Anesthetics Case Study

1. The local anesthetics dibucaine (basic pKa=8.8) and articaine (basic pKa=7.8) are frequently used as local anesthetics. What is the percentage of unionized drug present at pH 7.4? Why is the amount of unionized drug important for the action of local anesthetics? Inflammed tissue (caused by wounds or infections) frequently has a lower, more acidic pH environment. How would a more acidic pH affect the amount of unionized drug? (10 points)

Dibucaine (basic pKa= 8.8) pH= 7.4 (Healthy tissue)

Percent of ionization:

%ionized =

%ionized= 100/1+10 7.4-8.8 = 96.171%

%Unionized state: 100-96.171= 3.83% pH≈ 6.4 (Inflamed tissue)

%ionized= 100/1+10 6.4-8.8 = 99.603%

%Unionized state: 100-99.603= 0.396%

Articaine (basic pKa=7.8) pH= 7.4 (Healthy

2008; 1: 41–48. Published online 2008 Nov 13. PMCID: PMC3218719, retrieved on: 03/10/2016 from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3218719/

2- Foye’s Principles of Medicinal Chemistry, 6th edition, Chapter 16/Inhibitors of Nerve Conduction: Local Anesthetics; edited by: L.Lemke, Thomas;Williams, David A.; Roche, Victoria; Zito,S.William

3- Dr.Grundmann, Oliver, Pharmaceutical chemistry 1 (PHA6444), Module 8, Anesthetics, Spring 2016, University of Florida

4- Dr.Grundmann, Oliver, Fundamental of Pharmaceutical chemistry (PHA6432), Module 1, Drug action and drug discovery, Fall 2015

2. A publication by Wade and Stevens from 1981 (Anesth Analg. 1981 Sep;60(9):666-82) states that isoflurane is a significant improvement over other inhalable anesthetics. Explain this statement and list advantages and disadvantages of isoflurane. What significant advancements have been made since then and how is isoflurane mainly used today (5

Select a drug discussed in this module and describe its mechanism of action, structure-activity relationship, and general metabolic pathways (5 points).

Ropivacaine is the first optically active, amino-amide, type local anesthesia, which is marketed recent years.

Ropivacaine was developed, to decrease cardiotoxicity, the major side effect associated with bupivacaine, and also improve relative motor and sensory blockage profile.

Ropivacaine exhibits its mechanism of action by inhibiting sodium ion influx. Sodium influx is essential for production of signal propagation and also action potential. Hence, Ropivacaine halts impulse conduction in nerve fibers. In compare to bupivacaine, Ropivacaine, is less lipophilic, therefore it cannot penetrate into the large myelinated motor fibers. Hence, it acts more selectively on the pain-transmitting A B and C nerves.

Ropivacaine plasma concentration is depends on the dose and total administration route, and also the hemodynamic of the patient.

Ropivacaine plasma bounding is 94% , and largely binds to α1-acid glycoprotein. It has a half life of 108 mins, with pKa of 8.1, therefore at physiological Ph (7.4),16.6% of Ropivacaine is in its un-ionized