Saturday, 5 March 2011

thiazide diuretics


Thiazide is a term used to describe a type of molecule and a class of diuretics often used to treat hypertension (high blood pressure) and edema (such as that caused by heart, liver, or kidney disease).
The members of this class of diuretics are derived from benzothiadiazine. They work by inhibiting reabsorption of sodium (Na+) and chloride (Cl) ions from the distal convoluted tubules in thekidneys by blocking the thiazide-sensitive Na+-Cl symporter. Thiazides also cause loss ofpotassium and an increase in serum uric acid. The term "thiazide" is also often used for drugs with a similar action that do not have the thiazide chemical structure, such as chlortalidone andmetolazone. These agents are more properly termed thiazide-like diuretics.
The thiazides and thiazide-like diuretics reduce the risk of death, stroke, heart attack and heart failure due to hypertension. In most countries, the thiazides are the cheapest antihypertensive drugs available


That thiazide refers to both the type of molecule and the medication can sometimes lead to confusion, because some molecules (thiazide-like diuretics) are often considered as thiazide diuretics, although they are not thiazides from a chemical perspective. In this context, "thiazide" is taken to refer to a drug which acts at a "thiazide receptor", which is believed to be a sodium-chloride symporter.

Primary uses

Thiazides are often used to treat hypertension, although they are also used to treat congestive heart failure and symptomatic edema. They are the recommended first-line treatment in the US guidelines and the National Institute for Health and Clinical Excellence/British Hypertension Society guidelines[ and a recommended treatment in the European guidelines. Whilst once regarded as the first choice of treatment for cases of uncomplicated hypertension when pharmacotherapy is indicated, they have been replaced by ACE inhibitorsin Australia due to their propensity to increase risk of diabetes mellitus type 2. They have been shown to prevent hypertension-relatedmorbidity and mortality, although how they lower blood pressure in the long term is not fully understood. When administered acutely thiazides lower blood pressure by causing diuresis, a fall in plasma volume and a reduction in cardiac output. However, after chronic use thiazides cause a reduction in blood pressure by lowering peripheral resistance (i.e. vasodilation). The mechanism of this effect is uncertain but it may involve effects on 'whole body' or renal autoregulation, or direct vasodilator actions either through inhibition of carbonic anhydrase[10] or bydesensitizing the vascular smooth muscle cells to the rise in intracellular calcium induced by norepinephrine.

Other uses

Thiazides also lower urinary calcium excretion, making them useful in preventing calcium-containing kidney stones. This effect is associated with positive calcium balance and is associated with an increase in bone mineral density and reductions in fracture rates attributable toosteoporosis. By a lesser understood mechanism, thiazides directly stimulate osteoblast differentiation and bone mineral formation, further slowing the course of osteoporosis.[
Because of their promotion of calcium retention, thiazides are used in the treatment of Dent's Disease or idiopathic hypercalciuria.
Thiazide may be combined with ACE inhibitors to increase diuresis without changing plasma potassium concentrations. While ACE inhibitorscause diuresis with potassium retention, thiazide increases potassium excretion. Their combined effects on potassium cancel each other out. Thiazides have no major effect on renal blood flow, but are likely to decrease glomerular filtration rate.

Breast milk

Thiazides pass through breast milk, and in some cases, decrease the flow of breast milk. There is no specific information regarding the use of thiazides in children, but it is still advised that mothers avoid using thiazides during the first month of breast feeding.


Thiazides reduce the clearance of uric acid and are therefore to be used with caution in patients with gout or hyperuricemia.
Thiazides can decrease placental perfusion and adversely affect the fetus so should be avoided in pregnancy.

