Acetazolamide

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Acetazolamide
Acetazolamide.svg
Acetazolamide 3D ball.png
Clinical data
Trade names Diamox, Diacarb, others
AHFS/Drugs.com Monograph
Pregnancy
category
  • AU:B3
Routes of
administration 		By mouth, intravenous
Drug class Carbonic anhydrase inhibitor
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding 70–90% [1]
Metabolism None [1]
Elimination half-life 2–4 hours [1]
Excretion Urine (90%) [1]
Identifiers
  • N-(5-Sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.400 OOjs UI icon edit-ltr-progressive.svg
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)
  • NS(=O)(=O)c1nnc(s1)NC(=O)C
  • InChI=1S/C4H6N4O3S2/c1-2(9)6-3-7-8-4(12-3)13(5,10)11/h1H3,(H2,5,10,11)(H,6,7,9) Yes check.svgY
  • Key:BZKPWHYZMXOIDC-UHFFFAOYSA-N Yes check.svgY
   (verify)

Acetazolamide, sold under the trade name Diamox among others, is a medication used to treat glaucoma, 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 of open angle glaucoma and short term for acute angle closure glaucoma until surgery can be carried out. [4] It is taken by mouth or injection into a vein. [2] Acetazolamide is a first generation carbonic anhydrase inhibitor and it decreases the ocular fluid and osmolality in the eye to decrease intraocular pressure. [5] [6]

Contents

Common side effects include numbness, ringing in the ears, loss of appetite, vomiting, and sleepiness. [2] It is not recommended in those with significant kidney problems, liver problems, or who are allergic to sulfonamides. [2] [4] Acetazolamide is in the diuretic and carbonic anhydrase inhibitor families of medication. [2] It works by decreasing the formation of hydrogen ions and bicarbonate from carbon dioxide and water. [2]

Acetazolamide came into medical use in 1952. [7] It is on the World Health Organization's List of Essential Medicines. [8] Acetazolamide is available as a generic medication. [2]

Medical uses

It is used in the treatment of glaucoma, drug-induced edema, heart failure-induced edema, epilepsy and in reducing intraocular pressure after surgery. [9] [10] It has also been used in the treatment of altitude 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 with chronic obstructive pulmonary disease as an off-label indication. [13]

In epilepsy, the main use of acetazolamide is in menstrual-related epilepsy and as an add on to other treatments in refractory epilepsy. [9] [14] Though various websites on the internet report that acetazolamide can be used to treat dural ectasia in individuals with Marfan 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. [15] [16] 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. [17] 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. [18]

It has also been used to prevent methotrexate-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 prevent hemiplegic migraine. [20]

Open-angle glaucoma

Acetazolamide is used in the treatment of open-angle glaucoma. The carbonic anhydrase inhibitor is able to decrease ocular fluid and osmolality of the fluid in the humor of the eye and decrease intraocular pressure in the eye. The medication comes in the form of an oral tablet used for this indication.[ medical citation needed ]

High altitude sickness

Acetazolamide is also used for the treatment of acute mountain sickness. In the prevention or treatment of mountain sickness, acetazolamide inhibits the ability of the kidneys to reabsorb bicarbonate, the conjugate base of carbonic 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 the acclimatization 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]

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. [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]

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 stool, polyuria, kidney stones, metabolic acidosis and electrolyte changes (hypokalemia, hyponatremia). [9] Whereas less common adverse effects include Stevens–Johnson syndrome, anaphylaxis and blood dyscrasias. [9]

Contraindications

Contraindications include: [10]

Interactions

It is possible that it might interact with: [10]

Mechanism of action

Carbonic anhydrase (ribbon) complex with a sulfonamide inhibitor (ball-and-sticks) 4ITO2.png
Carbonic anhydrase (ribbon) complex with a sulfonamide inhibitor (ball-and-sticks)
Proximal convoluted tubule. Urinary space is on left. Proximal convoluted tubule.jpg
Proximal convoluted tubule. Urinary space is on left.

