, lithium, NSAIDs.
- Pregnancy & Breastfeeding: Use with caution; potential for fetal/neonatal harm.
- Dosage: Edema: 5-20 mg/day; Hypertension: 2.5-5 mg/day. Dose adjustments based on various factors including patient responses and age.
- Monitoring Parameters: Blood pressure, electrolytes (especially potassium, sodium, chloride), renal function, blood glucose, uric acid.
Popular Combinations
Metolazone is sometimes used in combination with loop diuretics like furosemide in patients with resistant edema. The combination enhances diuresis by blocking sodium reabsorption at multiple sites in the nephron.
Precautions
- General Precautions: Monitor for electrolyte imbalances, dehydration, and changes in renal function. Careful assessment is needed in patients with pre-existing medical conditions such as renal/hepatic dysfunction, diabetes, gout, or SLE.
- Specific Populations: Monitor pregnant women for volume depletion to ensure adequate placental perfusion. Avoid use during breastfeeding due to excretion in breast milk. Start with lower doses in children and the elderly and monitor closely.
- Lifestyle Considerations: Advise patients to avoid alcohol, stay hydrated, and be cautious about activities requiring alertness due to potential dizziness.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Metolazone?
A: The recommended dosage for adults varies depending on the condition being treated. For edema, it is typically 5-20 mg once daily. For hypertension, the initial dose is 2.5-5 mg once daily, with titration to 20mg if required. Pediatric and geriatric dosages should be determined by the physician and require careful monitoring.
Q2: What are the common side effects of Metolazone?
A: Common side effects include dizziness, lightheadedness, dry mouth, constipation or diarrhea, headache, and blurred vision.
Q3: What are the serious side effects of Metolazone?
A: Serious side effects can include severe electrolyte imbalances (hypokalemia, hyponatremia), liver problems, pancreatitis, blood disorders, and allergic reactions.
Q4: Can Metolazone be used during pregnancy or breastfeeding?
A: Metolazone should be used cautiously during pregnancy and only if the potential benefit outweighs the risk to the fetus. It’s recommended to avoid Metolazone during breastfeeding as it can pass into breast milk.
Q5: What are the contraindications to using Metolazone?
A: Contraindications include anuria, hepatic coma, and hypersensitivity to metolazone or sulfonamides.
Q6: How does Metolazone interact with other medications?
A: Metolazone can interact with numerous drugs including other antihypertensives, digoxin, lithium, NSAIDs, corticosteroids, and diabetes medications. Always check for potential interactions before prescribing Metolazone.
Q7: What should I monitor in a patient taking Metolazone?
A: Monitor blood pressure, electrolytes (especially potassium, sodium), kidney function, blood glucose, and uric acid levels.
A: No, do not interchange formulations like Zaroxolyn and Mykrox (or its bioequivalent) without careful dose adjustment by a physician. Mykrox is absorbed much more rapidly than other formulations.
Q9: What are the signs of Metolazone overdose?
A: Overdose can manifest as orthostatic hypotension, dizziness, drowsiness, syncope, and severe electrolyte imbalances.
Q10: What is the mechanism of action of Metolazone?
A: Metolazone inhibits the reabsorption of sodium and chloride in the distal convoluted tubules of the kidneys, leading to increased diuresis and subsequent lowering of blood pressure.
