Antihypoxic drugs are vital for protecting cells from oxygen deprivation in ischemia, stroke and heart failure. Despite their clinical potential, a unified understanding of their mechanisms and optimization strategies remains limited. This review addresses this gap by exploring how these agents interact with mitochondrial and cardiovascular ion channels to preserve cellular viability under hypoxic stress. We focus on their modulation of mitochondrial permeability transition pores (mPTP), ATP-sensitive potassium (K-ATP) channels and calcium flux through L-type and R-type channels, which are central to maintaining mitochondrial integrity and vascular function. Additionally, we examine how these compounds regulate hypoxia-inducible factor 1-alpha (HIF-1α), promote efficient electron transport and sustain redox homeostasis. Key strategies for enhancing therapeutic efficacy such as increasing lipophilicity, introducing conjugated π-systems and modifying functional groups are discussed in relation to membrane permeability and intracellular delivery. Particular emphasis is placed on the physicochemical properties that influence bilayer penetration and target specificity. Overall, this review highlights the structural and functional features that underlie the effectiveness of antihypoxic agents and provides insight into their optimization for improved clinical performance in hypoxia-related pathologies.
