Metolazone

Metolazone is a diuretic antihypertensive drug for the treatment of edema.

Metolazone is a quinazoline diuretic, with properties generally similar to the thiazide diuretics. 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. A proximal action 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.

The antihypertensive mechanism of action of metolazone is not fully understood but is presumed to be related to its saluretic and diuretic properties.

Animal Pharmacodynamics

The dominant pharmacologic actions of metolazone in animals are saluresis and diuresis. These effects have been demonstrated in rats and dogs and indicate an interference with the renal tubular mechanism of electrolyte reabsorption. The pattern of water and electrolyte excretion appears to be similar to that of some thiazides. Studies with desoxycorticosterone acetate saline-induced hypertension in rats have also demonstrated metolazone to be an effective antihypertensive agent; hypertension was reduced by metolazone, as well as inhibited by pretreatment with the drug.

Renal Effects

Metolazone interferes with the renal tubular mechanism of electrolyte reabsorption and acts primarily to inhibit sodium reabsorption at the cortical diluting site of the distal segment and in the proximal convoluted tubule. Sodium and chloride ions are excreted in approximately equivalent amounts. Metolazone may also evoke a significant increase of potassium excretion in an amount sufficient to produce hypokalemia. With inhibition of sodium reabsorption, a higher concentration of this cation reaches the distal segment of the nephron and provides a more favorable milieu for the exchange process.

Metolazone produces a decrease in free water clearance in man and animals.

Metolazone possesses some carbonic anhydrase inhibitory action, and probably has a very slight action on bicarbonate transport by the kidney. The inhibition occurs in vitro only at high concentrations and, therefore, would appear to play little, if any, part in the diuretic action of the drug. The renal effects of the drug are virtually independent of alterations in acid-base balance.

Metolazone does not significantly decrease the glomerular filtration rate in man, although in animals the effect is variable under different experimental conditions.

The drug exerted its natriuretic and diuretic effects on both normal and adrenalectomized rats. Its action, therefore, does not depend on aldosterone inhibition.

Metolazone is absorbed rapidly; however, rate and extent of absorption is dependent on the formulation.

Studies in several species of animals indicate that metolazone is readily absorbed with an onset of diuretic effect within one (1) hour. Absorption is dose related up to levels of 50 mg/kg orally; the maximum effect is attained within 3-6 hours of oral administration.

Within 48 hours of an oral dose, 95% of the administered dose of metolazone is eliminated in the urine and feces of rats, dogs and monkeys. An average of 50% is eliminated unchanged.

Rat studies have shown metolazone to be distributed mainly in the soft tissue with little, if any, in the nerves, brain, bones or eyes. Metolazone passes readily through the placental barrier to the fetus and is found in the milk of lactating animals.

Acute Toxicology

A single oral dose of 10 gm/kg was not lethal in rats, and a single intraperitoneal dose of 5 gm/kg was not lethal in mice. Acute effects in susceptible animals include electrolyte imbalance. Administration of single high doses (100 to 200 mg/kg) of metolazone intraperitoneally to rats caused a hyperglycemic effect, a decrease in liver glycogen, and an increase in plasma-free fatty acids. Adrenalectomy, nephrectomy, or pretreatment with α- and β-adrenergic blocking agents reduced this hyperglycemia significantly, suggesting than an adrenergic mechanism (possibly stress), as well as a renal mechanism, were involved.

Chronic Toxicity

Daily doses up to 50 mg/kg given orally for one year did not produce noticeable toxic effects in rats, dogs, or monkeys. Mild hypokalemia and slight elevation of blood urea nitrogen occurred in some of the dogs. In the majority of these cases, the abnormal value returned to near normal before the study ended and while the animals were still under treatment.