Metolazone

Metolazone is an antihypertensive agent belonging to Thiazide Diuretics.

Metolazone is a thiazide diuretic used to treat fluid retention (edema) in people with congestive heart failure, or a kidney disorder such as nephrotic syndrome. Metolazone is also used to treat hypertension.

The bioavailability of Metolazone is about 40-65%. After administration of oral Metolazone, the onset of action takes place at 1 hour. Peak plasma time was found to be around 8 hours. In the blood, approximately 95% of the drug is bound to plasma proteins. 50%-70% bound to erythrocytes, up to 33% bound to plasma proteins, and 2-5% of the drug in circulation is unbound. The mean plasma half-life of Metolazone is about 20 hours. 80% is excreted unchanged in urine via glomerular filtration and 10% via bile.

Metolazone shows common side effects Constipation, dry mouth, stomach pain, blurred vision, Diarrhoea, headache, etc.

Metolazone is available in the form of Oral Tablets.

Metolazone is available in India, US, UK, Canada, Singapore, and China.

Metolazone belonging to the Thiazide Diuretics acts as an antihypertensive agent.

The actions of metolazone result from interference with the renal tubular mechanism of electrolyte reabsorption. Metolazone 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. Metolazone does not inhibit carbonic anhydrase. The antihypertensive mechanism of action of metolazone is not fully understood but is presumed to be related to its saluretic and diuretic properties.

The onset of action of Metolazone occurs within 1 hour of its administration.

The Duration of Action for Metolazone in the body is approximately 24 hours.

The Tmax was found within 8 hours and Cmax above 0.002 ng/mL following the administration of Metolazone.

Metolazone comes as an Oral Tablet taken by mouth. It is usually taken once daily in the morning to avoid nocturia.

Metolazone is an antihypertensive agent belonging to Thiazide Diuretics.

Metolazone acts primarily to inhibit sodium reabsorption at the cortical diluting site and to a lesser extent in the proximal convoluted tubule. It causes the kidneys to decrease the amount of water and salt in the body by increasing the amount of urine.

Metolazone is approved for use in the following clinical indications

• Edema

Edema accompanying congestive heart failure, renal diseases including nephrotic syndrome, and states of diminished renal function.

• Hypertension

Metolazone tablets are also indicated for the treatment of hypertension, alone or in combination with other antihypertensive drugs of a different class. Metolazone Tablets, a more rapidly available form of metolazone, are intended for the treatment of new patients with mild to moderate hypertension.

• Edema

Metolazone tablets 2.5 to 10 mg once daily.

• Hypertension

Metolazone tablets 2.5 to 5 mg once daily.

Metolazone is available in the form of Oral Tablets.

Dosage Adjustment in Kidney Patient

Not necessary to supplement dose in haemodialysis or peritoneal dialysis

Avoid consumption of a high-salt or high-sodium diet while taking Metolazone.

Metolazone is contraindicated in patients with

• Anuria, hepatic coma or precoma, known allergy or hypersensitivity to Metolazone.

• Rapid Onset Hyponatremia And/or Hypokalemia

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. Parenteral electrolytes may be required. The appropriateness of therapy with this class of drugs should be carefully reevaluated.

• Hypokalemia

Hypokalemia may occur with consequent weakness, cramps, and cardiac dysrhythmias. Serum potassium should be determined at regular and appropriate intervals, and dose reduction, potassium supplementation or addition of a potassium-sparing diuretic instituted whenever indicated. Hypokalemia is a particular hazard in patients who are digitalized or who have or have had a ventricular arrhythmia; dangerous or fatal arrhythmias may be precipitated. Hypokalemia is dose related.

• Concomitant Therapy

Lithium

In general, diuretics should not be given concomitantly with lithium because they reduce its renal clearance and add a high risk of lithium toxicity. Read prescribing information for lithium preparations before use of such concomitant therapy.

Furosemide

Unusually large or prolonged losses of fluids and electrolytes may result when metolazone tablets, are administered concomitantly to patients receiving furosemide.

• Other Antihypertensive Drugs

When metolazone tablets, are used with other antihypertensive drugs, particular care must be taken to avoid excessive reduction of blood pressure, especially during initial therapy.

• Cross-Allergy

Cross-allergy may occur when Metolazone tablets, are given to patients known to be allergic to sulfonamide-derived drugs, thiazides, or quinethazone.

• Sensitivity Reactions

Sensitivity reactions (e.g., angioedema, bronchospasm) may occur with or without a history of allergy or bronchial asthma and may occur with the first dose of metolazone tablets.

Consumption of alcohol is not recommended while taking Metolazone. Their combination may increase the risk of dizziness, fainting, and very low blood pressure.

