WordNet

increased secretion of urine; if not due to increased liquid intake or to the action of a diuretic drug it can be a symptom of diabetes mellitus

PrepTutorEJDIC

排尿促進の,利尿の / 利尿剤

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/09/13 09:25:36」(JST)

wiki en

A diuretic is any substance that promotes the 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, or antidiuretic hormone, is an agent or drug which reduces the excretion of water in urine.

1 Medical uses
2 Types
- 2.1 High ceiling/loop diuretic
- 2.2 Thiazides
- 2.3 Carbonic anhydrase inhibitors
- 2.4 Potassium-sparing diuretics
- 2.5 Calcium-sparing diuretics
- 2.6 Osmotic diuretics
- 2.7 Low ceiling diuretics
3 Mechanism of action
4 Adverse effects
5 Banned use in sports
6 See also
7 References
8 External links

Medical uses

In medicine, diuretics are used to treat heart failure, liver cirrhosis, hypertension, 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 often abused by sufferers of eating disorders, especially bulimics, in attempts at weight loss.

The antihypertensive actions of some diuretics (thiazides and loop diuretics in particular) are independent of their diuretic effect.^{[citation needed]} 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.

Types

High ceiling/loop diuretic

High ceiling diuretics may cause a substantial diuresis – up to 20%^[1] 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 torsemide.

Thiazides

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 long-term anti-hypertensive action is based on the fact that thiazides decrease preload, decreasing blood pressure. On the other hand the short-term effect is due to an unknown vasodilator effect that decreases blood pressure by decreasing resistance.

Carbonic anhydrase inhibitors

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.

Potassium-sparing diuretics

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:

Aldosterone antagonists: spironolactone, which is a competitive antagonist of aldosterone. Aldosterone normally adds sodium channels in the principal cells of the collecting duct and late distal tubule of the nephron. Spironolactone prevents aldosterone from entering the principal cells, preventing sodium reabsorption. Similar agents are eplerenone and potassium canreonate.

Epithelial sodium channel blockers: amiloride and triamterene.

Calcium-sparing diuretics

The term "calcium-sparing diuretic" is sometimes used to identify agents that result in a relatively low rate of excretion of calcium.^[2]

The reduced concentration of calcium in the urine can lead to an increased rate of calcium in serum. The sparing effect on calcium can be beneficial in hypocalcemia, or unwanted in hypercalcemia.

The thiazides and potassium-sparing diuretics are considered to be calcium-sparing diuretics.^[3]

The thiazides cause a net decrease in calcium lost in urine.^[4]
The potassium-sparing diuretics cause a net increase in calcium lost in urine, but the increase is much smaller than the increase associated with other diuretic classes.^[4]

By contrast, loop diuretics promote a significant increase in calcium excretion.^[5] This can increase risk of reduced bone density.^[6]

Osmotic diuretics

Osmotic diuretics (e.g. mannitol) are substances that increase osmolality 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.^[7]

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.

Low ceiling diuretics

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). It refers to a pharmacological profile, not a chemical structure. However, certain classes of diuretic tae usually fall into this category, such as the thiazides.^[8]

Mechanism of action

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.^[9] Classification of common diuretics and their mechanisms of action.

	Examples	Mechanism	Location (numbered in distance along nephron)
–	ethanol, water	Inhibits vasopressin secretion
Acidifying salts	CaCl₂, NH₄Cl		1.
Arginine vasopressin receptor 2 antagonists	amphotericin B, lithium citrate	Inhibits vasopressin's action	5. collecting duct
Aquaretics	Goldenrod^{[citation needed]}, Juniper^{[citation needed]}	Increases blood flow in kidneys^{[citation needed]}	1.^{[citation needed]}
Na-H exchanger antagonists	dopamine^[10]	Promotes Na⁺ excretion	2. proximal tubule^[10]
Carbonic anhydrase inhibitors	acetazolamide,^[10] dorzolamide	Inhibits H⁺ secretion, resultant promotion of Na⁺ and K⁺ excretion	2: proximal tubule
Loop diuretics	bumetanide,^[10] ethacrynic acid,^[10] furosemide,^[10] 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^[10]	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.

