Acetazolamide

From Wikipedia, the free encyclopedia - View original article

Acetazolamide
Systematic (IUPAC) name
N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide
Clinical data
Trade namesDiamox
AHFS/Drugs.commonograph
Pregnancy cat.B3 (AU) C (US)
Legal statusPOM (UK) -only (US)
Routesoral or intravenous
Pharmacokinetic data
MetabolismNone
Half-lifethree to nine hours
Excretionrenal
Identifiers
CAS number59-66-5 YesY
ATC codeS01EC01
PubChemCID 1986
DrugBankDB00819
ChemSpider1909 YesY
UNIIO3FX965V0I YesY
KEGGD00218 YesY
ChEBICHEBI:27690 YesY
ChEMBLCHEMBL20 YesY
Chemical data
FormulaC4H6N4O3S2 
Mol. mass222.245 g/mol
 YesY (what is this?)  (verify)
 
Jump to: navigation, search
Acetazolamide
Systematic (IUPAC) name
N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide
Clinical data
Trade namesDiamox
AHFS/Drugs.commonograph
Pregnancy cat.B3 (AU) C (US)
Legal statusPOM (UK) -only (US)
Routesoral or intravenous
Pharmacokinetic data
MetabolismNone
Half-lifethree to nine hours
Excretionrenal
Identifiers
CAS number59-66-5 YesY
ATC codeS01EC01
PubChemCID 1986
DrugBankDB00819
ChemSpider1909 YesY
UNIIO3FX965V0I YesY
KEGGD00218 YesY
ChEBICHEBI:27690 YesY
ChEMBLCHEMBL20 YesY
Chemical data
FormulaC4H6N4O3S2 
Mol. mass222.245 g/mol
 YesY (what is this?)  (verify)

Acetazolamide, sometimes 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 (a.k.a. pseudotumor cerebri), 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.

Mechanism of action[edit]

Acetazolamide is a carbonic anhydrase inhibitor. It can be used for the medical treatment of moderate to severe metabolic or respiratory alkalosis. Acetazolamide does this by interfering with bicarbonate (HCO3-) reabsorption in the kidneys, thereby reacidifying the blood – hence alkalyzing the urine.

Carbonic anhydrase (CA) catalyzes the first part of the following reversible reaction in which carbon dioxide (CO2) and water (H2O) are converted to carbonic acid (H2CO3) and vice-versa (the second half happens spontaneously, favouring production of H+ + HCO3-):

CO2 + H2O <--CA--> H2CO3 <--> H+ + HCO3-

In the kidney tubules, locally secreted hydrogen ions normally combine with filtered bicarbonate (HCO3-) to form carbonic acid (H2CO3). Carbonic acid in turn is normally acted upon by carbonic anhydrase, leading to formation of CO2. As CO2 rapidly leaves the tubules by diffusing across cell membranes, the above reaction normally runs shifted strongly to the left (i.e. reversed), and more bicarbonate can be continuously reabsorbed from the preurine. However, in the presence of acetazolamide, carbonic anhydrase is inhibited and carbonic acid levels build up. The inhibition of carbonic anhydrase in turn leads to a slowing of the reverse reaction and a decrease in the body's ability to reabsorb serum bicarbonate, resulting in urinary bicarbonate wasting. This leads to a decreased ability to exchange Na+ for H+ in the presence of acetazolamide (in proximal convoluted tubules of kidney) resulting in a mild diuresis.[1] By contrast, the H+ that is also present in the lumen is reabsorbed via an alternative pathway along with Cl-; it then passes into the bloodstream, leading to hyperchloremic metabolic acidosis.[2] This effect can also be used for therapeutic correction of alkalosis seen in altitude sickness or other forms of respiratory alkalosis.

Uses[edit]

Acetazolamide is often used in the treatment of various diseases.

Glaucoma[edit]

Acetazolamide has been used for the treatment of sufferers of glaucoma. When used to treat glaucoma, acetazolamide inhibits production of HCO3-. In health, it is the production of HCO3- which draws Na+ into the eye; water follows by osmosis to form the aqueous humour. In glaucoma treatment, the goal is often to reduce the intraocular pressure and acetazolamide does this by reducing production of aqueous humour.[3]

Neurologic[edit]

In epilepsy, the main use of acetazolamide is in absence seizures and myoclonic seizures.[4] It can be used in both episodic ataxia types 1 and 2 (although the mechanisms are presumed to be different between the two).

In catamenial epilepsy, an increase in seizure frequency around menses, acetazolamide can be an adjunct to an anti-seizure medication regimen to aid in decreasing seizure frequency around menses.

Acetazolamide is also used to decrease the production of cerebrospinal fluid in idiopathic intracranial hypertension as well as hydrocephalus to delay surgical intervention[5] and has shown efficacy in some forms of periodic paralysis.[6]

Acetazolamide is administered in nuclear medicine before studies of the brain with the radioisotope technetium-99m to increase the specificity of the study for brain death (?).

Marfan's syndrome[edit]

It's been demonstrated in drug trials to relieve symptoms associated with dural ectasia in individuals with Marfan's Syndrome.[7]

Central sleep apnea[edit]

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.[8]

Acute mountain sickness[edit]

To reduce the incidence of Acute Mountain Sickness acetazolamide is sometimes taken prophylactically, anywhere between 125 milligrams (mg) to 1000 mg per day,[9][10] starting a few days before going to higher altitudes. Such use is recommended for those ascending from sea level to 3000 meters (9800 feet) in one day, or for those ascending more than 600 meters (2000 feet) per day once above an altitude of 2500 meters (8200 feet).[11][12] Also, prophylactic use is recommended for those with a significant history of acute 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.[12] 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.[13][14] At high altitudes, climbers hyperventilate in response to lower oxygen levels. The hyperventilation results in reduced carbon dioxide (an acid) and a respiratory alkalosis. The normal physiologic response to a respiratory alkalosis is for the kidneys to increase excretion of bicarbonate (a base) to compensate for the loss of carbon dioxide. This kidney response takes a few days, however acetazolamide in a sense accelerates this process by leading to a more rapid renal bicarbonate loss (metabolic acidosis).

