DOCSLIB.ORG

Pharmacology

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

An ntegrated oal-directed arrative for the n- raining xam I G N I T E JEFFREY B HORN MD STEPHEN H. SAMS MD FIRST EDITION WHITNEY FALLAHIAN MD JASON HAFER MD An Integrated Goal-directed Narrative for the In-Training Exam Successful and unsuccessful people do not vary greatly in their abilities. They vary in their desires to reach their potential. – John Maxwell IGNITE PHARM(B)-2 [An Integrated Goal-directed Narrative for the In-Training Exam] PHARMACOLOGHY – BASIC EXAM FUNDAMENTALS OF PHARMACOLOGY RELATIONSHIP BETWEEN RELATIONSHIP BETWEEN Drug Dose Drug Dose PHARMACODYNAMICS Tissue Concentration PHARMACOKINETICS Tissue Concentration Elapsed Time Time After Administration “WHAT THE DRUG DOES TO THE BODY” “WHAT THE BODY DOES TO THE DRUG” TAXONOMY ELIMINATION Drug Removal (Biotransformation & Excretion) CLEARANCE Rate of Elimination Site of Administration ABSORPTION BIOTRANSFORMATION Alteration of a Substance by a Metabolic Process ENTERING THE BLOODSTREAM Fraction of UNCHANGED DRUG Reaching MEDIAN LETHAL DOSE BIOAVAILABILITY Dose Leading to DEATH in 50% of the Population Systemic Circulation (LD50) RATIO of: Median Lethal Dose VOLUME OF DISTRIBUTION Theoretical Volume in Which a Drug Is Distributed THERAPEUTIC INDEX (TI) Median Effective Dose MEDIAN EFFECTIVE DOSE (ED50) Dose of Drug Necessary to Generate GIVEN EFFECT IN 50% OF POPULATION Ç Potency of Drug à È ED50 An Integrated Goal-directed Narrative for the In-Training Exam 2. Which of the Following Drugs is Associated with PRO-DRUG PAIN ON INJECTION? A Drug that has Minimal/No Inherent Activity & MUST A. Dexmedetomidine C. Thiopental be METABOLIZED to Exert its Intended Effect B. Fospropofol D. Methohexital DRUG EFFECTIVENESS EFFECT EXAMPLE FULL AGONIST AGONIST Activates Receptor Benzodiazepine Opposes Receptor Response COMPETITIVE ANTAGONIST Neuromuscular Blocker PARTIAL AGONIST (Can OVERCOME with Agonist) Opposes Receptor Response WEAK PARTIAL NON-COMPETITIVE ANTAGONIST Phenoxybenzamine (CANNOT OVERCOME with Agonist) AGONIST PARTIAL AGONIST Partial Receptor Response Buprenorphine NEUTRAL MIXED AGONIST-ANTAGONIST Augments/Opposes Response Nalbuphine IGNITE PHARM(B)-3 [An Integrated Goal-directed Narrative for the In-Training Exam] PHARMACOLOGHY – BASIC EXAM PHARMACOLOGY ELIMINATION HALF-LIFE Time Required for Drug Concentration to È 50% Diazepam TIME TO RECOVERY È Plasma Concentration Necessary for Patient to Awaken Thiopental Time to Achieve È Drug Concentration CONTEXT SENSITIVE HALF-LIFE Midazolam PREDETERMINED PERCENTAGE after STOPPING A CONTINUOUS INFUSION EFFECT SITE EQUILIBRATION Delay Between IV ADMINISTRATION of Drug & ONSET of Clinical Efficacy Propofol Ketamine STEADY STATE Administration = Elimination Etomidate CONTEXT SENSITIVE HALF LIFE DOSE RESPONSE CURVES AFFINITY The Inherent Nature of the Drug to Bind a Receptor POTENCY Measures Activity of a Drug (Amount Required to Produce an Effect of a Given Intensity) EFFICACY Maximum Magnitude of Effect of the Drug SLOPE Depicts the Relationship Between a Drug & Action An Integrated Goal-directed Narrative for the In-Training Exam 2. Which of the Following Drugs is Associated with PRO-DRUG PAIN ON INJECTION? A Drug that has Minimal/No Inherent Activity & MUST A. Dexmedetomidine C. Thiopental be METABOLIZED to Exert its Intended Effect B. Fospropofol D. Methohexital PHARMACOKINETICS ABSORPTION Drug LEAVES ADMINISTRATION SITE & Enters Bloodstream (UNCHARGED Drugs àÇ Absorption) Protein Binding pKa Influences END-ORGAN Accumulation INFLUENCED BY DISTRIBUTION Lipid Solubility Volume of Distribution Alteration of a Substance by a Metabolic Process (LIVERàPrimary Organ Responsible) PHASE 1 REACTION BIOTRANSFORMATION Transformation to Polar Metabolite (OXIDATION, REDUCTION, HYDROLYSIS) PHASE 2 REACTION Couples Drug or Metabolite to Endogenous Substrate (Ç Polarity for Excretion in Urine) IGNITE PHARM(B)-4 [An Integrated Goal-directed Narrative for the In-Training Exam] PHARMACOLOGHY – BASIC EXAM MOLECULE CHARACTERISTICS BIOTRANSFORMATION