DOCSLIB.ORG

Searching for Pharmacophores in Large Coordinate Data Bases and Its Use in Drug Design (Topographic/Three-Dimensional Substructure/Concord) ROBERT P

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Searching for Pharmacophores in Large Coordinate Data Bases and Its Use in Drug Design (Topographic/Three-Dimensional Substructure/Concord) ROBERT P Proc. Nati. Acad. Sci. USA Vol. 86, pp. 8165-8169, October 1989 Pharmacology Searching for pharmacophores in large coordinate data bases and its use in drug design (topographic/three-dimensional substructure/coNcoRD) ROBERT P. SHERIDAN, ANDREW RuSINKO III, RAMASWAMY NILAKANTAN, AND R. VENKATARAGHAVAN Medical Research Division, Lederle Laboratories, American Cyanamid, Pearl River, NY 10965 Communicated by F. W. McLafferty, May 25, 1989 (receivedfor review February 25, 1989) ABSTRACT Pharmacophores, three-dimensional ar- available (crystal coordinates or computer-generated confor- rangements ofchemical groups essential for biological activity, mations ofa few compounds) were -mall. Now, however, the are being proposed in increasing numbers. We have developed data base ofcrystal coordinates maintained by Cambridge (6) a system to search data bases of three-dimensional coordinates has >60,000 entries. Moreover, practical methods to trans- for compounds that contain a particular pharmacophore. The form large data bases ofconnection tables to coordinate form coordinates can be derived from experiment (e.g., Cambridge (7) have recently become available. Also, computer algo- Crystal Database) or be generated from data bases of connec- rithms for doing three-dimensional substructure searches tion tables (e.g., Cyanamid Laboratories proprietary com- (8-10) have improved. pounds) via the program CONCORD. We discuss the results of Searching for pharmacophores in large data bases has now searches for three sample pharmacophores. Two have been become a practical way to exploit geometric structure- proposed by others based on the conformational analysis of activity information. In this paper, we discuss the results of active compounds, and one is inferred from the crystal struc- searching for three sample pharmacophores. Our primary ture of a protein-igand complex. These examples show that goal is to demonstrate the type of insight that can come from such searches can identify classes of compounds that are pharmacophore searches. structurally different from the compounds from which the pharmacophore was derived but are known to have the ap- METHODS propriate biological activity. Occasionally, the searches find bond "frameworks" in which the important groups are rigidly We have been working with two large data bases of coordi- held in the proper geometry. These may suggest new structural nates: CCD, a subset of the Cambridge Crystal Database (6), classes for synthesis. and CLFIL, a three-dimensional version of the CL File, the set of proprietary structures from American Cyanamid. The 29,828 structures in CCD are those for which we could relate The function of rational drug design is to relate chemical the coordinate and connection table information provided by structure to a specific biological activity and then to use the the Cambridge Crystallographic Data Centre. The 223,988 relationship to select existing compounds for testing or to structures in CLFIL were generated from a MACCS data suggest new compounds for synthesis. Now that three- base by using CONCORD. [MACCS (Molecular ACCess Sys- dimensional molecular modeling is widely used, "pharma- tem) is the tradename for a chemical data base management cophore" models for a variety of biological activities are system supplied by Molecular Design Ltd., San Leandro, appearing in the literature in increasing numbers. The con- CA.] CONCORD is a rule-based system that generates a single cept of a pharmacophore, although based on many simplify- set of three-dimensional coordinates