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]
Contents
1Medical uses
1.1Glaucoma
1.2Diuretic
1.3Epilepsy
1.4Altitude sickness
2Contraindications
3Adverse effects
4Natural sources
5References
6External links
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.[citation needed]
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.[citation needed]
Diuretic
Some diuretics[9] inhibit the activity of carbonic anhydrase in proximal convoluted tubules and prevent reabsorption of bicarbonates from renal tubules, resulting in osmotic diuresis. Acetazolamide is a carbonic anhydrase inhibitor. Other examples are;
Dorzolamide
Methazolamide
Brinzolamide
dichlorphenamide
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.
Altitude sickness
Main article: 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
Hepatic cirrhosis[14]
Adverse effects
Loss of bicarbonate may result in metabolic acidosis.[15]
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.[16]
References
^Supuran CT, Scozzafava A, Conway J, eds. (2004). Carbonic anhydrase: its inhibitors and activators. Boca Raton: CRC Press. ISBN 978-0-415-30673-7.[page needed]
^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.
^Reynolds JEF (Ed): Martle: The Extra Pharmacopoeia (electronic version). Micromedex, Inc. Englewood, CO. 1995.[page needed]
^"Diuretics Pharmacology : Classification Of Diuretics & Medicinal Uses - PDF Download". my-pharma-notes.blogspot.com. 6 January 2018.
^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.
^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. PMID 26801895.
^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.
^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.
^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.
^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.
^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)
Biophysical chemistry.Biophys Chem.2015 Oct;205:51-65. doi: 10.1016/j.bpc.2015.05.009. Epub 2015 Jun 6.
Para substituted tetrafluorobenzenesulfonamides bind to carbonic anhydrases (CAs) extremely tightly and exhibit some of the strongest known protein-small ligand interactions, reaching an intrinsic affinity of 2 pM as determined by displacement isothermal titration calorimetry (ITC). The enthalpy and
The Antarctic bacterium Pseudoalteromonas haloplanktis encodes for a γ-class carbonic anhydrase (CA, EC 4.2.1.1), which was cloned, purified and characterized. The enzyme (PhaCAγ) has a good catalytic activity for the physiologic reaction of CO2 hydration to bicarbonate and protons, with a kcat of
