Metolactone

Uses

Metolazone is used for the treatment of salt and water retention including:

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

Metolazone is also used for the treatment of hypertension, alone or in combination with other antihypertensive drugs of a different class.

Spironolactone is used for Congestive heart failure, Hepatic cirrhosis with ascites and oedema, Nephrotic syndrome, Primary hyperaldosteronism, Essential hypertension, For the treatment of patients with hypokalemia

Spironolactone is a long-acting aldosterone antagonist. Spironolactone is a specific pharmacologic antagonist of aldosterone, acting primarily through competitive binding of receptors at the aldosterone dependent sodium-potassium exchange site in the distal convoluted renal tubule. Spironolactone causes increased amounts of sodium and water to be excreted, while potassium and magnesium is retained.

Metolactone is also used to associated treatment for these conditions: Edema, Mild Hypertension, Moderate HypertensionAcne, Ascites, Congestive Heart Failure (CHF), Edema, High Blood Pressure (Hypertension), Hypokalemia, Idiopathic Hirsutism, Nephrotic Syndrome, Primary Hyperaldosteronism, Secondary hyperaldosteronism, Chronic heart failure with reduced ejection fraction (NYHA Class III), Chronic heart failure with reduced ejection fraction (NYHA Class IV), Idiopathic hyperaldosteronism

How Metolactone works

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.

Spironolactone competitively inhibits aldosterone dependant sodium potassium exchange channels in the distal convoluted tubule. This action leads to increased sodium and water excretion, but more potassium retention. The increased excretion of water leads to diuretic and also antihypertensive effects.

Dosage

Metolactone dosage

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: Metolazone tablets 5 to 20 mg once daily.

Edema of Renal Disease: Metolazone tablets 5 to 20 mg once daily.

Mild to Moderate Essential Hypertension: Metolazone tablets 2.5 to 5 mg once daily.New patients- If considered desirable to switch patients currently on Zaroxolyn tablets and other formulations of Metolazone that share its slow and incomplete bioavailability to Mykrox , 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.

Treatment Of Edematous States: The time interval required for the initial dosage to produce an effect may vary.Diuresisand 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 drugs or diuretics are given concurrently with Metolazone tablets, more careful dosage adjustment may be necessary. For patients who tend to experience paroxysmal nocturnaldyspnea, it may be advisable to employ a larger dose to ensure prolongation of diuresis and saluresis for a full 24-hour period.

Treatment Of Hypertension: The time interval required for the initial dosage regimen to show effect may vary from three or 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.

Edema in adults (congestive heart failure, hepatic cirrhosis, or nephrotic syndrome): An initial daily dosage of 100 mg of Spironolactone administered in either single or divided doses is recommended, but may range from 25 to 200 mg daily. Combined therapy with other diuretics is indicated when more rapid diuresis is desired.

Primary hyperaldosteronism: After the diagnosis of hyperaldosteronism has been established, Spironolactone may be administered in doses of 100 to 400 mg daily in preparation for surgery. For patients who are considered unsuitable for surgery, Spironolactone may be employed for long-term maintenance therapy at the lowest effective dosage determined for the individual patient.

Essential hypertension: For adults, an initial daily dosage of 50 to 100 mg of Spironolactone administered in either single or divided doses is recommended.

Hypokalemia: Spironolactone in a dosage ranging from 25 mg to 100 mg daily is useful in treating a diuretic-induced hypokalemia.

Side Effects

Chest pain, palpitation, necrotising angiitis, orthostatic hypotension, syncope, venous thrombosis, vertigo, volume depletion; depression, dizziness, chills, drowsiness, fatigue, restlessness, headache, lightheadedness; petechiae, photosensitivity, hypersensitivity reactions; gout attacks, electrolyte disturbances; abdominal bloating, diarrhoea, abdominal pain, anorexia, constipation, epigastric distress, nausea, xerostomia, pancreatitis, vomiting; impotence; aplastic anaemia, thrombocytopenia, haemoconcentration, leukopenia; cholestatic jaundice, hepatitis; joint pain, muscle cramps, weakness, neuropathy, paraesthesia; blurred vision; increased BUN, glucosuria.

Gynaecomastia may develop in association with the use of Spironolactone. Other adverse reactions are: GI symptoms including cramping and diarrhoea, drowsiness, lethargy, headache, urticaria, mental confusion, impotence, irregular menses or amenorrhoea and post-menopausal bleeding.

Toxicity

Symptoms of overdose include difficulty breathing, dizziness, dizziness on standing up, drowsiness, fainting, irritation of the stomach and intestines, and lethargy leading to coma.

