Acetazolamide metabolic acidosis with

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. 

In a 9-year-old girl recombinant human growth hormone 6 mg/week caused idiopathic intracranial hypertension (pseudotumor cerebri), which was treated with acetazolamide [28 ]. After 4 days the dose was increased to 30 mg/kg/day, and 2 days later she developed a severe metabolic acidosis, with a pH of 7.29. 

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... 

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. 

Acetazolamide, others Inhibition of the enzyme prevents dehydration of H2CO3 and hydration of CO2 Reduces reabsorption of HC03 in the kidney, causing self-limited diuresis hyperchloremic metabolic acidosis reduces body pH, reduces intraocular pressure Glaucoma, mountain sickness, edema with alkalosis Oral and topical preparations available duration of action 8-12 h Toxicity Metabolic acidosis, renal stones, hyperammonemia in cirrhotics... 

Four preterm neonates with posthemorrhagic ventricular dilatation developed severe metabolic acidosis after being given acetazolamide (33). The acidosis suddenly disappeared after a transfusion of packed erythrocytes, which was attributed to the citrate contained in the blood. 

Acetazolamide can cause a metabolic acidosis in 50% of elderly patients (SEDA-11,199) occasionally (particularly if salicylates are being given or renal function is poor) the acidosis can be severe. It does this by inhibiting renal bicarbonate reabsorption. This effect is of particular use in treating patients with chronic respiratory acidosis with superimposed metabolic alkalosis. Life-threatening metabolic acidosis is rarely observed in the absence of renal insufficiency and/or diabetes mellitus. In three patients with central nervous system pathology alone conventional doses of acetazolamide resulted in severe metabolic acidosis (34). After withdrawal it took up to 48 hours for the metabolic acidosis and accompanying hyperventilation to resolve. 

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. 

CAIs alter renal function primarily by inhibiting carbonic anhydrase in the proximal tubule, which results in decreased bicarbonate reabsorption. The net effect of the renal actions of acetazolamide therapy is alkaliniza-tion of the urine and metabolic acidosis. Metabolic acidosis results from the initial bicarbonate loss and persists with continued acetazolamide use. Moderate metabolic acidosis develops in most patients. Reabsorption of bicarbonate independent of carbonic anhydrase prevents severe acidosis. Initially, acetazolamide produces diuresis, but urinary output decreases with the development of metabolic acidosis. In addition, decreased urinary citrate excretion follows acetazolamide therapy and has been attributed to the metabolic acidosis it produces. A high urinary pH and low urinary citrate concentration are conducive to precipitation of calcium phosphate in both the renal papillae and the urinary tract. 

Contraindications to the use of methazolamide are the same as those associated with the use of acetazolamide. Methazolamide, however, can be used more safely in patients with a history of kidney stones or renal impairment. Patients with COPD may tolerate methazolamide better than acetazolamide, because the metabolic acidosis is less pronounced. 

Acetazolamide toxicity was suspected, because of the temporal association between drug treatment and the onset of the neurological sjmptoms, together with metabolic acidosis. Gerstmann sjmdrome is usually due to an acute stroke. Although a brain CT scan was negative, such an event was likely in this patient, who had a history of cerebrovascular disease and multiple risk factors, and a causal relation to acetazolamide must be considered tenuous. 

Chronic acetazolamide therapy is associated with greater spinal bone mineral density. This is probably the result of metabolic acidosis urine calcium is increased and serum phosphate reduced. Osteomalacia has been reported during long-term therapy in combination with barbiturates in two patients. 

A 12-month-old girl, weighing 10 kg, developed metabolic acidosis after taking 500-1250 mg of acetazolamide (26). The maximum base deficit recorded was 11.6. She was treated with sodium bicarbonate and recovered completely. 

A 50-year-old woman with chronic renal insufficiency treated with acetazolamide for simple glaucoma developed confusion, cerebellar ataxia, and metabolic acidosis 2 weeks after starting to take aspirin for acute pericarditis (30). A diagnosis of salicylism was made despite low serum salicylate concentrations. 

Venkatesha SL, Umamaheswara Rao GS. Metabolic acidosis and hyperventilation induced by acetazolamide in patients with central nervous system pathology. Anesthesiology 2000 93(6) 1546-8. 

Around 60-70% of the filtered sodium is usually reabsorbed in the proximal tubule therefore, acetazolamide could be expected to have a rather potent diuretic effect. However, it produces rather modest diuresis because most of the excess sodium leaving the proximal tubule can be reabsorbed in the more distal segments of the nephron. Furthermore, its diuretic action is progressively diminished by the development of hyperchloremic metabolic acidosis caused by the loss of bicarbonate ions into the urine (Martinez-Maldonado Cordova 1990, Rose 1989, 1991, Wilcox 1991). In humans, the primary indication for acetazolamide (as a diuretic agent) is the treatment of edema with metabolic alkalosis. 

Add-base balance Acetazolamide causes a metabolic acidosis, which is usually mild, but can be associated with hypokalemia. In nine subjects who took acetazolamide 250 mg or placebo every 8 hours for 3 days in a double-blind, randomized, crossover... 

Metabolic alkalosis is generally treated by correction of abnormalities in total body K+, intravascular volume, or mineralocorticoid levels. However, when the alkalosis is due to excessive use of diuretics in patients with severe heart failure, replacement of intravascular volume may be contraindicated. In these cases, acetazolamide can be useful in correcting the alkalosis as well as producing a small additional diuresis for correction of volume overload. Acetazolamide can also be used to rapidly correct the metabolic alkalosis that may develop in the setting of respiratory acidosis. 

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