Carbonic anhydrase inhibitors

1. Introduction

• Carbonic anhydrase inhibitors (CAIs) are drugs that block the activity of carbonic anhydrase (CA), an enzyme that catalyzes the reversible hydration of carbon dioxide to carbonic acid.

• Inhibition leads to decreased hydrogen ion production, reduced bicarbonate reabsorption, and subsequent alterations in fluid and electrolyte balance.

• Used in ophthalmology, neurology, nephrology, and altitude medicine.

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2. Mechanism of Action

• Carbonic anhydrase is present in many tissues, notably:

  • Proximal renal tubule: facilitates bicarbonate reabsorption.

  • Ciliary body of the eye: produces aqueous humor.

  • Choroid plexus: produces cerebrospinal fluid (CSF).

  • Red blood cells: participates in CO₂ transport.

• CAIs inhibit the enzyme →

  • ↓ Na⁺ and bicarbonate reabsorption in proximal tubule → increased urinary excretion of bicarbonate, sodium, water, and potassium.

  • ↓ aqueous humor formation → reduced intraocular pressure.

  • ↓ CSF production → lowered intracranial pressure.

  • Induce mild metabolic acidosis, which stimulates ventilation at high altitudes.

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3. Common Agents

• Acetazolamide (oral, IV) – most widely used systemic CAI.

• Methazolamide (oral) – similar to acetazolamide but more potent and longer acting.

• Dorzolamide (topical, ophthalmic).

• Brinzolamide (topical, ophthalmic).

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4. Pharmacokinetics (General Trends)

• Absorption: acetazolamide and methazolamide well absorbed orally; topical agents act locally in the eye.

• Distribution: widely distributed; cross into aqueous humor and CSF.

• Metabolism: methazolamide partially metabolized in liver; acetazolamide largely excreted unchanged.

• Elimination: primarily renal excretion.

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5. Clinical Indications

Ophthalmic

• Open-angle glaucoma (reduce intraocular pressure by lowering aqueous humor production).

• Acute angle-closure glaucoma (adjunctive to other measures).

Neurological

• Idiopathic intracranial hypertension (pseudotumor cerebri).

• Adjunct in certain epilepsies (e.g., absence seizures).

Renal/Metabolic

• Prevention/treatment of acute mountain sickness (stimulates ventilation via metabolic acidosis).

• Alkalinization of urine (enhances excretion of weak acids such as certain drugs).

Other

• Adjunct in periodic paralysis (off-label).

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6. Contraindications

• Hypersensitivity to sulfonamides (CAIs are sulfonamide derivatives).

• Severe hepatic disease (risk of hepatic encephalopathy due to alkalinized urine and ammonia retention).

• Severe renal dysfunction (reduced drug clearance and risk of acidosis).

• Hyponatremia or hypokalemia.

• Adrenal gland insufficiency.

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7. Adverse Effects

Metabolic/Electrolyte

• Metabolic acidosis.

• Hypokalemia, hyponatremia.

Renal

• Nephrolithiasis (due to increased urinary pH and calcium phosphate precipitation).

Neurological

• Paresthesia, drowsiness, confusion.

Other

• Taste alteration, GI upset.

• Rare: severe skin reactions (Stevens–Johnson syndrome).

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8. Drug Interactions

• May increase toxicity of salicylates and lithium (altered excretion).

• Enhanced hypokalemia with other potassium-wasting drugs (loop/thiazide diuretics, corticosteroids).

• Additive CNS depression with sedatives.

• May reduce efficacy of certain anticonvulsants by altering pH and renal clearance.

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9. Monitoring

• Serum electrolytes and bicarbonate during prolonged use.

• Renal and hepatic function tests.

• In glaucoma: intraocular pressure measurements.

• In intracranial hypertension: visual field testing and symptom monitoring.

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10. Advantages and Limitations

Advantages

• Useful in diverse conditions involving fluid dynamics and pressure regulation.

• Topical forms minimize systemic side effects in ocular use.

Limitations

• Systemic use limited by metabolic acidosis and electrolyte disturbances.

• Sulfonamide allergy risk limits use in sensitive patients.