Metolazone

Last updated
Metolazone
Metolazone.svg
Metolazone ball-and-stick.png
Clinical data
Trade names Zaroxolyn
AHFS/Drugs.com Monograph
MedlinePlus a682345
Pregnancy
category
  • B
Routes of
administration
By mouth
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability ~65%
Metabolism kidney (minimal)
Elimination half-life 14 hours
Excretion primarily urine
Identifiers
  • 7-chloro-2-methyl-4-oxo-3-o-tolyl-1,2,3,4-tetrahydroquinazoline-6-sulfonamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.037.748 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C16H16ClN3O3S
Molar mass 365.83 g·mol−1
3D model (JSmol)
Melting point 260 °C (500 °F)
  • O=S(=O)(c3c(Cl)cc2c(C(=O)N(c1ccccc1C)C(N2)C)c3)N
  • InChI=1S/C16H16ClN3O3S/c1-9-5-3-4-6-14(9)20-10(2)19-13-8-12(17)15(24(18,22)23)7-11(13)16(20)21/h3-8,10,19H,1-2H3,(H2,18,22,23) Yes check.svgY
  • Key:AQCHWTWZEMGIFD-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Metolazone is a thiazide-like diuretic marketed under the brand names Zytanix, Metoz, Zaroxolyn, and Mykrox. It is primarily used to treat congestive heart failure and high blood pressure. Metolazone indirectly decreases the amount of water reabsorbed into the bloodstream by the kidney, so that blood volume decreases and urine volume increases. This lowers blood pressure and prevents excess fluid accumulation in heart failure. Metolazone is sometimes used together with loop diuretics such as furosemide or bumetanide, but these highly effective combinations can lead to dehydration and electrolyte abnormalities.

Contents

It was patented in 1966 and approved for medical use in 1974. [1]

Medical uses

One of the primary uses of metolazone is for treating edema (fluid retention) associated with congestive heart failure (CHF). In mild heart failure, metolazone or another diuretic may be used alone, or combined with other diuretics for moderate or severe heart failure. In addition to preventing fluid buildup, the use of metolazone may allow the patient to relax the amount of sodium restriction that is required. Although most thiazide diuretics lose their effectiveness in kidney failure, metolazone remains active even when the glomerular filtration rate (GFR) is below 30–40 mL/min (moderate chronic kidney disease).[ citation needed ] This gives it a considerable advantage over other thiazide diuretics, since renal and heart failure often coexist and contribute to fluid retention. [2]

Metolazone may also be used in kidney disease, such as chronic kidney disease or the nephrotic syndrome. Chronic kidney disease causes excess fluid retention that is often treated with diet adjustments and diuretics. [2] Metolazone may be combined with other diuretics (typically loop diuretics) to treat diuretic resistance in congestive heart failure, chronic kidney disease, and nephrotic syndrome. [3] Metolazone and a loop diuretic will synergistically enhance diuresis over the use of either agent alone. Using this combination, diuretic effects will occur at two different segments of the nephron; namely, the loop diuretic will act at the loop of Henle, and metolazone will act at the distal convoluted tubule. Metolazone is frequently prescribed in addition to the loop diuretic. Metolazone may be used for edema caused by liver cirrhosis as well.

The other major use of metolazone is in treating hypertension (high blood pressure). Thiazide diuretics, though usually not metolazone, are very often used alone as first-line treatment for mild hypertension. They are also used in combination with other drugs for difficult-to-treat or more severe hypertension. "The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure" (JNC 7) recommends thiazide diuretics as the initial medication for treatment of hypertension. Hydrochlorothiazide is by far the most commonly used, as it is both better-studied and cheaper (about four times) than metolazone, although as mentioned above metolazone is used in patients with moderate chronic kidney disease. [4]

