Acetazolamide

Not to be confused with acetohexamide.

Acetazolamide

File:Acetazolamide skeletal.svg
File:Acetazolamide 3D.png
Systematic (IUPAC) name
N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide
Clinical data
Pregnancy category	AU: B3 US: C (Risk not ruled out)
Routes of administration	Oral, IV
Legal status
Legal status	UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Metabolism	None
Biological half-life	3 to 9 hours
Excretion	Renal
Identifiers
CAS Number	59-66-5
ATC code	S01EC01 (WHO)
PubChem	CID 1986
DrugBank	APRD00119
ChemSpider	1909
UNII	O3FX965V0I
Chemical data
Formula	C4H6N4O3S2
Molar mass	222.245 g/mol[[]]
(verify)

Acetazolamide, sold under the trade name Diamox, is a carbonic anhydrase inhibitor that is used to treat glaucoma, epileptic seizures, benign intracranial hypertension (pseudotumor cerebri), altitude sickness, cystinuria, and dural ectasia. Acetazolamide is available as a generic drug and is also used as a diuretic.

Mechanism of action

Acetazolamide is a carbonic anhydrase inhibitor, which means that it forces the kidneys to excrete bicarbonate (HCO₃^-), thus re-acidifying the blood.

Carbonic anhydrase (CA) catalyzes the forward motion of molecules in the following equation:

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

where CA converts carbon dioxide (CO₂) and water (H₂O) to carbonic acid (H₂CO₃), but this is only the case when the current concentration of carbonic acid is less than it would be at equilibrium. Enzymes do not catalyze only one direction of a chemical reaction. Nevertheless, in situations where pCO2 is increased, CA does catalyze the formation of carbonic acid which then dissociates to a hydrogen ion (H⁺, an acidic proton), and a bicarbonate ion (HCO₃^-, a basic anion). In some tissues (particularly plants), the steady state displacement from equilibrium is such that the net reaction catalyzed by CA is conversion of carbonic acid to carbon dioxide and water.

Carbonic acid inhibitors, such as acetazolamide, inhibit CA in tissue and fluid, causing less movement of carbonic acid toward CO₂ production. In the kidneys, blocking CA leads to bicarbonate wasting in the tubules (alkalizes urine), loss of bicarbonate subsequently leads to a metabolic acidosis. In the meantime, H⁺ backs up due to acetazolamide CA inhibition in the tubule and enters the cell with Cl^-, then passes into the bloodstream, creating a hyperchloremic metabolic acidosis. This effect can also be used for therapeutic correction of respiratory alkalosis.

Uses

Acetazolamide is often used in the treatment of various diseases.

Glaucoma

It has been used for glaucoma sufferers. The drug decreases fluid formation in the eye resulting in lower intraocular pressure.

Neurologic

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

In catamential 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.

It is also used to decrease generation of cerebrospinal fluid in idiopathic intracranial hypertension and has shown efficacy in some forms of periodic paralysis.

Marfan syndrome

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

Sleep apnea

Off-label uses include acetazolamide as a conjunction drug to merely assist patients with sleep apnea by lowering blood pH and encourage respiration.

Acute mountain sickness

Acetazolamide is sometimes taken prophylactically, anywhere between 125 milligrams (mg) to 1000 mg per day, 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). Also, prophylactic use is recommended for those with a significant history of acute mountain sickness.

The drug 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. Acidifying the blood stimulates ventilation, which increases the amount of oxygen in the blood. 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).

Note that acetazolamide is not an immediate fix for acute mountain sickness; it speeds up part of the acclimatization process which in turn helps to relieve symptoms. 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 is considered mandatory unless other circumstances present greater danger.

Side-effects

Common side effects of using this drug include numbness and tingling in the fingers and toes, and taste alterations (parageusia), especially for carbonated drinks. 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.

Contraindications

Acetazolamide should not be taken by individuals if:

• They have sickle cell anemia
• They are allergic to sulfa medications
• They are allergic to any carbonic anhydrase inhibitor
• They have liver or kidney disease
• They have adrenal gland failure (i.e. Addison's disease)
• They are pregnant or nursing mothers

Chemistry

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

References

de:Acetazolamid zh:乙酰唑胺