Drug interactions of carbonic anhydrase inhibitors and activators

ABSTRACT

Introduction

Carbonic anhydrases (CAs, EC 4.2.1.1) have been established drug targets for decades, with their inhibitors and activators possessing relevant pharmacological activity and applications in various fields. At least 11 sulfonamides/sulfamates are clinically used as diuretics, antiglaucoma, antiepileptic, or antiobesity agents and one derivative, SLC-0111, is in clinical trials as antitumor/antimetastatic agent. The activators were less investigated with no clinically used agent.

Areas covered

Drug interactions between CA inhibitors/activators and various other agents are reviewed in publications from the period March 2020 - January 2024.

Expert opinion

Drug interactions involving these agents revealed several interesting findings. Acetazolamide plus loop diuretics is highy effective in acute decompensated heart failure, whereas ocular diseases such as X-linked retinoschisis and macular edema were treated by acetazolamide plus bevacizumab or topical NSAIDs. Potent anti-infective effects of acetazolamide and other CAIs, alone or in combination with other agents were demonstrated for the management of Neisseria gonorrhoea, vancomycin resistant enterococci, Acanthamoeba castellanii, Trichinella spiralis, and Cryptococcus neoformans infections. Topiramate, in combination with phentermine is incresingly used for the management of obesity, whereas zonisamide plus levodopa is highly effective for Parkinson’s disease. Acetazolamide, methazolamide, ethoxzolamide, and SLC-0111 showed synergistic antitumor/antimetastatic action in combination with many other antitumor drugs.

KEYWORDS:

• Carbonic anhydrase
• inhibitor
• activator
• acetazolamide
• methazolamide
• dorzolamide
• SLC-0111
• memory therapy

Article highlights

• sulfonamide/sulfamate CA inhibitors (CAIs) have been in clinical use for decades for the management of a variety of disorders whereas the CA activators did not yet reach the clinics

• the use of CAIs as diuretic, antiglaucoma, antiepileptic, antiobesity and antitumor agents is associated with a number of drug-drug interactions with other pharmacological agents

• acetazolamide in combination with loop diuretics was recently shown to be highly effective in patients with acute decompensated heart failure

• acetazolamide and topically acting drugs (dorzolamide, brinzolamide) showed effectiveness for the management of X-linked retinoschisis and macular edema, in combination with bevacizumab or topical NSAID

• the antiinfective action of acetazolamide and other CAIs as antibacterial, antifungal or antiprotozoan/antihelminthic drugs in combination with other agents was demonstrated recently

• topiramate plus phentermine is increasingly used for the management of obesity and for the prevention and treatment of migraine, in addition to its primary action as an antiepileptic

• zonisamide plus levodopa was reported to be highly effective in the management of Parkinson’s disease

• SLC-0111 in combination with other antitumor drugs showed potent anticancer/antimetastatic activity

• CA activators such as D-Phe were shown to have procognitive efects in animal models, enhancing memory and positively modulating emotional, social and extinction memory

Declaration of interest

The author declares conflict of interest being one of the discoverers of SLC-0111. Otherwise, the author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.