Acetazolamide for the treatment of idiopathic intracranial hypertension

Abstract

Idiopathic intracranial hypertension (IIH) is characterized by an increase of intracranial pressure in the absence of neurologic tumors. The sulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitor (CAI) acetazolamide (AAZ), a compound developed in the 1950s as a diuretic drug and presently used as an antiglaucoma, antiepileptic and diuretic agent, is effective in the treatment of IIH. AAZ is a low nanomolar inhibitor of CA isoforms involved in cerebrospinal fluid (CSF) secretion. Inhibition of brain/choroid plexus CA II, IV, VA and XII leads to a decreased CSF fluid secretion and control of the intracranial pressure. Although many sulfonamide/sulfamate CAIs are in clinical use for decades, apparently only AAZ is being currently used clinically for IIH. We speculate that more lipophilic CAIs such as methazolamide, zonisamide or topiramate should lead to a more effective control of increased intracranial pressure, thus having the opportunity to become useful in the management of IIH.

Keywords:

• acetazolamide
• carbonic anhydrase
• choroid plexus
• idiopathic intracranial hypertension
• methazolamide
• topiramate

Information resources

The following books deal extensively with carbonic anhydrase and its inhibitors, dealing also with the various clinical applications of acetazolamide

The Carbonic Anhydrases as Biocatalysts, Supuran, C.T.; De Simone, G.; Eds., Elsevier, Amsterdam, 2015, pp. 1 – 381

Targeting Carbonic Anhydrases, Supuran, C.T.; Capasso, C. Eds., Future Science Ltd., London, 2014, pp. 1 – 169.

Carbonic Anhydrase: Mechanism, regulation, Links to Disease, and Industrial Applications, McKenna, R.; Frost, S. Eds., Springer Verlag, Heidelberg, 2014, pp. 1–430.

Drug Design of Zinc-Enzyme Inhibitors: Functional, Structural, and Disease Applications, Supuran, C.T.; Winum, J.Y. Eds., Wiley, Hoboken, 2009, pp. 1 – 1022.

Carbonic anhydrase – Its Inhibitors and Activators, C.T. Supuran, A. Scozzafava, J. Conway Eds., CRC Press, Boca Raton (FL), 2004, pp. 1–364.

Acknowledgements

Research from the author’s laboratory was financed in part by several grants of the 6th and 7th Framework Programme of the European Union (DeZnIT, Metoxia, Gums and Joints, and Dynano projects).

Financial & competing interests disclosure

CT Supuran has received research grants from EU in the FP6 and FP7 projects (Euroxy, DeZnIT, Methoxia and Dynano.) 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.

Key issues

• IIH is a neurologic syndrome of unknown etiology characterized by increased ICP.

• Apart from surgery, only acetazolamide (AAZ) was used as a pharmacologic treatment of the syndrome.

• AAZ is a potent sulfonamide CA inhibitor, with low nanomolar potency against isoforms CA II and XII present in the brain and choroid plexus.

• Choroid plexus CAs are involved in the secretion of CSF and reduction of the secretion leads to diminished ICP.

• Other sulfonamide/sulfamate clinically used drugs, such as methazolamide, topiramate and zonisamide, show appropriate inhibitory action on CA isoforms involved in CSF formation.

• Further clinical trials for IIH treatment may include the use of methazolamide, topiramate and zonisamide as alternatives to AAZ.

• The clinical safety of AAZ is remarkable, although the drug shows a series of nonlethal side effects.

Notes