Kidney carbonic anhydrase

Carbonic anhydrase is an enzyme that produces free hydrogen ions, which are then exchanged for sodium ions in the kidney tubules. Carbonic anhydrase inhibitors inhibit the action of the enzyme carbonic anhydrase This effect results in the excretion of sodium, potassium, bicarbonate, and water. Carbonic anhydrase inhibitors also decrease the production of aqueous humor in the eye, which in turn decreases intraocular pressure (IOP) (ie, the pressure within the eye). 

The carbonic anhydrase inhibitors are contraindicated in patients with known hypersensitivity to the dru , electrolyte imbalances, severe kidney or liver dysfunction, or anuria, and for long-term use in chronic non-congestive angle-closure glaucoma (may mask worsening glaucoma). 

Structure and physiology of the kidney glomerular filtration tubular activity selective reabsorption and secretion, often using specific carrier mechanisms carbonic anhydrase and acid-base balance. The kidney also produces, and is sensitive to, hormones actions of the hormones ADH, aldosterone and PTH the kidney as a secretory organ erythropoietin, the renin-angiotensin system vitamin D3. 

Carbonate anhydrase (carbonic anhydrase, EC 4.2.1.1) catalyzes the reversible interconversion of C02 and HCO3 (see Sect. 3.7.3). The enzyme is found in erythrocytes, and in kidney and gastric juices where it contributes to the control of the acid-base balance. The esterase activity of carbonic anhydrase is probably due to the similarity between its active site and that of the zinc proteases. A possible physiological role of the esterase activity of this enzyme remains to be established. 

Diuretics are drugs that increase secretion of excess water and salt that accumulates in tissues and urine. An excess qnantity of intercellnlar flnid is formed in the organism as a result of an inability of the kidneys to release sodinm ions fast enongh to ensure that a sufficient quantity of water is excreted along with them. Therefore, efficacy of a diuretic depends first and foremost on its ability to release sodinm ions from the body, since they are accompanied by an osmotically eqnivalent amonnt of water that is released from interstitial fluids. The exceptions are dinretics classified as carbonic anhydrase inhibitors. 

Acetazolamide is an aromatic sulfonamide used as a carbonic anhydrase inhibitor. It facilitates production of alkahne urine with an elevated biocarbonate, sodium, and potassium ion concentrations. By inhibiting carbonic anhydrase, the drug suppresses reabsorption of sodium ions in exchange for hydrogen ions, increases reflux of bicarbonate and sodium ions and reduces reflux of chloride ions. During this process, chloride ions are kept in the kidneys to cover of insufficiency of bicarbonate ions, and for keeping an ion balance. Electrolytic contents of fluid secreted by the kidneys in patients taking carbonic anhydrase inhibitors are characterized by elevated levels of sodium, potassium, and bicarbonate ions and a moderate increase in water level. Urine becomes basic, and the concentration of bicarbonate in the plasma is reduced. 

An explanation for the association of topiramate and kidney stones may lie in the fact that topiramate is a weak carbonic anhydrase inhibitor. Carbonic anhydrase P.740... 

The answer is C. Ingestion of an acid or excess production by the body, such as in diabetic ketoacidosis, may induce metabolic acidosis, a condition in which both pH and HCOj become depressed. In response to this condition, the carbonic acid-bicarbonate system is capable of disposing of the excess acid in the form of CO2. The equilibrium between bicarbonate and carbonic acid shifts toward formation of carbonic acid, which is converted to COj and HjO in the RBC catalyzed by carbonic anhydrase, an enzyme found mainly in the RBC. The excess CO2 is then expired by the lungs as a result of respiratory compensation for the acidosis (Figure 1-2). The main role of the kidneys in managing acidosis is through excretion of H" rather than CO2. 

In the red blood cell this reaction plays an important role in COj transport from the tissues to the lungs. In the kidney, the protons of the H3O+ are exchanged for Na+ ions, which are reabsorbed, while HCO3 is decomposed through a shift of the equilibrium to the left. Carbonic anhydrase therefore plays a crucial role in maintaining the ion and water balance between the tissues and urine. 

When carbonic anhydrase inhibitors block the enzyme in the kidney, HjCOj formation— and consequently the availability of H3O+ (i.e., protons)—decreases. Since the Na+ ions in the filtrate cannot be exchanged, sodium is excreted, together with large amounts of water, as a result of ion hydration and osmotic effects. The result is diuresis, accompanied by a dramatic increase in urine volume. There is also failure to remove HCOj" ions because there is no H3O+ to form HjCOj, which would decompose to COj -1- HjO. Therefore, the normally slightly acidic urine becomes alkaline. The strong carbonic anhydrase inhibitors also increase K+ excretion, an undesirable effect. 

The most important function of the proximal tubular cell is the conservation of filtered Na+ and the reabsorption of water. The PCT is also the main site of FICO-3 reabsorption. This is achieved by the transfer of Na+ and FICO-3 from the tubular lumen into the cell and then into the extracellular fluid (ECF) accompanied by the passive reabsorption of approximately 70% of the filtered water via the tight junctions between the tubular cells. The presence of the enzyme carbonic anhydrase in the cytoplasm and luminal epithelium of the cells of the PCT allows the kidney to eliminate FI+ while simultaneously retaining FICO-3. 

