Carbonic anhydrase inhibitors and high altitude illnesses

Carbonic anhydrase (CA) inhibitors, particularly acetazolamide, have been used at high altitude for decades to prevent or reduce acute mountain sickness (AMS), a syndrome of symptomatic intolerance to altitude characterized by headache, nausea, fatigue, anorexia and poor sleep. Principally CA inhibitors act to further augment ventilation over and above that stimulated by the hypoxia of high altitude by virtue of renal and endothelial cell CA inhibition which oppose the hypocapnic alkalosis resulting from the hypoxic ventilatory response (HVR), which acts to limit the full expression of the HVR. The result is even greater arterial oxygenation than that driven by hypoxia alone and greater altitude tolerance. The severity of several additional diseases of high attitude may also be reduced by acetazolamide, including high altitude cerebral edema (HACE), high altitude pulmonary edema (HAPE) and chronic mountain sickness (CMS), both by its CA-inhibiting action as described above, but also by more recently discovered non-CA inhibiting actions, that seem almost unique to this prototypical CA inhibitor and are of most relevance to HAPE. This chapter will relate the history of CA inhibitor use at high altitude, discuss what tissues and organs containing carbonic anhydrase play a role in adaptation and maladaptation to high altitude, explore the role of the enzyme and its inhibition at those sites for the prevention and/or treatment of the four major forms of illness at high altitude.