Mechanism of Action of Acetazolamide in Treating Ocular Hypertension
Acetazolamide reduces intraocular pressure (IOP) by inhibiting carbonic anhydrase, which decreases aqueous humor production in the eye.
Primary Mechanism
Acetazolamide acts as a potent carbonic anhydrase inhibitor with a specific mechanism in the eye:
- Enzyme inhibition: Acetazolamide specifically inhibits carbonic anhydrase, the enzyme that catalyzes the reversible reaction involving the hydration of carbon dioxide and dehydration of carbonic acid 1, 2
- Decreased aqueous humor secretion: This inhibitory action reduces the secretion of aqueous humor from the ciliary body 1, 2
- IOP reduction: The decreased aqueous humor production results in lower intraocular pressure 1, 2
Pharmacodynamics
The relationship between acetazolamide dosing and IOP reduction has been well-characterized:
- A 45% reduction in outflow pressure is achieved with acetazolamide serum concentrations of 15-20 μg/mL 3
- Even at lower doses (63 mg), acetazolamide can produce significant IOP reduction (average fall of 8.2 mm Hg) 4
- Maximum plasma levels typically occur at one hour after administration, with minimum IOP occurring at two hours 4
- The IOP-lowering effect is dose-dependent up to certain plasma levels (4-5 μg/mL), with limited additional benefit at higher concentrations 4
Clinical Application in Glaucoma Management
In the management of ocular hypertension and glaucoma:
- Acetazolamide is classified as an oral carbonic anhydrase inhibitor in glaucoma treatment guidelines 5
- It can reduce IOP by 20-30% from baseline levels 5
- Acetazolamide is typically used when topical medications are insufficient or as an adjunct therapy 5
Dosing Considerations
The dosing of acetazolamide for ocular hypertension is important:
- Standard dosing is typically 250 mg 2-4 times daily or 500 mg sustained-release capsules once or twice daily 3
- Sustained-release formulations (500 mg once daily) offer pressure-lowering effects lasting at least 23 hours, though with less magnitude than higher dosages 3
- One 500 mg sustained-release capsule twice daily appears to be as effective as 250 mg tablets four times daily 3
Combination Therapy
Acetazolamide can be used effectively in combination with other glaucoma medications:
- When combined with topical prostaglandin analogs like latanoprost, acetazolamide demonstrates an additive ocular hypotensive effect 6
- In one study, adding latanoprost to patients already on acetazolamide resulted in an additional 15% reduction in IOP (2.9 mmHg) 6
Side Effects and Precautions
Important considerations when using acetazolamide include:
- Common adverse effects: paresthesia, fatigue, nausea, dysgeusia (metallic taste), diarrhea, and depression 5
- More serious but rare side effects: kidney stones, blood dyscrasias (aplastic anemia, thrombocytopenia), Stevens-Johnson syndrome, and electrolyte imbalances 5
- Contraindications: sulfonamide allergy, kidney stones, aplastic anemia, and sickle cell disease 5
Clinical Pearls
- Acetazolamide is not typically used as first-line therapy for ocular hypertension; prostaglandin analogs are generally preferred due to better efficacy and tolerability 5
- In the Ocular Hypertension Treatment Study (OHTS), a reasonable target for IOP reduction in glaucoma suspects is 20% from baseline 5
- Interestingly, acetazolamide does not appear to reduce IOP in eyes without glaucoma, suggesting that normal systems can compensate for the medication's effects 7
By understanding acetazolamide's mechanism of action and appropriate clinical application, ophthalmologists can effectively incorporate this medication into treatment regimens for patients with ocular hypertension.