Metolazone

Metolazone is indicated for the treatment of edema accompanying congestive heart failure and edema accompanying renal diseases including the nephrotic syndrome, and states of diminished renal function. Metolazone 2.5 mg has also been used in the management of mild to moderate essential hypertension, alone or in combination with other antihypertensive drugs of a different class.

Metolazone is a diuretic antihypertensive drug for the treatment of edema. Merozolyn is a quinazoline diuretic, with properties generally similar to the thiazide diuretics. The actions of Merozolyn result from interference with the renal tubular mechanism of electrolyte reabsorption. Merozolyn acts primarily to inhibit sodium reabsorption at the cortical diluting site and to a lesser extent in the proximal convoluted tubule. Sodium and chloride ions are excreted in approximately equivalent amounts. The increased delivery of sodium to the distal-tubular exchange site results in increased potassium excretion.

Merozolyn does not inhibit carbonic anhydrase. A proximal action has been shown in humans by increased excretion of phosphate and magnesium ions, and by a markedly increased fractional excretion of sodium in patients with severely compromised glomerular filtration.

The antihypertensive mechanism of action of metolazone is not fully understood but is presumed to be related to its saluretic and diuretic properties.

Pharmacokinetics: Metolazone is absorbed rapidly; however, rate and extent of absorption is dependent on the formulation. Clinical studies have shown that ninety to nine-five percent of metolazone is bound to red blood cells and plasma protein. The prolonged duration of action of metolazone is attributed to its protein binding and allows for once a day dosing. Only a small amount of metolazone is metabolized. Most of the drug is excreted in the unconverted form in the urine. When Metolazone is given, diuresis and saluresis usually begin within one hour and persist for 24 hours depending on the dose. The effect may be prolonged beyond 24 hours particularly at the higher recommended dosages.

Effective dosage of Metolazone should be individualized according to indications and patient response. A single daily dose is recommended. Therapy with Merozolyn should be titrated to gain an initial therapeutic response and to determine the minimal dose possible to maintain the desired therapeutic response.

Usual Dosages-

• Edema of cardiac failure: Metolazone 5-10 mg, once daily
• Edema of renal disease: Metolazone 5-20 mg, once daily

Treatment of Edematous States: The time interval for the initial dosage to show effect may vary; diuresis and saluresis usually begin within one hour and persist for 12 to 24 hours, depending on dosage. When a desired therapeutic effect has been obtained, it may be advisable to reduce the dose, if possible. The daily dose depends on the severity of the patients condition, sodium intake and responsiveness. A decision to change the daily dose should be based upon the results of thorough clinical and laboratory determinations. If antihypertensive drugs or diuretics are given concurrently with Merozolyn, more careful dosage adjustment may be necessary. For patients with congestive cardiac failure who tend to experience paroxysmal nocturnal dyspnea, it is usually advisable to employ a dosage near the upper end of the range to ensure prolongation of diuresis and saluresis for a full 24-hour period.

Hypertension: Mild to moderate essential hypertension: Metolazone 2.5-5 mg, once daily.

Treatment of Hypertension: The time interval required for the initial dosage regimen of Metolazone to show effect may vary from three to four days, to three to six weeks, in the treatment of elevated blood pressure. Doses should be adjusted at appropriate intervals to achieve maximum therapeutic effect.

Antihypertensives: When metolazone is used with other antihypertensive drugs, particular care must be taken, especially during initial therapy. Dosage of other antihypertensive agents, especially the ganglionic blockers and quanethidine, should be reduced. Hydralazine in therapeutic doses may interfere with the natruretic action of metolazone.

Corticosteroids or ACTH Therapy: May increase the risk of hypokalemia and increase salt and water retention.

Curariform Drugs: Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine). The most serious effect would be respiratory depression which could proceed to apnea.

Drugs Used to Treat Gout: Dosage adjustment of the gout medication may be necessary to control hyperuricemia and gout.

Furosemide and Other Loop Diuretics: Unusually large or prolonged losses of fluids and electrolytes may result.

Insulin and Oral Antidiabetic Agents: Adjustment of dosage may be necessary.

Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone.

Salicylates and Other Nonsteroidal Anti-inflammatory Agents: May antagonize natruretic, diuretic and antihypertensive effects of metolazone. Patients should be monitored carefully.

