Carbonic Anhydrase Inhibitors

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 water excretion and a decrease in blood pressure. The resulting changes in acid-base balance make CAIs useful in treating altitude sickness by counteracting 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.

Administration

Carbonic anhydrase inhibitors may be administered via topical, oral, or IV routes. Examples of carbonic inhibitor medications currently available are acetazolamide, methazolamide, dorzolamide, brinzolamide, diclofenamide, ethoxzolamide, and zonisamide.

The carbonic anhydrase inhibitor medications used for glaucoma are divided 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 and in acute angle-closure glaucoma when vomiting may necessitate the parenteral route.[9]

Acetazolamide is available 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 carbonic anhydrase inhibitor medication requires lower doses.[10] 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.[11]

Adverse Effects

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 carbonic anhydrase inhibitors 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.[6] The alkalinization of urine resulting from increased bicarbonate excretion may promote the development of calcium oxalate kidney stones.[10][7]

Contraindications

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.[10]

Patients with hypersensitivity to sulfonamides should use carbonic anhydrase inhibitors with caution due to the risk of fatal anaphylactic shock.[10] 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 initiating methazolamide in Korean and Japanese patients.[12][13]

Carbonic anhydrase inhibitors may cause electrolyte imbalances and are therefore not recommended in patients with hypokalemia, hyponatremia, metabolic acidosis, hyperchloremic acidosis, adrenal insufficiency, or marked renal impairment. Drug interactions of carbonic anhydrase inhibitors have been reported using nonsteroidal anti-inflammatory drugs (NSAIDs), beta-blockers, oral contraceptives, antifungals, lithium, metformin, clopidogrel, diuretics, and antiepileptics.[8] Carbonic anhydrase inhibitor causes alkalization of urine, which is presumed to interact with the excretion of many medications. 

Monitoring

Blood urea nitrogen to creatinine ratio, complete blood count, platelets, and electrolytes should be examined at baseline before initiating 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 carbonic anhydrase inhibitors.

Toxicity

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.[14] Similarly, patients on dialysis should avoid this class of drugs due to inhibited renal function and the risk of elevated serum concentrations.[15] Symptoms of toxicity resolve a few days after discontinuing the medication. There is no reported antidote for carbonic anhydrase inhibitor 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 (MDs, DOs, NPs, and PAs), 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. Nurses can participate in patient counseling and serve as a contact point for clinicians. Pharmacists should verify appropriate dosing based on indication, perform medication reconciliation to check for drug-drug interactions, and can also counsel the patient on dosing, administration, and potential adverse events. When prescribing carbonic anhydrase inhibitors, this interprofessional approach to care will drive improved outcomes and reduce potential adverse events.

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 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.[16] [Level 1]