NON-IONIZED IONIZED LIVER >>> Kidney, Lung GI Tract PHARMACOLOGIC EFFECT ACTIVE NOT ACTIVE DEPENDENT UPON Hepatic Blood Flow SOLUBILITY ACTIVE NOT ACTIVE HEPATIC CLEARANCE Protein Binding CROSSES LIPID BARRIERS YES NO Intrinsic Activity of Enzymes RENAL EXCRETION NO YES EXTRACTION RATIO RATE OF PLASMA DRUG REMOVED BY ORGAN OF ELIMINATION HEPATIC METABOLISM YES NO FORMULA RATE OF PRESENTATION OF THE DRUG An Integrated Goal-directed Narrative for the In-Training Exam DRUG DISTRIBUTION TISSUE GROUP LOCATION BODY MASS PERCENTAGE (%) CARDIAC OUTPUT PERCENTAGE BRAIN HEART KIDNEY VESSEL-RICH 10 LIVER ENDOCRINE GLANDS 75 MUSCLE MUSCLE SKIN 50 20 FAT ADIPOSE 20 4 VESSEL-POOR BONE LIGAMENT CARTILAGE 20 1 3. How many Half-Lives Are Required for Complete Elimination of a Drug? TRANSFER ACROSS A LIPID BILAYER A. Two È Degree of Ionization È Molecular Weight B. Three Ç Lipid Solubility Ç Concentration Gradient C. Four D. Five Hepatic Disease Renal Disease TEMPORARY RESERVOIR OF DRUG Congestive Heart Failure PROTEIN BINDING Protein Bound DrugàUnavailable for End Organ Uptake INFLUENCED BY Cancer (Ç Size & Polarityà Unable to Pass Through Membranes) Myocardial Infarction Pregnancy Nutrition ALBUMIN Binds ACIDIC Drugs ⍺-1-ACID GLYCOPROTEIN Binds BASIC drugs ACUTE INFLAMMATORY STATE Ç ⍺-1-Acid Glycoprotein È Albumin END STAGE LIVER DISEASE & PREGNANCY PHYSIOLOGIC STATES AFFECTING PROTEIN BINDING È ⍺-1-Acid Glycoprotein È Albumin ELDERLY Unchanged ⍺-1-Acid Glycoprotein È Albumin IGNITE PHARM(B)-5 [An Integrated Goal-directed Narrative for the In-Training Exam] PHARMACOLOGHY – BASIC EXAM DRUG ELIMINATION ZERO ORDER KINETICS FIRST ORDER KINETICS Drug Cleared at CONSTANT RATE ZERO-ORDER KINETICS NOT DEPENDENT UPON PLASMA CONCENTRATION ELIMINATION PROPORTIONAL TO CONCENTRATION OF DRUG HALF-LIFE FIRST-ORDER KINETICS Describes Time Required for Concentration to Fall to 50% of Original Value An Integrated Goal-directed Narrative for the In-Training Exam 2-COMPARTMENT MODEL VOLUME OF DISTRIBUTION (VD) VD = Dose of Drug Administered Describes How the Body Theoretically Handles Drugs Administered as IV Bolus FORMULA Plasma Concentration SEQUENCE OF EVENTS A Theoretical Volume into Which Drug has Been Distributed FIRST Instantaneous Rise in Drug Concentration NOT A REAL NUMBER DISTRIBUTION/ ALPHA PHASE Represents Volume of Plasma to Account for Observed Plasma Concentration SECOND Initial Rapid È in Drug Concentration SMALL VD LARGE VD Redistribution of Drug Ç Intravascular Concentration È Intravascular Concentration (CENTRAL COMPARTMENT to PERIPHERAL COMPARTMENT) Hydrophilic Drugs Hydrophobic Drugs ELIMINATION/ BETA PHASE Ç Protein Binding È Protein Binding THIRD È Redistribution Ionized Drugs Non-Ionized Drugs (Elimination from the CENTRAL COMPARTMENT) È Lipid Solubility Ç Lipid Solubility QUESTION ANSWER KEY 1. B 2. D 3. D 4. C 4. Which of the Following is Associated with a LARGE Volume of Distribution (VD)? THERAPEUTIC WINDOW A. Intravascular concentration The Range Between Concentration Associated with Desired Therapeutic B. Ionized Drugs Effect and Concentration Associated with Toxic Drug Response C. Ç Lipid Solubility Narrow Window = Dangerous Medication D. Ç Protein Binding IGNITE PHARM(B)-6 [An Integrated Goal-directed Narrative for the In-Training Exam] PHARMACOLOGHY – BASIC EXAM BASIC EXAM STATISTICS (2015-2018) KEYWORDS YEAR NATIONAL PERCENT (%) CORRECT UNIVERSITY OF UTAH PERCENT (%) CORRECT DRUG METABOLISM: CLEARANCE 2015 74.8 42.9 DRUG ELIMINATION HALF-LIFE 2015 94.5 100 CONTEXT SENSITIVE HALF LIFE 2017 89.9 83.3 CONTEXT SENSITIVE HALF LIFE 2018 76.8 50 PHARMACODYNAMICS: DOSE RESPONSE CURVE 2018 98.7 100 83.4 100 2016 46.3 50 DRUG ELIMINATION KINETICS 2017 43.2 16.7 2018 84.6 80 PHARMACOKINETICS: FIRST ORDER 2015 76.9 83.3 PHARMACOKINETIC PRINCIPLES 2015 97 100 FIRST ORDER PHARMACOKINETICS 2017 68 55.7 PHARMACOKINETICS: FIRST ORDER 2018 78.8 83.3 VOLUME OF DISTRIBUTION: DETERMINANTS 2015 81.8 80 An Integrated Goal-directed Narrative for the In-Training Exam IGNITE PHARM(B)-7 .
Recommended publications
  • Pharmacodynamics - I

