Carbonic anhydrase inhibitor

Carbonic anhydrase inhibitors are a class of pharmaceuticals that suppress the activity of carbonic anhydrase. Their clinical use has been established as antiglaucoma agents, diuretics, antiepileptics, in the management of mountain sickness, gastric and duodenal ulcers, neurological disorders, or osteoporosis.^[1][2][3]

Medical Uses

Carbonic anhydrase inhibitors are primarily used for the treatment of glaucoma. They may also be used to treat seizure disorder and acute mountain sickness. Because they encourage solubilization and excretion of uric acid, they can be used in the treatment of gout.^[4]

Glaucoma

Acetazolamide is an inhibitor of carbonic anhydrase. It is used for glaucoma, epilepsy (rarely), idiopathic intracranial hypertension, and altitude sickness.

Methazolamide is also a carbonic anhydrase inhibitor. It has a longer elimination half-life than acetazolamide and is less associated with adverse effects to the kidney.^[5][6][7]

Dorzolamide is a sulfonamide and topical carbonic anhydrase II inhibitor. It is indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension and who are insufficiently responsive to beta-blockers. Inhibition of carbonic anhydrase II in the ciliary processes of the eye decreases aqueous humor secretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport.

Brinzolamide (trade names Azopt, Alcon Laboratories, Inc, Befardin Fardi Medicals) is a carbonic anhydrase inhibitor used to lower intraocular pressure in patients with open-angle glaucoma or ocular hypertension. It exists as a number of isoenzymes, the most active of which is carbonic anhydrase II (CA-II). The combination of brinzolamide with timolol is marketed under the trade name Azarga.

Diuretic

Acetazolamide can act as a mild diuretic by reducing NaCl and bicarbonate reabsorption in the proximal tubule. However, the distal segment partially compensates for the sodium loss, and the bicarbonaturia will produce a metabolic acidosis, further reducing the effect.

Epilepsy

Topiramate is a weak inhibitor of carbonic anhydrase, particularly subtypes II and IV. It is a sulfamate-substituted monosaccharide, related to fructose. In the US, it is approved by the U.S. Food and Drug Administration (FDA) as an anticonvulsant to treat epilepsy and Lennox-Gastaut syndrome, and also to prevent migraine headaches. In rare cases, the inhibition of carbonic anhydrase may be strong enough to cause metabolic acidosis of clinical importance.

Altitude Sickness

At high altitude, the partial pressure of oxygen is lower and people have to breathe more rapidly to get adequate oxygen. When this happens, the partial pressure of CO2 in the lungs (pCO2) decreases (is "blown off"), causing a respiratory alkalosis. This would normally be compensated by the kidney excreting bicarbonate and causing compensatory metabolic acidosis, but this mechanism takes several days. A more immediate treatment is carbonic anhydrase inhibitors, which prevent bicarbonate uptake in the kidney and help correct the alkalosis.^[8] Carbonic anhydrase inhibitors have also been shown to improve chronic mountain sickness by increasing erythropoietin and the resulting polycytemia.^[9]

Contraindications

• Hepatic cirrhosis^[10]

Adverse effects

Loss of bicarbonate may result in metabolic acidosis.^[11] Alkaline urine may increase the likelihood of kidney stones.

Natural sources

Ellagitannins extracted from the pericarps of Punica granatum, the pomegranate, such as punicalin, punicalagin, granatin B, gallagyldilactone, casuarinin, pedunculagin and tellimagrandin I, are carbonic anhydrase inhibitors.^[12]

References

1. Supuran CT, Scozzafava A, Conway J, ed. (2004). Carbonic anhydrase: its inhibitors and activators. Boca Raton: CRC Press. ISBN 978-0-415-30673-7.
2. Supuran, Claudiu T; Scozzafava, Andrea (2000). "Carbonic anhydrase inhibitors and their therapeutic potential". Expert Opinion on Therapeutic Patents 10 (5): 575–600. doi:10.1517/13543776.10.5.575.
3. Supuran, Claudiu T.; Scozzafava, Andrea; Casini, Angela (2003). "Carbonic anhydrase inhibitors". Medicinal Research Reviews 23 (2): 146–89. doi:10.1002/med.10025. PMID 12500287.
4. Hyperuricemia Medication~medication at eMedicine
5. Bennett WM, Aronoff GR, Golper TA, et al, Drug Prescribing in Renal Failure, American College of Physicians, Philadelphia, PA, 1987
6. Product Information: Neptazane(R), methazolamide. Storz Ophthalmics Inc, Clearwater, FL, 1995a
7. Reynolds JEF (Ed): Martle: The Extra Pharmacopoeia (electronic version). Micromedex, Inc. Englewood, CO. 1995.
8. Swenson, Erik R. (2014). "Carbonic Anhydrase Inhibitors and High Altitude Illnesses". In Frost, Susan C.; McKenna, Robert. Carbonic Anhydrase: Mechanism, Regulation, Links to Disease, and Industrial Applications. Subcellular Biochemistry 75. pp. 361–86. doi:10.1007/978-94-007-7359-2_18. ISBN 978-94-007-7358-5. PMID 24146388.
9. Richalet, Jean-Paul; Rivera, Maria; Bouchet, Patrick; Chirinos, Eduardo; Onnen, Igor; Petitjean, Olivier; Bienvenu, Annick; Lasne, Francçoise; Moutereau, Stéphane; León-Velarde, Fabiola (2005). "Acetazolamide". American Journal of Respiratory and Critical Care Medicine 172 (11): 1427–33. doi:10.1164/rccm.200505-807OC. PMID 16126936.
10. Webster, L. T.; Davidson, C. S. (1956). "Production of Impending Hepatic Coma by a Carbonic Anhydrase Inhibitor, Diamox". Experimental Biology and Medicine 91 (1): 27–31. doi:10.3181/00379727-91-22159. PMID 13297699.
11. Leaf, Alexander; Schwartz, William B.; Relman, Arnold S. (1954). "Oral Administration of a Potent Carbonic Anhydrase Inhibitor (Diamox)". New England Journal of Medicine 250 (18): 759–64. doi:10.1056/NEJM195405062501803. PMID 13165895.
12. Satomi, H; Umemura, K; Ueno, A; Hatano, T; Okuda, T; Noro, T (1993). "Carbonic anhydrase inhibitors from the pericarps of Punica granatum L". Biological & Pharmaceutical Bulletin 16 (8): 787–90. doi:10.1248/bpb.16.787. PMID 8220326.

External links

• Carbonic anhydrase inhibitors at the US National Library of Medicine Medical Subject Headings (MeSH)
• MedlinePlus DrugInfo uspdi-202114