Carbonic Anhydrase Inhibitors

Systemic carbonic anhydrase inhibitors (CAIs) such as acetazolamide and methazolamide are approved for the treatment of glaucoma and idiopathic intracranial hypertension (IIH, also known as pseudotumor cerebri), in addition to other systemic conditions. They may also be effective in treating cystoid macular edema (CME). See Table 16-10.

Systemic CAIs are administered orally and/or parenterally. The longer half-life of methazolamide allows it to be used twice daily; acetazolamide is also available in a 500-mg sustained-release form used twice daily. Neither of these compounds has the ideal combination of high potency (low binding affinity, Ki), good ocular penetration (high penetration percentage in the nonionized form and high lipid solubility to facilitate passage through the blood–ocular barrier), high proportion of the drug present in the blood in unbound form, and long plasma half-life. The mechanism of action of this class of medications is via inhibition of carbonic anhydrase.

The amount of carbonic anhydrase present in tissues is much higher than that needed to supply the amount of bicarbonate () required. Calculations based on the Kcat (catalysis constant) and Km (apparent affinity constant) of the enzyme and on the concentrations of substrates and product indicate that the amount of enzyme present in the ciliary body is 100 times greater than needed. Correspondingly, in clinical use, the enzyme must be more than 99% inhibited to significantly reduce aqueous flow. In contrast, the amount of enzyme in the kidney, which is 1000-fold greater than needed, must be more than 99.9% inhibited to affect the usual pathway for reabsorption.

Table 16-10 Carbonic Anhydrase Inhibitors

In addition to lowering IOP by inhibiting ciliary body carbonic anhydrase, each drug at high doses further lowers IOP by causing renal metabolic acidosis. The mechanism by which acidosis lowers secretion is uncertain, but it probably involves reduction in formation and activity of Na⁺,K⁺-ATPase.

At the onset of acidosis, renal effects cause alkaline diuresis, with loss of Na⁺, K⁺, and . In patients receiving CAI therapy concurrently with diuretics, steroids, or adrenocorticotropic hormone (ACTH), severe hypokalemia can result. This situation may be dangerous for patients using digitalis, in whom hypokalemia may elicit arrhythmias. When such patients are receiving long-term CAI therapy, they should have their potassium levels checked at regular intervals, preferably by their primary care physician.

Over time, the acidosis prompts a renal mechanism for reabsorption unrelated to carbonic anhydrase; this mechanism limits the degree of acidosis and halts both the diuresis and K⁺ loss after the first few days of treatment.

In certain systemic conditions, CAI therapy may cause or contribute to additional adverse effects. Alkalinization of the urine, present during initial CAI treatment, prevents excretion of ammonium (NH4⁺), a factor to consider in patients with cirrhosis of the liver. Metabolic acidosis may exacerbate diabetic ketoacidosis or precipitate sickle cell crisis. In patients with severe chronic obstructive pulmonary disease, respiratory acidosis may be caused by impairment of CO2 transfer from the pulmonary vasculature to the alveoli. Elderly patients have physiologically reduced renal function, which predisposes them to severe metabolic acidosis with the use of systemic CAIs.

The use of acetazolamide has been linked to the formation of stones in the urinary tract. A retrospective case-control series showed that the incidence of stones was 11 times higher in patients using this drug than in those not using it. The increased risk occurred primarily during the first year of therapy. Continued use after occurrence of a stone was associated with a high risk of recurrent stone formation. However, a history of spontaneous stone formation more than 5 years prior to acetazolamide therapy did not appear to increase risk. The mechanisms responsible for stone formation may be related to metabolic acidosis and associated pH changes, as well as to decreased excretion of citrate.

Nearly 50% of patients are intolerant of systemic CAIs because of CNS and gastrointestinal adverse effects. They include numbness and tingling of the hands, feet, and lips; malaise; metallic taste when drinking carbonated beverages; anorexia and weight loss; nausea; somnolence; impotence and loss of libido; and depression. When the clinical situation allows, it is wise to begin therapy at low dosages (eg, 125 mg of acetazolamide 4 times daily or 25–50 mg methazolamide twice daily) to reduce the incidence and severity of adverse effects. Patients should be informed of the potential adverse effects of these drugs; otherwise, they may fail to associate their systemic symptoms with the medication prescribed by their ophthalmologists.

Rare adverse effects from this class of drugs include those common to other members of the sulfonamide family, such as transient myopia, hypersensitive nephropathy, skin rash, Stevens-Johnson syndrome, and thrombocytopenia. One potential adverse effect, aplastic anemia, is idiosyncratic. Blood cell counts do not identify susceptible patients. CAIs have also been associated with teratogenic effects (forelimb deformity) in rodents, and their use is not advised during pregnancy. However, these systemic adverse effects are rare with topical CAIs (see the section “Sulfonamides” later in the chapter for discussion of allergies to sulfonamides).

The topical CAIs—dorzolamide and brinzolamide—are also available for long-term treatment of glaucoma. They penetrate the cornea easily and are water soluble. When administered as solution 3 times per day, these drugs effectively inhibit carbonic anhydrase II while avoiding the systemic adverse effects of oral administration. The 2 medications are equally effective and reduce IOP by 14%–17%. Adverse effects of topical CAIs include burning on instillation, punctate keratitis, local allergy, and bitter taste. The hypotensive effects of topical and oral CAIs are probably not additive when adequate doses of each are used.

Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.