MBBS Stage 1 - Fundamentals of Pharmacology 1 PDF

Life Sciences & Medicine Fundamental Principles of Pharmacology 1 Professor Ian McFadzean Pharmacology & Therapeutics MBBS Stage 1 – Physiology & Anatomy of Systems After this lecture you should be able to...

Life Sciences & Medicine Fundamental Principles of Pharmacology 1 Professor Ian McFadzean Pharmacology & Therapeutics MBBS Stage 1 – Physiology & Anatomy of Systems After this lecture you should be able to: Explain how drugs are categorized and give examples of how they are named. Describe the concept of ‘receptor’ and molecular targets in the context of drug mechanisms. Explain what is meant by the term “pharmacokinetics” and distinguish this from ‘pharmacodynamics’. Distinguish between preclinical drug discovery and clinical drug development. What is a drug? A drug can be defined as; a chemical substance of known structure, other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect. What makes a good medicinal drug? Can we deliver Will it do it to its site of anything once action? it gets there? Does it stay there? How are drugs named Drugs that are used therapeutically typically have at least three names!!!!!!  chemical name – e.g. (RS)-2-(4-(2-methylpropyl)phenyl)propanoic acid  common name – ibuprofen  Proprietary (trade) names – e.g. “Nurofen”; Usually grouped according to therapeutic use e.g. analgesics, antihypertensives, antibiotics Or sometimes by mechanism of action e.g. cyclooxygenase inhibitor, beta- blocker Ibuprofen is a cyclooxygenase inhibitor that acts as an analgesic How do drugs produce their effects? Drugs are exogenous molecules that mimic or block the actions of endogenous molecules “A drug will not work unless it is bound” Paul Ehrlich (1854-1915) The vast majority of drugs bind to molecular targets (often called receptors) that are important proteins within the body Target proteins include  Receptors for neurotransmitters or hormones  Enzymes  Ion channels  Carrier or transporter molecules The concept of “complementarity” B A A little bit of jargon. Target The small drug molecules protein that bind to large target C proteins are called “ligands” Modern computer modelling techniques allow drugs to be designed in silico https://www.creative-proteomics.com/services/protein-ligand-bindi ng-site-prediction-service.htm It all comes down to chemistry! How well a drug “fits” into its binding site is governed by the size and flexibility of the drug (steric factors) How well the drug binds to its target protein is determined by the nature of the chemical bonds that form between the drug molecule and its binding site Most drugs (ligands) bind reversibly to the target protein through hydrophobic and hydrogen bonds plus weaker van der Waals interaction. Some bind irreversibly through covalent interactions Ultimately this leads to the formation of a ligand-protein complex which will alter the activity of the protein in some way Specificity vs selectivity For a drug to be useful therapeutically it must be very selective in its action; an antihypertensive drug that lowers blood pressure, but at the same time causes severe gastrointestinal problems, is not going to be useful in treating patients with high blood pressure One way of achieving selectivity might be to design a drug that binds to only one molecular target and no others; in other words, a drug that is specific If that molecular target is found only in the cardiovascular system, then the drug might lower blood pressure with no gastrointestinal side effects i.e. be selective in its action If, however, that same molecular target was found in both the gastrointestinal system and the cardiovascular system, despite being specific, the drug would be non- selective in its action Pharmacodynamics and Pharmacokinetics Pharmacodynamics (PD) can be defined as “what the drug does to the body” i.e. the consequences of the drug’s actions at a molecular level on the physiology of an organism Pharmacokinetics (PK) can be defined as “what the body does to the drug” i.e. how the drug is “handled” by the organism. For example how it gets to its site of action, how it is metabolised or how it is distributed to the different organs When drugs are being developed for therapeutic use, a true understanding of the drug’s effectiveness only comes when pharmacodynamics and pharmacokinetics are considered together, so-called PK/PD studies Absorption, Distribution, Metabolism, Excretion (ADME) These are the critical elements of pharmacokinetics Each can be influenced by the properties of the drug – for example absorption of a drug from the gut will be influenced by whether the drug is stable in the acid environment of the stomach - or the characteristics of the person