Mechanisms of hypokalemia

There are several mechanisms by which thiazide diuretics cause hypokalemia (decreased plasma potassium concentration):
§                     Increased delivery of sodium to the collecting ducts causes the Na/K exchanger to more actively exchange Na for K resulting in K loss. (Moreover, the increased delivery of K to the collecting ducts facilitates the exchange of K for H by the H/K exchangers on the intercalated alpha cells, resulting in loss of H [metabolic alkalosis].)
§                     Activation of renin-angiotensin-aldosterone system by the diuretic hypovolemia: body responds to hypovolemia by opposing diuresis, one effect of which is to produce aldosterone which stimulates the Na/K exchanger, resulting in further loss of potassium. For this reason,ACE inhibitors, which inhibit angiotensin II production and therefore aldosterone activation, are frequently used in combination with thiazides to combat hypokalemia.
§                     Flow rate in nephron is increased under diuresis, reducing potassium concentration in the lumen, thus increasing the potassium gradient. Potassium loss through the many potassium channels, such as ROMK. These are not exchangers; they allow facilitated diffusion, so the increased gradient is directly responsible for increased diffusion.
Benzthiazide is a diuretic for oral administration. Each tablet contains 50 mg benzthiazide.
Benzthiazide Inactive Ingredients:
Corn starch, dibasic calcium phosphate, FD&C yellow 5, lactose, magnesium stearate, polyethylene glycol, sodium lauryl sulfate.
Benzthiazide is a white, crystalline powder with a characteristic odor, freely soluble in alkaline solution. The chemical structure is: 6-chloro-3[((phenylmethyl)thio)methyl]-2H-1,2,4-benzothiadiazine-7-sulfonamide 1,1-dioxide
Benzthiazide is a diuretic and antihypertensive. It affects the renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage, all thiazides are approximately equal in their diuretic potency. The mechanism whereby thiazides function in the control of hypertension is unknown. Benzthiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate.
In humans, benzthiazide is excreted in the urine almost entirely unchanged. Following a single oral dose of benzthiazide tablets or benzthiazide solution, 1% and 4.3% of the respective doses were recovered in the urine in 24 hr. The relative bioavailability of benzthiazide tablets was determined to be about 25% in reference to benzthiazide solution.
Benzthiazide is indicated as adjunctive therapy in edema associated with congestive heart failure, hepatic cirrhosis and corticosteroid and estrogen therapy.
Benzthiazide has also been found useful in edema due to various forms of renal dysfunction as: nephrotic syndrome; acute glomerulonephritis; and chronic renal failure.
Benzthiazide is indicated in the management of hypertension either as the sole therapeutic agent or to enhance the effectiveness of other antihypertensive drugs in the more severe forms of hypertension.
Use in Pregnancy:
The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy, and there is no satisfactory evidence that they are useful in the treatment of developed toxemia.
Edema during pregnancy may arise from pathological causes or from the physiologic and mechanical consequences of pregnancy. Thiazides are indicated in pregnancy when edema is due to pathologic causes, just as they are in the absence of pregnancy (however, see WARNINGS). Dependent edema in pregnancy, resulting from restriction of venous return by the expanded uterus, is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is illogical and unnecessary. There is hypervolemia during normal pregnancy which is harmful to neither the fetus nor the mother (in the absence of cardiovascular disease), but which is associated with edema, including generalized edema, in the majority of pregnant women. If this edema produces discomfort, increased recumbency will often provide relief. In rare instances, this edema may cause extreme discomfort which is not relieved by rest. In these cases, a short course of diuretics may provide relief and may be appropriate.
Anuria. Hypersensitivity to this or other sulfonamide-derived drugs.
Thiazides should be used with caution in severe renal disease. In patients with renal disease, thiazides may precipitate azotemia. Cumulative effects of the drug may develop in patients with impaired renal function.
Thiazides should be used with caution in patients with impaired hepatic function or progressive liver disease, since minor alterations of fluid and electrolyte balance may precipitate hepatic coma.
Thiazides may add to or potentiate the action of other antihypertensive drugs. Potentiation occurs with ganglionic or peripheral adrenergic blocking drugs.
Sensitivity reactions may occur in patients with a history of allergy or bronchial asthma.
The possibility of exacerbation or activation of systemic lupus erythematosus has been reported.
All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte imbalance; namely, hyponatremia, hypochloremic alkalosis, and hypokalemia. Warning signs are dryness of mouth, thirst, or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbance such as nausea and vomiting.
Dilutional hyponatremia may occur in edematous patients in hot weather; appropriate therapy is water restriction, rather than administration of salt except in rare instances when hyponatremia is life threatening.
In actual salt depletion, appropriate replacement is the therapy of choice. Any chloride deficit is generally mild and usually does not require specific treatment except under extraordinary circumstances (as in liver disease or renal disease).
Hypokalemia may develop with thiazides as with any other potent diuretic especially with brisk diuresis. Inadequate oral electrolyte intake will also contribute to hypokalemia.
Thiazide diuretics have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.
Calcium excretion is decreased by thiazide diuretics. Pathological changes in the parathyroid gland with hypercalcemia and hypophosphatemia have been observed in a few patients on thiazide therapy. The common complications few patients on thiazide therapy. The common complications of hyperparathyroidism such as renal lithiasis, bone resorption and peptic ulceration have not been seen.
If progressive renal failure becomes evident, a careful reappraisal of therapy is indicated with consideration given to withholding or discontinuing diuretic therapy.