Toxicity

Since thiazide diuretics affect the transport of electrolytes and water in the kidney, they can be responsible for abnormalities of water balance and electrolyte levels. Removal of too much fluid can cause volume depletion and hypotension. Various electrolyte abnormalities may result, including hyponatremia (low sodium), hypokalemia (low potassium), hypochloremia (low chloride), hypomagnesemia (low magnesium), hypercalcemia (high calcium), and hyperuricemia (high uric acid). These may result in dizziness, headache, or heart arrhythmias (palpitations). [4] Serious, though rare, side effects include aplastic anemia, pancreatitis, agranulocytosis, and angioedema. Metolazone, like other thiazide diuretics, may unmask latent diabetes mellitus or exacerbate gout, especially by interacting with medicines used to treat gout. In addition, thiazide diuretics, including metolazone, are sulfonamides; those with hypersensitivity to sulfonamides ("sulfa allergy") may also be allergic to metolazone. [4]

Mechanism of action

Schematic of a nephron. The distal convoluted tubule and proximal convoluted tubule are labeled in Latin ("tubulus contortus proximalis" and "tubulus contortus distalis") in this illustration. Kidney nephron.png
Schematic of a nephron. The distal convoluted tubule and proximal convoluted tubule are labeled in Latin ("tubulus contortus proximalis" and "tubulus contortus distalis") in this illustration.

The primary target of all thiazide diuretics, including metolazone, is the distal convoluted tubule, part of the nephron in the kidney, where they inhibit the sodium-chloride symporter.

In the kidney, blood is filtered into the lumen, or open space, of the nephron tubule. Whatever remains in the tubule will travel to the bladder as urine and eventually be excreted. The cells lining the tubule modify the fluid inside, absorbing some material and excreting others. One side of the cell (the apical side) faces the lumen; the opposite side (the basolateral side) faces the interstitial space near blood vessels. The other sides are tightly joined to neighboring cells.

As with other regions, tubule cells in the distal convoluted tubule possess the ATP-powered sodium-potassium antiporter (Na+/K+-ATPase), which uses energy from ATP to transfer three sodium ions out from the basolateral surface (toward blood vessels) while simultaneously transferring two potassium ions in. The distal convoluted tubule cells also possess a sodium-chloride symporter on the apical side, which passively allows one sodium ion and one chloride ion to diffuse together in from the lumen (where urine is forming) into the cell interior. As sodium is pumped out of the cell by the ATPase, its intracellular concentration falls, and additional sodium begins to diffuse in from the tubule lumen as replacement. The symporter requires chloride to be transported in as well. Water passively follows to maintain isotonicity; excess chloride and potassium passively diffuse out the cell through basolateral channels into the interstitial space, and water accompanies them. The water and chloride, as well as the sodium pumped out by the ATPase, will be absorbed into the bloodstream.

Metolazone and the other thiazide diuretics inhibit the function of the sodium-chloride symporter, preventing sodium and chloride, and therefore water too, from leaving the lumen to enter the tubule cell. As a result, water remains in the lumen and is excreted as urine, instead of being reabsorbed into the bloodstream. Since most of the sodium in the lumen has already been reabsorbed by the time the filtrate reaches the distal convoluted tubule, thiazide diuretics have limited effects on water balance and on electrolyte levels. [4] Nevertheless, they can be associated with low sodium levels, volume depletion, and low blood pressure, among other adverse effects.

Pharmacokinetics

Metolazone is only available in oral preparations. Approximately 65% of the amount ingested becomes available in the bloodstream. Its half-life is approximately fourteen hours, similar to indapamide but considerably longer than hydrochlorothiazide. Metolazone is around ten times as potent as hydrochlorothiazide. The primary form of excretion is in the urine (around 80%); the remaining fifth is evenly split between biliary excretion and metabolism into inactive forms. [4]

Chemistry

The use of activated anthranilic acid derivatives facilitates the preparation of the amides in those cases where the amines are either unreactive or difficult to obtain.