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 discontinue the drug, taking into account the importance of the drug to the mother.

The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes the mother and fetus to unnecessary hazards. Diuretics do not prevent the development of toxemia in pregnancy, and there is no evidence that they are useful in the treatment of developed toxemia.

Avoid consumption of a high-salt or high-sodium diet while taking Metolazone.

• Common Adverse effects

Dizziness, weakness, tiredness, back pain, muscle cramps, feeling anxious or agitated, headache, runny nose.

• Rare Adverse effects

Drowsiness, lack of energy, feeling tired, leg cramps, muscle weakness or limp feeling, severe weakness, loss of coordination, feeling unsteady, fast or irregular heartbeats, fluttering in your chest, feeling restless, numbness or tingling, vomiting, constipation.

• Other Diuretics

Furosemide and probably other loop diuretics are given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes.

• Other Antihypertensives

When metolazone tablets, are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary.

• Alcohol, Barbiturates, And Narcotics

The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy.

• Digitalis Glycosides

Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result.

• Corticosteroids Or ACTH

May increase the risk of hypokalemia and increase salt and water retention.

• Lithium

Serum lithium levels may increase.

• Curariform Drugs

Diuretic-induced hypokalemia may enhance the neuromuscular blocking effects of curariform drugs (such as tubocurarine) – the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue metolazone tablets, three days before elective surgery.

• Salicylates And Other Non-Steroidal Anti-Inflammatory Drugs

May decrease the antihypertensive effects of metolazone tablets.

• Sympathomimetics

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

• Insulin And Oral Antidiabetic Agents

Metolazone may raise blood glucose concentrations possibly causing hyperglycemia and glycosuria in patients with diabetes or latent diabetes.

• Methenamine

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

• Anticoagulants

Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemia response to anticoagulants; dosage adjustments may be necessary.

The common side of Metolazone includes the following

• Common
  

Stomach pain, dizziness, dry mouth, diarrhea, increased urination, itching or rash, weakness.

• Rare

Chest pain, joint pain, stiffness and swelling, cramping, trembling, abdominal pain.

• Pregnancy

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 on 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.

• 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 discontinue the drug, taking into account the importance of the drug to the mother.

• Pediatric Use

Safety and effectiveness in pediatric patients have not been established in controlled clinical trials. There is limited experience with the use of metolazone tablets, in pediatric patients with congestive heart failure, hypertension, bronchopulmonary dysplasia, nephrotic syndrome, and nephrogenic diabetes insipidus. Doses used generally ranged from 0.05 to 0.1 mg/kg administered once daily and usually resulted in a 1 to 2.8 kg weight loss and 150 to 300 cc increase in urine output. Not all patients responded and some gained weight. Those patients who did respond did so in the first few days of treatment. Prolonged use (beyond a few days) was generally associated with no further beneficial effect or a return to baseline status and is not recommended. There is limited experience with the combination of metolazone tablets, and furosemide in pediatric patients with furosemide-resistant edema. Some benefited while others did not or had an exaggerated response with hypovolemia, tachycardia, and orthostatic hypotension requiring fluid replacement. Severe hypokalemia was reported and there was a tendency for diuresis to persist for up to 24 hours after metolazone tablets, were discontinued. Hyperbilirubinemia has been reported in 1 neonate. Close clinical and laboratory monitoring of all children treated with diuretics is indicated.

• Geriatric Use

Clinical studies of metolazone tablets did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Intentional overdosage has been reported rarely with metolazone and similar diuretic drugs.

Pharmacodynamic

Metolazone is a quinazoline diuretic, with properties generally similar to the thiazide diuretics. A proximal action of metolazone 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. This action has been demonstrated in animals by micropuncture studies.

Pharmacokinetics

• Absorption

The bioavailability of Metolazone is about 40-65%. After administration of oral Metolazone, the onset of action takes place at 1 hour. Peak plasma time was found to be around 8 hours.

• Distribution

In the blood, approximately 95% of the drug is bound to plasma proteins. 50-70% bound to erythrocytes, up to 33% bound to plasma proteins, and 2-5% of the drug in circulation is unbound.

• Metabolism and Excretion

The mean plasma half-life of Metolazone is about 20 hours. 80% is excreted unchanged in urine via glomerular filtration and 10% via bile.

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/017386s043lbl.pdf
• https://www.rxlist.com/metolazone-drug.htm#dosage
• https://reference.medscape.com/drug/zaroxolyn-metolazone-342416#0
• https://www.practo.com/medicine-info/metolazone-629-api
• https://www.drugs.com/dosage/metolazone.html#Usual_Adult_Dose_for_Edema