Sympathomimetics: May decrease the antihypertensive effect of metolazone. Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use.

Metolazone is contraindicated in anuria, in hepatic coma or pre-coma, and in cases of known allergy and hypersensitivity to metolazone.

Rarely, the rapid onset of severe hyponatremia and/or hypokalemia has been reported following initial doses of thiazide and non-thiazide diuretics. When symptoms consistent with severe electrolyte imbalance appear rapidly, the drug should be discontinued and supportive measures should be initiated immediately. The appropriateness of therapy with this class of drug should be carefully re-evaluated. Hypokalemia may occur, with consequent weakness, cramps, and cardiac arrhythmias. Hypokalemia is a particular hazard in digitalized patients or those who have had or have a ventricular arrhythmia; dangerous or fatal arrhythmias may be precipitated. Serum potassium should be determined at regular intervals, and dose reduction, potassium supplementation or addition of a potassium sparing diuretic instituted if indicated. Hypokalemia is dose related.

Azotemia and hyperuricemia may be noted or precipitated during the administration of Metolazone. Infrequently, gouty attacks have been reported in persons with a history of gout. If azotemia and oliguria worsen during treatment of patients with severe renal disease, metolazone should be discontinued.

Unusually large or prolonged losses of fluid and electrolytes may result when metolazone is administered concomitantly to patients receiving furosemide.

Particular care must be taken, especially during initial therapy, when metolazone is used with other antihypertensive drugs of a different class to avoid excessive reduction in blood pressure.

The following adverse reactions have been reported. Several are single or comparably rare occurrences. Adverse reactions are listed in decreasing order of severity within body systems.

Cardiovascular: Chest pain/discomfort, orthostatic hypotension, excessive volume depletion, hemoconcentration, venous thrombosis, palpitations.

Central and Peripheral Nervous System: Syncope, neuropathy, vertigo, paresthesias, psychotic depression, impotence, dizziness/lightheadedness, drowsiness, fatigue, weakness, restlessness, sometimes resulting in insomnia), headache.

Dermatologic/Hypersensitivity: Necrotizing angitis (cutaneous vasculitis), purpura, dermatitis (photosensitivity), urticaria and skin rashes.

Gastrointestinal: Hepatitis: intrahepatic cholestatic jaundice, pancreatitis, vomiting, nausea, epigastric distress, diarrhea, constipation, anorexia, abdominal bloating.

Hematologic: Aplastic/hypolastic anemia, agranulocytosis, leukopenia.

Metabolic: Hypokalemia, hyponatremia, hyperuricemia, hypochloremia, hypochloremic alkalosis, hyperglycemia, glycosuria, increase in serum urea nitrogen (BUN) or creatinine, hypophosphatemia

Musculoskeletal: Joint pain, acute gouty attacks, muscle cramps or spasm.

Other: Transient blurred vision, chills.

In addition, adverse reactions reported with similar antihypertensive diuretics, but which have not been reported to date for Merozolyn include: bitter taste, dry mouth, sialadenitis, xanthopsia, respiratory distress (including pneumonitis), thrombocytopenia and anaphylactic reactions. These reactions should be considered as possible occurrences with clinical usage of Merozolyn.

Whenever adverse reactions are moderate or severe, Merozolyn dosage should be reduced or therapy withdrawn.

Use in Pregnancy: Since metolazone crosses the placenta and appears in cord blood, its administration to women of childbearing age requires that the potential benefits of the drug be weighed against its possible hazards to the fetus. The potential effects on the fetus include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions which have occurred in the adult. However, teratogenic studies in mice, rats and rabbits, have not shown teratologic effects in these animals.

Nursing Mothers: Metolazone appears in breast milk. Thus, it is possible that the effects of metolazone may occur in the newborn under these circumstances. If the use of metolazone is deemed essential for a nursing mother, the patient should stop nursing.

Pre-diabetes or DM; gout; SLE; hepatic and renal impairment; hypercholesterolaemia. Correct electrolyte disturbances prior to therapy. Risk of cross-sensitivity with sulfonamides, sulfonylureas, carbonic anhydrase inhibitors, thiazides and loop diuretics. Lactation.

Use in Children: Safety and effectiveness in children have not been established; therefore, metolazone is not recommended for use in the pediatric age group.

Thiazide diuretics & related drugs