Adobe Systems Department of Pharmacology 1 INTRODUCTION TO THE STUDY OF PHARMACOLOGY [USEMAP] Adobe Systems Department of Pharmacology 2 Copyright notice The presentation is copyrighted work created by employees of Masaryk university. Students are allowed to make copies for learning purposes only. Any unauthorised reproduction or distribution of the presentation or individual slidesis against the law. Adobe Systems Pharmacology, definition, aims „pharmacon“ + „logos“ / „logia“ ̶ Scientific discipline dealing with INTERACTIONS BETWEEN SUBSTANCES.. introduced into the organism from the environment ..AND THE LIVING ORGANISM on all levels of complexity: molecular cellular organ organism as a whole Adobe Systems DRUG „substance or mixture of substances, suppopsed to be administered to the humans or animals for prevention, treatment or diagnosis of diseases or its symptomes or for physiological function adjustment“ Drugs are administered for - Prevention, - Diagnosis, - Treatment of disseases [USEMAP] Adobe Systems Pharmacon/um – 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, mitigation, 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) [USEMAP] Adobe Systems A synthesis of several biomedical sciences…. Pharmacology …but unique in its own right [USEMAP] Adobe Systems Pharmacologists study science at every level [USEMAP] Adobe Systems What Pharmacology is NOT... v Pharmacy This is a separate profession responsible for the preparation and dispensation of medication. v Pharmaceutical Science Adobe Systems Basic Pharmacology General principles Systems Pharmacology Adobe Systems General principles Principles which predestinate the interactions of the drug and body - General Pharmacokinetics - - General Pharmacodynamics Two important and interrelated areas: [USEMAP] Adobe Systems Pharmacokinetics (PK) Deals with the fate of the drug in the body – processes of Absorption, Distribution Metabolism Excretion …“ADME“ „What the body makes with the drug“ Pharmacodynamics (PD) deals with the mechanism of action (e.g. receptor sites, molecular level of action..) „How does it work“ Adobe Systems Systems Pharmacology Is focused on individual organ systems and its pharmacotherapy e.g. Autonomic drugs Psychoactive drugs Drugs used in cardiovascular diseases…. [USEMAP] Adobe Systems Systems Pharmacology v Neuropharmacology: study of the effect of drugs on components of the nervous system (brain, spinal cord, nerves) Example: treatment of Alzheimer‘s disease v Cardiovascular Pharmacology: study of the effects of drugs on heart, vasculature, kidney, nervous and endocrine systems that participate in cardiovascular function. Example: treatment of high blood pressure (hypertension) Adobe Systems Branches of 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) Sub-branches of clinical pharmacology: Clinical Pharmacokinetics, clin. Pharmacodynamics, Rational prescribing, Clinical toxicology [USEMAP] Adobe Systems Toxicology the study of the toxic effects of chemicals on living organisms study of symptoms, mechanisms, treatments and detection of poisoning experimental (in vitro, in vivo) clinical - poisoning prophylaxis, diagnosis, treatment forensic toxicology… Adobe Systems 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 Adobe Systems Pharmacogenetics 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. [USEMAP] Adobe Systems Biochemical and molecular pharmacology detail study of the mechanism of action at molecular level Chronopharmacology Study of the action of the drugs with respect to the biorhythm (antiasthmatics, glukocorticoids, statins, etc. ) [USEMAP] Adobe Systems 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…) [USEMAP] Adobe Systems Pharmacoeconomy - 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 [USEMAP] Adobe Systems 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 Drug safety monitoring AIM: to minimize the risk of adverse effects Adobe Systems Experimental pharmacology Biological experiment in vitro – isolated structures or organs, cell cultures, microorganisms - regulatory factors we have to satisfy: J ethical (replacement, refinement, reduction) J small amounts of drugs J use of human cells L elimination of systhemic reaction of the whole body [USEMAP] Adobe Systems Biological experiment in silico – use of IT, especially computer modelling (f-kinetics), databases [USEMAP] Adobe Systems Biological experiment in vivo – whole animal - systhemic effects - we record toxicity, possible adverse and alergic effects - impact on memory and other cognitive faculties, learning abilities, depression [USEMAP] Adobe Systems Experimental animal Experimental animal (is born, breed and maintained for experimental purposes) Defined genetic features: - randombred – natural breeding - heterozygots - inbred – breeding of brosthers and sisters, approx. 20 generations homozygots diabetic mice, hypercholesterolemic mice, hypertonic mice… [USEMAP] Adobe Systems Defined microbial settlement: - SPF – have 4-5 saprofyte patogens - Gnotobiotic animals – are born by hysterectomy, pathogens free - Conventional breeding – not defined settlement Experimental animal Adobe Systems Mammals RODENTS: mouse, hamster, rat, guinea-pig NON-RODENTS (e.g. Lagomorpha): rabbit Experimental animal Adobe Systems Mammals carnivores: dog, cat, ferret Experimental animal Mammals monkeys: macaque (Macacus sp.), green monkey (Erythrocebus sp.) Birds common quail, hen, duck Amphibians Xenopus sp. Fish guppy (Poecilia reticulata), carp, trout Crustaceans Cladocera, Cyclops strenuus [USEMAP] Adobe Systems Laws EU 1986 Council of Europe – rules of protection for vertebrates used for experimental purposes in Europe Principle 3R: replacement reduction refinement [USEMAP] Adobe Systems Laws Czech Republic Law no. 149/2004 „na ochranu zvířat proti týrání“ – about animal protection against cruelty Notice no. 207/2004 „o ochraně, chovu a využití pokusných zvířat“ - about protection, breeding and use of laboratory animals Authorities encharged of animal protection: Ministry of agriculture, Comission for animal protection, veterinary authorities, ethical comitties [USEMAP] Adobe Systems Drug names Chemical name according to the IUPAC nomenclature rules e.g.: N-acetyl-para aminophenol Generic name (non-proprietary) INN (International Non-proprietary Name) not registered, 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 formed from the chemical name (shortness) accordingly with the rules (WHO) each drug has its own CAS No (Chemical Abstracts Sevice Number) e.g. paracetamol ̶ [USEMAP] Adobe Systems Trade name (proprietary) registered, patent-protected ® has to be acompanied with the INN e.g. Panadol, Coldrex, Paralen Officinal name latin name in Pharmacopoeia (e.g. Paracetamolum) usually very similar to INN has to be prescribed on Rx formulary in case of individually prescribed medicines established name for a drug substance is usually found in the originating country's Pharmacopeia Paracetamolum … Drug names [USEMAP] Adobe Systems Some drug-family names -olol betareceptor antagonists -caine local anaestethics -tidine histamine receptor antagonists -dipine calcium channel blockers of dihydropyridine type -statin inhibitors of HMG CoA transferase [USEMAP] Adobe Systems DOSE A specified quantity of a therapeutic agent, prescribed to be taken at one time or at stated intervals. If administered in the body, desintegrates, solutes, and distribute across the barriers in the body compartments. Than it is measured like „concentration“ [USEMAP] Adobe Systems DOSIS SINGULA - single dose DOSIS PRO DIE - daily dose - for 24 h !! DOSIS CHRONICA - (adjusted) dose in the chronic treatment (long-term) DOSE on Rx ! [USEMAP] Adobe Systems DOSIS CURATIVA - total dose of the drug needed for whole period of treatment DOSE [USEMAP] Adobe Systems DOSE (from effect point of view) Sub-threshold - cause no observed biological effect Threshold - minimally effective dose; dose, after which can be observed any effect Therapeutic dose - produces mostly beneficial effects; ►MAXIMAL - does not produce harmfull effects ►►DOSIS MAXIMA SINGULA ►►DOSIS MAXIMA PRO DIE TOXIC – mostly harmfull effects (RISK>BENEFIT) LETHAL – cause death [USEMAP] Adobe Systems