FFP1-54 Intro to Pcol STS 2023 (2).pptx

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn FFP1-54 Introduction to Pharmacology Prof Steve Safrany 341 [email protected] Dr. Roger Preston Learning outcomes • Explain the differences between chemistry-led and target-led drug discovery • Describe the advantag...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn FFP1-54 Introduction to Pharmacology Prof Steve Safrany 341 [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 a drug? • Substance that has biological activity • Does not include dietary factors such as vitamins • However, when used in excess of normal dietary intake they are drugs What is pharmacology? • “The interaction of substances with living organisms” What is pharmacology? • Pharmacodynamics – Why we take a drug – Effect on the body / biological system • Pharmacokinetics – How we take a drug – How often we take a drug Where do drugs come from? • Originally herbal extracts • Traditionally considered to be small synthetic molecules • More recently new approaches mean that proteins, nucleic acids, microbial products and animal products more Plants as drugs • Rather than use plant extracts we now purify active ingredients • One approach is to take a known herbal remedy and extract the active ingredient • Another approach is to screen plant Drugs from herbal medicine • Many active ingredients have been extracted from herbal medicines and used in their pure form: – Digitalis (Foxglove) – Quinine (Cinchona tree) – Morphine (Poppy) Aspirin Diamorphine Drugs from herbal medicine St John’s wort Herb from Hypericum species Effective in treatment of depression Induces cytochrome P450 (CYP3A4 & 2C9 + others) • Causes many drug interactions • • • • – Oral Contraceptive Pill – Anti-retrovirals (HIV) Microbe-derived drugs • Anti-microbial agents isolated from microbes • Microbes produce many different products • Some can have biological activity • Screening supernatants allows Microbe-derived drugs Penicillin • Derived from fungus (Penicillium notatum) • Identified by its ability to kill Staphylococcus aureus • Many antibiotics Microbe-derived drugs immunosuppressants • Cyclosporine isolated from Tolypocladium inflatum Gams, a soil fungus • Tacrolimus isolated from bacteria - Streptomyces tsukubaensis • Rapamycin isolated from Streptomyces hygroscopics Modern use of animal tissue as drugs • More recently animals have provided a useful source of drugs • Heparin (anticoagulant) from pigs and cattle • Hirudin (anticoagulant) from leeches • Eptifibatide (anti- 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 Drug discovery approaches • Chemistry-led discovery – Select a chemical – Screen for biological activity – Often mechanism unknown but effect known • Target-led discovery – Choose a drug target (protein) – Screen chemicals for binding to target – Mechanism Chemistry-based drug development • Anti-epileptic drugs – Barbital (1903) the first blockbuster – Phenobarbital (1911) – Phenytoin • Sulfonamides (1935) the first anti-bacterial • Anti-histamines (1937) used for urticaria/allergies • Nitrogen mustards (1946) the first anticancer • Mercaptopurine (1951) the first antimetabolite Chemistry-based drug development • Histamine H2 antagonists by James Black 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 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 been used as drugs • Purification of insulin and its use to treat diabetes in 1922 • Since then, other hormones and coagulation factors have been purified • ADVANTAGES: plentiful, effective and easy to isolate? • DISADVANTAGES: require blood donation, infection risk, difficult to further modify • Recombinant proteins solve this Recombinant protein therapies • Protein not isolated, but proteinencoding 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 single antigen • It is not necessary to use animals in the production* • Large amounts of antibody can be produced • Predictable batch properties • Expensive to make • Have to be given IV 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 single “sense” molecule • Complementary mRNA chain can bind and inhibit transcription 2. Aptamers are PATISARAN FDA-approved RNAi therapy for hereditary amyloidosis with polyneuropathy (or malfunction of nerves) 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 Adoptive cell transfer therapy 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 reocclusion 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