Table 2 Medications for high altitude illness

Acetazolamide

As a sulfonamide, acetazolamide inhibits carbonic anhydrase, which reduces the reabsorption of bicarbonate in the kidneys.⁴⁶⁴ The increased bicarbonate excretion compensates for altitude-induced respiratory alkalosis and shifts toward metabolic acidosis, thereby optimizing respiratory drive and adaptation to high altitude. It also effectively improves altitude-related sleep disorders, primarily periodic breathing, further facilitating acclimatization to hypobaric hypoxia by enhancing sleep quality.⁴⁶⁵ Moreover, emerging research has revealed that acetazolamide can directly affect brain fluid balance by modifying aquaporin and Na channels to decrease water influx into cells.^466,467 Additionally, it possesses anti-inflammatory and antioxidant properties.⁴⁶⁸ These multifaceted mechanisms collectively contribute to its efficacy in preventing AMS and HACE.

Although acetazolamide contains a sulfa moiety, the risk of an allergic reaction in those with sulfonamide allergies is extremely low.⁴⁶⁹ However, for individuals with a history of a severe allergic reactions to sulfonamide medications or Stevens-Johnson syndrome should avoid using acetazolamide. Moreover, it is contraindicated in cases of decreased sodium and/or potassium serum levels, severe kidney and liver diseases or dysfunctions, adrenal gland failure, hyperchloraemic acidosis, and cirrhosis.³⁶⁹

The primary side effect, arising from increased diuresis, is paraesthesias, particularly a “tingling” feeling in the extremities.⁴⁶⁴ Additionally, dizziness, hearing dysfunction or tinnitus, loss of appetite, taste alteration, gastrointestinal disturbances, as well as potential occurrences of kidney stones, myopia, drowsiness, and confusion may also be observed.³⁶⁹ Nevertheless, some of these adverse events can be minimized by using a low-dose regimen.

(1) Prevention: AMS

16 trials (randomized, placebo-controlled); 2301 participants (1255 with acetazolamide and 1046 with placebo).³⁶⁹ Acetazolamide effectively reduced AMS risk.

HACE

6 trials (randomized, placebo-controlled); 1126 participants (586 with acetazolamide and 540 with placebo).³⁶⁹ Acetazolamide effectively reduced HACE risk.

(2) Treatment: AMS

1 trial (randomized, placebo-controlled); 12 participants (6 with acetazolamide and 6 with placebo).⁴²⁷ Acetazolamide improved PaO₂ and AMS.

CMS

3 trials (randomized, placebo-controlled); 127 participants (82 with acetazolamide and 45 with placebo).^60,448,461 Acetazolamide reduced erythrocytosis and improved pulmonary circulation without adverse effects.

Methazolamide

Methazolamide is a potent inhibitor of carbonic anhydrase. By enhancing systemic metabolic acidosis it improves ventilation and oxygenation levels, an effect comparable to that of acetazolamide, which is crucial in reducing the incidence and severity of AMS.⁴⁷⁰ The elevated oxygenation level consequently diminishes the production of ROS,⁴⁷¹ alleviating cerebral edema and HPV,⁴⁷⁰ eliminating hypoxic fatigue, and mitigating excessive erythrocytosis.⁴⁴⁹ Beyond its role as a carbonic anhydrase inhibitor, methazolamide directly activates the antioxidant nuclear factor-related factor 2 (Nrf2) and inhibits the release of interleukin-1β (IL-1β).⁴⁷² This carbonic anhydrase inhibition-independent antioxidative stress ability suggests that methazolamide may be more effective than acetazolamide in reducing ROS levels, positioning it as a superior option for the prevention and treatment of high-altitude illness.

Methazolamide is contraindicated in cases of decreased sodium and/or potassium serum levels, marked kidney and liver diseases or dysfunctions, adrenal gland failure, hyperchloraemic acidosis, and cirrhosis.³⁶⁹

There are several adverse reactions that may occur, especially early in the therapy.³⁶⁹ The most prominent one is paraesthesias, specifically a “tingling” feeling in the extremities. Additionally, hearing dysfunction or tinnitus; fatigue; malaise; loss of appetite; taste alteration; gastrointestinal disturbances such as nausea, vomiting, and diarrhoea; polyuria; and occasional instances of drowsiness and confusion may also be observed.

(1) Prevention: AMS

1 trial (randomized, placebo-controlled); 96 participants (29 with methazolamide and 67 with placebo).³⁷³ Methazolamide significantly lowered AMS incidence.

(2) Treatment: AMS

1 trial (randomized, placebo-controlled); 15 participants (8 with methazolamide and 7 with placebo).⁴⁷³ Methazolamide notably improved AMS.

