Continuing Education Activity
Carbonic anhydrase inhibitors are a medication used in the management and treatment of glaucoma, idiopathic intracranial hypertension, altitude sickness, congestive heart failure, and epilepsy, among other diseases. Carbonic anhydrase inhibitors are considered part of the diuretic class of medications. This article reviews the indications, action, and contraindications for carbonic anhydrase inhibitors as valuable agents in the treatment of glaucoma and idiopathic intracranial hypertension as well as other disorders. This activity will highlight the mechanism of action, adverse event profile, and other key factors, e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, and relevant interactions pertinent for members of the interprofessional healthcare team in the treatment of patients with glaucoma, idiopathic intracranial hypertension, and related conditions.
- Identify the mechanism of action of carbonic anhydrase inhibitors.
- Describe the adverse effects of carbonic anhydrase inhibitors.
- Review the appropriate monitoring and toxicity of carbonic anhydrase inhibitors.
- Outline interprofessional team strategies for improving care coordination and communication to improve outcomes in patients receiving treatment with carbonic anhydrase inhibitors.
Carbonic anhydrase inhibitors are diuretic drugs with a wide variety of FDA-approved applications and have more recently been demonstrated to be beneficial for several other off-label clinical uses.
- Elevated intraocular pressure (angle-closure and open-angle glaucoma)
- Pseudotumor cerebri
- Edema due to congestive heart failure
- Centrenchephalic epilepsies
- Altitude sickness prophylaxis
Examples of Non-FDA-Approved Indications
- Sleep apnea
- Cerebrospinal fluid leak
- Reversal of metabolic alkalosis in chronic obstructive pulmonary disease
- Prevention of contrast-induced nephropathy
In the kidneys, carbonic anhydrase inhibitors (CAIs) result in the inhibition of bicarbonate uptake by the proximal tubule, resulting in alkalization of urine. In the eyes, CAIs are classically used in the management of glaucoma due to their ability to reduce the secretion of aqueous humor, thereby lowering the intraocular pressure. Furthermore, CAIs are used for chronic open-angle glaucoma and acute angle-closure glaucoma before surgery. Similarly, CAIs reduce cerebrospinal fluid production, allowing them to be useful in the management of idiopathic intracranial hypertension. The effect of mild metabolic acidosis makes CAIs favorable for the prevention and management of acute mountain sickness, an illness that occurs due to conditions of hypoxia. Urinary alkalinization occurs as a result of increased bicarbonate excretion. Carbonic anhydrase inhibitor acetazolamide may be used to alkalize urine to solubilize uric acid and cystine stones.
The adverse effects of CAIs that researchers and patients have reported include fatigue, vomiting, nausea, and abdominal pain. Stevens-Johnson syndrome is a rare side effect. The alkalization of urine may promote the formation of calcium oxalate stones. Acetazolamide, dichlorphenamide, methazolamide, dorzolamide, and brinzolamide are currently used primarily to treat glaucoma. Zonisamide and ethoxzolamide are used as antiepileptic medications.
CAIs may be used topically, orally, or through the intravenous route. The use of these drugs requires caution and routine monitoring in patients with decreased kidney or liver function. The dose ranges are different for the use of glaucoma, altitude sickness, and diuresis, depending on the route of drug administration.
Mechanism of Action
Carbonic anhydrase in the lumen of the proximal tubule of the kidney converts carbonic acid to water and carbon dioxide. Water and carbonic dioxide enter the intracellular space via diffusion. The intracellular carbonic anhydrase enzyme converts water and carbon dioxide back to carbonic acid, which dissociates into H+ and bicarbonate. By inhibition of the enzyme, CAI medications result in the inhibition of the resorption of bicarbonate by the tubular cells, leading to retention of bicarbonate in the tubular lumen. The overall effect is the alkalization of urine as there is greater bicarbonate in the urine, and the blood becomes more acidic, given the excretion of bicarbonate. The diuretic effect causes increased excretion of water and a decrease in blood pressure. The resulting changes in acid-base balance make CAIs useful in treating altitude sickness by counteracting with the respiratory alkalosis due to hyperventilation.
In the eyes, carbonic anhydrase inhibitors reduce the production of aqueous humor by the epithelium of the ciliary body by reducing the production of bicarbonate ions and presumably reducing fluid flow. The reduction in aqueous humor production lowers the intraocular pressure, making these drugs favorable in patients with glaucoma.
Carbonic anhydrase inhibitors may be administered through topical, oral, or IV routes. Examples of carbonic inhibitor medications currently available are acetazolamide, methazolamide, dorzolamide, brinzolamide, diclofenamide, ethoxzolamide, and zonisamide.
The CAI medications used for glaucoma divide into topical and systemic subgroups. Topical carbonic anhydrase inhibitors, including dorzolamide and brinzolamide, can reach the ciliary body through corneal penetration. These medications may be used as monotherapy but are often used in combination with other glaucoma medications. Dorzolamide hydrochloride preparation is available as a 2% solution, and brinzolamide is available as a 1% suspension; the recommended dosage for medications is 1 drop in both eyes three times daily when used alone or twice daily when used with other glaucoma medications. Dorzolamide is also available in combination with timolol in a 2%/0.5% solution. Systemic carbonic inhibitors, such as acetazolamide, methazolamide, ethoxzolamide, and dichlorphenamide, are indicated when intraocular pressure cannot be reduced via topical administration, as well as in acute angle-closure glaucoma when vomiting may necessitate the parenteral route.