Metolazone center: Metolazone.png
Metolazone center:

Thus, reaction of (1) with phosgene gives the reactive the isatoic anhydride (2). Condensation of that with ortho-toluidine leads to the acylation product (3) formed with a simultaneous loss of carbon dioxide. This is then converted to the quinazolone (4) by heating with acetic anhydride. Reaction with sodium borohydride in the presence of aluminum chloride selectively reduces the double bond to yield the diuretic agent metolazone (5).

Structure and classification

Metolazone is a quinazoline, a derivative of the similar diuretic quinethazone, as well as a sulfonamide. It is related to analogs of 1,2,4-benzothiadizine-1,1-dioxide (benzothiadiazine). Such drugs are called benzothiadiazides, or thiazides for short; however, in terms of chemistry, metolazone is not a substituted benzothiadiazine, and therefore is not technically a thiazide. Since metolazone (as well as other drugs like indapamide) acts on the same target as thiazides and behave in a similar pharmacologic fashion, it is, however, considered a "thiazide-like diuretic." Therefore, metolazone and similar drugs are often categorized with thiazide diuretics despite not being thiazides themselves. [4]

History

Metolazone was developed in the 1970s. Its creator, Indian born chemist Dr. Bola Vithal Shetty has been active in helping the U.S. Food and Drug Administration review drug applications, and in the development of new medicines. [6] Metolazone quickly gained popularity due to its lower kidney toxicity compared to other diuretics (especially thiazides) in patients with chronic kidney disease.

Related Research Articles

<span class="mw-page-title-main">Diabetes insipidus</span> Condition characterized by large amounts of dilute urine and increased thirst

Diabetes insipidus (DI), alternately called arginine vasopressin deficiency (AVP-D) or arginine vasopressin resistance (AVP-R), is a condition characterized by large amounts of dilute urine and increased thirst. The amount of urine produced can be nearly 20 liters per day. Reduction of fluid has little effect on the concentration of the urine. Complications may include dehydration or seizures.

<span class="mw-page-title-main">Nephron</span> Microscopic structural and functional unit of the kidney.

The nephron is the minute or microscopic structural and functional unit of the kidney. It is composed of a renal corpuscle and a renal tubule. The renal corpuscle consists of a tuft of capillaries called a glomerulus and a cup-shaped structure called Bowman's capsule. The renal tubule extends from the capsule. The capsule and tubule are connected and are composed of epithelial cells with a lumen. A healthy adult has 1 to 1.5 million nephrons in each kidney. Blood is filtered as it passes through three layers: the endothelial cells of the capillary wall, its basement membrane, and between the foot processes of the podocytes of the lining of the capsule. The tubule has adjacent peritubular capillaries that run between the descending and ascending portions of the tubule. As the fluid from the capsule flows down into the tubule, it is processed by the epithelial cells lining the tubule: water is reabsorbed and substances are exchanged ; first with the interstitial fluid outside the tubules, and then into the plasma in the adjacent peritubular capillaries through the endothelial cells lining that capillary. This process regulates the volume of body fluid as well as levels of many body substances. At the end of the tubule, the remaining fluid—urine—exits: it is composed of water, metabolic waste, and toxins.

<span class="mw-page-title-main">Distal convoluted tubule</span> Feature of kidney anatomy

The distal convoluted tubule (DCT) is a portion of kidney nephron between the loop of Henle and the collecting tubule.

<span class="mw-page-title-main">Renal physiology</span> Study of the physiology of the kidney

Renal physiology is the study of the physiology of the kidney. This encompasses all functions of the kidney, including maintenance of acid-base balance; regulation of fluid balance; regulation of sodium, potassium, and other electrolytes; clearance of toxins; absorption of glucose, amino acids, and other small molecules; regulation of blood pressure; production of various hormones, such as erythropoietin; and activation of vitamin D.

