A diuretic is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. There are several categories of diuretics. All diuretics increase the excretion of water from bodies, although each class does so in a distinct way. Alternatively, an antidiuretic, such as vasopressin (antidiuretic hormone), is an agent or drug which reduces the excretion of water in urine.
|Use||Forced diuresis, hypertension|
In medicine, diuretics are used to treat heart failure, liver cirrhosis, hypertension, influenza, water poisoning, and certain kidney diseases. Some diuretics, such as acetazolamide, help to make the urine more alkaline and are helpful in increasing excretion of substances such as aspirin in cases of overdose or poisoning. Diuretics are sometimes abused by people with an eating disorder, especially people with bulimia nervosa, with the goal of losing weight.
The antihypertensive actions of some diuretics (thiazides and loop diuretics in particular) are independent of their diuretic effect. That is, the reduction in blood pressure is not due to decreased blood volume resulting from increased urine production, but occurs through other mechanisms and at lower doses than that required to produce diuresis. Indapamide was specifically designed with this in mind, and has a larger therapeutic window for hypertension (without pronounced diuresis) than most other diuretics.
High ceiling diuretics may cause a substantial diuresis – up to 20% of the filtered load of NaCl (salt) and water. This is large in comparison to normal renal sodium reabsorption which leaves only about 0.4% of filtered sodium in the urine. Loop diuretics have this ability, and are therefore often synonymous with high ceiling diuretics. Loop diuretics, such as furosemide, inhibit the body's ability to reabsorb sodium at the ascending loop in the nephron, which leads to an excretion of water in the urine, whereas water normally follows sodium back into the extracellular fluid. Other examples of high ceiling loop diuretics include ethacrynic acid and torasemide.
Thiazide-type diuretics such as hydrochlorothiazide act on the distal convoluted tubule and inhibit the sodium-chloride symporter leading to a retention of water in the urine, as water normally follows penetrating solutes. Frequent urination is due to the increased loss of water that has not been retained from the body as a result of a concomitant relationship with sodium loss from the convoluted tubule. The short-term anti-hypertensive action is based on the fact that thiazides decrease preload, decreasing blood pressure. On the other hand, the long-term effect is due to an unknown vasodilator effect that decreases blood pressure by decreasing resistance.
Carbonic anhydrase inhibitors inhibit the enzyme carbonic anhydrase which is found in the proximal convoluted tubule. This results in several effects including bicarbonate accumulation in the urine and decreased sodium absorption. Drugs in this class include acetazolamide and methazolamide.
These are diuretics which do not promote the secretion of potassium into the urine; thus, potassium is retained and not lost as much as with other diuretics. The term "potassium-sparing" refers to an effect rather than a mechanism or location; nonetheless, the term almost always refers to two specific classes that have their effect at similar locations:
Osmotic diuretics (e.g. mannitol) are substances that increase osmolarity but have limited tubular epithelial cell permeability. They work primarily by expanding extracellular fluid and plasma volume, therefore increasing blood flow to the kidney, particularly the peritubular capillaries. This reduces medullary osmolality and thus impairs the concentration of urine in the loop of Henle (which usually uses the high osmotic and solute gradient to transport solutes and water). Furthermore, the limited tubular epithelial cell permeability increases osmolality and thus water retention in the filtrate.
It was previously believed that the primary mechanism of osmotic diuretics such as mannitol is that they are filtered in the glomerulus, but cannot be reabsorbed. Thus their presence leads to an increase in the osmolarity of the filtrate and to maintain osmotic balance, water is retained in the urine.
Glucose, like mannitol, is a sugar that can behave as an osmotic diuretic. Unlike mannitol, glucose is commonly found in the blood. However, in certain conditions, such as diabetes mellitus, the concentration of glucose in the blood (hyperglycemia) exceeds the maximum reabsorption capacity of the kidney. When this happens, glucose remains in the filtrate, leading to the osmotic retention of water in the urine. Glucosuria causes a loss of hypotonic water and Na+, leading to a hypertonic state with signs of volume depletion, such as dry mucosa, hypotension, tachycardia, and decreased turgor of the skin. Use of some drugs, especially stimulants, may also increase blood glucose and thus increase urination.
