Pharmacodynamics Textbook PDF

PHARMACODYNAMICS Sonia Guadalupe Barreno Rocha MD, PhD [email protected] WE MAKE DOCTORS Objectives Give examples of the main uses and applications of pharmacodynamics. Describe and exemplify the different drug receptors, th...

PHARMACODYNAMICS Sonia Guadalupe Barreno Rocha MD, PhD [email protected] WE MAKE DOCTORS Objectives Give examples of the main uses and applications of pharmacodynamics. Describe and exemplify the different drug receptors, their families and receptor types. Outline the different types of receptors involved in the drug- receptor interaction and their classification. Summarize the main drug-receptor interactions. “In modern pharmacology it's so clear that even if you have a fixed dose of a drug, the individuals respond very differently to one and the same dose”. - Arvid Carlsson Definition Study of the detailed mechanism of action by which drugs produce their pharmacologic effects. Reminder about ligands A ligand is a molecule or substance that binds to a biological molecule and produces or initiates a biological response. An endogenous ligand is one that is naturally produced by the body. Most of the ligands bind to proteins on the cell surface called receptors. Types of Drug Receptors Drugs produce their effects by interacting with specific cell molecules called receptors. Most ligands (drugs or neurotransmitters) bind to protein molecules, although some agents act directly on DNA or membrane lipids. Most receptors for drug targets and endogenous ligands are cloned and their aminoacid sequences determined. Families of receptor types are grouped by their sequence similarity. Each type of receptor corresponds to a single, unique gene with subtypes of receptors.  RECEPTOR CLASSIFICATION Type 1: Ligand- Type 2: G protein- Type 3: Receptor Type 4: Nuclear gated ion coupled kinases receptors channels receptors Location Membrane Membrane Membrane Intracellular Effector Ion channels Channel or Protein kinases Gene transcription enzyme Coupling Direct G protein or Direct Via DNA arrestin Examples Nicotinic Muscarinic Insulin, growth Steroid receptors acetylcholine acetylcholine factors, cytokine receptor, GABAA receptor, receptors receptor adrenoreceptors Ligand-gated ion channels Also known ionotropic receptors Ion channels are gateways in cell membranes that selecteively allow the passage of particular ions Open only when one or more agonist molecules are bound, the binding is needed to activate them Common example: Nicotinic acetylcholine receptor Molecular architecture of ligand-gated ion channels G protein–coupled receptors (GPCRs) Commonest single class of targets for therapeutic drugs. Heptahelical structure GPCR family: Go-between proteins, but were actually Muscarinic called AChRs because of their G proteins Adrenoceptors interaction with the guanine nucleotides, Dopamine GTP and GDP. receptors 5-HT (serotonin) receptors Receptors Guanine for many peptides, nucleotides bind to purine the α receptors subunit, and has which manyenzymic others, (GTPase) chemoreceptors activity, involved catalysing the in olfaction conversion of GTP M2 muscarinic receptor. and pheromone detection to GDP. ‘Orphans’ receptors G Proteins and their role Targets for G Proteins Ion channels Adenylyl Phospholipase (Ca2+ & K+ cyclase C channels) Rho A/Rho MAP kinase kinase Kinase-Linked and Related Receptors Activated by a wide variety of protein mediators (growth factors and cytokines), and hormones such as insulin and leptin. This receptors are large proteins of a single chain. Major role in controlling cell division, intermediary metabolism, growth, differentiation, inflammation, tissue repair, apoptosis and immune responses. The main types are: Receptor Receptor Cytokines tyrosine kinases serine/threonine receptors (RTKs) kinases Lack intrinsic These receptors They phosphorylate enzyme activity. incorporate a serine and/or They activate tyrosine kinase threonine residues various tyrosine moiety in the rather than tyrosine kinases, such as intracellular region Transforming growth factor (TGF) Jak (the Janus Growth factors kinase). Ligands (EGF, NGF), TLRs, include: INFs and insulin repcetor CSF Central role of protein kinases in signal transduction pathways Nuclear Receptors 48 soluble receptors that sense lipid and hormonal signals and modulate gene transcription Can control the transcription and expression of many genes and proteins Key players in regulating metabolic, developmental and other critical physiological processes Not generally embedded in membranes (like GPCRs) but are present in