Biopharmacy Practice

Total Page:16

File Type:pdf, Size:1020Kb

Biopharmacy Practice University of Szeged Biopharmacy practice Editor: Árpád Márki, Ph.D. Authors: Árpád Márki, Ph.D. Adrienn Seres, Ph.D. Anita Sztojkov-Ivanov, Ph.D. Reviewed by: Szilárd Pál, Ph.D. Szeged, 2015. This work is supported by the European Union, co-financed by the European Social Fund, within the framework of "Coordinated, practice-oriented, student-friendly modernization of biomedical education in three Hungarian universities (Pécs, Debrecen, Szeged), with focus on the strengthening of international competitiveness" TÁMOP-4.1.1.C-13/1/KONV-2014-0001 project. The curriculum cannot be sold in any form! Contents Contents ...................................................................................................................................... 2 1. Definitions, routes of drug administration ............................................................................. 6 1.1. Definitions ....................................................................................................................... 6 1.2. Routes of drug administration ......................................................................................... 7 1.3. Questions ....................................................................................................................... 10 2. Receptors .............................................................................................................................. 11 2.1. Definitions ..................................................................................................................... 11 2.2. Characterization of receptors......................................................................................... 11 2.3. Classification of receptors ............................................................................................. 12 2.4. Questions ....................................................................................................................... 13 3. Dose vs. response curves ...................................................................................................... 14 3.1. Definitions ..................................................................................................................... 14 3.2. Standard dose vs. response curve .................................................................................. 15 3.2.1. Exercise 1 ............................................................................................................... 16 3.3. Semilogarithmic dose vs. response curve ..................................................................... 17 3.3.1. Exercise 2 ............................................................................................................... 18 3.4. Double reciprocal dose vs. response curve ................................................................... 18 3.4.1. Exercise 3 ............................................................................................................... 20 3.5. Specific activity ............................................................................................................. 21 3.6. Questions ....................................................................................................................... 22 4. Drug absorption .................................................................................................................... 23 4.1. Definitions ..................................................................................................................... 23 4.2. Factors affecting drug absorption .................................................................................. 23 4.3. Transport mechanisms during absorption ..................................................................... 23 4.4. Drug absorption from different sites ............................................................................. 24 4.4.1. Drug absorption from the oral cavity ..................................................................... 24 4.4.2. Drug absorption from the stomach ......................................................................... 24 4.4.3. Drug absorption from the intestines ....................................................................... 24 4.4.4. Pulmonary absorption ............................................................................................ 25 4.4.5. Transdermal absorption .......................................................................................... 25 4.4.6. Intramuscular and subcutaneous absorption .......................................................... 25 4.5. Questions ....................................................................................................................... 26 5. Distribution of drugs ............................................................................................................ 27 5.1. Volume of distribution .................................................................................................. 27 5.2. Factors influencing distribution .................................................................................... 27 5.2.1 The physicochemical properties of the drugs .......................................................... 27 5.2.2. The permeability of the membranes ....................................................................... 28 5.2.3. The effects of pH .................................................................................................... 29 5.2.4. The binding of the drugs to the tissues ................................................................... 29 5.2.5. The binding of the drugs to the plasma proteins .................................................... 30 5.3. Specialized distribution of drugs ................................................................................... 32 5.3.1. Distribution of drugs into the central nervous system (CNS) ................................ 32 5.3.2. The placental barrier ............................................................................................... 32 5.4. Exercises ........................................................................................................................ 33 5.5. Questions ....................................................................................................................... 37 6. Drug metabolism .................................................................................................................. 38 6.1. Definitions ..................................................................................................................... 