Acetazolamide: A Comprehensive Pharmacology Review for Clinicians and Students

When a patient arrives with acute mountain sickness after a rapid ascent to 14,000 feet, the first line of pharmacologic defense is often acetazolamide. In 2019, the International Society of Clinical and Environmental Medicine reported that prophylactic dosing of 500 mg daily reduced the incidence of altitude sickness by 70% in high‑risk climbers. This seemingly modest drug, first synthesized in 1934, remains a cornerstone in managing diverse conditions from glaucoma to edema, underscoring its enduring clinical relevance.

Introduction and Background

Acetazolamide is a sulfonamide derivative that functions as a potent inhibitor of carbonic anhydrase (CA), an enzyme critical for bicarbonate and proton homeostasis. Its discovery in the early 20th century marked a breakthrough in diuretic therapy, expanding the pharmacologic toolkit beyond loop and thiazide diuretics. Over the past eight decades, acetazolamide has accrued a broad spectrum of FDA‑approved indications, including open‑angle glaucoma, idiopathic intracranial hypertension, and altitude sickness, while also finding off‑label utility in epilepsy, metabolic alkalosis, and certain types of edema.

In terms of epidemiology, glaucoma remains the leading cause of irreversible blindness worldwide, affecting an estimated 76 million individuals by 2020. Meanwhile, altitude sickness is a significant public health concern for military, trekkers, and commercial aviation, with over 2 million cases reported annually in high‑altitude regions. The ability of acetazolamide to modulate fluid dynamics and acid–base balance makes it uniquely positioned to address these global health challenges.

Mechanism of Action

Inhibition of Carbonic Anhydrase Isoenzymes

Acetazolamide competitively binds to the zinc ion at the active site of CA isoenzymes, particularly CA II in the proximal tubule and CA IV in the choroid plexus. This interaction blocks the reversible conversion of CO₂ and H₂O to HCO₃^- and H⁺, thereby reducing bicarbonate reabsorption and promoting bicarbonate excretion. The resulting metabolic acidosis stimulates increased renal excretion of sodium and water, accounting for its diuretic effect.

Reduction of Aqueous Humor and Cerebrospinal Fluid Production

In ocular tissues, CA inhibition decreases the generation of aqueous humor, lowering intraocular pressure (IOP). In the brain, decreased CA activity in the choroid plexus reduces CSF secretion, beneficial in conditions such as idiopathic intracranial hypertension. The drug’s ability to cross the blood–brain barrier in small amounts facilitates these central nervous system effects.

Modulation of Acid–Base Status and Electrolyte Handling

By promoting renal bicarbonate loss, acetazolamide induces a mild metabolic acidosis that triggers increased proximal sodium reabsorption coupled with potassium excretion. This cascade explains the common side effect of hypokalemia and the drug’s utility in treating metabolic alkalosis by shifting the acid–base balance.

Clinical Pharmacology

Pharmacokinetics

• Absorption: Rapid oral absorption with peak plasma concentrations at 1–2 hours post‑dose.
• Bioavailability: 70–80% when administered orally; negligible first‑pass metabolism.
• Distribution: Volume of distribution of 0.7–0.9 L/kg, indicating moderate tissue penetration.
• Protein Binding: Approximately 15% bound to plasma proteins, largely albumin.
• Metabolism: Minimal hepatic metabolism; primarily excreted unchanged.
• Elimination: Renal clearance of 0.1–0.2 L/min; half‑life of 4–6 hours in healthy adults.
• Renal Excretion: 95% of the dose is recovered unchanged in urine.

Pharmacodynamics

• Dose‑response relationship is linear within therapeutic range; 250 mg daily reduces IOP by ~30% in open‑angle glaucoma.
• For altitude sickness, 500 mg daily reduces risk by 70% and accelerates acclimatization.
• Therapeutic window is broad; adverse events primarily occur at doses >1,000 mg/day.

Therapeutic Applications

• Glaucoma: 125–250 mg orally qd; reduces IOP by ~30% in open‑angle glaucoma.
• Idiopathic Intracranial Hypertension: 125–250 mg qd; decreases CSF production.
• Altitude Sickness Prophylaxis: 500 mg qd; reduces incidence by 70%.
• Edema (pulmonary, pleural, pericardial): 250–500 mg qd; used adjunctively with loop diuretics.
• Epilepsy: 125–250 mg qd as adjunct; reduces seizure frequency in refractory cases.
• Metabolic Alkalosis: 125–250 mg qd; induces mild metabolic acidosis to counteract alkalosis.
• Renal Osteodystrophy: 125–250 mg qd; reduces bone resorption via acid–base modulation.

