Concepts In Pharmacology Lectures 1 & 2 (University of Bradford) PDF

Concepts in pharmacology – lectures 1 and 2 CLS4011-U 1 29 October, 2024  What the body does to Pharmacokinetics drugs… Pharmacology What drugs do to the body Pharmacodynamics 2 29 Octob...

Concepts in pharmacology – lectures 1 and 2 CLS4011-U 1 29 October, 2024  What the body does to Pharmacokinetics drugs… Pharmacology What drugs do to the body Pharmacodynamics 2 29 October, 2024  Pharmacokinetics 3 29 October, 2024  Pharmacokinetics · oral administration Describes the processes of… · IV nasal Topical intestine · respiratory large Absorption – How drugs get into the body/tissues/cells Distribution – Where drugs go in the body Metabolism – What chemical changes happen to the drug Excretion – How the drug leaves the body 4 29 October, 2024  Pharmacokinetics (Plasma level of drog measured ↑ Drug Dose into body A M Absorption Metabolic activation A D Drug bound to D M Free active drug in Metabolic plasma proteins plasma inactivation D D E E Tissue Reservoirs M D Excretion from body Active drug available at required site of action 5 29 October, 2024  Factors affecting drug absorption microvilli on small Physiochemical = SA Environmental Membrane intestine properties of ↑ rate of absorbance While sleeping pH surface area = drug absorption ↓ Drug Presence of Blood concentration transporters flow/supply (gradient) Presence of Gastric Age food emptying Genetic Health status Diet variation 6 29 October, 2024  Drug distribution Important as drugs need to get to required site of action to have desired pharmacological effect. Plasma protein binding Lipophilic compounds can limit amount of free accumulation in fat Drug depot effect drug in blood deposits Presence of transporters Compartmental barriers can concentrate drug can affect drug access to intracellularly compared tissues/organs (e.g., to plasma concentrations blood-brain barrier) 7 29 October, 2024  Drug metabolism Oxidative Reductive Conjugative Range of different Done by enzyme Can happen before or enzyme systems (e.g., systems such as after oxidative or Cytochromes P450s, cytochromes P450s reductive metabolism Flavin monooxygenases) Expose functional Addition of a chemical groups group (e.g., sugar, Expose functional amino acid, peptide groups (e.g., -OH) Usually occur in low chain, sulfate) to make which can be further oxygen environments molecules more water metabolised soluble and more likely to be excreted 8 29 October, 2024  Drug metabolism Oxidation Is DoneLoss Oxidative Reductive Conjugative Range of different by enzyme Can happen before or enzyme systems (e.g., systems such as after oxidative or Cytochromes P450s, cytochromes P450s reductive metabolism Flavin monooxygenases) Reduction Expose functional groups Addition of a chemical group (e.g., sugar, Expose functional groups (e.g., -OH) Is Usually occur in low amino acid, peptide chain, sulfate) to make Gain which can be further oxygen environments molecules more water metabolised soluble and more likely to be excreted (of electrons) 9 29 October, 2024  Measuring drug concentrations - Concentrations are an amount (moles) in a given volume (litres) - One mole (mol) is 6.023 x 1023 atoms or molecules of a substance and is measured in grams (g) - Use techniques such as liquid-chromatography mass spectrometry (LC-MS) - Liquid chromatography allows the separation of several compounds in a complex mixture so that they can be detected individually and quantified 10 29 October, 2024  Calculating concentrations Number of moles (mol) = mass of substance (g)/mass of 6.023x10 23 molecules of substance (g) Number of moles (mol) = Volume (Litres) x Concentration (Molar) You should remember these equations and how to use them from school/college 11 29 October, 2024  How do we describe drug PK? intravenous oral 12 29 October, 2024  What does this tell us? Factor What does it tell us? Area under curve (AUC) Drug exposure Half life (t1/2) Time taken for half of drug concentration to be excreted Cmax Maximum concentration of drug Tmax Time to maximum concentration of drug 13 29 October, 2024  Pharmacodynamics 14 29 October, 2024  How do drugs work? Change in target/cellular DNA function RNA Protein receptor Enzyme activation/inhibition Enzyme Altered gene expression Protein stabilization/degradation Drug binds cellular Changes in target physiology 15 29 October, 2024  Types of cellular targets – Enzymes - E.g., statins (HMG-CoA reductase inhibitors) - Reduce synthesis of cholesterol in the liver - Reduced liver cholesterol synthesis increases LDL binding by the liver - Both of these result in reduced blood cholesterol markers