Loop diuretic
Loop diuretics are a group diuretic medications ( diuretics) that act at the loop of Henle, a part of the harnbildenden system of the kidneys. They are highly effective over a short time and, as they show a wide range of doses a nearly linear concentration-response relationship, referred to as "high ceiling" diuretics. With the appropriate liquid transfer it is possible to achieve a flow of urine from 35 to 45 liters per day. Chemically, it is in the loop diuretics to various substances that all have the same mechanism of action. The inhibition of a transport protein in the renal tubules leads to reduced re-uptake of ions from the primary, and thus due to the variation of the osmotic pressure for increased water excretion.
Representatives and chemical composition
Loop diuretics can be chemically distinguished in sulfonamide and non - sulfonamide derivatives. The sulfonamide derivatives include the active ingredients furosemide, bumetanide and Piretanid, all of which also carry a carboxy group on the central benzene ring. Azosemide is also a sulfonamide, but without carboxy group. Torasemide is a Pyridinsulfonylharnstoffderivat.
Ethacrynic acid, however, is a halogenated phenoxy acetic acid, with attached ketone and methyl groups. The methyl group is a bond with a cysteine , thereby forming the active form of the drug. Another representative is Etozolin.
When the mercury diuretics are organic mercury compounds, but these are no longer used due to their high toxicity.
Pharmacology
Mechanism of Action
In the kidney, metabolic waste products are filtered from the blood and excreted in the urine. Here, about 180 to 200 liters of primary urine are first produced every day, then in the following system of tubules, Henle's loop is concentrated (after Friedrich Gustav Jakob Henle) and collecting ducts by absorption of water until only about 1 to 1.5 liters of final urine or Sekundärharn remain. Furthermore, important substances such as glucose, amino acids and electrolytes are absorbed.
Loop diuretics act in the thick ascending limb of Henle's loop, a major site of absorption, absorbed into the blood back into the up to 25% of the excreted sodium ( absorbed ) are. This resumption of sodium ions is performed using a transport protein, the Na K 2 Cl - symporter ( cotransporter ). It is located on the luminal ( urine -facing ) side of the tubule cells and transported in addition to sodium, chloride and potassium ions into the tubule. Driving force is the active transport of sodium out of the cell into the blood by the sodium - potassium pump, as this builds up a concentration gradient between the tubule and the urine within the renal tubule. Also causes the transportation, that the interior of the cell is negatively charged. This negative charge drives the absorption by passive transport of magnesium ( Mg2 ) and calcium ions (Ca2 ) in the spaces between the tubules. Since the wall of the tubule is only slightly permeable to water, there is a relative dilution of the urine.
Loop diuretics act now, by the Na K 2 Cl - symporter inhibit reversible ( reversible). Sodium can not be reabsorbed, so the urine is concentrated. This leads to increased excretion of water by osmosis. Since no negative membrane potential can be established, calcium and magnesium ions remain in the urine and leave the body are lost.
Loop diuretics inhibit the Na K 2 Cl - symporter of the macula densa making it (GFR ) is an increase in glomerular filtration rate. (see: glomerular feedback)
After discontinuation of the drug is to be noted that the body tries to compensate for the water and sodium ion loss by the natural counter-regulation mechanisms of the sympathikoadrenalen and the renin- angiotensin -aldosterone system are set in motion. In consequence of reduced glomerular filtration rate and, ultimately, the urine volume. This process is referred to as postdiuretische sodium retention.
Indications
The indications for loop diuretics are similar to those of other diuretics. They are mainly used in the treatment of acute pulmonary edema and other localized, caused by cardiac, renal and hepatic insufficiency edema. The strong leaching of calcium, they are also used in the treatment of hypercalcaemia.
Further indications are acute renal failure, to the water balance to be able to still check for a certain time, hyperkalemia and earlier for Forced diuresis in poisoning eg with anions (especially bromide, fluoride and iodide ) or rhabdomyolysis. What is important is the simultaneous intake of adequate amounts of water, sodium and chloride in the form of electrolyte solutions.
Due to its strong efficacy of loop diuretics should be used cautiously. The accounting of the water balance and the adequate replacement of electrolytes (eg liver cirrhosis) indicated, as the compensation ability is particularly poor, especially in patients with disorders of electrolyte or acid - base balance.
Contraindications
The contraindications are the same as those of most other diuretics. These include sodium and potassium deficiency as well as hypercalciuria (increased calcium excretion in the urine ), as they are reinforced and hypovolemia, so the lack of circulating water volume. There is too much calcium in the urine favors the formation of kidney stones, loop diuretics should not be used in already known kidney stones. Similarly, the application is in anuria, so if no more urine flow is present, contraindicated.
Should the use of loop diuretics but be absolutely necessary despite the existence of contraindications, so an exact accounting, in particular the electrolyte balance is performed concomitantly. Representatives of the sulfonamide derivatives may not be used in principle against other sulfonamides with a known allergy.
