Thiazide () refers to both a class of sulfur-containing organic molecules and a class of
diuretic
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 ...
s 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
Chlorothiazide, sold under the brand name Diuril among others, is an organic compound used as a diuretic and as an antihypertensive.
It is used both within the hospital setting or for personal use to manage excess fluid associated with congestiv ...
, was marketed under the trade name
Diuril
Chlorothiazide, sold under the brand name Diuril among others, is an organic compound used as a diuretic and as an antihypertensive.
It is used both within the hospital setting or for personal use to manage excess fluid associated with congestiv ...
beginning in 1958.
In most countries, thiazides are the least expensive
antihypertensive drugs available.
Thiazide organic molecules are bi-cyclic structures that contain adjacent sulfur and nitrogen atoms on one ring.
Confusion sometimes occurs because
thiazide-like diuretics such as
indapamide
Indapamide is a thiazide-like diuretic drug used in the treatment of hypertension, as well as decompensated heart failure. Combination preparations with perindopril (an ACE inhibitor antihypertensive) are available. The thiazide-like diuretics ...
are referred to as thiazides despite not having the thiazide chemical structure.
When used this way, "thiazide" refers to a drug which acts at the thiazide receptor. The thiazide receptor is a
sodium-chloride transporter that pulls
NaCl
Sodium chloride , commonly known as edible salt, is an ionic compound with the chemical formula NaCl, representing a 1:1 ratio of sodium and chloride ions. It is transparent or translucent, brittle, hygroscopic, and occurs as the mineral hali ...
from the
lumen in the
distal convoluted tubule
The distal convoluted tubule (DCT) is a portion of kidney nephron between the loop of Henle and the collecting tubule.
Physiology
It is partly responsible for the regulation of potassium, sodium, calcium, and pH.
On its apical surface (lum ...
. Thiazide diuretics inhibit this receptor, causing the body to release NaCl and water into the lumen, thereby increasing the amount of urine produced each day.
An example of a molecule that is chemically a thiazide but not used as a diuretic is
methylchloroisothiazolinone, often found as an
antimicrobial
An antimicrobial is an agent that kills microorganisms (microbicide) or stops their growth (bacteriostatic agent). Antimicrobial medicines can be grouped according to the microorganisms they are used to treat. For example, antibiotics are used aga ...
in cosmetics.
Medical uses
Thiazide diuretics are primarily used to treat the
hypertension
Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...
(high blood pressure) and
edema
Edema (American English), also spelled oedema (British English), and also known as fluid retention, swelling, dropsy and hydropsy, is the build-up of fluid in the body's tissue (biology), tissue. Most commonly, the legs or arms are affected. S ...
(swelling) caused by water overload as well as certain conditions related to unbalanced calcium metabolism.
Water balance
Hypertension
There are many causes of
hypertension
Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...
(high blood pressure), including advancing age, smoking and
obesity
Obesity is a medical condition, considered by multiple organizations to be a disease, in which excess Adipose tissue, body fat has accumulated to such an extent that it can potentially have negative effects on health. People are classifi ...
.
Sometimes the underlying cause of hypertension cannot be determined, resulting in a diagnosis of idiopathic hypertension. Regardless of the cause, someone may have very high hypertension without any initial symptoms. Uncontrolled hypertension will eventually cause damage to the heart, kidneys and eyes. Lifestyle changes, including reducing dietary salt, increasing exercise and losing weight can help to reduce blood pressure.
Thiazides and thiazide-like diuretics have been in constant use since their introduction in 1958. Decades as a cornerstone of hypertension treatment show how well these drugs perform for most patients. Low-dose thiazides are tolerated as well as the other classes of medications for hypertension, including
ACE inhibitor
Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of high blood pressure and heart failure. This class of medicine works by causing relaxation of blood vessels as well as a decr ...
s,
beta blocker
Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms ( arrhythmia), and to protect the heart from a second heart attack after a first heart attack ( secondary prevention ...
s and
calcium channel blocker
Calcium channel blockers (CCB), calcium channel antagonists or calcium antagonists are a group of medications that disrupt the movement of calcium () through calcium channels. Calcium channel blockers are used as antihypertensive drugs, i.e., as ...
s.
In general, the thiazides and
thiazide-like diuretics reduce the risk of death, stroke,
heart attack
A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...
, and heart failure due to hypertension.