Acetazolamide is a carbonic anhydrase inhibitor, hence causing the accumulation of carbonic acid. [12] Carbonic anhydrase is an enzyme found in red blood cells and many other tissues that catalyses the following reaction: [26]

H2CO3 ⇌ H2O + CO2

hence lowering blood pH, by means of the following reaction that carbonic acid undergoes: [27]

H2CO3 ⇌ HCO3− + H+

which has a pKa of 6.3. [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 in aqueous 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 to bicarbonate (HCO3−) and an H+ ion (a proton), 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]

History

An early description of this compound (as 2-acetylamino-1,3,4-thiadiazole-5-sulfonamide) and its synthesis has been patented. [29]

Research

Smaller clinical trials have also shown promising results in the treatment of normal pressure hydrocephalus (NPH). [30] [31] [32] [33] [34]

Related Research Articles

<span class="mw-page-title-main">Carbonic acid</span> Chemical compound

Carbonic acid is a chemical compound with the chemical formula H2CO3. The molecule rapidly converts to water and carbon dioxide in the presence of water. However, in the absence of water, it is quite stable at room temperature. The interconversion of carbon dioxide and carbonic acid is related to the breathing cycle of animals and the acidification of natural waters.

Diuresis is the excretion of urine, especially when excessive (polyuria). The term collectively denotes the physiologic processes underpinning increased urine production by the kidneys during maintenance of fluid balance.

<span class="mw-page-title-main">Renal physiology</span> Study of the physiology of the kidney

Renal physiology is the study of the physiology of the kidney. This encompasses all functions of the kidney, including maintenance of acid-base balance; regulation of fluid balance; regulation of sodium, potassium, and other electrolytes; clearance of toxins; absorption of glucose, amino acids, and other small molecules; regulation of blood pressure; production of various hormones, such as erythropoietin; and activation of vitamin D.

<span class="mw-page-title-main">Gastric acid</span> Digestive fluid formed in the stomach

Gastric acid or stomach acid is the acidic component – hydrochloric acid of gastric juice, produced by parietal cells in the gastric glands of the stomach lining. With a pH of between one and three, gastric acid plays a key role in the digestion of proteins by activating digestive enzymes, which together break down the long chains of amino acids of proteins. Gastric acid is regulated in feedback systems to increase production when needed, such as after a meal. Other cells in the stomach produce bicarbonate, a base, to buffer the fluid, ensuring a regulated pH. These cells also produce mucus – a viscous barrier to prevent gastric acid from damaging the stomach. The pancreas further produces large amounts of bicarbonate and secretes bicarbonate through the pancreatic duct to the duodenum to neutralize gastric acid passing into the digestive tract.

<span class="mw-page-title-main">Metabolic acidosis</span> Medical condition

Metabolic acidosis is a serious electrolyte disorder characterized by an imbalance in the body's acid-base balance. Metabolic acidosis has three main root causes: increased acid production, loss of bicarbonate, and a reduced ability of the kidneys to excrete excess acids. Metabolic acidosis can lead to acidemia, which is defined as arterial blood pH that is lower than 7.35. Acidemia and acidosis are not mutually exclusive – pH and hydrogen ion concentrations also depend on the coexistence of other acid-base disorders; therefore, pH levels in people with metabolic acidosis can range from low to high.

<span class="mw-page-title-main">Respiratory acidosis</span> Medical condition

Respiratory acidosis is a state in which decreased ventilation (hypoventilation) increases the concentration of carbon dioxide in the blood and decreases the blood's pH.

<span class="mw-page-title-main">Respiratory alkalosis</span> Medical condition

Respiratory alkalosis is a medical condition in which increased respiration elevates the blood pH beyond the normal range (7.35–7.45) with a concurrent reduction in arterial levels of carbon dioxide. This condition is one of the four primary disturbance of acid–base homeostasis.

<span class="mw-page-title-main">Metabolic alkalosis</span> Medical condition

Metabolic alkalosis is a metabolic condition in which the pH of tissue is elevated beyond the normal range (7.35–7.45). This is the result of decreased hydrogen ion concentration, leading to increased bicarbonate, or alternatively a direct result of increased bicarbonate concentrations. The condition typically cannot last long if the kidneys are functioning properly.

<span class="mw-page-title-main">Band 3 anion transport protein</span> Mammalian protein found in Homo sapiens

Band 3 anion transport protein, also known as anion exchanger 1 (AE1) or band 3 or solute carrier family 4 member 1 (SLC4A1), is a protein that is encoded by the SLC4A1 gene in humans.

