Continuing Education Activity

Metolazone is a cardiovascular agent, specifically a quinazoline diuretic related to the thiazide class. Metolazone works by inhibiting sodium transport across the epithelium of the renal tubules (mostly in the distal tubules), decreasing sodium reabsorption, and increasing sodium, chloride, and water excretion. The FDA has approved metolazone to treat salt and water retention, causing edema accompanying congestive heart failure or kidney disease. 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 interprofessional team members in treating 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 adjuvant therapy and loop diuretics for treating 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.[2] Failure to decrease extracellular fluid volume despite using diuretics appropriately is termed ‘diuretic resistance.’  Diuretic resistance can be expressed as a fractional excretion of sodium (FENa) of <0.2% despite high dose diuretics. Metolazone is specifically used for diuretic resistance in the therapeutic management of edema and volume overload.[3]

The drug can be used to treat edema associated with nephrotic syndrome alone or in combination with spironolactone. Also, metolazone is indicated to treat hypertension alone or in combination with other antihypertensive drugs of a different class.[4] According to 2022 AHA/ACC/HFSA guidelines, in patients with congestive heart failure, the addition of metolazone to treatment with a loop diuretic should be reserved for patients who do not respond to moderate or high-dose loop diuretics to minimize electrolyte abnormalities.[5]

Mechanism of Action

Metolazone works by inhibiting sodium transport across the epithelium of the renal tubules (mostly in the distal tubules), decreasing sodium reabsorption, and increasing 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. It can be used in patients with a reduced GFR.[6] 

Moreover, unlike loop diuretics, metolazone does not prompt renin secretion at the macula densa due to the stimulation of the renin-angiotensin-aldosterone system. The use of thiazide-like diuretic (e.g., metolazone) in combination with a loop diuretic interferes with compensatory distal tubular sodium reabsorption, leading to increased natriuresis.[5] According to KDIGO (Kidney Disease Improving Global Outcomes) 2021 guidelines,  combining a loop diuretic with a thiazide-like diuretic (hydrochlorothiazide, metolazone) can be an effective oral regimen to overcome diuretic resistance by blocking sodium resorption at several sites within the nephron.[7]

Pharmacokinetics

The data extrapolated from the recent study regarding the pharmacokinetics of metolazone is as follows.[8]

Absorption: Oral Metolazone is rapidly absorbed after oral administration. Food delays the absorption of metolazone. The time to maximum plasma concentration is approximately 1.5 hours. 

Distribution: Volume of distribution ranges from 108.7± 21.3 Liters to 126.3 ± 53.4 Liters(Dose range 0.5 mg to 2 mg). Metolazone exhibits high plasma protein binding- PPB is 95%. [9]

Metabolism: Metolazone undergoes enterohepatic circulation. A study also indicates that metolazone affects the hPXR-mediated expression of CYP3A4 and MDR1 in human hepatocytes and increases CYP3A4 activity in various cell lines.[10]

Elimination: The mean elimination half-life of metolazone is between 6 to 8 hours. Metolazone is primarily excreted in the urine.

Administration

Metolazone is an oral agent, available in 2.5 mg, 5 mg, and 10 mg tablets. A dose of 5 to 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.[11] 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.[12]  

Metolazone is recommended to be taken in the morning due to its prolonged absorption and duration of action. According to guidelines, metolazone should be administered two to five hours before loop diuretic so that peak drug levels of metolazone are attained with the loop diuretic administration and maximum blockade of distal sodium reabsorption is accomplished.[7]

Use in Specific Patient Populations

Patients with Hepatic Impairment: No dose adjustment is required for patients with hepatic impairment

Patients with Renal Impairment: No dose adjustment is required for patients with renal impairment or with concurrent use of hemodialysis. Older patients are more likely to have decreased renal function; thus, care should be taken in dose selection, and renal function should be monitored.

Pregnancy Considerations: Metolazone is former FDA category B.  Metolazone crosses the placenta. Monitor for volume depletion to ensure adequate placental perfusion. The risk of exposure to the infant should be weighed against the benefit of treatment for the mother.[13]

Breastfeeding Considerations: Metolazone is also excreted in breast milk, so the potential for adverse reactions in nursing infants exists.[13] Metolazone tablets are indicated in pregnancy when it is pathological. The risk of exposure to the infant should be weighed against the benefit of treatment for the mother. Also, Severe diuresis with large doses of metolazone may decrease breast milk production. Other diuretics in low doses are preferred over metolazone.[14]

Adverse Effects

Hyperuricemia is a common adverse effect due to competitive inhibition of uric acid secretion and a decrease in extracellular fluid from diuretic effects. Other fluid and electrolyte imbalances may occur, especially hyponatremia, hypokalemia, and hypomagnesemia. Any electrolyte imbalances must be corrected before starting treatment.[15] Metolazone may impair glucose tolerance, causing hyperglycemia and glycosuria. Diabetic patients should monitor their blood and urine glucose levels while on this therapy.[16] 

