Receptor Site Theory.pdf

James E Beaulieu, PharmD Department Coordinator Lifespan Pharmacy [email protected] Please allow me to introduce myself  Department Coordinator: Lifespan Pharmacy  Facilitator Lifespan Formulary Management Programs and Pharmacy and Therapeutics Committee  Co-Chair Lifespan Jo...

James E Beaulieu, PharmD Department Coordinator Lifespan Pharmacy [email protected] Please allow me to introduce myself  Department Coordinator: Lifespan Pharmacy  Facilitator Lifespan Formulary Management Programs and Pharmacy and Therapeutics Committee  Co-Chair Lifespan Joint Order Set Committee  JWU PA Program Therapeutics course coordinator  Passions outside of work  Flyfishing  Vegetable Garden  Philately Objectives 1. Identify and recognize the definitions of pharmacology, pharmacotherapeutics, and pharmacokinetics 2. Differentiate between an agonist, a partial agonist, and an antagonist 3. Understand receptor desensitization, upregulation and down regulation. 7/16/2024 3 Receptor Site Theory Introduction  For most drugs site of action is at a specific macromolecule (receptor)  Receptors may be a membrane protein, a cytoplasmic or extracellular enzyme, or a nucleic acid  A drug may show organ or tissue selectivity (e.g., cardiac vs. pulmonary) 7/16/2024 4  Receptor Site Theory Rules  Drug response  Molecule and biological target must come together before response can take place  Molecular level recognition  Most binding sites are on proteins, glycoproteins, or proteolipids (form 3D structures) 7/16/2024 5 Receptor Site Theory Rules  Receptor  Generally reserved for proteins embedded in a cellular or subcellular membrane  Facilitate communication between two sides of a membrane.  Large number of subtypes exist in human tissues  Therapeutically important as sub-type selective drugs are developed 7/16/2024 6 Receptor Site Theory Mechanistic Concepts  Receptors are proteins having one or more binding sites  Signal Transduction  Binding of endogenous ligand activates receptor and transmits molecular event to intracellular side of membrane.  Magnitude of signal determined by fraction of total receptors occupied by the ligand and concentration of drug receptor exposed 7/16/2024 7 Receptor Site Theory Mechanistic Concepts  Drugs can enhance, diminish, or block generation, transmission, or receipt of ligand-generated signals by several mechanisms.  If a drug acts on a receptor that is common to most tissues its action will be wide spread (increased chance of SE)  Agonist and antagonist describe ligands and/or drugs that act via receptors to enhance or diminish a cellular response 7/16/2024 8 Receptor Site Theory Agonists  Drug or ligand that binds to same site as endogenous and produces same signal  Magnitude of signal usually equal to or less than that produced by endogenous ligand  Allosteric action:  Drug binds to a different site on extracellular side of receptor than does agonist without producing an effect  Enhanced response is produced when endogenous ligand binds 7/16/2024 9 Receptor Site Theory Antagonists  Drug binds to site used by endogenous ligand and acts competitively to diminish or block signal produced by endogenous ligand  Drugs may also bind to an allosteric site on extracellular side of receptor and act noncompetitively to diminish signal produced by endogenous ligand 7/16/2024 10 Receptor Site Theory 7/16/2024 11 Examples of Classical Receptors Type Subtype Endogenous Transmitter Ion Channel Acetylcholine Nicotinic Acetylcholine X Muscarinic M1, M2 M3, M4, M5 Acetylcholine ____ Adrenergic α1, α2 Epinephrine and ____ Norepinephrine β1 β2 β3 Epinephrine and ____ Norepinephrine GABA A GABA X B GABA ? Opiate μ1 μ2 κ δ Enkephlins X Serotonin 5-HT1, 5-HT2, 5HT3, 5-HT4 5-HT ____ Dopamine D1, D2, D3, D4 Dopamine ____ Histamine H1, H2, H3 Histamine ____ Insulin Insulin ____ Glucagon Glucagon ____ ACTH ACTH ____ 7/16/2024 12 Gamma