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Midazolam configurations. The midazolam molecule exists in an open ring, water soluble state while in formulated solutions for parenteral injection. When subjected to physiologic pH upon administration, the ring closes, rendering the molecule highly lipid soluble.

Drug absorption. Following oral (PO) or topical administration, a drug requires lipid solubility in order to diffuse through the epithelium to reach the capillaries. When administered by intramuscular (IM) or subcutaneous (SC) injection, lipid solubility is not required to reach the capillaries. Once absorbed following PO administration, a drug must travel through the portal system to liver before reaching systemic circulation (venae cavae). See text for further explanation.

Drug distribution. Drug molecules (D) circulate in blood stream unbound and bound to plasma proteins. Only unbound drug is free to distribute into tissues. Systemically, distribution is a simple matter of diffusion through the loosely-joined endothelium of the capillaries. Distribution to the brain requires lipid solubility because the capillary endothelium is tightly bound and wrapped with astrocytes.

Circulation and distribution. Drug (D) circulating in the bloodstream can distribute easily through systemic capillaries into most body tissues. Distribution through central nervous system capillaries (blood-brain barrier) requires lipid solubility. Notice that a portion of the total drug circulating may be temporarily bound to plasma protein but readily dissociates to distribute into tissues. See text for further explanation.

Onset and duration of sedation. Following absorption, serum concentrations are high and drug distributes to tissues in proportion to their degree of perfusion; brain, muscle, and finally adipose tissues. As distribution proceeds, serum level declines and high concentrations in brain redistribute into the bloodstream. These processes occur more rapidly with highly lipid soluble drugs and account for rapid onset but shortened duration of sedation. Drug elimination follows subsequently.

Local anesthetic action. An injected local anesthetic exists in equilibrium as a quaternary salt (BH⁺) and tertiary base (B). The proportion of each is determined by the pKa of the anesthetic and the pH of the tissue. The lipid-soluble species (B) is essential for penetration of both the epineurium and neuronal membrane. Once the molecule reaches the axoplasm of the neuron, the amine gains a hydrogen ion, and this ionized, quaternary form (BH⁺) is responsible for the actual blockade of the sodium channel. Presumably, it binds within the sodium channel near the inner surface of the neuronal membrane.

Local anesthetic action. An injected local anesthetic exists in equilibrium as a quaternary salt (BH⁺) and tertiary base (B). The proportion of each is determined by the pKa of the anesthetic and the pH of the tissue. The lipid-soluble base (B) is essential for penetration of both the epineurium and neuronal membrane. Once the molecule reaches the axoplasm of the neuron, the amine gains a hydrogen ion, and this ionized, quaternary form (BH⁺) is responsible for the actual blockade of the sodium channel. The equilibrium between (BH⁺) and (B) is determined by the pH of the tissues and the pKa of the anesthetic (pH/pKa).

Mechanism of N₂O-induced anxiolysis. N₂O is thought to cause activation of the benzodiazepine (BZ) binding site as its effects are blocked by flumazenil. This action facilitates γ-aminobutyric acid (GABA) activation of its binding site, resulting in chloride ion influx. The increased chloride ion concentration in the neuron might cause activation of calmodulin (CaM), which then activates the enzyme nitric oxide synthase (NOS). NOS converts the amino acid L-arginine (L-Arg) to L-citrulline (L-Cit) and NO, which stimulates the enzyme soluble guanylyl cyclase producing the second messenger cyclic guanosine monophosphate (cyclic GMP). The cyclic GMP, in turn, stimulates a cyclic GMP-dependent protein kinase (PKG) that leads to the anxiolytic drug effect.