Clinical practice guideline
A medical guideline (also called a clinical guideline, standard treatment guideline, or clinical practice guideline) is a document with the aim of guiding decisions and criteria regarding diagnosis, management, and treatment in specific areas of ...
s regarding the use of thiazides vary by geographic region. Guidelines in the United States recommend thiazides as a first-line treatment for hypertension (JNC VIII). A
systematic review
A systematic review is a scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from published studies on ...
by the
Cochrane Collaboration
Cochrane is a British international charitable organisation formed to synthesize medical research findings to facilitate evidence-based choices about health interventions involving health professionals, patients and policy makers. It includes ...
specifically recommended that low-dose thiazides be used as the initial
pharmacological therapy for high blood pressure.
Low-dose thiazides are more effective at treating hypertension than
beta blocker
Beta blockers, also spelled β-blockers, are a class of medications that are predominantly used to manage abnormal heart rhythms ( arrhythmia), and to protect the heart from a second heart attack after a first heart attack ( secondary prevention ...
s and are similar to
angiotensin-converting enzyme
Angiotensin-converting enzyme (), or ACE, is a central component of the renin–angiotensin system (RAS), which controls blood pressure by regulating the volume of fluids in the body. It converts the hormone angiotensin I to the active vasocon ...
(ACE) inhibitors.
Thiazides are a recommended treatment for hypertension in Europe (ESC/ESH). Thiazides should be considered as initial treatment if the patient has a high risk of developing heart failure.
[National Institute for Health and Clinical Excellence (NICE) guideline on the management of primary hypertension in adults (CG127) accessed 5/3/2012 at ] Thiazides have also been replaced by
ACE inhibitor
Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of high blood pressure and heart failure. This class of medicine works by causing relaxation of blood vessels as well as a decr ...
s in Australia due to the association between thaizide use and increased risk of developing
diabetes mellitus type 2
Type 2 diabetes (T2D), formerly known as adult-onset diabetes, is a form of diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. Common symptoms include increased thirst, frequent ...
.
[Guide to management of hypertension 2008. National Heart Foundation Australia. 2008. accessed online at ]
Diabetes insipidus
Thiazides can be used to paradoxically decrease urine flow in people with
nephrogenic diabetes insipidus. Thiazides may also be useful in treating
hyponatremia
Hyponatremia or hyponatraemia is a low concentration of sodium in the Serum (blood), blood. It is generally defined as a sodium concentration of less than 135 mmol/L (135 mEq/L), with severe hyponatremia being below 120 mEq/L. Symp ...
(low blood sodium) in infants with
central diabetes insipidus
Central diabetes insipidus, recently renamed arginine vasopressin deficiency (AVP-D), is a form of diabetes insipidus that is due to a lack of vasopressin (ADH) production in the brain. Vasopressin acts to increase the blood volume, volume of bl ...
.
Calcium balance
Urinary stones
Thiazides are useful in treating
kidney stones
Kidney stone disease (known as nephrolithiasis, renal calculus disease, or urolithiasis) is a crystallopathy and occurs when there are too many minerals in the urine and not enough liquid or hydration. This imbalance causes tiny pieces of cr ...
and
bladder stones that result from
hypercalciuria (high urine calcium levels). Thiazides increase the uptake of calcium in the distal tubules, to moderately reduce urinary calcium. Thiazides combined with
potassium citrate
Potassium citrate (also known as tripotassium citrate) is a potassium salt of citric acid with the molecular formula K3C6H5O7. It is a white, hygroscopic crystalline powder. It is odorless with a saline taste. It contains 38.28% potassium by mass ...
, increased water intake and decreased dietary
oxalate
Oxalate (systematic IUPAC name: ethanedioate) is an anion with the chemical formula . This dianion is colorless. It occurs naturally, including in some foods. It forms a variety of salts, for example sodium oxalate (), and several esters such as ...
and sodium can slow or even reverse the formation of calcium-containing kidney stones. High-dose therapy with the thiazide-like diuretic
indapamide
Indapamide is a thiazide-like diuretic drug used in the treatment of hypertension, as well as decompensated heart failure. Combination preparations with perindopril (an ACE inhibitor antihypertensive) are available. The thiazide-like diuretics ...
can be used to treat
idiopathic hypercalcinuria (high urine calcium with unknown cause).
Osteoporosis
Hypocalcemia
Hypocalcemia is a medical condition characterized by low calcium levels in the blood serum. The normal range of blood calcium is typically between 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L), while levels less than 2.1  ...
