INTRODUCTION TO THE STUDY OF PHARMACOLOGY REGINA DEMLOVA Dept. of Pharmacology, LF MU Lecture Content ̶ Definition of pharmacology and its subdivisions ̶ Basic pharmacological terms ̶ Development of new drugs, clinical trials ̶ Principles of correct drug use – types of pharmacotherapy and rational pharmacotherapy. Organisation remarks, literature ̶ periodic lessons, weeks 2-16 ̶ practical lessons as follow-up to lectures ̶ basic knowledge from the lectures ̶ practical tasks, worksheets, problem oriented learning ̶ self-study of selected topics, the interim evaluation system ̶ Rang, H.P. a kol. Rang and Dale‘s pharmacology 8th ed. (2016) http://search.ebscohost.com/login.aspx?direct=true&db=nlebk&AN=1160493&si te=ehost-live&ebv=EB&ppid=pp_cover Pharmacology as science pharmacology ≠ pharmacy ̶ pharmakon (φάρµακον) = „drug“ + logos (λόγος) = „science“ ̶ INTERACTIONS BETWEEN SUBSTANCES.. introduced into the organism from the environment ..AND THE LIVING ORGANISM on all levels of complexity: molecular, cellular, organ and organism as a whole… Pharmacology as science History of the Pharmacology ̶ Founder of specific drug effects - physiologist Newport Langley (1852–1925) and immunologist Paul Ehrlich (1854 – 1915). ̶ Langley – pharmacology of vegetative nervous system and hormonal regulations History of the Pharmacology ̶ Theory of specific drug effects was supported by the research of Raymond P. Ahlquist - „A study of the adrenotropic receptors“ published in 1948 in American Journal of Physiology /α a β receptors/ ̶ 1964 british clinical pharmacologist James W. Black developed „propranolol“ – the first beta-blocker History of the Pharmacology Discovery of DNA double helix, James D. Watson a Francis Crick, Nature 1953 ̶ 1972 - recombinant DNA firstly produced (rDNA) ̶ 1975 - first mAb – monoclonal antibody developed (mAb) ̶ 1982 - first fully recombinant drug used clinically - insulinn (Genentech) ̶ Chemical substances ̶ Biotechnological drugs (monoclonal antibodies) ̶ Advanced Therapy Medicinal Products (ATMP) ̶ Gene therapy medicinal products ̶ Somatic cell therapy medicinal products ̶ Tissue engineered products Acetylsalicylic acid1 ~ 180 daltons Insulin2 ~ 5,700 daltons Growth hormone3 191 amino acids ~ 22,000 daltons Monoclonal antibodies (mAb)4 ~ 1,300 amino acids5 ~ 150,000 daltons6 BiologicsSmall Molecule Generic Small Biologic Large Biologic Same Structure Highly Similar Structure Jimenez AG, et al. Presented at: ICH GCG ASEAN Training Workshop on ICH Q5C; May 30‒31, 2011 „Chemical“ versus „biotechnological“ drugs Branches of Pharmacology ̶ Basic Pharmacology (general principles + pharmacology of the systems ̶ Experimental Pharmacology (preclinical pharmacology) ̶ Clinical Pharmacology (subbranches) ̶ Clinical pharmacokinetic (TDM) ̶ Pharmacogenetics / pharmacogenomics ̶ Toxicology ̶ Pharmacoepidemiology ̶ Pharmacovigilance ̶ Pharmacoeconomics Pharmacology Pharmacology as the synthesis of several biomedical sciences…. …but unique in its own right Basic Pharmacology - General principles - Systems Pharmacology General Principles - Principles which predestinate the interactions of the drug and body - General Pharmacokinetics - General Pharmacodynamics Two important and interrelated areas: Pharmacokinetics (PK) Pharmacodynamics (PD) Deals with the fate of the drug in the body – processes of Absorption, Distribution Metabolism Excretion …“ADME“ deals with the mechanism of action (e.g. receptor sites, molecular level of action..) „What the body makes with the drug“ „How does it work“ General Principles Pharmacokinetics A. RECEPTORS B. ION CHANNELS C. ENZYMES D. CARRIERS Agonist Antagonist Direct Signal Transduction No effect Endogenous mediator blocked Ion channels Open/closed Enzymes Activation/inhibition n channel modulation DNA transcription Blockers Modulators Flow is blocked Increasing or decreasing probability of opening Inhibitor False substrate Prodrug Reaction is inhibited Abnormal metabolites Active substance normal transport Inhibitor Transport is blocked Rang and Dale Pharmacology, 2012 Pharmacodynamics Experimental pharmacology ̶ Experimental science ̶ Biological experiment ̶ In silico ̶ In vitro ̶ In vivo ̶ Self-study – study material IS ❖ Neuropharmacology: study of the effect of drugs on components of the nervous system (brain, spinal cord, nerves) ❖ Cardiovascular Pharmacology: study of the effects of drugs on heart, vasculature, kidney, nervous and endocrine systems that participate in cardiovascular function. Example: treatment of Alzheimer's dissease Example: treatment of high blood pressure (hypertension) Systems pharmacology Clinical Pharmacology ̶ deals with different drugs and their varied