Carbonic Anhydrase Inhibitors & Osmotic Diuretics

Carbonic anhydrase is the enzyme that catalyzes the reversible hydration of carbon dioxide and dehydration of carbonic acid. It sits in the proximal tubule and in red blood cells, where it helps reabsorb sodium, bicarbonate and chloride. Acetazolamide and methazolamide inhibit it. Bicarbonate is lost in the urine and carries sodium, water and potassium out with it, so the urine turns alkaline, a diuresis follows, and plasma bicarbonate falls, which can produce metabolic acidosis.

The diuresis is weak and does not build. Increasing the acetazolamide dose does not increase the diuresis and often decreases it, and its label gives edema doses intermittently so the kidney can recover from the inhibition. Methazolamide has only a weak and transient diuretic effect and should not be used as a diuretic. What these drugs are really used for are the same carbonic anhydrase effects in other tissues.

In the eye, carbonic anhydrase inhibition decreases aqueous humor secretion and lowers intraocular pressure. Both oral drugs treat chronic open-angle and secondary glaucoma and lower the pressure before surgery for acute angle-closure glaucoma; IV acetazolamide can relieve ocular tension rapidly in acute cases. The eye-drop carbonic anhydrase inhibitors dorzolamide and brinzolamide are taught on the Glaucoma Agents page.

Acetazolamide is also used to prevent or lessen acute mountain sickness in climbers making a rapid ascent; it does not remove the need for prompt descent if high-altitude pulmonary or cerebral edema develops. It reduces cerebrospinal fluid production, which is why it is used in idiopathic intracranial hypertension, and it is an adjunct for centrencephalic epilepsies.

Acetazolamide and methazolamide are sulfonamide derivatives without antibacterial activity. They share the rare reactions of all sulfonamides, which have been fatal: Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, agranulocytosis, aplastic anemia and other blood dyscrasias. Hypersensitivity can recur whenever a sulfonamide is given again, by any route, and cross-sensitivity between acetazolamide and other sulfonamides is possible. A baseline CBC and platelet count, repeated at intervals, screens for the blood reactions.

Mannitol is a six-carbon sugar alcohol given IV as an osmotic diuretic. It stays largely in the extracellular space, is filtered by the glomeruli, and less than 10% is reabsorbed by the tubules. By raising the osmolarity of the glomerular filtrate it hinders water reabsorption and increases sodium and chloride excretion. In the blood, the same rise in extracellular osmolarity draws water out of cells, which is how it reduces intracranial pressure, cerebral edema and intraocular pressure.

The danger is the order of events. Mannitol expands the circulation before it is excreted, so hypervolemia can cause or worsen heart failure, and a patient with oliguric kidney injury who becomes anuric on mannitol is at risk of heart failure, pulmonary edema, hypertensive crisis, coma and death. It can also cause kidney injury (osmotic nephrosis), dehydration, sodium and potassium swings, CNS toxicity, and a rebound rise in intracranial pressure hours after the infusion.