(low blood calcium) can be caused by a variety of conditions that reduce dietary calcium absorption, increase calcium excretion or both. Positive calcium balance occurs when calcium excretion is decreased and intake remains constant so that calcium is retained within the body.
[Aung K, Htay T. Thiazide diuretics and the risk of hip fracture. Cochrane Database of Systematic Reviews 2011, Issue 10. Art. No.: CD005185. DOI: 10.1002/14651858.CD005185.pub2.] Higher levels of retained calcium are associated with increased
bone mineral density
Bone density, or bone mineral density, is the amount of bone mineral in bone tissue. The concept is of mass of mineral per volume of bone (relating to density in the physics sense), although clinically it is measured by proxy according to opti ...
and fewer fractures in individuals with
osteoporosis
Osteoporosis is a systemic skeletal disorder characterized by low bone mass, micro-architectural deterioration of bone tissue leading to more porous bone, and consequent increase in Bone fracture, fracture risk.
It is the most common reason f ...
.
By a poorly understood mechanism, thiazides directly stimulate
osteoblast
Osteoblasts (from the Greek combining forms for " bone", ὀστέο-, ''osteo-'' and βλαστάνω, ''blastanō'' "germinate") are cells with a single nucleus that synthesize bone. However, in the process of bone formation, osteoblasts fu ...
differentiation and bone mineral formation, further slowing the course of osteoporosis.
Dent's disease
Thiazides may be used to treat the symptoms of
Dent's disease, an
X-linked genetic condition that results in electrolyte imbalance with repeated episodes of kidney stones. A case study of two brothers with the condition, two years of treatment with
hydrochlorothiazide
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 t ...
reduced the incidence of kidney stones and improved kidney function. The thiazide-like diuretic
chlortalidone reduced urine
calcium oxalate
Calcium oxalate (in archaic terminology, oxalate of lime) is a calcium salt of oxalic acid with the chemical formula or . It forms hydrates , where ''n'' varies from 1 to 3. Anhydrous and all hydrated forms are colorless or white. The monohydr ...
in seven of the eight males with inactivated
CLCN5 gene that participated in the study. Inactivation of the CLCN5 gene causes Dent's disease Type 1.
The rare nature of Dent's disease makes it difficult to coordinate large controlled studies, so most evidence for thiazide use is with too few patients to make broad recommendations possible.
Long-term thiazide use may not be advisable due to the risk of significant adverse side effects.
Other uses
Bromine intoxication can be treated by giving
intravenous
Intravenous therapy (abbreviated as IV therapy) is a medical technique that administers fluids, medications and nutrients directly into a person's vein. The intravenous route of administration is commonly used for rehydration or to provide nutr ...
saline with either thiazides or
Loop diuretic
Loop diuretics are pharmacological agents that primarily inhibit the Na-K-Cl cotransporter located on the luminal membrane of cells along the thick ascending limb of the loop of Henle. They are often used for the treatment of hypertension and e ...
s.
Contraindications
Contraindications include:
*
Hypotension
Hypotension, also known as low blood pressure, is a cardiovascular condition characterized by abnormally reduced blood pressure. Blood pressure is the force of blood pushing against the walls of the arteries as the heart pumps out blood and is ...
* Allergy to sulphur-containing medications
*
Gout
Gout ( ) is a form of inflammatory arthritis characterized by recurrent attacks of pain in a red, tender, hot, and Joint effusion, swollen joint, caused by the deposition of needle-like crystals of uric acid known as monosodium urate crysta ...
*
Kidney failure
Kidney failure, also known as renal failure or end-stage renal disease (ESRD), is a medical condition in which the kidneys can no longer adequately filter waste products from the blood, functioning at less than 15% of normal levels. Kidney fa ...
*
Lithium therapy
*
Hypokalemia
Hypokalemia is a low level of potassium (K+) in the blood serum. Mild low potassium does not typically cause symptoms. Symptoms may include feeling tired, leg cramps, weakness, and constipation. Low potassium also increases the risk of an a ...
* May worsen
diabetes
Diabetes mellitus, commonly known as diabetes, is a group of common endocrine diseases characterized by sustained high blood sugar levels. Diabetes is due to either the pancreas not producing enough of the hormone insulin, or the cells of th ...
