Acetazolamide

Article Author:
Khashayar Farzam
Article Editor:
Muhammad Abdullah
Updated:
12/24/2018 11:02:17 AM
PubMed Link:
Acetazolamide

Indications

Acetazolamide is a diuretic and carbonic anhydrase inhibitor medication that is used to treat several illnesses.[1]

FDA-Approved Indications[2]

  • Glaucoma
  • Idiopathic intracranial hypertension
  • Congestive heart failure
  • Altitude sickness
  • Periodic paralysis
  • Epilepsy

Non-FDA-Approved Indications

  • Central sleep apnea
  • Dural ectasia in Marfan's syndrome
  • Methotrexate-induced renal damage

It is a classic treatment option for glaucoma as it causes a reduction in the aqueous humor. As well, it is used for the treatment of altitude sickness given its basic mechanism of action. The medication works to excrete bicarbonate. By doing so, it alkalizes the urine as there is greater bicarbonate in the urine. As a result, the blood is more acidic given that the bicarbonate has been excreted out. There are mechanisms which equate the carbon dioxide levels in the body to the acidity level. This results in an artificial compensatory mechanism to what the body believes to be excess carbon dioxide. This results in faster and deeper breathing. The outcome of that is higher levels of oxygen in the body. This improves the ability of the body to adjust itself to the higher altitude levels.[3]

Common side effects seen with this medication include fatigue, abdominal pain, nausea, vomiting, and also paresthesia. Rare side effects such as Stevens-Johnson syndrome also exist. The medication is used via the oral route as well as the intravascular route. It should not be used by those with impaired renal or hepatic function. The medication is also known to interact with certain antibiotics, sodium bicarbonate, amphetamines, and salicylates. [4]

The dose range recommended for the treatment of glaucoma is 250 mg per day to 1000 mg per day. Typically, the dose will be 250 to 500 mg per day. The range of 500 to 1000 mg per day is used for treating altitude sickness.[5] Lower doses are recommended when treating edema, epilepsy and for diuresis in congestive heart failure. The range used for those conditions is usually 250 to 375 mg. However, epilepsy may require higher dosages that go up to 1000 mg per day.

Mechanism of Action

Acetazolamide is a carbonic anhydrase inhibitor. That means this drug works to cause an accumulation of carbonic acid by preventing its breakdown. The result is lower blood pH given the increased carbonic acid, which has a reversible reaction into bicarbonate and a hydrogen ion.

Carbonic anhydrase is found in red blood cells and also the proximal tubule of the kidney. It works to reabsorb sodium, bicarbonate, and chloride. Once acetazolamide inhibits carbonic anhydrase, the sodium, bicarbonate, and chloride are excreted rather than reabsorbed. This also leads to excretion of excess water. The clinical result is decreased blood pressure, decreased intracranial pressure and also decreased intraocular pressure. The excretion of bicarbonate also increases the acidity of the blood. Aqueous humor levels decrease in the eyes, and there are compensatory mechanisms for increased blood acidity, for example, (ex. hyperventilation).

The entire process of excretion that is inhibited by carbonic anhydrase is essentially working to acidify the urine and reabsorb bicarbonate. Acetazolamide will derange the entire process by increasing sodium in the urine as well as increasing bicarbonate in the urine which alkalinizes the urine. Diuresis is the other result.[3][6]

Administration

Acetazolamide is taken orally. It may be taken with or without food, and the patient should drink plenty of fluids with the medication. Available dosages are 125-mg, 250-mg, and 500-mg tablets.[5] These are also available in instant-release and extended-release forms.

Intravenous (IV) administration of acetazolamide is available. However, intramuscular (IM) administration of acetazolamide is not recommended.

Adverse Effects

There is a broad range of general and specific adverse effects that can be induced via the usage of acetazolamide. Fatigue, nausea, vomiting, abdominal pain, and diarrhea are commonly seen in patients. Some other patients will experience paresthesia, black stools, decreased libido, tinnitus, and taste alteration. There are also reports of patients developing depression while using acetazolamide or developing a bitter or metallic taste. Less commonly, there exists a risk of developing metabolic acidosis as well as hyponatremia and hypokalemia. Kidney stones can also be seen but are uncommon. Rarely, patients develop Stevens-Johnson syndrome, aplastic anemia, agranulocytosis, toxic epidermal necrolysis or fulminant hepatic necrosis.[4][7]

Contraindications

Given that acetazolamide decreases the clearance of ammonia, patients who have decreased liver function or liver disease should not use acetazolamide.[8] Usage may precipitate the development of hepatic encephalopathy.

Acetazolamide can induce electrolyte abnormalities. As such, those with hypokalemia or hyponatremia should not use it. Similarly, it can decrease kidney function and should be avoided by anyone with kidney disease or decreased kidney function.

Patients with hyperchloremic acidosis should not use acetazolamide.[9]

Although acetazolamide does not cause prolongation of the QT interval; those with prolonged QT should use it cautiously and have their potassium levels monitored given the drug's ability to cause hypokalemia.

Patients with an allergy to sulfonamides should not use acetazolamide.[10][9]

Acetazolamide is known to interact with several classes of medications. If a patient is on amphetamines, they are likely to develop reduced clearance of the amphetamines. This is because acetazolamide increases the pH of urine. In contrast, it increases the excretion of lithium, and hence the efficacy of lithium may be reduced. Acetazolamide also decreases the excretion of phenytoin, primidone, and quinidine. Patients on these medications may develop toxicity if they also use acetazolamide.[11][12]

Patients on salicylates can develop toxicity if they begin acetazolamide. As well, patients on sodium bicarbonate increase their risk of kidney stone formation if acetazolamide is used at the same time.

