Acetazolamide

Not to be confused with acetohexamide or methazolamide.
Acetazolamide
Skeletal formula of acetazolamide
Ball-and-stick model of the acetazolamide molecule
Systematic (IUPAC) name
N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide
Clinical data
Trade names Diamox
AHFS/Drugs.com monograph
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Legal status
Routes of
administration		 oral or intravenous
Pharmacokinetic data
Protein binding 70-90%[1]
Metabolism None[1]
Biological half-life 2-4 hours[1]
Excretion Urine (90%)[1]
Identifiers
CAS Number 59-66-5 YesY
ATC code S01EC01
PubChem CID 1986
IUPHAR/BPS 6792
DrugBank DB00819 YesY
ChemSpider 1909 YesY
UNII O3FX965V0I YesY
KEGG D00218 YesY
ChEBI CHEBI:27690 YesY
ChEMBL CHEMBL20 YesY
PDB ligand ID AZM (PDBe, RCSB PDB)
Chemical data
Formula C4H6N4O3S2
Molar mass 222.245 g/mol
Physical data
Melting point 258 to 259 °C (496 to 498 °F)
  (verify)

Acetazolamide, usually sold under the trade name Diamox in some countries, is a carbonic anhydrase inhibitor that is used for the medical treatment of glaucoma, epileptic seizure, idiopathic intracranial hypertension, altitude sickness, cystinuria, periodic paralysis, central sleep apnea, and dural ectasia. Acetazolamide is a diuretic, and it is available as a generic drug in the United States. Diamox is now available as Diamox Sequels in the United States since the original product is no longer made or sold there.[1][2]

It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.[3]

Medical uses

It is used in the treatment of glaucoma, drug-induced edema, heart failure-induced edema, centrencephalic epilepsy and in reducing intraocular pressure after surgery.[4][5] It has also been used in the treatment of mountain sickness,[6] Ménière's disease, increased intracranial pressure and neuromuscular disorders.[2]

In epilepsy, the main use of acetazolamide is in menstrual-related epilepsy and as an adjunct in refractory epilepsy.[4][7] It has been demonstrated in drug trials to relieve symptoms associated with dural ectasia in individuals with Marfan's Syndrome.[8] A 2012 review and meta-analysis found that there was "limited supporting evidence" but that acetazolamide "may be considered" for the treatment of central (as opposed to obstructive) sleep apnea.[9] In the treatment of mountain sickness, acetazolamide forces the kidneys to excrete bicarbonate, the conjugate base of carbonic acid. By increasing the amount of bicarbonate excreted in the urine, the blood becomes more acidic.[2] As the body equates acidity of the blood to its CO2 concentration, artificially acidifying the blood fools the body into thinking it has an excess of CO2, and it excretes this imaginary excess CO2 by deeper and faster breathing, which in turn increases the amount of oxygen in the blood.[10][11] Acetazolamide is not an immediate cure for acute mountain sickness; rather, it speeds up part of the acclimatization process which in turn helps to relieve symptoms.[12]

It has also been used to prevent methotrexate-induced kidney damage by alkalinalizing one's urine, hence speeding up methotrexate excretion by increasing its solubility in urine.[2][13]

Pregnancy and lactation

Acetazolamide is pregnancy category B3 in Australia, which means that studies in rats, mice and rabbits in which acetazolamide was given intravenously or orally caused an increased risk of fetal malformations, including defects of the limbs.[5] Despite this there is insufficient evidence from studies in humans to either support or discount this evidence.[5] It is also excreted in breast milk and hence breastfeeding is advised against in mothers taking this drug.[5]

Side-effects

Common adverse effects of acetazolamide include the following: paraesthesia, fatigue, drowsiness, depression, decreased libido, bitter or metallic taste, nausea, vomiting, abdominal cramps, diarrhea, black feces, polyuria, kidney stones, metabolic acidosis and electrolyte changes (hypokalemia, hyponatremia).[4] Whereas less common adverse effects include: Stevens-Johnson syndrome, anaphylaxis and blood dyscrasias.[4]

Contraindications

Contraindications include:[5]

Interactions

It is possible that it might interact with:[5]

Mechanism of action

Carbonic anhydrase complex with a sulfonamide inhibitor.