    Pharmacodynamics - I

    Pharmacodynamics - I Dr. Jyoti M. Benni Dept. of Pharmacology USM-KLE, IMP Belgaum Learning outcomes • Describe the principles of pharmacodynamics with regard to the potential targets of -drug action -receptor types -dose-response relationship (curve) -therapeutic index 2 Introduction: PK & PD 3 Pharmacodynamics Pharmacodynamics is the study of actions of the drug on the body and their mechanism of action. Stimulation Depression Irritation Replacement Modify immune status Anti-infective / Cytotoxic action 4 Mechanisms of Drug Action Non-receptor mediated Receptor mediated • Physical • Receptors on the cell • Chemical membrane • Enzymes • Ion channels • Transporters • Receptors inside the cell • Antibody • Placebo 5 Non – receptor mediated mechanisms… Physical property . Physical property of the drug is responsible E.g. Adsorption: activated charcoal in treatment of poisoning Osmotic activity: magnesium sulfate for constipation Radioactivity: radioactive iodine (I131 ) for hyperthyroidism Radioopacity: barium sulfate as contrast media 6 Non – receptor mediated mechanisms… Chemical action Antacids - neutralize gastric acid Chelating agents (EDTA) Used in heavy metal (LEAD)poisoning treatment Oxidizing agents potassium permanganate as germicidal agent 7 Non – receptor mediated mechanisms… Enzymes as targets of drug action Enzymes Inhibition Stimulation Enzyme Nonspecific Specific induction Competitive Noncompetitive 8 Non – receptor mediated mechanisms… Enzyme stimulation: • Reactivation e.g. Injection pralidoxime → for treatment of Organophosphorus
  • Activity Intrinsic

