Amiloride has mild diuretic and anti-hypertensive activity. It acts primarily in the distal tubule and does not require aldosterone for its action. Amiloride is a mild natriuretic which does not initiate a concomitant decrease in potassium levels. The mechanism of action includes inhibition of the electrogenic entry of sodium thus causing a fall in the electrical potential across the tubular epithelium. Since this potential is one of the main causes of the secretion of potassium, this mechanism is likely to be the basis of the potassium sparing effect. By blocking the sodium channels, amiloride may also reduce exchange of Na+ ions and H+ ions. A combination of the amiloride with a benzothiadazine diuretic will cause less magnesium excretion than the diuretic alone.
Amiloride is incompletely absorbed from the gastro-intestinal tract; only about 50% is recovered unchanged in the urine following an oral dose. The drug is not metabolised and can, therefore, be useful in patients with liver disease. Peak plasma concentrations are reached about 3-4 hours after oral administration and the plasma half-life is in the range of 6-9 hours.
In a 70Kg man, the distribution volume is about 5L/Kg, suggesting that the drug is widely distributed in the tissues. Amiloride appears to be weakly bound to plasma proteins as determined by electrophoretic and gel filtration studies. It is not known whether the drug is excreted in breast milk, although studies have shown the presence of amiloride in the breast milk of rats.
Amiloride is excreted unchanged in the urine. In two studies in which single doses of 14C-Amiloride were used, approximately 50% was recovered in urine and 40% in the faeces within 72 hours. In radioactive studies, peak plasma levels of 38 – 40µg/L were seen three to four hours after a single 20mg oral dose. These low plasma levels are thought to be due to extravascular distribution as evidenced by the large volume of distribution.
In man, the calculate renal clearance of amiloride exceed in the glomerular filtration, suggesting that there is a tubular secretory pathway. Renal clearance of the drug does not appear to be affected by probenecid, pH of the urine or urinary flow rate.
Preclinical Safety Data