Acetazolamide is a carbonic anhydrase inhibitor, hence causing the accumulation of carbonic acid[2] Carbonic anhydrase is an enzyme found in red blood cells that catalyses the following reaction:[14]

\textrm{H}_2 \textrm{CO}_3 \rightleftharpoons \textrm{H}_2 \textrm{O} + \textrm{CO}_2

hence lowering blood pH, by means of the following reaction that carbonic acid undergoes:[15]

\textrm{H}_2 \textrm{CO}_3 \rightleftharpoons \textrm{HCO}_3^- + \textrm{H}^+

which has a pKa of 6.3.[15]

In the eye this results in a reduction in aqueous humour.[5]

The mechanism of diuresis involves the proximal tubule of the kidney. The enzyme carbonic anhydrase is found here, allowing the reabsorption of bicarbonate, sodium, and chloride. By inhibiting this enzyme, these ions are excreted, along with excess water, lowering blood pressure, intracranial pressure, and intraocular pressure. By excreting bicarbonate, the blood becomes acidic, causing compensatory hyperventilation, increasing levels of oxygen and decreasing levels of carbon dioxide in the blood.[16]

References

  1. 1 2 3 4 5 "Diamox Sequels (acetazolamide) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 10 April 2014.
  2. 1 2 3 4 5 Brayfield, A, ed. (7 January 2014). "Acetazolamide". Martindale: The Complete Drug Reference. Pharmaceutical Press. Retrieved 10 April 2014.
  3. ↑ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014.
  4. 1 2 3 4 Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
  5. 1 2 3 4 5 6 7 "PRODUCT INFORMATION DIAMOX® ACETAZOLAMIDE TABLETS" (PDF). TGA eBusiness Services. Aspen Pharma Pty Ltd. 25 February 2005. Retrieved 10 April 2014.
  6. ↑ Low, EV; Avery, AJ; Gupta, V; Schedlbauer, A; Grocott, MP (October 2012). "Identifying the lowest effective dose of acetazolamide for the prophylaxis of acute mountain sickness: systematic review and meta-analysis." (PDF). BMJ 345: e6779. doi:10.1136/bmj.e6779. PMC 3475644. PMID 23081689.
  7. ↑ Reiss, WG; Oles, KS (May 1996). "Acetazolamide in the treatment of seizures.". The Annals of Pharmacotherapy 30 (5): 514–9. doi:10.1177/106002809603000515. PMID 8740334.
  8. ↑ Scoliosis Research Society (2006-11-27). "Dural Ectasia in the Marfan Spine: Symptoms and Treatment.also it's been used in high-altitude mountain sickness". SpineUniverse. Retrieved 2007-11-15.
  9. ↑ Aurora, RN; Chowdhuri, S; Ramar, K; Bista, SR; Casey, KR; Lamm, CI; Kristo, DA; Mallea, JM; Rowley, JA; Zak, RS; Tracy, SL (January 2012). "The treatment of central sleep apnea syndromes in adults: practice parameters with an evidence-based literature review and meta-analyses." (PDF). Sleep 35 (1): 17–40. doi:10.5665/sleep.1580. PMC 3242685. PMID 22215916.
  10. ↑ "Altitude.org". 2004. Retrieved 2009-06-05.
  11. ↑ Leaf DE, Goldfarb DS (April 2007). "Mechanisms of action of acetazolamide in the prophylaxis and treatment of acute mountain sickness". J. Appl. Physiol. 102 (4): 1313–22. doi:10.1152/japplphysiol.01572.2005. PMID 17023566.
  12. ↑ Muza, SR; Fulco, CS; Cymerman, A (2004). "Altitude Acclimatization Guide". US Army Research Inst. of Environmental Medicine Thermal and Mountain Medicine Division Technical Report (USARIEM–TN–04–05).
  13. ↑ Shamash, J; Earl, H; Souhami, R (1991). "Acetazolamide for alkalinisation of urine in patients receiving high-dose methotrexate.". Cancer Chemotherapy and Pharmacology 28 (2): 150–1. doi:10.1007/BF00689708. PMID 2060085.
  14. ↑ Dutta, S; Goodsell, D (January 2004). "January 2004: Carbonic Anhydrase" (PDF). RCSB PDB Protein Data Bank. Retrieved 10 April 2014.
  15. 1 2 Larsen, D. "Carbonic Anhydrase 2". UC Davis Chemwiki. University of California. Retrieved 10 April 2014.
  16. ↑ http://www.life.illinois.edu/ib/426/handouts/Diamox%20mechanism_review_2007.pdf
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