The term "low ceiling diuretic" is used to indicate a diuretic has a rapidly flattening dose effect curve (in contrast to "high ceiling", where the relationship is close to linear). Certain classes of diuretic are in this category, such as the thiazides.
Diuretics are tools of considerable therapeutic importance. First, they effectively reduce blood pressure. Loop and thiazide diuretics are secreted from the proximal tubule via the organic anion transporter-1 and exert their diuretic action by binding to the Na(+)-K(+)-2Cl(-) co-transporter type 2 in the thick ascending limb and the Na(+)-Cl(-) co-transporter in the distal convoluted tubule, respectively. Classification of common diuretics and their mechanisms of action.
|Examples||Mechanism||Location (numbered in distance along nephron)|
|–||ethanol, water||Inhibits vasopressin secretion|
|Acidifying salts||calcium chloride, ammonium chloride||1.|
receptor 2 antagonists
|amphotericin B, lithium||Inhibits vasopressin's action||5. collecting duct|
|Selective vasopressin V2 antagonist (sometimes called aquaretics)||tolvaptan, conivaptan||Competitive vasopressin antagonism leads to decreased number of aquaporin channels in the apical membrane of the renal collecting ducts in kidneys, causing decreased water reabsorption. This causes an increase in renal free water excretion (aquaresis), an increase in serum sodium concentration, a decrease in urine osmolality, and an increase in urine output.||5. collecting duct|
|Na-H exchanger antagonists||dopamine||Promotes Na+ excretion||2. proximal tubule|
|Carbonic anhydrase inhibitors||acetazolamide, dorzolamide||Inhibits H+ secretion, resultant promotion of Na+ and K+ excretion||2: proximal tubule|
|Loop diuretics||bumetanide, ethacrynic acid, furosemide, torsemide||Inhibits the Na-K-2Cl symporter||3. medullary thick ascending limb|
|Osmotic diuretics||glucose (especially in uncontrolled diabetes), mannitol||Promotes osmotic diuresis||2. proximal tubule, descending limb|
|Potassium-sparing diuretics||amiloride, spironolactone, eplerenone, triamterene, potassium canrenoate.||Inhibition of Na+/K+ exchanger: Spironolactone inhibits aldosterone action, Amiloride inhibits epithelial sodium channels||5. cortical collecting ducts|
|Thiazides||bendroflumethiazide, hydrochlorothiazide||Inhibits reabsorption by Na+/Cl− symporter||4. distal convoluted tubules|
|Xanthines||caffeine, theophylline, theobromine||Inhibits reabsorption of Na+, increase glomerular filtration rate||1. tubules|
Chemically, diuretics are a diverse group of compounds that either stimulate or inhibit various hormones that naturally occur in the body to regulate urine production by the kidneys.
As a diuretic is any substance that promotes the production of urine, aquaretics that cause the excretion of free water are a sub-class. This includes all the hypotonic aqueous preparations, including pure water, black and green teas, and teas prepared from herbal medications. Any given herbal medication will include a vast range of plant-derived compounds, some of which will be active drugs that may also have independent diuretic action.
A common application of diuretics is for the purposes of invalidating drug tests. Diuretics increase the urine volume and dilute doping agents and their metabolites. Another use is to rapidly lose weight to meet a weight category in sports like boxing and wrestling.
