Anesthetics ionization

Miyazaki, J. Hideg, K. Marsh, D., Inerfacial ionization and partitioning of membrane-bound local anesthetics, Biochim. Biophys. Acta 1103, 62-68 (1992). 

Structural and theoretical chemistry studies of phenytoin and carbamazepine suggest that they bind to the Na+ channel via a pharmacophore that consists of an aromatic ring and an amide linkage. This pharmacophore consists of two of the three structural features found in local anesthetics. The ionizable group, which is characteristic of local anesthetics, precludes the ability to diffuse across the blood-brain barrier. 

Most local anesthetic agents consist of a lipophilic group (eg, an aromatic ring) connected by an intermediate chain via an ester or amide to an ionizable group (eg, a tertiary amine) (Table 26-1). In addition to the general physical properties of the molecules, specific stereochemical configurations are associated with differences in the potency of stereoisomers (eg, levobupivacaine, ropivacaine). Because ester links are more prone to hydrolysis than amide links, esters usually have a shorter duration of action. 

The local anesthetics are converted in the liver (amide type) or in plasma (ester type) to more water-soluble metabolites, which are excreted in the urine. Since local anesthetics in the uncharged form diffuse readily through lipid membranes, little or no urinary excretion of the neutral form occurs. Acidification of urine promotes ionization of the tertiary amine base to the more water-soluble charged form, leading to more rapid elimination. 

Anesthetics that associate by donor-acceptor (charge transfer) complex formation, either as electron donors (low ionization potential) or as electron acceptors (high electron affinities). There are no confirmed examples of this but fluorocarbon anesthetics containing higher halogens seem to be eligible. 

Ionization Potentials and Ultraviolet Spectra of Anesthetic Molecules... 

Concluding this section all that one can say is that we found no relationship between anesthetic potency and either the ionization potentials or the frequency of the lowest ultraviolet absorption band. The observation that replacement of a fluorine atom by a hydrogen usually lowers the IP is probably of some value. However, as was pointed out above this could only indicate the possibility of charge transfer interaction if the electron affinities followed the same trend. Unfortunately these have not been determined and the variations in the frequencies of the broad UV bands are too irregular to draw conclusions. It seems that there exists an indirect relationship between the acidity of these molecules and their IPs and what counts is their proton donor ability connected with the acidic hydrogen as has been concluded from the infrared studies described in previous sections. 

The pK , values uf a local anesthetic agents have been used asumca.sure of its ionization and, hence, of the lipophilic-tev hydrophilic ratio. At physiological pH. the ratio of ionized to un-ionized molecules in solution may be calculated by asing the appropriate form of the Hcnderson-Ha.sselbalch equation, which states for weak monobasic acids., . Inoii-ionized form)... 

Local anesthetics are weak bases and are usually made as HCl salts which are soluble and stable in water. The pK of the compound determines when the ionized and unionized forms are equal (see Table 1 for values of pK and percentage ionization at pH 7.4). The time of onset of the block is related to diffusion of the anesthetic into the nerve fiber, which occurs only in the unionized, or non-proton-ated form. Sodium bicarbonate is often added (1 mEq(lOml) lidocaine or 0.1 mEq(lOml) ... 

The existence of the blood-brain barrier does not preclude the passage of chemicals into the brain. As is the case with all other cellular membranes in the body, lipid-soluble nonionized chemicals enter the brain by passive diffusion. Anesthetics, ethanol, and CNS depressants, for instance, rapidly diffuse into the brain in a matter of a few seconds or minutes. They also exit the brain rapidly when the concentration gradient between blood and brain is reversed. Elemental mercury, methylmercury, and tetraethyl lead are examples of lipid-soluble forms of metals that easily enter the brain, while the ionized, much less lipid-soluble inorganic salts of mercury and lead penetrate only poorly. 

Agin, Hersh and Holtzman have shown that eq 3 gives an excellent correlation for the relation between minimum blocking concentration (MBC) of 39 local anesthetics in frog sartorius muscle with polarizability (a) and the ionization potential (I) of the drugs. 

Ionization potentials play a certain role in interactions through dispersion forces (eq. [1]). They are an important factor too in associations involving charge transfer. While anesthesia does not involve excited states, knowledge of the latter might be useful in assessing the possibility of charge transfer. Therefore, the photoelectron and ultraviolet absorption spectra of a number of anesthetics and similar molecules have been measured and are briefly described here. 

Answer B. Back to Basic Principles and the Henderson-Hasselbalch relationship. From the table, pH - pKa = -2.2. For a weak base, a value of -2 represents 1% nonionized, so in the present case the percentage of the local anesthetic in the nonionized form is <1%. Local anesthetics usually have reduced activity when injected into tissue that is septic because only a small fraction of the molecules are in the form capable of crossing biomembranes. Remember that this is not the form that interacts with the Na ion channel—that s the ionized form of the local anesthetic. 

Tricaine methanesulfonate (MS-222). Tricaine methanesulfonate (3-aminobenzoic acid ethyl ester methanesulfonate MS-222) is widely used for the sedation and anesthetization of fish. The compound is 0.01% ionized at body pH and has a partition coefficient of 312. This relatively nonpolar lipophilic drug is rapidly absorbed from water and eliminated in freshwater and marine fish species. 

In the solid (crystalline) form the barbituric acid exists in the triketo or lactam form. In aqueous solution tautomerism to the enolic lactim occurs the enolic hydroxyl (at C-2) is acidic acid and is ionized according to the particular drug s pKa (e.g., pentobarbital = 8.0, phenobarbital = 7.5). Titrating such a solution with a stoichiometric equivalent of base such as NaOH will convert the lactam quantitatively to the barbiturate s sodium salt, which can be isolated. Many barbiturates are commercially produced both in the lactam and in the sodium enolate salt form. Of course, the salts are water soluble and thus are used to formulate injectable dosage forms including those for IV anesthetic use. 

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