38 6.2. Phases of drug metabolism ............................................................................................ 38 6.2.1. Phase 1 reactions .................................................................................................... 38 6.2.2. Phase 2 reactions .................................................................................................... 40 6.2.3. Phase 3 reactions .................................................................................................... 41 6.3. Exercise ......................................................................................................................... 41 6.4. Questions ....................................................................................................................... 43 7. Drug elimination .................................................................................................................. 44 7.1. Excretion of drugs ......................................................................................................... 44 7.1.1. Renal excretion ....................................................................................................... 44 7.1.2. Biliary excretion of drugs ....................................................................................... 46 7.1.3. Excretion in the saliva ............................................................................................ 46 7.1.4. Excretion in the breast milk ................................................................................... 47 7.1.5. Pulmonary excretion of drugs ................................................................................ 47 7.1.6. Excretion in the sweat ............................................................................................ 47 7.2. Multiple dosing - Exercise ............................................................................................ 47 7.2.1. Determination of the kinetic parameters of a drug ................................................. 48 7.2.2. Calculation of the maintenance dose of a drug ...................................................... 48 7.2.3. Administration of the loading dose ........................................................................ 48 7.3. Questions ....................................................................................................................... 49 8. Continuous infusion and multiple drug administration ........................................................ 50 8.1. Infusion .......................................................................................................................... 50 8.2. Multiple dosing ............................................................................................................. 53 8.3. Planning a continuous intravenous infusion .................................................................. 55 8.3.1. Calculation of the kinetic
Recommended publications
  • Principle of Pharmacodynamics
    Principle of pharmacodynamics Dr. M. Emamghoreishi Full Professor Department of Pharmacology Medical School Shiraz University of Medical Sciences Email:[email protected] Reference: Basic & Clinical Pharmacology: Bertrum G. Katzung and Anthony J. Treveror, 13th edition, 2015, chapter 20, p. 336-351 Learning Objectives: At the end of sessions, students should be able to: 1. Define pharmacology and explain its importance for a clinician. 2. Define ―drug receptor‖. 3. Explain the nature of drug receptors. 4. Describe other sites of drug actions. 5. Explain the drug-receptor interaction. 6. Define the terms ―affinity‖, ―intrinsic activity‖ and ―Kd‖. 7. Explain the terms ―agonist‖ and ―antagonist‖ and their different types. 8. Explain chemical and physiological antagonists. 9. Explain the differences in drug responsiveness. 10. Explain tolerance, tachyphylaxis, and overshoot. 11. Define different dose-response curves. 12. Explain the information that can be obtained from a graded dose-response curve. 13. Describe the potency and efficacy of drugs. 14. Explain shift of dose-response curves in the presence of competitive and irreversible antagonists and its importance in clinical application of antagonists. 15. Explain the information that can be obtained from a quantal dose-response curve. 16. Define the terms ED50, TD50, LD50, therapeutic index and certain safety factor. What is Pharmacology?It is defined as the study of drugs (substances used to prevent, diagnose, and treat disease). Pharmacology is the science that deals with the interactions betweena drug and the bodyor living systems. The interactions between a drug and the body are conveniently divided into two classes. The actions of the drug on the body are termed pharmacodynamicprocesses.These properties determine the group in which the drug is classified, and they play the major role in deciding whether that group is appropriate therapy for a particular symptom or disease.
    [Show full text]
  • Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity Kelly A
    International Journal of Neuropsychopharmacology (2018) 21(10): 962–977 doi:10.1093/ijnp/pyy071 Advance Access Publication: August 6, 2018 Review review Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity Kelly A. Berg and William P. Clarke Department of Pharmacology, University of Texas Health, San Antonio, Texas. Correspondence: William P. Clarke, PhD, Department of Pharmacology, Mail Stop 7764, UT Health at San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229 ([email protected]). Abstract Constitutive receptor activity/inverse agonism and functional selectivity/biased agonism are 2 concepts in contemporary pharmacology that have major implications for the use of drugs in medicine and research as well as for the processes of new drug development. Traditional receptor theory postulated that receptors in a population are quiescent unless activated by a ligand. Within this framework ligands could act as agonists with various degrees of intrinsic efficacy, or as antagonists with zero intrinsic efficacy. We now know that receptors can be active without an activating ligand and thus display “constitutive” activity. As a result, a new class of ligand was discovered that can reduce the constitutive activity of a receptor. These ligands produce the opposite effect of an agonist and are called inverse agonists. The second topic discussed is functional selectivity, also commonly referred to as biased agonism. Traditional receptor theory also posited that intrinsic efficacy is a single drug property independent of the system in which the drug acts. However, we now know that a drug, acting at a single receptor subtype, can have multiple intrinsic efficacies that differ depending on which of the multiple responses coupled to a receptor is measured.