Bumetanide (trade names Bumex or Burinex) is a loop diuretic of the sulfamyl category, most often used to treat heart failure. It is often used in people in whom high doses of furosemide or other diuretics are ineffective. It is marketed by Hoffmann-La Roche. The main difference between bumetanide and furosemide is in their bioavailability and potency. About 60% of furosemide is absorbed in the intestine, and there are substantial inter- and intraindividual differences in bioavailability (range 10-90%). About 80% of bumetanide is absorbed, and its absorption does not change when it is taken with food. It is said to be a more predictable diuretic, meaning that the predictable absorption is reflected in a more predictable effect.Bumetanide is 40 times more potent than furosemide for patients with normal renal function.In the brain, bumetanide blocks the NKCC1 cation-chloride co-transporter, and thus decreases internal chloride concentration in neurons. In turn, this concentration change makes the action of GABA more hyperpolarizing, which may be useful for treatment of neonatal seizures, which quite often are not responsive to traditional GABA-targeted treatment, such as barbiturates. Bumetanide is therefore currently under evaluation as a prospective antiepileptic drug.Chlortalidone
Chlortalidone (INN/BAN) or chlorthalidone (USAN) is a diuretic medication used to treat high blood pressure, enlargement of the main pumping chamber of the heart, swelling and fluid retention, Ménière's disease, and inability of an injured kidney to produce concentrated urine. Chlortalidone is also used to prevent calcium oxalate kidney stones and bone fracture due to reduced bone mass. It is a thiazide-like diuretic of the sulfonamide class.
Chlortalidone is more effective than the similar medication, hydrochlorothiazide, for lowering blood pressure, reversing enlargement of the main pumping chamber of the heart, and also for preventing calcium oxalate kidney stones. Chlortalidone and hydrochlorothiazide have a similar risk of causing low blood potassium levels and other adverse effects at the usual doses prescribed in routine clinical practice. Chlortalidone is sometimes used as a single-drug therapy for treating high blood pressure.
It is also often used in combination with an angiotensin converting enzyme inhibitor or angiotensin II receptor blocker or other antihypertensive drugs for lowering blood pressure, and also as an adjuvant medication for treating edema caused by heart failure and kidney disorders, such as nephrotic syndrome. Chlortalidone has a long duration of action, 24 to 72 hours, and can be given once a day.Etacrynic acid
Etacrynic acid (INN) or ethacrynic acid (USAN), trade name Edecrin, is a loop diuretic used to treat high blood pressure and the swelling caused by diseases like congestive heart failure, liver failure, and kidney failure.
Unlike the other loop diuretics, etacrynic acid is not a sulfonamide and thus, its use is not contraindicated in those with sulfa allergies.
Ethacrynic acid is a phenoxyacetic acid derivative containing a ketone group and a methylene group. A cysteine adduct is formed with the methylene group and this is the active form.Ethoxzolamide
Ethoxzolamide (alternatively known as ethoxyzolamide) is a sulfonamide medication that functions as a carbonic anhydrase inhibitor. It is used in the treatment of glaucoma and duodenal ulcers, and as a diuretic. It may also be used in the treatment of some forms of epilepsy.Furosemide
Furosemide, sold under the brand name Lasix among others, is a medication used to treat fluid build-up due to heart failure, liver scarring, or kidney disease. It may also be used for the treatment of high blood pressure. It can be taken intravenously or by mouth. When taken by mouth, it typically begins working within an hour, while intravenously, it typically begins working within five minutes.Common side effects include low blood pressure with standing, ringing in the ears, and sensitivity to sunlight. Potentially serious side effects include electrolyte abnormalities, low blood pressure, and hearing loss. Blood tests are recommended regularly for those on treatment. Furosemide is a type of loop diuretic that works by decreasing the reabsorption of sodium by the kidneys.Furosemide was discovered in 1962 and was approved for medical use in the United States in 1966. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. The wholesale price in the developing world is between US$0.004 and US$0.02 per day. In the United States it is available as a generic medication and costs about US$0.15 per day. In 2016 it was the 15th most prescribed medication in the United States with more than 32 million prescriptions. is on the World Anti-Doping Agency's banned drug list due to concerns that it may mask other drugs. It has also been used in race horses for the treatment and prevention of exercise-induced pulmonary hemorrhage.Loop diuretic
Loop diuretics are diuretics that act at the ascending limb of the 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. While thiazide diuretics are more effective in patients with normal kidney function, loop diuretics are more effective in patients with impaired kidney function.Mercurial diuretic
Mercurial diuretics are a form of renal diuretic containing mercury.