from a connection table ing assumptions, is a useful one: a particular spatial arrange- that contains only "organic" atoms. Structures in either data ment of chemical groups (usually atoms), common to all base are stored as a set of atom types and coordinates for active molecules, that is recognized by a single receptor. nonhydrogen atoms. The atom type consists of five fields: Pharmacophores can be inferred from the structure ofligand- element, number of neighbors (i.e., bonded atoms), the receptor complexes or, when the structure of the receptor is number of pi electrons, the number of attached hydrogens at not known, can be deduced by conformational analysis of physiological pH, and formal charge. Four types of dummy active compounds, as in the "active analog" approach (1-3). atoms were added: D5 and D6 (the centroids of planar 5- and A pharmacophore is usually expressed in three-dimensional 6-membered rings), DP (along the perpendiculars to these terms (distances, angles, volumes), and its atoms may be rings), and DL (attached to each heteroatom along the vector described by a physical property (cation, hydrogen bond sum ofthe bonds from its neighbors). These are equivalent to donor, etc.). Often, a pharmacophore will contain one or the types of dummy atoms most often used in describing more "dummy" atoms, which are used to define a geometric pharmacophore geometries. Details of how the data bases entity (centroid of a ring, a lone pair direction, etc.). were generated will be given elsewhere (7). More than 10 years ago, Gund (4, 5) pointed out how, once We have developed a system 3DSEARCH (8) that allows a a pharmacophore is defined for a particular biological activ- user to define a three-dimensional substructure "query," a ity, one could gain further insight by finding structures that set of atoms and a -description of the spatial relationship contain the pharmacophore but are structurally different between them, and to search for it in large data bases of from the compounds from which the pharmacophore was coordinates. The user can specify upper and lower bounds to derived. He described one of the first methods (MOLPAT) to selected distances, angles, and dihedral angles. Excluded search for pharmacophores in data bases of three- volumes (regions that are not allowed to be occupied) can dimensional coordinates. At that time, the usefulness of such also be taken into account. We can define several possible searches was limited since the three-dimensional data bases atom types for each query atom, making it possible to specify "generic" types (cations, hydrogen-bond donors, etc). The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" Abbreviations: CNS, central nervous system; ACE, angiotensin- in accordance with 18 U.S.C. §1734 solely to indicate this fact. converting enzyme. 8165 Downloaded by guest on October 2, 2021 8166 Pharmacology: Sheridan et al. Proc. Natl. Acad. Sci. USA 86 (1989) 3DSEARCH uses a two-part search strategy: a rapid screen descriptors defined by pairs of atoms and the distances using a key-search algorithm and a slower atom-by-atom between them. We applied an "inverted" key-indexing geometric search on the structures that pass the screen scheme, in contrast to the "direct" scheme described by (typically a few percent of the original list). The keys are others (10) using similar keys. In an inverted key scheme, the a c e93 ~~~~~111 ej 4.9 to 5.9 1 70 to 1 10 90 to 130 -v 4 0.4 to0.6 \ ) /0.9 to 1.1 3 4.5 to 5.5 1.1 1--2--3--4 -30 to -90 Protein volume represented by 122 outriggers. Atom Type Element Neighbors Pi H's Chg Atom Type Element Neighbors Pi H's Chg 1 1 DP 0 0 0 0 1 1 N 1 0 3 1 2 1 D6 0 0 0 0 2 N 2 0 2 1 3 N 3 0 1 1 3 1 N 3 0 1 1 4 N 4 0 0 1 5 N 3 1 0 1 4 1 DL 0 0 0 0 6 P 4 0 0 1 7 S 3 0 0 1 2 1 C 3 1 0 0 b 2 N WI 1 0 0 3 S Wi WI0 0 4 P Wi WI0 0 3 1 D5 0 0 0 0 2 D6 0 0 0 0 4 1 0 1 0 0 -1 2 0 1 1 0 -1 FIG. 1. Pharmacophores