other compartments of the cell Steroid receptor RXR Responsible for the biological effects of approximately 10%–15% of all prescription drugs. They can recognize small hydrophobic molecules, which may exhibit full or partial agonist, antagonist or inverse agonist activity TYPES OF NUCLEAR RECEPTORS Receptor name Abbreviation Ligand Drugs Location Ligand Mechanism of binding action Type I Androgen AR Testosterone All natural and Cytosolic Homodimers Translocation to synthetic nucleus. Binding to Oestrogen ERα, β 17β-oestradiol glucocorticoid, HREs with two half- mineralocorticoids sites with an inverted Glucocorticoid GRα Cortisol, and sex steroids sequence. corticosterone together with their Recruitment of co- Progesterone PR Progesterone antagonists (e.g. activators, raloxifene, 4-hydroxy- transcription factors Mineralocorticoid MR Aldosterone tamoxifen and and other proteins mifepristone) Type II Retinoid X RXR α,β,γ 9- cis- retinoic Retinoid drugs Nuclear Heterodimers Binding to HREs with acid often with RXR two half-sites with an inverted or simple Retinoic acid RAR α,β,γ Vitamin A repeat sequence. Thyroid hormone TR α,β T3, T4 Thyroid hormone Complexed with co- drugs repressors, which are displaced following Peroxisome PPAR α,β,γ,δ Fatty acids, Rosiglitazone, ligand binding, proliferator prostaglandins pioglitazone allowing the binding Constitutive CAR Androstane Stimulation of CYP of co-activators androstane synthesis and alteration of drug Pregnane X PXR Xenobiotics metabolism Orphan Receptors Receptor-like proteins predicted from the human genome for which an endogenous ligand is not identified. They represent targets for the development of new drugs. Drug-Receptor Interactions Signal Transduction Describes the pathway from ligand binding to conformational changes in the receptor, receptor interaction with an effector molecule (if present), and other downstream molecules called second messengers. This cascade of receptor-mediated biochemical events ultimately leads to one or more pharmacologic effects. In signal transduction we have the involvement of: Ligand-gated ion channels Drugs that bind to this alter the conductance (g) of ions through the channel protein. There are no second messengers directly activated Membrane bound enzymes, classified as: Receptor guanylate cyclase Receptor tyrosine kinase Tyrosine kinase–associated receptor Receptor tyrosine phosphatase Receptor serine/threonine kinase. Second Messengers cAMP IP3 and DAG Activates a number of tissue-specific Evoke the reléase of Ca = augment of cAMP dependent protein kinases calcium-mediated processes IC processes: ion channel activity, Muscle contraction release of neurotransmitter, Glandular secretion regulation of transcription Neurotransmitter reléase Example: epinephrine -> B2- Also activate calcium-dependent adrenoreceptors on muscle -> cAMP kinases activation -> Kinase A -> ↑ breakdown of glycogen to free glucose  Examples of receptors and signal transduction pathways Family and Type of Receptor Mechanism of Signal Example of Effect in Tissue or Transduction Cell G Protein-Coupled Receptors α1-adrenoceptor Activation of phospholipase C Vasoconstriction α2-adrenoceptor Inhibition of adenylyl cyclase Release of norepinephrine decreased Β-adrenoceptor Stimulation of adenylyl cyclase Heart rate increased Muscarinic receptor Activation of phospholipase C Glandular secretion increased Ligand-Gated Ion Channels GABA a receptors Chloride ion influx Hyperpolarization of neuron Nicotinic receptors Sodium ion influx Skeletal muscle contraction Membrane-Bound Enzymes Atrial natriuretic factor receptors Stimulation of guanylyl cyclase Sodium excretion increased Insulin receptors Activation of tyrosine kinase Glucose uptake stimulated Nuclear receptors Steroid receptors Activation of gene transcription Reduced cytokie production Thyroid hormone receptors Activation of gene transcription Oxygen consumption increased Drug-Receptor Interactions Drugs of high potency The binding can be measured generally have a high affinity directly the activation of an for the receptors and thus enzyme, or a behavioural occupy a significant proportion response, that we are interested of the receptors even at low in, and this is often plotted as a concentrations. concentration–effect curve (in vitro) or dose–response curve. Drug Efficacy The ability of a drug to initiate a cellular response and produced a maximal response Not directly related to receptor affinity Agonist: receptor affinity and efficacy Antagonist: receptor affinity, lack efficacy Efficacy is represented by Emax. Activation