https://www.rcpath.org/profession/publications/college-bulletin/july-2018/the- development-of-a-new-service-for-patients-with-hyperlipidaemia-and-ischaemic-heart- disease.html 16 29 October, 2024  Types of cellular targets – Receptors 17 29 October, 2024  Ligand-gated ion channels Ligand binds to receptor which results in opening of a pore in the membrane allowing ions to cross membrane C. Side view 6 nm 3 nm 2 nm receptor gate ( helices) 18 29 October, 2024  G-protein coupled receptors Significant drug target and key mechanism underpinning a range of signaling pathways within cells 19 29 October, 2024  G-protein coupled receptors How do they work? Receptor  GDP   20 29 October, 2024  G-protein coupled receptors When an agonist binds to the receptor it causes association between receptor and G-protein which results in a change in confirmation of alpha subunit Agonist Effector protein Receptor  GDP   21 29 October, 2024  G-protein coupled receptors When an agonist binds to the receptor it causes association between receptor and G-protein which results in a change in confirmation of alpha subunit Alpha subunit releases GDP and replaces it with GTP which causes release of alpha subunit from beta and gamma subunits Agonist Effector protein Receptor  GTP   GDP 22 29 October, 2024  G-protein coupled receptors When an agonist binds to the receptor it causes association between receptor and G-protein which results in a change in confirmation of alpha subunit Alpha subunit releases GDP and replaces it with GTP which causes release of alpha subunit from beta and gamma subunits Agonist Effector protein Receptor    GTP 23 29 October, 2024  G-protein coupled receptors Activated alpha subunit can associate with a target protein (e.g., adenylyl cyclase) and activates it Agonist Effector protein Receptor    GTP 24 29 October, 2024  G-protein coupled receptors Target protein activation results in down-stream signaling, while the hydrolysed GTP is converted to GDP and the alpha subunit reassociates with the beta and gamma subunits – resets the system. Agonist Effector protein Receptor  GDP   Down-stream signalling 25 29 October, 2024  G-protein coupled receptors - Different receptors can have different effects (e.g., can be inhibitory or activating - Determined by alpha subunit type - E.g., αs subunit stimulates adenylyl cyclase whereas αi/o subunit inhibits adenylyl cyclase 26 29 October, 2024  G-protein coupled receptors Down-stream signalling can result in mobilization of calcium stores, activation of kinase signalling pathways, opening of ion channels, etc. 27 29 October, 2024  Enzyme-linked receptors Receptor has a domain for binding ligands and a catalytic domain which can phosphorylate serine, threonine or tyrosine residues on the receptor protein Known as autophosphorylation (the receptor enzyme activity phosphorylates itself) 28 29 October, 2024  Enzyme-linked receptors 29 29 October, 2024  Enzyme-linked receptors Binding of ligand 30 29 October, 2024  Enzyme-linked receptors Receptor dimerisation 31 29 October, 2024  Enzyme-linked receptors Phosphorylation of serine, threonine or tyrosine residues results in recruitment of accessory proteins – bind via SH2 domains 32 29 October, 2024  Enzyme-linked receptors Accessory proteins activate cellular kinase pathways which result in transcription factor activity and gene expression changes 33 29 October, 2024  Enzyme-linked receptors Receptor type Notes Receptor tyrosine kinases Protein contains its own tyrosine kinase enzyme activity located in the intracellular part of the protein e.g., growth factor receptors, insulin receptor Receptor Similar to receptor tyrosine kinases but phosphorylates serine/threonine kinases serine/threonine residues instead of tyrosine Cytokine receptors Lack their own tyrosine kinase activity but can recruit cytosolic kinase activities instead when ligand binding occurs Guanylyl cyclase receptors Similar to receptor tyrosine kinases but intrinsic enzyme activity produces cyclic GMP (cGMP) rather than autophosphorylation 34 29 October, 2024  Down-stream signalling of GPCR and enzyme-linked receptors 35 29 October, 2024  Nuclear receptors Receptors which are not found associated with the membrane (in cytosol or nucleus) Ligand binding activates receptor to translocate to nucleus and bind to DNA – regulates gene expression 36 29 October, 2024  Nuclear receptors 37 29 October, 2024  Nuclear receptors DNA binding happens because nuclear receptors contain a structure called zinc finger domains 38 29 October, 2024  Nuclear receptors e.g., glucocorticoid receptor - Dexamethasone activates the receptor resulting in reduction of expression of pro-inflammatory molecules (e.g., cytokines) 39 29 October, 2024  Receptor summary 40 29 October, 2024