Drug interaction considerations in the therapeutic use of carbonic anhydrase inhibitors

ABSTRACT

Introduction: Carbonic anhydrase inhibitors (CAIs) of the sulfonamide and sulfamate type are clinically used drugs as diuretics, antiglaucoma, antiepileptic, antiobesity and anti-high altitude disease agents. Anticancer agents based on CAIs are also in clinical development for the management of hypoxic, metastatic tumors. Acetazolamide, methazolamide, dichlorophenamide, dorzolamide and brinzolamide are mainly used as antiglaucoma drugs, sulthiame, topiramate and zonisamide as antiepileptic/antiobesity agents, celecoxib and polmacoxib are dual carbonic anhydrase/cycloxygenase inhibitors. Girentuximab, a monoclonal antibody and SLC-0111, a sulfonamide inhibitor, are in clinical trials as anticancer agents.

Areas covered: The drug interactions with many classes of pharmacological agents are reviewed. Some of these drugs, such as acetazolamide, topiramate and celecoxib show a large number of interactions with non-steroidal anti-inflammatory drugs (NSAIDs), diuretics, antiepileptics, immunosupressants, anticholinesterase drugs, β-blockers, anesthetics, oral contraceptives, anticancer agents, antifungals, anti-mycobacterials, lithium, metformin and clopidogrel.

Expert opinion: The multiple drug interactions in which CAIs are involved should be carefully considered when such drugs are used in combination with the drug classes mentioned above, as the risks of developing toxicity and serious side effects if the dosages are not adjusted are high. There are also synergistic effects between CAIs and some NSAIDs, anticancer agents and benzodiazepines for the management of cystoid macular edema, some tumor types and neuropathic pain, respectively.

KEYWORDS:

• acetazolamide
• brinzolamide
• carbonic anhydrase
• celecoxib
• dorzolamide
• inhibitor
• methazolamide
• sultiame
• topiramate
• zonisamide

Article highlights

• Carbonic anhydrase (CA) catalyzes the reversible hydration of CO₂ to bicarbonate and protons.

• CA inhibitors (CAIs) of the sulfonamide and sulfamate types are clinically used drugs as diuretics, antiglaucoma, antiepileptic, antiobesity, and anti-high altitude disease agents.

• Anticancer agents based on CAIs are in clinical development for the management of hypoxic, metastatic solid tumors.

• Acetazolamide, methazolamide, dichlorophenamide, dorzolamide, brinzolamide sulthiame, topiramate, zonisamide, and celecoxib are clinically used drugs, whereas polmacoxib, girentuximab, and SLC-0111, are in Phase I–II clinical development.

• A large number of drug interactions of the CAIs were reported with nonsteroidal anti-inflammatory drugs (NSAIDs), diuretics, antiepileptics, immunosupressants, anticholinesterase drugs, β-blockers, anesthetics, oral contraceptives, anticancer agents, antifungals, antimycobacterials, lithium, metformin, and clopidogrel.

• The risks of developing toxicity and serious side effects should be considered when CAIs are used in combination with these drugs.

• There are also synergistic effects between CAIs and some NSAIDs, anticancer agents and benzodiazepines, which represent opportunities for the management of cystoid macular edema, some tumor types, cerebral ischemia, and neuropathic pain.

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Declaration of Interest

Research from the author’s laboratory was financed in part by several grants of the 6th and 7th Framework Programme of the European Union (Euroxy, DeZnIT, Metoxia, Gums and Joints, and Dynano projects). The author has no other 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 apart from those disclosed.