Acetazolamide is available generically and under the brand name Diamox in 125, 200, and 500 mg tablets. Patients with glaucoma may take nearly 250 mg to 1000 mg per day. The dose range is higher for the treatment of altitude sickness. The treatment of edema, epilepsy, and diuresis in congestive heart failure with a CAI medication requires lower doses. It is also available in IV form; the maximal effect through intravenous administration occurs as quickly as 20 minutes.
Methazolamide is available in 25 mg and 50 mg tablets. The recommended dosing of methazolamide for glaucoma is 50 to 100 mg twice daily (BID) or three times daily (TID), whereas dosing for altitude sickness is 150 to 200 mg once daily. Dichlorphenamide, used in the treatment of open-angle glaucoma as well as preoperative acute closed-angle glaucoma, is available as a 50 mg tablet by mouth.
Recommendations for patients taking carbonic anhydrase inhibitors include drinking water at the time of administration to avoid the formation of kidney stones due to increased urinary alkalinization.
Carbonic anhydrase inhibitors may have many adverse effects, including changes in taste, fatigue, abdominal pain, diarrhea, nausea, vomiting, blurred vision, tinnitus, paresthesia, and headache. Both oral and topical drugs are sulfonamide derivatives. Sulfonamide structure can cause allergic reactions such as rash, anaphylaxis, and in rare cases, Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). Adverse effects of topical carbonic anhydrase inhibitors include burning, superficial punctate keratopathy, and local inflammatory reactions of the conjunctiva. A bitter aftertaste is a common effect reported by patients. Systemic CAIs correlate with increased side effects, such as those previously mentioned, and serious effects such as metabolic acidosis, hypokalemia, aplastic anemia, agranulocytosis, nephrolithiasis, and fulminant hepatic necrosis. The alkalinization of urine resulting from increased bicarbonate excretion may promote the development of calcium oxalate kidney stones.
Due to the risk of fulminant hepatic necrosis, carbonic anhydrase inhibitors should not be used in patients with hepatic disease, such as cirrhosis or impaired hepatic function. Liver injury is a rare side effect, but there have been several case reports. The mechanism of hepatic injury is presumed to be due to cross-reactivity with sulfonamide reactions. The damage occurs days to weeks after medication administration. The severity of the hepatic injury ranges from elevations of serum enzymes in a mixed or hepatocellular pattern to acute fulminant liver failure.
Patients with hypersensitivity to sulfonamides should use CAIs with caution due to the risk of fatal anaphylactic shock. Any patient with a history of a serious drug-induced rash should avoid this class of medications. Certain HLA genotypes, particularly HLA-B*5901, are strongly associated with methazolamide-induced SJS/TEN, warranting genetic screening as a useful predictor of SJS/TEN before initiation of methazolamide in Korean and Japanese patients.
Carbonic anhydrase inhibitors may cause electrolyte imbalances, and therefore are not recommended in patients with hypokalemia, hyponatremia, metabolic acidosis, hyperchloremic acidosis, adrenal insufficiency, or marked renal impairment. Drug interactions of CAIs have been reported using nonsteroidal anti-inflammatory drugs (NSAIDs), beta-blockers, oral contraceptives, antifungals, lithium, metformin, clopidogrel, diuretics, and antiepileptics. CAI causes alkalization of urine, which is presumed to interact with the excretion of many medications.
Blood urea nitrogen to creatinine ratio, complete blood count, platelets, and electrolytes should be examined at baseline before the initiation of acetazolamide and methazolamide and monitored periodically. Potassium and sodium bicarbonate levels, in particular, should be monitored.
A rare adverse effect of this drug is hepatotoxicity. Liver injury is precipitated by cross-reactivity of acetazolamide to sulfonamide reactions, indicated by elevation of liver enzymes days to weeks after the initiation of the drug. Monitoring liver enzymes may be necessary upon initiation of systemic CAI.
There have been reports of toxicity in a few cases in chronically receiving aspirin therapy and patients undergoing hemodialysis. Symptoms of toxicity are lethargy, confusion, fatigue, and incontinence. Salicylate may compete with acetazolamide plasma protein binding and inhibit renal clearance. Similarly, patients on dialysis should avoid this class of drugs due to inhibited renal function and the risk of elevated serum concentrations. Symptoms of toxicity resolve a few days after discontinuing the medication. There is no reported antidote for CAI toxicity.
Enhancing Healthcare Team Outcomes
Due to the risks of serious adverse effects such as toxicity, hepatic failure, and SJS/TEN, carbonic anhydrase inhibitors should be prescribed cautiously. It is essential for all interprofessional healthcare team members, including clinicians, nurses, and pharmacists, to know the contraindications and recognize the side effects of these medications. Effective communication between the team and the patient is essential to reduce adverse effects. There is no antidote for carbonic anhydrase inhibitors; therefore, medication use in patients with impaired renal and liver function requires close monitoring.
It is the job of the interprofessional healthcare team to ensure that the patient understands the difference in administration through oral or topical routes. In the setting of severe glaucoma, patients may be taking several topical and oral intraocular pressure-lowering drugs and should be careful to use the recommended dosages. Ophthalmic eye drop bottles with different cap colors may help to avoid confusion and over administration. Many randomized-control trials and meta-analyses have confirmed the safety and efficacy of topical carbonic anhydrase inhibitors, such as dorzolamide and brinzolamide, combined with other glaucoma medications such as prostaglandin analogs or beta-blockers. [Level 1]