Continuing Education Activity

Acetazolamide is a diuretic and carbonic anhydrase inhibitor medication used to treat several illnesses. It works to cause an accumulation of carbonic acid by preventing its breakdown. FDA-approved indications include glaucoma, idiopathic intracranial hypertension, congestive heart failure, altitude sickness, periodic paralysis, and epilepsy. In addition, it is used off-label for central sleep apnea, Marfan syndrome, prevention of high-dose methotrexate nephrotoxicity, and prevention of contrast-induced nephropathy. 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 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 with indicated conditions.

Indications

Acetazolamide is a diuretic and carbonic anhydrase inhibitor medication used to treat several illnesses, as summarized below.[1]

FDA-approved Indications

• Glaucoma[2]
• Idiopathic intracranial hypertension[3]
• Congestive heart failure[4]
• Altitude sickness[5]
• Periodic paralysis[6]
• Epilepsy[7]

Non-FDA-approved Indications

• Central sleep apnea[8]
• Marfan syndrome[9]
• Prevention of high-dose methotrexate nephrotoxicity[10]
• Prevention of contrast-induced nephropathy[11]

Acetazolamide is a classic treatment option for glaucoma as it causes a reduction in aqueous humor. It is also useful for treating altitude sickness because of its underlying mechanism of action. The medication works to excrete bicarbonate. Doing so 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. Some mechanisms equate the carbon dioxide concentrations in the body to the degree of acidity, resulting in an artificial compensatory mechanism for what the body believes to be excess carbon dioxide. This compensation results in faster and deeper breathing. The outcome of that is higher oxygen concentrations in the body, which improves the ability of the body to adjust itself to the higher altitude levels.[12]

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 the proximal tubule of the nephron and red blood cells. 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 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 and increasing bicarbonate which alkalinizes the urine. Diuresis is the other result.[12]

In the eye, the inhibitory activity of acetazolamide reduces the secretion of aqueous humor resulting in a reduction in intraocular pressure, which is beneficial for glaucoma. Acetazolamide is also used in treating idiopathic intracranial hypertension, as it inhibits enzymes in the choroid plexus and reduces the production of CSF, resulting in a decrease in intracranial pressure(ICP).[13]

In epilepsy, inhibition of carbonic anhydrase by acetazolamide seems to retard abnormal, excessive, paroxysmal electrical discharge from neurons. Carbonic anhydrase expression is extensively detected in CNS. Carbonic anhydrase inhibitor acetazolamide affects the delicate equilibrium among CO2, H+, and HCO3- in the neurons and modulates the activity of ligand-gated ion channels at the neuronal level, such as GABA-A signaling. In addition, studies report their capacity to modulate Ca2+ kinetics through ligand-gated Ca2+ channels and voltage-gated Ca2+ channels (VGCC). Carbonic anhydrases rapidly decrease or increase H+ and HCO3 − in the neurons. Acetazolamide modulates the abnormal GABA-A-mediated depolarization that generates epileptic waves and has been shown to block epileptiform activity by inhibiting HCO3 -efflux. The integration of the above-illustrated mechanisms may explain the antiepileptic effect of acetazolamide.[14]

Pharmacokinetics 

Absorption: Well absorbed

Distribution: Carbonic anhydrase inhibitors such as acetazolamide are avidly bound by carbonic anhydrase; consequently, tissues rich in enzymes, such as kidneys and RBC, will have higher concentrations of carbonic anhydrase inhibitors (acetazolamide)

Metabolism: Acetazolamide does not undergo metabolic alteration.

Excretion: Plasma half-Life: 6-9 hours; renal excretion is the primary route of elimination.

Administration

Patients take acetazolamide with or without food and should drink plenty of fluids with the medication. Available dosages are 125 mg, 250 mg, and 500 mg tablets.[15] 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.

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.[15] 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, up to 1000 mg daily.

Use in Specific Patient Population

Patients with Renal Impairment: Use is not recommended in cases of marked kidney disease.

Patients with Hepatic Impairment: Acetazolamide is contraindicated in cirrhosis because of the risk of developing hepatic encephalopathy.

Pregnancy Considerations: The use of acetazolamide in pregnancy has not been recommended because of teratogenic effects in preclinical studies. But in a study of pregnant patients with idiopathic intracranial hypertension, no conclusive evidence of the adverse effects of acetazolamide during pregnancy was observed.[16] 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. Consequently, clinicians should prescribe acetazolamide only when indicated.

Breastfeeding Considerations: Data suggests that maternal doses of acetazolamide up to 1000 mg daily deliver low levels in milk and would not be anticipated to cause any adverse effects in breastfed infants. In addition, various international professional guidelines consensus that carbonic anhydrase inhibitors such as acetazolamide are acceptable in breastfeeding.[17]

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. 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 is a risk of developing metabolic acidosis, hyponatremia, and hypokalemia. Kidney stones can also be seen but are uncommon. Occasionally, patients develop Stevens-Johnson syndrome, aplastic anemia, agranulocytosis, toxic epidermal necrolysis, or fulminant hepatic necrosis.[18]

Common side effects of this medication include fatigue, abdominal pain, nausea, vomiting, and 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.[19]

Contraindications

Since acetazolamide decreases the clearance of ammonia, patients with impaired liver function or liver disease should not use acetazolamide.[20] 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.[21]

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.[22][21]

Acetazolamide is known to interact with several classes of medications. A patient on amphetamines will likely develop reduced amphetamine clearance because acetazolamide increases the urine pH. In contrast, it increases the excretion of lithium, and hence its efficacy 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.[23][24]

Patients on salicylates can develop toxicity if they begin acetazolamide. In addition, patients on sodium bicarbonate therapy have an increased risk of nephrolithiasis if using acetazolamide simultaneously.

Patients using anti-folates, including methotrexate and trimethoprim, should not use acetazolamide. Also, patients 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.[25]

Monitoring

CBC and platelet counts are obtained on patients at initiation of acetazolamide therapy and at regular intervals during therapy as acetazolamide is a sulfa drug. If there is a significant change from the baseline, discontinue the therapy. It is also recommended to monitor serum electrolytes periodically.[26]

Toxicity

There have been reports of central nervous system (CNS) toxicity with coma.[27] In addition, hyperchloremic metabolic acidosis and electrolyte disturbances are usually seen in acetazolamide overdose. Therefore, clinicians should rapidly obtain serum electrolyte levels (especially serum potassium) and arterial blood gas analysis. According to product labeling, there is no specific antidote to acetazolamide; hence treatment is usually supportive. Bicarbonate administration can usually correct metabolic acidosis. Despite its plasma protein binding and high RBC distribution, acetazolamide may be dialyzable. Dialysis may be especially valuable in managing acetazolamide overdosage complicated with acute kidney injury.

Enhancing Healthcare Team Outcomes

Acetazolamide is not frequently used in clinical medicine, but clinicians need 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 no drug-drug interactions. The prescriber should also use Tall Man (mixed case) lettering for the prescription of acetazolamide which is included in look-alike-sound-alike drugs.[11]

Pharmacists should also verify that the prescription as acetazolamide is included in the ISMP (Institute for Safe Medication Practices) medication list to avoid confusion.[28] The nurse should be able to monitor the patient on subsequent visits, counsel on medication administration, and verify patient adherence. Nursing is often a bridge between the prescriber, pharmacist, and other clinicians. All interprofessional team members must document their findings in the patient's record whenever they interact with them. They are also responsible for communicating to the appropriate team members if any changes in the patient's status may merit attention. The interprofessional healthcare team can optimize therapy with acetazolamide while minimizing adverse events, resulting in better therapeutic outcomes for the patient. [Level 5]