Metolazone

Metolazone tablets are indicated for the treatment of salt and water retention including: ? ? Metolazone tablets are also indicated for the treatment of hypertension, alone or in combination with other antihypertensive drugs of a different class

Thiazide diuretics & related drugs

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 tablets should be individualized according to indication and patient response. A single daily dose is recommended. Therapy with metolazone tablets should be titrated to gain an initial therapeutic response and to determine the minimal dose possible to maintain the desired therapeutic response. Usual Single Daily Dosage Schedules Suitable initial dosages will usually fall in the ranges given. Edema of cardiac failure: Edema of renal disease: Mild to moderate essential hypertension: Treatment of Edematous States The time interval required for the initial dosage to produce an effect may vary. Diuresis and saluresis usually begin within one hour and persist for 24 hours or longer. 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 patient's condition, sodium intake, and responsiveness. A decision to change the daily dose should be based on the results of thorough clinical and laboratory evaluations. If antihypertensive Metolazone tablets 5 to 20 mg once daily. Metolazone tablets 5 to 20 mg once daily. Metolazone tablets 2.5 to 5 mg once daily. New patients- If considered desirable to switch patients currently on this tablets and other formulations of metolazone that share its slow and incomplete bioavailability to it , the dose should be determined by titration starting at one tablet (0.5 mg) once daily and increasing to two tablets (1 mg) once daily if needed.

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.

Anuria, hepatic coma or precoma, known allergy or hypersensitivity to metolazone.

Cardiovas cular: 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/Hypers ensitivity: Toxic epidermal necrolysis (TEN), Stevens-Johnson Syndrome, necrotizing angiitis (cutaneous vasculitis), skin necrosis, purpura, petechiae, dermatitis (photosensitivity), urticaria, pruritus, skin rashes. Gastrointestinal: Hepatitis, intrahepatic cholestatic jaundice, pancreatitis, vomiting, nausea, epigastric distress, diarrhea, constipation, anorexia, abdominal bloating, abdominal pain. Hematologic: Aplastic/hypoplastic anemia, agranulocytosis, leukopenia, thrombocytopenia. Metabolic: Hypokalemia, hyponatremia, hyperuricemia, hypochloremia, hypochloremic alkalosis, hyperglycemia, glycosuria, increase in serum urea nitrogen (BUN) or creatinine, hypophosphatemia, hypomagnesemia, hypercalcemia. Mus culoskeletal:Joint pain, acute gouty attacks, muscle cramps or spasm. Other: Transient blurred vision, chills, dry mouth.

Teratogenic Effects. Pregnancy Category B Reproduction studies performed in mice, rabbits, and rats treated during the appropriate period of gestation at doses up to 50 mg/kg/day have revealed no evidence of harm to the fetus due to metolazone. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, metolazone tablets should be used during pregnancy only if clearly needed. Metolazone crosses the placental barrier and appears in cord blood. Non-Teratogenic Effects The use of metolazone tablets in pregnant women requires that the anticipated benefit be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions which have occurred in the adult. It is not known what effect the use of the drug during pregnancy has on the later growth, development, and functional maturation of the child. No such effects have been reported with metolazone. Labor and Delivery Based on clinical studies in which women received metolazone in late pregnancy until the time of delivery, there is no evidence that the drug has any adverse effects on the normal course of labor or delivery. Nursing Mothers Metolazone appears in breast milk. Because of the potential for serious adverse reactions in nursing infants from metolazone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Intentional overdosage has been reported rarely with metolazone and similar diuretic drugs. Signs and Symptoms Orthostatic hypotension, dizziness, drowsiness, syncope, electrolyte abnormalities, hemoconcentration and hemodynamic changes due to plasma volume depletion may occur. In some instances depressed respiration may be observed. At high doses, lethargy of varying degree may progress to coma within a few hours. The mechanism of CNS depression with thiazide overdosage is unknown. Also, GI irritation and hypermotility may occur. Temporary elevation of BUN has been reported, especially in patients with impairment of renal function. Serum electrolyte changes and cardiovascular and renal function should be closely monitored.

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