Source: Health Products and Food Branch (CA) Revision Year: 2014
NOVAMILOR (amiloride hydrochloride and hydrochlorothiazide) is a diuretic-antihypertensive that combines the potent natriuretic action of hydrochlorothiazide with the potassium-conserving property of amiloride hydrochloride. Amiloride hydrochloride’s diuretic and antihypertensive actions are additive with the natriuretic, diuretic and antihypertensive activities of the thiazide while potassium loss is minimized and the possibility of acid-base imbalance is decreased. The onset of the diuretic action occurs within 1 to 2 hours of administration and this action appears to be sustained for approximately 24 hours.
Amiloride hydrochloride is an antikaliuretic drug. It has mild natriuretic, diuretic and antihypertensive activities which may be additive to the actions of thiazides or other salureticdiuretic agents. The principal use of amiloride hydrochloride is to conserve potassium in patients who are receiving kaliuretic-diuretic agents. Amiloride hydrochloride is not an aldosterone antagonist and thus its action is not related to the level of aldosterone excretion. It acts directly on the distal portion of the nephron resulting in an increase in sodium excretion and a decrease in potassium and hydrogen ion excretion. Chloride excretion may remain unchanged; however, prolonged therapy may result in a gradual increase in chloride.
Approximately 50% of an oral dose is absorbed. The onset of drug action occurs within 2 hours of oral administration and lasts about 24 hours. The peak electrolyte effect occurs between 6 and 10 hours after administration. Plasma levels reach a peak between 3 and 4 hours and the plasma half-life varies from 6 to 9 hours. The bioavailability of amiloride hydrochloride is decreased by 25 to 42% when taken with food but is not affected by coadministration of hydrochlorothiazide.
Clinical studies have shown that amiloride hydrochloride has little effect on the glomerular filtration rate or renal blood flow. It is not metabolized by the liver. Approximately 50% of an oral dose is excreted unchanged in the urine and 38-40% is excreted unchanged in the stool within 72 hours.
Hydrochlorothiazide is a diuretic and antihypertensive agent that affects the renal tubular mechanism of electrolyte reabsorption. It increases excretion of both sodium and chloride in approximately equal amounts. A minimal amount of bicarbonate may also be lost. An increase in potassium excretion usually accompanies the natriuretic action.
Hydrochlorothiazide does not usually decrease normal blood pressure. The antihypertensive effect of the thiazides may be related to the redistribution and excretion of body sodium.
Approximately 55 to 60% of an oral dose is absorbed. The bioavailability decreases with fasting but remains constant when the drug is administered in combination with amiloride hydrochloride. Hydrochlorothiazide is rapidly excreted by the kidneys.
The onset of the diuretic action usually occurs within 2 hours of administration reaching peak action after approximately 4 hours. The duration of diuretic action is 6 to 12 hours.
A comparative, two-way, single-dose bioavailability study was performed on NOVAMILOR and MODURET Tablets. The pharmacokinetic data calculated for the NOVAMILOR and MODURET Tablet formulations are tabulated below:
| Pharmacokinetic Indices for Amiloride HCI: | |||
|---|---|---|---|
| NOVAMILOR 2 × 5 mg | MODURET 2 × 5 mg | Percentage of MODURET | |
| AUCT* (ng·h/mL) | 107.8 (35) | 107.8 (40) | 100 |
| AUCI* (ng·h/mL) | 141.2 (35) | 139.8 (41) | 101 |
| Cmax* (ng/mL) | 9.12 (30) | 9.12 (30) | 100 |
| Tmax+ (h) | 3.92 (0.83) | 4.17 (1.01) | - - |
| T½+ (h) | 15.29 (10.70) | 16.15 (16.43) | - - |
* Geometric means (CV)
+ Arithmetic means (SD)
| Pharmacokinetic Indices for Hydrochlorothiazide: | |||
|---|---|---|---|
| NOVAMILOR 2 × 50 mg | MODURET 2 × 50 mg | Percentage of MODURET | |
| AUCT* (ng·h/mL) | 2253 (33) | 2231 (40) | 101 |
| AUCI* (ng·h/mL) | 2592 (32) | 2592 (41) | 100 |
| Cmax* (ng/mL) | 365 (26) | 358 (30) | 102 |
| Tmax+ (h) | 2.33 (0.73) | 2.67 (1.01) | - - |
| T½+ (h) | 5.95 (2.26) | 6.62 (16.43) | - - |
* Geometric means (CV)
+ Arithmetic means (SD)
Amiloride hydrochloride is a salt of a moderately strong base (pka 8.7). It is not chemically related to any other antikaliuretic or diuretic agent.
At an oral dose of 0.1 mg/kg or less, amiloride hydrochloride increases the excretion of sodium and, to a lesser extent, chloride in dogs and rats. Potassium excretion was not increased at this dose.
