Carbonic anhydrase inhibitors

General adverse effects and adverse reactions

Symptoms of depression, confusion, fatigue, impotence, irritability, malaise, nervousness, and weight loss are often present to some extent in patients taking long-term acetazolamide or methazolamide. These symptoms may be related to systemic metabolic acidosis (due to renal excretion of bicarbonate), which is often accompanied by a reduction in serum potassium concentration [ ]. Gastrointestinal intolerance, manifested as abdominal cramping, dyspepsia, and nausea, with or without diarrhea, is another common problem. Carbonic anhydrase inhibitors reduce the urinary excretion of citrate and uric acid, which may lead to renal calculi and gouty arthritis. Pulmonary edema, taste disorders, and alopecia have also been reported. The most serious adverse effect of carbonic anhydrase inhibitors is bone-marrow depression.

Comparative studies

In 56 patients with glaucoma (28 men and 28 women, 22 with normal-tension glaucoma and 34 with primary open-angle glaucoma) who had used dorzolamide 1% eye drops tds for at least 3 months, an open switch to twice-daily 1% brinzolamide was associated with fewer local adverse effects [ ]. The mean ocular comfort scores were 1.1 dorzolamide and 0.2 for brinzolamide. At 1 month after switching, 50 patients said that they preferred brinzolamide. The local adverse effects after switching to brinzolamide were stinging (n = 3), blurred vision (2), superficial punctate keratopathy (2), the sensation of a foreign body (1), dryness (1), and hyperemia (1); the only systemic adverse effect was a disturbance of taste sensation in one patient.

Cardiovascular

Anaphylactic shock has been reported after a single oral dose of acetazolamide [ ].

• 70-year-old man was given acetazolamide 250 mg to control postoperative intravascular pressure 5 hours after cataract removal under local anesthetic. Thirty minutes later he complained of nausea, became cyanotic, and had an acute respiratory arrest. His systolic blood pressure was 70 mmHg, his heart rate was 180/minute, and there was tachypnea (40/minute). Arterial gases confirmed hypoxemia (PaO ₂ 6.34 kPa, 47 mmHg). Pulmonary embolism and high-pressure pulmonary edema were excluded by perfusion lung scanning and heart catheterization. Management was with ventilatory support, vasopressors, intravenous hydrocortisone, and diphenhydramine. Clinical improvement occurred over 12 hours. After stabilization, sulfonamide hypersensitivity was confirmed by skin testing, suggesting cross-sensitivity with a sulfonamide derivative (acetazolamide).

Physicians should be aware of the risk of anaphylaxis to acetazolamide, particularly in patients with a history of allergy to sulfonamides.

Nervous system

A case of possible Gerstmann syndrome has been attributed to acetazolamide [ ].

• A 60-year-old woman became acutely confused 2 days after the removal of a cataract. She had long-standing diabetes mellitus, hypertension, and ischemic heart disease. There had been a minor stroke with complete recovery 2 years before. Her medication included aspirin, indapamide, enalapril, and oral hypoglycemic agents. Acetazolamide 500 mg bd was added shortly after her eye operation. Neurological examination showed finger agnosia, nominal and receptive dysphasia, acalculia, astereognosis, and left–right disorientation. Other systems were normal. Withdrawal of acetazolamide resulted in rapid improvement with no residual neurological signs two days after admission.

Acetazolamide toxicity was suspected, because of the temporal association between drug treatment and the onset of the neurological symptoms, together with metabolic acidosis. Gerstmann syndrome is usually due to an acute stroke. Although a brain CT scan was negative, such an event was likely in this patient, who had a history of cerebrovascular disease and multiple risk factors, and a causal relation to acetazolamide must be considered tenuous.

Acetazolamide typically causes increased cerebral blood flow as a result of vasodilatation. In patients with stenosis or occlusion of cerebral vessels, perfusion pressure drops and cerebral autoregulatory mechanisms are called into play to maintain cerebral blood flow. In such patients, cerebral blood flow may not increase appropriately after acetazolamide, and it may redistribute, potentially stealing blood from areas that are liable to underperfusion injury (stroke).

