Carbonic anhydrase inhibition

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-... 

Phenobarbital-like promotion Crystalluria, carbonic anhydrase inhibition, urine pH extremes, melamine, saccharine, carbonic anhydrase inhibitors, dietary phosphates... 

Although chlorothiazide and its subsequently developed congeners (Table 21.2) retain the sulfamyl group SO2NH2, which is necessary for carbonic anhydrase inhibition, their primary effect does not rely on carbonic anhydrase inhibition. 

The thiazidelike compounds, including chlorthalidone Hygrown), quinethazone (Hydromox), and metolazone (Zaroxolyn) have similar mechanisms of action, but they differ substantially from one another in their duration of action, the degree of carbonic anhydrase inhibition, and the dose required for maximum natriuretic activity. 

Especially at higher doses, administration of some of the thiazides results in some degree of carbonic anhydrase inhibition. However, at usual doses, only chlorothiazide shows any appreciable carbonic anhydrase inhibitory activity. 

Furosemide (Lasix), torsemide (Demadex), and bumetanide (Bumex) possess some carbonic anhydrase inhibiting activity (about one-tenth that of chlorothiazide). This property may account for the increased bicarbonate and phosphate excretion seen after large doses of these diuretics. The elevated HCOj" loss probably indicates some proximal tubular effects for furosemide and bumetanide. 

TOPAMAX, a sulfamate-substituted monosaccharide approved for use as an antiepileptic drug at oral doses of up to 400 mg per day, exhibits carbonic anhydrase inhibition activity [15]. A 21-month dietary study in mice with TOPAMAX resulted in increased incidence of bladder tumors similar to those observed in the mouse carcinogenicity bioassay with brinzolamide at two years. 

W.M. Grant and I.H. Leopold, Antiglaucoma Drugs Problems with a Carbonic Anhydrase Inhibition , in Symposium on Ocular Therapy, C.V. Mosby, ed., St. Louis, 1973, pp. 19-38. 

The benzothiadiazides and the newer thiazide-like diuretics antagonise the absorption of Na-i- and Cl- in the DCT by inhibition of the Na+/CI- symport mechanism in the luminal membrane (Figure 12.4). They do not have any effect on the LoH. Some of the thiazides are thought to have a minor action on the PCT but this is minimal and is not due to inhibition of the Na-i-/CI- symporter. It may be due to carbonic anhydrase inhibition which is a feature of sulphonamide-derived drugs. 

Acetazolamide is a diuretic whose main action is the inhibition of carbonic anhydrase (see Chapter 15). Mild acidosis in the brain may be the mechanism by which the drug exerts its antiseizure activity alternatively, the depolarizing action of bicarbonate ions moving out of neurons via GABA receptor ion channels may be diminished by carbonic anhydrase inhibition. Acetazolamide has been used for all types of seizures but is severely limited by the rapid development of tolerance, with return of seizures usually within a few weeks. The drug may have a special role in epileptic women who experience seizure exacerbations at the time of menses seizure control may be improved and tolerance may not develop because the drug is not administered continuously. The usual dosage is approximately 10 mg/kg/d to a maximum of 1000 mg/d. 

Sulfanilamides, 1, 145 carbonic anhydrase inhibition by, 1, 173 Sulfaphenazole antibacterial activity, 5, 291 Sulfapyridine, 1, 161 as antibacterial, 2, 517 veterinary use, 1, 209 Sulfaquinoxaline coccidiostat veterinary use, 1, 212 Sulfasomidine, 3, 151 Sulfasomizole... 

Freeman, J. A. Influence of carbonic anhydrase inhibition on shell growth of a fresh-water snail, Physa heterostropha. Biol. Bull. 118, 413-429 (1960). 

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. 

In vitro and in situ Assessments — 96 Carbonic Anhydrase Inhibition... 

Determination of carbonic anhydrase inhibition is of value to characterize the activity spectrum of sulfonamide diuretics. 

The ratio (ion quotient) is calculated to estimate carbonic anhydrase inhibition. 

Carbonic anhydrase inhibition can be excluded at ratios between 1.0 and 0.8. With decreasing ratios slight to strong carbonic anhydrase inhibition can be assumed. 

Massive doses of sulfanilamide, as well as of other sulfonamides, caused alkaline diuresis as a side effect. From 1940 onwards, the mechanism of this side effect was further investigated it was confirmed that carbonic anhydrase inhibition was responsible for the diuresis. Presenting the whole story of the development of... 

As mentioned in the introduction, sulfonamides derived from 1,3,4-thiadiazoles directed interest on this ring system. The first compounds were 5-substituted 2-sulfanilamido-1,3,4-thiadiazoles, but later l,3,4-thiadiazole-2-sulfonamides came into focus due to the discovery by Miller et of the carbonic anhydrase inhibiting effect... 

Ptacek That is thought to be the case. It isn t clear, however, whether it is through action on the Na+ channel itself. In muscle CLCl in the Cl channel is extremely sensitive to pH. It could be acting on some other channel, but many people think it is pH. Supporting this in the more generali2ed way is the fact that carbonic anhydrase inhibitors help some patients with migraine. Topiramate has some carbonic anhydrase inhibition properties, although it is not clear that these play any role in its anticonvulsant effects. 

De Benedetti PG, Menziani MC, Cocchi M, Frassineti C. A quantum chemical QSAR analysis of carbonic anhydrase inhibition by heterocyclic sulfonamides. Sulfonamide carbonic anhydrase inhibitors Quantum chemical QSAR. Quant Struct-Act Relat 1987 6 51-53. 

EFFECTS ON URINARY EXCRETION Loop diuretics profoundly increase the urinary excretion of Na+ and Cl" (i.e., up to 25% of the filtered load of Na+) and markedly increase the excretion of Ca + and Mg +. Furosemide but not bumetanide also has weak carbonic anhydrase-inhibiting activity that increases the urinary excretion of HCO " and phosphate. AU inhibitors of the Na+-K+-2CL symporter increase the urinary excretion of K+ and titratable acid, due in part to increased delivery of Na+ to the distal tubule. The mechanism by which increased distal delivery of Na+ enhances excretion of K+ and H+ is discussed in the section on inhibitors of Na+ channels. Other mechanisms contributing to enhanced K+ and H+ excretion include flow-dependent enhancement of ion secretion by the collecting duct, nonosmotic vasopressin release, and activation of the renin-angiotensin-aldosterone axis. Loop diuretics acutely increase the excretion of uric acid, whereas their chronic administration reduces uric acid excretion, possibly due to enhanced transport in the proximal tubule secondary to volume depletion or to competition between the diuretic and uric acid for the organic acid secretory mechanism in the proximal tubule. 

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