Thiazides reduce the clearance of
uric acid
Uric acid is a heterocyclic compound of carbon, nitrogen, oxygen, and hydrogen with the Chemical formula, formula C5H4N4O3. It forms ions and salts known as urates and acid urates, such as ammonium acid urate. Uric acid is a product of the meta ...
since they compete for the same transporter, and therefore raise the levels of uric acid in the blood. Hence, they are prescribed with caution in patients with gout or
hyperuricemia
Hyperuricaemia or hyperuricemia is an abnormally high level of uric acid in the blood. In the pH conditions of body fluid, uric acid exists largely as urate, the ion form. Serum uric acid concentrations greater than 6 mg/dL for females, 7 ...
.
Chronic administration of thiazides is associated with the increase of insulin resistance which can lead to
hyperglycemia
Hyperglycemia is a condition where unusually high amount of glucose is present in blood. It is defined as blood glucose level exceeding 6.9 mmol/L (125 mg/dL) after fasting for 8 hours or 10 mmol/L (180 mg/dL) 2 hours after eating.
Blood gluc ...
.
Thiazides cause loss of blood
potassium
Potassium is a chemical element; it has Symbol (chemistry), symbol K (from Neo-Latin ) and atomic number19. It is a silvery white metal that is soft enough to easily cut with a knife. Potassium metal reacts rapidly with atmospheric oxygen to ...
, while conserving blood calcium.
Thiazides can decrease placental perfusion and adversely affect the fetus, so should be avoided in
pregnancy
Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins.
Conception (biology), Conception usually occurs ...
.
Adverse effects
*

Hypokalemia
Hypokalemia is a low level of potassium (K+) in the blood serum. Mild low potassium does not typically cause symptoms. Symptoms may include feeling tired, leg cramps, weakness, and constipation. Low potassium also increases the risk of an a ...
– Thiazide diuretics reduce potassium concentration in blood through two indirect mechanisms: inhibition of
sodium-chloride symporter
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 ...
at
distal convoluted tubule
The distal convoluted tubule (DCT) is a portion of kidney nephron between the loop of Henle and the collecting tubule.
Physiology
It is partly responsible for the regulation of potassium, sodium, calcium, and pH.
On its apical surface (lum ...
of a
nephron
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 structu ...
and stimulation of
aldosterone
Aldosterone is the main mineralocorticoid steroid hormone produced by the zona glomerulosa of the adrenal cortex in the adrenal gland. It is essential for sodium conservation in the kidney, salivary glands, sweat glands, and colon. It plays ...
that activates
Na+/K+-ATPase at
collecting duct
The collecting duct system of the kidney consists of a series of tubules and ducts that physically connect nephrons to a minor calyx or directly to the renal pelvis. The collecting duct participates in electrolyte and fluid balance through rea ...
. Inhibition of sodium-chloride symporter increases availability of sodium and chloride in urine. When the urine reaches the collecting duct, the increase in sodium and chloride availability activates Na+/K+-ATPase, which increases the absorption of sodium and excretion of potassium into the urine. Long term administration of thiazide diuretics reduces total body blood volume. This activates the
renin–angiotensin system
The renin–angiotensin system (RAS), or renin–angiotensin–aldosterone system (RAAS), is a hormone system that regulates blood pressure, fluid, and electrolyte balance, and systemic vascular resistance.
When renal blood flow is reduced, ...
, stimulates the secretion of aldosterone, thus activating Na+/K+-ATPase, increasing excretion of potassium in urine. Therefore,
ACE inhibitor and thiazide combination is used to prevent hypokalemia.
*
Hyperglycemia
Hyperglycemia is a condition where unusually high amount of glucose is present in blood. It is defined as blood glucose level exceeding 6.9 mmol/L (125 mg/dL) after fasting for 8 hours or 10 mmol/L (180 mg/dL) 2 hours after eating.
Blood gluc ...
*
Hyperlipidemia
Hyperlipidemia is abnormally high levels of any or all lipids (e.g. fats, triglycerides, cholesterol, phospholipids) or lipoproteins in the blood. citing: and The term ''hyperlipidemia'' refers to the laboratory finding itself and is also use ...
*
Hyperuricemia
Hyperuricaemia or hyperuricemia is an abnormally high level of uric acid in the blood. In the pH conditions of body fluid, uric acid exists largely as urate, the ion form. Serum uric acid concentrations greater than 6 mg/dL for females, 7 ...
