Carbonic anhydrase inhibitors
Carbonic anhydrase is a zinc metalloenzyme activating the hydration of CO2 in carbonic acid according to the reaction:
CO2 + H2 ¾® CO3H2 <=> CO3H- + H+
There are seven carbonic anhydrase isoenzymes, the most known being type II. Carbonic anhydrase is present in the renal tubule, the ciliary body, the choroid plexus, the central nervous system, the digestive tract.
Carbonic anhydrase inhibitors have a diuretic effect when inhibition reaches 99% of enzyme activity, which decreases the concentration of CO3H- and H+ ions.
This inhibition leads to the urinary elimination of potassium and bicarbonate eliminated instead of protons (and the urine becomes alkaline). The urinary chloride elimination decreases ; the bicarbonate elimination increases. The urinary elimination of sodium increases moderately. The alkalization of the urines is accompanied by an acidification of the plasma by bicarbonate loss.
Among carbonic anhydrase inhibitors which were marketed as diuretics, acetazolamide alone is still used in therapeutics not as diuretic, but for particular therapeutic uses:
- chronic glaucoma, because it decreases the secretion of the aqueous humor
- high-altitude disorders, because it decreases the formation of cerebrospinal fluid at the level of choroid plexus and improves pulmonary ventilation by lowering the plasma pH and increase of the sensitivity of chemoreceptors to hypoxia
- certain resistant epilepsies, perhaps by storage of the Cl- ions
- hypercapnia by inducing a plasma acidification
- certain periodic palsies.
The prescription of acetazolamide as a diuretic was discontinuous, it is continuous in the current therapeutic uses.
Acetazolamide (Diamox*) induces various adverse effects: headache, dizziness, tiredness, paresthesia, drowsiness and exceptionally leukopenia, agranulocytosis, thrombopenia and hypokalemia.
As acetazolamide has a beneficial effect in glaucoma. Other carbonic anhydrase inhibitors were marketed, dorzolamide (Trusopt*) and brinzolamide (Azopt*), which are not used by general route but only in the form of ophthalmic solution. In glaucoma their efficacy is about equivalent to that of the beta-blockers which act by a different mechanism.
Administered in the form of ophthalmic solution, dorzolamide and brinzolamide pass in blood circulation and can be at the origin of general adverse effects, headache, paresthesia.
There is an ophtalmic solution associating dorsolamide and a beta-blocker.
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