Antikaliuretic – Diuretic
Action And Clinical Pharmacology: Amiloride is an antikaliuretic drug with mild natriuretic diuretic and antihypertensive activity. The activities may be additive to the effects of thiazides or other saluretic-diuretic agents. The principal use is to conserve potassium in selected patients receiving kaliuretic-diuretic agents. Amiloride interferes with the mechanism involved in the exchange of sodium for potassium in the distal convoluted tubule and collecting duct of the nephron. An increase in sodium and a decrease in potassium and hydrogen ion excretion are induced in the presence or absence of aldosterone, thereby suggesting a direct tubular action of the drug. Chloride excretion may remain unchanged or increase slowly with continued therapy.
Amiloride, when administered with hydrochlorothiazide, has been shown to result in less excretion of magnesium than thiazide or loop diuretics used alone.
Approximately 50% of an oral dose is absorbed. Amiloride usually begins to act within 2 hours after an oral dose. Its effect on electrolyte excretion reaches a peak between 6 and 10 hours and lasts about 24 hours. Peak plasma levels are obtained in 3 to 4 hours and plasma half-life varies from 6 to 9 hours.
Amiloride is not metabolized by the liver. About 50% of a 20 mg dose is excreted unchanged in the urine and 40% is excreted in the stool within 72 hours. In clinical studies amiloride was found to have little effect on glomerular filtration rate or renal blood flow.
Indications And Clinical Uses: For use alone or concomitantly with thiazide diuretics or other kaliuretic-diuretic agents in the treatment of patients with cirrhosis of the liver with ascites and edema.
Amiloride is indicated as an adjunct to the treatment with thiazide diuretics or other kaliuretic-diuretic agents in those patients with edema of cardiac origin or hypertension who: have hypokalemia, or in whom maintenance of normal serum potassium levels is considered to be clinically important, e.g., digitalized patients, patients in whom adequate dietary intake of potassium is not feasible or patients with cardiac arrhythmias.
Use in hepatic cirrhosis with ascites and edema: Amiloride used alone may provide satisfactory diuresis with diminished potassium loss and with a reduced risk of metabolic alkalosis. In resistant cases amiloride may be used with kaliuretic diuretic agents to help produce satisfactory diuresis, while maintaining a more balanced serum electrolyte pattern. As with all therapy for the ascites of hepatic cirrhosis, gradual weight loss and avoidance of electrolyte imbalance are the chief objectives (see Precautions).
Contra-Indications: Hyperkalemia: Should not be used in the presence of elevated serum potassium levels (see Warnings).
Antikaliuretic Therapy or Potassium Salts: Other antikaliuretic agents and potassium supplements are contraindicated in patients receiving amiloride (such combination therapy is commonly associated with rapid increases in plasma potassium levels).
Impaired Renal Function: Anuria, acute renal failure, severe or progressive renal disease, and diabetic nephropathy (see Warnings).
Hypersensitivity to any component of this product.
Manufacturers’ Warnings In Clinical States: Hyperkalemia: Hyperkalemia, e.g., serum potassium levels over 5.5 mEq/L, has been observed in some patients who received amiloride either alone or with diuretics. This has been noted particularly in elderly patients, in diabetic patients, and in hospitalized patients with hepatic cirrhosis or cardiac edema who had known renal impairment, were seriously ill, or were receiving vigorous diuretic therapy. Since fatalities have occurred, patients should be monitored carefully for clinical, laboratory, and ECG evidence of hyperkalemia and for acidosis. Monitoring of the serum potassium level is important because hyperkalemia is not always associated with an abnormal ECG.
Warning signs or symptoms of hyperkalemia include paresthesias, muscular weakness, fatigue, flaccid paralysis of the extremities, bradycardia, shock, and ECG abnormalities.
When abnormal, the ECG in hyperkalemia is characterized primarily by tall, peaked T waves or elevations from previous tracings. There may also be lowering of the R wave and increased depth of the S wave, widening and even disappearance of the P wave, progressive widening of the QRS complex, prolongation of the PR interval, and ST depression.