Increases of cholesterol and triglyceride and triglyceride levels may be associated with thiazide diuretic therapy.
Latent diabetes mellitus may become manifest during thiazide administration: hyperuricemia or frank gout may also be precipitated in certain patients. The antihypertensive effect of the drug may be enhanced in the postsympathectomy patient.
This product contains FD&C yellow No. 5 (tartrazine) which may cause allergic-type reactions (including bronchial asthma) in certain susceptible individuals. Although the overall incidence of FD&C yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who have aspirin hypersensitivity.
Information for the Patient:
Warning signs of electrolyte imbalance are: dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting.
Laboratory Tests:
Periodic determination of serum electrolytes to detect possible electrolyte imbalance should be performed at appropriate intervals. When the patient is vomiting excessively or receiving parenteral fluids, serum and urine electrolyte determinations are particularly important.
In patients with renal impairment, nonprotein nitrogen or blood urea nitrogen level should be tested periodically; rising values would indicate progressive renal impairment and careful reappraisal of therapy is necessary with consideration given to withholding or discontinuing diuretic therapy.
Drug/Laboratory Tests Interactions:
Thiazides may decrease serum PBI levels without signs of thyroid disturbance.
Thiazides should be discontinued before carrying out tests for parathyroid function (see PRECAUTIONS, General).
Carcinogenesis, Mutagenesis, and Impairment of Fertility:
Studies to evaluate the carcinogenic or mutagenic potential of benzthiazide or the potential of the drug to affect fertility adversely have not been performed.
Pregnancy Category C:
Teratogenic Effects:
Benzthiazide has an embryocidal effect in rats when given in doses several hundred times the human dose. There are no adequate and well-controlled studies in pregnant women. Benzthiazide should be used during pregnancy only if clearly needed.
Nonteratogenic Effects:
Thiazides cross the placental barrier and appear in cord blood. There is a risk of fetal or neonatal jaundice, thrombocytopenia and possibly other adverse reactions that have occurred in adults.
Nursing Mothers:
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Exna is administered to a nursing mother.
Pediatric Use:
Safety and effectiveness in children have not been established.
When given concurrently the following drugs may interact with thiazide diuretics.
Alcohol, Barbiturates, Or Narcotics:
Potentiation of orthostatic hypotension may occur.
Antidiabetic Drugs (Oral Agents and Insulin):
Dosage adjustment of the antidiabetic drug may be required.
Other Antihypertensive Drugs:
Additive effect or potentiation occurs with ganglionic or peripheral adrenergic-blocking drugs.
Medication such as digitalis may also influence serum electrolytes. Digitalis therapy may exaggerate metabolic effects of hypokalemia especially with reference to myocardial activity (e.g., increased ventricular irritability).
Pressor Amines (e.g., Norepinephrine):
Possible decreased response to pressor amines. This diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use.
Skeletal Muscle Relaxants, Nondepolarizing (e.g., Tubocurarine):
possible increased responsiveness to the muscle relaxant.
Generally should not be given with diuretics. Diuretic agents reduce the renal clearance of lithium and add a high risk of lithium toxicity. Refer to the package insert for lithium preparations before use of such preparations with Exna.
Nonsteroidal Anti-Inflammatory Drugs:
In some patients, the administration of a nonsteroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics. Therefore, when Exna and nonsteroidal anti-inflammatory agents are used concomitantly, the patient should be observed closely to determine if the desired effect of the diuretic is obtained.
Cholestyramine Resin And Colestipol HCl:
May delay decrease absorption of thiazide diuretics.
Amphotericin B, Corticosteroids or Corticotropin:
(ACTH): May intensify electrolyte imbalance, particularly hypokalemia.
The following adverse reactions have been observed, but there is not enough systematic collection of data to support an estimate of their frequency.
Gastrointestinal System:
Jaundice (intrahepatic cholestatic jaundice); pancreatitis; gastric irritation; vomiting; cramping; nausea; anorexia; diarrhea; constipation.
Central Nervous System:
Dizziness; restlessness; paresthesia; headache; xanthopsia.
Aplastic anemia; thrombocytopenia; agranulocytosis; leukopenia.
Necrotizing angiitis (vasculitis) (cutaneous vasculitis); purpura; urticaria; rash; photosensitivity.
Orthostatic hypotension may occur and may be aggravated by alcohol, barbiturates or narcotics.
Hyperglycemia; glycosuria; hyperuricemia; weakness; muscle spasm.
Whenever adverse reactions are moderate or severe, thiazide dosage should be reduced or therapy withdrawn.
Symptoms of overdosage include electrolyte imbalance and signs of potassium deficiency such as confusion, dizziness, muscular weakness, and gastrointestinal disturbances. General supportive measures including replacement of fluids and electrolytes may be indicated in treatment of overdosage.
Therapy should be individualized according to patient response. This therapy should be titrated to gain maximal therapeutic response as well as the minimal dose possible to maintain that therapeutic response as shown in TABLE 1.
Initiation of diuresis.
50 to 200 mg daily should be used for several days, or until dry weight is attained. With 100 mg or more daily, it is generally preferable to administer benzthiazide in two doses, following morning and evening meals.
Maintenance of diuresis.
50 to 150 mg daily depending upon the patient's response. To maintain effectiveness, reduction to minimal effective dosage should be gradual.
Initiation of antihypertensive therapy.
50 to 100 mg daily is the average dose. It may be given in two doses of 25 mg or 50 mg each after breakfast and after lunch. This dosage may be continued until a therapeutic drop in blood pressure occurs.
Maintenance of antihypertensive therapy.
Dosage should be adjusted according to the patient response, either upward to as much as 50 mg q.i.d. or downward to the minimal effective dosage level.
Store at controlled room temperature, between 20°C and 25°C (68°F and 77°F).
Dispense in tight container.


