Sodium Carbonic anhydrase

Among one of the more unusual side effects noticed as the use of the sulfonamides became widespread was the increased urine output of many patients treated with these drugs. The fact that the urine was unusually alkaline led to the suspicion, later (Confirmed by independent means, that these agents were responsible for partial inhibition of the enzyme carbonic anhydrase. Inhibition of this enzyme causes increased excretion of sodium and bicarbonate ions as well as water, in effect bringing about diure-... 

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). 

Carbonic anhydrase (CA) exists in three known soluble forms in humans. All three isozymes (CA I, CA II, and CA III) are monomeric, zinc metalloenzymes with a molecular weight of approximately 29,000. The enzymes catalyze the reaction for the reversible hydration of C02. The CA I deficiency is known to cause renal tubular acidosis and nerve deafness. Deficiency of CA II produces osteopetrosis, renal tubular acidosis, and cerebral calcification. More than 40 CA II-defi-cient patients with a wide variety of ethnic origins have been reported. Both syndromes are autosomal recessive disorders. Enzymatic confirmation can be made by quantitating the CA I and CA II levels in red blood cells. Normally, CA I and CAII each contribute about 50% of the total activity, and the CAI activity is completely abolished by the addition of sodium iodide in the assay system (S22). The cDNA and genomic DNA for human CA I and II have been isolated and sequenced (B34, M33, V9). Structural gene mutations, such as missense mutation, nonsense... 

Gudiksen, K.L., Gitlin, I., Moustakas, D.T., Whitesides, G.M. (2006a). Increasing the net charge and decreasing the hydrophobicity of bovine carbonic anhydrase decreases the rate of denaturation with sodium dodecyl sulfate. Biophys. J. 91, 298-310. 

Zonisamide is a broad-spectrum sulfonamide AED that blocks voltage-sensitive sodium channels by reducing voltage-dependent T-type Ca channels it also weakly inhibits carbonic anhydrase, and inhibits glutamate release. 

Figure 2. Sodium and chloride uptake across an idealised freshwater-adapted gill epithelium (chloride cell), which has the typical characteristics of ion-transporting epithelia in eukaryotes. In the example, the abundance of fixed negative charges (muco-proteins) in the unstirred layer may generate a Donnan potential (mucus positive with respect to the water) which is a major part of the net transepithelial potential (serosal positive with respect to water). Mucus also contains carbonic anhydrase (CA) which facilitates dissipation of the [H+] and [HCO(] to CO2, thus maintaining the concentration gradients for these counter ions which partly contribute to Na+ import (secondary transport), whilst the main driving force is derived from the electrogenic sodium pump (see the text for details). Large arrow indicates water flow...

Fig. 21. Separation of cytochrome (peak 1), ribonuclease, (peak 2), carbonic anhydrase (peak 3), lysozyme (peak 4), and chymotrypsinogen (peak 5) by hydrophobic interaction chromatography on a molded poly(acrylamide-co-butylmethacrylate-co-N,AT,-methylenebisacry-lamide) monolithic column. (Reprinted with permission from [ 135]. Copyright 1998 Elsevier). Conditions column, 50 x8 mm i.d., 10% butyl methacrylate,mobile phase gradient from 1.5 to 0.1 mol/1 ammonium sulfate in 0.01 mol/l sodium phosphate buffer (pH 7) in 3 min, gradient time 3.3 min, flow rate 3 ml/min...

Drugs of this group inhibit activity of carbonic anhydrase, an enzyme that catalyzes the reversible reaction of water and carbon dioxide, which forms carbonic acid. The mechanism of action of this group of drags is not fuUy understood. However, inhibition of carbonic anhydrase activity leads to a reduction of carbonic acid formation and an increase in bicarbonate, sodium, and potassium excretion with urine, which eventually leads to a significant increase in the process of excreting water from the organism. 

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. 

Hydrochlorothiazide is one of the most widely used drugs of this series, and it is used for the same indications, as is chlorothiazide. Hydrochlorothiazide causes less inhibition of carbonic anhydrase, but causes 5-10 times more diuresis of sodium ions than chlorothiazide using the same dose. Synonyms of this drug are chlorozide, diaqua, esidrix, hydrodiuril, hydrozide, hypothiazide, novohydrazide, urozide, and others. 