and queries derived from them. In the queries, all distances are given in angstroms and all angle/dihedral 5 constraints are given in degrees. The distances to dummy atoms (D) are determined by the arbitrary distance we used to generate dummy .0to 1.7 6.6 to 8.3 atoms in the coordinate data bases (ref. 7). In each case the possible allowed atom types for each of the query atoms are shown. A "Wi" ("wild card") means any value is allowed. Pi, pi electrons; H's, 3.1to5.1 2.8to4.8 attached hydrogens at physiological pH; Chg, formal charge; Neigh- bors, bonded atoms. For explanations of D5, D6, DP, and DL, see 88 to 148 \0.9 to 1.0 Methods. (a) CNS pharmacophore as proposed by Lloyd and An- drews (12). Shown on the top is the relationship of a basic tertiary 1-2--3-4 -135to-1800r 135to 180 amine to the phenyl ring in their "common model." Below is the 1--2-3--5 -90 to 90 query derived from this relationship. Atom 2 is the centroid of a flat 6-membered ring, atom 3 is the basic amine, atom 1 indicates the perpendicular to the ring, and atom 4 indicates the direction of the Atom Type Element Neighbors Pi H's Chg long pair on the amine. (b) The angiotensin-converting enzyme inhibitor pharmacophore proposed by Mayer et al. (14). A structure 1 1 S 1 o Wi Wi ofa semirigid inhibitor (15), with distances indicating the relationship 2 0 1 0 0 -1 between essential atoms, including the enzyme-bound Zn, is shown 3 0 1 1 0 -1 at the top. Below this is shown the pharmacophore derived from 10 2 1 N 2 1 0 0 distance geometry solutions of the inhibitor given those distances. 2 N 1 2 0 0 Atom 1 is a potential Zn ligand (sulfhydryl or carboxylate oxygen), 3 0 2 0 0 0 atom 2 is a neutral H-bond acceptor, atom 3 is an anion (deprotonated 4 0 1 1 0 0 sulfur or charged oxygen), atom 4 indicates the direction of a 5 F 1 0 0 0 hydrogen bond to atom 2, and atom 5 is the central atom of a carboxylate, sulfate, or phosphate of which atom 3 is an oxygen or 3 1 S 1 0 0 -1 an unsaturated carbon when atom 3 is a deprotonated sulfur.
Load more

Recommended publications
  • The Direct Effects of the Angiotensin-Converting Enzyme
    European Journal of Endocrinology (2006) 154 355–361 ISSN 0804-4643 EXPERIMENTAL STUDY The direct effects of the angiotensin-converting enzyme inhibitors, zofenoprilat and enalaprilat, on isolated human pancreatic islets Roberto Lupi, Silvia Del Guerra, Marco Bugliani, Ugo Boggi1, Franco Mosca1, Scilla Torri, Stefano Del Prato and Piero Marchetti Metabolic Unit, Department of Endocrinology and Metabolism, University of Pisa, Ospedale Cisanello, via Paradisa 2, 56100 Pisa, Italy and 1Transplant Unit, Department of Oncology, University of Pisa, Pisa, Italy, Menarini Ricerche SpA, Florence, Italy (Correspondence should be addressed to P Marchetti; Email: [email protected]) Abstract Objective: Data from prospective studies suggest a significant reduction in the risk of new diabetes from drug therapies containing angiotensin-converting enzyme (ACE) inhibitors. Since the renin–angio- tensin system (RAS) has been found locally in several tissues and cells, including pancreatic islets, we hypothesized that the positive metabolic effects of ACE inhibitors may be due to a beneficial action of these compounds on insulin-secreting b-cells. Design and methods: Isolated human pancreatic islets were studied after 24 h of incubation with 22.2 mmol/l glucose, with or without the presence in the incubation medium of 0.5–6.0 mmol/l zofe- noprilat or enalaprilat, ACE inhibitor drugs which differ by the presence of a sulphydryl or a carboxyl group in their structural formula. Functional and molecular studies were then performed to assess insulin secretion, redox balance, mRNA and protein expression. Results: Angiotensinogen, ACE and angiotensin type 1 receptor mRNA expression increased in islets cultured in high glucose; this was similarly prevented by the presence of either ACE inhibitor.
