Acetazolamide renal effects

Almost all diuretics exert their action at the luminal surface of the renal tubule cells. Their mechanism of action includes interaction with specific membrane transport proteins like thiazides, furosemide etc., osmotic effects which prevent the water permeable segments of the nephron from absorbing water like mannitol, and specific interaction with enzyme like carbonic anhydrase inhibitors i.e. acetazolamide, and hormone receptors in renal epithelial cells like spironolactone. 

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 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. 

Many diuretic agents (loop diuretics, thiazides, amiloride, and triamterene) 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 (spironolactone). 

Uric acid, cystine, and some other weak acids are relatively insoluble in, and easily reabsorbed from, acidic urine. Renal excretion of these compounds can be enhanced by increasing urinary pH with carbonic anhydrase inhibitors. In the absence of continuous bicarbonate administration, these effects of acetazolamide are of relatively short duration (2-3 days). Prolonged therapy requires bicarbonate administration. 

Quinidine Metabolism inducible. Inhibits CYP2D6. Renal excretion susceptible to changes in urine pH. Additive effects with other agents that prolong the QTC interval. Acetazolamide [P] Decreased renal quinidine excretion due to increased urinary pH elevated serum quinidine. 

LITHIUM ACETAZOLAMIDE 1 plasma concentrations of lithium, with risk of inadequate therapeutic effect T renal elimination of lithium Monitor clinically and by measuring blood lithium levels to ensure adequate therapeutic efficacy... 

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. 

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 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... 

Fransen R, BoerWH, Boer P, Dorhout Mees EJ, Koomans HA. Effects of furosemide or acetazolamide infusion on renal handling of lithium a micropuncture study in rats. Am J Physiol 1993 264 129-34. 

One must keep in mind that older patients with uric acid kidney stones also may have hypertension, congestive heart failure, or renal insufficiency, and obviously should not be exposed to overload with aUcalinizing sodium salts or unlimited fluid intake. Acetazolamide, a carbonic anhydrase inhibitor, produces rapid and effective urinary alkalinization and sometimes is used in conjunction with alkali therapy. When a 250-mg dose of acetazolamide is given at bedtime, the excretion of an acidic urine in the early morning hours is avoided. The usual tachyphylaxis (rapid tolerance) to this drug is obviated by a daily repletion dose of bicarbonate. 

On average, only 30% to 60% of patients are able to tolerate oral CAI therapy for prolonged periods. Intolerance to CAI therapy results most commonly from a symptom complex attributable to systemic acidosis and including malaise, fatigue, anorexia, nausea, weight loss, altered taste, depression, and decreased libido. Other adverse effects include renal calculi, increased uric acid, blood dyscrasias, diuresis, and myopia. Elderly patients do not tolerate CAIs as well as younger patients. The three available CAIs produce the same spectrum of adverse effects however, the drugs differ in the frequency and severity of the adverse effects listed. Acetazolamide (standard or sustained-release capsules) and methazolamide are considered the best-tolerated CAIs. 

Diuretics may cause reductions in glomerular filtration rate either by a direct effect to constrict the renal arterial supply or secondary to their induction of extracellular fluid volume contraction. Listed in Table 1 are the renal hemodynamic alterations induced in the experimental animal or in man by the most commonly employed currently available diuretic agents. Acetazolamide, a proximally active agent and the prototypical carbonic anhydrase inhibitor (Figure 1), consistently reduces renal blood flow by 25 to 37% and... 

Gordon EE, Sheps SG. Effect of acetazolamide on citrate excretion and formation of renal calculi. N Engl J Med 1957 256 1215-1219. 

Theophylline HPLC Acetazolamide cephalosporins endogenous xanthines and accumulated theophylline metabolites in renal failure (minor effect). 

There appear to be no reports of adverse interactions between chlorpropamide and drugs that can alter urinary pH, but prescribers should be aware of the possibilities a reduced response if the pH is raised significantly and renal clearance predominates (e.g. with sodium bicarbonate, acetazolamide, some antacids) an increased response if the pH is made more acid than usual and metabolic clearance predominates (e.g. with ammonium chloride). Perhaps more importantly, the effects of drugs that alter the hepatic clearance of chlorpropamide are likely to be more significant when its renal clearance is low (i.e. when the urine is acid). ... 

In rats orally administered single doses of 50 or 100 mg/ kg of water or ethanol extracts of pill-bearing spurge daily, a time-dependent increase in urine output was observed. The water extract increased the urine excretion of sodium, potassium, and bicarbonate. In contrast, the ethanol extract increased the excretion of bicarbonate, decreased the loss of potassium, and had little effect on renal removal of sodium. The activity of pill-bearing spurge was noted as similar to the drug acetazolamide (Johnson et al. 1999). 

Absolute Accuracy of Measurement, 13-20 Accuracy of K Microelectrode, 77-85 Acetazolamide, 95-98, 100 Acetylcholine Effects, 58, 61 Acidification, Renal Tubular, 89 Antimony Microelectrodes, 43, 89 Aplysia Neurons, 57 Artificial Beta Cell, 189 Artificial Pancreas, 189... 

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