    Activity Intrinsic

    Vol. (Suppl. ) Intrinsic 201 Activity www.IntrinsicActivity.org Published by th ISSN 2309-8503 Austrian Pharmacological Society Dopamine 2016 Vienna, 5–8 September 2016 MAEETING BSTRACTS Intrinsic Activity is an online, open-access publication medium published by the Austrian Pharmacological Society (APHAR). The Journal welcomes contributions in the fields of Pharmacology, Pharmacotherapy and other fields in biomedicine. Contributions may be of type meeting abstracts, research articles, position papers, commentaries or similar. For submission instructions and all other information regarding publication in the journal visit: www.IntrinsicActivity.org Correspondence Intrinsic Activity c/o Institute for Experimental and Clinical Pharmacology Medical University of Graz Universitätsplatz 4 8010 Graz, Austria Tel.: +43 (316) 380-4305 Fax: +43 (316) 380-9645 E-mail: [email protected] Website: www.IntrinsicActivity.org ISSN: 2309-8503 Austrian Pharmacological Society c/o Institute of Pharmacology Centre for Physiology and Pharmacology Medical University of Vienna Währinger Straße 13a 1090 Wien, Austria E-mail: [email protected] Copyright, open access and permission to use Articles are published under a Creative Commons license (Creative Commons, attribution, non-commercial), that allows reuse subject only to the use being non-commercial and the article being fully attributed. The Publisher and Austrian Pharmacological Society retain the license that allows publishing of the articles in Intrinsic Activity, any derivative product or any other Intrinsic Activity product (present or future) and allows sub-licensing such rights and exploit all subsidiary rights. Authors retain the license to use their articles for their own non-commercial purposes, specifically: Posting a pdf of their own article on their own personal or institutional website for which no charge for access is made.
  • Principle of Pharmacodynamics

    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.
  • Pharmacodynamics Drug Receptor Interactions Part-2

    Pharmacodynamics Drug Receptor Interactions Part-2

    Pharmacodynamics: (Drug Receptor Interactions, Part 2) ………………………………………………………………………………………………………………………………………………………………………………………………………………… VPT: Unit I; Lecture-22 (Dated 03.12.2020) Dr. Nirbhay Kumar Asstt. Professor & Head Deptt. of Veterinary Pharmacology & Toxicology Bihar Veterinary College, Bihar Animal Sciences University, Patna Drug Receptor Interactions Agonist It is a drug that possesses affinity for a particular receptor and causes a change in the receptor that result in an observable effect. Full agonist: Produces a maximal response by occupying all or a fraction of receptors. (Affinity=1, Efficacy=1) Partial agonist: Produces less than a maximal response even when the drug occupies all of the receptors. (Affinity=1, Efficacy= 0 to 1) Inverse agonist: Activates a receptor to produce an effect in the opposite direction to that of the well recognized agonist. (Affinity=1, Efficacy= –1 to 0). Source: Rang & Dale’s Pharmacology, Elsevier Source: Good & Gilman’s The Pharmacological Basis of Therapeutics, 13th Edn. Antagonist An antagonist is a drug that blocks the response produced by an agonist. Antagonists interact with the receptor or other components of the effector mechanism, but antagonists are devoid of intrinsic activity (Affinity=1, Efficacy=0). Antagonist contd… Competitive Antagonism: It is completely reversible; an increase in the concentration of the agonist in the bio-phase will overcome the effect of the antagonist. Example: Atropine (Antimuscarinic agent) Diphenhydramine (H1 receptor blocker) Non-competitive antagonism: The agonist has no influence upon the degree of antagonism or its reversibility. Example: Platelet inhibiting action of aspirin (The thromboxane synthase enzyme of platelets is irreversibly inhibited by aspirin, a process that is reversed only by production of new platelets).
  • Pharmacogenomic and Structural Analysis of Constitutive G Protein–Coupled Receptor Activity

    Pharmacogenomic and Structural Analysis of Constitutive G Protein–Coupled Receptor Activity