*
Hypercalcemia
Hypercalcemia, also spelled hypercalcaemia, is a high calcium (Ca2+) level in the blood serum. The normal range for total calcium is 2.1–2.6 mmol/L (8.8–10.7 mg/dL, 4.3–5.2 mEq/L), with levels greater than 2.6 mmol/L def ...
*
Hyponatremia
Hyponatremia or hyponatraemia is a low concentration of sodium in the Serum (blood), blood. It is generally defined as a sodium concentration of less than 135 mmol/L (135 mEq/L), with severe hyponatremia being below 120 mEq/L. Symp ...
** According to a 2025 retrospective study patients who experience early hyponatremia after beginning thiazide diuretics have a higher risk of mortality compared to those with stable sodium levels. Researchers also found that these patients faced an increased likelihood of complications such as
sepsis
Sepsis is a potentially life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs.
This initial stage of sepsis is followed by suppression of the immune system. Common signs and s ...
,
pneumonia
Pneumonia is an Inflammation, inflammatory condition of the lung primarily affecting the small air sacs known as Pulmonary alveolus, alveoli. Symptoms typically include some combination of Cough#Classification, productive or dry cough, ches ...
,
urinary tract infections
A urinary tract infection (UTI) is an infection that affects a part of the urinary tract. Lower urinary tract infections may involve the bladder (cystitis) or urethra ( urethritis) while upper urinary tract infections affect the kidney (pye ...
,
cellulitis
Cellulitis is usually a bacterial infection involving the inner layers of the skin. It specifically affects the dermis and subcutaneous fat. Signs and symptoms include an area of redness which increases in size over a few days. The borders of ...
,
myocardial infarction
A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...
, stroke,
congestive heart failure
Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome caused by an impairment in the heart's ability to fill with and pump blood.
Although symptoms vary based on which side of the heart is affected, HF typically pr ...
,
ataxia
Ataxia (from Greek α- negative prefix+ -τάξις rder= "lack of order") is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in e ...
, and
hip fractures.
*
Hypomagnesemia
Magnesium deficiency is an electrolyte disturbance in which there is a low level of magnesium in the body. Symptoms include tremor, poor coordination, muscle spasms, loss of appetite, personality changes, and nystagmus. Complications may in ...
*
Hypocalciuria
*
Metabolic alkalosis
Metabolic alkalosis is an acid-base disorder in which the pH of tissue is elevated beyond the normal range (7.35–7.45). This is the result of decreased hydrogen ion concentration, leading to increased bicarbonate (), or alternatively a dire ...
Mechanism of action

Thiazide diuretics control hypertension in part by inhibiting
reabsorption
In renal physiology, reabsorption, more specifically tubular reabsorption, is the process by which the nephron removes water and solutes from the tubular fluid (pre-urine) and returns them to the circulating blood. It is called ''reabsorption' ...
of
sodium
Sodium is a chemical element; it has Symbol (chemistry), symbol Na (from Neo-Latin ) and atomic number 11. It is a soft, silvery-white, highly reactive metal. Sodium is an alkali metal, being in group 1 element, group 1 of the peri ...
(Na
+) and
chloride
The term chloride refers to a compound or molecule that contains either a chlorine anion (), which is a negatively charged chlorine atom, or a non-charged chlorine atom covalently bonded to the rest of the molecule by a single bond (). The pr ...
(Cl
−)
ion
An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...
s from the
distal convoluted tubule
The distal convoluted tubule (DCT) is a portion of kidney nephron between the loop of Henle and the collecting tubule.
Physiology
It is partly responsible for the regulation of potassium, sodium, calcium, and pH.
On its apical surface (lum ...
s in the
kidney
In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...
s by blocking the thiazide-sensitive
Na+-Cl− symporter.
The term "thiazide" is also often used for drugs with a similar action that do not have the thiazide chemical structure, such as
chlorthalidone,
metolazone
Metolazone is a thiazide diuretic, thiazide-like diuretic marketed under the brand names Zytanix, Metoz, Zaroxolyn, and Mykrox. It is primarily used to treat congestive heart failure and hypertension, high blood pressure. Metolazone indirectly d ...
and
indapamide
Indapamide is a thiazide-like diuretic drug used in the treatment of hypertension, as well as decompensated heart failure. Combination preparations with perindopril (an ACE inhibitor antihypertensive) are available. The thiazide-like diuretics ...
