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Abstract/Syllabus:
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Mechanisms of Drug Actions
Fall 2005
Three sets of brain scans from a young adult given a placebo (top) and two different doses of methylphenidate (bottom), showing the ability of methylphenidate to block the transporter "gates" by which the brain chemical dopamine returns to its home cell after sending a pleasure signal. (Image courtesy of the Brookhaven National Laboratory.)
Course Highlights
This course features a complete set of assignments.
Course Description
This course covers the chemical and biological analysis of the metabolism and distribution of drugs, toxins and chemicals in animals and humans, and the mechanism by which they cause therapeutic and toxic responses. Metabolism and toxicity as a basis for drug development is also covered.
Syllabus
Overview
This course covers the chemical and biological analysis of the metabolism and distribution of drugs, toxins and chemicals in animals and humans, and the mechanism by which they cause therapeutic and toxic responses. Metabolism and toxicity as a basis for drug development, metabolic polymorphisms and biomarkers of exposure are also covered.
Texts
Required
Golan, David E., Editor-in-chief; Armen H. Tashjian, Deputy Editor; Ehrin J. Armstrong, et al., eds. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. Baltimore, MD: Lippincott Williams & Wilkins, 2004. ISBN: 9780781746786.
Recommended
Klaassen, Curtis D., ed. Casarett and Doull's Toxicology: The Basic Science of Poisons. 6th ed. New York, NY: McGraw-Hill Medical Pub Division, 2001. ISBN: 9780071347211.
The Biochemistry you need to know or learn for this course
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Structures and Functional Groups
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Nucleophiles/Electrophiles
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Bonding
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Reduction/Oxidation
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Thermodynamics and Equilibria
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Acid/Base Chemistry
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Reaction Kinetics and Mechanisms
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Enzymes
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Lipids
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Mitochondrial Structure and Function
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Metabolism and ATP Generation
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DNA Structure
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Bases, Nucleosides, Nucleotides
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Primary, Secondary Structure
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Proteins/Peptides
Recitations
There will be a recitation session offered throughout the term. Several of these sessions will consist of seminars presented by scientists from local pharmaceutical and biotechnology companies. The other sessions will be run by the TA and will entail answering questions relating to the lecture material, homework assignments, and projects and providing background help with concepts in several areas, including elements of chemistry and biochemistry.
Homework Assignments and Readings
Additional assignments will include:
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specific papers and book chapters;
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problem sets associated with the reading; and
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problem sets relevant to lecture material.
The homework is due as noted in the lecture schedule. There is a 20% reduction in the grade for each day the assignment is late.
Quizzes
There will be two quizzes during the term. All are non-comprehensive, in-class quizzes given during the regular lecture period. There is no final examination.
Team Projects
The class will be divided into groups of 3-5 students (depending on class size) to work as a team on a project to investigate a drug. The investigation will center on concepts developed during the term, with emphasis on understanding drug mechanisms and the successful development of drugs.
Grading Policy
Percentage contributions to the final grade are as follows:
Grading criteria.
ACTIVITIES |
PERCENTAGES |
Quizzes (30% each) |
60% |
Paper |
10% |
Final Team Presentation of Project |
10% |
Homework Assignments |
10% |
Class Participation |
10% |
Calendar
PCD = Prof. Peter Dedon
SRT = Prof. Steven Tannenbaum
Course calendar.