Adverse effects

The main adverse effects of diuretics are hypovolemia, hypokalemia, hyperkalemia, hyponatremia, metabolic alkalosis, metabolic acidosis, and hyperuricemia.^[10]

Adverse effect	Diuretics	Symptoms
Hypovolemia	loop diuretics^[10] thiazides^[10]	lassitude^[10] thirst^[10] muscle cramps^[10] hypotension^[10]
hypokalemia	acetazolamides^[10] loop diuretics^[10] thiazides^[10]	muscle weakness^[10] paralysis^[10] arrhythmia^[10]
Hyperkalemia	amilorides^[10] triamterenes^[10] spironolactone^[10]	arrhythmia^[10] muscle cramps^[10] paralysis^[10]
hyponatremia	thiazides^[10] furosemides^[10]	CNS symptoms^[10] coma^[10]
metabolic alkalosis	loop diuretics^[10] thiazides^[10]	arrhythmia^[10] CNS symptoms^[10]
metabolic acidosis	acetazolamides^[10] amilorides^[10] triamterene^[10]	Kussmaul respirations^[10] muscle weakness neurological symptoms^[10] lethargy coma seizures stupor
hypercalcemia	thiazides^[10]	gout tissue calcification^[10] fatigue depression confusion anorexia nausea vomiting constipation pancreatitis increased urination
hyperuricemia	thiazides^[10] loop diuretics^[10]	gout^[10]

Banned use in sports

A common application of diuretics is for the purposes of invalidating drug test.^[11] Diuretics increase the urine volume and dilute doping agents and their metabolites. The other use would be to rapidly lose weight to meet a weight category in sports like boxing, wrestling and others.^[12]^[13]

References

^ Drug Monitor – Diuretics
^ Shankaran S, Liang KC, Ilagan N, Fleischmann L (April 1995). "Mineral excretion following furosemide compared with bumetanide therapy in premature infants". Pediatr. Nephrol. 9 (2): 159–62. doi:10.1007/BF00860731. PMID 7794709.
^ Bakhireva LN, Barrett-Connor E, Kritz-Silverstein D, Morton DJ (June 2004). "Modifiable predictors of bone loss in older men: a prospective study". Am J Prev Med 26 (5): 436–42. doi:10.1016/j.amepre.2004.02.013. PMID 15165661.
^ ^a ^b Champe, Pamela C.; Richard Hubbard Howland; Mary Julia Mycek; Harvey, Richard P. (2006). Pharmacology. Philadelphia: Lippincott William & Wilkins. p. 269. ISBN 0-7817-4118-1.
^ Rejnmark L, Vestergaard P, Pedersen AR, Heickendorff L, Andreasen F, Mosekilde L (January 2003). "Dose-effect relations of loop- and thiazide-diuretics on calcium homeostasis: a randomized, double-blinded Latin-square multiple cross-over study in postmenopausal osteopenic women". Eur. J. Clin. Invest. 33 (1): 41–50. doi:10.1046/j.1365-2362.2003.01103.x. PMID 12492451.
^ Rejnmark L, Vestergaard P, Heickendorff L, Andreasen F, Mosekilde L (January 2006). "Loop diuretics increase bone turnover and decrease BMD in osteopenic postmenopausal women: results from a randomized controlled study with bumetanide". J. Bone Miner. Res. 21 (1): 163–70. doi:10.1359/JBMR.051003. PMID 16355285.
^ https://www.uic.edu/classes/pcol/pcol425/restricted/Du/diuretics.PDF
^ Mutschler, Ernst (1995). Drug actions: basic principles and therapeutic aspects. Stuttgart, German: Medpharm Scientific Pub. p. 460. ISBN 0-8493-7774-9.
^ Ali SS, Sharma PK, Garg VK, Singh AK, Mondal SC (Apr 2012). "The target-specific transporter and current status of diuretics as antihypertensive". Fundam Clin Pharmacol 26 (2): 175–9. doi:10.1111/j.1472-8206.2011.01012.x. PMID 22145583.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m ⁿ ^o ^p ^q ^r ^s ^t ^u ^v ^w ^x ^y ^z ^aa ^ab ^ac ^ad ^ae ^af ^ag ^ah ^ai ^aj ^ak ^al ^am ^an ^ao ^ap ^aq ^ar Boron, Walter F. (2004). Medical Physiology: A Cellular And Molecular Approach. Elsevier/Saunders. p. 875. ISBN 1-4160-2328-3.
^ Bahrke, Michael (2002). Performance-Enhancing Substances in Sport and Exercise.
^ Agence France Presse (2012-07-17). "UCI announces adverse analytical finding for Frank Schleck". VeloNews. Retrieved 2012-07-18.
^ The abuse of diuretics as performance-enhancing drugs and masking agents in sport doping: pharmacology, toxicology and analysis, British Journal of Pharmacology, 2010-09.

