Thiazide
Encyclopedia
Diuretic
A diuretic provides a means of forced diuresis which elevates the rate of urination. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way.- Medical uses :...
s often used to treat 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) and edema
Edema
Edema or oedema ; both words from the Greek , oídēma "swelling"), formerly known as dropsy or hydropsy, is an abnormal accumulation of fluid beneath the skin or in one or more cavities of the body that produces swelling...
(such as that caused by heart, liver, or kidney disease).
The thiazides and thiazide-like diuretics reduce the risk of death, stroke, heart attack
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
and heart failure due to hypertension. In most countries, the thiazides are the cheapest antihypertensive drugs available.
Mechanism of action
The members of this class of diureticDiuretic
A diuretic provides a means of forced diuresis which elevates the rate of urination. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way.- Medical uses :...
s are derived from 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...
. They control hypertension in part by inhibiting reabsorption of 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...
(Na+) and chloride
Chloride
The chloride ion is formed when the element chlorine, a halogen, picks up one electron to form an anion Cl−. The salts of hydrochloric acid HCl contain chloride ions and can also be called chlorides. The chloride ion, and its salts such as sodium chloride, are very soluble in water...
(Cl−) ion
Ion
An ion is an atom or molecule in which the total number of electrons is not equal to the total number of protons, giving it a net positive or negative electrical charge. The name was given by physicist Michael Faraday for the substances that allow a current to pass between electrodes in a...
s from 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...
s 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...
s by blocking the thiazide-sensitive Na+-Cl− 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...
. Thiazides also cause loss of 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...
and an increase in serum
Blood plasma
Blood plasma is the straw-colored liquid component of blood in which the blood cells in whole blood are normally suspended. It makes up about 55% of the total blood volume. It is the intravascular fluid part of extracellular fluid...
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...
. The term "thiazide" is also often used for drugs with a similar action that do not have the thiazide chemical structure, such as chlortalidone
Chlortalidone
Chlortalidone or chlorthalidone is a diuretic drug used to treat hypertension, originally marketed as Hygroton in the USA. It is described as a thiazide diuretic...
and metolazone
Metolazone
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 and high blood pressure. Metolazone indirectly decreases the amount of water reabsorbed into the bloodstream by the kidney,...
. These agents are more properly termed thiazide-like diuretics
Thiazide-like diuretic
A thiazide-like diuretic is a sulfonamide diuretic that has similar physiological properties to a thiazide diuretic, but doesn't have the chemical properties of a thiazide, lacking the benzothiadiazine molecular structure....
.
Denomination
That thiazide refers to both the type of molecule and the medicationMedication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
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
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...
.
Primary uses
Thiazides are often used to treat hypertensionHypertension
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...
, although they are also used to treat congestive heart failure and symptomatic edema. They are the recommended first-line treatment in the US (JNC VII) guidelines and the National Institute for Health and Clinical Excellence/British Hypertension Society guidelines and a recommended treatment in the European (ESC/ESH) 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 inhibitor
ACE inhibitor
ACE inhibitors or angiotensin-converting enzyme inhibitors are a group of drugs used primarily for the treatment of hypertension and congestive heart failure...
s in Australia due to their propensity to increase risk of diabetes mellitus type 2
Diabetes mellitus type 2
Diabetes mellitus type 2formerly non-insulin-dependent diabetes mellitus or adult-onset diabetesis a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance and relative insulin deficiency. Diabetes is often initially managed by increasing exercise and...
. Low-dose Thiazides have been shown to reduce hypertension-related morbidity and mortality
Death
Death is the permanent termination of the biological functions that sustain a living organism. Phenomena which commonly bring about death include old age, predation, malnutrition, disease, and accidents or trauma resulting in terminal injury....
, although how they lower blood pressure in the long term is not fully understood. When administered acutely thiazides lower blood pressure by causing diuresis
Diuresis
Diuresis may refer to:* Urine production, as an aspect of fluid balance* Excessive urine production - see polyuria* Immersion 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
Vasodilation
Vasodilation refers to the widening of blood vessels resulting from relaxation of smooth muscle cells within the vessel walls, particularly in the large arteries, smaller arterioles and large veins. The process is essentially the opposite of vasoconstriction, or the narrowing of blood vessels. When...