LEC # |
TOPICS |
LECTURERS |
KEY DATES |
1 |
Introduction and Principles |
PCD |
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2 |
Chemistry/Biochemistry Review |
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3 |
Overview of Drug Development |
Guest: Dr. Robert Rubin |
Homework 1 due |
4 |
Uptake/Transport/Distribution of Drugs |
PCD |
|
5 |
Drug Transporters |
Guest: Dr. Keith Hoffmaster |
Homework 2 due |
6 |
Bioethics Seminar |
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7 |
Drug Transporters (cont.) |
Guest: Dr. Keith Hoffmaster |
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8 |
Introduction to Drug Metabolism |
SRT |
|
9 |
Liver Lecture |
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Project teams assigned |
10 |
Drug Metabolism 2 |
SRT |
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11 |
Drug Metabolism 3 |
Guest: Dr. Sean Harriman |
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12 |
Drug Metabolism 4 |
Guest: Dr. Sean Harriman |
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13 |
Quiz Review |
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Homework 3 due one day after Lec #13 |
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Quiz 1 |
SRT |
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14 |
Oxygen Radicals in Drug Toxicity |
SRT |
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15 |
Drug Toxicities |
SRT |
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16 |
Drug Toxicities (cont.) |
SRT |
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17 |
Bioethics Seminar |
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18 |
Pharmacokinetics |
PCD |
Project summaries due
Homework 4 due
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19 |
Pharmacokinetics (cont.) |
PCD |
Homework 5 due |
20 |
Receptors and Case Study - Omeprazole |
PCD |
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21 |
Case Study - Omeprazole |
PCD |
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22 |
Case Study - Omeprazole (cont.) |
PCD |
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23 |
Case Study - Acetaminophen |
SRT |
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24 |
Case Study - Acetaminophen (cont.) |
SRT |
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25 |
Case Study - Statins |
SRT/PCD |
Presentation schedule ready |
26 |
Case Study - Statins (cont.) |
SRT/PCD |
Papers due |
27 |
Drug Industry Seminar |
Guest: Mark Trusheim (Massachusetts Biotech Council) |
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28 |
Case Study - Statins (cont.) |
SRT/PCD |
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29 |
Student Presentations |
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30 |
Quiz Review |
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31 |
Student Presentations (cont.) |
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Quiz 2 |
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Further Reading:
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Readings
A sessionwise listing of readings is included in the table below.
Required Text
[Golan]: Golan, David E., Editor-in-chief; Armen H. Tashjian, Deputy Editor; Ehrin J. Armstrong, et al., eds. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. Baltimore, MD: Lippincott Williams & Wilkins, 2005. ISBN: 9780781746786.
Recommended Text
[C&D]: Klaassen, Curtis D., ed. Casarett and Doull's Toxicology: The Basic Science of Poisons. 6th ed. New York, NY: McGraw-Hill Medical Pub Division, 2001. ISBN: 9780071347211.
Additional Useful Resources
Guyton, Arthur C., and John E. Hall. Textbook of Medical Physiology. 11th ed. Philadelphia, PA: Elsevier Saunders, 2005. ISBN: 9780721602400.
Vander, Arthur, James Sherman, and Dorothy Luciano. Human Physiology: The Mechanisms of Body Function. 8th ed. Boston, MA: McGraw-Hill, 2001. ISBN: 9780072554991.
Gilman, A. G., T. W. Rall, A. S. Nies, and P. Taylor, eds. The Pharmacological Basis of Therapeutics. 8th ed. New York, NY: McGraw-Hill, 2000. ISBN: 9780080402963.
Junqueira, Luiz Carlos, José Carneiro, and Robert O. Kelley. Basic Histology. 9th ed. New York, NY: McGraw-Hill, 1998. ISBN: 9780838505908.
Bloom, William, and Don W. Fawcett. A Textbook of Histology. 10th ed. Philadelphia, PA: W.B. Saunders, 1975. ISBN: 9780721617572.
Readings by Session
Course readings.
LEC # |
TOPICS |
READINGS |
1 |
Introduction and Principles |
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2 |
Chemistry/Biochemistry Review |
|
3 |
Overview of Drug Development |
Golan. Chapters 48 and 51. |
4 |
Uptake/Transport/Distribution of Drugs |
Golan. pp. 27-33. |
5 |
Drug Transporters |
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6 |
Bioethics Seminar |
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7 |
Drug Transporters (cont.) |
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8 |
Introduction to Drug Metabolism |
Golan. Chapter 4.
C&D. Chapter 6.
|
9 |
Liver Lecture |
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10 |
Drug Metabolism 2 |
Golan. Chapter 4.
C&D. Chapter 6.
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11 |
Drug Metabolism 3 |
Golan. Chapter 4.
C&D. Chapter 6.
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12 |
Drug Metabolism 4 |
Golan. Chapter 4.
C&D. Chapter 6.
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13 |
Quiz Review |
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14 |
Oxygen Radicals in Drug Toxicity |
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15 |
Drug Toxicities |
Golan. Chapter 47. |
16 |
Drug Toxicities (cont.) |
Golan. Chapter 47. |
17 |
Bioethics Seminar |
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18 |
Pharmacokinetics |
Golan. Chapter 3. |
19 |
Pharmacokinetics (cont.) |
Golan. Chapter 3.