External links

Diagram at cvpharmacology.com
"Caffeine and Electrolyte Imbalance" by Dana George August 23, 2011

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. 利尿剤の作用機序 mechanism of action of diuretics
2. 心不全患者における利尿剤の使用 use of diuretics in patients with heart failure
3. ループ利尿剤：最大有効量および主な副作用 loop diuretics maximum effective dose and major side effects
4. 高血圧治療におけるサイアザイド系利尿剤とループ利尿剤の比較 thiazides versus loop diuretics in treatment of hypertension
5. 成人における浮腫に対する治療の一般原則 general principles of the treatment of edema in adults

English Journal

Detection of mutations in KLHL3 and CUL3 in families with FHHt (familial hyperkalaemic hypertension or Gordon's syndrome).

Glover M1, Ware JS, Henry A1, Wolley M2, Walsh R3, Wain LV4, Xu S2, Van't Hoff WG5, Tobin MD4, Hall IP1, Cook S, Gordon RD2, Stowasser M2, O'Shaughnessy KM6.Author information 1*Division of Therapeutics and Molecular Medicine, University of Nottingham, Nottingham, U.K.2§Endocrine Hypertension Research Centre, University of Queensland School of Medicine, Brisbane, Australia.3†NIHR Biomedical Research Unit in Cardiovascular Disease at Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, London, U.K.4¶Genetic Epidemiology Group, University of Leicester, Leicester, U.K.5∥Paediatric Nephrology Department, Great Ormond Street Hospital for Children, London, U.K.6‡‡Clinical Pharmacology Unit, University of Cambridge, Cambridge, U.K.AbstractThe study of families with rare inherited forms of hypo- and hyper-tension has been one of the most successful strategies to probe the molecular pathophysiology of blood pressure control and has revealed dysregulation of distal nephron Na+ reabsorption to be a common mechanism. FHHt (familial hyperkalaemic hypertension; also known as Gordon's syndrome) is a salt-dependent form of hypertension caused by mutations in the regulators of the thiazide-sensitive Na+-Cl- co-transporter NCC [also known as SLC12A3 (solute carrier family 12 member 3)] and is effectively treated by thiazide diuretics and/or dietary salt restriction. Variation in at least four genes can cause FHHt, including WNK1 [With No lysine (=K) 1] and WNK4, KLHL3 (kelch-like family member 3), and CUL3 (cullin 3). In the present study we have identified novel disease-causing variants in CUL3 and KLHL3 segregating in 63% of the pedigrees with previously unexplained FHHt, confirming the importance of these recently described FHHt genes. We have demonstrated conclusively, in two unrelated affected individuals, that rare intronic variants in CUL3 cause the skipping of exon 9 as has been proposed previously. KLHL3 variants all occur in kelch-repeat domains and so probably disrupt WNK complex binding. We have found no evidence of any plausible disease-causing variants within SLC4A8 (an alternative thiazide-sensitive sodium transporter) in this population. The results of the present study support the existing evidence that the CUL3 and KLHL3 gene products are physiologically important regulators of thiazide-sensitive distal nephron NaCl reabsorption, and hence potentially interesting novel anti-hypertensive drug targets. As a third of our non-WNK FHHt families do not have plausible CUL3 or KLHL3 variants, there are probably additional, as yet undiscovered, regulators of the thiazide-sensitive pathways.
Clinical science (London, England : 1979).Clin Sci (Lond).2014 May 1;126(10):721-6. doi: 10.1042/CS20130326.
The study of families with rare inherited forms of hypo- and hyper-tension has been one of the most successful strategies to probe the molecular pathophysiology of blood pressure control and has revealed dysregulation of distal nephron Na+ reabsorption to be a common mechanism. FHHt (familial hyperk
PMID 24266877