). The mechanism of this effect is uncertain but it may involve effects on 'whole body' or renal autoregulation
Autoregulation
Autoregulation is a process within many biological systems, resulting from some internal adaptive mechanism that works to adjust the systems response to stimuli. While most systems of the body show some degree of autoregulation, it is most clearly observed in the kidney, the heart, and the brain...
, or direct vasodilator actions either through inhibition of carbonic anhydrase
Carbonic anhydrase
The carbonic anhydrases form a family of enzymes that catalyze the rapid interconversion of carbon dioxide and water to bicarbonate and protons , a reversible reaction that occurs rather slowly in the absence of a catalyst...
or by desensitizing
Desensitization
Desensitization can refer to:* Desensitization * Desensitization * Desensitization * Desensitization of explosives, see Phlegmatized...
the vascular smooth muscle
Vascular smooth muscle
Vascular smooth muscle refers to the particular type of smooth muscle found within, and composing the majority of the wall of blood vessels.Vascular smooth muscle contracts or relaxes to both change the volume of blood vessels and the local blood pressure, a mechanism that is responsible for the...
cells to the rise in intracellular 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...
induced by norepinephrine
Norepinephrine
Norepinephrine is the US name for noradrenaline , a catecholamine with multiple roles including as a hormone and a neurotransmitter...
.
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 to osteoporosisOsteoporosis
Osteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
. By a lesser understood mechanism, thiazides directly stimulate osteoblast
Osteoblast
Osteoblasts are mononucleate cells that are responsible for bone formation; in essence, osteoblasts are specialized fibroblasts that in addition to fibroblastic products, express bone sialoprotein and osteocalcin.Osteoblasts produce a matrix of osteoid, which is composed mainly of Type I collagen...
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
Dent's disease
Dent's disease is a rare X-linked recessive inherited condition that affects the proximal renal tubules of the kidney. It is one cause of Fanconi syndrome, and is characterized by tubular proteinuria, hypercalciuria, calcium nephrolithiasis, nephrocalcinosis and chronic renal failure."Dent's...
or idiopathic
Idiopathic
Idiopathic is an adjective used primarily in medicine meaning arising spontaneously or from an obscure or unknown cause. From Greek ἴδιος, idios + πάθος, pathos , it means approximately "a disease of its own kind". It is technically a term from nosology, the classification of disease...
hypercalciuria
Hypercalciuria
Hypercalciuria or hypercalcinuria is the condition of elevated calcium in the urine. Chronic hypercalcinuria may lead to impairment of renal function, nephrocalcinosis, and renal insufficiency....
.
Thiazide may be combined with ACE inhibitors to increase diuresis without changing plasma potassium concentrations. While ACE inhibitors cause 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.Contraindications
Thiazides reduce the clearance of uric acid and are therefore to be used with caution in patients with goutGout
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...
or 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:...
.
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 increased cellular uptake of Na from the lumen by apical Epithelial Na Channels (ENaCs). This then causes the basolateral Na/K exchanger to more actively exchange Na for K, which is then passively secreted into the lumen through apical channels, 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 aldosteroneAldosteroneAldosterone is a hormone that increases the reabsorption of sodium ions and water and the release of potassium in the collecting ducts and distal convoluted tubule of the kidneys' functional unit, the nephron. This increases blood volume and, therefore, increases blood pressure. Drugs that...
which stimulates the Na/K exchanger, resulting in further loss of potassium. For this reason, ACE inhibitorACE inhibitorACE inhibitors or angiotensin-converting enzyme inhibitors are a group of drugs used primarily for the treatment of hypertension and congestive heart failure...
s, 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.
Complications
- HyperglycemiaHyperglycemiaHyperglycemia or Hyperglycæmia, or high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a glucose level higher than 13.5mmol/l , but symptoms may not start to become noticeable until even higher values such as 15-20 mmol/l...
- HyperlipidemiaHyperlipidemiaHyperlipidemia, hyperlipoproteinemia, or hyperlipidaemia is the condition of abnormally elevated levels of any or all lipids and/or lipoproteins in the blood...
- HyperuricemiaHyperuricemiaHyperuricemia 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:...
- Hypercalcemia
- HypokalemiaHypokalemiaHypokalemia or hypokalaemia , also hypopotassemia or hypopotassaemia , refers to the condition in which the concentration of potassium in the blood is low...
- HyponatremiaHyponatremiaHyponatremia 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...