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.[9][15] This may take up to a day or two, and requires waiting without any further rapid ascent. It is often advisable to descend if even mild acute mountain sickness is experienced. If serious sickness is encountered, descent to a lower elevation is considered to be mandatory unless other circumstances present greater danger.

Congestive Heart Failure[edit]

For diuresis in congestive heart failure, the starting dose is usually 250 to 375 mg once daily in the morning (five mg per kg). If, after an initial response, the patient fails to continue to lose edema fluid, do not increase the dose but allow for kidney recovery by skipping medication for a day.

Acetazolamide yields best diuretic results when given on alternate days, or for two days alternating with a day of rest.

Failures in therapy may be due to overdosage or too frequent dosage. The use of Acetazolamide does not eliminate the need for other therapy such as digitalis, bed rest, and salt restriction.

Drug-induced edema[edit]

Recommended dosage is 250 to 375 mg of Acetazolamide once a day for one or two days, alternating with a day of rest.

Note: The dosage recommendations for glaucoma and epilepsy differ considerably from those for congestive heart failure, since the first two conditions are not dependent upon carbonic anhydrase inhibition in the kidney which requires intermittent dosage if it is to recover from inhibitory effect of the therapeutic agent.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Contraindications[edit]

Acetazolamide should not be taken by individuals if:

Side-effects[edit]

Common side effects of using this drug include numbness and tingling in the fingers and toes, and taste alterations (parageusia), especially for carbonated drinks. Also possible gastrointestinal disturbances such as nausea, vomiting and diarrhea; polyuria, and occasional instances of drowsiness and confusion. Some may also experience blurred vision but this usually disappears shortly after stopping the medication. Acetazolamide also increases the risk of developing calcium oxalate and calcium phosphate kidney stones. Everyone will experience more frequent urination as a result of using acetazolamide. One should drink more fluids than usual to prevent dehydration and headaches. Acetazolamide prolongs the effects of amphetamines and related drugs. Acetazolamide also causes metabolic acidosis.

Chemistry[edit]

The result: Almost white crystalline powder: Acetazolamide

Acetazolamide syn.png

Roblin, Richard O.; Clapp, James W. (1950). Journal of the American Chemical Society 72 (11): 4890. doi:10.1021/ja01167a011. 

External links[edit]

References[edit]

  1. ^ Lippincott's Illustrated Reviews: Pharmacology, 4th edition page 428
  2. ^ Renal and Electrolyte Disorders Schrier 1976: page 89
  3. ^ Kaur IP, Smitha R, Aggarwal D, Kapil M (November 2002). "Acetazolamide: future perspective in topical glaucoma therapeutics". Int J Pharm 248 (1–2): 1–14. doi:10.1016/S0378-5173(02)00438-6. PMID 12429455. 
  4. ^ "Treatment of Epilepsy | Comprehensive Epilepsy Center | NYU Medical Center, New York, NY". Archived from the original on 27 December 2008. Retrieved 2008-12-19. 
  5. ^ Celebisoy N, Gökçay F, Sirin H, Akyürekli O (November 2007). "Treatment of idiopathic intracranial hypertension: topiramate vs acetazolamide, an open-label study". Acta Neurol. Scand. 116 (5): 322–7. doi:10.1111/j.1600-0404.2007.00905.x. PMID 17922725. 
  6. ^ Ptáĉek LJ, Tawil R, Griggs RC, et al. (August 1994). "Sodium channel mutations in acetazolamide-responsive myotonia congenita, paramyotonia congenita, and hyperkalemic periodic paralysis". Neurology 44 (8): 1500–3. PMID 8058156. 
  7. ^ 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. 
  8. ^ Aurora RN et al. The treatment of central sleep apnea syndromes in adults: practice parameters with an evidence-based literature review and meta-analyses Sleep. 2012 Jan 1;35(1):17-40.
  9. ^ a b Cymerman, A; Rock, PB. Medical Problems in High Mountain Environments. A Handbook for Medical Officers. USARIEM-TN94-2. US Army Research Inst. of Environmental Medicine Thermal and Mountain Medicine Division Technical Report. Retrieved 2010-09-06. 
  10. ^ "FDA drug information, acetazolamide capsule, extended release". Barr Laboratories, Inc. Retrieved 2010-09-06. 
  11. ^ Hackett, P.H. & Roach, R.C. (2001). "High-altitude illness". The New England Journal of Medicine 345 (2): 107–114. doi:10.1056/NEJM200107123450206. PMID 11450659. 
  12. ^ a b Fulco, CS; Ditzler, D; Soares, R; Lammi, E; Muza, SR; Degroot, DW (2002). "Effect of Acetazolamide on Isolated Quadriceps Muscle Endurance Performance at Sea Level and During Acute Altitude Exposure". US Army Research Inst. of Environmental Medicine Thermal and Mountain Medicine Division Technical Report (USARIEM–TR–T02/9). Retrieved 2008-09-30. 
  13. ^ "Altitude.org". 2004. Retrieved 2009-06-05. 
  14. ^ 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. 
  15. ^ 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). Retrieved 2009-03-05.