•Notes for Students •This study material is exclusively for students of general medicine and stomatology in Pharmacology I course. It contains only basic notes of discussed topics, which should be completed with more details and actual information during practical courses to make a complete material for test or exam studies. Which means that without your own notes from the lesson this presentation IS NOT SUFFICIENT for proper preparation for neither tests in practicals nor the final exam. INTRODUCTION TO THE STUDY OF PHARMACOLOGY Literature •Rang, H.P. a kol. Rang and Dale‘s pharmacology 8th ed.(2016) • • •http://web.b.ebscohost.com/ehost/ebookviewer/ebook/bmxlYmtfXzExNjA0OTNfX0FO0?sid=82e7fdcf-dd4c-43d 3-b3a3-7b4b24c21b8e@sessionmgr103&vid=0&format=EB&lpid=lp_1&rid=0 • Literature •Rang & Dale's pharmacology • •8th ed. Churchill Livingstone, 2016. • • •available online • •http://www.elsevier-etextbooks.com/bookshelf • • •Hard copy available • •BOOKSHOP IN CAMPUS Literature •Pharmacology. Edited by R. D. Howland,M.J. Mycek. 3rd ed. •Philadelphia : Lippincott Williams & Wilkins, 2006. Literature •Textbook of Clinical Pharmacology and Therapeutics • •Ritter, Lewis, Mant, Ferro. 5th Ed., •Hodder Arnold, 2008. •ISBN 978-0-340-90046-8 Literature •Pharmaceutical Practice •3rd Ed. Winfield, A.J. & Richards, R.M.E., •Churchill Livingstone, 2004, • •ISBN 0443 07206 X •Practicals in Pharmacology, 2006 • •Hadasova, Novakova, Pistovcakova, •Vinklerova, Sulcova, Starobova •Literature •Pdf available at: IS.muni.cz 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 •Pharmaceutics • •the general area of study concerned with the formulation, manufacture, stability, and effectiveness of pharmaceutical dosage forms • • „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 • •DRUG 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) • • • • • • • •Pharmacology •A synthesis of several biomedical sciences…. •…but unique in its own right •Pharmacologists Study Science at Every Level v Pharmacy • This is a separate profession responsible for the • preparation and dispensation of medication. • v Pharmaceutical Science •What Pharmacology is •NOT... 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..) • •„How does it work“ •„What the body makes with the drug“ Systems Pharmacology •Is focused on individual organ systems and its pharmacotherapy • •e.g. •Autonomic drugs •Psychoactive drugs •Drugs used in cardiovascular diseases…. Systems Pharmacology v Neuropharmacology: study of the effect of drugs on •components of the nervous system (brain, spinal cord, nerves) 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 Alzheimer's • dissease •Example: treatment of high blood pressure (hypertension) 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 • • 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… • • • • • 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 • 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. • 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. ) •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 •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…) •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 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 Biological experiment •in silico – use of IT, especially computer modelling (f-kinetics), databases • • •MODELLER is a software used for homology or comparative modeling of protein three-dimensional structures 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 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… Experimental animal •Defined microbial settlement •SPF – have 4-5 saprofyte patogens • •Gnotobiotic animals – are born by hysterectomy, pathogens free • •Conventional breeding – not defined settlement (there may be: brucela, leptospira, mycobakteria, salmonela, toxoplasma…) Experimental animals •Mammals •RODENTS: mouse, hamster, rat, guinea-pig • •NON-RODENTS (e.g. Lagomorpha): rabbit •Mammals • carnivores: dog, cat, ferret • Experimental animals •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 • Project – experiment - protocol •Certificates • for quarters, stabling and handling conditions, qualified staff kralici600-02 psi600-01 Experimental design •Suitable animal •Homogeneity of the group • - gender, weight, age, feeding •Control experiment • - the same treatment and number of animals •Repetition of the experiment –- Limitation of influence of the individual variability Protocol of the experiment in pharmacology 1.Name of the experiment, aims 2.methods -Data about the animals -Description of the method 3.results 4.Discussion (evaluation), statistics 5.conclusion 6.date, number, support, statement of interests Laws •EU •1986 Council of Europe – rules of protection for vertebrates used for experimental purposes in Europe •Principle 3R: replacement • reduction • refinement 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 protercion, veterinary authorities, ethical comitties 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 • • • Drug names •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 •… •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 •„GENERICS“ •Drug which is produced and distributed after ending of patent protection - mostly manufactured by other company which has not developed the original drug (the same active substance!) •Mostly cheaper than original preparation •Assumed to be identical in dose, strength, route of administration, safety, efficacy, and intended use •Bioequivalent trials are needed before registration • •Registration procedures are much easier than in