The receptor is affected by the bound molecule in such a way as to alter the function of the cell and elicit a tissue response. Affinity Tendency of a drug to bind to the receptor Potency Concentration of drug that produces half of the maximal response. Represented by EC50. Drug Action on Receptors Agonist Antagonist Partial Full agonist antagonist Partial Competitive agonist antagonism Non Inverse competitive agonist antagonism Agonist Binding and activation represent two distinct steps in the generation of the receptor-mediated response by an agonist. Agonists also possess significant efficacy. ‘Activate’ the receptors. Full agonist The efficacy of which is sufficient that they can elicit a maximal tissue response. Partial agonist Drugs with intermediate levels of efficacy, such that even when 100% of the receptors are occupied the tissue response is submaximal. The efficacy of which is sufficient that they can elicit a maximal tissue response. Inverse agonist Ligand that binds to the same receptor-binding site as an agonist and not only antagonizes the effects of an agonist but, moreover, exerts the opposite effect by suppressing spontaneous receptor signaling. Antagonist Receptor antagonist: drug who binds to the receptor without causing activation and thereby prevents the agonist from binding. Tends to produce inhibitory effect Don’t have efficacy. Competitive antagonism The agonist occupancy at a given agonist concentration is reduced, because the receptor can accommodate only one molecule at a time. Raising the agonist concentration can restore the agonist occupancy. Reversible competitive antagonism Agonist and competitive antagonist molecules do not stay bound to the receptor but dissociate and rebind continuously. Irreversible competitive antagonism Occurs when the antagonist binds to the same site on the receptor as the agonist but dissociates very slowly, or not at all, from the receptors, with the result that no change in the antagonist occupancy takes place when the agonist is applied. Non competitive antagonism Receptor Regulation and Drug Tolerance The continuous or repeated exposure to agonists can desensitize receptors. Phosphorylation of the receptor reduces the G protein–coupling efficiency and alters the binding affinity (tachyphylaxis). Down regulation Up-regulation Supersensitivity Drug tolerance: same dose given repeatedly loses its effect or greater doses are needed to achieve the previous effect Drug tolerance Same dose given repeatedly loses its effect or greater doses are needed to achieve the previous effect Pharmacodynamic tolerance Adaptations to chronic drug exposure at the tissue and receptor level Pharmacokinetic tolerance Caused by accelerated drug elimination, usually resulting from an up-regulation of the enzymes that metabolize the drug Pharmacodynamics Curves Drug plasma concentration curves Elimination half-life Steady-state drug concentration Terminology to comprehend Cmax: Maximum concentration of a drug after a dose is given. Tmax: Maximum time for a drug to reach Cmax. AUC: Area Under the Curve. T½: Time required for plasma concentration of a drug to decrease by 50%. Cmin: Minimum plasma concentration reached by a drug during time interval between doses. DL50: The amount of a substance or drug that is sufficient to kill 50% of a population of animals within a certain time Cl50: The lethal concentration required to kill 50% of the population. ED50: Median effective dose. Is the dose produces 50% of the maximal response. that The ratio between the dose that is lethal in 1% CSF of subjects (LD1) and the dose that produces a therapeutic effect in 99% of subjects (ED99). Is a more realistic estimate of drug safety. Cl Clearence. Is the factor that predicts the rate of elimination in relation to the drug concentration Cltot Volume of plasma which contains the total amount of drug that is removed from the body in unit time. QUIZ Password: Ligand References 1. Stevens CW. Pharmacodynamics or What the Drug Does to the Body. In: Stevens CW editor. Brenner and Stevens' Pharmacology. 6th edition. Philadelphia: Elsevier; 2023. 27-34. - Chapter 3. Available in: https://bibliodig.uag.mx:2113/#!/content/book/3-s2.0- B9780323758987000031 2. Ritter JM, Flower R, Henderson G, Konge-Loke Y, MacEwan D, Rang HP. How Drus Act: General Principles. In: Ritter JM, Flower R, Henderson G, Konge-Loke Y, MacEwan D, Rang HP editors. Rang and Dale's Pharmacology. Tenth edition. China: Elsevier; 2024. 6-23. - Chapter 2. Available in: https://bibliodig.uag.mx:2113/#!/content/book/3-s2.0- B9780702074486000020