Metolazone
Encyclopedia
Not to be confused with Metaxalone
Metaxalone
Metaxalone is a muscle relaxant used to relax muscles and relieve pain caused by strains, sprains, and other musculoskeletal conditions. Its exact mechanism of action is not known, but it may be due to general central nervous system depression...

, a muscle relaxant.

Metolazone is a thiazide-like diuretic marketed under the brand names Zytanix from Zydus Cadila, Zaroxolyn, and Mykrox. It is primarily used to treat congestive heart failure
Congestive heart failure
Heart failure often called congestive heart failure is generally defined as the inability of the heart to supply sufficient blood flow to meet the needs of the body. Heart failure can cause a number of symptoms including shortness of breath, leg swelling, and exercise intolerance. The condition...

 and high blood pressure
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...

. Metolazone indirectly decreases the amount of water reabsorbed into the bloodstream by the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...

, 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 diuretic
Loop diuretic
Loop diuretics are diuretics that act on the ascending loop of Henle in the kidney. They are primarily used in medicine to treat hypertension and edema often due to congestive heart failure or renal insufficiency...

s such as furosemide
Furosemide
Furosemide or frusemide is a loop diuretic used in the treatment of congestive heart failure and edema. It is most commonly marketed by Sanofi-Aventis under the brand name Lasix...

 or bumetanide
Bumetanide
Bumetanide is a loop diuretic of the sulfamyl category to treat heart failure. It is often used in people in whom high doses of furosemide are ineffective. It is marketed by Hoffmann-La Roche. The main difference between the two substances is in bioavailability and pharmacodynamic potency...

, but these highly effective combinations can lead to dehydration
Dehydration
In physiology and medicine, dehydration is defined as the excessive loss of body fluid. It is literally the removal of water from an object; however, in physiological terms, it entails a deficiency of fluid within an organism...

 and electrolyte abnormalities
Electrolyte disturbance
Electrolytes play a vital role in maintaining homeostasis within the body. They help to regulate myocardial and neurological function, fluid balance, oxygen delivery, acid-base balance and much more. Electrolyte imbalances can develop by the following mechanisms: excessive ingestion; diminished...

.

History

Metolazone was developed in the 1970s. Its creator, India
India
India , officially the Republic of India , is a country in South Asia. It is the seventh-largest country by geographical area, the second-most populous country with over 1.2 billion people, and the most populous democracy in the world...

n born chemist Dr. Bola Vithal Shetty
B. Vithal Shetty
Dr. Bola Vithal Shetty is an India born American scientist who developed Metolazone and was associated with the Food and Drug Administration agency.-References:...

 has been active in helping the U.S.
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...

 Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

 review drug applications, and in the development of new medicines.
Metolazone quickly gained popularity due to its lower renal toxicity compared to other diuretics (especially thiazides) in patients with renal insufficiency.
It is marketed as various brands such as MELA by RPG Lifesciences and Zytanix by Zydus

Structure

Metolazone is a quinazoline
Quinazoline
Quinazoline is a compound made up of two fused six-membered simple aromatic rings, a benzene ring and a pyrimidine ring. Its chemical formula is C8H6N2. Quinazoline is yellow and crystalline...

, a derivative of the similar diuretic quinethazone
Quinethazone
Quinethazone is a thiazide diuretic used to treat hypertension. Common side effects include dizziness, dry mouth, nausea, and low potassium levels.-References:...

, as well as a sulfonamide
Sulfonamide (medicine)
Sulfonamide or sulphonamide is the basis of several groups of drugs. The original antibacterial sulfonamides are synthetic antimicrobial agents that contain the sulfonamide group. Some sulfonamides are also devoid of antibacterial activity, e.g., the anticonvulsant sultiame...

. It is related to analogs of 1,2,4-benzothiadizine-1,1-dioxide (benzothiadiazine
Benzothiadiazine
Benzothiadiazine is a bicyclic heterocyclic benzene derivative with the heterocycle containing two nitrogens and one sulfur.Benzothiadiazine derivatives include:* bendroflumethiazide* chlorothiazide* cyclothiazide* hydrochlorothiazide* diazoxide...

). These drugs are called benzothiadiazides, or thiazides for short. Chemically, metolazone is not a substituted benzothiadiazine, and therefore is not technically a thiazide
Thiazide
Thiazide is a term used to describe a type of molecule and a class of diuretics often used to treat hypertension and edema ....

