What are the potential side effects of acetazolamide, particularly in patients with a history of sulfa allergy or those taking it for glaucoma or altitude sickness?

Acetazolamide Side Effects

Acetazolamide causes common dose-dependent side effects including paresthesias (affecting 1 in 2-3 patients), dysgeusia, polyuria, and fatigue, along with rare but potentially fatal reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, and blood dyscrasias that mandate immediate discontinuation if hypersensitivity occurs. 1

Most Common Side Effects

Neurological and Sensory

• Paresthesias are the most frequent side effect, occurring in approximately 1 in 2-3 patients, with significantly increased risk at higher doses 2, 3
• Dysgeusia (metallic taste) affects approximately 1 in 18 patients, with dose-dependent risk increasing at higher doses 2, 3
• Tinnitus and vertigo are recognized adverse effects 4, 2
• Cognitive slowing and depression can occur, particularly concerning for patients requiring mental acuity 4, 2

Gastrointestinal

• Nausea, vomiting, and diarrhea are well-documented side effects 2
• Anorexia can occur, particularly with concomitant high-dose aspirin use 1

Systemic

• Fatigue occurs in approximately 1 in 11 patients, with a trend toward dose-dependence 2, 3
• Polyuria affects approximately 1 in 17 patients 2, 3

Serious and Life-Threatening Adverse Effects

Hypersensitivity Reactions

• Fatalities have occurred from Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatic necrosis, and anaphylaxis 1
• Sensitization may recur when a sulfonamide is readministered regardless of route 1
• Contraindicated in patients with known sulfonamide allergy 4

Hematologic

• Agranulocytosis, aplastic anemia, thrombocytopenia, and other blood dyscrasias can occur 1
• Contraindicated in patients with aplastic anemia or sickle cell disease 4

Metabolic and Renal

• Electrolyte imbalances, particularly hypokalemia and hyperchloremia, are serious adverse effects requiring monitoring 2, 5
• Plasma chloride concentrations can become elevated above normal range and correlate with erythrocyte acetazolamide concentration 5
• Renal calculi occur rarely but are a recognized complication 4, 2
• Metabolic acidosis can develop, particularly in overdose situations 2, 1

Ophthalmic

• Bilateral choroidal effusions and acute myopia have been reported, even after a single 125 mg dose 6

Dose-Dependent Relationships

• Risk of paresthesias increases significantly with higher doses (beta=1.8, p=0.01) 3
• Risk of dysgeusia increases with higher doses (beta=3.1, p=0.02) 3
• Fatigue shows a trend toward increased risk with higher doses but non-significantly (beta=2.6, p=0.14) 3
• Patients with erythrocyte acetazolamide concentrations >20 mcg/mL have higher incidences of side effects 5

Clinical Discontinuation Rates

• In clinical practice, 48% of patients discontinue acetazolamide at mean doses of 1.5 g/day due to side effects 2
• Only 44% of patients tolerate the maximum 4 g/day dose 2

Special Populations and Contraindications

Pregnancy

• Pregnancy is a contraindication due to potential teratogenic risks 2
• FDA Pregnancy Category C 4

Drug Interactions

• Caution is advised with concomitant high-dose aspirin, as anorexia, tachypnea, lethargy, metabolic acidosis, coma, and death have been reported 1
• Cross-sensitivity may exist with other sulfonamides, thiazide diuretics, and oral hypoglycemic agents 4

Other Contraindications

• Kidney stones 4
• Marked hepatic damage or severe renal insufficiency when renal function cannot be monitored 4

Strategies to Minimize Side Effects

• Start with low doses (250-500 mg daily) and titrate gradually to minimize initial side effect burden 2
• For altitude sickness prophylaxis, 250 mg/day has similar efficacy to higher doses with a more favorable side-effect profile 7
• Periodical monitoring of erythrocyte acetazolamide concentration and plasma chloride ion can prevent overdosage and side effects in elderly glaucoma patients on long-term therapy 5
• Discontinue immediately if signs of hypersensitivity or serious reactions occur 1

Monitoring Recommendations

• Monitor serum electrolytes, particularly potassium and chloride 2, 5
• Monitor renal function in patients with renal insufficiency 4
• Consider monitoring erythrocyte acetazolamide levels in elderly patients on chronic therapy 5