Pharmacology of acute mountain sickness: old drugs and newer thinking

Pharmacotherapy in acute mountain sickness (AMS) for the past half century has largely rested on the use of carbonic anhydrase (CA) inhibitors, such as acetazolamide, and corticosteroids, such as dexamethasone. The benefits of CA inhibitors are thought to arise from their known ventilatory stimulation and resultant greater arterial oxygenation from inhibition of renal CA and generation of a mild metabolic acidosis. The benefits of corticosteroids include their broad-based anti-inflammatory and anti-edemagenic effects. What has emerged from more recent work is the strong likelihood that drugs in both classes act on other pathways and signaling beyond their classical actions to prevent and treat AMS. For the CA inhibitors, these include reduction in aquaporin-mediated transmembrane water transport, anti-oxidant actions, vasodilation, and anti-inflammatory effects. In the case of corticosteroids, these include protection against increases in vascular endothelial and blood-brain barrier permeability, suppression of inflammatory cytokines and reactive oxygen species production, and sympatholysis. The loci of action of both classes of drug include the brain, but may also involve the lung as revealed by benefits that arise with selective administration to the lungs by inhalation. Greater understanding of their pluripotent actions and sites of action in AMS may help guide development of better drugs with more selective action and fewer side effects.