• A 62-year-old woman with symptoms compatible with vertebral artery disease underwent a CT perfusion scan in anticipation of possible vertebral artery bypass [ ]. She underwent a routine unenhanced CT scan, followed by dynamic enhanced perfusion CT before and after intravenous administration of acetazolamide 1000 mg. Almost immediately she noted dizziness and perioral numbness and shortly thereafter slurred speech and ataxia. Her symptoms resolved entirely within 24 hours without any therapy. It was thought that she had had a transient ischemic attack possibly related to a steal phenomenon.

In this case, the shift in regional cerebral blood flow produced by acetazolamide resulted in significant underperfusion. Patients with significant cerebrovascular disease should be monitored carefully when they are given acetazolamide.

Acetazolamide is used to reduce the frequency of attacks of ataxia in patients with episodic ataxia type 2. However, the metabolic acidosis that acetazolamide causes can result in nervous system complications [ ].

• A 49-year-old man with episodic ataxia type 2 responded to acetazolamide 250 mg qds. However, during an attack of ataxia he developed gaze-evoked nystagmus, positional nystagmus, dysarthria, and aggravated gait ataxia; he was also excessively drowsy and unable to speak unless subjected to painful stimuli. Imaging studies and laboratory data were normal, except for hyperammonemia (1.58 mg/l, reference range 0.08–0.48 mg/l) and a compensated metabolic acidosis. Acetazolamide was continued, but 3 days later the ammonia concentration increased to 6.6 mg/l, with worsening of the ataxia and dysarthria. Acetazolamide was withdrawn, and within 10 days his symptoms had almost completely resolved and the serum ammonia concentration had fallen to 1.22 mg/l.

This is the first report of ataxia secondary to acetazolamide-induced hyperammonemia in a patient with episodic ataxia type 2. Acetazolamide increases the renal production of NH3, and the consequent metabolic acidosis can cause hyperammonemia. Acetazolamide should therefore be used cautiously in patients with a history of hepatic or renal disease (conditions that predispose to hyperammonemia).

Metabolic acidosis due to acetazolamide causes increased minute ventilation, which can cause increased intracranial pressure and result in neurological complications [ ].

• A 19-year-old woman with postoperative bilateral raised intracranial pressure was given intravenous acetazolamide 500 mg followed by 250 mg every 6 hours. After 3 days she developed a metabolic acidosis (serum HCO ₃ 18 mmol/l), which was attributed to acetazolamide. The metabolic acidosis progressed over the next 3 days (HCO ₃ 15 mmol/l) with appropriate hypocapnia (PaCO ₂ 3.2–3.6 kPa). After 6 days she became agitated, and a propofol infusion was begun, but her mechanical respiratory rate was not increased to maintain her prior hypocapnia. After 5 hours her PaCO ₂ was 4.7 kPa and her arterial pH was 7.26. She developed extreme hypertension and a tachycardia. A CT scan of the brain showed cerebral edema, brain stem herniation, and bilateral watershed infarcts. At post mortem there were multiple fat emboli in the brain and lungs.

The use of acetazolamide in the presence of unrecognized cerebral edema due to fat embolism, with sudden normalization of brain CO ₂ , as occurred in this patient when her previous state of hypocapnia was no longer sustained by ventilatory effort, resulted in cerebral acidosis, vasodilatation, and a further increase in intracranial pressure. This proved catastrophic and led to brainstem herniation and brain death. Acetazolamide should be avoided if at all possible in patients with bony and traumatic brain injuries, particularly during weaning from mechanical ventilation, since it can precipitate coning in patients with raised intracranial pressure.

Sensory systems

Endocrine

Thyrotoxic periodic paralysis occurs only occasionally in Caucasians, but for unknown reasons it can be worsened by acetazolamide [ ].