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What is the role of parenteral thiazide diuretics?

In the world of parenteral diuretics, the cost of a thiazide is remarkably higher than that of loop diuretics.¹ Chlorothiazide, the only parenteral thiazide dosage form, is extremely expensive at over $200 per vial. In contrast, parenteral loop diuretics such as furosemide and bumetanide are less than $2 per vial, as shown in Table 1. Mindful of this cost difference, the role of parenteral thiazide diuretics needs to be elucidated in an effort to provide cost-efficient and quality healthcare to patients.

Table 1. Usual intravenous dose and cost of parenteral loop and thiazide diuretics.^1,2

Indications for chlorothiazide
As shown in Table 2, the parenteral dosage form of chlorothiazide has a labeled indication for edema associated with heart failure, corticosteroids, estrogen therapy, and hepatic cirrhosis.² In addition, parenteral chlorothiazide has shown benefit in treating edema due to acute glomerulonephritis, chronic renal failure, and nephrotic syndrome. Other off-label uses for the drug, while not necessarily the parenteral dosage form, include calcium nephrolithiasis, osteoporosis, and diabetes insipidus. Parenteral chlorothiazide is not indicated for the treatment of hypertension as it has no known effect on blood pressure. Parenteral chlorothiazide is to be used only when the patient is unable to take medications orally or in emergency situations. The parenteral dosage formulation is not labeled for use in pediatric patients, and experience in this population is limited.

For the approved and off-label indications for chlorothiazide, is a loop diuretic a suitable alternative?
Parenteral loop diuretics and parenteral chlorothiazide can be used for edema associated with heart failure, hepatic cirrhosis, chronic renal failure, glomerulonephritis, or nephrotic syndrome.² Thiazides are considered relatively weak diuretics and are therefore rarely used alone in heart failure; however, they may be used in patients with mild fluid retention.^3,4 Loop diuretics are the chief diuretic class used in the treatment of heart failure. In disease states such as renal failure, glomerulonephritis, and nephrotic syndrome, loop diuretics are the drugs of choice in management of the associated edema.⁵

Patients may require large doses of loop diuretics, and the addition of thiazide diuretics in this setting has shown to provide additional diuresis.⁵ The addition of a thiazide diuretic to loop diuretic therapy may be beneficial due to the different mechanisms of action of the 2 drug classes. The loop diuretics inhibit reabsorption of sodium and chloride in the ascending loop of Henle and distal tubule. Interference with the chloride-binding co-transport system causes an increased excretion of water, sodium, chloride, magnesium, and calcium. Thiazides act on the distal tubule, which lies distal to the site of action of loop diuretics; they cause an increased excretion of water, sodium, chloride, potassium, hydrogen, magnesium, phosphate, and bicarbonate. Blockade of sodium reabsorption by the thiazide diuretics in the distal tubule should eliminate the compensatory increase in sodium reabsorption seen after administration of loop diuretics and thus enhance the efficacy of loop diuretics. Concomitant use of a loop and a thiazide diuretic, through sequential nephron blockade, produces effective diuresis in the setting of acute decompensated heart failure with diuretic resistance.^3,4 The addition of thiazide diuretic, rather than increasing the dose of the loop diuretic, may also aid in reducing the adverse effects of high doses of loop diuretics such as ototoxicity and hypocalcemia.^2,5 The characteristic electrolyte changes seen with the administration of loop and thiazide diuretics and a patient’s electrolyte balance may influence diuretic selection.

There are some conditions for which a thiazide diuretic is indicated and a loop diuretic may not be an appropriate substitute; however, these indications do not necessitate parenteral thiazide diuretic therapy unless the patient is unable to take oral medications.² For example, thiazide diuretics are indicated for the treatment of edema due to corticosteroids, whereas hypokalemia may ensue from administering corticosteroids with loop diuretics.⁶ However, thiazides are also capable of causing hypokalemia; therefore, potassium must be closely monitored regardless.

Pharmacokinetic differences exist between oral and parenteral chlorothiazide that may affect dosage form selection. With parenteral chlorothiazide, the onset of action is 15 minutes with a maximal effect at 30 minutes.² Oral chlorothiazide has an onset of action of 2 hours, with a peak at 4 hours, and duration of action of 6 to 12 hours. Both oral and parenteral forms are dosed once or twice daily. When administering parenteral chlorothiazide, care should be taken to avoid extravasation.

Clinical treatment guidelines
Although thiazide diuretics have a labeled indication for use in edema due to hepatic cirrhosis, the American Association for the Study of Liver Diseases practice guidelines recommend furosemide and spironolactone as the diuretics of choice.⁷ As a result, thiazide diuretics do not have a prominent role in the pharmacotherapy of hepatic cirrhosis. In regard to heart failure, the American College of Cardiology/American Heart Association guidelines state that using intravenous (IV) diuretics, including continuous infusions, or using two different diuretics together, such as a loop and a thiazide, are 2 methods to overcome diuretic resistance that can occur in patients with reduced responses to high doses of diuretics.⁴

Table 2. Indications and place in therapy for loop and thiazide diuretics.^2,4,7

Thiazide diuretics, unlike loop diuretics, are known to reduce calciuria and therefore have a role in pediatric hypercalciuria, osteoporosis, and calcium nephrolithiasis. Loop diuretics are not indicated for these conditions as they can increase calciuria, reduce bone mineral density, and may precipitate nephrolithiasis. Although thiazide diuretics may be used off-label for osteoporosis, they are not included in guidelines for the management of osteoporosis.⁸ Thiazide diuretics can help prevent nephrolithiasis by reducing the amount of calcium excreted in the urine, thereby reducing the chance for kidney stone formation.⁹

Mainstays in treating nephrogenic diabetes insipidus are thiazide diuretics and dietary sodium restriction.¹⁰ In the treatment of this polyuric disease, the mechanism of thiazide diuretics is not fully elucidated.¹¹ However, the most widely accepted hypothesis is that thiazide diuretics increase renal sodium excretion which leads to a contraction in extracellular fluid (ECF).¹² In response to reduced ECF, there is an increase in sodium and water reabsorption in the proximal tubule. With less solute and water entering the distal tubule, less solute and water are lost in the urine. Furosemide, a more potent volume-depleting diuretic, may not be appropriate in diabetes insipidus as excessive volume depletion may worsen the hypernatremia.

