Carbonic anhydrase inhibitors diuretic effects

With prolonged use of the carbonic anhydrase Inhibitor diuretics, the urine becomes more alkaline, and the blood becomes more acidic. When acidosis occurs, the carbonic anhydrase Inhibitors lose their effectiveness as diuretics. They remain Ineffective until normal acid-base balance In the body has been regained. For this reason, this class of compounds Is limited In Its diuretic use. Today, they are most commonly used In the treatment of glaucoma. In which they reduce the rate of aqueous humor formation and, subsequently, reduce the Intraocular pressure. These compounds also have found some limited use In the treatment of absence seizures, to alkallnize the urine, to treat familial periodic paralysis, to reduce metabolic alkalosis, and prophylactically, to reduce acute mountain sickness. 

Inhibition of proximal tubule brush border carbonic anhydrase decreases bicarbonate reabsorption, and this accounts for their diuretic effect. In addition, carbonic anhydrase inhibitors affect both distal tubule and collecting duct H+ secretion by inhibiting intracellular carbonic anhydrase. 

Acetazolamide (a carbonic anhydrase inhibitor) used as diuretic by increasing bicarbonate excretion and thus acidosis occur as side effect which is related to its pharmacological action. 

Almost all diuretics exert their action at the luminal surface of the renal tubule cells. Their mechanism of action includes interaction with specific membrane transport proteins like thiazides, furosemide etc., osmotic effects which prevent the water permeable segments of the nephron from absorbing water like mannitol, and specific interaction with enzyme like carbonic anhydrase inhibitors i.e. acetazolamide, and hormone receptors in renal epithelial cells like spironolactone. 

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. 

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. 

Acidosis predictably results from chronic reduction of body HC03 stores by carbonic anhydrase inhibitors (Table 15-2) and limits the diuretic efficacy of these drugs to 2 or 3 days. Unlike the diuretic effect, acidosis persists as long as the drug is continued. 

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. 

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. 

Figure 2.5 In addition to its antibacterial activity, sulfanilamide 11 (Figure 2.4) inhibits the enzyme carbonic anhydrase. Acetazolamide 12 is much more potent as a carbonic anhydrase inhibitor but its clinical use as diuretic was impaired by some serious side effects. Hydrochlorothiazide 13 is the prototype of orally active saluretic sulfonamide diuretics. Furosemide (frusemide) 14 and bumetanide 15 are so-called loop diuretics .

MEXILETINE DIURETICS-CARBONIC ANHYDRASE INHIBITORS, LOOP DIURETICS, THIAZIDES Effect of mexiletine 1 by hypokalaemia Uncertain Normalize potassium levels before starting mexiletine... 

SOTALOL DIURETICS-CARBONIC ANHYDRASE INHIBITORS, LOOP DIURETICS, THIAZIDES t risk of ventricular arrhythmias, particularly torsades de pointes ventricular tachycardia, caused by sotalol Hypokalaemia, a side-effect of these diuretics, predisposes to arrhythmias during sotalol therapy Normalize potassium levels before starting sotalol in patients already taking these diuretics. When starting these diuretics in patients already taking sotalol, monitor potassium levels eveiy 4-6 weeks until stable... 

METHENAMINE DIURETICS-CARBONIC ANHYDRASE INHIBITORS 1 efficacy of methenamine Methenamine is only effective at a low pH raising the urinary pH i its effect Avoid co-administration... 

BETA-2 AGONISTS DIURETICS-CARBONIC ANHYDRASE INHIBITORS, LOOP AND THIAZIDES Risk of hypokalaemia Additive effects Monitor blood potassium levels prior to concomitant administration and during therapy. Administer potassium supplements to prevent hypokalaemia... 

SAFETY PROFILE Poison by subcutaneous and intravenous routes. Moderately toxic by intraperitoneal route. Human systemic effects by ingestion dyspnea. An experimental teratogen by many routes. Other experimental reproductive effects. When heated to decomposition it emits ver toxic fumes of NOx and SOx. A carbonic anhydrase inhibitor and diuretic used to treat glaucoma. 

The carbonic anhydrase inhibitors, of which acetazol-amide (rINN), a non-competitive inhibitor, is the prototype, are not suitable for normal diuretic use, because tolerance soon develops. However, they are well suited to brief intermittent use, particularly in the relief of glaucoma and in the prevention of acute mountain sickness. Acetazolamide and methazolamide (rINN) should be used with caution in the long-term control of glaucoma because of its serious systemic adverse effects. However, brinzolamide (rINN) and dorzolamide (rINN) are available for long-term topical administration. 

Diuretics may cause reductions in glomerular filtration rate either by a direct effect to constrict the renal arterial supply or secondary to their induction of extracellular fluid volume contraction. Listed in Table 1 are the renal hemodynamic alterations induced in the experimental animal or in man by the most commonly employed currently available diuretic agents. Acetazolamide, a proximally active agent and the prototypical carbonic anhydrase inhibitor (Figure 1), consistently reduces renal blood flow by 25 to 37% and... 

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. 

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