Introduction To Pharmacology RCSI FFP1-54 2024 PDF

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn FFP1-54 Introduction to Pharmacology Prof Will Ford 337 [email protected] Dr. Roger Preston ...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn FFP1-54 Introduction to Pharmacology Prof Will Ford 337 [email protected] Dr. Roger Preston  Learning outcomes Explain the differences between chemistry-led and target-led drug discovery Describe the advantages and disadvantages of protein-based therapeutics Explain the generation, activity and applications of monoclonal antibodies Discuss new areas of therapeutics that overlap with pharmacology, such as cell therapies Discuss new areas of therapeutics that overlap with pharmacology, such gene-based therapies Recommended Reading  What is pharmacology? What happens to Pharmacokinetics PHARMACOLOG drugs in the body Pharmacodynamics What drugs do in the body PharmacotherapeuticsHow drugs are used Y Study of drugs from Pharmacognosy naturally occurring sources Toxicology Study of adverse effects  The evolution of pharmacology 3400BC Egyptian inhalation of herbs to relieve asthma symptoms 1000BC Ma huang ingested to alleviate asthma symptoms Chemical structures of morphine, cocaine determined ynthesis of aspirin 1897  What is a drug? “A drug is a chemical that when applied to a physiological system affects it in a specific way.” Rang and Dale’s Pharmacology 2018, Chapter 2, p29. Where do drugs come from? Source Drug Plant Foxglove Digitalis Animal Viper Eptifibati de Penicillium notatum Microbe (fungus) Penicillin  Drugs vs herbal vs ‘alternative’ medicine Drugs Herbal Homeopathy Biologically active Biologically active No biological activity 1 active component >1 active component No active component (?) Dose is known Dose is an estimate Dose = 0 (?) Manufacture/sale Manufacture/sale Manufacture/sale regulated generally unregulated unregulated Biological > placebo Biological > placebo effect Placebo effect only effect Link to information about homeopathy: https://www.nccih.nih.gov/health/homeopathy  What can drugs target? Receptors Enzymes Ion channels Transporters  Drug discovery approaches Chemistry-led discovery Target-led discovery  Identify chemical with biological  Identify drug target of interest activity  Screen chemicals for binding to  Modify chemical structure to target make library of analogues  Design chemical entities based  Screen analogues for biological on computer modelling of ligand activity docking to 3D protein structures  Generate structure-activity  Mechanism known and effect relationships to inform further predicted development  Mechanism often unknown and Example treatment basedof receptor structure modelling. Rang & Dale onthbiological Pharmacology, 9 edition 2018 p59 effect  Mepyramine binding to H1 receptors Wang et al. Molecular mechanism of antihistamines recognition and regulation of the histamine H1 receptor. Nat Commun 15, 84 (2024)  An example of chemistry-based drug development: Ranitidine [Sir James Black] 1948 Histamine antagonists already clinically used (H1 receptor selective) Histamine caused gastric acid secretion – insensitive to available antagonists Proposal of another histamine receptor (H2) Clinical utility for treatment of peptic ulcers (none available at that time) 1964 Program established at SKF with Sir James Black to develop antagonists of H2 receptors Synthesis of histamine analogues testing for H2 selectivity  Compound development 1. Dissociation constants CH2CH2NH2 H1 H2 H2/H1 Histamine 0.5 μM 0.5 μM 1 N N H CH2CH2CH2CH2NH-C-NHCH3 S Burimamide 320 μM 70 nM 5,000 N N H Poor oral absorption H3C CH2SCH2CH2NH-C-NHCH3 S N N Metiamide >500 μM 2.5 μM >200 H Granulocytopenia  Compound development 2. Dissociation constants H3C CH2SCH2CH2NH-C-NHCH3 H1 H2 H2/H1 NCN Cimetidine 450 μM 33 μM 14 N N H Cyp450 drug interactions CH2SCH2CH2NH-C-NHCH3 CHNO2 O Ranitidine >500 μM 1 μM >500 CH2NCH2CH3 General features Aromatic Polar H- Flexible chain ring bonding group Functional evidence of selectivity  Modern drug development Conventional pharmacology uses small synthetic molecules Origins in early 19th