Anesthetics physicochemical properties

In this chapter, the voltammetric study of local anesthetics (procaine and related compounds) [14—16], antihistamines (doxylamine and related compounds) [17,22], and uncouplers (2,4-dinitrophenol and related compounds) [18] at nitrobenzene (NB]Uwater (W) and 1,2-dichloroethane (DCE)-water (W) interfaces is discussed. Potential step voltammetry (chronoamperometry) or normal pulse voltammetry (NPV) and potential sweep voltammetry or cyclic voltammetry (CV) have been employed. Theoretical equations of the half-wave potential vs. pH diagram are derived and applied to interpret the midpoint potential or half-wave potential vs. pH plots to evaluate physicochemical properties, including the partition coefficients and dissociation constants of the drugs. Voltammetric study of the kinetics of protonation of base (procaine) in aqueous solution is also discussed. Finally, application to structure-activity relationship and mode of action study will be discussed briefly. 

TABLE 1 Physicochemical Properties of Local Anesthetics at the NB/W Interface... 

Most local anesthetics exist in part in the cationic amphiphilic form (cf. p. 208). This physicochemical property favors incorporation into membrane interphases, boundary regions between polar and apolar domains. These are found in phospholipid membranes and also in ion-channel proteins. Some evidence suggests that Na+-channel blockade results from binding of local anesthetics to the channel protein. It appears certain that the site of action is reached from the cytosol, implying that the drug must first penetrate the cell membrane (p. 206). 

The rate of absorption of a local anesthetic into the bloodstream is affected by the dose administered, the vascularity at the site of injection, and the specific physicochemical properties of the drug itself. Local anesthetics gain entrance into the bloodstream by absorption from the injection site, direct intravenous injection, or absorption across the mucous membranes after topical application. Direct intravascular injection occurs accidentally when the needle used for infiltration of the local anesthetic lies within a blood vessel, or it occurs intentionally when Udocaine is used for the control of cardiac arrhythmias. 

Ensuring an adequate depth of anesthesia depends on achieving a therapeutic concentration of the anesthetic in the CNS. The rate at which an effective brain concentration is achieved (ie, time to induction of general anesthesia) depends on multiple pharmacokinetic factors that influence the brain uptake and tissue distribution of the anesthetic agent. The pharmacokinetic properties of the intravenous anesthetics (Table 25-1) and the physicochemical properties of the inhaled agents (Table 25-2) directly influence the pharmacodynamic effects of these drugs. These factors also influence the rate of recovery when the administration of anesthetic is discontinued. 

The induction of unconsciousness may be the result of exposure to excessive concentrations of toxic solvents such as carbon tetrachloride or vinyl chloride, as occasionally occurs in industrial situations (solvent narcosis). Also, volatile and nonvolatile anesthetic drugs such as halothane and thiopental, respectively, cause the same physiological effect. The mechanism(s) underlying anesthesia is not fully understood, although various theories have been proposed. Many of these have centered on the correlation between certain physicochemical properties and anesthetic potency. Thus, the oil/water partition coefficient, the ability to reduce surface tension, and the ability to induce the formation of clathrate compounds with water are all correlated with anesthetic potency. It seems that each of these characteristics are all connected to hydrophobicity, and so the site of action may be a hydrophobic region in a membrane or protein. Thus, again, physicochemical properties determine biological activity. 

The pharmacological activity of LAs is determined by several physicochemical properties including lipophilicity, protein binding, and pKa which can be explained by their mechanism of action. A general structure - activity relationship was described by Courtney and Strichartz (1987), according to which an increase in the hydrophobicity leads to a parallel increase in anesthetic... 

Table 4. Local anesthetic drugs Physicochemical properties and plasma protein binding.

Propofol is an alkylphenol compound that is highly lipid soluble but water insoluble. Its lipid solubility allows rapid penetration of the blood-brain barrier after i.v. administration, with rapid onset of CNS effects. This physicochemical property also means that rapid redistribution of propofol from the brain to other body tissues plays a significant role in the termination of the anesthetic effect. 

With the difficulties associated with accurate estimation of permeability based only on physicochemical properties, a variety of methods of measuring permeability have been developed and used, among which are (l)cul-tured monolayer cell systems, such as Caco-2 or MDCK ( 2 diffusion cell systems that use small sections of intestinal mucosa between two chambers (3) in situ intestinal perfusion experiments performed in anesthetized animals such as rats and (4)intestinal perfusion studies performed in humans (40,54-62). All of these methods offer opportunities to study transport of drug across biological membranes under well-controlledconditions. Caco-2 mono-layer systems in particular have become increasingly commonly used in recent years and human intestinal perfusion methods are also becoming more commonly available. Correlations between Caco-2 permeability and absorption in humans have been developed in several laboratories (63-72). As shown in Fig. 

The production and maintenance of the anesthetic state is believed by most to be dependent on the concentration, or partial pressure, of the anesthetic agent in yet unknown areas of the brain. Obviously, the concentration of the anesthetic agent in the gas mixture administered, as well as the rate and depth of respiration of the patient, will influence the rate of anesthesia induction. The rate at which delivery of anesthetic agents to these sites occurs is dependent on their physicochemical properties, particularly their solubility in lipid and blood. 

Local anesthetic drugs probably bind to sodium channels in a charged form after they have penetrated the lipid plasma membrane in an uncharged form which explains why physicochemical porperties largely determine their clinical properties including potency, onset and duration of action, and toxicitiy... 

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