Chlorothiazide sodium (Diuril) is a diuretic used within the hospital setting or for personal use to manage excess fluid associated with congestive heart failure. It is also used as anantihypertensive.
Most often taken in pill form, it is usually taken orally once or twice a day. In the ICU setting, chlorothiazide is given to diurese a patient in addition to furosemide (Lasix). Working in a separate mechanism than furosemide, and absorbed enterically as a reconstituted suspension administered through a nasogastric tube (NG tube), the two drugs potentiate one another without risk of toxicity. Because it is absorbed enterically there are no risks associated with chlorothiazide as there are with furosemide administration.


§                     Large amount of excess fluid including:
§                                 Diagnosed congested heart failure
§                                 Peripheral edema
§                                 Rales / Rhonchi
§                                 Hypertension


§                     Renal failure or insufficiency
§                     Allergies to sulfa drugs


§                     500 mg–1 g once or twice a day, by mouth or through NG tube (reconstituted suspension)
§                     May also be given intravenously, and should be given first if given in combination with IV lasix since it potentiate's the diuretic effect of furosemide.

Side effects

§                     Nausea / Vomiting
§                     Headache
§                     Dizziness
§                     Excess urine production
§                     Dehydration
§                     Hypoelectrolytemia (esp. hypokalemia / hypomagnesia)


Hydrochlorothiazide, abbreviated HCTZ, HCT, or HZT, is a first line diuretic drug of the thiazideclass that acts by inhibiting the kidneys' ability to retain water. This reduces the volume of theblood, decreasing blood return to the heart and thus cardiac output and, by other mechanisms, is believed to lower peripheral vascular resistance. Hydrochlorothiazide is sold both as a generic drug and under a large number of brand names, including Apo-Hydro, Aquazide H,Dichlotride, Hydrodiuril, HydroSaluric, Microzide, Esidrex, and Oretic.
Hydrochlorothiazide is also used in combination with many popular drugs used to treat hypertension such as Diovan HCT, Zestoretic, Benicar HCT, Atacand HCT, and Lotensin HCT, Temax-H and others.