    [Show full text]
  • When Simple Agonism Is Not Enough: Emerging Modalities of GPCR Ligands Nicola J
    When simple agonism is not enough: emerging modalities of GPCR ligands Nicola J. Smith, Kirstie A. Bennett, Graeme Milligan To cite this version: Nicola J. Smith, Kirstie A. Bennett, Graeme Milligan. When simple agonism is not enough: emerging modalities of GPCR ligands. Molecular and Cellular Endocrinology, Elsevier, 2010, 331 (2), pp.241. 10.1016/j.mce.2010.07.009. hal-00654484 HAL Id: hal-00654484 https://hal.archives-ouvertes.fr/hal-00654484 Submitted on 22 Dec 2011 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Accepted Manuscript Title: When simple agonism is not enough: emerging modalities of GPCR ligands Authors: Nicola J. Smith, Kirstie A. Bennett, Graeme Milligan PII: S0303-7207(10)00370-9 DOI: doi:10.1016/j.mce.2010.07.009 Reference: MCE 7596 To appear in: Molecular and Cellular Endocrinology Received date: 15-1-2010 Revised date: 15-6-2010 Accepted date: 13-7-2010 Please cite this article as: Smith, N.J., Bennett, K.A., Milligan, G., When simple agonism is not enough: emerging modalities of GPCR ligands, Molecular and Cellular Endocrinology (2010), doi:10.1016/j.mce.2010.07.009 This is a PDF file of an unedited manuscript that has been accepted for publication.
    [Show full text]
  • Drug Action-Receptor Theory
    Drug action-Receptor Theory Molecules (eg, drugs, hormones, neurotransmitters) that bind to a receptor are called ligands. The binding can be specific and reversible. A ligand may activate or inactivate a receptor; activation may increase or decrease a particular cell function. Each ligand may interact with multiple receptor subtypes. Few if any drugs are absolutely specific for one receptor or subtype, but most have relative selectivity. Selectivity is the degree to which a drug acts on a given site relative to other sites; selectivity relates largely to physicochemical binding of the drug to cellular receptors. A drug’s ability to affect a given receptor is related to the drug’s affinity (probability of the drug occupying a receptor at any given instant) and intrinsic efficacy (intrinsic activity—degree to which a ligand activates receptors and leads to cellular response). A drug’s affinity and activity are determined by its chemical structure. The pharmacologic effect is also determined by the duration of time that the drug-receptor complex persists (residence time). The lifetime of the drug-receptor complex is affected by dynamic processes (conformation changes) that control the rate of drug association and dissociation from the target. A longer residence time explains a prolonged pharmacologic effect. Drugs with long residence times include finasteride and darunavir. A longer residence time can be a potential disadvantage when it prolongs a drug's toxicity. For some receptors, transient drug occupancy produces the desired pharmacologic effect, whereas prolonged occupancy causes toxicity. Ability to bind to a receptor is influenced by external factors as well as by intracellular regulatory mechanisms.