    ANRV298-PA47-02 ARI 4 December 2006 20:18 Pharmacogenomic and Structural Analysis of Constitutive G Protein–Coupled Receptor Activity Martine J. Smit,1 Henry F. Vischer,1 Remko A. Bakker,1 Aldo Jongejan,1 Henk Timmerman,1 Leonardo Pardo,2 and Rob Leurs1 1Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Vrije Universiteit, Faculty of Sciences, Department of Chemistry, 1081 HV Amsterdam, The Netherlands; email: [email protected] 2Laboratorio de Medicina Computacional, Unidad de Bioestadistica, Facultad de Medicina, Universidad Autonoma de Barcelona, Barcelona, Spain Annu. Rev. Pharmacol. Toxicol. 2007. 47:53–87 Key Words First published online as a Review in Advance on constitutive activity; inverse agonism, receptor structure, receptor October 9, 2006 motifs The Annual Review of Pharmacology and Toxicology is online at http://pharmtox.annualreviews.org Abstract This article’s doi: G protein–coupled receptors (GPCRs) respond to a chemically di- 10.1146/annurev.pharmtox.47.120505.105126 verse plethora of signal transduction molecules. The notion that Copyright c 2007 by Annual Reviews. GPCRs also signal without an external chemical trigger, i.e., in a All rights reserved constitutive or spontaneous manner, resulted in a paradigm shift by Universitat Autonoma de Barcelona on 01/09/07. For personal use only. 0362-1642/07/0210-0053$20.00 in the field of GPCR pharmacology. The discovery of constitutive GPCR activity and the fact that GPCR binding and signaling can be strongly affected by a single point mutation drew attention to Annu. Rev. Pharmacol. Toxicol. 2007.47:53-87. Downloaded from arjournals.annualreviews.org the evolving area of GPCR pharmacogenomics.
  • Different Inverse Agonist Activities of P»-Adrenergic Receptor Antagonists—Pharmacological Characterization and Therapeutical

    Different Inverse Agonist Activities of P»-Adrenergic Receptor Antagonists—Pharmacological Characterization and Therapeutical

    International Congress Series 1249 (2003) 39-53 Different inverse agonist activities of p»-adrenergic receptor antagonists—pharmacological characterization and therapeutical implications in the treatment of chronic heart failure Christoph Maack*, Michael Bòhm Medizinische Klinik und Poliklinik fiir Innere Medizin III, Universitat des Saarlandes, 66421 Homburg/Saai; Germany Received 16 April 2003; accepted 16 April 2003 Abstract The treatment of chronic heart failure with most p-adrenergic receptor (p-AR) antagonists leads to an improvement of symptoms and left ventricular function. However, only metoprolol, bisoprolol and carvedilol have been shown to reduce mortality in these patients. Bucindolol did not reduce mortality and xamoterol even increased it. These differences may be related to different inverse agonist or partial agonist activity of p-AR antagonists. This review focusses on the determination of different intrinsic activity of the mentioned p-AR antagonists in the human myocardium. Furthermore, the clinical impact of these differences is examined. In this regard, the effect of the different p-AR antagonists on p-AR regulation, minimum heart rate and exercise tolerance, as well as prognosis, is highlighted. It is concluded that the degree of inverse agonism of a p-AR antagonist determines the degree of p-AR resensitization, reduction of minimum heart rate, improvement of exercise tolerance and possibly also improvement of prognosis of patients with chronic heart failure. © 2003 Elsevier Science B.V. All rights reserved. Key\vords: Inverse agonism; p-adrenergic receptors; p-blockers, Heart faitee * Corresponding author. Current address: The Johns Hopkins University, Institute of Molecular Cardio- biology, Division of Cardiology, 720 Rutland Ave., 844 Ross Bldg., Baltimore, MD 21205-2195, USA.
  • The Pharmacological Studies on Intrinsic Activities of Acetylcholine, Methacholine, and Carbachol (Homologous Drugs) on Isolated Rat Ileum Preparation

    The Pharmacological Studies on Intrinsic Activities of Acetylcholine, Methacholine, and Carbachol (Homologous Drugs) on Isolated Rat Ileum Preparation

