Lecture 1 - Handout (Pharmacology -1 Y24/25) - PDF

Pharmacology -1 (Y24/25) S2 Lecture 1 Introduction to Pharmacology: Pharmacodynamics Dr. Rasha Tawfiq The British University in E gypt - BUE 0 Lecture outline 1) The difference between pharmacod...

Pharmacology -1 (Y24/25) S2 Lecture 1 Introduction to Pharmacology: Pharmacodynamics Dr. Rasha Tawfiq The British University in E gypt - BUE 0 Lecture outline 1) The difference between pharmacodynamics & pharmacokinetics of drugs. 2) Definition of some pharmacological terms (pharmacology, drug, receptor, ligand, cell signaling or transduction, drug affinity, drug efficacy, & intrinsic activity. 3) Types of receptors. What is pharmacology? The study of the interaction between a chemical substance & living system. Pharmakon= drug or poison, OLOGO= science What is a Drug? A chemical substance, of natural or synthetic origin, that can affect a biological or living system (human, animal, insect body, or cells). What are the main 2 subdivisions of pharmacology that will be concerned in the module? 1- Pharmacodynamics Describe the effect of a drug on the body, as well as the mechanism of its action & its binding to a receptor or the interaction between them. 2- Pharmacokinetics Describe the effect of the body on the drug. It determines how quickly & to what extent the drug will appear in the target site. Study the journey of the drug inside the body, starting from absorption, distribution, and metabolism, ending with drug elimination. N.B. Pharmacotherapeutics is another subdivision of pharmacology that is concerned with the clinical purpose or indication for a given drug. Toxicology is the branch that is concerned with the toxic effects of a drug or a toxin. 1 DR. RASHA TAWFIQ – S2-24/25 Cell signaling It is how cells communicate together. It defines the ability of a cell to receive, process & transmit signals to its environment & itself. Cells communicate together either: 1- electrically (by neuronal transmission), or 2- chemically (by using chemical compounds that act as messengers, called “Ligand”). In chemical signaling, these chemical messages or signals (ligands), which are proteins (like hormones) or other molecules (like neurotransmitters) produced by a sending cell, are often secreted from the sending cell & released into the extracellular space. There, they can float carrying messages to a target cell where a receiver (protein in nature) of these messages is present on or in the target cell, called a “receptor”. When a signaling molecule binds to its receptor, it alters the shape or activity of the receptor, triggering a change inside the cell. In short, cells communicate together through 4 steps: a) Signaling --- sending a 1ry messenger (ligand) e.g. hormone is floating in the blood b) Reception --- receiving the ligand on the recipient cell c) Transduction --- series of biochemical and/or molecular alterations d) Response --- occurrence of an effect Transduction https://www.khanacademy.org/science/ap-biology/cell-communication-and-cell-cycle/cell-communication/a/introduction-to-cell-signaling There are 3 types of cell signaling depending on the distance between communicating cells: 1- Autocrine signaling --- when the signal is sent from the cell to itself i.e. the cell targets itself 2- Paracrine signaling --- when the signal is sent from the cell to a neighboring cell 3- Endocrine signaling --- when the signal is sent from the cell to a remote one 2 DR. RASHA TAWFIQ – S2-24/25  Define receptor, ligand, & signal transduction. Receptor Is a macromolecule structure made of protein chains that is present on or inside the cell. It receives and interacts with endogenous substances (neurotransmitters or hormones) or a drug (ligand) to produce a physiological or pharmacological effect. It is the site at which a drug binds to produce a response. A receptor can recognize a specific ligand and it’s named by the name of its ligand (E.g. the receptors of dopamine are called dopamine receptors). Ligand It’s a small molecule that can interact with a specific cell receptor on a specific binding site. It can be either a naturally occurring (endogenous) molecule, like a hormone or a neurotransmitter, or a chemical drug. It is also called “signaling molecule or 1ry messenger”. The specific binding region of the receptor is called the Ligand- Binding Site or Recognition Site. A ligand binds to a specific receptor. Signal transduction When a ligand (signaling molecule) binds to a receptor (signal detector) Þ Drug- receptor complex is formed Þ conformational changes in the receptor occur + activation or inactivation of other chemical compounds inside the cell (called 2ry messengers) Þ Biological response. The series of biochemical and molecular activity changes (activation or inactivation of other chemical compounds) occurring inside the cell following ligand-receptor binding is called Signal Transduction. https://www.khanacademy.org/science/ap-biology/cell-communication-and-cell-cycle/cell-communication/a/introduction-to-cell-signaling 3 DR. RASHA TAWFIQ – S2-24/25  What are the major types of receptors? Receptors are classified into 2 main categories according to their cellular location: 1- Cell surface or transmembrane receptor a. Binds to hydrophilic molecules b. Has a transmembrane moiety c. The ligand-binding site is extracellular d. Coupled with either an ion channel, enzyme, or a G-protein. 