Patients experiencing an overdose may present with drowsiness, mental confusion, maculopapular or erythematous rash, nausea, vomiting, dizziness, or diarrhea. Vomiting is generally induced or a gastric lavage is performed. Supportive treatment involves maintining hydration, electrolyte balance, and vital functions.

The oral LD50 in mice, rats, and rabbits is >1g/kg.

Spironolactone should be avoided in pregnancy due to reports of feminization of male fetuses in animal studies. Active metabolites of spironolactone are present in breast milk and levels that are likely inconsequential, though the long term effects have not been studied.

In animal studies, spironolactone slowed follicle development, ovulation, and implantation. Spironolactone increased the incidence of benign adenomas in the testes of male rats, benign uterine endometrial stromal polyps in female rats, and thyroid follicular cell adenomas in both sexes of rats. Spironolactone and canrenone are generally not considered to be mutagenic in tests but canrenone occasionally tests positive for mutagenicity with metabolic activation and spironolactone has occasionally tested inconclusive though slightly positive for mutagenicity.

Precaution

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.

All patients receiving diuretic therapy should be observed for evidence of fluid or electrolyte imbalance. Hyperkalemia may occur in patients with impaired renal function or excessive potassium intake and can cause cardiac irregularities, which may be fatal.

Interaction

Hypotensive and nephrotoxic effects of ACE inhibitors may be enhanced. Absorption may be reduced with bile acid sequestrants. Hyperglycaemic effect may be enhanced with diazoxide. May increase serum concentration and QTc-prolonging effect of dofetilide. May reduce lithium excretion. Hypotensive effect may be increased with alcohol.

ACE inhibitors: Concomitant administration of ACE inhibitors with potassium-sparing diuretics has been associated with severe hyperkalemia.

Alcohol, barbiturates, or narcotics: Potentiation of orthostatic hypotension may occur.

Corticosteroids, ACTH: Intensified electrolyte depletion, particularly hypokalemia, may occur.

Lithium: Lithium generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity.

Digoxin: Spironolactone has been shown to increase the half-life of digoxin.

Volume of Distribution

Volume of distribution data is not readily available.

Elimination Route

Peak blood levels are obtained within 2 to 4 hours of oral administration. The rate and extent of absorption are formulation dependent.

Spironolactone reaches a maximum concentration in 2.6 hours and an active metabolite (canrenone) reaches a maximum concentration in 4.3 hours. When taken with food, the bioavailability of spironolactone increases to 95.4%.

Giving spironolactone with food increases the maximum concentration from 209ng/mL to 301ng/mL. The time to maximum concentration also increases from 2.28 hours to 3.05 hours. The area under the curve varies from 2103ng/mL*hr to 4544ng/mL*hr.

Half Life

Approximately 14 hours.

1.4 hours.

Canrenone has a half life of 16.5 hours, 7-α-thiomethylspirolactone has a half life of 13.8 hours, and 6-ß-hydroxy-7-α-thiomethylspirolactone has a half life of 15 hours.

Clearance

Clearance data is not readily available.

Elimination Route

Most of the drug is excreted in the unconverted form in the urine.

Metabolites of spironolactone are excreted 42-56% in urine, and 14.2-14.6% in the feces. No unmetabolized spironolactone is present in the urine.

Pregnancy & Breastfeeding use

Pregnancy Category B: Either animal-reproduction studies have not demonstrated a foetal risk but there are no controlled studies in pregnant women or animal-reproduction studies have shown an adverse effect (other than a decrease in fertility) that was not confirmed in controlled studies in women in the 1st trimester (and there is no evidence of a risk in later trimesters).

If used in gestational HTN: Pregnancy Category D: There is positive evidence of human foetal risk, but the benefits from use in pregnant women may be acceptable despite the risk (e.g., if the drug is needed in a life-threatening situation or for a serious disease for which safer drugs cannot be used or are ineffective).

Pregnancy: Spironolactone should not be used during pregnancy

Lactation: Canrenone, an active metabolite of Spironolactone, appears in breast milk. If use of the drug is deemed essential an alternative method of infant feeding should be instituted.

Contraindication

Anuria; hepatic coma or pre-coma. Pregnancy.

Spironolactone is contraindicated in patients with acute renal insufficiency, significant impairment of renal function, anuria, hyperkalaemia or sensitivity to Spironolactone.

Acute Overdose

Symptoms: Orthostatic hypotension, dizziness, drowsiness, syncope, haemoconcentration and haemodynamic changes due to plasma volume depletion.

Management: Symptomatic and supportive.

Symptoms of overdosage include drowsiness, mental confusion, dizziness, diarrhea and vomiting etc. Patients should induce vomiting or evacuate the stomach by lavage during Spironolactone overdoasge.

Storage Condition

Store in a cool and dry place protected from light. Keep out of reach of children.

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