Pharmacokinetics
All loop diuretics, both orally ( in tablet form ) and be administered parenterally ( by injection or infusion). The gastro-intestinal absorption is almost as complete as the parenteral ( good oral bioavailability). Loop diuretics act very quickly depending on the dosage form within five minutes ( intravenously) to half an hour (oral). They reach their maximum effect after about two hours, she holds between six and eight hours. The half-life is dependent on renal function. Two-thirds are excreted by the kidneys through both glomerular filtration and tubular secretion, with the remaining third is made in the liver into the bile and ultimately excreted in the stool. The hepatic metabolism is low. Metabolic end products of furosemide and ethacrynic acid were identified. However, it is unknown whether they exert a diuretic effect. Torasemide, however, has two active metabolic products, which are referred to as M1 and M3.
Since they exert their effect on the luminal side of the tubule, the loop diuretics, in order to be effective, are in the primary urine. However, their strong binding to plasma proteins inhibits glomerular filtration. As a weak organic acids but they are secreted into the proximal tubule cells. However, this can be reduced by other organic acids, such as nonsteroidal anti-inflammatory drugs (NSAID) or probenecid, or in some renal diseases, which ultimately affects the efficiency.
Side effects
Due to the strong effect of loop diuretics periodic monitoring of serum electrolyte level is necessary - especially with long term use - hypovolemia due to excessive drainage to prevent with resulting dizziness, headache, tendency to collapse and orthostatic hypotension. In severe cases it can lead to dehydration and dehydration.
The increased excretion of potassium ions ( K ) and protons (H ) can lead to hypokalämischer metabolic alkalosis, a condition which can be corrected by administration of potassium and treatment of hypovolemia. Sodium deficiency occurs although less frequent than with thiazide diuretics, but if patients take as a result of hypovolemia to large amounts of water to itself, this may result in a reduced sodium levels in the blood. As a result of hypovolemia also uric acid is amplified reabsorbed in the proximal tubule, which can lead to increased blood uric acid levels ( hyperuricemia ) and thus to gout attacks. Furthermore, the long-term use often leads to reduced magnesium and calcium in the blood ( or hypocalcemia hypomagnesemia ).
For all loop diuretics hearing loss in the high frequencies to deafness can by inhibition of the Na K 2 Cl - symporter occur because no potassium concentration gradient (gradient ) can be constructed ( ototoxicity ). This effect is dose-dependent and, in general, only during the treatment, only with the use of ethacrynic acid which damage may be permanent nature.
By sulfonamide derivatives may occur in allergic reactions, characterized by rash, eosinophilia and interstitial nephritis in rare cases in patients with hypersensitivity to sulfonamides. After discontinuation of substances these effects disappear. In this ethacrynic acid hypersensitivity does not occur due to the different type of chemical structure.
Interactions
The pressure caused by loop diuretics potassium and magnesium deficiency enhances the effect of cardiac glycosides. Since glucocorticoids, and laxatives also increase potassium excretion, favors the formation of potassium depletion when used with loop diuretics. The effect of salicylate, theophylline, curareartigen muscle relaxants and other antihypertensive drugs is enhanced, as well as toxic effects of lithium on the heart and nervous system as the excretion is reduced, and thus ultimately of the lithium levels are elevated in the blood.
The hypoglycemic effect of antidiabetic drugs is reduced. The pressor effect of adrenaline and noradrenaline is attenuated because the decreased blood volume counteracts its effect. Other drugs that damage hearing ( ototoxic ) act, such as aminoglycosides and cisplatin, the harmful effects on the hearing may increase.
Because loop diuretics stimulate the kidney to synthesize prostaglandins and this contributes to the diuretic effect, but this synthesis is hampered by nonsteroidal antiinflammatory drugs, these weaken the diuretic and antihypertensive effects of loop diuretics. In otherwise healthy patients, this effect is only slight, in patients with renal failure and those with cirrhosis, however, he tends to occur.
History
When first used loop diuretics mercury compounds can be considered. Their diuretic effect was accidentally discovered in 1919 rather than a side effect of the drug then used against syphilis Novasurol. However, their frequent use has led to numerous cases of mercury poisoning. Nevertheless, organic mercury compounds were for the next forty years the standard in the treatment of edema. However, their lack of oral availability, toxicity and the rapid development of tolerance restricted its utility a strong. A less toxic alternative was developed in 1924 by Hoechst mersalyl. Since it was much more effective than has been available since 1957, chlorothiazide, it was, in spite of the higher toxicity, are still used.
With the increasing understanding of the formation of urine began to search for more effective and less toxic drugs. The researchers from MSD synthesized starting from chlorothiazide ethacrynic acid. Hoechst synthesized in 1959, starting from the structure of Sulfonamyl, first furosemide.