Amiloride hydrochloride administration has resulted in potassium retention in experimental animals. This effect is most evident when potassium excretion is high such as, upon loading with potassium chloride, following acetazolamide or thiazide pretreatment, or in adrenalectomized rats that are treated with deoxycorticosterone. The decrease in hydrogen ion excretion which accompanies the natriuresis causes an increase in urinary pH.
Amiloride hydrochloride administered orally in dogs causes an increase in the sodium excretion rate. This effect is not as pronounced as that seen with more potent agents but is of increased duration. The effect on sodium excretion lasts more than 6 hours. Increasing the oral dose from 0.25 to 4.0 mg/kg results in only moderate increases in natriuresls.
When amiloride hydrochloride is given in conjunction with chlorothiazide, hydrochlorothiazide or acetazolamide in rats, sodium excretion is increased.
The kaliuretic effect of the other diuretics is antagonized by amiloride hydrochloride. Amiloride hydrochloride (0.1 to 0.5 mg/kg oral) administered in conjunction with ethacrynic acid (1.0 mg/kg oral) or hydrochlorothiazide (0.5 mg/kg oral) to dogs resulted in an increased sodium excretion and a decrease in potassium excretion.
The Na+/K+ excretion ratio is increased in adrenalectomized rats given amiloride hydrochloride. Amiloride hydrochloride reverses the sodium retention induced by steroids in adrenalectomized rats treated with aldosterone, deoxycorticosterone or hydrocortisone. It also increases the Na+/K+ excretion ratio to above that of untreated adrenalectomized rats.
Renal clearance studies show that intravenous administration of 1.0 mg/kg does not affect the glomerular filtration rate, renal plasma flow or reabsorption of glucose in dogs. Amiloride hydrochloride acts directly on the distal portion of the nephron inhibiting tubular secretion of potassium and reabsorption of sodium. It is not known whether the affect of amiloride hydrochloride on the nephron is enzymatically based. Amiloride hydrochloride does not inhibit the actions of carbonic anhydrase, glutaminase, histidine decarboxylase, adenyl cyclase, or membrane ATP-ase, even when administered at high doses.
A profound reduction in blood pressure and changes in the electrocardiogram are seen in anesthetized dogs when amiloride hydrochloride is administered parenterally (2.5 to 5.0 mg/kg). If amiloride hydrochloride is injected slowly or is given at lower doses, the effects that are coincident with histamine release into the plasma are not seen. Oral doses of 0.5 to 2.0 mg/kg produce a slight increase in gastric secretion and intestinal motility in dogs. The response of dogs to ouabain is not altered by several days of oral pretreatment with amiloride hydrochloride (5.0 mg/kg/day).
Hydrochlorothiazide has diuretic and antihypertensive properties which increase the excretion of sodium and chloride in approximately equal amounts and cause a simultaneous usually minimal loss of bicarbonate. Ammonia excretion is decreased slightly which may result in an increase in blood ammonia levels. Hydrochlorothiazide also causes an increase in potassium and magnesium excretion and a decrease in calcium excretion.
Hydrochlorothiazide is eliminated rapidly by the kidneys. The coadministration of probenecid decreases the rate of elimination without reducing diuresis.
| Oral LD50 (mg/kg) | ||||
|---|---|---|---|---|
| Route | Animal | Amiloride Hydrochloride | Hydrochlorothiazide | Amiloride Hydrochloride/Hydrochlorothiazide 5/50 |
| Oral | Mice | 56 | >10,000 | 189 |
| Rats | 36-85 | >10,000 | 422 (females) 377 (males) | |
Acute oral toxicity studies in mice and rats showed that the toxicity of an amiloride plus hydrochlorothiazide (5/25 and 5/50 mg/kg) combination depends upon the amiloride content. The LD50 values of the mixtures were not significantly different from the LD50 values of amiloride.
Rats tolerated the oral combination of amiloride/hydrochlorothiazide at 5/100 mg/kg 5 days per week for 25 weeks but experienced high mortality rates at 10/500 mg/kg amiloride/hydrochlorothiazide. Dogs tolerated oral combinations of 1/5 mg/kg amiloride/hydrochlorothiazide and 4/40 mg/kg amiloride/hydrochlorothiazide 5 to 7 days per week for 25 weeks but did not tolerate 5/50 mg/kg amiloride/hydrochlorothiazide 7 days per week for 13 weeks.
The toxic effects of the amiloride/hydrochlorothiazide combination in rats and dogs (adrenal zona glomerulosa hyperplasia, electrolyte imbalance, elevated BUN, ECG disturbances and focal tubular fatty changes of kidney) may be attributed to exaggerated pharmacological effects of the drugs since similar effects are caused by other diuretics.
