Diuretic

Diuretic
Drug class
Class identifiers
Use	Forced diuresis, hypertension
ATC code	C03
External links
MeSH	D004232

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.

Medical uses

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 often abused by those with eating disorders, especially bulimics, in attempts to lose 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.

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.<ref name">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.</ref>

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.^[2]

• The thiazides cause a net decrease in calcium lost in urine.^[3]
• 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.^[3]

By contrast, loop diuretics promote a significant increase in calcium excretion.^[4] This can increase risk of reduced bone density.^[5]

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.^[6]

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.^[7]

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.^[8] 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
Selective Vasopressin V2 antagonist (Sometimes called Aquaretics)	Tolvaptan Conivaptan,	Bind aquaporin channels in the apical membrane of the renal collecting ducts in kidneys causing an increase in renal free water excretion or aquaresis, an increase in urine serum sodium concentrations, a decrease in urine osmolality, and an increase in urine output	5. collecting duct
Na-H exchanger antagonists	dopamine[9]	Promotes Na^+ excretion	2. proximal tubule[9]
Carbonic anhydrase inhibitors	acetazolamide,[9] dorzolamide	Inhibits H^+ secretion, resultant promotion of Na^+ and K^+ excretion	2: proximal tubule
Loop diuretics	bumetanide,[9] ethacrynic acid,[9] furosemide,[9] 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[9]	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.^[9]

Adverse effect	Diuretics	Symptoms
Hypovolemia	loop diuretics[9] thiazides[9]	lassitude[9] thirst[9] muscle cramps[9] hypotension[9]
hypokalemia	acetazolamides[9] loop diuretics[9] thiazides[9]	muscle weakness[9] paralysis[9] arrhythmia[9]
Hyperkalemia	amilorides[9] triamterenes[9] spironolactone[9]	arrhythmia[9] muscle cramps[9] paralysis[9]
hyponatremia	thiazides[9] furosemides[9]	CNS symptoms[9] coma[9]
metabolic alkalosis	loop diuretics[9] thiazides[9]	arrhythmia[9] CNS symptoms[9]
metabolic acidosis	acetazolamides[9] amilorides[9] triamterene[9]	Kussmaul respirations[9] muscle weakness neurological symptoms[9] lethargy coma seizures stupor
hypercalcemia	thiazides[9]	gout tissue calcification[9] fatigue depression confusion anorexia nausea vomiting constipation pancreatitis increased urination
hyperuricemia	thiazides[9] loop diuretics[9]	gout[9]

Banned use in sports

A common application of diuretics is for the purposes of invalidating drug tests.^[10] 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.^[11][12]

See also

• antidiuretic

References

1. Drug Monitor – Diuretics
2. 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.
3. 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.
4. 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.
5. 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.
6. https://www.uic.edu/classes/pcol/pcol425/restricted/Du/diuretics.PDF
7. Mutschler, Ernst (1995). Drug actions: basic principles and therapeutic aspects. Stuttgart, German: Medpharm Scientific Pub. p. 460. ISBN 0-8493-7774-9.
8. 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.
9. Boron, Walter F. (2004). Medical Physiology: A Cellular And Molecular Approach. Elsevier/Saunders. p. 875. ISBN 1-4160-2328-3.
10. Bahrke, Michael (2002). Performance-Enhancing Substances in Sport and Exercise.
11. Agence France Presse (2012-07-17). "UCI announces adverse analytical finding for Frank Schleck". VeloNews. Retrieved 2012-07-18.
12. 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