Pharmacology
Summary
The proximal convoluted tubule (PCT) is an integral segment of the nephron involved in solute and water reabsorption. Key to its function is the Na+/K+ ATPase on the basolateral membrane, which maintains the intracellular sodium concentration. On the apical membrane, the Na+/H+ exchanger facilitates the secretion of hydrogen ions (H+) into the tubular lumen, where it combines with bicarbonate (HCO3-) to form carbonic acid (H2CO3). This acid is then converted by luminal carbonic anhydrase (CA) into water (H2O) and carbon dioxide (CO2), both of which diffuse into the intracellular compartment. Within the cell, intracellular CA converts them back into H2CO3, which dissociates into H+ and HCO3-. While H+ returns to the lumen via the Na+/H+ exchanger, bicarb is absorbed basolaterally. Notably, the PCT is the site of action for drugs like acetazolamide and mannitol. Acetazolamide, a CA inhibitor, impedes bicarb reabsorption, leading to its retention in the tubular lumen, alkalinization of urine, natriuresis, and an associated normal anion gap metabolic acidosis. Furthermore, CA inhibitors prove useful in managing conditions like glaucoma, idiopathic intracranial hypertension, and mountain sickness, although they can cause hypokalemia and promote calcium phosphate stone formation.
Acetazolamide belongs to the class of sulfa drugs and its inhibition of CA carries implications in both the renal and ocular systems. By hindering aqueous humor production, it aids in managing glaucoma. Similarly, by reducing cerebrospinal fluid (CSF) production, it benefits patients with idiopathic intracranial hypertension. However, its effects can induce a type 2 renal tubular acidosis due to a defect bicarb reabsorption at the proximal convoluted tubule. On the other hand, mannitol, an osmotic diuretic, acts at both the PCT and the descending limb of the loop of Henle. Beyond its renal effects, mannitol can draw free water out of the CNS, aiding in the treatment of increased intracranial and intraocular pressures. However, the osmotic actions of mannitol can result in an overly expanded extracellular volume that can cause pulmonary edema, hyponatremia, and exacerbation of heart failure. Conversely, excessive diuresis from mannitol might result in water loss significant enough to cause hypernatremia.
Lesson Outline
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FAQs
Acetazolamide functions as a carbonic anhydrase (CA) inhibitor, predominantly within the proximal convoluted tubule. By inhibiting CA, the drug disrupts the sequential conversion of bicarbonate and hydrogen ions to carbonic acid and subsequently into water and carbon dioxide. This impedes bicarbonate and sodium reabsorption, causing both to remain in the tubular lumen. This retention results in increased sodium excretion (natriuresis) and a more alkaline urine (urine alkalinization). The impaired bicarbonate reabsorption can precipitate a normal anion gap metabolic acidosis.
Acetazolamide finds its application in various conditions such as glaucoma, idiopathic intracranial hypertension, and mountain sickness. In the context of glaucoma, it curtails the production of aqueous humor, which subsequently lowers intraocular pressure. For idiopathic intracranial hypertension, acetazolamide decreases cerebrospinal fluid (CSF) production, thereby alleviating elevated intracranial pressure. In the case of mountain sickness, the drug's action helps mitigate symptoms associated with changes in altitude.
Treatment with carbonic anhydrase inhibitors can lead to several side effects. Among these are hypokalemia, attributable to potassium wasting, and type 2 renal tubular acidosis due to impaired bicarbonate reabsorption in the proximal tubule. Furthermore, the acidic urinary environment they create can foster the formation of calcium phosphate stones, which are poorly soluble in alkaline conditions. Since acetazolamide belongs to the sulfa drug class, patients with known sulfa allergies should be monitored closely when on this medication.
Mannitol acts as an effective osmotic diuretic primarily within the proximal convoluted tubule and the descending limb of the loop of Henle. Its non-reabsorbable nature means it stays within the nephron's lumen, drawing water due to its osmotic properties, and thus amplifying urine production. Its capacity to attract water can lead to reduced intracranial and intraocular pressures by removing water from the central nervous system and the eyes.
Mannitol is primarily employed to reduce elevated intracranial and intraocular pressures. However, its mechanism of expanding extracellular volume can cause several complications, including exacerbating heart failure, precipitating pulmonary edema, or leading to hyponatremia. Conversely, excessive diuresis from mannitol might result in water loss significant enough to cause hypernatremia.
