Carbonic Anhydrase Inhibitors

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Chapter: Essential pharmacology : Diuretics

Carbonic anhydrase (CAse) is an enzyme which catalyses the reversible reaction H2O + CO2 ←→ H2CO3. Carbonic acid spontaneously ionizes H2CO3←→H+ +HCO¯3 .



Carbonic anhydrase (CAse) is an enzyme which catalyses the reversible reaction H2O + CO2 ←→ H2CO3. Carbonic acid spontaneously ionizes H2CO3←→H+HCO¯3  (Fig. IX.2). Carbonic anhydrase thus functions in CO2  and HCO3¯ transport and in H+ ion secretion. The enzyme is present in renal tubular cell (especially PT) gastric mucosa, exocrine pancreas, ciliary body of eye, brain and RBC. In these tissues a gross excess of CAse is present, more than 99% inhibition is required to produce effects.




It is a sulfonamide derivative which noncompetitively but reversibly inhibits CAse in PT cells resulting in slowing of hydration of CO2  decreased availability of H+ to exchange with luminal Na+ through the Na+H+ antiporter. Inhibition of brush border CAse retards dehydration of H2CO3 in the tubular fluid so that less CO2 diffuses back into the cells. The net effect is inhibition of HCO¯ (and accompanying Na+) reabsorption in PT  prompt but mild alkaline diuresis ensues.


Secretion of H+ in DT and CD is also inhibited. Though H+ is secreted at this site by a H+ATPase, it is generated in the cell by CAse mediated reaction. As such, this is a subsidiary site of action of CAse inhibitors. When CAse inhibitors are given, the distal Na+ exchange takes place only with K+ which is lost in excess. For the same degree of natriuresis CAse inhibitors cause the most marked kaliuresis compared to other diuretics. The urine produced under acetazolamide action is alkaline and rich in HCO¯ which is matched by both Na+ and K+. Continued action of acetazolamide depletes body HCO3¯ and causes acidosis; less HCO3¯ (on which its diuretic action depends) is filtered at the glomerulus  selflimiting diuretic action. The extrarenal actions of acetazolamide are:


·            Lowering of intraocular tension due to decreased formation of aqueous humour (it is rich in HCO¯)3.


·            Decreased gastric HCl and pancreatic NaHCO3 secretion: This action requires very high doses—clinically not significant.


·            Raised level of CO2 in brain and lowering of pH  sedation and elevation of seizure threshold.


·            Alteration of CO2 transport in lungs and tissues: these actions are masked by compensatory mechanisms.




Acetazolamide is well absorbed orally and excreted unchanged in urine. Action of a single dose lasts 8–12 hours.




Because of selflimiting action, production of acidosis and hypokalaemia, acetazolamide is not used as diuretic. Its current clinical uses are:


1. Glaucoma: as adjuvant to other ocular hypotensives (see Ch. No. 10).

2. To alkalinise urine: for urinary tract infection or to promote excretion of certain acidic drugs.

3. Epilepsy: as adjuvant in absence seizures when primary drugs are not fully effective.

4. Acute mountain sickness: for symptomatic relief as well as prophylaxis. Benefit occurs probably due to reduced CSF formation as well as lowering of CSF and brain pH.

5. Periodic paralysis.


Dose: 250 mg OD–BD; DIAMOX, SYNOMAX 250 mg tab. IOPARSR 250 mg SR cap.


Adverse Effects are frequent.


Acidosis, hypokalaemia, drowsiness, paresthesias, fatigue, abdominal discomfort. Hypersensitivity reactions—fever, rashes. Bone marrow depression is rare but serious. It is contraindicated in liver disease: may precipitate hepatic coma by interfering with urinary elimination of NH3 (due to alkaline urine). Acidosis is more likely to occur in patients of COPD.


Some topical CAse inhibitors have been introduced for use in glaucoma (see Ch. No. 10).


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