Drug Targets 1 PDF

Pharmacodynamics 1: Drug Targets Robert Sims HA209 [email protected] Guide to my lectures: All material is examinable unless clearly stated otherwise Usually indicated on slide, may be in recording and/or slide notes. Red text indicates concepts or drugs that are high importance...

Pharmacodynamics 1: Drug Targets Robert Sims HA209 [email protected] Guide to my lectures: All material is examinable unless clearly stated otherwise Usually indicated on slide, may be in recording and/or slide notes. Red text indicates concepts or drugs that are high importance Grey text indicates concepts or drug that are low importance Importance is for that lecture. What is not important in one may be important in another: don’t assume grey text means you’ll never need to know it! Lecture Objectives Pharmacodynamics Human proteins as main targets of drugs; cellular communication Most common drug targets: receptors enzymes ion channels membrane transporters Selectivity & specificity Adverse drug reactions, tolerance, withdrawal Pharmacology Pharmacology is a relatively recent science (late 1800s) Early use of drugs focused on clinical effect, not mechanism More highly developed throughout early 1900s Ability to identify targets led to understand of drug-target action Propranolol (1965) – landmark drug discovery Understanding of drug mechanism now highly developed and important element of drug design & testing What is a drug? A natural or synthetic chemical (that is not food) introduced to the body from the outside that causes a physiological response. Ligand: something that binds to a biological target Endogenous ligand: a natural chemical produced by the body to bind to the biological target Drug: an exogenous ligand that generates a physiological response. Pharmacodynamics Pharmacodynamics is the study of how drugs affect the body Mechanism of action: The specific biochemical interaction between a drug and its molecular target(s) Mode of action: The subsequent cellular and physiological effects that generate a clinical effect Note that sometimes “mechanism of action” is used in a wider sense to refer to both mechanism and mode of action. The relationship of concentration (dose) and effect (response) Drugs – physiology By altering the activity of molecules and cells with drugs, we can control the activity of higher organisational structures, up to the entire organism. Drugs Molecules “Mechanism of action (MoA)” Cells “Mode of action”: functional or Tissues anatomical changes (usually cellular level or above) Organs Organisms Drug targets – proteins Santos et al. (2017) Nat Rev Drug Discov: Others 12% Receptors 44% 1,591 medical drugs Transporters 15% 1,414 target known proteins Ligand gated ion Ion channels 8% channel 9% 1,194 target known human proteins GPCR-coupled 19% Enzymes 29% 667 different therapeutic proteins Rask-Anderson (2011) Nat Rev Most prescribed primary care drugs (UK 2018) DRUG CONDITION TARGET 1 Atorvastatin & simvastatin High Cholesterol Enzyme 2 Omeprazole & lansoprazole Gastric acid Transporter 3 Levothyroxine Hypothyroidism Receptor 4 Amlodipine Hypertension Ion channel 5 Ramipril Thromboembolism Enzyme 6 Bisoprolol Hypertension Receptor 7 Colecalciferol (Vit. D) Calcium metabolism Receptor 8 Aspirin Thromboembolism Enzyme 9 Metformin Diabetes Enzyme 10 Salbutamol Asthma / COPD Receptor Other drugs / drug targets Pathogens, fungi, parasites, etc. (e.g. antibiotics) Dietary supplements Direct DNA interaction Amino acids Chemical messengers (e.g. antibody drugs) Unknown mechanism (!) Molecules → Cells C Secondary Receptor messenger 1 x 2 Enzyme “Outcome” A 5 8 3 4 Cells have a huge range of biochemical pathways 6 Drugs can interact with many points of these pathways B 7 Adverse drug reactions? NUCLEUS CELL Receptors Key “detecting” elements of cellular communication Endocrine, paracrine (+ neurotransmission), juxtacrine, autocrine 4 superfamilies: G-protein coupled Ligand-gated ion channels Kinase linked receptors Nuclear receptors Generally named after ligands (endogenous, pharmacological) G-protein coupled receptors (GPCRs) Largest receptor family – ~900 known human GPCRs Ligand-activated receptors; single polypeptide, 7 TM domains Linked to intracellular effectors: G-proteins Activate enzymatic signalling cascade: metabotropic slow (induction 100+ ms; initial effects for seconds – minutes) Gs proteins Ligand Stimulate adenylate cyclase (AC): ↑ cAMP (/PKA) GPCR Cell membrane α AC βγ G-protein GDP GTP cAMP CYTOPLASM Gs proteins Ligand Inhibit adenylate cyclase (AC): ↓ cAMP (/ PKA) GPCR Cell membrane α AC βγ G-protein GDP GTP cAMP CYTOPLASM Gq proteins Ligand Activate phospholipase C (PLC): ↑ intracellular calcium (& PKC) GPCR Cell membrane α PLC βγ G-protein DAG GDP IP3 GTP ↑Ca2+ CYTOPLASM Examples of GPCRs Muscarinic acetylcholine receptors – CNS, lungs, GI tract Adrenergic receptors – Heart, vasculature, lungs, CNS Histamine receptors – Heart, vasculature, GI tract, nociception Prostaglandin receptors – inflammation, GI tract, CNS. Opioid receptors – nociception, GI tract, CNS Ligand-gated ion channels Ligand binds to receptor Channel in receptor opens allowing ion movement across membrane: ionotropic Very fast (milliseconds) Neurotransmission Examples of ligand-gated ion channels Nicotinic acetylcholine receptors – CNS, peripheral nerves, NMJ NMDA glutamate receptors – CNS GABAA receptors – CNS P2X receptors – ligand purines (ATP). CNS, peripheral nerves, blood cells Enzyme-linked & nuclear receptors Often activated by signalling molecules like cytokines, hormones Usually involved in regulation of cell processes and gene expression Slow induction of effects, very long-lasting effects (gene regulation) Enzyme-linked e.g. receptor tyrosine kinase (RTK), receptor serine / threonine kinase (RSTK) Kinase-linked receptors Activate protein phosphorylation