clinical usage ̶ interdisciplinary branch, which integrates basic and experimental Pharmacology with the clinical and complementary branches… AIM: to study and evaluate the effect of the drug using objective methods (EBM) Toxicology ̶ the study of the toxic effects of chemicals on living organism ̶ study of symptoms, mechanisms, treatments and detection of poisoning ✓Experimental (in vitro, in vivo) ✓Clinical - poisoning prophylaxis, diagnosis, treatment ✓Forensic toxicology… Pharmacogenetics ̶ deals with the influence of genetic variation on Pharmacokinetics and Pharmacodynamics ̶ study of the drug response in patients by correlating gene expression or single-nucleotide polymorphisms with a drug's efficacy or toxicity ̶ consequences can be either quantitative or qualitative ̶ Drugs metabolized by cytochrome P450 ̶ Glucose-6-phosphate dehydrogenase deficiency ̶ Succinylcholine - prolonged apnea ̶ Altered kinetics of butyrylcholinesterase ̶ Isoniazid - fast and slow acetylation ̶ Mutation of the N-acetyltransferase gene Pharmacogenetics, pharmacogenomics ̶ 1959 Friedrich Vogel used first time term „pharmacogenetics“ ̶ 1997 First time used term “Pharmacogenomics“ Pharmacogenetics considers one or at most a few genes of interest, while pharmacogenomics considers the entire genome. Pharmacovigilance ̶ Pharmacological science relating to the detection, assessment, understanding and prevention of adverse effects ̶ collecting, monitoring, researching and evaluating information from healthcare providers and patients on the adverse effects of medication ̶ AIM: to minimize the risk of adverse effects S t á t n í ú st av p r o k o n t r o l u léčiv Regulatory Agency_CZ and EU Pharmacoepidemiology ̶ Study of the effect of drugs on populations; questions dealing with the influence of genetics are particularly important ̶ Risks and benefits of the therapy using epidemiological methods ̶ Approach of the health specialists (GP, pharmacist) ✓ patient (compliance) ✓ society (drug abuse, marketing, financial resources…) Pharmacoeconomics ̶ rationalize the use of sources in health care ̶ Compares the costs of therapeutic approaches by the pharmacoeconomical analyses ̶ The goal is not „to decrease total money spent in health care“ , but to use the sources effectively Basic Terms: Pharmacon / Drug classical WHO definition: ̶ „Any substance (other than normal body components or substances necessary for normal body functions (food, water, oxygen), that, after administration into the organism evokes a change of a body function“ More precise definition according to Ph.Eur.: ̶ Substances or their mixtures designed to the administration in humans or animals with a purpose of treatment, prevention or diagnose of a disease or its symptoms and also to modulation of physiological substances. ̶ European Pharmacopoea (Ph. Eur. 6th Ed.) ̶ Pharmacopoea Bohemica 2009 (Ph. B. 2009) Medicinal product ̶ a substance or combination of substances ̶ presented as having therapeutic or preventive properties or as having influence over physiological functions, or administered to set the medical diagnosis. ̶ Prevention ̶ Diagnosis ̶ Treatment of disease Generics ̶ Original MPs – originally conceived MPs ̶ Generic MPs – equivalents to original MPs that may enter the market: ̶ once the patent protection of the original MPs expires ̶ once the principle of fundamental similarity with the original MP is met ̶ the price of generic MPs is usually lower than the price of original MPs Biosimilars ̶ „Legal copies” of biotechnological pharmaceuticals after the patent protection of the original biotechnological pharmaceutical expires ̶ Called Follow-on-Biologics, or FOBs for short, overseas. Drug names ̶ Chemical name (according to chemicals structure) ̶ Generic name (non-proprietary) supposed to be used internationally has to be printed on the packing of the drug (under the registered trade name) for the universal terminological identification of the medicines e.g. paracetamol Drug names Trade name (proprietary) registered, patent-protected ® e.g. Panadol, Coldrex, Paralen Officinal name latin name in Pharmacopoeia (e.g. Paracetamolum) has to be prescribed on Rx formulary in case of individually prescribed medicines Paracetamolum Some drug-family names… ̶ „-olol“ betareceptor antagonists ̶ „-caine“ local anaestethics ̶ „-tidine“ histamine 2 receptor antagonists ̶ „-dipine“ calcium channel blockers of dihydropyridine type ̶ „-statin“ inhibitors of HMG CoA transferase Drug Life-Cycle Clinical Trial Phases (Preclinical research) Phase I trials Phase II trials Phase III trials Phase IV trials Pre-clinical Phase Involve in vitro (test tube or laboratory) studies and