## Mechanism of Cyanide Toxicity **Key Point:** Cyanide binds with high affinity to the ferric iron (Fe³⁺) in cytochrome c oxidase (Complex IV), the terminal enzyme of the electron transport chain. ### Pathophysiology 1. **Binding site**: Cyanide forms a stable complex with the Fe³⁺ in the heme a₃ prosthetic group of cytochrome c oxidase 2. **Result**: Blocks electron transfer to oxygen, halting aerobic respiration 3. **Consequence**: Cells shift to anaerobic metabolism → lactic acidosis and cellular hypoxia despite normal oxygen saturation ### Why Complex IV? Cytochrome c oxidase is the terminal enzyme where electrons are finally transferred to O₂. Cyanide's affinity for Fe³⁺ is extremely high (Kd in the nanomolar range), making this binding essentially irreversible at physiologic concentrations. **High-Yield:** This is why cyanide poisoning causes **histotoxic hypoxia** — cells cannot use oxygen even when it is available. Arterial oxygen saturation and PaO₂ remain normal, but tissues cannot extract oxygen. **Clinical Pearl:** The brain and heart are most vulnerable due to their high metabolic demand and dependence on aerobic respiration.
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