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Pharmacodynamics Ed Bilsky, Ph.D. Department of Pharmacology University of New England The New York Tomes, February 20, 2005 For Pain Management, Doctors Prescribe Caution By MARY DUENWALD "All of us have been reacting to the news as it comes forward, as to whether some of our tools will be taken off the market," said Dr. Raymond Gaeta, an anesthesiologist who directs Stanford's pain management clinic. "This is good news for patients over all. Clearly there are side effects with every medication, but it's really important to weigh the potential side effects versus the benefits for an individual patient." Transmembrane Signaling Katzung, 2-8 Molecular Drug Targets Target Drugs opioid receptors morphine, naloxone b receptors albuterol, metoprolol estrogen receptors ethinyl estradiol, tamoxifen voltage gated Na+ channels lidocaine acetylcholinesterase neostigmine, organophosphates cyclooxygenase aspirin catecholamine reuptake cocaine Drug/Receptor Interactions Downloaded from: StudentConsult (on 30 January 2006 03:27 AM) © 2005 Elsevier Glucocorticoid Action Katzung, 2-9 Epidermal Growth Factor Receptor Katzung, 2-10 Ion Channels Katzung, 2-12 G-Protein Coupled Receptors Katzung, 2-12 Graded Responses Downloaded from: StudentConsult (on 30 January 2006 03:27 AM) © 2005 Elsevier Concentration-Response Curve Downloaded from: StudentConsult (on 30 January 2006 03:27 AM) © 2005 Elsevier Quantal Dose-Response Curve Downloaded from: StudentConsult (on 30 January 2006 03:27 AM) © 2005 Elsevier Affinity and Potency How well does the drug bind to the receptor? Drug A Drug B % Positive respnose (analgesia) 100 50 0 ED50 Drug A ED50 Drug B Dose of Compound Potency Fentanyl Morphine % Positive respnose (analgesia) 100 50 0 0.1 mg 10 mg Dose of Compound Efficacy How well is the receptor/transduction process activated? % Measured Effect 100 Full Agonist Partial Agonist 50 Antagonist 0 Dose of Compound Efficacy and Opioid Analgesics % Measured Effect 100 Morphine Severe Pain Codeine Moderate Pain 50 Aspirin Naloxone 0 Dose of Compound Mild Pain Therapeutic Index • The relative safety of a drug is sometimes expressed as a therapeutic index (TI) • Ratio of the dose of the drug lethal in 50% of a tested population (LD50) to the dose of the drug therapeutically effective in 50% of the tested population (ED50) TI= LD50 ED50 % Animals Showing Effect Therapeutic Index Analgesia 100 Death 50 0 3 mg 600 mg Drug Interactions • Antagonism – pharmacological (heroin and naloxone) – physiological (norepinephrine and acetylcholine) • Additive effect – morphine and fentanyl • Synergistic effect – alcohol and diazepam Drug Interactions Addition Synergy Measured Effect Antagonism A B A+B A B A+B A B A+B Competitive Antagonism Downloaded from: StudentConsult (on 30 January 2006 03:27 AM) © 2005 Elsevier Partial Agonists Downloaded from: StudentConsult (on 30 January 2006 03:27 AM) © 2005 Elsevier Some Drug Interactions are Favorable LeWitt P. N Engl J Med 2008;359:2468-2476 Tolerance Definition: – decreased effectiveness of a drug that results from repeated drug exposure – necessitates an increase in the dose of the drug in order to maintain a given level of effect Related Terms: – cross-tolerance (morphine/fentanyl) – tachyphylaxis Different Types of Tolerance Metabolic: – Repeated administration of alcohol induces the enzyme alcohol dehydrogenase --> increased metabolism leads to a decreased drug effect Pharmacodynamic: – Repeated administration of morphine produces changes to opioid receptors and second messenger systems Behavioral: – Development of tolerance can be influenced by learning and conditioning processes Drug Dependence and Withdrawal Definition: – Continual exposure to a drug produces physiological adaptations at the cellular level (physical dependence) – Cessation of drug administration can results in a rebound effect --> withdrawal syndrome (e.g., heroin withdrawal) Related Term: – psychological dependence