    [Show full text]
  • Angiotensin-Converting Enzyme (ACE) Inhibitors
    Angiotensin-Converting Enzyme (ACE) Inhibitors Summary Blood pressure reduction is similar for the ACE inhibitors class, with no clinically meaningful differences between agents. Side effects are infrequent with ACE inhibitors, and are usually mild in severity; the most commonly occurring include cough and hypotension. Captopril and lisinopril do not require hepatic conversion to active metabolites and may be preferred in patients with severe hepatic impairment. Captopril differs from other oral ACE inhibitors in its rapid onset and shorter duration of action, which requires it to be given 2-3 times per day; enalaprilat, an injectable ACE inhibitor also has a rapid onset and shorter duration of action. Pharmacology Angiotensin Converting Enzyme Inhibitors (ACE inhibitors) block the conversion of angiotensin I to angiotensin II through competitive inhibition of the angiotensin converting enzyme. Angiotensin is formed via the renin-angiotensin-aldosterone system (RAAS), an enzymatic cascade that leads to the proteolytic cleavage of angiotensin I by ACEs to angiotensin II. RAAS impacts cardiovascular, renal and adrenal functions via the regulation of systemic blood pressure and electrolyte and fluid balance. Reduction in plasma levels of angiotensin II, a potent vasoconstrictor and negative feedback mediator for renin activity, by ACE inhibitors leads to increased plasma renin activity and decreased blood pressure, vasopressin secretion, sympathetic activation and cell growth. Decreases in plasma angiotensin II levels also results in a reduction in aldosterone secretion, with a subsequent decrease in sodium and water retention.[51035][51036][50907][51037][24005] ACE is found in both the plasma and tissue, but the concentration appears to be greater in tissue (primarily vascular endothelial cells, but also present in other organs including the heart).
    [Show full text]
  • Lisinopril (Ethics) Lisinopril Tablets 5 Mg, 10 Mg, 20 Mg
    New Zealand Data Sheet Lisinopril (Ethics) Lisinopril Tablets 5 mg, 10 mg, 20 mg 1. NAME OF THE MEDICINAL PRODUCT LISINOPRIL (Ethics) 5 mg, tablet LISINOPRIL (Ethics) 10 mg, tablet LISINOPRIL (Ethics) 20 mg, tablet 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Lisinopril (Ethics) tablets come in three strengths and contain lisinopril dihydrate equivalent to 5 mg, 10 mg or 20 mg lisinopril. 3. PHARMACEUTICAL FORM 5 mg tablet: A light pink coloured, circular, biconvex uncoated tablet. The tablet has a break line and is embossed with ‘5’ on one side and embossed with ‘BL’ on the other side. 10 mg tablet: A light pink coloured, circular, biconvex uncoated tablet. The tablet is embossed with ‘10’ on one side and embossed with ‘BL’ on the other side. 20 mg tablet: A pink, circular, biconvex uncoated tablet. The tablet is embossed with ‘20’ on one side and embossed with ‘BL’ on the other side. Lisinopril dihydrate. The chemical name for lisinopril dihydrate is N-[N-[(1S)-1-carboxy-3- phenylpropyl]-L-lysyl]-L-proline dihydrate. Its structural formula is: C21H31N3O5.2H2O, Molecular weight: 441.53, CAS No.: 83915-83-7 Lisinopril dihydrate is a white to off-white crystalline powder that is soluble in water, sparingly soluble in methanol and practically insoluble in ethanol. A synthetic peptide derivative, lisinopril dihydrate is an oral long acting angiotensin converting enzyme inhibitor. It is a lysine analogue of enalaprilat (active metabolite of enalapril). 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Lisinopril is indicated in the treatment of essential hypertension and in renovascular hypertension. It may be used alone or concomitantly with other classes of antihypertensive agents.
