PY 420 - Med. Chem. I

Case Study #2

Read the following case-study then answer the questions that follow. Email your answers labeled Answers 1 through 6 to Dr. Riley. Deadline for receipt of answers is before or on November 8, 1996.

Erramouspe recently reported (Hospital Pharmacy 1996;31:1275-1282) on the buffering of "local anesthetic solutions". Clinical results indicate that local injection of unbuffered "local anesthetic solutions" is often accompanied by significant pain. "Local anesthetic solutions" for injection may range in pH from 2.8 to 6.4. Buffering of these products to a nearly neutral pH assist in minimizing pain of local injection.

Answers are in red!

1. Explain why the dissolution of local anesthetics in water result in acidic solutions? Also, explain why there are pH differences for aqueous solutions of different local anesthetics.

Local anesthetics of sufficient potency to be used parenterally are strong organic bases and therefore can only dissolved in water as an acid salt. Dissolution of acid salts of local anesthetics confers an acidic pH on the solvent.
Local anesthetic amines differ in their base strengths because of differences in structure and electronic influences (inductive and resonance effects) on the strength of the amine base function and therefore the conjugate acid salts of these amines will differ in acidity.

2. Addition of epinephrine to local anesthetic solutions, a technique used to assist in localizing the pharmacological actions of the local anesthetics, is reported to produce even more acidic aqueous solutions. Explain how this might occur.

Epinephrine, a secondary aliphatic amine, is also a strong organic base and must be incorporated in aqeuous solutions as the conjugate acid salt. Hence, addition of an acid salt of epinephrine to a solution of an acid salt of a local anesthetic will further acidify the squeous solution.

3. Buffered anesthetic injections are reported to have shortened times to onset of analgesia/sensory blockade compared to unbuffered preparations. Provide a rational explanation for this observation.

Buffered solutions of local anesthetics will contain higher concentrations of the unionized local anesthetic compared to more acidic, nonbuffered solutions. Because local anesthetics diffuse to their membrane channel sites of action in the unionized forms, the onset of action will be facilitated in the case of administration of buffered solutions.

4. In preparing buffered injectable solutions of local anesthetics care must be taken to not elevate pH too high so as to avoid formation of a precipitate in the solution as well as to minimize chemical decomposition of the local anesthetic itself over time.

a. Describe the chemistry associated with the formation of a precipitate in these solutions.

Exceeding a certain pH by buffering local anesthetic solutions runs the risk of exceeding the aqeuous solubility of the unionized form of the drug whose concentration increases as the pH is raised.

b. Describe the most likely chemical decomposition that might occur with buffered solutions of bupivacaine (refer to lecture guide, page 17, for structure).

Bupivacaine contains an amide (anilide) function that is subject to alkali-catalyzed hydrolysis that may occur over a protracted period of time in buffered solutions with too high a pH.

5. NaHCO3 and NaOH are commonly used to buffer acidic parenteral solutions. Organic bases, including tromethamine (see structure below) are also useful. Chemically explain how tromethamine can function as a buffer in these cases.

Sodium bicarbonate and sodium hydroxyide are examples of inorganic bases while tromethamine is an organic base that utilizes its primary amine function to accept a proton.

6. Why do these injectable solutions of local anesthetics produce tissue irritation upon administration?

The acidic pH of the local anesthetic solution may contribute to local pain produced by their injection. The precise mechanism of pain induction is not known.

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