Only about 10% of the Na-i- filtered by the glomerulus is reabsorbed by the distal convoluted tubule (DCT) and therefore the capacity of the thiazide group of diuretics to influence the elimination of Na-H in the urine is limited compared to the loop agents. Thiazides can prevent the reabsorption of up to 5% of the total filtered Na+, whereas the equivalent figure for loop diuretics is about 20%. Thiazides can still produce a moderate naturesis and diuresis compared to carbonic anhydrase inhibitors and the K+-sparing agents. Most thiazides are ineffective at low glomerular filtration rates. They also hinder the ability of the kidneys to produce a dilute urine. 

At present, the major clinical applications of acetazolamide involve carbonic anhydrase-dependent HC03 and fluid transport at sites other than the kidney. The ciliary body of the eye secretes HC03 from the blood into the aqueous humor. Likewise, formation of cerebrospinal fluid by the choroid plexus involves HC03 secretion. Although these processes remove HC03 from the blood (the direction opposite of that in the proximal tubule), they are similarly inhibited by carbonic anhydrase inhibitors. 

From a nutritional viewpoint, Cu2+ competes with zinc ion, as does the very toxic Cd2+. The latter accumulates in the cortex of the kidney. Dietary cadmium in concentrations less than those found in human kidneys shortens the lives of rats and mice. However, some marine diatoms contain a cadmium-dependent carbonic anhydrase.11 Although zinc deficiency was once regarded as unlikely in humans, it is now recognized as occurring mider a variety of circumstances0 p and is well-known in domestic animals.01 Consumption of excessive amounts of protein as well as alcoholism, malabsorption, sickle cell anemia, and chronic kidney disease can all be accompanied by zinc deficiency. 

Because of the ease with which dimercaptopropanol can be broken down in the body there is a danger that chelation, followed by breakdown, will simply result in the translocation of the metal ions to other tissues such as brain or liver. High doses of dimercaptopropanol can adversely affect a number of essential metal-activated enzymes, such as catalase, carbonic anhydrase and peroxidase, and also produce dangerous systemic effects. Dimercaptopropanol cannot be used to remove cadmium because its cadmium complex is toxic to kidney tissue54). 

Diuretics work by increasing the amount of sodium and fluids excreted by the kidneys. Less fluid means less total blood volume and improved circulation and blood pressure. There are five main classes of the drug loop diuretics, thiazide diuretics, potassium-sparing diuretics, osmotic diuretics, and carbonic anhydrase inhibitors. 

Inhibition of carbonic anhydrase activity profoundly depresses bicarbonate reabsorption in the proximal tubule. At its maximal safely administered dosage, 85% of the bicarbonate reabsorptive capacity of the superficial proximal tubule is inhibited. Some bicarbonate can still be absorbed at other nephron sites by carbonic anhydrase-independent mechanisms, and the overall effect of maximal acetazolamide dosage is about 45% inhibition of whole kidney bicarbonate reabsorption. Nevertheless, carbonic anhydrase inhibition causes significant bicarbonate losses and hyperchloremic metabolic acidosis. Because of this and the fact that HCO3" depletion leads to enhanced NaCl reabsorption by the remainder of the nephron, the diuretic efficacy of acetazolamide decreases significantly with use over several days. 

The thiazides are the most widely used of the diuretic drugs. They are sulfonamide derivatives and are related in structure to the carbonic anhydrase inhibitors. The thiazides have significantly greater diuretic activity than acetazolamide, and they act on the kidney by different mechanisms. All thiazides affect the distal tubule, and all have equal maximum diuretic effect, differing only in potency, expressed on a per -milligram basis. 

Weak inhibition ot carbonic anhydrase may lead to kidney stones and paresthesias... 

Topiramate may interact A/ith carbonic anhydrase inhibitors to increase the risk of kidney stones... 

Diuretics are highly efficient drugs for the treatment of edema associated with congestive heart failure. They are also used to increase the volume of urine excreted by the kidneys [9]. For example, duranide, 81, a dichlorinated benzene disulfonamide, is an oral carbonic anhydrase inhibitor. Duranide reduces intraocular pressure by partially suppressing the secretion of aqueous humor [11]. Diuril, 82, has an antihypertensive activity and is issued to control blood pressure [9]. Edecrin, 83, is an unsaturated ketone derivative of an aryloxyacetic acid. Edecrin is used in the treatment of the edema associated with congestive heart failure, renal disease, and cirrhosis of the liver [11]. Amiloride, 84, is also used as an adjunctive treatment with thiazide diuretics in congestive heart failure hypertension. 

The enzyme carbonic anhydrase facilitates the reaction between carbon dioxide and water to form carbonic acid, which then breaks down to hydrogen (H" ) and bicarbonate (HCOj") ions. This process is fundamental to the production of either acid or alkaline secretions and high concentrations of carbonic anhydrase are present in the gastric mucosa, pancreas, eye and kidney. Because the number of available to exchange with Na" in the proximal tubule is reduced, sodium loss and diuresis occur. But HCOg reabsorption from the tubule is also reduced, and its loss in the urine leads within days to metabolic acidosis, which attenuates the diuretic... 

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