Carbonic Anhydrase Inhibitors

Carbonic anhydrase inhibitors (CA inhibitors) are drugs that inhibit the activity of carbonic anhydrase enzyme.
The most commonly used carbonic anhydrase inhibitor is acetazolamide. Some other FDA approved carbonic anhydrase inhibitors are
- Methazolamide
- Dichlorphenamide
- Dorzolamide
- Brinzolamide
Structurally, they are sulfonamide derivative.

Mechanism of action of carbonic anhydrase inhibitors

Figure 1- Mechanism of action of carbonic anhydrase inhibitors (CA- Carbonic Anhydrase enzyme)

The enzyme carbonic anhydrase is present in kidney, eyes, gastric mucosa, RBC, CNS and pancreas. It catalyzes the following reaction

The H⁺ions is available for Na⁺ reabsorption. Carbonic anhydrase also allows reabsorption of chloride and bicarbonate ions.

Carbonic anhydrase inhibitors inhibit the carbonic anhydrase enzyme and thus inhibit formation of carbonic acid (H₂CO₃). Thus, hydrogen ions become less available for reabsorption of Na⁺ This increase in excretion of sodium, chloride and bicarbonate ions and lead to excretion of excess water resulting in lowering of blood pressure, intracranial pressure and intraocular pressure.

Kidney and electrolytes

Carbonic anhydrase enzyme play an important role in tubular reabsorption of sodium and bicarbonate. Carbonic anhydrase inhibitors inhibit carbonic anhydrase enzyme of both cytoplasm and membrane. It causes loss of sodium, bicarbonate, phosphate and potassium ions.
The increased diffusion of bicarbonate ions in urine make it alkaline.

Eye

Carbonic anhydrase is present in ciliary process of eye and helps in production of aqueous humor. Aqueous humor is transparent watery fluid which fills both anterior and posterior chamber of eye. It helps to maintain intraocular pressure and provide nutrients to eye.
Carbonic anhydrase inhibitors reduce intraocular pressure by inhibiting the carbonic anhydrase enzyme.

CNS (Central Nervous System)

Pharmacokinetics

Administered through oral or IV route. Topical administration is also available. Well absorbed through oral route.
It produces urinary alkylation within 30 minutes. Maximum effect is observed within 3-4 hours.
Single dose effects lasts for about 12 hours.

To treat chronic open angle glaucoma. Topical dorzolamide and brinzolamide are preferred over due to less systemic side effects with topical use.
Used in prophylaxis and treatment of high-altitude illness. Acetazolamide is most commonly used. At high altitude, partial pressure of oxygen is low which make people to breathe more frequently to inhale adequate oxygen. This causes decrease in partial pressure of CO₂ in lungs leading to respiratory alkalosis. Carbonic anhydrase inhibitors prevent bicarbonate uptake in kidney and help to correct alkalosis. It prevents weakness, breathlessness, nausea, cerebral and pulmonary edema which occur during high-altitude illness.
For treating resistant epilepsy.
In idiopathic intracranial hypertension.
To prevent attacks of periodic paralysis.
It is a weak diuretic. However, its use as diuretic is not recommended nowadays.

Hypokalemia may occur due to excessive potassium loss. It can cause metabolic acidosis, renal stone formation, drowsiness and paresthesia.
Due to structural resemblance to sulfonamide it may cause some rare side effects like skin rashes, urticaria, photosensitivity, blood dyscrasias, Steven-Johnson syndrome and kidney damage.
Ocular use is associated with adverse ocular reactions, dysgeusia (an unpleasant taste in mouth) and superficial punctate keratitis (corneal disease).
CNS toxicity are reported sometime with symptoms like confusion and lethargy. It can be managed by discontinuing the drug.

When used together with salicylates, may result in accumulation and toxicity of CA inhibitors, leading to central nervous system toxicity as well as severe metabolic acidosis.
Acetazolamide may decrease excretion of drugs like amphetamine, phenytoin, quinidine and primidone by increasing urine pH. It may increase excretion of lithium.
Concurrent use with sodium bicarbonate increases risk of kidney stone formation.

Should be contraindicated in patients with known hypersensitivity to sulfonamide.
It should not be used in patients with liver disease because it may precipitate development of hepatic encephalopathy.
Should be avoided in patients with hypokalemia or hyponatremia.
It should be avoided in kidney disease or decreased kidney function.
In patients with hyperchloremic acidosis.
It should be used in pregnancy and breastfeeding mother only if benefits outweigh the risks.

https://www.ncbi.nlm.nih.gov/books/NBK532282/
Carbonic Anhydrases. Biochemistry and Pharmacology of an Evergreen Pharmaceutical Target. 2019; Pages 269-285.
Elsevier’s Integrated Review Pharmacology (Second Edition).
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Leaf DE, Goldfarb DS. Mechanisms of action of acetazolamide in the prophylaxis and treatment of acute mountain sickness. J Appl Physiol. 2007;102: 1313–1322.
Lippincott Illustrated Reviews Pharmacology. 6th edition.
Pharmacology and pharmacotherapeutics. 24th edition.