Anesthetic molecules

A number of anesthetic molecules, including procaine, benzocaine, chloroprocaine, butyl -aininobenzoate, and 2-aminopicoUne, possess primary amino groups. These groups provide a means for the attachment of the bioactive molecules to a pol3 hosphazene skeleton through the chemistry shown in Scheme I (33). 

The object of inhalation anesthetics is to obtain a concentration (partial pressure) of the drug in the brain sufficient to reach the desired level of anesthesia. In order to do this, anesthetic molecules must pass through the lungs into the brain through various biological phases. Therefore, inhalation anesthetics must be soluble in blood and interstitial tissue. 

Hydrate hypothesis Anesthetic molecules can form hydrates with stractured water, which can stop brain function in corresponding areas. However, the correlation between the ability to form hydrates and the activity of inhalation anesthetics is not known. 

Membrane conformational changes are observed on exposure to anesthetics, further supporting the importance of physical interactions that lead to perturbation of membrane macromolecules. For example, exposure of membranes to clinically relevant concentrations of anesthetics causes membranes to expand beyond a critical volume (critical volume hypothesis) associated with normal cellular function. Additionally, membrane structure becomes disorganized, so that the insertion of anesthetic molecules into the lipid membrane causes an increase in the mobility of the fatty acid chains in the phospholipid bilayer (membrane fluidization theory) or prevent the interconversion of membrane lipids from a gel to a liquid form, a process that is assumed necessary for normal neuronal function (lateral phase separation hypothesis). 

FIGURE 11-2 Schematic illustration of two possible ways general anesthetics may act on the nerve membrane. In the general perturbation theory, anesthetic molecules lodge in the lipid bilayer and inhibit sodium channel function by disrupting membrane structure. In the specific receptor theory, anesthetics inhibit the opening of the sodium channel by binding directly to the channel protein. 

Exactly how local anesthetics inhibit the sodium channel from opening has been the subject of much debate. Although several theories exist, the current consensus is that local anesthetics temporarily attach to a binding site or receptor located on or within the sodium channel.16,36,60 These receptors probably control the opening of the channel, and when bound by the anesthetic molecule, the sodium channel is maintained in a closed, inactivated position. Several sites have been proposed to explain exactly where the local... 

Fig. 3.18 (A) Schematic drawing of a phospholipid bilayer containing a membrane-solvated globular protein that has a sodium channel in the closed configuration. (B) The globular protein has expanded in conformation to allow a sodium ion influx. (C) Anesthetic molecules have fluidized the entire bilayer and destroyed the regions of solid phase.

Interesting calculations have been carried out by others dealing with the interaction of anesthetic molecules on lipids and proteins. For example, at the MAC, the concentration of anesthetic molecules in the hydrophobic phase is approximately 50 mM. Assuming that the anesthetic molecules are uniformly distributed throughout the lipid bilayer of a cell membrane of thickness 50 A, there would be only one anesthetic molecule for every 60 lipid molecules (i.e., 1.5 percent of the molecules in the membrane and only 0.5 percent of the membrane volume). Under these circumstances, the anesthetic molecules would be distributed too diffusely to have a significant effect on membrane status. If, however, anesthetic molecules became preferentially located adjacent to a protein, then a local effect on protein function might occur. 

Anesthetic molecules whose associations are determined essentially by their polarizabilities. This relates to non-polar anesthetics where all the assodation energy is due to dispersion forces only or to dispersion forces and ion or dipole-... 

Ionization Potentials and Ultraviolet Spectra of Anesthetic Molecules... 

The bands of next higher energy in these spectra correspond to orbitals strongly populated in the C—X (X=Cl, Br or I) bonds, followed by those of mainly C—H character. Table 5 lists a few data for simple halogenated methane derivatives relevant to the subsequent discussion on anesthetic molecules ... 

Each local anesthetic molecule has three general areas a lipophilic portion containing an aromatic ring, an intermediate chain and a hydrophilic amine functionality. The structure-activity relationships for local anesthetics can be described in terms of structural modifications to each of these three areas. Depending on the structure of the intermediate chain, local anesthetics are classified as either esters or amides. 

With EMLA, liposoluble anesthetic molecules penetrate the stratum comeum and the rest of the epidermal barrier and soon reach the skin nerve endings. The phenol, which is also liposoluble, can get through the epidermis more quickly. On the surface the shorter contact time between the epidermis and the phenol could reduce epidermal liquefaction. Deep down, a higher concentration of phenol in the reticular dermis could cause the formation of retractile scar tissue. The concentration gradient created in the perivascular spaces of the dermis speeds up the absorption of phenol. The risk of systemic toxicity can also increase. EMLA causes vasoconstriction followed by vasodilation. Vasodilation can sometimes be seen after only 30 minutes of EMLA under occlusion. How will these vasomotor changes affect the effectiveness or absorption of phenol - and therefore its toxicity ... 

Anesthetic molecules whose associations are determined essentially by their... 

Table 2. Chemical shifts of some anesthetic molecules determined with a JEOL JNM 4-H-lOO spectrometer — in absence of a proton acceptor with pyridine as proton acceptor...

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