Any patients using anti-folates, including methotrexate and trimethoprim, should not use acetazolamide. As well, any patient on any other carbonic anhydrase inhibitor should avoid this medication as well. Patients with a previous history of developing a serious rash should avoid usage of acetazolamide as it can induce Stevens-Johnson syndrome.[13]

Acetazolamide is a Category C drug and should only be used in pregnancy if the benefits outweigh the risks to the unborn baby. There are reports of teratogenicity in animal studies. Similarly, it should only be used in nursing mothers if the benefits outweigh the risks.[14][15]

Toxicity

There have been reports of central nervous system (CNS) toxicity with positive symptoms including fatigue, lethargy, and confusion. Symptoms self-resolve after discontinuation of acetazolamide.[16]

There is no specific antidote to an overdose of acetazolamide.

Enhancing Healthcare Team Outcomes

Acetazolamide is not a frequently used medication in clinical medicine, but it is important for healthcare workers (eg nurse practitioner, primary care physician, emergency department) to know the drug's adverse effects and contraindications.  Patients should be educated by the team including the clinician, nurse, and pharmacist on the dose and indications of the drug and to report any side effects. Because there is no antidote to acetazolamide, it is important to emphasize to the patient to seek immediate care if there is an overdose.


References

[1] Kassamali R,Sica DA, Acetazolamide: a forgotten diuretic agent. Cardiology in review. 2011 Nov-Dec     [PubMed PMID: 21983315]
[2] Van Berkel MA,Elefritz JL, Evaluating off-label uses of acetazolamide. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. 2018 Apr 15     [PubMed PMID: 29626002]
[3] Leaf DE,Goldfarb DS, Mechanisms of action of acetazolamide in the prophylaxis and treatment of acute mountain sickness. Journal of applied physiology (Bethesda, Md. : 1985). 2007 Apr     [PubMed PMID: 17023566]
[4] Saito H,Ogasawara K,Suzuki T,Kuroda H,Kobayashi M,Yoshida K,Kubo Y,Ogawa A, Adverse effects of intravenous acetazolamide administration for evaluation of cerebrovascular reactivity using brain perfusion single-photon emission computed tomography in patients with major cerebral artery steno-occlusive diseases. Neurologia medico-chirurgica. 2011     [PubMed PMID: 21785240]
[5] Low EV,Avery AJ,Gupta V,Schedlbauer A,Grocott MP, Identifying the lowest effective dose of acetazolamide for the prophylaxis of acute mountain sickness: systematic review and meta-analysis. BMJ (Clinical research ed.). 2012 Oct 18     [PubMed PMID: 23081689]
[6] Coote JH, Pharmacological control of altitude sickness. Trends in pharmacological sciences. 1991 Dec     [PubMed PMID: 1792688]
[7] Katayama F,Miura H,Takanashi S, Long-term effectiveness and side effects of acetazolamide as an adjunct to other anticonvulsants in the treatment of refractory epilepsies. Brain     [PubMed PMID: 11934510]
[8] Zaidi FH,Kinnear PE, Acetazolamide, alternate carbonic anhydrase inhibitors and hypoglycaemic agents: comparing enzymatic with diuresis induced metabolic acidosis following intraocular surgery in diabetes. The British journal of ophthalmology. 2004 May     [PubMed PMID: 15090429]
[9] Moviat M,Pickkers P,van der Voort PH,van der Hoeven JG, Acetazolamide-mediated decrease in strong ion difference accounts for the correction of metabolic alkalosis in critically ill patients. Critical care (London, England). 2006 Feb     [PubMed PMID: 16420662]
[10] Platt D,Griggs RC, Use of acetazolamide in sulfonamide-allergic patients with neurologic channelopathies. Archives of neurology. 2012 Apr     [PubMed PMID: 22158718]
[11] Macau RA,da Silva TN,Silva JR,Ferreira AG,Bravo P, Use of acetazolamide in lithium-induced nephrogenic diabetes insipidus: a case report. Endocrinology, diabetes     [PubMed PMID: 29479446]
[12] Gordon CE,Vantzelfde S,Francis JM, Acetazolamide in Lithium-Induced Nephrogenic Diabetes Insipidus. The New England journal of medicine. 2016 Nov 17     [PubMed PMID: 27959610]
[13] Her Y,Kil MS,Park JH,Kim CW,Kim SS, Stevens-Johnson syndrome induced by acetazolamide. The Journal of dermatology. 2011 Mar     [PubMed PMID: 21342230]
[14] Falardeau J,Lobb BM,Golden S,Maxfield SD,Tanne E, The use of acetazolamide during pregnancy in intracranial hypertension patients. Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society. 2013 Mar     [PubMed PMID: 22635167]
[15] Lee AG,Pless M,Falardeau J,Capozzoli T,Wall M,Kardon RH, The use of acetazolamide in idiopathic intracranial hypertension during pregnancy. American journal of ophthalmology. 2005 May     [PubMed PMID: 15860291]
[16] Schwenk MH,St Peter WL,Meese MG,Singhal PC, Acetazolamide toxicity and pharmacokinetics in patients receiving hemodialysis. Pharmacotherapy. 1995 Jul-Aug     [PubMed PMID: 7479208]