Farris, F. F., et al. "Cisplatin Pharmacokinetics: Applications of a Physiological Model." Toxicol Lett 43, nos. 1-3 (October 1988): 117-37.
Kartalou, M., and J. M. Essigmann. "Recognition of Cisplatin Adducts by Cellular Proteins." Mutat Res 478, nos. 1-2 (July 1, 2001): 1-21.
Pinto, A. L., and S. J. Lippard. "Binding of the Antitumor Drug Cis-diamminedichloroplatinum(II) (Cisplatin) to DNA." Biochim Biophys Acta 780, no. 3 (1985): 167-80.
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20 |
Receptors and Case Study - Omeprazole |
Golan. Chapters 1, 2, and 44.
de Morais, S. M., et al. "The Major Genetic Defect Responsible for the Polymorphism of S-mephenytoin Metabolism in Humans." J Biol Chem 269, no. 22 (June 3, 1994): 15419-22.
Goldstein, J. A. "Clinical Relevance of Genetic Polymorphisms in the Human CYP2C Subfamily." Br J Clin Pharmacol 52, no. 4 (October 2001): 349-55.
Kendall, M. J. "Review Article: Esomeprazole - The First Proton Pump Inhibitor to be Developed as an Isomer." Aliment Pharmacol Ther 17, no. 1 (February 2003): 1-4.
Lindberg, P., et al. "Review Article: Esomeprazole - Enhanced Bio-availability, Specificity for the Proton Pump and Inhibition of Acid Secretion." Aliment Pharmacol Ther 17, no. 4 (February 15, 2003): 481-8.
———. "The Mechanism of Action of the Gastric Acid Secretion Inhibitor Omeprazole." J Med Chem 29, no. 8 (August 1986): 1327-9.
Sachs, G., et al. "The Pharmacology of the Gastric Acid Pump: The H+,K+ ATPase." Annu Rev Pharmacol Toxicol 35 (1995): 277-305.
Chang, M., et al. "Interphenotype Differences in Disposition and Effect on Gastrin Levels of Omeprazole - Suitability of Omeprazole as a probe for CYP2C19." BR J Clin Pharmacol 39, no. 5 (May 1995): 511-8.
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21 |
Case Study - Omeprazole |
Golan. Chapter 52.
Papers from Lecture 20.
|
22 |
Case Study - Omeprazole (cont.) |
Golan. Chapter 52.
Papers from Lecture 20.
|
23 |
Case Study - Acetaminophen |
Golan. Chapter 40.
Hogestatt, E. D., et al. "Conversion of Acetaminophen to the Bioactive N-acylphenolamine AM404 via Fatty Acid Amide Hydrolase-dependent Arachidonic Acid Conjugation in the Nervous System." J Biol Chem 280, no. 36 (September 9, 2005): 31405-12. Epub (June 29, 2005).
Zhang, J., et al. "Modulation of Acetaminophen-induced Hepatotoxicity by the Xenobiotic Receptor CAR." Science 298, no. 5592 (October 11, 2002): 422-4.
Sueyoshi, T., et al. "The Repressed Nuclear Receptor CAR Responds to Phenobarbital in Activating the Human CYP2B6 Gene." J Biol Chem 274, no. 10 (March 5, 1999): 6043-6.
Knight, T. R., et al. "Peroxynitrite is a Critical Mediator of Acetaminophen Hepatotoxicity in Murine Livers: Protection by Glutathione." J Pharmacol Exp Ther 303, no. 2 (November 2002): 468-75.
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24 |
Case Study - Acetaminophen (cont.) |
Golan. Chapter 40.
Papers from Lecture 23.
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25 |
Case Study - Statins |
Golan. Chapter 22.
Zipes, D. P., et al. "Rosuvastatin: An Independent Analysis of Risks and Benefits." MedGenMed 8, no. 73 (2006).
Alawi, A., et al. "The Safety of Rosuvastatin as used in Common Clinical Practice." Circulation 111 (2005): 3051-3057.
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26 |
Case Study - Statins (cont.) |
Golan. Chapter 22.
Papers from Lecture 25.
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27 |
Drug Industry Seminar |
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28 |
Case Study - Statins (cont.) |
Golan. Chapter 22.
Papers from Lecture 25.
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29 |
Student Presentations |
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30 |
Quiz Review |
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31 |
Student Presentations (cont.) |
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