Continuing Education Activity

Metolazone is a cardiovascular agent, specifically a quinazoline diuretic related to the thiazide class. It is available in a generic formulation in the United States. It is used alone or with other diuretics in congestive heart failure, to treat hypertension, and in other conditions where diuresis provides a clinical benefit. This activity will highlight the mechanism of action, adverse event profile, pharmacology, monitoring, and relevant interactions of metolazone, pertinent for members of the interprofessional team in the treatment of patients with conditions where it is of clinical value.

Objectives:

• Identify the mechanism of action of metolazone.
• Review the various indications for using metolazone in patient care.
• Summarize the adverse events associated with metolazone therapy.
• Outline the contraindications to metolazone therapy.

Indications

Metolazone is a quinazoline sulphonamide diuretic related to the thiazide class. The Food and Drug Administration (FDA) has approved metolazone to treat salt and water retention, causing edema accompanying congestive heart failure or chronic kidney disease. It is commonly used as an adjuvant therapy along with loop diuretics for the treatment of severe CHF to produce diuresis in patients refractory to loop diuretics monotherapy.[1] The synergy of these diuretics may help overcome the resistance that can develop with continued loop diuretic use. It can be used to treat edema associated with nephrotic syndrome, alone or in combination with spironolactone.[2]  Also, metolazone is indicated to treat hypertension alone or in combination with other antihypertensive drugs of a different class.[2] 

Mechanism of Action

Metolazone works by inhibiting sodium transport across the epithelium of the renal tubules (mostly in the distal tubules), resulting in a decrease in sodium reabsorption and an increase in sodium, chloride, and water excretion. The shift in water and electrolytes results in hypovolemia, keeping the peripheral vascular resistance low and returning the cardiac output to normal. This production of diuresis resolves edema and contributes to the antihypertensive effect. While metolazone is similar to thiazide diuretics in its mechanism of action, it does differ in its use in patients with impaired renal function. Thiazide diuretics decrease glomerular filtration rate (GFR) and are therefore less effective in patients with renal impairment. Because metolazone works primarily in the distal convoluted tubule, rather than the proximal convoluted tubule, it has little effect on GFR and can be used in patients with a reduced GFR.[3] Moreover, dissimilar to loop diuretics, metolazone does not prompt renin secretion at the macula densa due to the stimulation of the renin-angiotensin-aldosterone system. Because of these actions, metolazone, even with no randomized trials, is recommended as decongestant therapy in the heart failure guidelines.

Administration

Metolazone is an oral agent, available in 2.5 mg, 5 mg, and 10 mg tablets. A dose of 5-20 mg once daily is recommended as the initial to treat edema associated with congestive heart failure or kidney disease. The dose should be titrated to the patient's response, then continued at the lowest dose needed to maintain diuresis. For the treatment of hypertension, 2.5-10 mg once daily is recommended initially with titration to the response.[4] 

The safety and efficacy of specific pediatric dosing have not been established. However, one study suggests 0.2 to 0.4 mg/kg/day by mouth every 12 to 24 hours.[5] No dose adjustment is required for renal or hepatic impairment or with concurrent use of hemodialysis. Metolazone is recommended to be taken in the morning due to its prolonged absorption and duration of action. In patients resistant to loop diuretics, metolazone should be given one hour before the regular morning dose of furosemide.

Adverse Effects

Hyperuricemia is a common adverse effect and is due to competitive inhibition of uric acid secretion and a decrease in extracellular fluid from diuretic effects. Other fluid and electrolyte imbalances, especially hyponatremia, hypokalemia, and hypomagnesemia may occur. Any electrolyte imbalances must be corrected before starting treatment.[6][7] Metolazone may impair glucose tolerance, causing hyperglycemia and glycosuria. Diabetic patients should have their blood and urine glucose levels monitored while on this therapy.[8] Diuretic therapy may be associated with increased serum cholesterol and triglycerides; however, long-term studies have found that after approximately one year of therapy, serum cholesterol levels return to normal or trend below the baseline. These temporary effects do not significantly increase the risk of coronary heart disease.[9] 

