Diuretics, drugs commonly used in the treatment of hypertension and heart failure, consist of a group of drugs with diff ring pharmacokinetic and pharmacodynamic properties. Their primary effect is to increase urine flow and to promote diuresis. Most diuretics produce their clinical effect by blocking sodium (Na1) reabsorption in different locations of the nephron,1 resulting in increased sodium ion delivery to the distal tubules. The normal driving force for potassium (K1) excretion by distal renal tubules is the transtubular electrical potential difference created by sodium reabsorption. The presence of Na1 in the distal tubules promotes its reabsorption in exchange for secretion of K1 and results in hypokalemia. The sites of action of the different diuretics are illustrated in Figure 22-1. In general, diuretics with a site of action upstream of the collecting duct result in hyponatremia, hypokalemia, and metabolic alkalosis. In contrast, collecting duct diuretics result in hyperkalemia and metabolic acidosis.2
Carbonic Anhydrase Inhibitors
Acetazolamide is the prototype of a class of sulfonamide drugs that bind avidly to the enzyme carbonic anhydrase, producing noncompetitive inhibition of enzyme activity, principally in the proximal renal tubules as well as the collecting ducts (see Fig. 22-1; Table 22-1).3 A Na1-H1 exchanger allows absorption of Na1 in exchange for secretion of H1 into the renal tubule. HCO3
2 and H1
combine in the lumen of the proximal tubule to produce H2CO3. The enzyme carbonic anhydrase catalyzes the otherwise slow breakdown of H2CO3 into CO2 and H2O; CO2 diffuses readily into the tubular cells, where cytoplasmic carbonic anhydrase catalyses the reverse reaction leading to HCO3
2, which then follows an electrochemical gradient across the basal membrane into the interstitium. The net result is absorption of HCO3
2. Inhibition of carbonic
anhydrase in the proximal renal tubule by this class of diuretics results in decreased reabsorption of Na1, HCO3
2, and water.1,3
Pharmacokinetics and Pharmacodynamics After oral administration, acetazolamide is excreted unchanged by the kidneys. The dose should be adjusted in patients with renal failure and the elderly.4 Acetazolamide completely blocks membrane-bound and cytoplasmic carbonic anhydrase in the proximal tubule and to a lesser extent in the collecting ducts, preventing Na1 and HCO3
2 absorption.3 This increased excretion of HCO3 2 results in
an alkaline urine and metabolic acidosis. Natriuresis associated with carbonic anhydrase inhibitors is modest, with an increase in fractional Na1 excretion of up to 5%.3 Th increased delivery of Na1 to the distal tubules leads to potassium loss. Most of the chloride is reabsorbed in the loop of Henle,3 leading to the excretion of an alkaline urine in the presence of hyperchloremic metabolic acidosis.
Clinical Uses
In addition to its diuretic properties, acetazolamide is a dministered to decrease intraocular pressure in the treatment of glaucoma. There is a high concentration of the carbonic anhydrase enzyme in the ciliary processes; inhibition of the enzyme activity by acetazolamide results in decreased formation of aqueous humor and consequently a decrease in intraocular pressure.2 Similarly, formation of cerebrospinal fluid is also inhibited by acetazolamide. Accordingly, acetazolamide has been used in the treatment of idiopathic intracranial hypertension.2 Idiopathic intracranial hypertension, previously referred to as benign intracranial hypertension or pseudotumor cerebri, is characterized by increased intracranial pressure (ICP) in the absence of tumors or other causes and manifests with headaches, pulsatile tinnitus, and papilledema and visual changes secondary to the elevated ICP, which can progress to vision loss. Women are more likely to be affected, especially obese women in their third decade of life. When treatment with acetazolamide fails, surgical placement of a ventriculoperitoneal shunt to reduce the elevated ICP is an option.
Lumbar punctures, in addition to being diagnostic by providing direct measurement of the elevated ICP, can provide symptomatic relief via removal of cerebrospinal fluid. Acetazolamide may also be beneficial in the management of familial periodic paralysis because the drug-induced metabolic acidosis increases the local concentration of potassium in skeletal muscles.2 Similarly, acetazolamide, by producing metabolic acidosis, may stimulate the respiratory drive in patients who are hypoventilating in a compensatory response to respiratory alkalosis, as occurs with altitude sickness. Altitude sickness, which can be prevented by a slow acclimatization process, develops following rapid ascent to high altitudes.2 The hypoxia at high altitudes is counteracted by hyperventilation, which leads to respiratory alkalosis, which depresses ventilation. Acetazolamide-induced metabolic acidosis can reverse this hypoventilation.2 Conversely, the loss of bicarbonate ions necessary to buffer carbon dioxide may result in the exacerbation of respiratory acidosis in patients with chronic obstructive airway disease, leading to central nervous system (CNS) depression.
Side Effects
There is a high incidence of systemic side effects associated with the use of acetazolamide such as fatigue, decreased appetite, depression, and paresthesias,4 which could be secondary to the development of acidosis.4 Acetazolamide dose should be reduced in patients with chronic renal insufficiency and avoided in patients with severe chronic renal insufficiency because of the increased risk of metabolic acidosis.