ORIGIN OF DRUGS ̶Modification of the chemical structure of the already known drug ̶Searching for natural substances ̶Investigation (screening) of already known chemical compounds ̶Targeted synthesis of substances with a structure designed by computer modeling [USEMAP] Origin of drugs – synthesis/isolation Medicinal Plants (cardiac glycosides) Animal tissues (heparin) Microorganisms (penicillin) Human cells (autologue vaccines) Biotechnology (insulin, MAb) image [USEMAP] Thalidomide crisis Thalidomide - Contergan © 1950 - 1960 hypnosedative used by pregnant women It gave birth to 12,000 children with disabilities talidomid roehrchen_contergan2_400q missbild-bild5g [USEMAP] [USEMAP] Adobe Systems PRECLINICAL TRIALS : ̶Evaluation of effect in vitro ̶Evaluation of effect + toxicity in animal models (2 animal species at least) • In situ •Influencing organ systems that can not be studied in isolation (KVS , DS , GIT) Living animals •overall effects ( convulsions , sedation , anesthesia, temperature) •affecting cognitive function (learning, attention, memory ) •influence on the specialized function (immune system) . _40878137_fat4rats203 Adobe Systems Preclinical Trials: ̶Evaluation of acute and short term toxicity in animals. It Involves : -Lethal dose determination -Effect of dose at normal level for short/Long term ̶Assess how the drug is absorbed/distributed/metabolized and excreted in animals. Adobe Systems Phase 1 CLINICAL TRIALS : ̶All CTs has to be approved by SUKL (State institute for drug control)/EMA ̶ Drug given to 10-100 healthy volunteers ̶Duration could vary from 1 month to 1 year. ̶Following is studied here : ̶Drug absorption/Metabolism in human. ̶Effect on organs and tissues ̶Side affect of different dosages. Proceed to next Stage [USEMAP] Adobe Systems Phase 2 CLINICAL TRIALS : ̶1 st administration to the patient ̶randomized clinical trial tested the drug x = standard therapy x placebo •Often called „Blinding“ – blinding also in multicentric manner ̶It monitors the effect of the disease, dose , pharmacokinetics in patients ̶Informed consent , with no financial reward [USEMAP] Adobe Systems Phase 2 CLINICAL TRIALS : ̶Drug given to 100 - 300 patients - volunteers ̶Duration could vary from 1 year to 2 years ̶ Cost could vary from $10 - $100 million. ̶ Following is studied : Drug effectiveness in treating the disease. acute side effects in patients Less than 1/3rd of New Chemical Entities (NCE) enter phase 2 [USEMAP] Adobe Systems Phase 3 CLINICAL TRIALS : ̶Phase 3 - Extended trial ̶Patients 100-1000 ̶Comparison of the therapeutic efficacy and safety to standard therapy ̶In the Czech Republic a year to 300 proposals involving 30,000 patients ̶ Coordinates the SUKL/EMA/FDA ̶Approval for new substances to launch the market issued by the State Institute for Drug Control (SUKL)/EMA (European Medicines Agency) [USEMAP] Adobe Systems Phase 3 CLINICAL TRIALS : ̶FDA consulted before beginning phase 3 ̶Drug given to 1000-3000 patient volunteers ̶ Duration could vary from 3 years to 4 years. ̶ Cost could vary from $10 - $500 million ̶ Following is studied here : ̶Safety of Drug [ Benefits v/s risk analysis ] – ̶Long term side effects in patients ̶Proceed to next Stage - registration Adobe Systems Market Launch/Phase 4 : ̶4th phase - post-registration ̶post-marketing evaluation ̶verification of effects in broad clinical practice ̶An average of 5 years ̶Data on the incidence of adverse effects, interactions , differences in the age groups etc. ̶Comparison with standard therapy ̶The possibility of drug withrawal [USEMAP] Adobe Systems Market Launch/Phase 4 : ̶Additional post marketing testing of patients to ̶Support the use of the approved indication ̶ Finding new therapeutic opportunities ̶ Extending use of the drug to different classes of patients like children http://www.alzdiscovery.org/wp-content/uploads/2009/04/pre-discovery.jpg Adobe Systems Examples of drug withdrawals rofecoxib (HVLP Vioxx) CVS AE, - AMI clobutinol (HVLP Silomat) Heart dysrhytmias rosiglitazon CVS risk [USEMAP] Adobe Systems Reasons for drug withdrawal Adobe Systems 53 [USEMAP]