Figure 11-12 Distribution of fentanyl within the body compartments at the extracellular pH of 7.4. The accumulation of fentanyl by the tissue is assumed to be 13-fold. In the extracellular space, an equilibrium exists between the ionized fentanyl (F⁺ ), the free base (F), and the fentanyl molecules bound to macromolecules (F_b ). The concentration of ionized fentanyl within the interstitial fluid (encircled F⁺ ) determines the pharmacologic effect, because the opioid receptors are located at the cell surface. Fentanyl as free base readily penetrates into the cells and becomes bound to cytomembranes, lysosomes, and other structures (thick arrows) and thus accumulates in the cell. A small decrease of the extracellular pH will shift the equilibrium between F and F⁺ toward higher F⁺ concentrations and will induce a marked release of fentanyl from the cellular compartment as a result of the decrease of the concentration of F in the interstitium. An increase of the extracellular H⁺ concentration by pH 0.2 might roughly double the concentration of ionized fentanyl within the interstitial fluid and accordingly enhance its pharmacologic effect. (From Lullmann H, Martins BS, Peters T: pH-dependent accumulation of fentanyl, lofentanil and alfentanil by beating guinea pig atria. Br J Anaesth 57:1012–1017, 1985.)