    Journal of Medicine and Medical Science Vol. 2(8) pp. 1047-1049, August 2011 Available online@ http://www.interesjournals.org/JMMS Copyright © 2011 International Research Journals Short Communication The pharmacological studies on intrinsic activities of acetylcholine, methacholine, and carbachol (Homologous Drugs) on isolated rat ileum preparation Peter I. Aziba* 1, Sokan J.O. 2, Ifedayo O. 2 and Kasim L.S. 2 1*Department of Pharmacology and 2Department of Pharmaceutical Chemistry Olabisi Onabanjo university, Oachs, Ago_Iwoye. Accepted 24 August, 2011 This study investigated the intrinsic activities of equimolar concentrations of three homologous drugs Actylcholine (Ach), Methacholine (Mch) and Carbachol (Cch) on isolated rat ileum preparation. Contractions were monitored on smoked drum fixed on a kymograph. Heights of contractions were measured in (mm) in order to assess their efficacies.In some experiments Ach- induced contractions were measured in the presence of atropine a competitive muscarinic antagonist. The result showed order of potencies, ranked as Cch>Mch>Ach. This result may explain the low intrinsic activities of Ach when compared to Cch, Mch, due to effect of acetylcholinesterase an enzyme which hydrolyze Ach and limit its efficacy in therapeutic use. Keywords: Intrinsic, homologous drugs, rat ileum, efficacy. INTRODUCTION Theoretically, the term intrinsic activity of a drug was first MATERIALS AND METHODS introduced by Ariens and Van Rossum (1957). The term has been used a great deal in their attempt to explain Rats between (200-305g) were used. The animals were why all drugs do not act in accordance with Clark’s theory maintained in well ventilated conditions, under constant of drug receptor interaction.
  • International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on Terms and Symbols in Quantitative Pharmacology

    International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on Terms and Symbols in Quantitative Pharmacology

    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 Downloaded from 1. Concentration..................................................................... 598 2. Dose. ............................................................................ 598 B. General terms used to describe drug action ...........................................
  • International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on Terms and Symbols in Quantitative Pharmacology

    International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. XXXVIII. Update on Terms and Symbols in Quantitative Pharmacology

    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 Downloaded from 1. Concentration..................................................................... 598 2. Dose. ............................................................................ 598 B. General terms used to describe drug action ...........................................
  • Partial Dopamine D2/Serotonin 5-HT1A Receptor Agonists As New Therapeutic Agents Adeline Etievant#, Cécile Bétry#, and Nasser Haddjeri*,1

    Partial Dopamine D2/Serotonin 5-HT1A Receptor Agonists As New Therapeutic Agents Adeline Etievant#, Cécile Bétry#, and Nasser Haddjeri*,1

    The Open Neuropsychopharmacology Journal, 2010, 3, 1-12 1 Open Access Partial Dopamine D2/Serotonin 5-HT1A Receptor Agonists as New Therapeutic Agents Adeline Etievant#, Cécile Bétry#, and Nasser Haddjeri*,1 Laboratory of Neuropharmacology, Faculty of Pharmacy, University Lyon I, EAC CNRS 5006, 8 Avenue Rockefeller 69373 LYON Cedex 08 France Abstract: The therapeutic efficacy of current antipsychotic or antidepressant agents still present important drawbacks such as delayed onset of action and a high percentage of non-responders. Despite significant advancements in the devel- opment of new drugs with more acceptable side-effect profiles, patients with schizophrenia or major depression experi- ence substantial disability and burden of disease. The present review discusses the usefulness of partial dopamine D2/serotonin 5-HT1A receptors agonists in the treatment of schizophrenia, major depression and bipolar disorder as well as in Parkinson’s disease. Partial agonists can behave as modulators since their intrinsic activity or efficacy of a partial ago- nist depends on the target receptor population and the local concentrations of the natural neurotransmitter. Thus, these drugs may restore adequate neurotransmission while inducing less side effects. In schizophrenia, partial DA D2/5-HT1A receptor agonists (like aripiprazole or bifeprunox), by stabilizing DA system via a preferential reduction of phasic DA re- lease, reduce side effects i.e. extrapyramidal symptoms and improve cognition by acting on 5-HT1A receptors. Aripipra- zole appears also as a promising agent for the treatment of depression since it potentiates the effect of SSRIs in resistant treatment depression. Concerning bipolar disorders aripiprazole may have only a benefit effect in the treatment of manic episodes.
  • Mechanism of Action of Cariprazine