    [Show full text]
  • Biased Receptor Functionality Versus Biased Agonism in G-Protein-Coupled Receptors Journal Xyz 2017; 1 (2): 122–135
    BioMol Concepts 2018; 9: 143–154 Review Open Access Rafael Franco*, David Aguinaga, Jasmina Jiménez, Jaume Lillo, Eva Martínez-Pinilla*#, Gemma Navarro# Biased receptor functionality versus biased agonism in G-protein-coupled receptors Journal xyz 2017; 1 (2): 122–135 https://doi.org/10.1515/bmc-2018-0013 b-arrestins or calcium sensors are also provided. Each of receivedThe FirstJuly 19, Decade 2018; accepted (1964-1972) November 2, 2018. the functional GPCR units (which are finite in number) has Abstract:Research Functional Article selectivity is a property of G-protein- a specific conformation. Binding of agonist to a specific coupled receptors (GPCRs) by which activation by conformation, i.e. GPCR activation, is sensitive to the differentMax Musterman, agonists leads Paul to differentPlaceholder signal transduction kinetics of the agonist-receptor interactions. All these mechanisms. This phenomenon is also known as biased players are involved in the contrasting outputs obtained agonismWhat and Is has So attracted Different the interest Aboutof drug discovery when different agonists are assayed. programsNeuroenhancement? in both academy and industry. This relatively recent concept has raised concerns as to the validity and Keywords: conformational landscape; GPCR heteromer; realWas translational ist so value anders of the results am showing Neuroenhancement? bias; firstly cytocrin; effectors; dimer; oligomer; structure. biased agonism may vary significantly depending on the cellPharmacological type and the experimental and Mental constraints,
    [Show full text]
  • International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification
    0031-6997/03/5504-597–606$7.00 PHARMACOLOGICAL REVIEWS Vol. 55, No. 4 Copyright © 2003 by The American Society for Pharmacology and Experimental Therapeutics 30404/1114803 Pharmacol Rev 55:597–606, 2003 Printed in U.S.A International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on Terms and Symbols in Quantitative Pharmacology RICHARD R. NEUBIG, MICHAEL SPEDDING, TERRY KENAKIN, AND ARTHUR CHRISTOPOULOS Department of Pharmacology, University of Michigan, Ann Arbor, Michigan (R.R.N.); Institute de Recherches Internationales Servier, Neuilly sur Seine, France (M.S.); Systems Research, GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina (T.K.); and Department of Pharmacology, University of Melbourne, Parkville, Australia (A.C.) Abstract ............................................................................... 597 I. Introduction............................................................................ 597 II. Working definition of a receptor .......................................................... 598 III. Use of drugs in definition of receptors or of signaling pathways ............................. 598 A. The expression of amount of drug: concentration and dose ............................... 598 1. Concentration..................................................................... 598 2. Dose. ............................................................................ 598 B. General terms used to describe drug action ...........................................
    [Show full text]
  • P2Y6R Agonist
    Cognitive Vitality Reports® are reports written by neuroscientists at the Alzheimer’s Drug Discovery Foundation (ADDF). These scientific reports include analysis of drugs, drugs-in- development, drug targets, supplements, nutraceuticals, food/drink, non-pharmacologic interventions, and risk factors. Neuroscientists evaluate the potential benefit (or harm) for brain health, as well as for age-related health concerns that can affect brain health (e.g., cardiovascular diseases, cancers, diabetes/metabolic syndrome). In addition, these reports include evaluation of safety data, from clinical trials if available, and from preclinical models. P2Y6R Agonist Evidence Summary P2Y6R activation promotes microglial phagocytosis, but also drives vascular inflammation, so agonists may exacerbate cardiovascular disease. Short term safety is good, but long-term safety is unknown. Neuroprotective Benefit: P2Y6R stimulation promotes microglial activation and phagocytosis which may facilitate amyloid clearance, but may also promote neuroinflammation and neuronal loss. Aging and related health concerns: P2Y6R activity is associated with the exacerbation of hypertension, atherosclerosis, neuropathic pain, and cancer metastasis in preclinical models, but may benefit glaucoma. Safety: The agonist GC021109 was safe in short Phase 1 trials, but long-term safety has not been established. Effects may vary in different patient populations. 1 Availability: Research use Dose: Not established Endogenous agonist: UDP Chemical formula: C9H14N2O12P2 Half-life: Not reported BBB: Not reported MW: 404.16 g/mol Clinical trials: Two Phase 1 studies for Observational studies: GC021109 in healthy controls (n=44) None and mild/moderate AD (n=36). Source: PubChem What is it? The P2Y6 receptor (P2Y6R) is a G-protein coupled receptor (GPCR) which belongs to the class of purinergic receptors.