<span class="mw-page-title-main">Hydrochlorothiazide</span> Diuretic medication

Hydrochlorothiazide, sold under the brand name Hydrodiuril among others, is a diuretic medication used to treat hypertension and swelling due to fluid build-up. Other uses include treating diabetes insipidus and renal tubular acidosis and to decrease the risk of kidney stones in those with a high calcium level in the urine. Hydrochlorothiazide is taken by mouth and may be combined with other blood pressure medications as a single pill to increase effectiveness. Hydrochlorothiazide is a thiazide medication which inhibits reabsorption of sodium and chloride ions from the distal convoluted tubules of the kidneys, causing a natriuresis. This initially increases urine volume and lowers blood volume. It is believed to reduce peripheral vascular resistance.

<span class="mw-page-title-main">Loop of Henle</span> Part of kidney tissue

In the kidney, the loop of Henle is the portion of a nephron that leads from the proximal convoluted tubule to the distal convoluted tubule. Named after its discoverer, the German anatomist Friedrich Gustav Jakob Henle, the loop of Henle's main function is to create a concentration gradient in the medulla of the kidney.

<span class="mw-page-title-main">Loop diuretic</span> Diuretics that act at the ascending limb of the loop of Henle in the kidney

Loop diuretics are diuretics that act on the Na-K-Cl cotransporter along the thick ascending limb of the loop of Henle in nephrons of the kidneys. They are primarily used in medicine to treat hypertension and edema often due to congestive heart failure or chronic kidney disease. While thiazide diuretics are more effective in patients with normal kidney function, loop diuretics are more effective in patients with impaired kidney function.

<span class="mw-page-title-main">Amiloride</span> Medication

Amiloride, sold under the trade name Midamor among others, is a medication typically used with other medications to treat high blood pressure or swelling due to heart failure or cirrhosis of the liver. Amiloride is classified as a potassium-sparing diuretic. Amiloride is often used together with another diuretic, such as a thiazide or loop diuretic. It is taken by mouth. Onset of action is about two hours and it lasts for about a day.

<span class="mw-page-title-main">Chlortalidone</span> Thiazide-like diuretic drug

Chlortalidone, also known as chlorthalidone, is a thiazide-like diuretic drug used to treat high blood pressure, swelling, diabetes insipidus, and renal tubular acidosis. Because chlortalidone is reliably effective in most patients with high blood pressure, it is considered a preferred initial treatment. It is also used to prevent calcium-based kidney stones. It is taken by mouth. Effects generally begin within three hours and last for up to three days. Long-term treatment with chlortalidone is more effective than hydrochlorothiazide for prevention of heart attack or stroke.

<span class="mw-page-title-main">Bendroflumethiazide</span> Chemical compound

Bendroflumethiazide, formerly bendrofluazide, trade name Aprinox, is a thiazide diuretic used to treat hypertension.

<span class="mw-page-title-main">Thiazide</span> Class of chemical compounds

Thiazide refers to both a class of sulfur-containing organic molecules and a class of diuretics based on the chemical structure of benzothiadiazine. The thiazide drug class was discovered and developed at Merck and Co. in the 1950s. The first approved drug of this class, chlorothiazide, was marketed under the trade name Diuril beginning in 1958. In most countries, thiazides are the least expensive antihypertensive drugs available.

<span class="mw-page-title-main">Gitelman syndrome</span> Medical condition

Gitelman syndrome (GS) is an autosomal recessive kidney tubule disorder characterized by low blood levels of potassium and magnesium, decreased excretion of calcium in the urine, and elevated blood pH. It is the most frequent hereditary salt-losing tubulopathy. Gitelman syndrome is caused by disease-causing variants on both alleles of the SLC12A3 gene. The SLC12A3 gene encodes the thiazide-sensitive sodium-chloride cotransporter, which can be found in the distal convoluted tubule of the kidney.

<span class="mw-page-title-main">Potassium-sparing diuretic</span> Drugs that cause diuresis without causing potassium loss in the urine and leading to hyperkalemia

Potassium-sparing diuretics refers to drugs that cause diuresis without causing potassium loss in the urine. They are typically used as an adjunct in management of hypertension, cirrhosis, and congestive heart failure. The steroidal aldosterone antagonists can also be used for treatment of primary hyperaldosteronism. Spironolactone, a steroidal aldosterone antagonist, is also used in management of female hirsutism and acne from PCOS or other causes.

