Acetazolamide

Acetazolamide

Systematic (IUPAC) name
N-(5-sulfamoyl-1,3,4-thiadiazol-2-yl)acetamide
Clinical data
Trade names	Diamox
AHFS/Drugs.com	monograph
Pregnancy cat.	B3 (AU) C (US)
Legal status	POM (UK) ℞-only (US)
Routes	Oral, IV
Pharmacokinetic data
Metabolism	None
Half-life	3 to 9 hours
Excretion	Renal
Identifiers
CAS number	59-66-5 Y
ATC code	S01EC01
PubChem	CID 1986
DrugBank	DB00819
ChemSpider	1909 Y
UNII	O3FX965V0I Y
KEGG	D00218 Y
ChEBI	CHEBI:27690 Y
ChEMBL	CHEMBL20 Y
Chemical data
Formula	C4H6N4O3S2
Mol. mass	222.245 g/mol
SMILES	eMolecules & PubChem
InChI 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) Y Key:BZKPWHYZMXOIDC-UHFFFAOYSA-N Y
Y (what is this?)  (verify)

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

Mechanism of action

Acetazolamide is a carbonic anhydrase inhibitor. Medically it may be used to treat conditions of moderate to severe metabolic or respiratory alkalosis. It does this by interfering with bicarbonate (HCO₃^-) reabsorption in the kidneys, thereby re-acidifying the blood (and thus alkalinizing the urine).

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

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 serum. 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 convulated 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

Acetazolamide is often used in the treatment of various diseases.

Glaucoma

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

In epilepsy, its main use 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 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.

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

It is administered in nuclear medicine prior to brain studies with 99m-Technetium labeled HMPAO to increase the specificity of the study for brain death.

Marfan's syndrome

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

Central sleep apnea

Off-label uses include acetazolamide as a conjunction drug to merely assist patients with central sleep apnea by lowering blood pH and encouraging respiration.^[8]

Acute mountain sickness

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] Acidifying the blood stimulates ventilation, which 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).

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.^[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

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

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.

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. 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.

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 are nursing mothers

Chemistry

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

External links

• Acetazolamide bound to proteins in the PDB

References