Diuretic – Antihypertensive
Action And Clinical Pharmacology: Metolazone is a quinazoline diuretic/antihypertensive agent. The action of metolazone is to interfere with the renal tubular mechanism of electrolyte reabsorption. The mechanism of this action is unknown. Metolazone acts primarily to inhibit sodium reabsorption at the cortical diluting site and 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 may result in increased potassium excretion and hypokalemia.
Following a clinical oral dose, diuresis and saluresis usually begin within 1 hour and persist for 12 to 24 hours, depending on dosage. Peak effect occurs about 2 hours after administration. The action of the drug continues over 24 hours. A single daily dose is recommended, and the duration of effect can be varied by adjusting this dose.
Absorption is dose related up to levels of 50 mg/kg orally. The duration of the clinical effect varies from 12 to 24 hours and is dependent upon the dose given. Most of the drug is protein bound (90 to 95%). In man, the half-life of metolazone in erythrocytes is 10 hours and in plasma 5 hours. The prolonged duration of action is attributed to the protein binding and enterohepatic recycling.
Within 48 hours of oral dosing, approximately 95% of the administered dose is eliminated in the urine and feces. In man, about 80% is excreted unchanged and the rest undergoes conversion to hydroxylated and carboxylated derivatives. In animals, about 50% is eliminated unchanged. In the dog, 25% is excreted into the bile over a 24-hour period following 5 mg/kg dose.
Metolazone is distributed mainly to the soft tissues with little, if any, in the nerves, brain, bones or eyes. The drug passes readily through the placental barrier to the fetus and is found in the milk of lactating animals.
The mechanism whereby diuretics function in the control of hypertension is unknown; both renal and extrarenal actions may be involved. An antihypertensive effect may be seen as early as 3 to 4 days after metolazone has been started. Administration for 3 to 6 weeks, however, is usually required for maximum antihypertensive effect.
Indications And Clinical Uses: Edema accompanying congestive heart failure; edema accompanying renal diseases and states of diminished renal function, including the nephrotic syndrome.
Pregnancy: Diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of developed toxemia. Metolazone is indicated in pregnancy only when edema is due to pathological causes. Edema in pregnancy, resulting from restriction of venous return by the expanded uterus, is treated through elevation of the lower extremities and use of support hose. In rare instances, the edema may cause extreme discomfort which is not relieved by rest and a short course of diuretics may provide relief and may be appropriate.
Metolazone may be used in the reduction of blood pressure in the management of mild to moderate essential hypertension, either as the sole therapeutic agent or in combination with other antihypertensive therapy.
Contra-Indications: Anuria, hepatic coma or precoma, hypersensitivity to metolazone or other sulfonamide derivatives.
Precautions: Hypokalemia may occur, with consequent weakness, cramps, and cardiac dysrhythmias. Hypokalemia is a particular hazard in digitalized patients; dangerous or fatal arrhythmias may be precipitated.
Azotemia and hyperuricemia may be noted or precipitated during the administration of metolazone. (Infrequently, gouty attacks have been reported in persons with history of gout).
If azotemia and oliguria worsen during treatment of patients with severe renal disease, discontinue metolazone.
Metolazone will, on occasion, exhibit considerable potentiation when administered concurrently with furosemide. Excessive, massive volume and electrolyte depletion may result.
Observe patients receiving metolazone carefully and monitor serum electrolytes for signs and symptoms of fluid or electrolyte imbalance; namely, hyponatremia, hypochloremia and hypokalemia. Assess BUN, uric acid and glucose levels during therapy. Hypokalemia, an ever present hazard with most diuretic therapy, will be more common in association with intensive or prolonged diuretic therapy, with concomitant steroid or ACTH therapy and with inadequate electrolyte intake. Determine the serum potassium at regular intervals and institute potassium supplementation when indicated.
The clinical signs of electrolyte imbalance are: dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscle fatigue, hypotension, oliguria, tachycardia and gastrointestinal disturbances such as nausea and vomiting.
Metolazone may potentiate the effects of tubocurarine and decrease the arterial response to levaterenol. On this basis, it may be advisable to discontinue the drug at least 48 hours prior to elective surgery.
Special caution should be used in treating patients with severe hepatic disease since diuretics may induce metabolic alkalosis in cases of potassium depletion that may precipitate episodes of hepatic encephalopathy.
Orthostatic hypotension may occur and may be potentiated by alcohol, barbiturates, narcotics or concurrent therapy with other antihypertensives.
When metolazone is used with other antihypertensive drugs, take particular care, especially during initial therapy. Dosage of other antihypertensive agents, especially the ganglionic blockers and guanethidine, should be reduced. Hydralazine in therapeutic doses may interfere with the natriuretic action of metolazone.
Metolazone may be given with a potassium-sparing diuretic when indicated. In this circumstance, diuresis may be enhanced and dosages should be reduced. Potassium retention and hyperkalemia may result; determine the serum potassium frequently. Potassium supplementation is contraindicated when a potassium-sparing diuretic is given.
While not reported for metolazone, use of diuretics have on rare occasion been associated with pathologic changes in the parathyroid gland and with hypercalcemia and hypophosphatemia. Sulfonamide derivatives have been reported to exacerbate or activate systemic lupus erythematosus. These possibilities should be kept in mind with the use of metolazone.