Mechanism of action

Hydrochlorothiazide belongs to the thiazide class of diuretics, acting on the kidneys to reducesodium (Na) reabsorption in the distal convoluted tubule. The major site of action in the nephron appears on an electroneutral Na+-Cl- co-transporter by competing for the chloride site on the transporter. By impairing Na transport in the distal convoluted tubule, hydrochlorothiazide induces a natriuresis and concomitant water loss. Thiazides increase the reabsorption of calcium in this segment in a manner unrelated to sodium transport.


Hydrochlorothiazide is often used in the treatment of hypertension, congestive heart failure, symptomatic edema and the prevention of kidney stones. It is effective for nephrogenic diabetes insipidus and is also sometimes used for hypercalciuria, Dent's disease and Ménière's disease. For diabetes insipidus, the effect of thiazide diuretics is presumably mediated by a hypovolemia-induced increase in proximal sodium and water reabsorption, thereby diminishing water delivery to the ADH-sensitive sites in the collecting tubules and reducing the urine output.
Hypokalemia, an occasional side effect, can be usually prevented by potassium supplements or by combining hydrochlorothiazide with a potassium-sparing diuretic.
Thiazides are also used in the treatment of osteoporosis. Thiazides decrease mineral bone loss by promoting calcium retention in the kidney, and by directly stimulating osteoblastdifferentiation and bone mineral formation.

Side effects

§                     Hypokalemia
§                     Hypomagnesemia
§                     Hyperuricemia and gout
§                     High blood sugar
§                     Hyperlipidemia
§                     Hypercalcemia
§                     Headache
§                     Nausea/vomiting
§                     Photosensitivity
§                     Weight Gain

Nonthiazide Diuretics:-


Chlortalidone (INN/BAN) or chlorthalidone (USAN) is a diuretic drug used to treathypertension, originally marketed as Hygroton in the USA. It is described as a thiazide diuretic(or, rather, a thiazide-like diuretic because it acts similarly to the thiazides but does not contain the benzothiadiazine molecular structure). Compared with other medications of the thiazide class, chlorthalidone has the longest duration of action, but a similar diuretic effect at maximal therapeutic doses. It is often used in the management of hypertension and edema.
Unlike loop diuretics, chlorthalidone efficacy is diminished in patients with certain renal diseaes (e.g. Chronic Renal Disease). A clinical trial (ALLHAT) in 2002 compared chlorthalidone to doxazosin in the treatment of high-risk hypertensive patients. In this study, only chlorthalidone significantly reduced the risk of combined cardiovascular disease events, especially heart failure, when compared with drugs such as doxazosin. Chlorthalidone was approved by the FDA in 1960. The ALLHAT study conclusions showed that there was no significant difference in all-cause mortality, fatal heart disease, or non-fatal myocardial infarction when chlorthalidone was compared with lisinopril or amlodipine but did show decrease rates of heart failure after 6 years when compared with amlodipine and decreased rates of cerebrovascular disease after 6 years when compared with lisinopril leading the study conclusions to say that thiazide-type diuretics are preferred first-step in antihypertensive therapy.

Mechanism of action

Chlorthalidone increases the excretion of sodium, chloride, and water into the renal lumen by inhibiting sodium ion transport across the renal tubular epithelium. Its primary site of action is in the cortical diluting segment of the ascending limb of the loop of Henle. Thiazides and related compounds also decrease the glomerular filtration rate, which further reduces the drug's efficacy in patients with renal impairment (e.g. renal insufficiency). By increasing the delivery of sodium to the distal renal tubule, chlorthalidone indirectly increases potassium excretion via the sodium-potassium exchange mechanism (i.e. apical ROMK/Na channels coupled with basolateral NKATPases). This can result in hypokalemia and hypochloremia as well as a mild metabolic alkalosis; however, the diuretic efficacy of chlorthalidone is not affected by the acid-base balance of the patient being treated.
Initially, diuretics lower blood pressure by decreasing cardiac output and reducing plasma and extracellular fluid volume. Eventually, cardiac output returns to normal, and plasma and extracellular fluid volume return to slightly less than normal, but a reduction in peripheral vascular resistance is maintained, thus resulting in an overall lower blood pressure. The reduction in intravascular volume induces an elevation in plasma renin activity and aldosterone secretion, further contributing to the potassium loss associated with thiazide diuretic therapy.

Side Effects

Chlorthalidone has been studied thoroughly in clinical trials. In these studies, the side effects that occur in a group of people taking the drug are documented and are then compared to side effects that occur in another group of people not taking the medicine. This way, it is possible to see what side effects occur, how often they appear, and how they compare to the group not taking the medicine.