trials on animal populations. Wide ranging dosages of the compounds are introduced to the animal subjects or to an in vitro substrate. Obtain preliminary efficacy and pharmacokinetic information. Decisions are made during this phase regarding further development of the test compound, test item, or test article. Phases of Clinical Trials Category # of Participants Purpose Phase I Less than 10 Tests how to administer a new therapy, exam, or preventive option Phase II 30-40 Test patients responses to a new therapy, exam, or preventive option Phase III 100-1000+ Compares new therapy exam or preventive option to a standard one Phase IV Varies For marketing purposes, to compare the effectiveness of two therapies already on the market or to study new uses of therapies Phase I First step in testing in humans. Researchers look for safety and potentially harmful side effects. Usually include only a limited number of human subjects (20-80). This phase of testing usually takes several months. Early stopping of clinical trials-iFAAH, sildenafil Phase II Once a drug has shown to be safe, then it must be tested for efficacy. This phase may last from several months to two years. Usually involves several hundred patients Only about 1/3 of these studies successfully complete both phase I and phase II due to poor patient activity or toxic effects. Phase III Randomized control trials on large patient groups (300-3000). Compare the results of the patients on the experimental trial to those patients utilizing standard diagnostic studies or treatment. Studies move into this phase only after a diagnostic agent, modality, or treatments have shown promise in phase I and II trials. These trials are typically multi-center trials. Many phase III trials are randomized and blinded. Phase IV Involve safety surveillance and ongoing technical support of a drug. Sometimes mandated by the Regulatory authorities for additional testing including interactions with other drugs and testing on certain populations. Adverse effects detected by Phase IV trials may result in withdrawal or restriction of a drug -recent examples include Vioxx. Examples of drug withdrawals ̶ rofecoxib (HVLP Vioxx) ̶ CVS AE, - AMI ̶ clobutinol (HVLP Silomat) ̶ Heart dysrhytmias ̶ rosiglitazon ̶ CVS risk Reasons for drug withdrawal Clinical Trials Benefits & Risks Possible Benefits of Trials Possible Risks of Trials • Having access to potentially more effective therapies than those currently available • Receiving quality medical care from leading physicians • Being closely monitored for possible negative effects • Sometimes receiving treatment at a reduced rate or free of charge • Helping to further new research that may result in significant medical advances • For patients in cancer therapy trials assigned to control groups, they still receive the top standard therapy available today • Patients may not receive the therapy under investigation (may receive a placebo – inactive pill – instead) • The new therapy may not be more effective than the standard, thoroughly tested therapy • In Phase I trails, not knowing the safety consequences of the new therapy (risk is less in Phase III trials) • New therapy may have unexpected, possibly severe side effects or may be less effective than standard of care • Insurance companies may not cover all costs of clinical trials Drug information sources ̶ SÚKL www.sukl.cz ̶ EMA: http://www.ema.europa.eu/ema/ ̶ AISLP www.aislp.cz ̶ Drugs.com ̶ Medicines.org.uk ̶ Up-To-Date ̶ Micromedex ̶ Pharmindex Legal Regulations ̶ Research and Development ̶ Preclinical and clinical testing ̶ Registration – market access ̶ Pricing and reimbursement from health insuarance companies ̶ Tracking the safety of the marketed drug (pharmacovigilance) ̶ Production and distribution ̶ Drug dispensation (pharmacists) ̶ Advertisement and marketing KINDS OF PHARMACOTHERAPY ̶ CAUSAL / ETHIOLOGICAL – targeting the cause of the disease ̶ SUBSTITUTIONAL – administration of lacking hormone, peptide, enzyme… ̶ SYMPTOMATIC – treat only symptoms, not the root cause (because we usually do not know it) The rational use of drugs ̶ patients receive medications appropriate to their clinical needs, in doses that meet their own individual requirements for an adequate period of time, and at the lowest cost to them and their community. ̶ correct drug ̶ appropriate indication ̶ appropriate drug considering efficacy, safety, suitability for the patient, and cost ̶ appropriate dosage, administration, duration ̶ no contraindications ̶ correct dispensing, including appropriate information for patients ̶ patient adherence to treatment Thank you for your attention ! ̶ Next lecture: drug dosage forms