    [Show full text]
  • Enalaprilat Injection Has Been Used Concomitantly with Digitalis, Beta
    EN-2436 EN-2436 Enalaprilat Injection, USP Enalaprilat Injection, USP Rx only Rx only USE IN PREGNANCY When used in pregnancy during the second and third trimesters, ACE inhibitors can cause injury and even death to the developing fetus. When pregnancy is detected, Enalaprilat Injection, USP should be discontinued as soon as possible. See WARNINGS, Fetal/Neonatal Morbidity and Mortality. DESCRIPTION Enalaprilat Injection, USP is a sterile aqueous solution for intravenous administration. Enalaprilat is an angiotensin converting enzyme inhibitor. It is chemically described as (S)-1-[N-(1-carboxy-3-phenylpropyl)-L-alanyl]-L-proline Hospira, Inc., Lake Forest, IL 60045 USA USA 60045 IL Forest, Lake Inc., Hospira, dihydrate. Its molecular formula is C18H24N2O5 • 2H2O and its structural formula is: Printed in USA USA in Printed Enalaprilat is a white to off-white, crystalline powder with a molecular weight of 384.43. It is sparingly soluble in methanol and slightly soluble in water. Each milliliter contains 1.25 mg enalaprilat (anhydrous equivalent); sodium chloride to adjust tonicity; benzyl alcohol, 9 mg, added as a preservative. May contain sodium hydroxide for pH adjustment. CLINICAL PHARMACOLOGY Enalaprilat, an angiotensin-converting enzyme (ACE) inhibitor when administered intravenously, is the active metabolite of the orally administered pro-drug, enalapril maleate. Enalaprilat is poorly absorbed orally. Mechanism of Action Intravenous enalaprilat, or oral enalapril, after hydrolysis to enalaprilat, inhibits ACE in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion.
    [Show full text]
  • Different Effects of Imidapril and Enalapril on Aminopeptidase P Activity in the Mouse Trachea
    243 Hypertens Res Vol.28 (2005) No.3 p.243 Original Article Different Effects of Imidapril and Enalapril on Aminopeptidase P Activity in the Mouse Trachea Koh-ichi SAKAMOTO, Koh-ichi SUGIMOTO, Toshiaki SUDOH, and Akio FUJIMURA It has been reported that the incidence of angiotensin-converting enzyme (ACE) inhibitor-related dry cough is significantly less with the ACE inhibitor imidapril than with the ACE inhibitor enalapril in hypertensive patients. Bradykinin (BK) in the trachea is believed to play some role in this adverse effect. The present study was undertaken to evaluate the effects of imidapril and enalapril on the activity of aminopeptidase P (APP), one of the BK-metabolizing enzymes, in the mouse trachea. Imidapril (0.5 mg/kg) or enalapril (0.5 mg/ kg) was given orally to mice once daily for 7 days. Drug concentrations and APP activity in the trachea were determined at the end of the experiment. Active metabolites (imidaprilat and enalaprilat), but not parent drugs (imidapril and enalapril) were detected in the trachea after a repeated dose for 7 days. Tissue con- centrations of imidaprilat and enalaprilat did not significantly differ. The APP activity in the trachea did not significantly change after the 7th dose of imidapril. However, the enzyme activity was significantly inhibited after the final dose of enalapril. Thus, the present study showed that enalapril, but not imidapril inhibited the airway APP activity during repeated dosing. This finding is compatible with previous reports that the incidence of dry cough is lower with imidapril than with enalapril, and with the hypothesis that the dry cough induced by ACE inhibitors may be related to accumulation of BK in the trachea.