. These agents are more properly termed
thiazide-like diuretic.
Anyhow, the results regarding the importance of the kidney alone and the thiazide-sensitive receptor NCC
Sodium-chloride symporter
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 ...
in the anti-hypertensive effects of thiazides have been debated for decades providing evidence for the existence of an extrarenal target involved in the thiazide-mediated chronic inhibition of vascular constriction.
The membrane-associated phospholipase NAPE-PLD (
N-acyl phosphatidylethanolamine-specific phospholipase D) of the
endocannabinoid system
The endocannabinoid system (ECS) is a biological system composed of endocannabinoids, which are neurotransmitters that bind to cannabinoid receptors, and cannabinoid receptor proteins that are expressed throughout the central nervous system ( ...
is a renal and extrarenal target of "thiazide-type" (e.g.,
hydrochlorothiazide
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 t ...
) and "thiazide-like" diuretics (e.g.,
chlorthalidone and
indapamide
Indapamide is a thiazide-like diuretic drug used in the treatment of hypertension, as well as decompensated heart failure. Combination preparations with perindopril (an ACE inhibitor antihypertensive) are available. The thiazide-like diuretics ...
). NAPE-PLD accounts for both their acute (diuresis and accompanying decrease of plasma volume) and chronic (reduction of arterial pressure through vascular dilation) therapeutic effects.

Thiazide diuretics also increase calcium reabsorption at the
distal tubule
The distal convoluted tubule (DCT) is a portion of kidney nephron between the loop of Henle and the collecting tubule.
Physiology
It is partly responsible for the regulation of potassium, sodium, calcium, and pH.
On its Apical membrane, apica ...
. By lowering the sodium concentration in the tubule epithelial cells, thiazides indirectly increase the activity of the basolateral
Na+/Ca2+ antiporter to maintain intracellular Na
+ level, facilitating Ca
2+ to leave the epithelial cells into the renal interstitium. Thus, intracellular Ca
2+ concentration is decreased, which allows more Ca
2+ from the lumen of the tubules to enter epithelial cells via apical Ca
2+-selective channels (TRPV5). In other words, less Ca
2+ in the cell increases the driving force for reabsorption from the lumen.
Thiazides are also thought to increase the reabsorption of Ca
2+ by a mechanism involving the reabsorption of sodium and calcium in the
proximal tubule
The proximal tubule is the segment of the nephron in kidneys which begins from the renal (tubular) pole of the Bowman's capsule to the beginning of loop of Henle. At this location, the glomerular parietal epithelial cells (PECs) lining bowman’s ...
in response to sodium depletion. Some of this response is due to augmentation of the action of
parathyroid hormone
Parathyroid hormone (PTH), also called parathormone or parathyrin, is a peptide hormone secreted by the parathyroid glands that regulates serum calcium and phosphate through its actions on the bone, kidneys, and small intestine. PTH incre ...
.
Breastfeeding
Thiazides pass into
breast milk
Breast milk (sometimes spelled as breastmilk) or mother's milk is milk produced by the mammary glands in the breasts of women. Breast milk is the primary source of nutrition for newborn infants, comprising fats, proteins, carbohydrates, and a var ...
and can decrease the flow of breast milk.
Thiazides have been associated with significant
side effect
In medicine, a side effect is an effect of the use of a medicinal drug or other treatment, usually adverse but sometimes beneficial, that is unintended. Herbal and traditional medicines also have side effects.
A drug or procedure usually use ...
s in some nursing infants and should be administered to nursing mothers with caution.
History
The thiazide diuretics were developed by scientists Karl H. Beyer, James M. Sprague, John E. Baer, and Frederick C. Novello of
Merck and Co. in the 1950s,
and led to the marketing of the first drug of this class,
chlorothiazide
Chlorothiazide, sold under the brand name Diuril among others, is an organic compound used as a diuretic and as an antihypertensive.
It is used both within the hospital setting or for personal use to manage excess fluid associated with congestiv ...
, under the trade name Diuril in 1958. The research leading to the discovery of chlorothiazide, leading to "the saving of untold thousands of lives and the alleviation of the suffering of millions of victims of hypertension" was recognized by a special Public Health Award from the Lasker Foundation in 1975.
References
{{Membrane transport modulators
*
World Anti-Doping Agency prohibited substances
Nephrotoxins