. However, since metolazone, as well other drugs like indapamide
Indapamide
Indapamide is a thiazide diuretic drug marketed by Servier, generally used in the treatment of hypertension, as well as decompensated cardiac failure. The US trade name for indapamide is Lozol. Indapamide is marketed as Natrilix outside of the US, as Insig in Australia...

, act on the same target as thiazides and behave in a similar pharmacologic fashion, they are considered "thiazide-like diuretics". Therefore, they are often included in the thiazide diuretics despite not being thiazides themselves.

Mechanism of action

The primary target of all thiazide diuretics, including metolazone, is the distal convoluted tubule
Distal convoluted tubule
The distal convoluted tubule is a portion of kidney nephron between the loop of Henle and the collecting duct system.- Physiology :It is partly responsible for the regulation of potassium, sodium, calcium, and pH...

, part of the nephron
Nephron
The renal tubule is the portion of the nephron containing the tubular fluid filtered through the glomerulus. After passing through the renal tubule, the filtrate continues to the collecting duct system, which is not part of the nephron....

 in the kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...

, where they inhibit the sodium-chloride symporter
Sodium-chloride symporter
The sodium-chloride symporter 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...

.

In the kidney, blood is filtered into the lumen
Lumen (anatomy)
A lumen in biology is the inside space of a tubular structure, such as an artery or intestine...

, or open space, of the nephron tubule. Whatever remains in the tubule will travel to the bladder
Urinary bladder
The urinary bladder is the organ that collects urine excreted by the kidneys before disposal by urination. A hollow muscular, and distensible organ, the bladder sits on the pelvic floor...

 as urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...

 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
Adenosine triphosphate
Adenosine-5'-triphosphate is a multifunctional nucleoside triphosphate used in cells as a coenzyme. It is often called the "molecular unit of currency" of intracellular energy transfer. ATP transports chemical energy within cells for metabolism...

-powered sodium
Sodium
Sodium is a chemical element with the symbol Na and atomic number 11. It is a soft, silvery-white, highly reactive metal and is a member of the alkali metals; its only stable isotope is 23Na. It is an abundant element that exists in numerous minerals, most commonly as sodium chloride...

-potassium
Potassium
Potassium is the chemical element with the symbol K and atomic number 19. Elemental potassium is a soft silvery-white alkali metal that oxidizes rapidly in air and is very reactive with water, generating sufficient heat to ignite the hydrogen emitted in the reaction.Potassium and sodium are...

 antiporter
Antiporter
An antiporter is an integral membrane protein involved in secondary active transport of two or more different molecules or ions across a phospholipid membrane such as the plasma membrane in opposite directions.In secondary active transport, one species of solute moves along its electrochemical...

 (Na+/K+-ATPase
Na+/K+-ATPase
Na+/K+-ATPase is an enzyme located in the plasma membrane in all animals.- Sodium-potassium pumps :Active transport is responsible for cells containing relatively high...

), which uses energy from ATP to transfer three sodium ions out from the basolateral surface (toward blood vessel
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...

s) while simultaneously transferring two potassium ions in. The distal convoluted tubule cells also possess a sodium-chloride symporter
Sodium-chloride symporter
The sodium-chloride symporter 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...

 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 isotonic
Isotonic
The term isotonic may refer to;*Isotonic for the term associated with muscle contraction*An isotone in nuclear physics*Sports drinks are sometimes designed in an isotonic way to assist athletes rehydrate while balancing electrolytes...

ity; 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
Electrolyte
In chemistry, an electrolyte is any substance containing free ions that make the substance electrically conductive. The most typical electrolyte is an ionic solution, but molten electrolytes and solid electrolytes are also possible....

 levels. Nevertheless, they can be associated with low sodium levels
Hyponatremia
Hyponatremia is an electrolyte disturbance in which the sodium concentration in the serum is lower than normal. In the vast majority of cases, hyponatremia occurs as a result of excess body water diluting the serum sodium and is not due to sodium deficiency. Sodium is the dominant extracellular...

, volume depletion, and low blood pressure
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...

, among other adverse effects.