    [Show full text]
  • July-August 2010 Volume 32 No
    The News Magazine of the International Union of Pure and Applied Chemistry (IUPAC) CHEMISTRY International July-August 2010 Volume 32 No. 4 Analogue-Based Drug Design Understanding Climate Change Chemistry 2.0 From the Editor CHEMISTRY International hile joking over our iconic “C” logo for the 2011 International Year The News Magazine of the International Union of Pure and Wof Chemistry, a friend of mine suggested that the “C” should be Applied Chemistry (IUPAC) for Communication. “Yes,” I replied, and from there we went on debating the many communication challenges we all experience in our professional www.iupac.org/publications/ci and personal worlds. We agreed that most chemists are not at the forefront of exploiting Managing Editor: Fabienne Meyers communication opportunities readily available Production Editor: Chris Brouwer in the online world. Fortunately, we noted, Design: pubsimple there are “explorer chemists” out there who do adapt selected technologies, which then All correspondence to be addressed to: percolate into our world, bringing unforeseen Fabienne Meyers benefits to how we do things. It may be true IUPAC, c/o Department of Chemistry that other scientific communities embrace Boston University new tools much faster, but in the end, I am Metcalf Center for Science and Engineering sure we will get there. A new generation of chemists will undoubtedly 590 Commonwealth Ave. bring along new tools, some transferred from other social contexts. Boston, MA 02215, USA The discussion changed course when we realized that there are many folks, including specialists in communication, who are very inter- E-mail: [email protected] ested in the behavior of chemists and their challenges in communicat- Phone: +1 617 358 0410 ing.
    [Show full text]
  • Aliskiren, a Novel Oral Renin Inhibitor, Provides Dose-Dependent Efficacy and Placebo-Like Tolerability in Japanese Patients
    997 Hypertens Res Vol.29 (2006) No.12 p.997-1005 Original Article Aliskiren, a Novel Oral Renin Inhibitor, Provides Dose-Dependent Efficacy and Placebo-Like Tolerability in Japanese Patients with Hypertension Toshio KUSHIRO1), Hiroshige ITAKURA2), Yoshihisa ABO3), Hiromi GOTOU4), Shinji TERAO5), and Deborah L. KEEFE6) Aliskiren is a novel orally active renin inhibitor for the treatment of hypertension. This study evaluated the antihypertensive efficacy, safety and tolerability of aliskiren in Japanese patients with hypertension. Forty hundred and fifty-five Japanese men and women with a mean sitting diastolic blood pressure of 95–110 mmHg were randomized to receive once-daily double-blind treatment for 8 weeks with aliskiren 75, 150 or 300 mg or placebo. Aliskiren produced significant, dose-dependent reductions in mean sitting diastolic blood pressure (p<0.0005 vs. placebo for each dose) and mean sitting systolic blood pressure (p<0.001 vs. placebo for each dose). The placebo-corrected reductions in mean sitting systolic/diastolic blood pressure were 5.7/4.0, 5.9/4.5 and 11.2/7.5 mmHg in the aliskiren 75, 150 and 300 mg groups, respectively. After 8 weeks’ treatment, 27.8%, 47.8%, 48.2% and 63.7% of patients in the placebo and aliskiren 75, 150 and 300 mg groups, respectively, achieved a successful treatment response (diastolic blood pressure <90 mmHg and/or reduced by ≥10 mmHg from baseline; p<0.005 vs. placebo for each dose). Aliskiren treatment was well tolerated, with the incidence of adverse events reported in the active treatment groups (53–55%) being similar to that in the placebo group (50%).
    [Show full text]
  • Potential Chemical Contaminants in the Marine Environment
    Potential chemical contaminants in the marine environment An overview of main contaminant lists Victoria Tornero, Georg Hanke 2017 EUR 28925 EN This publication is a Technical report by the Joint Research Centre (JRC), the European Commission’s science and knowledge service. It aims to provide evidence-based scientific support to the European policymaking process. The scientific output expressed does not imply a policy position of the European Commission. Neither the European Commission nor any person acting on behalf of the Commission is responsible for the use that might be made of this publication. Contact information Name: Victoria Tornero Address: European Commission Joint Research Centre, Directorate D Sustainable Resources, Water and Marine Resources Unit, Via Enrico Fermi 2749, I-21027 Ispra (VA) Email: [email protected] Tel.: +39-0332-785984 JRC Science Hub https://ec.europa.eu/jrc JRC 108964 EUR 28925 EN PDF ISBN 978-92-79-77045-6 ISSN 1831-9424 doi:10.2760/337288 Luxembourg: Publications Office of the European Union, 2017 © European Union, 2017 The reuse of the document is authorised, provided the source is acknowledged and the original meaning or message of the texts are not distorted. The European Commission shall not be held liable for any consequences stemming from the reuse. How to cite this report: Tornero V, Hanke G. Potential chemical contaminants in the marine environment: An overview of main contaminant lists. ISBN 978-92-79-77045-6, EUR 28925, doi:10.2760/337288 All images © European Union 2017 Contents Acknowledgements ................................................................................................ 1 Abstract ............................................................................................................... 2 1 Introduction ...................................................................................................... 3 2 Compilation of substances of environmental concern .............................................
