Metabolic acidosis acetazolamide

Bietti G, Vimo M, Pecori-Giraldi ), Pellegrino N. Acetazolamide, metabolic acidosis, and intraocular pressure. Am) Ophthalmol 1975 80 360-369. 

Carbonic anhydrase inhibitors such as acetazolamide act in the proximal tubule. These drugs prevent the formation of H+ ions, which are transported out of the tubular epithelial cell in exchange for Na+ ions. These agents have limited clinical usefulness because they result in development of metabolic acidosis. 

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... 

Acetazolamide causes a metabolic acidosis that stimulates respiratory drive and may be beneficial for high altitude, heart failure, and idiopathic CSA. 

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. 

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. 

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... 

In 1940 sulfanilamide was shown to inhibit carbonic anhydrase. It was not useful as a diuretic because the doses required to produce diuresis were excessive. Investigation of some heterocyclic sulfonamides produced some clinically effective diuretics, for example ethoxzolamide (188), but the first really useful sulfonamide diuretic was acetazolamide (189). This compound also has anticonvulsant activity which is probably related to the presence of carbonic anhydrase in the CNS. Acetazolamide had the disadvantage of producing a metabolic acidosis through the excretion of HCO3- rather than Cl and it was found that some 1,3-disulfonamidobenzenes gave a more balanced diuresis. 

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. 

Metabolic acidosis due to acetazolamide causes increased minute ventilation, which can cause increased intracranial pressure and result in neurological complications (38). 

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. 

Adverse effects. High doses of acetazolamide may cause drowsiness and fever, rashes and paraesthesiae may occur, and blood disorders have been reported. Renal calculi may develop, because the urine calcium is in less soluble form owing to low citrate content of the urine, a consequence of metabolic acidosis. 

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. 

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... 

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. 

A ketogenic diet is sometimes used to control intractable seizures. Acetazolamide should be discontinued before starting the diet, because of the potential risk of severe secondary metabolic acidosis (31). Acetazolamide can be reintroduced once the acid-base status of the patient has stabilized. 

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. 

Malignant neoplasms Fanconi s syndrome Acute volume expansion Metabolic acidosis Renal transplantation Vitamin D deficiency and/or resistance Diuretics Acetazolamide Osmotic agents Glucocorticoids Sodium bicarbonate Internal redistribution Refeeding syndrome Parenteral nutrition... 

Metabolic acidosis can also result from loss of bicarbonate, such as in severe diarrhea, especially in infants or due to the depletion of bicarbonate when urine is delivered to the colon after transplantation of ureters into the colon. The administration of carbonic anhydrase inhibitors such as acetazolamide results in excretion of bicarbonate in urine and retention of hydrogen ions, leading to metabolic acidosis. Because of impaired hydrogen ion secretion potassium is... 

When sulfanilamide was introdnced as a chemotherapeutic agent, metabolic acidosis was recognized as a side effect. This observation led to the demonstration that snl-fanilamide is an inhibitor of carbonic anhydrase. Snbse-quently, an enormous number of sulfonamides were synthesized and tested for the ability to inhibit carbonic anhydrase of these componnds, acetazolamide has been studied most extensively. Three carbonic anhydrase inhibitors currently are available in the United States—acetazolamide, dichlorphenamide (Daranide), and methazolamide (GlaucTabs). The common molecnlar motif of available carbonic anhydrase inhibitors is an nnsnbstitnted sulfonamide moiety. 

Paresthesias and gastrointestinal distress are common adverse effects of acetazolamide, especially when it is taken chronically, as in glaucoma. The observation that the patient has metabolic acidosis also suggests the use of acetazolamide. The answer is (A). 

Ingestion of drugs and toxins acetazolamide causes acidosis. Methanol and ethylene glycol (antifreeze) metabolism produces an excess of protons, see Chapter 29 Diarrhoea causing massive loss of Intestinal HCOj" ... 

In renal disease (nephrosclerosis, nephrocalcinosis, acetazolamide therapy) in which sodium is lost without a corresponding loss of chloride, chloride is retained and metabolic acidosis develops. Overproduction of lactic acid leading to acidosis is observed in hypoxia, hemorrhagic shock, and physical exertion. 

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... 

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. 

There has been a previous report of metabolic acidosis in a 1-year-old girl who took 500-1250 mg of acetazolamide [29" ]. 

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