Why is acetazolamide used in the prevention of altitude sickness?

Why Acetazolamide is Used for Altitude Sickness Prevention

Acetazolamide prevents altitude sickness by inducing metabolic acidosis through carbonic anhydrase inhibition, which stimulates ventilation and improves oxygenation at high altitude. 1

Mechanism of Action

Acetazolamide works as a carbonic anhydrase inhibitor that produces several beneficial physiological effects at altitude:

• Induces metabolic acidosis that stimulates the respiratory drive, leading to increased ventilation even during sleep 1
• Improves arterial oxygen saturation by enhancing alveolar ventilation, with studies showing nocturnal oxygen saturation increases to 88-91% at altitude 2
• Reduces periodic breathing and central sleep apnea that commonly occurs at high altitude 2
• Produces mild diuresis that may help counteract fluid retention associated with altitude exposure 1

The drug essentially accelerates the natural acclimatization process by mimicking the respiratory compensation that would otherwise take days to develop naturally 3, 4.

Evidence of Effectiveness

A systematic review and meta-analysis demonstrated that acetazolamide prophylaxis provides a 48% relative risk reduction in acute mountain sickness (AMS) compared to placebo. 3

Key efficacy data includes:

• Reduces AMS incidence from 45% to 14% in high-risk rapid ascent scenarios (sea level to 4300m), with a number needed to treat of only 3 5
• Decreases symptom severity including headache, nausea, vomiting, and weakness 4
• Improves objective measures such as reduced proteinuria and peripheral edema 4
• Reduces blood pressure elevations at altitude by 7-10 mmHg systolic, which may protect against cardiovascular complications 2

Recommended Dosing

The standard prophylactic dose is 250 mg twice daily or 500 mg once daily, though lower doses of 125 mg twice daily (250 mg/day total) have similar efficacy with potentially fewer side effects. 1, 3

• Begin acetazolamide 1-3 days prior to ascent and continue during the initial days at altitude 1, 5
• Lower doses (250 mg/day) are equally effective as higher doses for AMS prevention and may have a more favorable side-effect profile 3
• The drug should be continued for 3-4 days after reaching terminal altitude 1

Special Populations and Considerations

Cardiovascular Patients

• May reduce subendocardial ischemia risk at high altitude in healthy subjects, though data in patients with coronary artery disease is lacking 2
• Lowers blood pressure at altitude while improving oxygen saturation and mountain sickness symptoms 2
• Use cautiously with other diuretics in heart failure patients due to increased risk of dehydration and electrolyte imbalances 2

Women

• Acetazolamide is recommended as preventive medication for women who may have increased vulnerability to AMS, though sex-specific dosing is not established 2

High-Risk Scenarios

• Particularly important for rapid ascent from sea level to >3350m (11,000 feet), where AMS risk ranges from 35-50% 6
• This risk level is comparable to traveler's diarrhea in high-risk destinations, making prophylaxis highly justified 6

Common Pitfalls and Side Effects

Adverse effects are common but generally mild and dose-related:

• Paresthesias (tingling in fingers, toes, lips) are the most frequent side effect 2
• Altered taste (particularly with carbonated beverages) 2
• Polyuria from the mild diuretic effect 1
• Vertigo in some individuals 2

Critical caveat: The drug's urinary excretion and efficacy are not significantly altered by altitude exposure itself, so standard dosing applies 7. However, adequate hydration must be maintained as dehydration can worsen altitude symptoms 1.

Comparison to Alternatives

While acetazolamide is first-line for AMS prevention 1:

• Dexamethasone is an alternative when acetazolamide is contraindicated, though it may work partly through euphoric effects 1, 4
• Nifedipine is specifically indicated for high-altitude pulmonary edema (HAPE) prevention, not general AMS 1
• Gradual ascent remains the most effective prevention method (300-600m/day above 2500m), with acetazolamide serving as an adjunct or alternative when rapid ascent is unavoidable 1