Carbonic anhydrase plays an important role in the secretion of aqueous humor [1,2]. This enzyme was first demonstrated to be present in the ciliary processes of the rabbit, and its presence was later confirmed in human ciliary processes [3,4]. Carbonic anhydrase is responsible for the generation of bicarbonate anions which are secreted from the ciliary process into the posterior chamber, with sodium being the counter ion. Inhibition of carbonic anhydrase in the ciliaiy processes of the eye decreases aqueous humor secretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport. The role of the enzyme in aqueous humor secretion has been reviewed in detail by Maren [1]. 

Mechanism of Action A carbonic anhydrase inhibitor that reduces formation of hydrogen and bicarbonate ions from carbon dioxide and water by inhibiting, in proximal renal tubule, the enzyme carbonic anhydrase, thereby promoting renal excretion of sodium, potassium, bicarbonate, and water. Ocular Reduces rate of aqueous humor formation, lowers intraocular pressure. Therapeutic Effect Produces anticonvulsant activity. 

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. 

Carbonic anhydrase influences the tubular reabsorption of sodium in proximal tubule where biocarbonate absorption occurs and in the distal tubule where sodium is exchanged for potassium or hydrogen ion and bicarbonate is formed as the accompanying anion. The hydration of carbon dioxide takes place under the influence of enzyme carbonic anhydrase which forms carbonic acid which dissociates and breaks into hydrogen and carbonate ions. 

Acetazolamide inhibits the enzyme carbonic anhydrase, and interferes with the ability of the renal tubules to produce and secrete hydrogen ions. And, the diuretic action is due to the decreased sodium biocarbonate absorption in proximal tubules and diminished hydrogensodium exchange in the distal tubules. 

Figure 12.2 Mechanism of action of carbonic anhydrase inhibitors on the proximai convoiuted tubuie. Carbonic anhydrase is an enzyme that cataiyses the interconversion of C02and H20 to H2C03and is found in the iuminai epitheiium of the proximai, and to a iesser extent, the distai convoiuted tubuie. It is essentiai for the conservation of body base in the form of HCO-3. An antiporter (1) mechanism (the movement of substances across a barrier in opposite directions) exchanges fiitrate Na+for ceiiuiar H+. The H+combines with fiitrate HCO-3to form carbonic acid which is converted to C02and H20 in the presence of carbonic anhydrase (CA). The C02is reabsorbed by the ceii thereby conserving HCO-3. Acetazoiamide inhibits the activity of carbonic anhydrase and limits the conversion of HCO-3to absorbable C02. The concentration of HCO-3in the filtrate increases as does the urinary loss. P, the sodium pump ECF, extracellular fluid.

Apical membrane Na+/H+ exchange (via NHE3) and bicarbonate reabsorption in the proximal convoluted tubule cell. Na+/K+ ATPase is present in the basolateral membrane to maintain intracellular sodium and potassium levels within the normal range. Because of rapid equilibration, concentrations of the solutes are approximately equal in the interstitial fluid and the blood. Carbonic anhydrase (CA) is found in other locations in addition to the brush border of the luminal membrane. 

Sodium sulfacetamide ophthalmic solution or ointment is effective in the treatment of bacterial conjunctivitis and as adjunctive therapy for trachoma. Another sulfonamide, mafenide acetate, is used topically but can be absorbed from burn sites. The drug and its primary metabolite inhibit carbonic anhydrase and can cause metabolic acidosis, a side effect that limits its usefulness. Silver sulfadiazine is a much less toxic topical sulfonamide and is preferred to mafenide for prevention of infection of burn wounds. 

It is about an active mechanism depending on the Na+-K+-ATPase enzyme located in the lateral plasma membrane of the endothelial cells. It enables the penetration of potassium into the cell against the excretion of sodium into the aqueous humor. Then this latter becomes hypertonic in comparison with the stroma and thus drains the water. In normal conditions, the pump can adapt to the physiological needs. Actually, the moves of the sodium ion are relative to those of the bicarbonate ion (responsible for the negative polarization of the back side of the endothelial cell) and to the pH variation. And yet, the bicarbonate comes from the aqueous humor and from the intracellular transformation of carbon dioxide and water by carbonic anhydrase. All of this shows the good functioning of the pumps depends on the integrity of the plasma... 

FIGURE 7-27. Shown here is an icon of topiramate s pharmacologic actions. By interfering with calcium channels and sodium channels, topiramate is thought both to enhance the inhibitory actions of gamma aminobutyric acid (GABA) and to reduce the excitatory actions of glutamate. Topiramate is also a carbonic anhydrase inhibitor (CAI) and as such has independent anticonvulsant actions. 

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