    [Show full text]
  • Pharmacology of Free Fatty Acid Receptors and Their Allosteric Modulators
    International Journal of Molecular Sciences Review Pharmacology of Free Fatty Acid Receptors and Their Allosteric Modulators Manuel Grundmann 1,* , Eckhard Bender 2, Jens Schamberger 2 and Frank Eitner 1 1 Research and Early Development, Bayer Pharmaceuticals, Bayer AG, 42096 Wuppertal, Germany; [email protected] 2 Drug Discovery Sciences, Bayer Pharmaceuticals, Bayer AG, 42096 Wuppertal, Germany; [email protected] (E.B.); [email protected] (J.S.) * Correspondence: [email protected] Abstract: The physiological function of free fatty acids (FFAs) has long been regarded as indirect in terms of their activities as educts and products in metabolic pathways. The observation that FFAs can also act as signaling molecules at FFA receptors (FFARs), a family of G protein-coupled receptors (GPCRs), has changed the understanding of the interplay of metabolites and host responses. Free fatty acids of different chain lengths and saturation statuses activate FFARs as endogenous agonists via binding at the orthosteric receptor site. After FFAR deorphanization, researchers from the pharmaceutical industry as well as academia have identified several ligands targeting allosteric sites of FFARs with the aim of developing drugs to treat various diseases such as metabolic, (auto)inflammatory, infectious, endocrinological, cardiovascular, and renal disorders. GPCRs are the largest group of transmembrane proteins and constitute the most successful drug targets in medical history. To leverage the rich biology of this target class, the drug industry seeks alternative approaches to address GPCR signaling. Allosteric GPCR ligands are recognized as attractive modalities because Citation: Grundmann, M.; Bender, of their auspicious pharmacological profiles compared to orthosteric ligands. While the majority of E.; Schamberger, J.; Eitner, F.
    [Show full text]
  • Peptides for Health Benefits 2019
    International Journal of Molecular Sciences Editorial Peptides for Health Benefits 2019 Cristina Martínez-Villaluenga 1 and Blanca Hernández-Ledesma 2,* 1 Institute of Food Science, Technology and Nutrition (ICTAN-CSIC), Juan de la Cierva 3, 28006 Madrid, Spain; [email protected] 2 Institute of Food Science Research (CIAL, CSIC-UAM, CEI UAM+CSIC), Nicolás Cabrera, 9, 28049 Madrid, Spain * Correspondence: [email protected] Received: 31 March 2020; Accepted: 2 April 2020; Published: 6 April 2020 In recent years, peptides have received increased interest in pharmaceutical, food, cosmetics and various other fields. The high potency, specificity and good safety profile are the main strengths of bioactive peptides as new and promising therapies that may fill the gap between small molecules and protein drugs. Peptides possess favorable tissue penetration and the capability to engage into specific and high-affinity interactions with endogenous receptors. These positive attributes of peptides have driven research in evaluating peptides as versatile tools for drug discovery and delivery. In addition, among bioactive peptides, those released from food protein sources have acquired importance as active components in functional foods and nutraceuticals because they are known to possess regulatory functions that can lead to health benefits. This Special Issue of International Journal of Molecular Sciences represents the second in a series dedicated to peptides. This issue includes thirty-six outstanding papers describing examples of the most recent advances in peptide research and its applicability. The Special Issue begins with a group of papers exploring aspects of synthetic peptides that are of significance to develop novel drugs for controlling and/or managing chronic diseases.
    [Show full text]
  • Allosteric Modulators of G Protein-Coupled Dopamine and Serotonin Receptors: a New Class of Atypical Antipsychotics
    pharmaceuticals Review Allosteric Modulators of G Protein-Coupled Dopamine and Serotonin Receptors: A New Class of Atypical Antipsychotics Irene Fasciani 1, Francesco Petragnano 1, Gabriella Aloisi 1, Francesco Marampon 2, Marco Carli 3 , Marco Scarselli 3, Roberto Maggio 1,* and Mario Rossi 4 1 Department of Biotechnological and Applied Clinical Sciences, University of l’Aquila, 67100 L’Aquila, Italy; [email protected] (I.F.); [email protected] (F.P.); [email protected] (G.A.) 2 Department of Radiotherapy, “Sapienza” University of Rome, Policlinico Umberto I, 00161 Rome, Italy; [email protected] 3 Department of Translational Research and New Technology in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy; [email protected] (M.C.); [email protected] (M.S.) 4 Institute of Molecular Cell and Systems Biology, University of Glasgow, Glasgow G12 8QQ, UK; [email protected] * Correspondence: [email protected] Received: 26 September 2020; Accepted: 11 November 2020; Published: 14 November 2020 Abstract: Schizophrenia was first described by Emil Krapelin in the 19th century as one of the major mental illnesses causing disability worldwide. Since the introduction of chlorpromazine in 1952, strategies aimed at modifying the activity of dopamine receptors have played a major role for the treatment of schizophrenia. The introduction of atypical antipsychotics with clozapine broadened the range of potential targets for the treatment of this psychiatric disease, as they also modify the activity of the serotoninergic receptors. Interestingly, all marketed drugs for schizophrenia bind to the orthosteric binding pocket of the receptor as competitive antagonists or partial agonists.