Amino Butyric Acid (GABA)Receptor 7/16/2024 13  Receptor Site Theory Desensitization  Decrease in responsiveness of a receptor – transmembrane signaling process after continued exposure to agonists - decrease in receptor numbers - altered affinity binding of agonist - receptor is changed by enzymes - uncoupling of receptor from second messenger system  Homologous – receptors occupied by a specific class of agonists are desensitization  Heterologous – receptor signaling system can be diminished by several classes of agonists 7/16/2024 14  Receptor Site Theory 7/16/2024 15 Receptor Site Theory Turnover (hormonal influence)  Downregulation - decrease in receptor numbers - continuous agonist exposure - mechanism that increases concentration neurotransmitters or hormones at cell surface  Upregulation - increase in receptor numbers - can result in receptor supersensitivity - can occur after exposure to antagonist - inhibit synthesis or release of neurotransmitter or hormone - hormones may increase receptor number (thyroid hormone and beta-adrenergic receptors) 7/16/2024 16 Receptor Site Theory Features of receptors: 1. Protein, lipoprotein, glycoprotein 2. Subunits, subtypes dependent on tissue 3. May require more than one drug molecule to bind to receptor and generate signal 1. Alosteric binding 4. Magnitude of signal is dependent 1. Degree of binding to each receptor site 2. Number of receptors 3. Amount of ligand 7/16/2024 17 Receptor Site Theory Features of receptors: 6. By acting on receptors, drugs (exogenous ligand) can enhance, diminish or block generation or transmission of signals 7. Drugs are receptor modulators that do not confer new properties on cells or tissues 8. Receptors can be upregulated and downregulated 7/16/2024 18 Peripheral, Autonomic Nervous System The Nervous System Peripheral Nervous System Central Nervous System Autonomic NS Somatic NS Parasympathetic NS Sympathetic NS 7/16/2024 19  Autonomic Nervous System  Innervates heart, blood vessels, visceral organs, glands, other organs which contain smooth muscle  Beyond conscious control (involuntary nervous system)  Composed of two neuron relay systems  Parasympathetic  Sympathetic  Modulate the activity of visceral organs by eliciting excitatory or inhibitory responses 7/16/2024 20 Autonomic Nervous System Preganglionic neuron  Cell body is in spinal cord  Controlled by higher brain centers and spinal reflexes  Forms a synaptic connection with cell body of the postganglionic nerve fiber Postganglionic neuron  Send axons directly to effector organs to complete the pathway of autonomic innervation 7/16/2024 21 Neurotransmitter Transmission and Release 7/16/2024 22 Neurotransmitters and Receptors Cholinergic Receptors Nicotinic Muscarinic Skeletal Neuronal Ganglionic M1 M3 M5 M2 M4 Muscle CNS 7/16/2024 23 Neurotransmitters and Receptors Adrenergic Receptors α1 α2 β β1 β2 7/16/2024 24 Autonomic Nervous System Parasympathetic Sympathetic Nervous System Nervous System Preganglionic Postganglionic Preganglionic Postganglionic Neuron Neuron Neuron Neuron Neurotransmitter Acetylcholine Acetylcholine Acetylcholine Norepinephrine (cholinergic) (adrenergic) 7/16/2024 25 Autonomic Regulation of Peripheral Organs  Most organs are innervated by both systems  Sympathetic more widespread  Two systems balance each other  Inhibition of one system leads to an increase in response by other  Activation of sympathetic outflow (fight or flight) - ↑HR, ↑ BP, blood flow is redirected from skin and splanchnic region to augment perfusion of muscle, ↑ Blood glucose, Dilate bronchioles and pupils 7/16/2024 26 Autonomic Regulation of Peripheral Organs  Activation of parasympathetic outflow  Conservation of energy and maintenance of organ function  Decrease HR, decrease BP  Activates GI movements  Emptying of bladder and large colon  Lacrimal, salivary, and mucous cells activated  Bronchial tree contracted 