Diuretic therapy may be associated with increased serum cholesterol and triglycerides; however, long-term studies have found that serum cholesterol levels return to normal or below the baseline after approximately one year of therapy. These temporary effects do not significantly increase the risk of coronary heart disease.[17] 

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.[18]  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.[19]  

Other rare adverse effects include agranulocytosis, photosensitization, aplastic anemia, Stevens-Johnson syndrome, and toxic epidermal necrolysis.[20]  

In a study of acute decompensated heart failure treatment metolazone with loop diuretics, metolazone therapy was associated with hypokalemia, hyponatremia, and deteriorating renal function in some patients.[19]

The BRASH syndrome is the term used for (Bradycardia, Renal failure, AV blockade, Shock, and Hyperkalaemia) and has been associated with metolazone therapy.[21]

Drug-induced cholestasis and hepatotoxicity have been reported.[9][22]

Contraindications

Different brands of metolazone are not therapeutically equivalent. FDA labeling recommended not to interchange formulations of metolazone. 

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.[23] 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.[24] Metolazone should not be used in patients experiencing a hepatic coma or hepatic encephalopathy because electrolyte disturbances can occur and exacerbate these disease processes.[25]

Anuric patients should have metolazone withheld. As the kidneys excrete metolazone, renal impairment can cause a dangerous accumulation of the metolazone. 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 before initiating metolazone.[15][19] 

Drug-Drug Interactions: Metolazone should be avoided in patients on lithium and digitalis as it can aggravate lithium and digitalis toxicity.[26]

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 managing 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.[11]

Additionally, because of the adverse effects of metolazone, serum electrolytes should be monitored at baseline and routinely while continuing therapy, including sodium, potassium, magnesium, and chloride.[15][19] Although evidence is controversial regarding hyperglycemia with metolazone, diabetic patients should monitor their serum glucose regularly while on this medication.[16]

Failure to decrease extracellular fluid volume despite using diuretics appropriately is termed ‘diuretic resistance.’  Diuretic resistance can be expressed as a fractional sodium excretion (FE) of <0.2%.[3]

Monitor the health-related quality of life by Kansas City Cardiomyopathy Questionnaire–12 (KCCQ-12).[27]

Toxicity

For diuretics in general, toxic doses are not well established. Chronic use is the most common cause of toxicity, such as hypotension and increased hematocrit due to plasma volume depletion and syncope. Hypokalemia, hyponatremia and reduced renal function, and increased mortality have been reported with the use of metolazone.[19] Sodium levels should be corrected according to serum glucose levels. 

There is no antidote to metolazone. Supportive measures should be instituted as soon as possible to maintain hydration, electrolyte balance, respiration, and cardiovascular and renal function. Due to its high plasma protein binding, it is not removed by dialysis.[9] Call the United states poison control center (800-222-1222) for the latest information regarding the management of specific overdoses.[28]

Enhancing Healthcare Team Outcomes

Congestive heart failure (CHF) patients can benefit from metolazone's diuretic effect. In one trial, adding metolazone to a loop diuretic (furosemide) in treating edema associated with CHF showed an increase in diuresis, urinary output, and weight loss compared to furosemide or metolazone alone.[29] Comparing metolazone to chlorothiazide in acutely decompensated heart failure patients with diuretic resistance, patients had an increase in 72-hour urine output and a shorter hospital stay when using metolazone.[30] [Level 3] Along with treating edema, low-dose metolazone can significantly change systolic and diastolic blood pressure in treating hypertension.[31] [Level 1] 

Effective treatment of edema associated with congestive heart failure and kidney disease requires the participation of every interprofessional healthcare team member. Metolazone is typically prescribed by clinicians (MDs, DOs, NPs, PAs) in patients with congestive heart failure with significant congestion and resistance to loop diuretics. Usually, heart failure specialist consultation is required to manage volume overload in acute decompensated heart failure. Nephrologist consultation is necessary for patients with edema due to kidney disease. Pharmacists should verify the dosing and check for potential drug interactions, reporting any concerns to the nursing staff or prescriber. Nursing should note any adverse events during metolazone therapy, monitor body weight and urine output, and reach out to the pharmacist if they have any questions. Both nursing and pharmacy have a significant responsibility in patient counseling.

In acute decompensated heart failure, close communication and collaboration between different team members are vital to optimize the outcomes related to metolazone therapy and minimize adverse drug reactions. According to  2022 AHA/ACC/HFSA guidelines, patients should receive treatment from multidisciplinary teams to facilitate the implementation of Goal-directed medical therapy (GDMT); hence; an interprofessional team approach and collaboration between cardiologists, HF specialists, nurses, pharmacists, dieticians, primary care clinicians, social workers, primary care clinicians, and additional specialists is crucial to optimize outcomes related to metolazone therapy with minimal adverse drug reactions.[5] [Level 1]