Literature on chlorothiazide
There is a serious paucity of published literature comparing IV chlorothiazide and loop diuretics. In fact, only one study was found that compared an IV loop diuretic alone with the addition of an IV thiazide diuretic to the loop diuretic.⁵ Although thiazides are thought to have no effect in patients with a glomerular filtration rate (GFR) <30 ml/min, Fliser and colleagues studied the effect of adding the thiazide diuretic butizide (a derivative of hydrochlorothiazide not commercially available in the United States) to the loop diuretic torsemide in a single-blind, randomized, placebo-controlled, single-dose, crossover study of 10 patients with advanced renal failure (GFR <30 ml/min). The objective was to compare the mean cumulative 24-hour excretion of sodium and chloride as compared to baseline with torsemide 50 mg IV plus butizide 20 mg IV (approximately equivalent to hydrochlorothiazide 30 mg) versus the loop diuretic alone. Torsemide alone led to a significant increase in sodium and chloride excretion from baseline (sodium: from 154 ± 30 to 232 ± 59 mmol/24h, chloride: from 128 ± 21 to 233 ± 84 mmol/24h, p<0.01). The addition of butizide resulted in a significantly higher excretion of sodium and chloride compared to torsemide alone (sodium: from 156 ± 33 to 290 ± 76 mmol/24h, chloride: from 128 ± 29 to 309 ± 99 mmol/24h, p<0.01). The authors stated that an additional 30% increase in excretion was seen with the combination over maximum doses of loop diuretics; therefore, the addition of a thiazide diuretic enhances the effect of loop diuretic therapy in advanced renal failure. This small study suggests a role for parenteral thiazide diuretics in patients with poor renal function when the oral route is not feasible.

Conclusion
In summary, the primary use for parenteral chlorothiazide over oral chlorothiazide is when the oral route is unavailable or when a quicker onset of action is desired. In treating edema, less expensive parenteral loop diuretics such as furosemide and bumetanide can often be substituted for parenteral chlorothiazide. The addition of a thiazide diuretic to loop diuretic therapy has been shown to enhance diuresis, even in patients with renal impairment. However, this does not necessitate parenteral therapy; therefore, oral thiazide therapy can be used in this setting. A patient’s electrolytes should be assessed and closely monitored during diuretic therapy. Thiazide diuretics can also lower the loop diuretic dose requirement, and subsequently reduce the incidence of adverse effects associated with high-dose loop diuretic therapy. Indications unique to thiazide diuretic therapy include osteoporosis, calcium nephrolithiasis, hypercalciuria, and diabetes insipidus; however, the oral dosage form is appropriate in these cases.

References

1. Murray L, ed. Redbook. Montvale, NJ: Thomson Healthcare; 2008.
2. Wickersham RM, ed. Facts and Comparisons. St. Louis, MO: Wolters Kluwer Health; 2008.
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4. Hunt SA, Abraham WT, Chin NH, et al. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult. Circulation. 2005;112(12):e154-e235.
5. Fliser D, Schröter M, Neubeck M, Ritz E. Coadministration of thiazides increases the efficacy of loop diuretics even in patients with advanced renal failure. Kidney Int. 1994;46(2):482-488.
6. Jackson EK. Diuretics. In: Brunton LL, Lazo JS, Parker KL, eds. Goodman and Gilman’s: The Pharmacological Basis of Therapeutics. 11^th ed. United States of America: McGraw-Hill Companies, Inc.; 2006. www.accesspharmacy.com/content.aspx?aID=943427. Accessed February 14, 2009.
7. Runyon BA. Management of adult patients with ascites due to cirrhosis. Hepatology. 2004;39(3):841-856.
8. Gonzales R, Kutner JS. Current practice guidelines in primary care, 2009. www.accessmedicine.com/guidelines.aspx. Accessed February 14, 2009.
9. Asplin JR, Coe FL, Favus MJ. Nephrolithiasis. In: Kasper DL, Braunwald E, Fauci AS, et al, eds. Harrison’s Principles of Internal Medicine. 17^th ed. United States of America: McGraw-Hill Companies, Inc.; 2008. www.accesspharmacy.com/content.aspx?aID=2874829. Accessed February 14, 2009.
10. Coyle JD, Joy MS. Disorders of sodium and water homeostasis. In: DiPiro JT, Talbert RL, Yee GC, et al. Pharmacotherapy: A Pathophysiologic Approach. 7^th ed. China: McGraw-Hill Companies, Inc.; 2008. www.accesspharmacy.com/content.aspx?aID=3183025. Accessed February 14, 2009.
11. Grønbeck L, Marples D, Nielsen S, Christensen S. Mechanism of antidiuresis caused by bendroflumethiazide in conscious rats with diabetes insipidus. Br J Pharmacol. 1998;123(4):737-745.
12. Loffing J. Paradoxical antidiuretic effect of thiazides in diabetes insipidus: another piece in the puzzle. J Am Soc Nephrol. 2004;15(11):2948-2950.

By Jamie Joseph, PharmD