7/16/2024 27 Neurotransmitter Transmission and Release 7/16/2024 28  α Adrenergic Receptors  Mediate vasoconstriction, intestinal relaxation, and pupillary dilatation  Epinephrine and NE are approximately equipotent as agonists  Postsynaptic or postjunctional - adrenergic receptors on effector cells α1  Prejunctional receptors on sympathetic nerve endings α2 7/16/2024 29  α Adrenergic Receptors  α1 receptor mediates the classic effects, (e.g., vasoconstriction)  α2 receptor  mediates presynaptic inhibition of NE release from adrenergic nerves  inhibition of ACh release from cholinergic nerves  inhibition of insulin secretion  stimulation of platelet aggregation  vasoconstriction in some vascular beds  within brainstem sympathetic centers regulate blood pressure 7/16/2024 30  β Adrenergic Receptors  stimulation of heart rate and contractility, vasodilation, bronchodilation, and lipolysis  β1 receptor responds equally to E and NE  mediates cardiac stimulation and lipolysis.  β2 receptor more responsive to E than to NE  mediates vasodilation and bronchodilation. 7/16/2024 31 Responses Elicited in Effector Organs Effector Organ Adrenergic Primary Cholinergic Dominant Response Receptor Response Response Involved Heart Rate of Contraction Increase β1 Decrease C Force of Contraction Increase Decrease C Blood Vessels Arteries (most) Vasoconstriction α1 (α 2) A Skeletal Muscle Vasodilation β2 A Veins Vasoconstriction α 2 (α1) A Bronchial Tree Bronchodilation β2 Bronchoconstriction C Gastrointestinal Tract Relaxation α2 Contraction C 7/16/2024 32 Responses Elicited in Effector Organs Effector Organ Adrenergic Primary Cholinergic Dominant Response Receptor Response Response Involved Eye Radial muscle, iris Contraction α1 A Circular muscle, iris Contraction C Ciliary muscle Relaxation β2 Contraction C Kidney Renin Secretion β1 A Insulin release from pancreas Decrease α1 A Fat cells Lipolysis β1 (β2) A Liver glycogenolysis Increase α1 (β2) A 7/16/2024 33 7/16/2024 34  Pharmacological Organization of the CNS  Neurons come in different shapes and sizes and have four common regions:  dendrites: elaborate branching processes where incoming messages from other neurons are received  cell body (soma): region surrounding nucleus of cell, main organelles of cytoplasm are grouped to perform basic processes to maintain cell  axon: elongated tube or cable-like process that can be very long (up to 1 meter)  axon terminal: electrical impulses are converted into chemical messages for transmission to nearby cells 7/16/2024 35  Pharmacological Organization of the CNS  Synaptic Transmission  Effective transfer and integration of information in CNS requires passage of information between adjacent neurons or other target cells  Axon terminals is separated from adjacent cells by a gap called a synapse (specialized area of communication) 7/16/2024 36 Pharmacological Organization of the CNS  Synaptic Transmission (con’t)  Synaptic terminals  Filled with mitochodria and numerous synaptic vesicles  Forms transmitting portion of synapse  Stores neurotransmitters  Postsynaptic cell  Specialized contact zone  Have receptors for detecting different neurotransmitters 7/16/2024 37  Pharmacological Organization of the CNS  Synaptic Transmission (con’t)  Neurotransmitters  Stored and synthesized in synaptic vesicles  Chemical messengers used to transfer information across synaptic junction  Depolarization of the presynaptic terminal causes release into synaptic cleft  Diffuse across synaptic cleft to act postsynaptic membrane to deliver message  Postsynaptic cell (receptor) responds to receive message 7/16/2024 38 Pharmacological Organization of the CNS  Neurotransmitter Inactivation  After release, transmitters are rapidly inactivated to ensure that action of neurotransmitter is reversed and to allow for further information transfer across synapse  Rapid enzymatic breakdown in synaptic cleft  