Diuretics sulfonamide derivatives

Anuria renal decompensation hypersensitivity to thiazides or related diuretics or sulfonamide-derived drugs hepatic coma or precoma (metolazone). 

Cross-sensitivity Cross-sensitivity between antibacterial sulfonamides and sulfonamide derivative diuretics, including acetazolamide and various thiazides, has been reported. 

Furosemide, torsemide, and bumetanide are sulfonamide derivatives, hence chemically related to the thiazides. They share the thiazides adverse effects of serum uric acid elevation and diabetogenic potential. Ethacrynic acid (Edecrin) is chemically unrelated to other diuretics and does not appear to have diabetogenic potential. 

Mechanism of Action A sulfonamide derivative that acts as a thiazide diuretic and antihypertensive. As a diuretic, blocks reabsorption of water and the electrolytes sodium and potassium at cortical diluting segment of distal tubule. As an antihypertensive, reduces plasma and extracellular fluid volume, decreases peripheral vascular resistance (PVR) by direct effect on blood vessels. Therapeutic Effect Promotes diuresis, reduces BP. 

The carbonic anhydrase inhibitors were the forerunners of modern diuretics. They are unsubstituted sulfonamide derivatives and 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 two prototypical drugs of this group are furosemide and ethacrynic acid. The structures of several loop diuretics are shown in Figure 15-7. Like the carbonic anhydrase inhibitors, furosemide, bumetanide, and torsemide are sulfonamide derivatives. 

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. 

The development of an acute interstitial inflammatory reaction in the kidney related to the administration of certain classes of drugs and leading to renal failure has been recognized for almost a century [42]. Antibiotics, in particular the sulfonamides [43] and semisynthetic penicillins [44, 45], were recognized as etio-logically associated in many instances. A retrospective review of 1068 kidney biopsies from 1%8 to 1997 by Schwarz et al. yielded acute interstitial nephritis in 6.5% of cases. In the majority of instances (85%) acute interstitial nephritis was drug related. Diuretics were implicated in 7.8 % of these cases [46]. Lyons et al. noted that four patients with proliferative glomerulonephritis and nephrotic syndrome treated with sulfonamide-derivative diuretics (furosemide or thiazides) developed severe renal failure, which reversed when the diuretic was withdrawn and prednisone was adminis-... 

A. Prototypes and Mechanism of Action Acetazolamide is the prototypical agent These diuretics are sulfonamide derivatives. The mechanism of action is inhibition of carbonic anhy-drase in the brush border and intracellular carbonic anhydrase in the PCT cells (Figure 15-3). Inhibition of carbonic anhydrase by acetazolamide occurs in other tissues of the body as well as in the kidney. 

D. Toxicity Drowsiness and paresthesias are commonly reported after oral therapy. Cross allergenicity between these and all other sulfonamide derivatives (other sulfonamide diuretics, hypoglycemic agents, antibacterial sulfonamides) is uncommon but does occur. Alkalinization of the urine by these drugs may cause precipitation of calcium salts and formation of renal stones. Renal potassium wasting may be marked. Patients with hepatic impairment may develop hepatic encephalopathy because of increased ammonia reabsorption. 

A. Prototypes and Mechanism of Action Furosemide is the prototypic loop agent. Furosem-ide, bumetanide, and torsemide are sulfonamide derivatives. Ethacrynic acid is a phenoxyacetic acid derivative it is not a sulfonamide but acts by the same mechanism. Loop diuretics inhibit the cotransport of sodium, potassium, and chloride (Figure 15-4). The loop diuretics are relatively short-acting (diuresis usually occurs over a 4-hour period following a dose). 

Muzolimine (710), a 1-substituted 2-pyrazolin-5-one derivative, is a highly active diuretic, differing from the structures of other diuretics since it contains neither a sulfonamide nor a carboxyl group. It has a saluretic effect similar to furosemide and acts in the proximal tubule and in the medullary portion of the ascending limb of the loop of Henle. Pharmacokinetic studies in dogs, healthy volunteers and in patients with renal insufficiency show that the compound is readily absorbed after oral administration (B-80MI40406). 

One of the side effects noted in the clinical use of the sulfonamide antibacterial agents was a diuretic effect caused by inhibition of the enzyme carbonic anhydrase. Attempts to capitalize on this side effect so as to obtain agents with greatly enhanced diuretic activity first met success when a heterocyclic ring was substituted for the benzene ring of the sulfonamide. Treatment of the hydrazine derivative, 151, with phosgene leads... 

The development of sulfonamide carbonic anhydrase inhibitors was based on the observation that antibacterial sulfanilamides produce alkaline urine. This discovery led to the development of acetazolamide (8.29), a thiadiazole derivative. It is not an ideal drug because it promotes K+ excretion and causes a very high urine pH. Since chloride ions are not excreted simultaneously, systemic acidosis also results. Much more useful are the chlorothiazide (8.30) derivatives, which are widely used as oral diuretic drugs. These compounds differ from one another mainly in the nature of the substituent on C3 ... 

Combined treatment is necessary in the long-term treatment of essential hypertension. (3-Blocker and diuretic properties in a same molecule would present a great interest for hypertension management. Few attempts to synthesize hybrid molecules by combining the structures of a (3-adrenorecep-tor antagonist and a diuretic were described (Figure 18.35). A hybrid sulfonamide was achieved by linking the (3-blocker propranolol derivative with the 2-chlorobenzene sulfonamide moiety of mefruside. ... 

An interesting sulfonamide diuretic that has little resemblance structurally to the thiazides is chlorthalidone, a benzophenone derivative. On a dose basis, it has an activity comparable to hydrochlorothiazide but is a much stronger carbonic anhydrase inhibitor than the thiazides, approximately 40 times sulfanilamide. Physical data indicate this compound to have the isoindoline structure rather than the benzophenone structure, I. The outstanding feature of this drug is its long duration of action, up to 72 hours (22, 32, 66). 

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