Although previously widely used, they have largely been superseded by safer diuretics such as thiazides, and are hardly used anymore.Mersalyl
Mersalyl (Mersal) is an organomercury compound (mercurial diuretic). It is only rarely used as a drug, having been superseded by diuretic medications that do not contain mercury and are therefore less toxic. It features a Hg(II) centre. Mersalyl was originally adapted from calomel (HgCl), a diuretic discovered by Paracelsus.Middle cerebral artery syndrome
Middle cerebral artery syndrome is a condition whereby the blood supply from the middle cerebral artery (MCA) is restricted, leading to a reduction of the function of the portions of the brain supplied by that vessel: the lateral aspects of frontal, temporal and parietal lobes, the corona radiata, globus pallidus, caudate and putamen. The MCA is the most common site for the occurrence of ischemic stroke.Depending upon the location and severity of the occlusion, signs and symptoms may vary within the population affected with MCA syndrome. More distal blockages tend to produce milder deficits due to more extensive branching of the artery and less ischemic response. In contrast, the most proximal occlusions result in widespread effects that can lead to significant cerebral edema, increased intracranial pressure, loss of consciousness and could even be fatal. In such occasions, mannitol (osmotic diuretic) or hypertonic saline are given to draw fluid out of the edematous cerebrum to minimise secondary injury. Hypertonic saline is better than mannitol, as mannitol being a diuretic will decrease the mean arterial pressure and since cerebral perfusion is mean arterial pressure minus intracranial pressure, mannitol will also cause a decrease in cerebral perfusion.
Contralateral hemiparesis and hemisensory loss of the face, upper and lower extremities is the most common presentation of MCA syndrome. Lower extremity function is more spared than that of the faciobrachial region. The majority of the primary motor and somatosensory cortices are supplied by the MCA and the cortical homunculus can, therefore, be used to localize the defects more precisely. Middle cerebral artery lesions mostly affect the dominant hemisphere i.e. the left cerebral hemisphere.Muzolimine
Muzolimine is a High-ceiling loop diuretic. It is a pyrazole diuretic which was used for treatment of hypertension but was withdrawn worldwide because of severe neurological side effects.Natriuresis
Natriuresis is the process of sodium excretion in the urine through the action of the kidneys. It is promoted by ventricular and atrial natriuretic peptides as well as calcitonin, and inhibited by chemicals such as aldosterone. Natriuresis lowers the concentration of sodium in the blood and also tends to lower blood volume because osmotic forces drag water out of the body's blood circulation and into the urine along with the sodium. Many diuretic drugs take advantage of this mechanism to treat medical conditions like hypernatremia and hypertension, which involve excess blood volume.
Excess natriuresis can be caused by:
Medullary cystic disease
Diuretic phase of acute tubular necrosis
Primary renal diseases
Congenital adrenal hyperplasia
Syndrome of inappropriate antidiuretic hormone hypersecretionEndogenous natriuretic hormones include:
Atrial natriuretic peptide
Brain natriuretic peptide
C-type natriuretic peptide This is a natural process in infants at the time of birth.Osmotic diuretic
An osmotic diuretic is a type of diuretic that inhibits reabsorption of water and sodium (Na). They are pharmacologically inert substances that are given intravenously. They increase the osmolarity of blood and renal filtrate.Two examples are mannitol and isosorbide.
In the nephron, osmotic diuretics act at the portions of the nephron that are water-permeable.Osmotic diuretics works by expanding extracellular fluid and plasma volume, therefore increasing blood flow to the kidney. This washes out the cortical medullary gradient in the kidney. This stops the loop of Henle from concentrating urine, which usually uses the high osmotic and solute gradient to transport solutes and water.