Rapid reuptake into nerve terminal by specific high- affinity pumps  Diffusion and nonspecific uptake https://www.youtube.com/watch?v=p5zFgT4aofA 7/16/2024 39 Pharmacological Organization of the CNS 7/16/2024 Lectu Pharmacological Organization of the CNS Substances that Play a Neurotransmitter Role  Acetylcholine  Enkephalins  Dopamine  Angiotensin II  Norepinephrine  Dynorphins  Epinephrine  β-Endorphins  Histamine  Glucagon  Serotonin  Adrenocorticotropic  GABA hormone (ACTH)  Insulin 7/16/2024 41 Pharmacological Organization of the CNS Receptors (targets)  Sensors by which cells detect incoming messages  Highly specialized recognition sites with rigid structural requirements for binding  Usually only bind one type of transmitter  Named after neurotransmitter that activates them  Transmitters can activate more than one receptor type  Multiple receptor subtypes for one transmitter can co-exist on the same cell - message may be opposing, complimentary, or independent 7/16/2024 42  Pharmacological Organization of the CNS Location and response of receptors  Postsynaptic cell adjacent to release site  Neurotransmitter can diffuse a distance away and act on an extrasynaptic area  Can act on an adjacent glial cell  Act on own presynaptic nerve terminal – autoreceptor  activation provides feedback about the quantity of neurotransmitter in synaptic cleft and regulates further synthysis and release of neurotransmitter 7/16/2024 43 Pharmacological Organization of the CNS 7/16/2024 44 Pharmacological Organization of the CNS Alterations in receptor sensitivity  Alterations in target cells can occur that alter postsynaptic response to a given concentration of transmitter  Desensitization - incoming nerve fires more rapidly than normal, increase transmitter, cell will decrease responsiveness to further input  Supersensitivity  Decrease in normal impulse traffic and increases responsiveness  magnifies effect of incoming cells signals when signal traffic is reduced 7/16/2024 45  Pharmacological Organization of the CNS  Alterations in receptor sensitivity  Desensitization and supersensitivity can be caused by changes in density of receptors  Chronic activation of receptor can decrease density of receptors – down regulation  Chronic decrease in synaptic activation can result in increased in receptor density – up regulated 7/16/2024 46 Pharmacological Organization of the CNS Sites of Drug Action  Drugs with primary action in CNS produce effects by modifying some aspect of chemical synaptic transmission  Drugs act on specific molecular targets to alter cell function  Distribution of targets determines which cells are affected by a particular drug and is primary determinant of specificity of drug action 7/16/2024 47 Pharmacological Organization of the CNS Select Targets of Centrally Acting Drugs Cellular Target Class of Drugs Opioid Receptor Opioid analgesics Opioid antagonists GABA receptors Benzodiazepines Adrenergic receptors Clonidine Histamine receptors Antihistamines Monoamine oxidase Monoamine oxidase inhibitors (MAOIs) 7/16/2024 48 Pharmacological Organization of the CNS Select Targets of Centrally Acting Drugs Cellular Target Class of Drugs NE reuptake Tricyclic Antidepressants Serotonin reuptake Selective serotonin reuptake inhibitors 7/16/2024 49 Pharmacological Organization of the CNS Blood-brain Barrier  Boundary between periphery and CNS  Permeability barrier to passive diffusion of sub- stances from the bloodstream into various regions of CNS  Little evidence of a barrier between the circulation and the peripheral nervous system  Retards movement of substances from brain to blood as well as from blood to brain 7/16/2024 50 Pharmacological Organization of the CNS Blood-brain Barrier  Factors which allow permeability:  Molecular weight  Charge  Lipophilicity  Active transport of certain agents may occur in either direction across barrier 7/16/2024 51