Acetazolamide

Acetazolamide

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
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 Registry Number  Y
ATC code S01
PubChem CID:
IUPHAR/BPS
DrugBank  Y
ChemSpider  Y
UNII  Y
KEGG  Y
ChEBI  Y
ChEMBL  Y
PDB ligand ID AZM (, )
Chemical data
Formula C4H6N4O3S2
Molecular mass 222.245 g/mol
Physical data
Melting point 258 to 259 °C (496 to 498 °F)
 Y   

Acetazolamide, usually sold under the trade name Diamox in some countries, is a health system.[3]

Contents

  • Medical uses 1
    • Pregnancy and lactation 1.1
  • Side-effects 2
    • Contraindications 2.1
    • Interactions 2.2
  • Mechanism of action 3
  • References 4

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 [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]

  • Hyperchloremic acidosis
  • Hypokalemia (low blood potassium)
  • Hyponatremia (low blood sodium)
  • Adrenal insufficiency
  • Impaired kidney function
  • Hypersensitivity to acetazolamide or other sulfonamides.
  • Marked liver disease or impairment of liver function, including cirrhosis because of the risk of development of hepatic encephalopathy. Acetazolamide decreases ammonia clearance.

Interactions

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

  • Amphetamines, due to the fact it increases the pH of the renal tubular urine, hence reducing the clearance of amphetamines.
  • Other carbonic anhydrase inhibitors - potential for additive inhibitory effects on carbonic anhydrase and hence potential for toxicity.
  • Ciclosporin, may increase plasma levels of ciclosporin.
  • Antifolates such as trimethoprim, methotrexate, pemetrexed and raltitrexed.
  • Hypoglycemics, acetazolamide can both increase or decrease blood glucose levels.
  • Lithium, increases excretion, hence reducing therapeutic effect.
  • Methenamine compounds, reduces the urinary secretion of methenamines.
  • Phenytoin, reduces phenytoin secretion, hence increasing the potential for toxicity.
  • Primidone, reduces plasma levels of primidone. Hence reducing anticonvulsant effect.
  • Quinidine, reduces urinary secretion of quinidine, hence increasing the potential for toxicity.
  • Salicylates, potential for severe toxicity.
  • Sodium bicarbonate, potential for kidney stone formation.
  • Anticoagulants, cardiac glycosides, may have their effects potentiated by acetazolamide.

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. ^ a b c d e "Diamox Sequels (acetazolamide) dosing, indications, interactions, adverse effects, and more". Medscape Reference. WebMD. Retrieved 10 April 2014. 
  2. ^ a b c d e 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. ^ a b c d Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust.  
  5. ^ a b c d e f g "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.  
  7. ^ Reiss, WG; Oles, KS (May 1996). "Acetazolamide in the treatment of seizures.". The Annals of Pharmacotherapy 30 (5): 514–9.  
  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.  
  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.  
  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.  
  14. ^ Dutta, S; Goodsell, D (January 2004). "January 2004: Carbonic Anhydrase" (PDF). RCSB PDB Protein Data Bank. Retrieved 10 April 2014. 
  15. ^ a b 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