Pharmacokinetics

Metolazone is only available in oral
Tablet
A tablet is a pharmaceutical dosage form. It comprises a mixture of active substances and excipients, usually in powder form, pressed or compacted from a powder into a solid dose...

 preparations. Approximately 65% of the amount ingested becomes available in the bloodstream. Its half-life
Half-life
Half-life, abbreviated t½, is the period of time it takes for the amount of a substance undergoing decay to decrease by half. The name was originally used to describe a characteristic of unstable atoms , but it may apply to any quantity which follows a set-rate decay.The original term, dating to...

 is approximately fourteen hours, similar to indapamide but considerably longer than hydrochlorothiazide
Hydrochlorothiazide
Hydrochlorothiazide, abbreviated HCTZ, HCT, or HZT, is a first-line diuretic drug of the thiazide class that acts by inhibiting the kidneys' ability to retain water. This reduces the volume of the blood, decreasing blood return to the heart and thus cardiac output and, by other mechanisms, is...

. 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
Bile
Bile or gall is a bitter-tasting, dark green to yellowish brown fluid, produced by the liver of most vertebrates, that aids the process of digestion of lipids in the small intestine. In many species, bile is stored in the gallbladder and upon eating is discharged into the duodenum...

 excretion and metabolism into inactive forms.

Use

One of the primary uses of metolazone is for treating oedema (fluid retention) associated with congestive heart failure
Congestive heart failure
Heart failure often called congestive heart failure is generally defined as the inability of the heart to supply sufficient blood flow to meet the needs of the body. Heart failure can cause a number of symptoms including shortness of breath, leg swelling, and exercise intolerance. The condition...

 (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 renal failure
Renal failure
Renal failure or kidney failure describes a medical condition in which the kidneys fail to adequately filter toxins and waste products from the blood...

, metolazone remains active even when the glomerular filtration rate (GFR) is below 30–40 mL/min (moderate renal failure). This gives it a considerable advantage over other thiazide diuretics, since renal and heart failure often coexist and contribute to fluid retention.

Metolazone may also be used in renal (kidney) disease, such as chronic renal failure
Chronic renal failure
Chronic kidney disease , also known as chronic renal disease, is a progressive loss in renal function over a period of months or years. The symptoms of worsening kidney function are unspecific, and might include feeling generally unwell and experiencing a reduced appetite...

 or the nephrotic syndrome
Nephrotic syndrome
Nephrotic syndrome is a nonspecific disorder in which the kidneys are damaged, causing them to leak large amounts of protein from the blood into the urine....

. Chronic renal failure causes excess fluid retention that is often treated with diet
Diet (nutrition)
In nutrition, diet is the sum of food consumed by a person or other organism. Dietary habits are the habitual decisions an individual or culture makes when choosing what foods to eat. With the word diet, it is often implied the use of specific intake of nutrition for health or weight-management...

 adjustments and diuretics Metolazone may be combined with other diuretics (typically loop diuretics) to treat diuretic resistance in CHF, chronic renal failure, and nephrotic syndrome. 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
Loop of Henle
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 F. G. J...

, 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
Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...

 as well.

The other major use of metolazone is in treating hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...

 (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
Hydrochlorothiazide
Hydrochlorothiazide, abbreviated HCTZ, HCT, or HZT, is a first-line diuretic drug of the thiazide class that acts by inhibiting the kidneys' ability to retain water. This reduces the volume of the blood, decreasing blood return to the heart and thus cardiac output and, by other mechanisms, is...

 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 renal failure.

Toxicity

Since thiazide diuretics affect the transport of electrolyte
Electrolyte
In chemistry, an electrolyte is any substance containing free ions that make the substance electrically conductive. The most typical electrolyte is an ionic solution, but molten electrolytes and solid electrolytes are also possible....

s 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
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...

. Various electrolyte abnormalities may result, including hyponatremia
Hyponatremia
Hyponatremia is an electrolyte disturbance in which the sodium concentration in the serum is lower than normal. In the vast majority of cases, hyponatremia occurs as a result of excess body water diluting the serum sodium and is not due to sodium deficiency. Sodium is the dominant extracellular...

 (low sodium), hypokalemia
Hypokalemia
Hypokalemia or hypokalaemia , also hypopotassemia or hypopotassaemia , refers to the condition in which the concentration of potassium in the blood is low...

