Acetazolamide, diuretic drugs

The answer is c. (Hardman, pp 6917 693 J Acetazolamide is a carbonic anhydrase inhibitor with its primary site of action at the proximal tubule of the nephron. Acetazolamide promotes a urinary excretion of Na, K, and bicarbonate There is a decrease in loss of Cl ions The increased excretion of bicarbonate makes the urine alkaline and may produce metabolic acidosis as a consequence of the loss of bicarbonate from the blood. None of the other diuretic drugs promote a reduction in the excretion of the Cl ion... 

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 ... 

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. 

It was soon learned that the sulfonamide portion of an active diuretic molecule could not be monosubstituted or disubstituted. It was reasoned that a more acidic sulfonamide would bind more tightly to the carbonic anhydrase enzyme. Synthesis of more acidic sulfonamides produced compounds more than 2,500-fold more active than sulfanilamide. Acetazolamide was Introduced In 1953 as an orally effective diuretic drug. Before that time, the organic mercurials, which commonly required Intramuscular Injection, were the principal diuretics available. 

Strong inhibitors of CA are mostly aromatic sulfonamides.Acetazolamide (19), with K of 6 nM against human carbonic anhydrase II (HCA II), is therapeutically prescribed as a diuretic drug. " The X-ray crystal-structure analysis of the HCA Il-acetazolamide complex confirmed that the V-deprotonated amide binds to in the active site (20) (Scheme 23). ... 

The phototoxic diuretic drug acetazolamide 7 is photolabile under aerobic and anaerobic conditions in methanoUc solution as well as in buffered aqueous medium (pH = 7.2). The quantum yield under aerobic conditions was 0 = 0.24, and the reaction led to the formation of photoproducts 7a (yield 75%) and 7b (yield 25%) (Figure 63.4). The results indicate that Oj is directly involved in the photol) is of acetazolamide. The study of the influence of oxygen radicals on the decomposition of acetazolamide (irradiations in the presence of singlet oxygen quenchers) indicate that Oj may lead to degradation of 7 by oxygenation. 

Vargas, F., M6ndez, H., and Rojas, J., Photolysis and photosensitized degradation of the diuretic drug acetazolamide, /. Photochem. Photobiol A Chem., 118,19, 1998. 

Drugs that may be affected by aspirin include ACE inhibitors, acetazolamide, anticoagulants, anticonvulsants (hydantoins, valproic acid), beta blockers, diuretics, methotrexate, NSAIDs, oral hypoglycemics, and uricosuric agents (probenecid, sulfinpyrazone). 

Drugs that may affect lithium include acetazolamide, carbamazepine, fluoxetine, haloperidol, loop diuretics, methyidopa, NSAIDs, osmotic diuretics, theophyllines. 

The history of pharmacology revealed that certain drugs have been developed from the observation of their side effects for example sulfonamide produce hypoglycemia and acidosis as side effect, which further gave an idea for developing a new compound related to sulfona-mide - sulfonylurea as hypoglycemic agent and acetazolamide as diuretic. 

Acidosis and alkalosis are infrequent. Metabolic acidosis is a side effect of acetazolamide therapy and is due to bicarbonate loss in the PCT. All the K+-sparing diuretics can cause metabolic acidosis by H+ retention in the cells of the collecting duct. Metabolic alkalosis is associated with the loop and thiazide drugs. Reflex responses to volume depletion cause reabsorption of HCO-3 in the PCT and H+ secretion in the collecting tubule. 

This chapter is divided into three sections. The first section covers renal tubule transport mechanisms. The nephron is divided structurally and functionally into several segments (Figure 15-1, Table 15-1). Many diuretics exert their effects on specific membrane transport proteins in renal tubular epithelial cells. Other diuretics exert osmotic effects that prevent water reabsorption (mannitol), inhibit enzymes (acetazolamide), or interfere with hormone receptors in renal epithelial cells (aldosterone receptor blockers). The physiology of each segment is closely linked to the basic pharmacology of the drugs acting there, which is discussed in the second section. Finally, the clinical applications of diuretics are discussed in the third section. 

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. 

Inhibition of Carbonic Anhydrase by Acetazolamide Carbonic anhydrase is strongly inhibited by the drug acetazolamide, which is used as a diuretic (i.e., to increase the production of urine) and to... 

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. 

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