Carbonic anhydrase is an enzyme found in red blood cells and many other tissues that catalyses the following reaction:
H2CO3 ⇌ H2O + CO2hence lowering blood pH, by means of the following reaction that carbonic acid undergoes:
H2CO3 ⇌ HCO3− + H+which has a pKa of 6.3.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. A general side effect of carbonic anhydrase inhibitors is loss of potassium due to this function. By excreting bicarbonate, the blood becomes acidic, causing compensatory hyperventilation with deep respiration (Kussmaul breathing), increasing levels of oxygen and decreasing levels of carbon dioxide in the blood.In the eye this results in a reduction in aqueous humour.Bicarbonate (HCO3−) has a pKa 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.
Side effects
Common adverse effects of acetazolamide include the following: paraesthesia, fatigue, drowsiness, depression, decreased libido, bitter or metallic taste, nausea, vomiting, abdominal cramps, diarrhea, black stool, polyuria, kidney stones, metabolic acidosis and electrolyte changes (hypokalemia, hyponatremia). Whereas less common adverse effects include Stevens–Johnson syndrome, anaphylaxis and blood dyscrasias. Contraindications
Contraindications include:
Hyperchloremic acidosis
Hypokalemia (low blood potassium)
Hyponatremia (low blood sodium)
Adrenal insufficiency
Impaired kidney function
Hypersensitivity to acetazolamide or other sulphonamides. Marked liver disease or impairment of liver function, including cirrhosis because of the risk of development of hepatic encephalopathy. Acetazolamide decreases ammonia clearance. Interactions
It is possible that it might interact with:
Amphetamines, because it increases the pH of the renal tubular urine, hence reducing the clearance of amphetamines. Other carbonic anhydrase inhibitors — potential for additive inhibitory effects on carbonic anhydrase and hence potential for toxicity. Ciclosporin, may increase plasma levels of ciclosporin. Antifolates such as trimethoprim, methotrexate, pemetrexed and raltitrexed. Hypoglycemics, acetazolamide can both increase or decrease blood glucose levels. Lithium, increases excretion, hence reducing therapeutic effect. Methenamine compounds, reduces the urinary excretion of methenamines. Phenytoin, reduces phenytoin excretion, hence increasing the potential for toxicity. Primidone, reduces plasma levels of primidone. Hence reducing anticonvulsant effect. Quinidine, reduces urinary excretion of quinidine, hence increasing the potential for toxicity. Salicylates, potential for severe toxicity. Sodium bicarbonate, potential for kidney stone formation. Anticoagulants, cardiac glycosides, may have their effects potentiated by acetazolamide. Mechanism of action
Acetazolamide is a carbonic anhydrase inhibitor, hence causing the accumulation of carbonic acid.