 (low potassium), hypochloremia
Hypochloremia
Hypochloremia is an electrolyte disturbance whereby there is an abnormally depleted level of the chloride ion in the blood.It rarely occurs in the absence of other abnormalities.It can be associated with hypoventilation....

 (low chloride), hypomagnesemia
Hypomagnesemia
Hypomagnesemia is an electrolyte disturbance in which there is an abnormally low level of magnesium in the blood. Usually a serum level less than 0.7 mmol/L is used as reference. The prefix hypo- means low . The middle 'magnes' refers to magnesium...

 (low magnesium
Magnesium
Magnesium is a chemical element with the symbol Mg, atomic number 12, and common oxidation number +2. It is an alkaline earth metal and the eighth most abundant element in the Earth's crust and ninth in the known universe as a whole...

), hypercalcemia (high calcium
Calcium
Calcium is the chemical element with the symbol Ca and atomic number 20. It has an atomic mass of 40.078 amu. Calcium is a soft gray alkaline earth metal, and is the fifth-most-abundant element by mass in the Earth's crust...

), and hyperuricemia
Hyperuricemia
Hyperuricemia is a level of uric acid in the blood that is abnormally high. In humans, the upper end of the normal range is 360 µmol/L for women and 400 µmol/L for men.-Causes:...

 (high uric acid
Uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the formula C5H4N4O3. It forms ions and salts known as urates and acid urates such as ammonium acid urate. Uric acid is created when the body breaks down purine nucleotides. High blood concentrations of uric acid...

). These may result in dizziness
Dizziness
Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....

, headache
Headache
A headache or cephalalgia is pain anywhere in the region of the head or neck. It can be a symptom of a number of different conditions of the head and neck. The brain tissue itself is not sensitive to pain because it lacks pain receptors. Rather, the pain is caused by disturbance of the...

, or heart arrhythmias (palpitations). Serious, though rare, side effects include aplastic anemia
Aplastic anemia
Aplastic anemia is a condition where bone marrow does not produce sufficient new cells to replenish blood cells. The condition, per its name, involves both aplasia and anemia...

, pancreatitis
Pancreatitis
Pancreatitis is inflammation of the pancreas. It occurs when pancreatic enzymes that digest food are activated in the pancreas instead of the small intestine. It may be acute – beginning suddenly and lasting a few days, or chronic – occurring over many years...

, agranulocytosis
Agranulocytosis
Granulopenia, also known as Agranulosis or Agranulocytosis, is an acute condition involving a severe and dangerous leukopenia , most commonly of neutrophils causing a neutropenia in the circulating blood. It represents a severe lack of one major class of infection-fighting white blood cells...

, and angioedema
Angioedema
Angioedema or Quincke's edema is the rapid swelling of the dermis, subcutaneous tissue, mucosa and submucosal tissues. It is very similar to urticaria, but urticaria, commonly known as hives, occurs in the upper dermis...

. Metolazone, like other thiazide diuretics, may unmask latent diabetes mellitus
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...

 or exacerbate gout
Gout
Gout is a medical condition usually characterized by recurrent attacks of acute inflammatory arthritis—a red, tender, hot, swollen joint. The metatarsal-phalangeal joint at the base of the big toe is the most commonly affected . However, it may also present as tophi, kidney stones, or urate...

, especially by interacting with medicines used to treat gout. In addition, thiazide diuretics, including metolazone, are sulfonamide
Sulfonamide (medicine)
Sulfonamide or sulphonamide is the basis of several groups of drugs. The original antibacterial sulfonamides are synthetic antimicrobial agents that contain the sulfonamide group. Some sulfonamides are also devoid of antibacterial activity, e.g., the anticonvulsant sultiame...

s; those with hypersensitivity to sulfonamides ("sulfa allergy") may also be allergic to metolazone.

Chemistry


External links

  • http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi?cid=4170. Accessed on January 25, 2006.
  • http://redpoll.pharmacy.ualberta.ca/drugbank/cgi-bin/getCard.cgi?CARD=APRD01109.txt. Accessed on January 25, 2006.
  • http://www.ijp-online.com/article.asp?issn=0253-7613;year=1974;volume=6;issue=1;spage=40;epage=53;aulast=Vithal;type=0. Accessed on January 25, 2006.
  • http://www.centaurpharma.com/pdf/news/metolaz-scrip.pdf [PDF]. Accessed on January 25, 2006.
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