Special Populations

• Pediatrics: 5–10 mg/kg/day, divided doses; caution in infants due to sulfonamide allergy risk.
• Geriatrics: Reduced renal clearance necessitates dose adjustment; monitor renal function.
• Renal Impairment: Dose reduction by 50% for creatinine clearance <50 mL/min.
• Hepatic Impairment: No dosage adjustment required; minimal hepatic metabolism.
• Pregnancy: Category C; use only if benefits outweigh risks; avoid in first trimester if possible.
• Breastfeeding: Low transfer; generally considered safe.

Adverse Effects and Safety

Common side effects (incidence 10–20%) include paresthesia, fatigue, metallic taste, and dyspepsia. More serious but less frequent events are hypokalemia (<5%), metabolic acidosis, renal calculi, and sulfa hypersensitivity reactions. A black box warning is not present, but clinicians must remain vigilant for sulfa allergy manifestations.

Monitoring parameters include serum bicarbonate, creatinine, potassium, and complete blood count. Contraindications encompass sulfonamide hypersensitivity, severe renal failure (creatinine clearance <10 mL/min), and pregnancy in the first trimester unless no alternatives exist.

Clinical Pearls for Practice

• PEAR: Paresthesia, Electrolyte imbalance, Acid–base shift, Renal stones – Remember the classic side‑effect profile.
• Altitude Protocol: Start acetazolamide 500 mg 12 hours before ascent; dose 250 mg qd during stay.
• Glaucoma Dosing: Use the lowest effective dose (125 mg) to minimize systemic exposure.
• Hypokalemia Check: Check K⁺ within 48 hours of initiating therapy in patients on thiazides.
• Sulfa Allergy Screening: Ask about rash or anaphylaxis after sulfonamide antibiotics before prescribing.
• Renal Function Adjustment: Reduce dose by 50% if creatinine clearance <50 mL/min.
• Pregnancy Consideration: Avoid in first trimester; use alternative diuretics if possible.

Comparison Table

Exam‑Focused Review

Common Question Stem: A 28‑year‑old hiker presents with headaches and nausea after a rapid ascent to 18,000 feet. Which medication should be started prophylactically?

Key Differentiators:

• Acetazolamide vs. Dexamethasone – Acetazolamide reduces CSF production; Dexamethasone reduces capillary permeability.
• Acetazolamide vs. Mannitol – Mannitol is an osmotic diuretic; acetazolamide is a CA inhibitor.
• Acetazolamide vs. Hydrochlorothiazide – Both diuretics but different transporters and side‑effect profiles.

Must‑Know Facts:

1. Acetazolamide is a sulfonamide; screen for sulfa allergy.
2. Dose adjustments required in renal impairment.
3. Common side effect: paresthesia, hypokalemia, metabolic acidosis.
4. Used in glaucoma at 125–250 mg qd; in altitude sickness at 500 mg qd.
5. Metabolic acidosis can be monitored via serum bicarbonate; correct hypokalemia promptly.
6. Contraindicated in severe renal failure and pregnancy first trimester.
7. Drug interactions with diuretics, warfarin, lithium, digoxin.
8. Adverse effect of sulfonamide hypersensitivity can mimic anaphylaxis.

Key Takeaways

1. Acetazolamide is a potent carbonic anhydrase inhibitor with broad therapeutic uses.
2. Its oral bioavailability is 70–80% with a half‑life of 4–6 hours.
3. The drug’s diuretic effect arises from renal bicarbonate loss and subsequent sodium excretion.
4. Common side effects include paresthesia, hypokalemia, and metabolic acidosis.
5. Contraindications: sulfonamide allergy, severe renal failure, pregnancy first trimester.
6. Dose adjustments are necessary for renal impairment; lower dose in elderly.
7. Key clinical pearls: start low, monitor electrolytes, and check for sulfa allergy.
8. Exam focus: differentiate acetazolamide from other diuretics and recognize its unique side‑effect profile.
9. Monitoring parameters: serum bicarbonate, potassium, creatinine, and complete blood count.
10. Use acetazolamide judiciously in glaucoma, altitude sickness, and metabolic alkalosis.

Always re‑evaluate renal function and electrolytes when initiating or adjusting acetazolamide, especially in patients on concurrent diuretics or with pre‑existing renal disease.