    Mechanism of Action of Cariprazine

    CNS Spectrums (2016), 21, 123–127. © Cambridge University Press 2016 doi:10.1017/S1092852916000043 BRAINSTORMS—Clinical Neuroscience Update Mechanism of action of cariprazine Stephen M. Stahl ISSUE: Cariprazine is a new therapeutic agent recently approved for the treatment of both schizophrenia and manic or mixed episodes associated with bipolar disorder, and is under investigation for the treatment of both bipolar depression and major depressive disorder. arises: What differentiates cariprazine from other Take-Home Points agents in its class? ’ Cariprazine is a dopamine multifunctional agent, but with pharmacologic properties that differentiate it from other agents in the atypical antipsychotic class. Cariprazine Has About the Same Intrinsic Activity as Brexpiprazole, but Less than Aripiprazole ’ Cariprazine is a dopamine and serotonin (5HT) receptor “ ” partial agonist with intrinsic activity at the D2 dopamine The dopamine agonist spectrum goes from silent receptor, similar to that of another new agent, antagonism on the far left of Figure 2, which is pure “ ” brexpiprazole. antagonism without any agonist activity, to full agonism on the far right of Figure 2, which is the ’ High affinity actions of cariprazine at D3 dopamine maximum amount of stimulation of the D2 receptor.1 receptors, as well as actions at 5HT1A, 5HT2A, and Almost all antipsychotics are silent antagonists and lie alpha 1B receptors, differentiate it pharmacologically to the far left on the spectrum. Dopamine itself is a full from other antipsychotics. agonist and lies to the far right on the spectrum. Note that toward the left-hand part of the spectrum ’ Clinical differentiation from other antipsychotics is only lie several interesting compounds that have been tested now evolving with a head-to-head comparison with as antipsychotics.
  • Population Modeling Integrating Pharmacokinetics, Pharmacodynamics, Pharmacogenetics, and Clinical Outcome in Patients with Sunitinib-Treated Cancer

    Population Modeling Integrating Pharmacokinetics, Pharmacodynamics, Pharmacogenetics, and Clinical Outcome in Patients with Sunitinib-Treated Cancer

    Citation: CPT Pharmacometrics Syst. Pharmacol. (2017) 00, 00; doi:10.1002/psp4.12210 VC 2017 ASCPT All rights reserved ORIGINAL ARTICLE Population Modeling Integrating Pharmacokinetics, Pharmacodynamics, Pharmacogenetics, and Clinical Outcome in Patients With Sunitinib-Treated Cancer MH Diekstra1†, A Fritsch2†, F Kanefendt2†, JJ Swen1, DJAR Moes1,FSorgel€ 3, M Kinzig3, C Stelzer3, D Schindele4, T Gauler5, S Hauser6, D Houtsma7, M Roessler8, B Moritz8, K Mross9, L Bergmann10, E Oosterwijk11, LA Kiemeney12, HJ Guchelaar1 and U Jaehde2* The tyrosine kinase inhibitor sunitinib is used as first-line therapy in patients with metastasized renal cell carcinoma (mRCC), given in fixed-dose regimens despite its high variability in pharmacokinetics (PKs). Interindividual variability of drug exposure may be responsible for differences in response. Therefore, dosing strategies based on pharmacokinetic/pharmacodynamic (PK/PD) models may be useful to optimize treatment. Plasma concentrations of sunitinib, its active metabolite SU12662, and the soluble vascular endothelial growth factor receptors sVEGFR-2 and sVEGFR-3, were measured in 26 patients with mRCC within the EuroTARGET project and 21 patients with metastasized colorectal cancer (mCRC) from the C-II-005 study. Based on these observations, PK/PD models with potential influence of genetic predictors were developed and linked to time-to-event (TTE) models. Baseline sVEGFR-2 levels were associated with clinical outcome in patients with mRCC, whereas active drug PKs seemed to be more predictive in patients with mCRC. The models provide the basis of PK/PD-guided strategies for the individualization of anti-angiogenic therapies. CPT Pharmacometrics Syst. Pharmacol. (2017) 00, 00; doi:10.1002/psp4.12210; published online on 0 Month 2017.