    [Show full text]
  • Agonist-Directed Signaling of the Serotonin 2A Receptor Depends On
    Agonist-directed signaling of the serotonin 2A SEE COMMENTARY receptor depends on ␤-arrestin-2 interactions in vivo Cullen L. Schmid, Kirsten M. Raehal, and Laura M. Bohn* Departments of Pharmacology and Psychiatry, Ohio State University College of Medicine, Columbus, OH 43210 Edited by Robert J. Lefkowitz, Duke University Medical Center, Durham, NC, and approved November 16, 2007 (received for review September 18, 2007) Visual and auditory hallucinations accompany certain neuropsy- Regulation of GPCRs can set the tone for receptor sensitivity to chiatric disorders, such as schizophrenia, and they also can be basal levels of neurotransmitters (4, 17). Although ␤-arrestins are induced by the use or abuse of certain drugs. The heptahelical important for the regulation of many GPCRs, their role in serotonin 2A receptors (5-HT2ARs) are molecular targets for drug- 5-HT2AR regulation and signaling remains unclear. Previous work induced hallucinations. However, the cellular mechanisms by has shown that the 5-HT2AR colocalizes with ␤-arrestin-1 and Ϫ2 which the 5-HT2AR mediates these effects are not well understood. in cortical neurons, and some colocalization is apparent in intra- Drugs acting at the 5-HT2AR can trigger diverse signaling path- cellular vesicles (18). Previous studies have shown that the role of ways that may be directed by the chemical properties of the drug. ␤-arrestins in mediating 5-HT2AR internalization can vary be- ␤-arrestins are intracellular proteins that bind to heptahelical tween cell lines (19), further emphasizing the importance of eval- receptors and represent a point where such divergences in ligand- uating ␤-arrestin’s impact on 5-HT2AR function and trafficking in directed functional signaling could occur.
    [Show full text]
  • Neuropsychopharmacology: the Fifth Generation of Progress
    Neuropsychopharmacology: The Fifth Generation of Progress This chapter is available for free viewing below. Each chapter of the book is available free for viewing at http://www.acnp.org/g5 Downloadable, printable chapters of the book are available for purchase at http://members.acnp.org/xcart/customer/home.php?cat=3 To purchase the hardcover book browse to http://www.acnp.org/click.php?action=go&to=5th 3 OPIOID PEPTIDES AND THEIR RECEPTORS: OVERVIEW AND FUNCTION IN PAIN MODULATION GAVAN P. MCNALLY AND HUDA AKIL Few neurotransmitter systems have fascinated the general information we possess on the endogenous opioid system. public as much as the endorphins, otherwise known as the However, we attempt to give the reader key information endogenous opioid peptides. They have been termed the ‘‘her- about the biochemical nature of the system, along with an oin within’’ and endowed with the power to relieve pain update on our understanding of the recently cloned recep- and allow one to experience ‘‘runner’s high’’ or enjoy the tors and their functions. Finally, we describe the regulation taste of chocolate. Although these powers may or may not of pain responsiveness as one example of a function me- withstand close scientific scrutiny, there is little question diated by opioids to illustrate the complexity of their role. that endogenous opioid systems play a critical role in modu- lating a large number of sensory, motivational, emotional, and cognitive functions. As inhibitory neuropeptide trans- mitters, they fine-tune neurotransmission across a wide OPIOID PEPTIDES AND THEIR RECEPTORS range of neuronal circuits, setting thresholds or upper limits.
    [Show full text]