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. The Food and Drug Administration (FDA) has approved metolazone to treat salt and water retention causing edema accompanying congestive heart failure or kidney disease. It is commonly used in the treatment of severe CHF to produce diuresis in combination with loop diuretics in patients refractory to loop diuretics alone. The synergy of these diuretics may help overcome the resistance that can develop with continued loop diuretic use. It can be used in the treatment of 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.
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 effects. 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.
Metolazone is an oral agent, available in 2.5mg, 5mg, and 10mg tablets. For the treatment of edema associated with congestive heart failure or kidney disease, a dose of 5-20mg once daily is recommended as the initial treatment. 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 the same as above. Specific pediatric dosing is not available through the manufacturer because safety and efficacy haven't been established. However, one study suggests 0.2-0.4 mg/kg/day by mouth every 12-24 hours. No dose adjustment is required for renal or hepatic impairment or with concurrent use of hemodialysis. Metolazone should be given in the morning, due to its prolonged absorption and duration of action.
A common adverse effect is hyperuricemia (an excess of uric acid in the blood). This is due to competitive inhibition of uric acid secretion and a decrease in extracellular fluid from diuretic effects. Other fluid and electrolyte imbalances may present, especially hyponatremia, hypokalemia, and hypomagnesemia. It is essential that any electrolyte imbalances be corrected before starting treatment. Metolazone may impair glucose tolerance, causing hyperglycemia and glycosuria. Diabetic patients should have their blood and urine glucose levels monitored while on this therapy. 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 baseline. These temporary effects do not significantly increase the risk of coronary heart disease.
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 old and older. 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. 
Other rare adverse effects include agranulocytosis, aplastic anemia, Steven-Johnson Syndrome, and toxic epidermal necrolysis.
Metolazone is excreted in breast-milk. Therefore, 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.
Therapy is contraindicated in those with known metalozone hypersensitivity. Although this medication is a thiazide-like diuretic, cross-reactivity is rarely seen between metalozone and other diuretics. There is limited evidence, however, 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. Metolazone should not be used in patients who are experiencing a hepatic coma or hepatic encephalopathy because electrolyte disturbances can occur and exacerbate or worsen these disease processes. Anuric patients should have metolazone withheld. It is excreted by the kidneys, so kidney 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. Lastly, a concurrent electrolyte imbalance is a contraindication to metolazone therapy as these should be corrected prior to initiating metolazone. 
To monitor the effectiveness of therapy in the treatment of 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 initiating therapy. Current guidelines for high blood pressure suggest assessing blood pressure monthly when starting or adjusting therapy, and every 3-6 months for patients at goal. Additionally, because of the adverse effects associated with metolazone, serum electrolytes should be monitored at baseline and routinely while continuing therapy; those include sodium, potassium, magnesium, and chloride. Although evidence is controversial in the incidence of hyperglycemia with metolazone, diabetic patients should monitor their serum glucose regularly while on this medication.
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.
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. [Level II] 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.[Level III] Along with treating edema, low dose metolazone can result in significant changes in both systolic and diastolic blood pressure in the treatment of hypertension. [Level I]
|||Rosenberg J,Gustafsson F,Galatius S,Hildebrandt PR, Combination therapy with metolazone and loop diuretics in outpatients with refractory heart failure: an observational study and review of the literature. Cardiovascular drugs and therapy. 2005 Aug [PubMed PMID: 16189620]|
|||Musini VM,Nazer M,Bassett K,Wright JM, Blood pressure-lowering efficacy of monotherapy with thiazide diuretics for primary hypertension. The Cochrane database of systematic reviews. 2014 May 29 [PubMed PMID: 24869750]|
|||Paton RR,Kane RE, Long-term diuretic therapy with metolazone of renal failure and the nephrotic syndrome. Journal of clinical pharmacology. 1977 Apr [PubMed PMID: 849998]|
|||Brook RD,Rajagopalan S, 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults. A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Journal of the American Society of Hypertension : JASH. 2018 Mar [PubMed PMID: 29396104]|
|||Arnold WC, Efficacy of metolazone and furosemide in children with furosemide-resistant edema. Pediatrics. 1984 Nov [PubMed PMID: 6493882]|
|||Shulenberger CE,Jiang A,Devabhakthuni S,Ivaturi V,Liu T,Reed BN, Efficacy and Safety of Intravenous Chlorothiazide versus Oral Metolazone in Patients with Acute Decompensated Heart Failure and Loop Diuretic Resistance. Pharmacotherapy. 2016 Aug [PubMed PMID: 27393709]|
|||Brisco-Bacik MA,Ter Maaten JM,Houser SR,Vedage NA,Rao V,Ahmad T,Wilson FP,Testani JM, Outcomes Associated With a Strategy of Adjuvant Metolazone or High-Dose Loop Diuretics in Acute Decompensated Heart Failure: A Propensity Analysis. Journal of the American Heart Association. 2018 Sep 18 [PubMed PMID: 30371181]|
|||Cooper-DeHoff RM,Wen S,Beitelshees AL,Zineh I,Gums JG,Turner ST,Gong Y,Hall K,Parekh V,Chapman AB,Boerwinkle E,Johnson JA, Impact of abdominal obesity on incidence of adverse metabolic effects associated with antihypertensive medications. Hypertension (Dallas, Tex. : 1979). 2010 Jan [PubMed PMID: 19917874]|
|||Freis ED, Critique of the clinical importance of diurectic-induced hypokalemia and elevated cholesterol level. Archives of internal medicine. 1989 Dec [PubMed PMID: 2688584]|
|||Leipzig RM,Cumming RG,Tinetti ME, Drugs and falls in older people: a systematic review and meta-analysis: II. Cardiac and analgesic drugs. Journal of the American Geriatrics Society. 1999 Jan [PubMed PMID: 9920228]|
|||Kumar P,Chauhan A,Charaniya R,Ghosh A,Tandon V, Metolazone Associated Stevens Johnson Syndrome-Toxic Epidermal Necrolysis Overlap. Journal of clinical and diagnostic research : JCDR. 2016 Mar [PubMed PMID: 27134890]|
|||Transfer of drugs and other chemicals into human milk. Pediatrics. 2001 Sep [PubMed PMID: 11533352]|
|||Sullivan TJ, Cross-reactions among furosemide, hydrochlorothiazide, and sulfonamides. JAMA. 1991 Jan 2 [PubMed PMID: 1984112]|
|||Healy R,Jankowski TA,Crownover B, Clinical inquiries. Which diuretics are safe and effective for patients with a sulfa allergy? The Journal of family practice. 2007 Jun [PubMed PMID: 17543262]|
|||Hillenbrand P,Sherlock S, Use of metolazone in the treatment of ascites due to liver disease. British medical journal. 1971 Oct 30 [PubMed PMID: 5123909]|
|||Grosskopf I,Rabinovitz M,Rosenfeld JB, Combination of furosemide and metolazone in the treatment of severe congestive heart failure. Israel journal of medical sciences. 1986 Nov [PubMed PMID: 3793436]|
|||Moranville MP,Choi S,Hogg J,Anderson AS,Rich JD, Comparison of metolazone versus chlorothiazide in acute decompensated heart failure with diuretic resistance. Cardiovascular therapeutics. 2015 Apr [PubMed PMID: 25712736]|
|||Curry CL,Janda SM,Harris R,MacKay JH,Nugent CA,Ryan J,Schnaper H,Schoenberger J, Clinical studies of a new, low-dose formulation of metolazone for the treatment of hypertension. Clinical therapeutics. 1986 [PubMed PMID: 3545477]|