orig. preparation • •Drug patents give 10 years of protection, but they are applied for before clinical trials begin, so the effective life of a drug patent tends to be between 7 and 12 years •„GENERIC PRESCRIPTION“ • prescription of the generic name (INN) on Rx formulary • + dose, number of doses • Pharmacist will chose apropriate ready-mady preparation after consultation with the patient • •„ GENERIC SUBSTITUTION“ – substitution of the prescribed preparation with another one (generic) 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“ DOSE •DOSIS SINGULA - single dose • •DOSIS PRO DIE - daily dose • - for 24 h !! •DOSIS CHRONICA • - (adjusted) dose in the chronic treatment (long-term) • • on Rx ! • DOSE •DOSIS CURATIVA • - total dose of the drug needed for whole period of treatment 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 • - produce 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 recept •Latin terminology in drug prescription •Insuarance number ØPharmacopoeia Ø Øpharmacon = drug Øpoieo = prepare •Substances in pharmacopoeia- called officinal drugs Definition •basic reference work for pharmaceutical drug specifications •published by the authority of a government or a medical or pharmaceutical society • •book containing directions for the identification of samples and the preparation of compound medicines •assures quality, efficacy, safety, standards •Pharmacopoeias may be: • • •National e.g. Brazilian, British, Chinese, Indian, Japanese, Mexican, Spanish, United States • •Regional e.g. European (Ph.Eur.) •The 7th Edition of the European Pharmacopoeia • • •International The International Pharmacopoeia •National and regional pharmacopoeias • • Cover medicines used in the relevant country or region •Are legally binding "official" in the relevant country or region •Are prepared by a national or regional authority •International Pharmacopoeia •A few dates… •The history of the International Pharmacopoeia dates back 1874… • •→ 1948 First World Health Assembly established • Expert Committee on Unification of Pharmacopoeia • •→ 1950 WHA approved publication of Pharmacopoeia Internationalis •International Pharmacopoeia •→implementation: “ready for use” by Member States •"The Ph.Int [… ] is intended to serve as source material for • reference or adaptation by any WHO Member State wishing to establish pharmaceutical requirements. The pharmacopoeia, or any part of it, shall have legal status, whenever a national or regional authority expressly introduces it into appropriate legislation." • •[World Health Assembly resolution WHA3.10, WHO Handbook of Resolutions and Decisions, Vol. 1, 1977, p. 127] •Scope since 1975 •→ Model Lists of Essential Medicines •→ Medicines recommended and specifications needed by WHO Programmes, e.g. to treat Malaria, TB, HIV/AIDS and •→ Medicines for children! •International Pharmacopoeia •A collection of monographs and requirements for: • •→ Drug substances •→ Excipients •→ Finished dosage forms •→ General methods and requirements: • dosage forms, e.g. tablets, liquid preparation for oral use • dissolution testing •→ Supplementary information, e.g. General guidelines for Chemical Reference Substances • •→ Infrared reference spectra •Specifications of substances • •Description, Chemistry, Solubility, Storage, Labelling • Definition, with information on polymorphism if relevant • Identification • Assay • Specific tests (sulphated ash, optical rotation, loss on drying…) • Related substances •Specifications of substances • •Precise description of analytical methods •Impurities (chemical names, structures, origin) •Any relevant information on • Performance testing (e.g. dissolution) • Stability • Validation of analytical methods •International Pharmacopoeia •current: 4th Edition + 1st Supplement •→ Consolidated in : 2 Volumes •Vol. 1: pharmaceutical substances (A-O) •Vol. 2: pharmaceutical substances (P-X) • + dosage forms + radiopharmaceuticals • + methods of analysis + reagents • •1st Supplement - new requirements and revisions PHARMACOPOEIA BOHEMICA Ø3 volumes + CD, 2009 ØTranslation of 7th ed. of Eur. Pharmacopoieia ØIssued by The Czech Ph. Comm. Of Ministry of Health • • ØVol. 1 General methods and requirements Ø ØVol. 2 Monographs A-N ØMedicines, excipients ØVol. 3 • - Monographs N-Z ØMedicines, excipients – –National part – -General methods and requirements -Tables (I-XII) • ØMedicines, excipients • • Ø •WHAT we can not find there ! • –pharmacological properties of drugs, their pharmacodynamics, pharmacokinetics – –indications, contra-indications –toxic effects •PHARMACOPOEIA • • •Doses divided into 3 age groups • • 0-1 1-6 6-15 • •Calculation according to the body surface • • body surface[m2] • Dose for children = -------------------------- x adult dose • 1,73 • • 7* age (yrs) + 45 •Body surface [m2] = -------------------------------------- • 100 • •Drug dosology in paediatrics. File0009 Doses for children •Interpolation • • d2 - d1 •d = d1 + -----------. nd • n • •d…..recommended dose for the given age • •d1.…recommended dose for lower limit of the age interval • •d2 … recommended dose for upper limit of the age interval • •n…..number of year intervals within the range of age • •nd….number of year intervals from the beginning of range of age to the age of the given child • • •Calculate the DTS of a substance X for 10 years old child, •if the dose interval from 6 to 15 years of age is 0,7-1,5 g. • • • • d2 - d1 •d = d1 + -----------. nd • n • • •d1 = 0,7 • •d2 = 1,5 • •n = 9 • •nd = 4 • • 1,5 – 0,7 •d = 0,7 + -----------. 4 = 0,7 + 0,088*4 = 1,05 g • 9 • •