The patient may experience orthostatic hypotension, which can be worsened by other antihypertensive agents, alcohol, or narcotic medications. A weak association has been made between diuretic use and falls in the elderly, so caution should be used in patients 60 years and older.[10]  Because metolazone exerts its main effect in the distal tubule of the nephron, a change in renal function can be expected and lead to occasional instances of acute kidney injury.  The likelihood of these events has not been established, and metolazone may be the only option indicated with reduced renal function.[6] [7]  

Other rare adverse effects include agranulocytosis, photosensitization, aplastic anemia, Stevens-Johnson syndrome, and toxic epidermal necrolysis.[11]  

As metolazone is also excreted in breast-milk, the potential for adverse reactions in nursing infants exists. The risk of exposure to the infant should be weighed against the benefit of treatment for the mother. Other safer alternatives are available for diuretic therapy in pregnant individuals, including hydrochlorothiazide and chlorthalidone.[12] 

Contraindications

Therapy is contraindicated in those with known metolazone hypersensitivity. Although this medication is a thiazide-like diuretic, cross-reactivity is rarely seen between metolazone and other diuretics.[13] However, there is limited evidence of cross-reactivity between sulfonamide agents and metolazone; nevertheless, caution should be used in those with a sulfonamide allergy because metolazone possesses the chemical side chain.[14] Metolazone should not be used in patients experiencing a hepatic coma or hepatic encephalopathy because electrolyte disturbances can occur and exacerbate these disease processes.[15]

Anuric patients should have metolazone withheld. As it is excreted by the kidneys, renal dysfunction can cause a dangerous accumulation of the drug. Metalozone is safe to use in mild to moderate renal impairment, unlike other thiazide diuretics, but extreme caution should be used in those with severe renal impairment or anuria. Concurrent electrolyte imbalance is a contraindication to metolazone therapy, as these should be corrected prior to initiating metolazone.[6][7] Metolazone should be avoided in patients on lithium and digitalis as it can aggravate lithium and digitalis toxicity.

Monitoring

To monitor the effectiveness of therapy in treating edema, the patient should show an increase in urine output and a decrease in total body weight. In the management of hypertension, a lowering in blood pressure should be seen within a few weeks of initiation of therapy. Current guidelines for high blood pressure treatment suggest assessing blood pressure monthly when starting or adjusting therapy and every 3 to 6 months for patients at goal.[4]

Additionally, because of the adverse effects associated with metolazone, serum electrolytes should be monitored at baseline and routinely while continuing therapy; including sodium, potassium, magnesium, and chloride.[6][7] Although evidence is controversial regarding hyperglycemia with metolazone, diabetic patients should monitor their serum glucose regularly while on this medication.[8]

Toxicity

For diuretics in general, toxic doses are not well established. Chronic use is the most common cause of toxicity. Comorbid conditions or a lack of adequate fluid replacement during diuresis may contribute to acute toxicity.

Enhancing Healthcare Team Outcomes

Effective treatment of edema associated with both congestive heart failure and kidney disease requires the participation of every member of the healthcare team. For example, urine output should be monitored continuously, and body weight should be recorded daily. If nurses fail to do this, the physician and pharmacist cannot ensure the treatment results in appropriate diuresis and removal of body fluid. The drug's actual effect is unknown and, therefore, cannot be adjusted accordingly. In this way, communication between health care providers is crucial for successful patient outcomes. When used and adjusted correctly, patients with congestive heart failure (CHF) can benefit from metolazone's diuretic effect. In one trial, adding metolazone to a loop diuretic (furosemide) in the treatment of edema associated with CHF showed an increase in diuresis, urinary output, and weight loss when compared to furosemide or metolazone alone.[16] [Level 2]

Comparing metolazone to chlorothiazide in acutely decompensated heart failure in patients with diuretic resistance, patients had an increase in 72-hour urine output and a shorter hospital duration of stay when using metolazone.[17][Level 3] Along with treating edema, low dose metolazone can result in significant changes in both systolic and diastolic blood pressure in the treatment of hypertension.[18] [Level 1]