<span class="mw-page-title-main">Bartter syndrome</span> Medical condition

Bartter syndrome (BS) is a rare inherited disease characterised by a defect in the thick ascending limb of the loop of Henle, which results in low potassium levels (hypokalemia), increased blood pH (alkalosis), and normal to low blood pressure. There are two types of Bartter syndrome: neonatal and classic. A closely associated disorder, Gitelman syndrome, is milder than both subtypes of Bartter syndrome.

<span class="mw-page-title-main">Sodium-chloride symporter</span> Protein-coding gene in the species Homo sapiens

The sodium-chloride symporter (also known as Na+-Cl cotransporter, NCC or NCCT, or as the thiazide-sensitive Na+-Cl cotransporter or TSC) is a cotransporter in the kidney which has the function of reabsorbing sodium and chloride ions from the tubular fluid into the cells of the distal convoluted tubule of the nephron. It is a member of the SLC12 cotransporter family of electroneutral cation-coupled chloride cotransporters. In humans, it is encoded by the SLC12A3 gene (solute carrier family 12 member 3) located in 16q13.

<span class="mw-page-title-main">Clopamide</span> Chemical compound

Clopamide is a piperidine diuretic.

<span class="mw-page-title-main">Ascending limb of loop of Henle</span>

Within the nephron of the kidney, the ascending limb of the loop of Henle is a segment of the heterogenous loop of Henle downstream of the descending limb, after the sharp bend of the loop. This part of the renal tubule is divided into a thin and thick ascending limb; the thick portion is also known as the distal straight tubule, in contrast with the distal convoluted tubule downstream.

<span class="mw-page-title-main">Dent's disease</span> Medical condition

Dent's disease is a rare X-linked recessive inherited condition that affects the proximal renal tubules of the kidney. It is one cause of Fanconi syndrome, and is characterized by tubular proteinuria, excess calcium in the urine, formation of calcium kidney stones, nephrocalcinosis, and chronic kidney failure.

<span class="mw-page-title-main">Xipamide</span> Chemical compound used as a diuretic

Xipamide is a sulfonamide diuretic drug marketed by Eli Lilly under the trade names Aquaphor and Aquaphoril. It is used for the treatment of oedema and hypertension.

<span class="mw-page-title-main">Diuretic</span> Substance that promotes the production of urine

A diuretic is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics increase the excretion of water from the body, through the kidneys. There exist several classes of diuretic, and each works in a distinct way. Alternatively, an antidiuretic, such as vasopressin, is an agent or drug which reduces the excretion of water in urine.

References

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  2. 1 2 Braunwald E (2005). "Heart Failure and Cor Pulmonale". In Kasper DL, et al. (eds.). Harrison's Principles of Internal Medicine (15th ed.). New York: McGraw-Hill.
  3. Rosenberg J, Gustafsson F, Galatius S, Hildebrandt PR (August 2005). "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. 19 (4): 301–6. doi:10.1007/s10557-005-3350-2. PMID   16189620. S2CID   23704590.
  4. 1 2 3 4 5 6 Jackson EK (2006). "Diuretics". In Brunton LL, et al. (eds.). Goodman & Gilman's The Pharmacological Basis of Therapeutics (11th ed.). New York: McGraw-Hill.
  5. Shetty BV, Campanella LA, Thomas TL, Fedorchuk M, Davidson TA, Michelson L, et al. (September 1970). "Synthesis and activity of some 3-aryl- and 3-aralkyl-1,2,3,4-tetrahydro-4-oxo-6-quinazolinesulfonamides". Journal of Medicinal Chemistry. 13 (5): 886–95. doi:10.1021/jm00299a022. PMID   5458377.
  6. Katague DB. "Chemistry Reviewer Still in Lab" (PDF). News Along the Pike. Food and Drug Administration' s Center for Drug Evaluation and Research. 2 (10).