Continuing Education Activity

Acetazolamide is a diuretic and carbonic anhydrase inhibitor medication that is used to treat several illnesses. FDA-approved indications include glaucoma, idiopathic intracranial hypertension, congestive heart failure, altitude sickness, periodic paralysis, and epilepsy. This activity outlines the indications, contraindications, interactions, monitoring, and other therapeutic information pertinent to members of an interprofessional team in the care of patients with conditions requiring the use of acetazolamide.

Objectives:

• Identify the indications for acetazolamide, both FDA-approved and off-label.
• Describe the mechanism of action of acetazolamide.
• Summarize the contraindications and adverse event profile of acetazolamide.
• Explain the importance of collaboration and coordination among the interprofessional team and how it can enhance patient care with acetazolamide therapy to improve patient outcomes for patients who have indicated conditions.

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 syndrome
• Methotrexate-induced renal damage

Acetazolamide is a classic treatment option for glaucoma as it causes a reduction in the aqueous humor. As well, it is useful for the treatment of altitude sickness, because of its underlying 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. Some mechanisms equate the carbon dioxide levels in the body to the acidity level, resulting in an artificial compensatory mechanism to what the body believes to be excess carbon dioxide. This compensation results in faster and deeper breathing. The outcome of that is higher levels of oxygen in the body, which 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 drug can be administered orally as well as via 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. For treating altitude sickness, the range is 250 to 500 mg daily in 2 oral doses.[5] Lower doses are recommended when treating edema, epilepsy, and 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 (i.e., more acidic), 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, sodium, bicarbonate, and chloride get excreted rather than reabsorbed; this also leads to the excretion of excess water. The clinical result is a decrease in blood pressure, decreased intracranial pressure, and decreased intraocular pressure. Bicarbonate excretion 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, 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 whole process by increasing sodium in the urine as well as increasing bicarbonate which alkalinizes the urine. Diuresis is the other result.[3][6]

Administration

Patients take acetazolamide 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 drug dosage 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 acetazolamide use can induce. Fatigue, nausea, vomiting, abdominal pain, and diarrhea are common 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 impaired 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 clinicians should avoid using it with 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 QTc interval, those with prolonged QTc should use it cautiously and have their potassium concentrations monitored, given the drug's ability to cause hypokalemia.

Patients with an allergy to sulfonamides (e.g., sulfa allergy) 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 amphetamine clearance; 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 concurrently.[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 using acetazolamide 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. Patients with a previous history of developing a serious rash should avoid the usage of acetazolamide as it can induce Stevens-Johnson syndrome.[13]

Acetazolamide was a Category C drug under the prior FDA pregnancy categorization system, 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 essential for healthcare workers (e.g., nurse practitioner, primary care physician, emergency department) to know the drug's adverse effects and contraindications. Patients require education from 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 essential to emphasize to the patient to seek immediate care if there is an overdose. The prescriber should work with the pharmacist on medication reconciliation to ensure there are no drug-drug interactions. The nurse should be able to monitor the patient on subsequent visits and counsel on medication administration, as well as verifying patient compliance. Nursing is often a bridge between the prescriber and the pharmacist and other clinicians. The interprofessional healthcare team can optimize therapy with acetazolamide while minimizing adverse events, resulting in better therapeutic outcomes for the patient. [Level 5]