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| Trade names | Diamox, Diacarb, others |
| AHFS/Drugs.com | Monograph |
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| Routes of administration | By mouth,intravenous |
| Drug class | Carbonic anhydrase inhibitor |
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| Pharmacokinetic data | |
| Protein binding | 70–90%[1] |
| Metabolism | None[1] |
| Eliminationhalf-life | 2–4 hours[1] |
| Excretion | Urine (90%)[1] |
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| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.000.400 |
| Chemical and physical data | |
| Formula | C4H6N4O3S2 |
| Molar mass | 222.24 g·mol−1 |
| 3D model (JSmol) | |
| Melting point | 258 to 259 °C (496 to 498 °F) |
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Acetazolamide, sold under the trade nameDiamox among others, is a medication used to treatglaucoma,epilepsy,acute mountain sickness,periodic paralysis,idiopathic intracranial hypertension (raised brain pressure of unclear cause),heart failure and to alkalinize urine.[2][3] It may be used long term for the treatment ofopen angle glaucoma and short term foracute angle closure glaucoma until surgery can be carried out.[4] It is takenby mouth orinjection into a vein.[2] Acetazolamide is a first generationcarbonic anhydrase inhibitor and it decreases the ocular fluid andosmolality in the eye to decrease intraocular pressure.[5][6]
Common side effects include numbness,ringing in the ears, loss of appetite, vomiting, and sleepiness.[2] It is not recommended in those with significantkidney problems,liver problems, or who areallergic to sulfonamides.[2][4] Acetazolamide is in thediuretic andcarbonic anhydrase inhibitor families of medication.[2] It works by decreasing the formation ofhydrogen ions andbicarbonate from carbon dioxide and water.[2]
Acetazolamide came into medical use in 1952.[7] It is on theWorld Health Organization's List of Essential Medicines.[8] Acetazolamide is available as ageneric medication.[2]
It is used in the treatment ofglaucoma, drug-inducededema, heart failure-induced edema,epilepsy and in reducing intraocular pressure after surgery.[9][10] It has also been used in the treatment ofaltitude sickness,[11]Ménière's disease,increased intracranial pressure and neuromuscular disorders.[12] Acetazolamide is also used in the critical care setting to stimulate respiratory drive in patients withchronic obstructive pulmonary disease as anoff-label indication.[13] 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.[14]
In epilepsy, the main use of acetazolamide is in menstrual-related epilepsy and as an add on to other treatments in refractory epilepsy.[9][15]
Though various websites on the internet report that acetazolamide can be used to treatdural ectasia in individuals withMarfan syndrome, the only supporting evidence for this assertion exists from a small study of 14 patients which was not peer-reviewed or submitted for publication.[16][17] Several published cases of intracranial hypotension related to Marfan syndrome would warrant caution in using acetazolamide in these patients unless there is a clear indication, as it could lower intracranial pressure further.[18]
It has also been used to preventmethotrexate-induced kidney damage by alkalinizing the urine, hence speeding up methotrexate excretion by increasing its solubility in urine.[12][19] There is some evidence to support its use to preventhemiplegic migraine.[20]
There is tentative evidence it might improvevisual snow symptoms for some.
Acetazolamide is also used for the treatment of acute mountain sickness. In the prevention or treatment of mountain sickness, acetazolamide inhibits the ability of thekidneys to reabsorbbicarbonate, theconjugate base ofcarbonic acid. Increasing the amount of bicarbonate excreted in the urine leads to acidification of the blood.[12] Because the body senses CO2 concentration indirectly via blood pH (increase in CO2 causes a decrease in pH), acidifying the blood through decreased renal reabsorption of bicarbonate is sensed as an increase in CO2. This, in turn, causes the body to increase minute ventilation (the amount of air breathed per minute) in order to "breathe off" CO2, which in turn increases the amount of oxygen in the blood.[21][22] Acetazolamide is not an immediate cure for acute mountain sickness; rather, it speeds up (or, when taking before traveling, forces the body to early start) part of theacclimatization process which in turn helps to relieve symptoms.[23] Acetazolamide is still effective if started early in the course of mountain sickness. As prevention, it is started one day before travel to altitude and continued for the first two days at altitude.[24]
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.[10] Despite this, there is insufficient evidence from studies in humans to either support or discount this evidence.[10]
Limited data are available on the effects of nursing mothers taking acetazolamide. Therapeutic doses create low levels in breast milk and are not expected to cause problems in infants.[25]
Common adverse effects of acetazolamide include the following:paraesthesia, fatigue, drowsiness, depression, decreased libido, bitter or metallic taste, nausea, vomiting, abdominal cramps, diarrhea, black stool,polyuria,kidney stones,metabolic acidosis and electrolyte changes (hypokalemia,hyponatremia).[9] Whereas less common adverse effects includeStevens–Johnson syndrome,anaphylaxis andblood dyscrasias.[9]
Contraindications include:[10]
It is possible that it might interact with:[10]
Acetazolamide is acarbonic anhydrase inhibitor, hence causing the accumulation ofcarbonic acid.[12] Carbonic anhydrase is an enzyme found inred blood cells and many other tissues that catalyses the following reaction:[26]
hence lowering blood pH, by means of the following reaction that carbonic acid undergoes:[27]
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. A general side effect of carbonic anhydrase inhibitors is loss of potassium due to this function. By excreting bicarbonate, the blood becomes acidic, causing compensatory hyperventilation with deep respiration (Kussmaul breathing), increasing levels of oxygen and decreasing levels of carbon dioxide in the blood.[22]
In the eye this results in a reduction inaqueous humour.[10]
Bicarbonate (HCO3−) has a pKa of 10.3 with carbonate (CO32−), far further from physiologic pH (7.35–7.45), and so it is more likely to accept a proton than to donate one, but it is also far less likely for it to do either, thus bicarbonate will be the major species at physiological pH.