If hyperkalemia occurs in patients taking amiloride, the drug should be discontinued immediately. If the serum potassium level exceeds 6.5 mEq/L, active measures should be taken to reduce it. Such measures include the i.v. administration of sodium bicarbonate solution or oral or parenteral glucose with a rapid-acting insulin preparation. If needed, a cation exchange resin such as sodium polystyrene sulfonate may be given orally or by enema. Patients with persistent hyperkalemia may require dialysis.
Diabetes Mellitus: In diabetic patients, hyperkalemia has been commonly reported with the use of amiloride, particularly if they have chronic renal disease or prerenal azotemia. Some deaths occurred in this last group of patients. Therefore, if therapy with amiloride is considered essential, the drug should be used with caution in diabetic or suspected diabetic patients and only after first determining the status of renal function.
Careful monitoring of serum potassium levels is required throughout the therapy.
One patient with poorly controlled diabetes mellitus who became severely hyperkalemic while on amiloride died following 2 repeated i.v. glucose tolerance tests. Therefore, amiloride should be discontinued at least 3 days before glucose tolerance testing.
Metabolic or Respiratory Acidosis: Antikaliuretic therapy should be instituted only with caution in patients in whom respiratory or metabolic acidosis may occur, such as patients with cardiopulmonary disease or diabetes. If amiloride is given to these patients, frequent monitoring of acid-base balance is necessary. Shifts in acid-base balance alter the ratio of extracellular/intracellular potassium, and the development of acidosis may be associated with rapid increases in serum potassium levels.
Impaired Renal Function: Patients with impaired renal function other than those listed under Contraindications and who have BUN levels over 30 mg/100 mL, serum creatinine levels over 1.5 mg/100 mL, or with whole blood urea values over 60 mg/100 mL, or with diabetes mellitus, should not receive the drug without careful, frequent monitoring of serum electrolytes, creatinine, and BUN levels. Potassium retention associated with the use of amiloride is accentuated in the presence of renal impairment and may result in the rapid development of hyperkalemia. Prolongation of amiloride excretion was observed in patients with renal impairment.
Precautions: Electrolyte Imbalance and BUN Increases: Hyponatremia and hypochloremia may occur when used with other diuretics. Increases in BUN levels have been reported. These increases usually have accompanied vigorous fluid elimination, especially when diuretic therapy was used in seriously ill patients, such as those who had hepatic cirrhosis with ascites and metabolic alkalosis, or those with resistant edema. Therefore, careful monitoring of serum electrolytes and BUN levels is important when using amiloride.
Effects Related to Diuresis in Cirrhotic Patients: Patients with hepatic cirrhosis and ascites are intolerant of acute shifts in electrolyte balance and often have pre-existing hypokalemia as a result of associated secondary hyperaldosteronism. When oral diuretic therapy is used, these patients should be carefully monitored and diuresis should be gradual.
Hepatic encephalopathy, manifested by tremors, confusion, and coma, has been reported in association with amiloride therapy.
In a few cirrhotic patients, pre-existing jaundice increased, but the relationship to drug is uncertain.
Obstetrics: Teratologic studies with amiloride in rabbits and mice revealed no evidence of harm to the fetus. Reproduction studies in rats showed no evidence of impaired fertility. At approximately 5 or more times the expected maximum daily dose for humans, some toxicity was seen in adult rats and rabbits and a decrease in rat pup growth and survival occurred.
In rats a trace of drug crossed the placental barrier.
Pregnancy: Because clinical experience is limited, amiloride is not recommended for use during pregnancy. The potential benefits of the drug must be weighed against possible hazards to the fetus if it is administered to a woman of childbearing age.
Lactation: It is not known whether amiloride is excreted in human milk. In rats secretion of amiloride in milk has been demonstrated. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions, 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.
Children: Safety in children has not been established; therefore amiloride is not recommended in the pediatric age group.
Drug Interactions: Lithium should generally not be given with diuretics because they reduce the renal clearance of lithium and add to the high risk of lithium toxicity.
When amiloride is administered concomitantly with an angiotensin-converting enzyme inhibitor, the risk of hyperkalemia may be increased. Therefore, if concomitant use of these agents is indicated because of demonstrated hypokalemia, they should be used with caution and with frequent monitoring of serum potassium.