<span class="mw-page-title-main">Renal tubular acidosis</span> Medical condition

Renal tubular acidosis (RTA) is a medical condition that involves an accumulation of acid in the body due to a failure of the kidneys to appropriately acidify the urine. In renal physiology, when blood is filtered by the kidney, the filtrate passes through the tubules of the nephron, allowing for exchange of salts, acid equivalents, and other solutes before it drains into the bladder as urine. The metabolic acidosis that results from RTA may be caused either by insufficient secretion of hydrogen ions into the latter portions of the nephron or by failure to reabsorb sufficient bicarbonate ions from the filtrate in the early portion of the nephron. Although a metabolic acidosis also occurs in those with chronic kidney disease, the term RTA is reserved for individuals with poor urinary acidification in otherwise well-functioning kidneys. Several different types of RTA exist, which all have different syndromes and different causes. RTA is usually an incidental finding based on routine blood draws that show abnormal results. Clinically, patients may present with vague symptoms such as dehydration, mental status changes, or delayed growth in adolescents.

The Haldane effect is a property of hemoglobin first described by John Scott Haldane, within which oxygenation of blood in the lungs displaces carbon dioxide from hemoglobin, increasing the removal of carbon dioxide. Consequently, oxygenated blood has a reduced affinity for carbon dioxide. Thus, the Haldane effect describes the ability of hemoglobin to carry increased amounts of carbon dioxide (CO2) in the deoxygenated state as opposed to the oxygenated state. Vice versa, it is true that a high concentration of CO2 facilitates dissociation of oxyhemoglobin, though this is the result of two distinct processes (Bohr effect and Margaria-Green effect) and should be distinguished from Haldane effect.

<span class="mw-page-title-main">Carbonic anhydrase inhibitor</span> Class of pharmaceuticals

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.

<span class="mw-page-title-main">Brinzolamide</span> Chemical compound

Brinzolamide is a carbonic anhydrase inhibitor used to lower intraocular pressure in patients with open-angle glaucoma or ocular hypertension.

<span class="mw-page-title-main">Dorzolamide</span> Chemical compound

Dorzolamide, sold under the brand name Trusopt among others, is a medication used to treat high pressure inside the eye, including in cases of glaucoma. It is used as an eye drop. Effects begin within three hours and last for at least eight hours. It is also available as the combination dorzolamide/timolol.

<span class="mw-page-title-main">Bicarbonate buffer system</span> Buffer system that maintains pH balance in humans

The bicarbonate buffer system is an acid-base homeostatic mechanism involving the balance of carbonic acid (H2CO3), bicarbonate ion (HCO−
3), and carbon dioxide (CO2) in order to maintain pH in the blood and duodenum, among other tissues, to support proper metabolic function. Catalyzed by carbonic anhydrase, carbon dioxide (CO2) reacts with water (H2O) to form carbonic acid (H2CO3), which in turn rapidly dissociates to form a bicarbonate ion (HCO−
3 ) and a hydrogen ion (H+) as shown in the following reaction:

Normal anion gap acidosis is an acidosis that is not accompanied by an abnormally increased anion gap.

<span class="mw-page-title-main">Chloride shift</span> Transfer of ions into red blood cells

Chloride shift (also known as the Hamburger phenomenon or lineas phenomenon, named after Hartog Jakob Hamburger) is a process which occurs in a cardiovascular system and refers to the exchange of bicarbonate (HCO3−) and chloride (Cl−) across the membrane of red blood cells (RBCs).

<span class="mw-page-title-main">Acid–base disorder</span> Medical condition

Acid–base imbalance is an abnormality of the human body's normal balance of acids and bases that causes the plasma pH to deviate out of the normal range. In the fetus, the normal range differs based on which umbilical vessel is sampled. It can exist in varying levels of severity, some life-threatening.

<span class="mw-page-title-main">Diuretic</span> Substance that promotes the production of urine

A diuretic is any substance that promotes diuresis, the increased production of urine. This includes forced diuresis. A diuretic tablet is sometimes colloquially called a water tablet. There are several categories of diuretics. All diuretics increase the excretion of water from the body, through the kidneys. There exist several classes of diuretic, and each works in a distinct way. Alternatively, an antidiuretic, such as vasopressin, is an agent or drug which reduces the excretion of water in urine.