Administer metolazone cautiously to patients with severely impaired renal function, since the drug is excreted primarily by the renal route.
Observe caution when administering metolazone to hyperuricemic or gouty patients. The drug exerts minimal effects on glucose metabolism; insulin requirements may be affected in diabetics, and hyperglycemia and glycosuria may occur in patients with latent diabetes.
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, teratologic studies in mice, rats and rabbits, conducted for 3 generations in rats, have not shown teratogenic effects in these animals.
Lactation: 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.
Diuretics enhance the cardiotoxic (e.g., ECG changes) and neurotoxic (e.g., ataxia, confusion and mental disorientation) effects of lithium, and these drugs should not be administered concurrently. In those rare instances when these drugs must be given together, patients should be observed closely for signs and symptoms of lithium toxicity. Close monitoring of serum electrolytes and maintenance of adequate fluid, potassium and sodium intake also are necessary.
Adverse Reactions: Gastrointestinal: constipation, nausea, vomiting, anorexia, diarrhea, abdominal bloating, epigastric distress, intrahepatic cholestatic jaundice, hepatitis, pancreatitis.
CNS: syncope, dizziness, drowsiness, vertigo, headache, neuropathy, paresthesias, psychotic depression, impotence, fatigue, weakness, restlessness.
Cardiovascular: orthostatic hypotension, excessive volume depletion, hemoconcentration, venous thrombosis, palpitation, chest pain.
Hematologic: leukopenia, aplastic/hypoplastic anemia, agranulocytosis.
Dermatologic: urticaria and other skin rashes, necrotizing angitis, purpura, photosensitivity.
Miscellaneous: dry mouth, symptomatic and asymptomatic hypokalemia, hyponatremia, hypochloremia, hypochloremic alkalosis, hyperuricemia, hyperglycemia, hypophosphatemia, glycosuria, increase in BUN or creatinine, joint pain, fatigue, muscle cramps or spasm, weakness, restlessness, chills, acute gouty attacks.
Adverse reactions which have occurred with other diuretics, but which have not been reported to date for metolazone include: xanthopsia and thrombocytopenia. These reactions should be considered as possible occurrences with clinical usage of metolazone.
Whenever adverse reactions are moderate or severe, metolazone dosage should be reduced or therapy withdrawn.
Symptoms And Treatment Of Overdose: Symptoms: Based on the pharmacological activities of metolazone, overdosage might lead to excessive diuresis with electrolyte depletion. In cirrhotic patients, overdosage might precipitate hepatic coma.
Treatment: There is no specific antidote. Treatment is symptomatic and supportive. Induce emesis or perform gastric lavage. Correct dehydration, electrolyte imbalance, hepatic coma, and hypotension by established procedures.
Dosage And Administration: Therapy should be individualized according to patient response. Programs of therapy with metolazone should be titrated to gain a maximal initial therapeutic response and to determine the minimal dose possible to maintain that therapeutic response. Metolazone is a drug with a prolonged, 12 to 24 hour duration of action. When an initially desired therapeutic effect has been obtained, it is ordinarily advisable to reduce the dosage of metolazone to a lower maintenance level.
The daily dosage depends on the severity of each patient’s condition, his sodium intake, and his responsiveness. Therefore, dosage adjustment is usually necessary during the course of therapy.
A decision to reduce the daily dosage of metolazone from a higher induction level to a lower maintenance level should be based on the results of thorough clinical and laboratory evaluations. If other diuretic or antihypertensive drugs are given concurrently with metolazone, the required dosage reduction should be carefully undertaken.
Children: Although metolazone has been used in a carefully selected group of pediatric patients under hospital conditions, the population of patients is not sufficient to establish a dosage level; therefore, metolazone is not recommended for use in the pediatric age group.
Initial Dosages: Edema of cardiac failure: 5 to 10 mg, once daily. Edema of renal disease: 5 to 20 mg, once daily. Mild to moderate essential hypertension: 2.5 to 5 mg, once daily.
Maintenance Dosage: The time interval required for the initial higher-dosage regimen may vary from days in edematous states to 3 or 6 weeks in the treatment of elevated blood pressure.
When the dose of metolazone has been reduced to 2.5 mg once daily, further reduction can be achieved by cutting back the frequency of administration to every other day.
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.
Availability And Storage: 2.5 mg: Each slightly biconvex, pink tablet, debossed with its numeric strength on one side and ZAROXOLYN on the other, contains: metolazone 2.5 mg. Nonmedicinal ingredients: cellulose, D&C Red No 3 aluminum lake and magnesium stearate. Alcohol-, gluten-, lactose-, paraben-, sucrose- and tartrazine-free. Bottles of 100.
5 mg: Each slightly biconvex, blue tablet, debossed with its numeric strength on one side and ZAROXOLYN on the other, contains: metolazone 5 mg. Nonmedicinal ingredients: cellulose, FD&C Blue No 2 aluminum lake and magnesium stearate. Alcohol-, gluten-, lactose-, paraben-, sucrose- and tartrazine-free. Bottles of 100.
Dispense metolazone in amber bottles. Store at room temperature and protect from light. (Shown in Product Recognition Section)
ZAROXOLYN® Rhône-Poulenc Rorer Metolazone Diuretic – Antihypertensive