Carbonic anhydrase inhibitor
Drug class
Acetazolamide
Class identifiers
UseGlaucoma
ATC codeS01EC
Biological targetCarbonic anhydrase
Clinical data
Drugs.comDrug Classes
External links
MeSHD002257
Legal status
In Wikidata

Carbonic anhydrase inhibitors are a class of pharmaceuticals that suppress the activity of carbonic anhydrase. Their clinical use has been established as anti-glaucoma agents, diuretics, antiepileptics, in the management of mountain sickness, gastric and duodenal ulcers, idiopathic intracranial hypertension, 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.

For the reduction of intraocular pressure (IOP), acetazolamide inactivates carbonic anhydrase and interferes with the sodium pump, which decreases aqueous humor formation and thus lowers IOP. Systemic effects include increased loss of sodium, potassium, and water in the urine, secondary to the drug's effects on the renal tubules, where valuable components of filtered blood are re-absorbed in the kidney. Arterial blood gases may show a mild hyperchloremic metabolic acidosis.[5]

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.[6][7][8]

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 name Azopt) 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

Some diuretics[9] inhibit the activity of carbonic anhydrase in proximal convoluted tubules and prevent reabsorption of bicarbonates from renal tubules. Lowered reabsorption of bicarbonates results in decreased activity of the apical sodium hydrogen exchanger, causing diuresis due to retention of sodium in the renal tubules. Acetazolamide is a carbonic anhydrase inhibitor. Other examples are:

  • Dorzolamide
  • Methazolamide
  • Brinzolamide
  • Dichlorphenamide

CSF regulation

Carbonic anhydrase inhibitors may be used to reduce the production of cerebrospinal fluid (CSF) in the brain. For instance, a cerebrospinal fluid leak may initially be treated medically with this medication to reduce the volume of leakage, and promote healing of the fistula. Similarly, in Idiopathic intracranial hypertension, reduction of CSF production by the choroid plexi may reduce intracranial pressures and reduce symptoms of elevated intracranial pressure such as retroorbital headaches and loss of vision. The mechanism is thought to involve inhibition of carbonic anhydrase (CA) within the choroidal epithelial cells, reducing the production of protons which are necessary for the osmotic transport of water and ions which constitute CSF.

Epilepsy

Acetazolamide is effective in the treatment of most types of seizures, including generalized tonic-clonic and focal seizures and especially absence seizures, although it has limited utility because tolerance develops with chronic use. The drug is occasionally used on an intermittent basis to prevent seizures in catamenial epilepsy.[10]

The sulfur-containing antiseizure and antimigraine drug topiramate is a weak inhibitor of carbonic anhydrase, particularly subtypes II and IV.[11] Whether carbonic anhydrase inhibition contributes to its clinical activity is not known. In rare cases, the inhibition of carbonic anhydrase may be strong enough to cause metabolic acidosis of clinical importance. Zonisamide is another sulfur containing antiseizure drug that weakly inhibits carbonic anhydrase.

Sultiame is also an example of an anticonvulsant drug of this class.

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.[12] Carbonic anhydrase inhibitors have also been shown to improve chronic mountain sickness.[13]

Contraindications

Adverse effects

Loss of bicarbonate may result in metabolic acidosis.[15]

In plants

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.[16]

References

  1. ↑ Supuran CT, Scozzafava A, Conway J, eds. (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. S2CID 86519198.
  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. ↑ "Acetazolamide: mechanism of action". www.openanesthesia.org. Retrieved 2017-05-10.
  6. ↑ Bennett WM, Aronoff GR, Golper TA, et al, Drug Prescribing in Renal Failure, American College of Physicians, Philadelphia, PA, 1987
  7. ↑ Product Information: Neptazane(R), methazolamide. Storz Ophthalmics Inc, Clearwater, FL, 1995a
  8. ↑ Reynolds JEF (Ed): Martle: The Extra Pharmacopoeia (electronic version). Micromedex, Inc. Englewood, CO. 1995.
  9. ↑ "Diuretics Pharmacology : Classification Of Diuretics & Medicinal Uses - PDF Download". my-pharma-notes.blogspot.com. 6 January 2018.
  10. ↑ Rogawski MA, Porter RJ (1990). "Antiepileptic drugs: pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds". Pharmacol. Rev. 42 (3): 223–86. PMID 2217531. Archived from the original on 2016-11-24. Retrieved 2016-11-24.
  11. ↑ Rogawski MA, Löscher W, Rho JM (2016). "Mechanisms of action of antiseizure drugs and the ketogenic diet". Cold Spring Harb Perspect Med. 6 (5): 223–86. doi:10.1101/cshperspect.a022780. PMC 4852797. PMID 26801895.
  12. ↑ Swenson, Erik R. (2014). "Carbonic Anhydrase Inhibitors and High Altitude Illnesses". In Frost, Susan C.; McKenna, Robert (eds.). Carbonic Anhydrase: Mechanism, Regulation, Links to Disease, and Industrial Applications. Subcellular Biochemistry. Vol. 75. pp. 361–86. doi:10.1007/978-94-007-7359-2_18. ISBN 978-94-007-7358-5. PMID 24146388.
  13. ↑ 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.
  14. ↑ 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. S2CID 40178475.
  15. ↑ 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.
  16. ↑ 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.
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