2- Intracellular receptor a. Binds to small hydrophobic drugs b. It’s located in the cytosol or inside the nucleus c. The ligand-binding site is intracellular d. Can be coupled with DNA or gene sequences Cell surface transmembrane receptors I. Ligand-gated ion channel receptors II. G-Protein coupled receptors (GPCRs) III. Enzyme-coupled receptors I. Ligand-gated ion channel receptors Ion channels are protein chains arranged to form pores that cross the plasma cell membrane (transmembraneous) allowing the selective transfer of certain ions (cations or anions) down their electrochemical gradient. When a ligand binds to this type of receptor Þ the receptor becomes activated (i.e. channel opens) Þ ions pass in the pores across the cell membranes Þ alters the electrical potential of the cell Þ a very rapid response (few milliseconds). These receptors are present in the ganglia and skeletal muscles …. why?? Example Þ Nicotinic muscular receptor (Nm) Acetylcholine (in the motor end plate in skeletal muscle) binds to the Nm Þ Na+ influx Þ contraction in skeletal muscle. N.B. Voltage-gated ion channel is another type of ion channel that is controlled by the change in membrane potential (opens by depolarization). e.g. Voltage-gated sodium channels within the nerves and excitable tissues. 3 DR. RASHA TAWFIQ – S2-23/24  https://www.news-medical.net/health/Types-of-Ion-Channels-in-the-Body.aspx II. G-Protein coupled receptor (GPCR) The most abundant type of receptors, and its activation accounts for the actions of most therapeutic agents. Its structure comprises a single helical polypeptide embedded in the cell membrane that has seven transmembrane-spanning regions (serpentine) that snake back and forth (spanning helices) through the cell membrane with ONE END of the protein protruding outside the membrane (ligand binding site) and the OTHER END inside the cytoplasm, couples to a specific G protein. The G-PROTEIN moiety is composed of three protein subunits, α, β, and γ, which are bound together. The α-subunit is attached to guanine nucleotides; guanosine diphosphate (GDP). The β and γ subunits function primarily to support the α-subunit interaction with the cell. When the α-subunit is attached to a GDP molecule, the receptor is inactive, but when attached to GTP it becomes active. https://gpcr.utep.edu/background How GPCRs work? When a ligand (1ry messenger) binds to the extracellular region of the receptor Þ α-subunit conformational change in the receptor occurs Þ releasing the GDP from the α-subunit Þ The empty binding site on the α-subunit is then occupied by guanosine triphosphate (GTP) that is present at high concentration in the cytoplasm (i.e. the receptor becomes active) Þ α-subunit dissociates from the receptor and binds to an 4 DR. RASHA TAWFIQ – S2-23/24  EFFECTOR (another protein component in the cell that can undergo further effect to produce a response. It can be voltage-gated ion channel or enzyme). https://blog.addgene.org/gpcrs-how-do-they-work-and-how-do-we-study-them If G-protein activates ion channel: Ions will move in or outside the cell Þ change in electrical potential across the cell Þ response. If G-protein activates an enzyme: I.e. the α-GTP binds to an enzyme as the effector Þ activation of SECOND MESSENGERS Þ biological effects within the cell that last several seconds to minutes. SECOND MESSENGERS They conduct and amplify signals coming from G protein-coupled receptors so that a cellular response occurs. (Remember that the first messenger is the ligand) Examples of several effectors and second messenger: Effector 2ry messenger Response of the 2ry messenger Adenylyl cyclase (AC) Cyclic adenosine Activates protein kinase A Þ response monophosphate (cAMP) Using ATP Guanylyl cyclase (GC) Cyclic guanosine Activates protein kinase G Þ response monophosphate (cGMP) Using GTP Phospholipase C (PLC) Diacyl glycerol (DAG). Activates protein kinase C (Ca2+-dependent Protein Kinases) Þ response Catalyzes the (It remains in the cleavage of memberane) phosphatidyl inositol biphosphate (PIP2) Inositol triphosphate (IP3). Releases stored Ca2+ into cytosol from endoplasmic reticulum Þ response (It migrates to the cytosol) OR Þ stimulation of secretions or contraction 5 DR. RASHA TAWFIQ – S2-23/24  https://www.khanacademy.org/science/biology/cell-signaling/mechanisms-of-cell-signaling/a/signal-perception There are three main classes of G protein: Gs: Stimulatory for AC enzyme Þ increase cAMP Þ activates protein kinase A Þ response. Gi: Inhibitory for AC enzyme mainly through converting GTP into GDP Þ decreases cAMP Þ NO response. Gq: Stimulatory for PLC enzyme: Þ increases DAG Þ activates protein kinase C Þ response. Þ increases IP3 Þ Releases stored Ca2+ from endoplasmic reticulum Þ response Fading of signal: For each signal, there is an end (signal fading). After exerting the response, the intrinsic GTPase activity of the α-subunit hydrolyses the bound GTP to GDP Þ inactivating itself Þ the GDP-bound α-subunit dissociates from the EFFECTOR Þ re-associates with the G- protein β-γ complex and ligand leaves the receptor inactive, it is now available for another cycle of receptor activation. 