Based on these studies, some of the possible side effects of chlorthalidone include:

· Loss of appetite
· Stomach irritation
· Nausea or vomiting
· Dizziness
· Vertigo (a spinning sensation)
· Abnormal sensations, such as burning or tingling (paresthesias)
· Vision changes
· Sensitivity to the sun

Serious Chlorthalidone Side Effects

Some side effects with chlorthalidone, while occurring infrequently, are potentially serious and should be reported immediately to your healthcare provider. These include but are not limited to:

· Dizziness, lightheadedness, or fainting spells

· Signs of dehydration or low electrolytes, such as:

o        Dry mouth
o        Thirst
o        Weakness
o        Lethargy
o        Drowsiness
o        Restlessness
o        Muscle pain or muscle cramps
o        Low blood pressure (hypotension)
o        Decreased urination
o        A rapid heart rate (tachycardia) or irregular heart rhythm (arrhythmia)
o        Nausea or vomiting

· Yellowing of the skin or the whites of the eyes

· High blood sugar (hyperglycemia)

· Signs of an allergic reaction, including:

o        Unexplained rash
o        Hives
o        Itching
o        Unexplained swelling
o        Wheezing
o        Difficulty breathing or swallowing.


Indapamide is a non-thiazide sulphonamide 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. Combination preparations with perindopril (an ACE inhibitor antihypertensive) are also available.
It is described as a thiazide-like diuretic

Form and composition

Indapamide is available generically as 1.25 mg and 2.5 mg non-scored tablets.[3]


Hypertension and edema due to congestive heart failure. Indapamide has been proven in the HYVET trial to reduce stroke and all cause mortality when given with or without perindopril to people over the age of 80 for the treatment of hypertension.

Dosage and administration

The adult dosage is 1.25 to 5 mg by orally once daily usually in the morning.


Indapamide is contraindicated in known hypersensitivity to sulfonamides, severe renal failure,hepatic encephalopathy or severe hepatic failure and hypokalemia (low blood potassium levels).
There is insufficient safety data to recommend indapamide use in pregnancy or breastfeeding.


Caution is advised in the combination of indapamide with lithium and nonantiarrhythmic drugs causing wave burst arrhythmia (astemizole, bepridil, IV erythromycin, halofantrine, pentamidine, sultopride, terfenadine, vincamine).


Monitoring of potassium and uric acid serum levels is recommended, especially in subjects with a predisposition or a sensitivity to hypokalemia and in patients with gout.

Adverse effects

Commonly reported adverse events are hypokalemia (low potassium levels), fatigue, orthostatic hypotension (blood pressure decrease on standing up) and allergic manifestations.


Symptoms of overdosage would be those associated with a diuretic effect: electrolyte disturbances, hypotension, and muscular weakness. Treatment should be symptomatic, directed at correcting the electrolyte abnormalities.


etolazone 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 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.


Metolazone was developed in the 1970s. Its creator, Indian born chemist Dr. Bola Vithal Shettyhas been active in helping the U.S. Food and Drug Administration 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.


Metolazone is a quinazoline, a derivative of the similar diuretic quinethazone, as well as asulfonamide. It is related to analogs of 1,2,4-benzothiadizine-1,1-dioxide (benzothiadiazine). These drugs are called benzothiadiazides, or thiazides for short. Chemically, metolazone is not a substituted benzothiadiazine, and therefore is not technically a thiazide. However, since metolazone, as well other drugs like indapamide, 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.[


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.[1] Metolazone quickly gained popularity due to its purportedly lower renal toxicity compared to other diuretics (especially thiazides) in patients with renal insufficiency.

Mechanism of action

Schematic of a nephron. The distal convoluted tubule is labelled "2nd convoluted tubule" (theproximal convoluted tubule is the first) 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-poweredsodium-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.[  Nevertheless, they can be associated with low sodium levels, volume depletion, and low blood pressure, among other adverse effects.


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 biliaryexcretion and metabolism into inactive forms.[


One of the primary uses of metolazone is for treating oedema (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 renal failure, 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 or the nephrotic syndrome. Chronic renal failure causes excess fluid retention that is often treated with diet 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, 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 renal failure.


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). 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

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