Acetazolamide: Old drug, new evidence?

Abstract

Acetazolamide is an old drug used as an antiepileptic agent, amongst other indications. The drug is seldom used, primarily due to perceived poor efficacy and adverse events. Acetazolamide acts as a noncompetitive inhibitor of carbonic anhydrase, of which there are several subtypes in humans. Acetazolamide causes an acidification of the intracellular and extracellular environments activating acid‐sensing ion channels, and these may account for the anti‐seizure effects of acetazolamide. Other potential mechanisms are modulation of neuroinflammation and attenuation of high‐frequency oscillations. The overall effect increases the seizure threshold in critical structures such as the hippocampus. The evidence for its clinical efficacy was from 12 observational studies of 941 patients. The 50% responder rate was 49%, 20% of patients were rendered seizure‐free, and 30% were noted to have had at least one adverse event. We conclude that the evidence from several observational studies may overestimate efficacy because they lack a comparator; hence, this drug would need further randomized placebo‐controlled trials to assess effectiveness and harm.

A concise study of acetazolamide in glucose transporter type 1 deficiency (G1D) epilepsy

“…Despite the great heterogeneity of reports spanning about 70 years, 48% of persons (or a combined total of 368 of 767 individuals) with numerous types of epilepsy treated with ACZ (generally as a first drug) exhibit a >50% reduction in seizure frequency, with individual studies suggesting that 23% to 79% of epileptic persons may be such responders. Twenty percent (122 of 607) of treated epileptic individuals were seizure‐free, with individual publications estimating that 6% to 63% of persons may remain seizure‐free 3 . In contrast, our individuals with G1D were medication refractory, with a mean number of previously used ineffective or minimally effective ASMs of 5.1 (Table 2).…”

“…Three kinds of observation substantiate this opportunity and provide the motivation for our investigation of acetazolamide (ACZ) as a potential treatment of G1D epilepsy. First, a wide variety of epilepsies can benefit from treatment with ACZ, 3 including those associated with ictal electrographic spike‐waves 4 . Because G1D epilepsy commonly exhibits similar spike‐waves 2 and since this form of epilepsy was treated with ACZ before the discovery of G1D, it is possible that some of these individuals with epilepsy harbored unrecognized G1D.…”

Fundamental Neurochemistry Review: GABAA receptor neurotransmission and epilepsy: Principles, disease mechanisms and pharmacotherapy

“…Topiramate, zonisamide and acetazolamide possess carbonic anhydrase activity and may in part exert their antiseizure effects by lowering intracellular HCO 3 − , however, intra and extracellular acidification also modulate other pathways, including acid-sensing ion channels (Auer et al, 2020;Shukralla et al, 2022).…”

“…An alternative strategy is to target the HCO 3 − transmembrane gradient which, as a result of a relatively depolarised HCO 3 − equilibrium potential of approximately ‐10mV plays an important role in regulating E GABA . Topiramate, zonisamide and acetazolamide possess carbonic anhydrase activity and may in part exert their antiseizure effects by lowering intracellular HCO 3 − , however, intra and extracellular acidification also modulate other pathways, including acid‐sensing ion channels (Auer et al, 2020; Shukralla et al, 2022).…”

Small Structural Differences Govern the Carbonic Anhydrase II Inhibition Activity of Cytotoxic Triterpene Acetazolamide Conjugates

“…The ubiquitous metalloenzymes carbonic anhydrases (CAs) [ 1 , 2 , 3 , 4 , 5 , 6 ] are present in bacteria [ 7 , 8 ] and fungi [ 9 , 10 , 11 , 12 ], plants and animals. Inhibitors of these enzymes have been clinically exploited for decades, and the discovery of multiple human isoforms [ 13 , 14 , 15 , 16 , 17 , 18 ] has led to many new applications and the development of new therapeutic principles, among them antiglaucoma [ 19 , 20 , 21 ] and antitumor drugs but also antiepileptic [ 22 , 23 , 24 , 25 , 26 ] and antiobesity drugs [ 27 , 28 , 29 ] as well as agents for the management of Alzheimer’s disease [ 30 , 31 ], neuropathic pain, cerebral ischemia, and some forms of arthritis [ 32 , 33 , 34 ]. Furthermore, the development of inhibitors for bacterial carbonic anhydrases is thought as a new concept to develop antibacterial drugs [ 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ].…”