6 DR. RASHA TAWFIQ – S2-23/24  Examples of GPCRs: Receptors for some neurotransmitters such as muscarinic, and adrenergic receptors. Exam Question: What is the signal transduction that may occur upon activation of Gs receptor? Answer: Gs Þ activates AC enzyme (effector) Þ cAMP (2ry messenger) Ý Þ activates protein kinase A Þ response. III. Enzyme-linked (Enzyme-coupled) receptor They are receptors that are directly linked to cytosolic enzymes. Comprises a ligand-binding domain (outside the membrane), transmembrane helix & cytosolic enzyme domain. The enzyme domain may be tyrosine kinase or serine kinase, so it’s sometimes called “Tyrosine kinase receptors”. When the ligand binds to the receptor Þ activation or inhibition of cytosolic enzyme activity. Duration of responses to stimulation of these receptors: minutes to hours. Examples Insulin, growth hormone, prolactin, and cytokines receptors are linked to Tyrosine kinase. https://www.blendspace.com/lessons/HziadL2dIeDLGw/what-the-cell-was-that-tyrosine-kinase-and-cell-signaling-by-andrew-colin-and-ginger 7 DR. RASHA TAWFIQ – S2-23/24 Intracellular receptors (DNA-Linked receptors) (gene-linked receptors) The receptor is entirely intracellular, therefore the ligand must be sufficiently lipid- soluble to cross the plasma cell membrane and interact with the receptor. The ligand-receptor complex migrates to the nucleus, where it binds to specific DNA sequences, regulating gene expression and consequently protein synthesis. Onset of response: DELAYED (up to hours) Duration of response: persists for a LONG TIME (hours up to days). Examples: Receptors for steroid hormones (glucocorticoids, mineralocorticoids, sex), thyroid hormone, vitamin D, and antineoplastic agents. https://courses.lumenlearning.com/wm-biology1/chapter/reading-signal-receptors/ https://slideplayer.com/slide/14109197/ What is drug affinity? Interaction of receptors with ligands involves the formation of a drug-receptor complex where chemical bonds between a drug and a receptor occur which are weak & stereospecific like hydrogen, ionic, or hydrophobic (Van der Waals) bonds. These weak bonds are reversible, thus the drug dissociates from the receptor when the tissue concentration declines. The ability of a drug to bind to a specific receptor is called “affinity”. 8 DR. RASHA TAWFIQ – S2-23/24 The closer the fit + greater number of bonds Þ stronger attractive forces Þ higher affinity of the drug to the receptor. N.B. If a drug binds by covalent bond, which is a strong permanent bond, the binding will be irreversible. This drug is considered a poison, e.g. organophosphorus compounds, as the receptor can’t receive any more signals and will be occupied with the ligand until its aging, which takes about 2 weeks. https://www.lecturio.com/magazine/biological-interaction/ What is drug efficacy (Intrinsic activity)? The ability of a drug to produce a biological effect which depends on the number of drug- receptors complexes. If number of drug-receptor complexes Ý Þ The intensity of the response Ý. Emax: Maximal response resulting from binding of a drug to all its receptors. When all receptors are occupied by a drug, the maximum effect is achieved & no increase in response will be observed when a higher concentration of the drug is used. N.B.: Not all drugs exert their effects (beneficial and/or adverse) via interacting with receptors. Few drugs act by their physicochemical properties e.g. antacids chemically neutralize gastric acid. Also, osmotic diuretics and laxatives act by their ability to increase water content in the urinary tract or bowel, respectively. Remember Drugs do not create effects de novo, they only modify biochemical and physiological processes End of lecture Dear Students …. Thank You This is to acknowledge the support of Prof. Dr. Marwa Safar for providing the material for this module 9 DR. RASHA TAWFIQ – S2-23/24  & for her continuous support Some helpful video links Cell signaling https://www.youtube.com/watch?v=-dbRterutHY https://www.youtube.com/watch?v=9sF_h-bAnIE https://www.youtube.com/watch?v=5ejPI6QqKBU Ligand-gated ion channel receptors https://www.youtube.com/watch?v=fuYTnksxtb0 Voltage gated ion channels https://www.youtube.com/watch?v=kxnb_TSqmFY G protein-coupled receptors https://www.youtube.com/watch?v=xT0mAQ4726s&t=5s https://www.youtube.com/watch?v=0nA2xhNiAow https://www.youtube.com/watch?v=jUwgET9ue2w Enzyme-linked receptors https://www.youtube.com/watch?v=kiHAdan2AOY https://www.youtube.com/watch?v=ObrsQl-vPA4 Intracellular receptors https://www.youtube.com/watch?v=m9jOXiYdMeY Drug-receptor types https://www.youtube.com/watch?v=BNUO9HQ3LOw 10 DR. RASHA TAWFIQ – S2-23/24