century with the purification of morphine, quinine, strychnine and cocaine One of the first drugs to be synthesized was  Small molecule drugs - problems While most drugs are ‘small molecules’ it has not always been possible to develop small molecule agents: – Many interactions are between proteins, and small molecule inhibitors are not possible – Chemistry is too difficult  Current drug approaches Recent advances in biotechnology has completely changed the options for therapy New therapies include: – Recombinant engineered proteins – Nucleic acid-based therapeutics – Gene therapy approaches – Cell-based therapies  Protein therapies Proteins have long ADVANTAGES: been used as plentiful, effective drugs and easy to isolate? Purification of insulin and its use DISADVANTAGES: to treat diabetes in require blood 1922 donation, infection risk, difficult to Since then, other further modify hormones and coagulation factors Recombinant have been purified proteins solve this and used problem  Recombinant protein therapies Protein not isolated, but protein- encoding gene cloned into cell line Cells generate ‘recombinant’ protein is expressed and purified Limited potential for viral contamination – Insulin – Erythropoietin – Interferon – Factor VIII and IX – Growth factors – Hirudin (Brassica napus)  Monoclonal antibody therapies Köhler and Milstein discovered a method to immortalize antibody-producing cells (1975) Antibody-producing cells from the spleen fused with myeloma cells (cancer cells) Using monoclonal antibodies to fight cancer  Value of monoclonal antibody therapies ADVANTAGES: DISADVANTAGES: Single epitope on a Expensive to make single antigen Have to be given IV It is not necessary to use animals in the production* Large amounts of antibody can be produced Predictable batch properties  Monoclonal antibody nomenclature Mouse Moabs -omab – Tositumomab Chimeric antibodies -ximab – Infliximab Humanised antibodies -zumab – Natalizumab, Trastuzumab Human antibodies -umab – Adalimumab  Antivenin / antivenom Antivenin is used to treat snake and spider bites Usually, serum from a horse that has been inoculated with snake venom is used* Horse serum is foreign and can trigger immune reactions Anti-horse antibodies  Nucleic acids as drugs Nucleic acids can be used as drugs: 1. ‘Antisense’ molecules mRNA exists as a PATISARAN single “sense” FDA-approved RNAi molecule therapy for hereditary amyloidosis with Complementary polyneuropathy (or mRNA chain can malfunction of bind and inhibit nerves) transcription 2. Aptamers are  Gene therapy There are a number of diseases in which a protein is not expressed due to a genetic mutation In other diseases the expression of a gene is  Cell-based therapies ‘Cell-based’ therapy can involve: The introduction of genetically-modified cells to treat disease …or the application of stem cells to renew existing cell defects or deficits – Embryonic, pluripotent – Self, multipotent  Stem cell therapy Stem cells have the potential to differentiate into an unlimited number of mature tissue-specific cell types Lots of potential uses, but most commonly used for treatment of leukaemias Stem cell grafts can be  Adoptive cell transfer therapy ‘Living drugs’ Chimeric antigen receptor (CAR)-T cell therapy: use patients own T cells being isolated and genetically modified to express synthetic receptors on their surface that recognise tumour antigens The CAR-T cells are then better able to destroy the malignant cells  Are medical devices drugs? Devices are regulated by different legislation to drugs Recently the divide between the two areas has blurred Use of stents is very important in cardiology where vessel re- occlusion is problematic – Drug-coated stents are  What we have learned… Explain the differences between chemistry-led and target-led drug discovery Describe the advantages and disadvantages of protein-based therapeutics Explain the generation, activity and applications of monoclonal antibodies Discuss new areas of therapeutics that overlap with pharmacology, such as cell therapies Discuss new areas of therapeutics that overlap with pharmacology, such gene-based therapies