CMS

Animal study⁴⁴⁹

Dexamethasone

Dexamethasone, a synthetic glucocorticoid, is rapidly absorbed from the gastrointestinal tract. Its primary mechanisms of preventing high-altitude illness include reducing the permeability of cellular and capillary walls, decreasing alveolar inflammatory fluid leakage, inhibiting the formation of substances such as histamine, as well as suppressing hypoxia-induced cyclooxygenase-2 expression and related prostaglandin synthesis.³⁷⁸ Consequently, mitigates edema formation and ICP.⁴⁷⁴

It is contraindicated in patients with systemic fungal infections.³⁶⁹

Common side effects include hyperglycemia, fluid retention, hypokalemic alkalosis, potassium loss, and sodium retention.³⁷⁸ Additionally, dexamethasone has significant side effects on the hypothalamic-pituitary-adrenal axis. It may also elevate heart rate, posing a particular risk to those susceptible to HAPE.

(1) Prevention: AMS

8 trials (randomized, placebo-controlled); 226 participants (116 with dexamethasone and 110 with placebo).³⁷⁸ Dexamethasone could reduce the AMS incidence.

(2) Treatment:

AMS

1 trial (randomized, placebo-controlled); 35 participants (17 with dexamethasone and 18 with placebo group).⁴³⁰ Dexamethasone was more effective than placebo in treating AMS.

Ibuprofen

Non-steroidal anti-inflammatory drugs (ibuprofen, paracetamol, aspirin) alleviate or prevent high-altitude headaches and AMS by inhibiting cyclooxygenase to reduce prostaglandin production, thereby suppressing trigeminovascular sensitization and cerebral microvascular permeability.⁴⁷⁵

Ibuprofen is contraindicated in individuals with a known allergy to aspirin.⁴⁷⁵

It is prone to gastrointestinal bleeding with increased dosage and prolonged use of ibuprofen.³⁸³

(1) Prevention:

AMS

3 trials (randomized, placebo-controlled); 437 participants (257 with ibuprofen and 180 with placebo).^379,380,381 Ibuprofen effectively prevented AMS.

Nifedipine

Since excessive HPV induces HAPE, nifedipine, a Ca2+ channel blocker, can reduce pulmonary vascular resistance by inbihiting Ca2+ influx, thus relieving pulmonary hypertension.²¹⁹

Nifedipine should not be administered to patients with cardiogenic shock as well as with known hypersensitivity to any of its components.³⁶⁹

Common side effects associated with nifedipine include headache, flushing/heat sensation, dizziness, fatigue/asthenia, and nausea.³⁶⁹ Additionally, although hypotension is generally not a concern with the extended-release formulation, it may occur in a few individuals.²⁰

(1) Prevention:

HAPE

1 trial (randomized, placebo-controlled); 21 participants (10 with nifedipine and 11 with placebo).³⁸⁴ Nifedipine lowered PAP and prevented HAPE.

(2) Treatment:

HAPE

2 trials (randomized, placebo-controlled); 201 participants (96 with supplemental O₂ and nifedipine 115 with supplemental O₂ and placebo).^437,439 Oxygen alone was adequate therapy for HAPE and that adjuvant pharmacotherapy with nifedipine did not hasten recovery.

PDE5 inhibitors (tadalafil and sildenafil)

Selective inhibitors of PDE5, such as tadalafil and sildenafil, can induce overproduction of NO, which, in turn, attenuates HPV, leading to a reduction in pulmonary hypertension.⁴⁷⁶

If a subject is using any form of organic nitrate regularly or intermittently, the PDE5 inhibitor is contraindicated as it potentiates the hypotensive effects of nitrates.³⁶⁹

The common side effects include headaches and flushing.³⁶⁹

(1) Prevention:

HAPE

1 trial (randomized, placebo-controlled); 17 participants (8 with tadalafil and 9 with placebo).²³¹ Tadalafil effectively prevented HAPE in susceptible individuals.

HAPH

Animal study^402,403,404

(2) Treatment:

HAPE

1 trial (randomized); 10 participants (7 with sildenafil and nifedipine while 3 with nifedipine alone).⁴³⁵ Limited case series suggested the therapeutic effect of sildenafil on HAPE.

HAPH

1 trial (randomized, placebo-controlled); 17 participants (9 with sildenafil and 8 with placebo).⁴⁵⁵ Sildenafil lowered PAP and improved HAPH.

Salmeterol

Salmeterol has high affinity to the human β2 adrenergic receptor (B2AR), which contributes to the reduction in HPV and PAP, thus relieving pulmonary hypertension.⁴⁷⁷ Additionally, salmeterol enhances alveolar clearance by stimulating amiloride-sensitive sodium (Na) channels, a mechanism that likely improves HAPE occurrence and progression.⁴⁷⁸

It is contraindicated in asthmatic patients and should be used with caution in those with cardiovascular disorders.³⁶⁹

The side - effects include an increased risk of asthma-related death and a range of symptoms such as seizures and abnormal blood pressure.³⁶⁹

(1) Prevention:

HAPE

1 trial (randomized, placebo-controlled); 37 participants (18 with salmeterol and 19 with placebo).²⁵⁸ Salmeterol reduced HAPE incidence but often caused tremor and tachycardia at high dose.