metolazone
Diulo, Mykrox, Zaroxolyn

Available forms
Available by prescription only
Tablets: 2.5 mg, 5 mg, 10 mg
Tablets (rapid-acting): 0.5 mg (Mykrox)

Indications and dosages
 Edema (heart failure). Regular tablets. Adults: 5 to 20 mg P.O. daily. Maintenance dosage may be lower.
 Edema (renal disease). Regular tablets. Adults: 5 to 20 mg P.O. daily. Maintenance dosage may be lower.
 Hypertension. Regular tablets. Adults: 2.5 to 5 mg P.O. daily; maintenance dosage based on patient’s blood pressure. If using stepped-care approach, initial dose is 1.25 to 2.5 mg.
Rapid-acting tablets
Adults: 0.5 mg P.O. once daily; may be increased to maximum of 1 mg daily.

Pharmacodynamics
Diuretic action: Metolazone increases urinary excretion of sodium and water by inhibiting sodium reabsorption in the cortical diluting tubule of the nephron, thus relieving edema. Metolazone may be more effective in edema caused by impaired renal function than thiazide or thiazide-like diuretics.
Antihypertensive action: Exact mechanism of antihypertensive effect of metolazone is unknown; it may result from direct arteriolar vasodilatation. Metolazone also reduces total body sodium levels and total peripheral resistance.

Pharmacokinetics
Absorption: About 65% of a given dose of metolazone is absorbed after oral administration to healthy subjects; in cardiac patients, absorption falls to 40%. However, rate and extent of absorption vary among preparations.
Distribution: Metolazone is 50% to 70% erythrocyte-bound and about 33% protein-bound. Drug crosses the placental barrier and is distributed into breast milk.
Metabolism: Insignificant.
Excretion: About 70% to 95% of metolazone is excreted unchanged in urine. Half-life is about 14 hours in healthy subjects; it may be prolonged in patients with decreased creatinine clearance.

Contraindications and precautions
Contraindicated in patients with anuria, hepatic coma or precoma, or hypersensitivity to thiazides or other sulfonamide-derived drugs. Use cautiously in patients with severely impaired renal or hepatic function.

Interactions
Drug-drug. Allopurinol: Increases risk of hypersensitivity to allopurinol. Use together cautiously.
Amphetamine, quinidine: Decreases urinary excretion. Monitor patient closely.
Antihypertensives: Potentiates effects. This may be used to therapeutic advantage.
Cholestyramine, colestipol: May bind metolazone, preventing its absorption. Give drugs 1 hour apart.
Diazoxide: May potentiate hyperglycemic, hypotensive, and hyperuricemic effects of diazoxide. Use together cautiously.
Digoxin: Increases risk of digoxin toxicity. Monitor electrolyte levels.
Furosemide: Causes excessive volume and electrolyte depletion. Monitor fluid and electrolytes.
Insulin, sulfonylurea: Increases requirements in diabetic patients. Monitor patient closely.
Lithium: Elevates serum lithium levels. May necessitate a 50% reduction in lithium dosage.
Methenamine mandelate: Decreases therapeutic effect. Monitor patient closely.
Drug-lifestyle. Sun exposure: Increases risk of photosensitivity reactions. Advise patient to take precautions.

Adverse reactions
CNS: dizziness, headache, fatigue, vertigo, paresthesia, weakness, restlessness, drowsiness, anxiety, depression, nervousness, blurred vision.
CV: volume depletion and dehydration, orthostatic hypotension, palpitations, vasculitis, chest pain.
GI: anorexia, nausea, pancreatitis, epigastric distress, vomiting, abdominal pain, diarrhea, constipation, dry mouth, abdominal bloating.
GU: nocturia, polyuria, frequent urination, impotence.
Hematologic: aplastic anemia, agranulocytosis, leukopenia.
Hepatic: jaundice, hepatitis.
Metabolic: hyperglycemia and glucose tolerance impairment; fluid and electrolyte imbalances, including hypokalemia, dilutional hyponatremia and hypochloremia, metabolic alkalosis, hypercalcemia.
Musculoskeletal: muscle cramps.
Skin: dermatitis, photosensitivity, rash, purpura, pruritus, urticaria.

Effects on lab test results
• May increase glucose, calcium, cholesterol, and triglyceride levels. May decrease potassium, sodium, magnesium, and chloride levels.
• May decrease hemoglobin and granulocyte and WBC counts.

Overdose and treatment
Signs and symptoms of overdose include orthostatic hypotension, dizziness, electrolyte abnormalities, GI irritation and hypermotility, syncope, confusion, drowsiness, muscular weakness, diuresis, and lethargy, which may progress to coma.
 Treatment is mainly supportive; monitor patient and assist respiratory, CV, and renal function as indicated. Monitor fluid and electrolyte balance. Induce vomiting with ipecac in conscious patient; otherwise, use gastric lavage to avoid aspiration. Don’t give cathartics; these promote additional loss of fluids and electrolytes.

Special considerations
• Drug is effective in patients with decreased renal function. If progressive impairment is evident, consider discontinuing or interrupting treatment.
• Metolazone is used as an adjunct in furosemide-resistant edema.
• Rapid-acting form (Mykrox) isn’t interchangeable with other forms of metolazone. Dosage and uses vary.
• Monitor renal and hepatic function, electrolytes (potassium, sodium, chloride, calcium), and serum glucose levels.
• Store at room temperature in tight, light-resistant containers.
• Drug therapy may interfere with tests for parathyroid function and should be discontinued before such tests.
Breast-feeding patients
• Drug appears in breast milk. Safety and efficacy in breast-feeding women haven’t been established.
Pediatric patients
• Safety and efficacy in children haven’t been established.
Geriatric patients
• Geriatric and debilitated patients need close observation and may need reduced dosages. They’re more sensitive to excess diuresis because of age-related changes in CV and renal function. Excess diuresis promotes orthostatic hypotension, dehydration, hypovolemia, hyponatremia, hypomagnesemia, and hypokalemia.

Patient education
• Tell patient to take drug in the morning to prevent nocturia.
• Advise patient to avoid sudden posture changes and to rise slowly to avoid orthostatic hypotension.
• Instruct patient to use a sunblock to prevent photosensitivity reactions.

Reactions may be common, uncommon, life-threatening, or COMMON AND LIFE THREATENING.
◆ Canada only
◇ Unlabeled clinical use