Under normal conditions in the proximal convoluted tubule of the kidney, most of the carbonic acid (H2CO3) produced intracellularly by the action of carbonic anhydrase quickly dissociates in the cell tobicarbonate (HCO3−) and an H+ ion (aproton), as previously mentioned. The bicarbonate (HCO3−) exits at the basal portion of the cell via sodium (Na+) symport and chloride (Cl−) antiport and re-enters circulation, where it may accept a proton if blood pH decreases, thus acting as a weak, basic buffer. The remaining H+ left over from the intracellular production of carbonic acid (H2CO3) exits the apical (urinary lumen) portion of the cell by Na+ antiport, acidifying the urine. There, it may join with another bicarbonate (HCO3−) that dissociated from its H+ in the lumen of the urinary space only after exiting the proximal convoluted kidney cells/glomerulus as carbonic acid (H2CO3) because bicarbonate (HCO3−) itself can not diffuse across the cell membrane in its polar state. This will replenish carbonic acid (H2CO3) so that it then may be reabsorbed into the cell as itself or CO2 and H2O (produced via a luminal carbonic anhydrase). As a result of this whole process, there is a greater net balance of H+ in the urinary lumen than bicarbonate (HCO3−), and so this space is more acidic than physiologic pH. Thus, there is an increased likelihood that any bicarbonate (HCO3−) that was left over in the lumen diffuses back into the cell as carbonic acid, CO2, or H2O.
In short, under normal conditions, the net effect of carbonic anhydrase in the urinary lumen and cells of the proximal convoluted tubule is to acidify the urine and transport bicarbonate (HCO3−) into the body. Another effect is excretion of Cl− as it is needed to maintain electroneutrality in the lumen, as well as the reabsorption of Na+ into the body.
Thus, by disrupting this process with acetazolamide, urinary Na+ and bicarbonate (HCO3−) are increased, and urinary H+ and Cl− are decreased. Inversely, serum Na+ and bicarbonate (HCO3−) are decreased, and serum H+ and Cl− are increased. H2O generally follows sodium, and so this is how the clinical diuretic effect is achieved, which reduces blood volume and thus preload on the heart to improve contractility and reduce blood pressure, or achieve other desired clinical effects of reduced blood volume such as reducing edema or intracranial pressure.[28]
An early description of this compound (as 2-acetylamino-1,3,4-thiadiazole-5-sulfonamide) and its synthesis has been patented in 1951.[29]
Smaller clinical trials have also shown promising results in the treatment ofnormal pressure hydrocephalus (NPH).[30][31][32][33][34]
Acetazolamide was originally used as a diuretic but has been largely supplanted by other drugs such asfurosemide.Carbonic anhydrase inhibitors are no longer the preferred method of treatingintraocular pressure in cases ofglaucoma but when a carbonic anhydrase inhibitor is usedmethazolamide is preferred, although acetazolamide is still used. Acetazolamide is also used to increase thealkalinity of urine to manageurinary calculi, but requiresbicarbonate supplementation. In horses it is used as a treatment forhyperkalaemic periodic paralysis.[35]
Acetazolamide has largely been supplanted by other drugs and therapies due to side effects such ashypokalaemia andrespiratory acidosis.[35]