taking the drug – for example a patient suffering from liver damage will not metabolise a drug as well as a patient with a healthy liver Dr Richard Amison's lecture will give more detail on pharmacokinetics The drug discovery process Basic Leads to better research in understanding of physiology universities and disease mechanisms for example Looking for molecular Identification targets (usually proteins) of potential that play a crucial role in drug targets the disease A drug that acts on that Hypothesis target to change its generated activity will be effective in treating disease The drug discovery process – an example The hormone adrenaline Basic (epinephrine) relaxes smooth research in muscle in the airway to cause universities bronchodilation for example Asthma causes bronchoconstriction Identification Adrenaline acts on a beta of potential receptor on bronchial smooth muscle drug targets A drug that mimics the effects of adrenaline Hypothesis will be effective in generated relieving the symptoms of asthma Drug discovery Hypothesis Natural products Compound Potential Assay Active chemicals libraries drugs systems Combinatorial Chemical optimisation chemistry Animal models Drug discovery and development Hypothesis Natural products Compound Potential Assay libraries drugs Active chemicals systems Combinatorial chemistry Chemical optimisation Animal Toxicology testing Pharmacokinetics models and “Safety pharmacology” drug candidate Clinical trials Up until now we have only considered “pre-clinical” development; our drug candidate has not yet been administered humans The preclinical stage typically takes 5-10 years, and will lead to one or two drug candidates being taken forward into human clinical trials Importantly, the patent for a new drug is granted early in the pre-clinical stage and lasts for 20 years, after which time anyone can copy the drug, without the associated development costs (so-called “generic” drugs) Pharmaceutical companies are under pressure therefore to get their drug to market as soon as possible and to recoup the development costs (including those for drugs that failed) before the patent expires Clinical Trials in Drug Development Pre-clinical Clinical Post-market Discovery Pre-clinical Overall: £250-500 million Phase I Phase II Phase III Phase IV Patent Patent granted expires Generics 0 5 10 15 20 25 years Phase I – Exploratory; first in human Chronic toxicity of the drug will have been assessed in at least 2 mammalian species (1 non rodent) Phase 1 trials last 6 months to a year and the purpose is to check for;  SAFETY (potentially dangerous side effects)  TOLERABILITY (unpleasant symptoms e.g. headache, nausea) Involve a small number (40 – 60) of healthy volunteers exposed to increasing doses. Carried out in specialised clinical facilities Placebo-controlled, randomized, double-blind May involve selected subject groups (male, female, elderly, different ethnicities) Phase II – Efficacy, proof of concept and safety Primary purpose is to determine how clinically effective the drug is in patients, and to confirm safety and tolerability Phase IIa  Exploratory  50-200 patients; lasts approximately 1 year  Dose and treatment regimen based on Phase 1 results  Usually placebo-controlled, randomized, double-blind Phase IIb  Confirmatory  200-500 patients; lasts approximately 2 years  Safety and efficacy compared to placebo or current treatment in randomized, double-blind design Phase III - Confirmatory Full scale evaluation of how EFFECTIVE and SAFE the treatment is compared to current standard treatment (or placebo) Drug is tested in typically 2000-10 000 patients, often in multi-centres, and including different groups (age etc) Last several years (especially in chronic disease scenario) Provides data to support registration; once completed can apply for registration for use in specified condition At last £££££!! Emma Walmsley CEO GSK Phase IV Clinical Trials (ongoing) Continue after drug is licensed and on the market;  Pharmacovigilance  post-market surveillance  “Yellow Card” system in UK Designed to monitor consequences of increasing exposure in tens of thousands of patients  rare or very rare long-term adverse effects  unpredictable drug interactions Also yield information on the drug’s efficacy in sub-groups of the population (elderly, young) After this lecture you should be able to: Explain how drugs are categorized and give examples of how they are named. Describe the concept of ‘receptor’ and molecular targets in the context of drug mechanisms. Explain what is meant by the term “pharmacokinetics” and distinguish this from ‘pharmacodynamics’. Distinguish between preclinical drug discovery and clinical drug development. https://bnf.nice.org.uk/