Acetazolamide

It is used in the treatment of glaucoma, drug-induced edema, heart failure-induced edema, epilepsy and in reducing intraocular pressure after surgery.[9][10] It has also been used in the treatment of altitude sickness,[11] Ménière's disease, increased intracranial pressure and neuromuscular disorders.[12]

In epilepsy, the main use of acetazolamide is in menstrual-related epilepsy and as an add on to other treatments in refractory epilepsy.[9][13] It has been demonstrated in drug trials to relieve symptoms associated with dural ectasia in individuals with Marfan's Syndrome.[14] A 2012 review and meta-analysis found that there was "limited supporting evidence" but that acetazolamide "may be considered" for the treatment of central (as opposed to obstructive) sleep apnea.[15]

It has also been used to prevent methotrexate-induced kidney damage by alkalinalizing the urine, hence speeding up methotrexate excretion by increasing its solubility in urine.[12][16] There is some evidence to support its use to prevent hemiplegic migraine.[17]

Common adverse effects of acetazolamide include the following: paraesthesia, fatigue, drowsiness, depression, decreased libido, bitter or metallic taste, nausea, vomiting, abdominal cramps, diarrhea, black feces, polyuria, kidney stones, metabolic acidosis and electrolyte changes (hypokalemia, hyponatremia).[9] Whereas less common adverse effects include Stevens–Johnson syndrome, anaphylaxis and blood dyscrasias.[9]

Carbonic anhydrase (ribbon) complex with a sulfonamide inhibitor (ball-and-sticks).

Proximal convoluted tubule. Urinary space is on left.

Acetazolamide is a carbonic anhydrase inhibitor, hence causing the accumulation of carbonic acid.[12] Carbonic anhydrase is an enzyme found in red blood cells and many other tissues that catalyses the following reaction:[23]

H₂CO₃ ⇌ H₂O + CO₂

hence lowering blood pH, by means of the following reaction that carbonic acid undergoes:[24]

H₂CO₃ ⇌ HCO₃⁻ + H⁺

which has a pK_a of 6.3.[24]

The mechanism of diuresis involves the proximal tubule of the kidney. The enzyme carbonic anhydrase is found here, allowing the reabsorption of bicarbonate, sodium, and chloride. By inhibiting this enzyme, these ions are excreted, along with excess water, lowering blood pressure, intracranial pressure, and intraocular pressure. By excreting bicarbonate, the blood becomes acidic, causing compensatory hyperventilation with deep respiration (Kussmaul respiration), increasing levels of oxygen and decreasing levels of carbon dioxide in the blood.[25]

In the eye this results in a reduction in aqueous humour.[10]

Bicarbonate (HCO₃⁻) has a pK_a of 10.3 with carbonate (CO₃²⁻), far further from physiologic pH (7.35–7.45), and so it is more likely to accept a proton than to donate one, but it is also far less likely for it to do either, thus bicarbonate will be the major species at physiological pH.

Under normal conditions in the proximal convoluted tubule of the kidney, most of the carbonic acid (H₂CO₃) produced intracellularly by the action of carbonic anhydrase quickly dissociates in the cell to bicarbonate (HCO₃⁻) and an H⁺ ion (a proton), as previously mentioned. The bicarbonate (HCO₃⁻) exits at the basal portion of the cell via sodium (Na⁺) symport and chloride (Cl⁻) antiport and re-enters circulation, where it may accept a proton if blood pH decreases, thus acting as a weak, basic buffer. The remaining H⁺ left over from the intracellular production of carbonic acid (H₂CO₃) exits the apical (urinary lumen) portion of the cell by Na⁺ antiport, acidifying the urine. There, it may join with another bicarbonate (HCO₃⁻) that dissociated from its H⁺ in the lumen of the urinary space only after exiting the proximal convoluted kidney cells/glomerulus as carbonic acid (H₂CO₃) because bicarbonate (HCO₃⁻) itself can not diffuse across the cell membrane in its polar state. This will replenish carbonic acid (H₂CO₃) so that it then may be reabsorbed into the cell as itself or CO₂ and H₂O (produced via a luminal carbonic anhydrase). As a result of this whole process, there is a greater net balance of H⁺ in the urinary lumen than bicarbonate (HCO₃⁻), and so this space is more acidic than physiologic pH. Thus, there is an increased likelihood that any bicarbonate (HCO₃⁻) that was left over in the lumen diffuses back into the cell as carbonic acid, CO₂, or H₂O.

In short, under normal conditions, the net effect of carbonic anhydrase in the urinary lumen and cells of the proximal convoluted tubule is to acidify the urine and transport bicarbonate (HCO₃⁻) into the body. Another effect is excretion of Cl⁻ as it is needed to maintain electroneutrality in the lumen, as well as the reabsorption of Na⁺ into the body.

Thus, by disrupting this process with acetazolamide, urinary Na⁺ and bicarbonate (HCO₃⁻) are increased, and urinary H⁺ and Cl⁻ are decreased. Inversely, serum Na⁺ and bicarbonate (HCO₃⁻) are decreased, and serum H⁺ and Cl⁻ are increased. H₂O generally follows sodium, and so this is how the clinical diuretic effect is achieved, which reduces blood volume and thus preload on the heart to improve contractility and reduce blood pressure, or achieve other desired clinical effects of reduced blood volume such as reducing edema or intracranial pressure.[26]

An early description of this compound (as 2-acetylamino-1,3,4-thiadiazole-5-sulfonamide) and its synthesis appears in U.S. Patent 2554816[27]