Drug Targets 2021-2022 PDF

Pharmacodynamics 1: Drug Targets Robert Sims HA209 [email protected]  Lecture Objectives Pharmacodynamics Human proteins as main targets of drugs; cellular communication Physiology of common drug targets: receptors enzymes...

Pharmacodynamics 1: Drug Targets Robert Sims HA209 [email protected]  Lecture Objectives Pharmacodynamics Human proteins as main targets of drugs; cellular communication Physiology of common drug targets: receptors enzymes ion channels transporters  Pharmacology I firmly believe that if the whole materia medica, as now used, could be sunk to the bottom of the sea, it would be better for mankind – and all the worse for the fishes Oliver Wendell Homes Sr.  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 How drugs affect the body: Mechanism of action – the biochemical interaction by which a drug causes its effects Resultant cellular biological, physiological and clinical effects (“mode of action”) The relationship of concentration and effect  Protein drug targets Rask-Anderson et al. (2011) Nature Reviews: Others 12% Receptors 44% 1,542 drugs Transporters 15% 1,236 target known proteins Ligand gated Ion channels 8% ion channel 9% 1,044 target known human proteins GPCR-coupled 19% 435 different therapeutic proteins Enzymes 29%  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 drug targets Pathogens, fungi, parasites, etc. (e.g. antibiotics) Dietary supplements Direct DNA interaction Amino acids Chemical messengers (e.g. antibody drugs) Unknown mechanism (!) Part 2: from molecules to man  Drugs – physiology Molecules Drugs Cells Tissues By altering the activity of molecules and cells with drugs, we can control Organs the activity of higher organisational structures, up to the entire Organisms organism.  Molecules → Cells C Receptor Enzyme Secondary messenger 1 2 A 5 8 Cells have a huge range of 3 4 biochemical pathways Drugs can interact with 6 many points of these pathways B 7 NUCLEUS CELL Side Effects? Cells → Organs Drug target present in other cells (same or different organ) Drug affects other targets (same or different organ)  Specificity and 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 Non-selective ligands have minimal difference in effectiveness between multiple targets Part 3: Receptors  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 Largest receptor family – 865 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 Stimulate adenylate cyclase (↑ cAMP / PKA) GPCR Cell membrane a AC G-protein bg GDP GTP cAMP CYTOPLASM  Gi proteins Inhibit adenylate cyclase (↓ cAMP / PKA) GPCR Cell membrane a AC G-protein bg GDP GTP CYTOPLASM  Gq proteins Activate phospholipase C (↑PKC, ↑[Ca2+]i) GPCR Cell membrane a PLC G-protein bg GDP IP3 GTP DAG 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 – 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. Growth factors are Intracellular domain often enzymatic common ligands  Nuclear receptors Ligand CELL In nucleus or cytoplasm Cytoplasm Regulate gene transcription NR Hormones and steroids target nuclear receptors Nucleus Can recognise foreign molecules and initiate 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 ligand gated ion channels; different subunit compositions in autonomic ganglia, CNS and NMJ Part 4: Enzymes, transporters, ion channels  Enzymes q.v. enzyme biochemistry: Regulation of metabolism key to physiology Feedback processes Modulation (+/-), inhibition, activation Intracellular and intercellular signalling; gene activation / suppression; etc. Enzymes also vital for pharmacokinetics; drug metabolism  Ion Channels Usually selective for either: cations (K+, Na+, Ca2+) anions (Cl-, rare others) Cation channels may be selective for a specific ion, or if non- specific, are usually permeable to all three. Ligand-gated channels Leak channels – low clinical usefulness Voltage-gated channels  Voltage-gated ion channels e.g. Voltage-gated sodium channel Na+ channel closed at normal Membrane depolarisation (-40mV) membrane potential (-70mV) causes Na+ channel to open  Local Anaesthetics Lidocaine Na+ Na+ Local anaesthetics cross the cell membrane and VGNaC bind to VG Na+ channels. Block the inside of the H+ channel pore; prevent Na+ flux H+  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)  Selective Serotonin Reuptake Inhibitors SSRI Serotonin transporter (SERT): SERT 5-HT receptor 5-HT is cleared from the synapse by reuptake into the presynaptic cell and 5-HT astrocytes. Reuptake inhibition increases the concentration of 5-HT at the synapse and increases 5-HT receptor activity Part 5: Factors affecting pharmacodynamics  Pharmacodynamic variations Drug responses can vary (potentially widely) by individual and by circumstances, due to factors such as: Genetics – variations in protein structure & activity Ageing – age-dependent alterations in protein activity Disease – disease mediated changes in protein activity Tolerance – adaptations to presence of drug Other drugs – interactions between different drugs  Tolerance & Withdrawal Homeostasis – the body’s attempt to maintain a constant environment 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 (“refractory”) Withdrawal: removal of the drug may cause a reverse rebound as the body has adjusted to a new baseline with drug  Desensitisation Desensitisation is the reduction of activity of a drug target in response to a drug Target desensitisation may be acute, rapid and transient (“tachyphylaxis”) It may be long-term due to chronic administration; often a basis of tolerance Numerous physiological causes  Protein modification & inhibition β-agonist Rapid desensitisation by feedback mechanisms such as: β2 receptor Phosphorylation and other protein modifications (e.g. adrenergic β2 G receptors) P Inhibitory products (e.g. enzymes) P G kinases Phosphorylation-mediated β2 receptor uncoupling from G-protein  Expression Opioid Desensitisation by drug induced changes in protein levels opioid receptor Decreased expression of target (e.g. opioids) Tolerance due to increased expression of proteins mediating Activity mediated opposite activity can also occur receptor internalisation by endocytosis  Other forms of tolerance Increases in “opposite” activity e.g. increased in excitatory signalling with CNS depressants Pharmacokinetic altered ADME, e.g. induction of liver enzymes Drug resistance developed mechanisms of drug inactivation e.g. antibiotics Behavioural learning how to handle drug (e.g. alcohol) Withdrawal – corticosteroids Systemic presence of corticosteroids activates adrenal hypothalamic pituitary system feedback to suppress endogenous cortisol production Removal of corticosteroids may lead to cortisol deficit  Summary – drug targets Drugs affect molecules to alter physiological activity. So in order to better understand pharmacology, learn the systems that drugs work on: know your cell biology and physiology. Receptors Enzymes Ion Channels Transporters Variations in responses to drugs; 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