Impact of anticoagulation on the effectiveness of loop diuretics in heart failure with cardiorenal syndrome and venous thromboembolism.

Targonski R1, Sadowski J, Cyganski PA.Author information 1aDepartament of Cardiology, City Hospital, Al. Niepodleglości 44, Olsztyn, Poland.AbstractThe limitations of diuretics in the treatment of acute decompensated heart failure (ADCHF) are progressive worsening of renal function and resistance to up-titrated doses. The occurrence of resistance to loop diuretics in patients with ADCHF is associated with worsening prognosis and increased mortality. In this study, we report two patients with ADCHF and resistance to loop diuretics suspected for venous thromboembolism, suggesting that heparin administered to ADCHF patients treated for venous thromboembolism with cardiorenal syndrome decreases right-ventricular overload and improves renal function. To our knowledge, these are the first reported cases describing restored responsiveness to loop diuretics in ADCHF patients after additional heparin administration.
Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.Blood Coagul Fibrinolysis.2014 Mar;25(2):180-2. doi: 10.1097/MBC.0000000000000012.
The limitations of diuretics in the treatment of acute decompensated heart failure (ADCHF) are progressive worsening of renal function and resistance to up-titrated doses. The occurrence of resistance to loop diuretics in patients with ADCHF is associated with worsening prognosis and increased morta
PMID 24284867

Novel drugs targeting transthyretin amyloidosis.

Hanna M.Author information Section of Heart Failure and Cardiac Transplantation, Cleveland Clinic, 9500 Euclid Avenue, Desk J3-4, Cleveland, OH, 44195, USA, hannam@ccf.org.AbstractTransthyretin amyloidosis (ATTR) is either a hereditary disease related to a mutation in the transthyretin gene that leads to neuropathy and/or cardiomyopathy or an acquired disease of the elderly that leads to restrictive cardiomyopathy. The prevalence of this disease is higher than once thought and awareness is likely to increase amongst physicians and in particular cardiologists. Until recently there have been no treatment options for this disease except to treat the heart failure with diuretics and the neuropathy symptomatically. However, there are several emerging pharmacologic therapies designed to slow or stop the progression of ATTR. This article reviews novel therapeutic drugs that work at different points in the pathogenesis of this disease attempting to change its natural history and improve outcomes.
Current heart failure reports.Curr Heart Fail Rep.2014 Mar;11(1):50-7. doi: 10.1007/s11897-013-0182-4.
Transthyretin amyloidosis (ATTR) is either a hereditary disease related to a mutation in the transthyretin gene that leads to neuropathy and/or cardiomyopathy or an acquired disease of the elderly that leads to restrictive cardiomyopathy. The prevalence of this disease is higher than once thought an
PMID 24464360

Japanese Journal

心筋梗塞の合併症としての心内血栓が感染した一症例

江口和男,荒川伸人,手塚康裕,大野彰二,黒田一,齋藤建
自治医科大学紀要 34, 75-79, 2012-03-01
症例は68歳男性,高熱と呼吸困難感を主訴に入院した。肺炎と心不全の診断で抗生剤と利尿剤で治療を開始した。一時軽快傾向となったが,CRP値6以上が持続していた。心エコーでは,び漫性壁運動低下と心尖部付近の心筋肥大がみられた。第18病日に致死的不整脈を発症し、CPRを行ったが,突然死した。病理解剖の結果,下壁の陳旧性心筋梗塞と前壁の急性心筋梗塞に伴う心尖部の感染性血栓がみつかった。本症例では,左室の壁 …
NAID 110008922596