Gene transcription Protein synthesis Large & heterogenous family. Intracellular domain often enzymatic Growth factors are common ligands Nuclear receptors Ligand In nucleus or cytoplasm – ligand must pass through membrane Cytoplasm Nuclear receptors regulate gene NR transcription Nuclear receptors often the targets of hormones Nucleus Can recognise foreign molecules and initiate CELL metabolic processes Receptor subtypes Structurally similar receptor proteins with different mechanisms of action and effects but the same endogenous ligand, e.g.: muscarinic acetylcholine receptors M1, M2, M3… Monomeric (?) GPCRs M1,3,5 are Gq-linked; M2,4 are Gi-linked nicotinic acetylcholine receptors Pentameric (5-subunit) ligand gated ion channels; different subunit compositions depending on location Enzymes q.v. enzyme biochemistry: Regulation of enzyme metabolism key to physiology Feedback processes Modulation (+/-), inhibition, activation Many functions of enzymes (e.g. signalling, metabolism): catalysis, protein modification (e.g. phosphorylation), gene activation / suppression; etc. Enzymes also vital for pharmacokinetics; drug metabolism (mostly hepatic) Enzyme activity is heavily regulated naturally; drugs can also alter enzyme activity Ion channels Usually selective for either: cations (K+, Na+, Ca2+) anions (Cl-, HCO3-) Cation channels may be selective for a specific ion, or if non-specific, are usually permeable to all three. Ligand-gated channels (usually receptors) Leak channels (low clinical usefulness) Voltage-gated channels (e.g. Na+, Ca2+ ) Other gated channels (e.g. TRP channels) Voltage-gated sodium channels e.g. Voltage-gated sodium channel (VGNaC) Na+ channel closed at normal Membrane depolarisation (-40mV) membrane potential (-70mV) causes Na+ channel to open Membrane transporters (“pumps”) Transporters are proteins that move ions and small molecules across the membrane: Why? May use electrochemical gradient or ATP hydrolysis May move multiple ions/molecules: symporters (co-transport) antiporters (exchange) Examples of membrane transporters Sodium / potassium exchanger 5-HT reuptake transporter Specificity & selectivity Drugs can affect multiple targets: Specific ligands are much more effective at a target than others (> 100x more potent) Selective ligands have mild-moderate greater effectiveness at a target than others (~10-100x) Non-specific / non-selective ligands have minimal difference in effectiveness between targets (10% of ADRs are forms of allergic reaction / hypersensitivity – these are often unpredictable and may not be dose dependent Some ADRs may only emerge with chronic administration Some ADRs may take a long time to appear after administration Some ADRs may occur when the drug treatment is stopped (withdrawal) Or a combination of the above Cautions / contraindications & drug interactions Drugs may be risky / inappropriate because of comorbidities (other conditions): vulnerabilities to adverse drug reactions Receiving multiple drugs may cause adverse drug interactions (pharmacodynamic or pharmacokinetic): Synergistic: additive effects of multiple drugs may cause excessive activity Antagonistic: one drug reducing the effect of another reduction in therapeutic benefit Tolerance & Withdrawal Homeostasis – the body’s attempt to maintain a constant environment: natural feedback systems Drugs may disrupt the body’s natural equilibrium; thus homeostatic activity will adapt physiological processes to drug presence: Tolerance: the drug may become less effective with repeated administration Withdrawal: adverse symptoms caused by removal of the drug; often “rebound” effects The same adaptations that cause tolerance are often also responsible for withdrawal Tolerance / desensitisation Tolerance usually develops due to chronic administration and may last a long time Some tolerance may be acute, rapid and transient (“tachyphylaxis” / “desensitisation”) Boundary between tachyphylaxis and normal tolerance not clear Numerous biochemical / physiological causes of tolerance Short term causes frequently temporary protein modification Longer-term often involve more complex systems, often protein transcription Tolerance / desensitisation – mechanisms Reduced target response to drug via protein modifications (e.g. phosphorylation) Reduced expression of drug target, e.g.: removal of receptors from plasma membrane reduced transcription of drug target Increases in “opposite” physiological activity e.g. increased in excitatory signalling with CNS depressants Pharmacokinetic altered ADME, e.g. induction of liver enzymes that break down drug Drug resistance developed mechanisms of drug inactivation e.g. antibiotics Behavioural learning how to handle drug (e.g. alcohol) Withdrawal – example corticosteroids Numerous causes; usually up- or downregulation of physiological systems to counteract drug effects With end of treatment, may be excessive opposite activity Systemic presence of corticosteroids activates adrenal hypothalamic pituitary system feedback to suppress endogenous cortisol production Removal of corticosteroids may then lead to cortisol deficit May be severe; hospitalisation Summary Drugs affect molecules to alter physiological activity. So in order to better understand pharmacology, learn the systems that drugs work on: know the cell biology and physiology Pharmacodynamics as a science of drug action on the body Drug targets: Receptors, enzymes, ion channels, transporters Specificity / selectivity Adverse drug reactions Tolerance & withdrawal MBBS Learning Outcomes M2.I.COR.PHM4: Identify the principles of pharmacodynamics and the differences which can affect drug response (e.g. receptor sensitivity, tolerance, organ disease) M2.I.COR.PHM5: Explain the molecular targets for drug action and describe how these actions translate into responses at the tissue and organ level