Lec 3. Dose Response Relationships Receptor Theory II, Dr. Hoang Nguyen- Full Slides.pdf

Fundamentals of Pharmacology-COM5082 Lecture 3: Dose Response Relationships Receptor Theory 2 Hoang Nguyen , MD., Ph.D., RPh., FACHE Assistant Professor of Foundational Sciences Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine (KCPCOM) Contact for questions or appoin...

Fundamentals of Pharmacology-COM5082 Lecture 3: Dose Response Relationships Receptor Theory 2 Hoang Nguyen , MD., Ph.D., RPh., FACHE Assistant Professor of Foundational Sciences Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine (KCPCOM) Contact for questions or appointment: [email protected] Learning Objectives After Completion of this section of Dose Response Receptor Theory 2, first year M1 students will be able to: 1. Identify Signal Transduction Mechanism 2. Drug Schedules Defined in the Federal Comprehensive Drug Abuse Prevention and Control Act 3. Common abbreviation on drug administration Signaling  Signal transduction is the process by which a chemical or physical signal is transmitted through a cell as a series of molecular events. It is initiated by ligand binding and ending with a pharmacologic effect.  Transmembrane signaling processes involves the recognition and binding of an extracellular signal by an integral membrane receptor protein and generation of intracellular signal by one or more effector protein. Signal Transduction K1 D R K2 D = Drug R = Receptor T = Transducer E = Effector K1 D+R DR K2 Extracellular Plasma Membrane Intracellular Signal Transduction D D = Drug R = Receptor T = Transducer E = Effector R T E Extracellular D+R K1 K2 DR Plasma Membrane [T/E] Intracellular Signal Transduction D D = Drug R = Receptor T = Transducer E = Effector R T E Extracellular D+R K1 K2 DR Plasma Membrane [T/E] Response Intracellular Response Signal Transduction D = Drug R = Receptor T = Transducer E = Effector K1 D R K2 T E Extracellular D+R K1 K2 DR Plasma Membrane [T/E] Response Intracellular Response Transmembrane signal mechanism 1. A lipid-soluble chemical signal crosses the plasma membrane and acts on an intracellular receptor 2. Drug bind to extracellular domain of a transmembrane protein, thereby activating an enzymatic activity of its cytoplasmic domain 3. Drug bind to extracellular domain of a transmembrane receptor bound to a separate protein Tyrosine Kinase, then become activate. 4. The signal bind to and directly regulates the opening of an ion channel. 5. The signal binds to a cell-surface receptor linked to an effector enzyme by a G protein * A,C: Substrates; *B,D: Products; *R: receptor; *G: protein; *E: Effector (enzyme or ion channel); *Y: Tyrosine; *P: Phosphate. (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) Intracellular Receptors  Lipid-soluble or diffusible agents that cross the membrane and combine with intracellular receptors  Types of intracellular receptors include: – Transcription Factors – Enzymes – Structural Proteins – Nucleic acids – Signal transduction molecules Intracellular Receptors -Transcription Factors: Exemplified by receptors for corticosteroids, glucocorticoid (Dexamethasone), sex steroids, thyroid hormone, and vitamin D. o Glucocorticoids diffuse across the cell membrane and bind to the receptor. The receptor has three distinct domains- one for binding ligand, a DNA binding domain and a transcription domain. o Ligand binding dissociates the HSP90 stabilizer and allows the DNA-binding and transcription domain to fold into active confirmation. o Steroid-receptor complex translocate to the nucleus, binds to DNA and initiates transcription of target genes, resulting in alterations in expression of proteins. Intracellular enzymes: Ligands can bind to enzymes, altering their activity, which has direct effects on cell physiology. ExNonsteroidal anti-inflammatory drugs (NSAIDs), such as aspirin, interact with and inhibit cyclooxygenase, a key enzyme in the production of prostaglandins -Structural Proteins: Ex- colchicine (for gout) binding to microtubules has effects on cell shape, mobility, division, and phagocytosis. -Nucleic acids: Ex- DNA is the target for the anticancer drug doxorubicin -Signal transduction molecules: mTOR (serine/threonine kinase) is the target for the anticancer drug everolimus. Steroid receptor: Transcription Factors (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) MembraneSpanning receptors – Receptors linked to ion channels – Activators of Second Messenger signaling • Ligand-regulated enzyme receptors (receptor tyrosine kinase) • Cytokine • G-Proteins couple receptors (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) GABA Receptor Receptors linked to Ion Channels (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) Receptor/Messenger Systems β M G Protein Adenylate Cyclase ATP camp G Protein Phospholipase C PIP2 IP3 Diacylglycerol Ca++ Protein kinase C Second Messenger Signaling Cascades • Gq phospholipase C increases in IP3,DAGincrease Ca2+ , protein kinase activity • Gs Adenylyl cyclase increase cAMP Increase Ca2+ influx, and enzyme activity • Gi adenylyl cyclase decrease cAMP decrease Ca2+ and enzyme activity, increase K+ efflux (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) Receptor Dynamics  Desensitization: decreased ability of a receptor to respond to stimulation by a drug or ligand occurs with continuous or repeated exposure  Tachyphylaxis: (decrease in response to a drug after repeated administration) short 12 time-scale (few minutes)  Tolerance longer time scale, (days or weeks) decreased receptor responsiveness  Sensitization: When receptor activation has been blocked for a prolonged period lack of stimulation or continuous exposure to a receptor antagonist) can cause an upregulation in the number of receptors. Up and Down Receptor Regulation (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) Common Abbreviations in Drug Administration (FYI) (Adapted, Lippincott Illustrated Pharmacology Review, 7th Edition, 2019) Question 1  A 23-year-old female came for routine visit. After she left, you found out there is prescription pad is lost. What should you do? A. Call the patient’s phone number and ask her to return the prescription pad. B. Since you know the address of the patient, you should drive to patient address and confront her to return. C. Call the patient and set up the appointment at Starbuck, so she can give you back the prescription pad D. Call the medical Board to report the loss of prescription pad. E. Call the police. Question 2  A 33-year-old female patient with diagnosis of diabetes mellitus type 2, and asthma. She is your sister and has the same medical condition as you even though you are not her medical provider. During her Christmas visit, she forgot to bring her asthma inhaler. What should you do as a physician? A. Call the pharmacy to prescribe her the sufficient dose of the same asthma inhaler, which is prescribed by her provider. B. Do not give her anything since you are not her provider. C. Refer her to emergency even though she is your sister D. Give different medication since you do not agree with her medication regimen prescribe by her provider E. Give the medication that you are currently taking now since you have the same medication condition as her. Resources  1. Basic and clinical pharmacology by Katzung, 15th edition.  2. Videos: https://sketchy.com/