Diuretic agents carbonic anhydrase inhibitors

BASIC PHARMACOLOGY OF DIURETIC AGENTS Carbonic Anhydrase Inhibitors... 

Carbonic anhydrase inhibitors were the forerunners of modern diuretics. They were discovered when it was found that bacteriostatic sulfonamides caused an alkaline diuresis and hyperchloremic metabolic acidosis. With the development of newer agents, carbonic anhydrase inhibitors are now rarely used as diuretics, but they still have several specific applications that are discussed below. The prototypical carbonic anhydrase inhibitor is acetazolamide. 

The sulfonamides were discovered in Germany in the middle of the twentieth century subsequent to investigation of diazo dyes (7,8). There have been a number of structural modifications of sulfonamides producing numerous medicinal agents including antibiotics, thiazide diuretics and carbonic anhydrase inhibitors (8). One modification of the sulfonamides involving the addition of indoline was responsible for the production of indapamide. The first patent and USA patent citations may be found in References 9 and 10, respectively. One of the first non-patent literature references to indapamide appeared in 1974 (II). 

Since the 1950s, diuretic therapy has changed dramatically. Earlier, the major diuretics were acidforming salts, xanthines, organomercurial compounds, and carbonic anhydrase inhibitors. Either because of toxicity or lack of efficacy, these agents are rarely if ever used. 

Endogenous macromolecules as nonmessenger targets (e.g., carbonic anhydrase inhibitors or other agents as diuretics, chapter 8)... 

Other drugs, such as verapamil, caffeine, theophylline, osmotic diuretics, carbonic anhydrase inhibitors, or aminophylline, can increase lithium excretion, possibly dropping plasma levels below the therapeutic threshold ( 329). Further, if doses are increased to compensate for this effect, care must be taken to readjust the lithium downward when these concomitant agents are reduced or discontinued. 

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. 

The reduction of aqueous humor formation by carbonic anhydrase inhibitors decreases the intraocular pressure. This effect is valuable in the management of glaucoma, making it the most common indication for use of carbonic anhydrase inhibitors. Topically active carbonic anhydrase inhibitors (dorzolamide, brinzolamide) are available and reduce intraocular pressure without producing detectable plasma levels. Thus, diuretic and systemic metabolic effects are eliminated for the topical agents. 

Loop diuretics selectively inhibit NaCI reabsorption in the TAL. Because of the large NaCI absorptive capacity of this segment and the fact that the diuretic action of these drugs is not limited by development of acidosis, as is the case with the carbonic anhydrase inhibitors, loop diuretics are the most efficacious diuretic agents currently available. 

Of the various solutes reabsorbed in the proximal tubule, the most relevant to diuretic action are sodium bicarbonate and sodium chloride. Of the currently available diuretics, only one group (carbonic anhydrase inhibitors, which block NaHC03 reabsorption) acts predominantly in the proximal tubule. In view of the large quantity of sodium chloride absorbed in the proximal tubule, a drug that specifically blocked reabsorption of this salt at this site might be a particularly powerful diuretic agent. No such drug is currently available. 

Acetazolamide [a set a ZOLE a mide] is a sulfonamide without antibacterial activity. Its main action is to inhibit the enzyme carbonic anhydrase in the proximal tubular epithelial cells. However, carbonic anhydrase inhibitors are more often used for their other pharmacologic actions rather than for their diuretic effect, because these agents are much less efficacious than the thiazides or loop diuretics. 

Diuretic agents can cause myopia. Transient myopia was associated with perimacular edema apparently caused from the use of 100 mg of hydrochlorothiazide. The drug induced approximately 3.00D of myopia, which resolved within 3 days. Carbonic anhydrase inhibitors are also known to cause myopia. A case of transient myopia associated with acetazolamide was reported, in which there was also narrowing of the anterior chamber angle. 

Diuretics may cause reductions in glomerular filtration rate (GFR) either by a direct constriction of the renal arterial network, or secondary to their induction of extracellular fluid (ECF) volume contraction. Listed in Table 1 are the renal hemodynamic alterations induced in the experimental animal or in man by the most commonly prescribed, currently available diuretic agents. Acetazolamide, a proximally active agent and the prototypical carbonic anhydrase inhibitor (Figure 1), consistently reduces renal blood flow (RBF) by... 

Inhibitors to the enzyme carbonic anhydrase. This enzyme is widely distributed in the body and has a fundamental role in the control of acid-base balance. In the 1920s it was noticed that the SULPHONAMIDE sulfanilamide had a weak diuretic action. Acetazolamide is a subsequent thiadiazole-sulphonamide derivative with potent carbonic anhydrase inhibitor activity. Clinically, it is used for antiglaucoma TREATMENT, is a weak diuretic and can be used to treat mountain sickness. Dichlorphenamide and dorzolamide are sulphonamide derivatives also used for antiglaucoma treatment. Methazolamide is used as a diuretic. Now that seven or more isoenzymes of carbonic anhydrase have been cloned. Isolated and mapped, some new initiatives are aimed at developing agents with more selective actions. 

Some major classes include ACE inhibitors (used mainly as ANTIHYPERTENSIVE AGENTS). MONOAMINE-OXIDASE INHIBITORS (used mainly as ANTIDEPRESSANTS). ANTICHOLINESTERASES (used for a number of purposes). CARBONIC ANHYDRASE INHIBITORS, (used mainly as diuretics). PHOSPHODIESTERASE INHIBITORS (used as BRONCHODILATORS, CNS STIMULANTS, INOTROPIC AGENTS). 

Acetazolamide is classified as an anticonvulsant, antiglau-comatous agent, and diuretic, and is a potent inhibitor of the enzyme carbonic anhydrase. The carbonic anhydrase inhibitors consist of acetazolamide (Diamox), ethoxzola-mide (Cardrase), and dichlorphenamide (Daranide). Acetazolamide is an old agent, whereas ethoxzolamide and dichlorphenamide are newer preparations. Dichlorphenamide is the most potent carbonic anhydrase inhibitor in use today. The presence of SO2NH2 (sulfonamide) causes such compounds to inhibit carbonic anhydrase (CA), which catalyzes the hydration of carbon dioxide as follows ... 

Carbonic anhydrase inhibitor Acetazolamide Osmotic agent Mannitol Loop Diuretics ... 

Altered renal excretion including aminoglycosides, antineoplastic agents, and diuretics Reduced renal reabsorption of bicarbonate and increased potassium excretion Carbonic anhydrase inhibitors Alteration of ECFrICF ratio... 

THERAPEUTIC USES The efficacy of carbonic anhydrase inhibitors as single agents for the treatment of edema is low. However, the combination of acetazolamide with diuretics that block Na+ reabsorption at more distal sites in the nephron causes a marked natriuretic response in patients with low basal fractional excretion of Na (<0.2%), who are resistant to diuretic monotherapy. Even so, the long-term usefulness of carbonic anhydrase inhibitors often is compromised by the development of metabohc acidosis. 

C. Clinical Uses The major application of carbonic anhydrase inhibitors is in the treatment of glaucoma. Acetazolamide must be administered orally, but topical analogs are now available (dorzolamide, brinzolamide) for use in the eye. Carbonic anhydrase inhibitors are also used to prevent acute mountain (high-altitude) sickness. These agents are used for their diuretic effect only if edema is accompanied by significant metabolic alkalosis. 

A diuretic agent (5-acetamido-l,3,4-thiadiazole-2-sul-fonamide) that acts as a potent noncompetitive inhibitor (Ki 10 M) of carbonic anhydrase. 

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