May 23, 2017
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Demadex

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Demadex




CLINICAL PHARMACOLOGY

Mechanism Of Action

Micropuncture studies in animals have shown that torsemide acts from within the lumen of the thick ascending portion of the loop of Henle, where it inhibits the Na+/K+/2Cl--carrier system. Clinical pharmacology studies have confirmed this site of action in humans, and effects in other segments of the nephron have not been demonstrated. Diuretic activity thus correlates better with the rate of drug excretion in the urine than with the concentration in the blood.

Torsemide increases the urinary excretion of sodium, chloride, and water, but it does not significantly alter glomerular filtration rate, renal plasma flow, or acid-base balance.

Pharmacodynamics

With oral dosing, the onset of diuresis occurs within 1 hour and the peak effect occurs during the first or second hour and diuresis lasts about 6 to 8 hours. In healthy subjects given single doses, the dose-response relationship for sodium excretion is linear over the dose range of 2.5 mg to 20 mg. The increase in potassium excretion is negligible after a single dose of up to 10 mg and only slight (5 mEq to 15 mEq) after a single dose of 20 mg.

Edema

DEMADEX has been studied in controlled trials in patients with New York Heart Association Class II to Class IV heart failure. Patients who received 10 mg to 20 mg of daily DEMADEX in these studies achieved significantly greater reductions in weight and edema than did patients who received placebo.

Hypertension

In patients with essential hypertension, DEMADEX has been shown in controlled studies to lower blood pressure when administered once a day at doses of 5 mg to 10 mg. The antihypertensive effect is near maximal after 4 to 6 weeks of treatment, but it may continue to increase for up to 12 weeks. Systolic and diastolic supine and standing blood pressures are all reduced. There is no significant orthostatic effect, and there is only a minimal peak-trough difference in blood pressure reduction.

The antihypertensive effects of DEMADEX are, like those of other diuretics, on the average greater in black patients (a low-renin population) than in nonblack patients.

When DEMADEX is first administered, daily urinary sodium excretion increases for at least a week. With chronic administration, however, daily sodium loss comes into balance with dietary sodium intake. If the administration of DEMADEX is suddenly stopped, blood pressure returns to pretreatment levels over several days, without overshoot.

DEMADEX has been administered together with β-adrenergic blocking agents, ACE inhibitors, and calcium-channel blockers. Adverse drug interactions have not been observed, and special dosage adjustment has not been necessary.

Pharmacokinetics

Absorption

The bioavailability of DEMADEX tablets is approximately 80%, with small inter-subject variation; the 90% confidence interval is 75% to 89%. The drug is absorbed with little first-pass metabolism, and the serum concentration reaches its peak (C max ) within 1 hour after oral administration. Cmax and area under the serum concentration-time curve (AUC) after oral administration are proportional to dose over the range of 2.5 mg to 200 mg. Simultaneous food intake delays the time to Cmax by about 30 minutes, but overall bioavailability (AUC) and diuretic activity are unchanged.

Distribution

The volume of distribution of torsemide is 12 to 15 liters in normal adults or in patients with mild to moderate renal failure or congestive heart failure. In patients with hepatic cirrhosis, the volume of distribution is approximately doubled. Torsemide is extensively bound to plasma protein ( > 99%).

Metabolism

Torsemide is metabolized by the hepatic cytochrome CYP2C9 and, to a minor extent, CYP2C8 and CYP2C18. Three main metabolites have been identified in humans. Metabolite M1 is formed by methyl-hydroxylation of torsemide, metabolite M3 is formed by ring hydroxylation of torsemide, and metabolite M5 is formed by oxidation of M1. The major metabolite in humans is the carboxylic acid derivative M5, which is biologically inactive. Metabolites M1 and M3 possess some pharmacological activity; however, their systemic exposures are much lower when compared to torsemide.

Elimination

In normal subjects the elimination half-life of torsemide is approximately 3.5 hours. Torsemide is cleared from the circulation by both hepatic metabolism (approximately 80% of total clearance) and excretion into the urine (approximately 20% of total clearance in patients with normal renal function).

Because torsemide is extensively bound to plasma protein ( > 99%), very little enters tubular urine via glomerular filtration. Most renal clearance of torsemide occurs via active secretion of the drug by the proximal tubules into tubular urine.

After a single oral dose, the amounts recovered in urine were: torsemide 21%, metabolite M1 12%, metabolite M3 2%, and metabolite M5 34%.

Renal Impairment In patients with renal failure, renal clearance of torsemide is markedly decreased but total plasma clearance is not significantly altered. A smaller fraction of the administered dose is delivered to the intraluminal site of action, and the natriuretic action of any given dose of diuretic is reduced.

Hepatic Impairment

In patients with hepatic cirrhosis, the volume of distribution, plasma half-life, and renal clearance are all increased, but total clearance is unchanged. Geriatric Patients The renal clearance of torsemide is lower in elderly subjects as compared to younger adults, which is related to the decline in renal function that commonly occurs with aging. However, total plasma clearance and elimination half-life remain unchanged.

Heart failure

In patients with decompensated congestive heart failure, hepatic and renal clearance are both reduced, probably because of hepatic congestion and decreased renal plasma flow, respectively. The total clearance of torsemide is approximately 50% of that seen in healthy volunteers, and the plasma half-life and AUC are correspondingly increased. Because of reduced renal clearance, a smaller fraction of any given dose is delivered to the intraluminal site of action, so at any given dose there is less natriuresis in patients with heart failure than in normal subjects.

Drug Interactions

Digoxin

Coadministration of digoxin is reported to increase the AUC for torsemide by 50%, but dose adjustment of DEMADEX is not necessary. Torsemide does not affect the pharmacokinetics of digoxin.

Spironolactone

In healthy subjects, coadministration of torsemide was associated with significant reduction in the renal clearance of spironolactone, with corresponding increases in the AUC. However, the pharmacokinetic profile and diuretic activity of torsemide are not altered by spironolactone.

Torsemide does not affect the protein binding of glyburide or warfarin.

Cimetidine

The pharmacokinetic profile and diuretic activity of torsemide are not altered by cimetidine.

Last reviewed on RxList: 3/17/2017
This monograph has been modified to include the generic and brand name in many instances.

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