MODERATE TO MARKED HYPERKALEMIA DEVELOPED AT DOSES GREATER THAN 8.0 mg/kg/day. ELECTROCARDIOGRAPHIC CHANGES WERE OBSERVED. SERUM SODIUM AND CHLORIDE DECREASED.
Rats tolerated amiloride at oral daily doses of 2.5 and 5 mg/kg for up to 18 months. Higher dosage levels (10-15 mg/kg/day) caused a high incidence of deaths probably due to severe electrolyte imbalance. Drug-induced changes considered to be related to the diuretic and antikaliuretic activity of amiloride included alterations in urinary and serum electrolytes, reversible hyperplasia of the adrenal zona glomerulosa (all dosage levels) and renal tubular dilation (10 mg/kg).
Other than the expected changes in body weight, water intake, and serum electrolytes, dogs tolerated oral doses of amiloride ranging from 2 to 8 mg/kg/day 5 days/week for 58 weeks. Histologically, hyperplasia of the adrenal zona glomerulosa was seen in all amiloride treated dogs.
Amiloride administered orally to dogs 7 days/week at 2 and 4 mg/kg/day in an 11-week electrolyte balance study did not alter tissue electrolytes in the atrium, skeletal muscle or ileum.
In a 6-week study, GI ulcerations were observed in 1 of 4 dogs at 2.5 mg/kg and 2 of 4 dogs at 10 mg/kg. This ulceration may be related to the histamine releasing action of amiloride in the dog. No GI ulcerations were observed in the 58-week dog study at comparable doses although positive fecal occult blood tests were noted.
Monkeys tolerated amiloride well at oral doses up to 9 mg/kg/day, 5 days/week for 49 weeks. Excitability, irritability and apparent electrolyte imbalance occurred at a higher dose (12 mg/kg). In contrast to the rat and dog, no adrenal hyperplasia occurred although adrenal weights were increased.
Special Toxicity Studies Belated to Adrenal Zona Glomerular Hyperplasia and Diabetes:
Subacute studies (3 months of dosing) in rats showed that the adrenal zona glomerulosa hyperplasia disappeared in 19 to 30 days after cessation of treatment and that adrenals were completely normal 30 and 58 days after withdrawal of treatment. The hyperplasia can also be reduced by substitution of physiologic saline for drinking water. Hyperplasia of the adrenal zona glomerulosa occurred in maternal mice but not in the offspring in a teratogenicity study. The hyperplasla is considered physiological and reversible, the result of altered serum electrolytes and/or inhibition of aldosterone activity.
Toxicity of amiloride and triamterene is the same in obese-diabetic Zucker rats and normal-thin rats showing that amiloride has no effect on carbohydrate metabolism in this model of diabetes. Furthermore, amiloride has no adverse effects on glucose tolerance in acute experiments in rats or in a chronic study in dogs.
Reported results of a 6 month chronic oral toxicity study in the rat using doses of up to 2 g/kg/day (5 days/week) showed no signs of toxicity.
In dogs, oral doses up to 500 mg/kg/day were given 7 days/week for as long as 45 weeks. Slight depression of plasma potassium and small amounts of yellow crystalline precipitate in the bladder in two of 12 dogs were found on gross examination. Histomorphologic examination showed no drug related changes.
Amiloride was not carcinogenic when administered at maximally tolerated oral doses of 10 mg/kg/day for 92 weeks to mice or 104 weeks to rats at 6 mg/kg/day.
Amiloride was devoid of mutagenic activity in several strains of Salmonella typhimurium (Arnes test) at concentrations up to 2000 µg/plate in the presence or absence of an in vitro mammalian metabolic activation system.
Amiloride had no effect on fertility or general reproductive performance in male or female rats given oral doses of 2, 4 or 8 mg/kg/day. No teratogenic effects on fetuses were noted when amiloride was given orally during the period of organogenesis to rabbits at doses up to 8 mg/kg/day or mice up to 10 mg/kg/day. Signs of maternal toxicity (body weight loss, anorexia) and deaths were evident in both species at these dosage levels. Amiloride was without effect on various peri-and postnatal parameters when given to rats during late gestation through weaning at doses of 2 or 4 mg/kg/day. Pup survival and growth were reduced at 8 mg/kg/day.
Teratogenicity studies showed that the drug combination had no adverse effect on fetal development at oral dosage levels up to 2/20 mg/kg amiloride/hydrochlorothiazide in the rabbit and 5/50 mg/kg amiloride/hydrochlorothiazide in the mouse. Male and female fertility in the rat was unimpaired at doses up to 5/50 mg/kg amiloride/hydrochlorothiazide. Other than a reduced maternal and alive pup body weight gain at 5/25 mg/kg amiloride/hydrochlorothiazide, perinatal and postnatal parameters in rats were unaffected by drug administration during late gestation and weaning.
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