Concomitant administration of non-steroidal anti-inflammatory drugs (NSAIDs) and potassium-sparing agents, including amiloride, may cause hyperkalemia and renal failure, particularly in elderly patients. Therefore, when amiloride is used concomitantly with NSAIDs, renal function and serum potassium levels should be carefully monitored.
Adverse Reactions: While rare, the most serious adverse effect of amiloride is symptomatic hyperkalemia (symptoms of hyperkalemia may include paresthesias, muscular weakness, fatigue, flaccid paralysis of the extremities, bradycardia, shock and ECG abnormalities) (see Contraindications and Warnings).
The following incidence of adverse reactions was determined from clinical trials (837 patients treated with amiloride).
A causal relationship could not be established with other reactions which have been reported rarely. However, the possibility could not be excluded. These were: Activation of probable pre-existing peptic ulcer, aplastic anemia, neutropenia, abnormalities of liver function tests.
In cirrhotic patients, jaundice associated with the underlying disease process has deepened in a few instances, but the relationship to drug is uncertain.
In patients with pre-existing severe liver disease, hepatic encephalopathy, manifested by tremors, confusion, and coma, and increased jaundice, have been reported in association with diuretics, including amiloride.
Symptoms And Treatment Of Overdose: Symptoms: No data are available in regard to overdosage in humans.
Treatment: It is not known whether the drug is dialyzable.
If hyperkalemia occurs, active measures should be taken to reduce the serum potassium levels (see Warnings). The most likely signs and symptoms to be expected with overdosage are dehydration and electrolyte imbalance. These can be treated by established procedures. Therapy with amiloride should be discontinued and the patient observed closely. There is no specific antidote. Emesis should be induced or gastric lavage performed. Treatment is symptomatic and supportive.
Dosage And Administration: The incidence of hyperkalemia is dose-related and this should be considered especially when daily doses over 10 mg are used.
Hepatic cirrhosis with ascites and edema: Treatment should be started with a small dose of amiloride, i.e., one 5 mg daily, plus a small dose of a diuretic agent (other than antikaliuretics). If necessary, dosages of both drugs may be increased gradually until effective diuresis is obtained. The dosage of amiloride should not exceed 4 tablets (20 mg) a day. Maintenance doses may be lower than those required to initiate diuresis; therefore, reduction in the daily dosage should be attempted when the patient’s weight is stabilized. In cirrhotic patients, gradual weight reduction is especially desirable to reduce the likelihood of untoward reactions associated with diuretic therapy.
In those instances where amiloride is used alone, the initial daily dosage should be two 5 mg tablets (as a single dose or one tablet twice a day). Dosage may be increased depending on the need. The total daily dosage should not exceed 4 tablets (20 mg). After diuresis has been achieved the dosage may be reduced by decrements of 1 tablet to the least amount required.
Edema of cardiac origin: Amiloride, one or two 5 mg tablets daily, may be given with the usual doses of a diuretic agent (other than antikaliuretics). This dose is sufficient in most cases. If potassium levels remain low, the dosage of amiloride may be increased gradually. The dosage of amiloride should not exceed 4 tablets (20 mg) a day.
The optimal dosage is determined by the serum potassium level. Reduction in dosage should be attempted for maintenance therapy. Maintenance therapy may be on an intermittent basis.
Hypertension: Amiloride, one or two 5 mg tablets daily, is given with the usual antihypertensive dosage of a diuretic agent (other than antikaliuretics). The dosage may be adjusted if necessary. More than two 5 mg tablets of amiloride daily usually is not needed; in any event, the maximum dosage is 4 tablets (20 mg) a day.
Availability And Storage: Each yellow, diamond shaped, compressed tablet, coded MSD 92 contains: amiloride HCl 5 mg. Nonmedicinal ingredients: calcium phosphate, cornstarch, D&C Yellow No. 10, iron oxides, magnesium stearate and quinoline yellow WS. Gluten- and tartrazine-free. Bottles of 100. (Shown in Product Recognition Section)
MIDAMOR® MSD Amiloride HCl Antikaliuretic – Diuretic
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