These agents can also act at other parts of the body. For example, they can be used to reduce intracranial and intra-ocular pressure. Osmotic diuretics increase plasma volume, but because they do not cross the blood-brain barrier, this does not affect the nervous system. In effect, this is the cause of their action reducing locally the plasma volume in the nervous system.Potassium-sparing diuretic
Potassium-sparing diuretics are diuretic drugs that do not promote the secretion of potassium into the urine.They are used as adjunctive therapy, together with other drugs, in the treatment of hypertension and management of congestive heart failure. However, at low doses the use of potassium-sparing diuretics has not been found to produce a clinically significant reduction in blood pressure.Potassium acetate
Potassium acetate (CH3COOK) is the potassium salt of acetic acid.Reserpine
Reserpine is a drug that is used for the treatment of high blood pressure, usually in combination with a thiazide diuretic or vasodilator. Large clinical trials have shown that combined treatment with reserpine plus a thiazide diuretic reduces mortality of people with hypertension. Although the use of reserpine as a solo drug has declined since it was first approved by the FDA in 1955, a review recommends use of reserpine and a thiazide diuretic or vasodilator in patients who do not achieve adequate lowering of blood pressure with first-line drug treatment alone. The reserpine-hydrochlorothiazide combo pill was the 17th most commonly prescribed of the 43 combination antihypertensive pills available In 2012.The antihypertensive actions of reserpine are largely due to its antinoradrenergic effects, which are a result of its ability to deplete catecholamines (among other monoamine neurotransmitters) from peripheral sympathetic nerve endings. These substances are normally involved in controlling heart rate, force of cardiac contraction and peripheral vascular resistance.At doses of 0.05 to 0.2 mg per day, reserpine is well tolerated; the most common adverse effect being nasal stuffiness.
Reserpine has also been used for relief of psychotic symptoms. A review found that in persons with schizophrenia, reserpine and chlorpromazine had similar rates of adverse effects, but that reserpine was less effective than chlorpromazine for improving a person's global state.Thiazide
Thiazide () is 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 failure, liver failure, or kidney failure).
The thiazides and thiazide-like diuretics reduce the risk of death, stroke, heart attack, and heart failure due to hypertension. The class was discovered and developed at Merck and Co. in the 1950s, and the first approved drug of this class, chlorothiazide, was marketed under the trade name Diuril beginning in 1958. In most countries, the thiazides are the least expensive antihypertensive drugs available.Thiazide-like diuretic
A thiazide-like diuretic is a sulfonamide diuretic that has similar physiological properties to a thiazide diuretic, but does not have the chemical properties of a thiazide, lacking the benzothiadiazine molecular structure.
Examples include metolazone.
Some, such as indapamide are considered thiazide-like diuretics, but do not necessarily have the same mechanism.Torasemide
Torasemide or torsemide is a pyridine-sulfonyl urea type loop diuretic mainly used in the management of edema associated with congestive heart failure. It is also used at low doses for the management of hypertension. It is marketed under the brand names Demadex, Diuver, and Examide.
Compared with other loop diuretics, torasemide has a more prolonged diuretic effect than equipotent doses of furosemide and relatively decreased potassium loss. No evidence of torasemide-induced ototoxicity has been demonstrated in humans.Recent publications suggest improved outcomes when used for heart failure compared with furosemide.Vasopressin
Vasopressin, also called antidiuretic hormone (ADH), arginine vasopressin (AVP) or argipressin, is a hormone synthesized as a peptide prohormone in neurons in the hypothalamus, and is converted to AVP. It then travels down the axon of that cell, which terminates in the posterior pituitary, and is released from vesicles into the circulation in response to extracellular fluid hypertonicity (hyperosmolality). AVP has two primary functions. First, it increases the amount of solute-free water reabsorbed back into the circulation from the filtrate in the kidney tubules of the nephrons. Second, AVP constricts arterioles, which increases peripheral vascular resistance and raises arterial blood pressure.A third function is possible. Some AVP may be released directly into the brain from the hypothalamus, and may play an important role in social behavior, sexual motivation and pair bonding, and maternal responses to stress.Vasopressin induces differential of stem cells into cardiomyocytes and promotes heart muscle homeostasis.It has a very short half-life, between 16–24 minutes.