[LookingForHelp1304]

I am a dermatologist currently studying the chemistry of anesthetics, and I wanted to know if someone could help me better grasp the following text by providing (1) a chemical equation showing the ionized and nonionized forms of lidocaine, (2) how that equation looks when buffering the lidocaine with sodium bicarbonate, and (3) what a pKa equation looks like?

Here is the text I was reading from "Dermatology" by Jean Bolognia

All local anesthetics consist of three parts: (1) a secondary or tertiary amine end, (2) an aromatic end, and (3) an intermediate connecting chain that contains an ester or amide. The aromatic portion is hydrophobic and lipophilic. This is essential to allow the anesthetic to diffuse through nerve cell membranes. The amine portion is hydrophilic and is responsible for the anesthetic's water solubility, which is important for preparing, storing and administering the anesthetic. Local anesthetics are weak organic bases, which, to be water soluble and injectable, require the addition of a hydrochloride salt. In aqueous solution, the salt equilibrates between the ionized and non-ionized form. The ionized form is water soluble, allowing injection into the tissue. However, it is the non-ionized, lipid-soluble base that diffuses through the tissue to the nerve cell membrane, where the ionized cation is responsible for blocking nerve conduction. The dissociation constant (pKa) of each anesthetic determines the proportion of the anesthetic base and its cation at a given pH. The pKa of all local anesthetics is higher than physiologic pH. For most local anesthetics at a pH of 7.4, 80% or more is in the cationic ionized form. An anesthetic with a low pKa will have a rapid onset of action. Alkalinization of the anesthetic solution, as is done with the addition of sodium bicarbonate, will speed its onset of action. However, if the pH is raised too much, the anesthetic may precipitate out of solution. Anesthetic sensitivity to pH also helps explain why infected tissue is difficult to effectively anesthetize. The inflammatory response surrounding the infection acidifies the site (reduces the pH), which reduces the proportion of the anesthetic in the non-ionized lipid-soluble form that is needed for anesthetic action at the nerve cell membrane.

Thank you for helping me understand this stuff. I have a background in organic chemistry, but it has been some time since I used it. I feel that having some acid base quations in front of me might help with my understanding.

Thanks in advance!

[Honclbrif]

1. There are two nitrogen atoms in lidocaine, the amide nitrogen (bonded to the carbonyl [C=O] and phenyl ring), and the tertiary amine (bonded to two ethyl groups [-CH₂CH₃]). Without getting too deep into why, the tertiary amine is the only one which will demonstrate appreciable acid/base properties around physiological pH because its lone pair is more accessible. In the cationic protonated form, this nitrogen atom is bonded to three carbon atoms and one hydrogen atom. In the nonionic free base form, it is bonded only to carbons. The acid base reaction you are considering is this nitrogen atom accepting or donating a hydrogen ion (we chemists like to call them protons).

2. Compare the pK_as of the lidocaine cation and the bicarbonate anion. The species with the lower pK_a is a better acid and will donate a proton. The species with the higher pK^a is a better base and will accept a proton. Make sure your masses and charges balance.

3. pK_a is the negative log of the K_a (acid dissociation constant). An acid dissociation constant is the equilibrium constant for an acid dissolved in water. An equilibrium constant is equal to the concentration of products over the concentration of reactants when the system is in equilibrium.

Consider the cationic acid HL⁺ dissociating in water. The equation would be:

HL⁺ + H₂O  H₃O⁺ + L

The Ka of this equation would be:

K_a = [H₃O⁺][L]/[HL⁺]

Square brackets are short hand for molar concentration

[Honclbrif]

Edit: all acid/base chemistry is relative. You can not say that something is and always will act as a base, or an acid. You have to consider its pK_a relative to the solution it is in.

pH = pK_a when the species is 50% ionized. So for lidocaine, when the concentration of lidocaine cation is equal to the concentration of lidocaine free base, the pH of the solution is equal to the pKa of the lidocaine cation.

Another way of looking at this, is if you put the lidocaine cation in a solution with a pH that is greater than its pK_a, it will overall act as an acid and donate protons to the solution. If you put the lidocaine cation in a solution with a pH lower than its pKa, it will overall act as a base and accept protons from the solution.