Carbonic anhydrase inhibitors for vertigo and related disorders.

Timothy C. Hain, MD

Last update: August 22, 2021 •Please read our disclaimer.

General information

Carbonic anhydrase inhibitors reduce the action of an enzyme called carbonic anhydrase (CA). This results in a diuretic effect, and can stabilize neurons involved in epilepsy and migraine. Carbonic anhydrase inhibitors "have long been studied as various classes of systemic anticonvulsants, anti-obesity, anti-pain, anti-tumor and topically acting anti-glaucoma agents, and agents for treating altitude sickness. " (Aggaral et al, 2012). As eye drops, they are used for treatment of glaucoma.

Carbonic anhydrase has 16 isoenzymes in humans (Suparin, 2010), and presumably some of the differences in effects between drugs may relate to differential effects on these forms of the enzyme.

The two common disorders where carbonic anhydrase inhibitors are used are migraine and meniere's disease -- two closely related "committee" diagnoses. In other words, these two disorders overlap heavily, are diagnosed using entirely subjective criteria, and could even be two faces of the same illness.

The main uncommon indication for carbonic anhydrase disorders are cerebellar degenerations, such as episodic ataxia. It has also been reported helpful in SCA and another very rare cerebellar disorder, PMM2-CDG.

Examples of Carbonic anhydrase inhitors (oral)

Examples of carbonic anhydrase inhibitors
Drug Strength Serum T 1/2
acetazolamide Strong 1.5 hours
methazolamide Strong 5 -10 hours
topiramate 10 to 100 times weaker than acetazolamide. (Dodgson et al, 2000) 21 hours.
zonisamide weak 63 hours

(Some abstracted from Table 9 of Maren TH, 1967).

According to Suparin (2010), there are approximately 30 clinically used drugs or drugs in clinical development which show significant CA inhibitor activity.

Triamterine is not a carbonic anhydrase inhibitor but rather is a sodium channel blocker, similar to amiloride. The combination of traimeterine and hydrochlorothazide is used to prevent hypokalemia because triamterine increases potassium.

Note that these drugs bind differentially to different tissues, and may persist for much longer even after the drug has disappeared from plasma and tissues. Thus for example, acetazolamide persists much longer in the renal cortex and choroid plexus (for days) compared to plasma where it is almost completely gone in 1 day. Methazolamide penetrates into spinal fluid better than acetazolamide, resulting on ratios of about 0.15 for methazolamide compared to 0.01 for acetazolamide. (Maren TH, 1967). Thus one would expect that methazolamide would result in more effect on the brain or inner ear, for a given amount of effect on the kidneys, than acetazolamide.

Many thiazide diuretics have some activity against carbonic anhydrase, but relatively little.

In the cat, accoding to Erulkar and Maren, all segments of the cat cochlea and endolymphatic sac have extremely high concentrations of carbonic anhydrase. Acetazolamide greatly reduced the very high K+ concentration in the endolymph. (Erulkar and Maren). Furuta et al also found that carbonic anhydrase localized to the endolymphatic sac of animals using immunochemistry. Yamashita reported carbonic anhydrase in the human fetal limbus spiralis and spiral ligament. Watanabe and Ogawa found carbonic anhydrase in the stria vascularis and dark cells of the vestibular labyrinth.

Carbonic anhydrase is also important to otolith calcification during fetal development and may regulate otoconial maintenance in fish.

Dichloirphenamide is a similar drug to acetazolamide, used mainly for inherited muscle disorders.

Side effects

Direct effects of carbonic anhydrase inhibition in the kidneys include hyperchloremic metabolic acidosis and an increase in calcium excretion. Aside from the effects on electrolytes, the main serious side effect of these drugs is kidney stones. Some of them are also associated with birth defects (e.g. topiramate). There generally is a lack of toxicity with very high doses of carbonic anhydrase inhibitors (such as acetazolamide) because the enzyme itself is not essential to life, and also because after a critical level is reached, carbonic anhydrase inhibition is essentially complete.