<span class="mw-page-title-main">Carbonic anhydrase</span> Class of enzymes

The carbonic anhydrases form a family of enzymes that catalyze the interconversion between carbon dioxide and water and the dissociated ions of carbonic acid. The active site of most carbonic anhydrases contains a zinc ion. They are therefore classified as metalloenzymes. The enzyme maintains acid-base balance and helps transport carbon dioxide.

References

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  5. ↑ Scozzafava A, Supuran CT (2014). "Glaucoma and the Applications of Carbonic Anhydrase Inhibitors". Carbonic Anhydrase: Mechanism, Regulation, Links to Disease, and Industrial Applications. Subcellular Biochemistry. Vol. 75. Springer. pp. 349–359. doi:10.1007/978-94-007-7359-2_17. ISBN   978-94-007-7358-5. PMID   24146387.
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  15. ↑ Ahn NU, Sponseller PD, Ahn UM, Nallamshetty L, Rose P, Buchowski J, et al. (July 2005). "Dural ectasia". SpineUniverse.com. Archived from the original on 26 September 2007.
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  17. ↑ Cheuret E, Edouard T, Mejdoubi M, Acar P, Pienkowski C, Cances C, et al. (April 2008). "Intracranial hypotension in a girl with Marfan syndrome: case report and review of the literature". Child's Nervous System. 24 (4): 509–513. doi:10.1007/s00381-007-0506-3. PMID   17906865. S2CID   5734726.
  18. ↑ Aurora RN, Chowdhuri S, Ramar K, Bista SR, Casey KR, Lamm CI, et al. (January 2012). "The treatment of central sleep apnea syndromes in adults: practice parameters with an evidence-based literature review and meta-analyses". Sleep. 35 (1): 17–40. doi:10.5665/sleep.1580. PMC   3242685 . PMID   22215916.
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  26. ↑ Dutta S, Goodsell D (January 2004). "January 2004: Carbonic Anhydrase" (PDF). RCSB PDB Protein Data Bank. Archived (PDF) from the original on 14 May 2013. Retrieved 10 April 2014.
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  28. ↑ Koeppen BM (December 2009). "The kidney and acid-base regulation". Advances in Physiology Education. 33 (4): 275–281. doi:10.1152/advan.00054.2009. PMID   19948674. Archived from the original on 20 April 2016.
  29. ↑ US 2554816,Clapp Jr JW, Roblin RO,"Heterocyclic sulfonamides and metyhods of preparation thereof",published 1951-05-29, assigned to American Cyanamid Company
  30. ↑ Alperin N, Oliu CJ, Bagci AM, Lee SH, Kovanlikaya I, Adams D, et al. (April 2014). "Low-dose acetazolamide reverses periventricular white matter hyperintensities in iNPH". Neurology. 82 (15): 1347–1351. doi:10.1212/WNL.0000000000000313. PMC   4001191 . PMID   24634454.
  31. ↑ Ivkovic M, Reiss-Zimmermann M, Katzen H, Preuss M, Kovanlikaya I, Heier L, et al. (April 2015). "MRI assessment of the effects of acetazolamide and external lumbar drainage in idiopathic normal pressure hydrocephalus". Fluids and Barriers of the CNS. 12 (1): 9. doi: 10.1186/s12987-015-0004-z . PMC   4432506 . PMID   25928394.
  32. ↑ Gilbert GJ (18 May 2022). "Acetazolamide in the treatment of Normal Pressure Hydrocephalus". Neurology– via n.neurology.org.
  33. ↑ Aimard G, Vighetto A, Gabet JY, Bret P, Henry E (21 May 1990). "[Acetazolamide: an alternative to shunting in normal pressure hydrocephalus? Preliminary results]". Revue Neurologique. 146 (6–7): 437–439. PMID   2399408.
  34. ↑ Clinical trial number NCT03779594 for "Acetazolamide for Treating NPH in Shunt-candidates Patients: an Open Label Feasibility Trial" at ClinicalTrials.gov
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