    [Show full text]
  • Beta Blocker and Blood Pressure Medication Guidelines
    Beta Blocker and Blood Pressure Medication Guidelines Beta Blockers Please take this medication as normally scheduled, even on the morning of surgery with a small sip of water, unless otherwise instructed by your surgeon. Acebutolol Bystolic InnoPran XL Metoprolol Tartrate/HTZ Propranolol/HTZ Toprol Atenolol Carteolol Kerlone Nadolol Sectral Toprol XL Atenolol/chlorthalidone Cartrol Labetalol Nadolol/bendroflumethiazide Sorine Trandate Betagan Carvediolol Levatol Nebivolol Sotalol Trandate HCL Betapace Coreg Levobetaxolol Nebivolol HCL Sotalol HCL Visken Betapace AF Corgard Levobunolol Nebivolol Hydrochloride Tenoretic Zebeta Betaxolol Corzide Lopressor Normodyne Tenormin Ziac Bisoprolol Esmolol Lopressor HCT Penbutolol Tenormin IV Bisoprolol/fumurate Inderal Lopressor HTZ Pindolol Timolide Bisoprolol/HTZ Inderal LA Metapranolol Propranolol Timolol Blocardren Inderide Metoprolol Propranolol HCL Timolol Maleate/HTZ Brevibloc Inderide LA Metoprolol/HTZ Propranolol Hydrochloride Timolol/ HTZ Ace Inhibitors (ACEI) Please DO NOT take this medication on the morning of surgery unless otherwise instructed by your surgeon. Accupril Enalapril maleate/diltiazem Lotensin HCT Prinzide Uniretic Accuretic Enalapril maleate/HCT Lotrel Quinapril Univasc Aceon Enalapril diltiazem Mavik Quinapril HCL Vaseretic Altace Enalapril/felodipine Moexipril Quinapril HCL/HCT Vasotec Benazepril Enalapril/HCT Moexipril HCL Quinapril HCT Zestoretic Benazepril/amlodipine Enalaprilat Moexipril HCL/HCT Quinaretic Zestril Benazepril HCL Fosinopril Moexipril HCT Ramipril
    [Show full text]
  • Pharmachologic Treatment of Hypertension
    Robert C Orchard MD Types of Hypertension Essential Secondary A disorder of unknown origin affecting the Secondary to other disease processes Blood Pressure regulating mechanisms **************************************************** Environmental Factors Stress Na+ Intake Obesity Smoking Normal Blood Pressure Regulation ! Hydraulic equation: Blood Pressure = Cardiac output (CO) X Resistance to passage of blood through precapillary arterioles (PVR) ! Physiologically CO and PVR is maintained minute to minute by – arterioles (1) postcapillary venules (2) and Heart (3) ! Kidney is the fourth site – volume of intravascular fluid ! Baroreflex, humoral mechanism and renin-angiotensin- aldosterone system regulate the above 4 sites ! Local agents like Nitric oxide ! In hypertensives – Baroreflex and renal blood-volume control system – set at higher level ! All anti-hypertensives act via interfering with normal mechanisms Antihypertensive Drugs ! Diuretics: ! Thiazides: Hydrochlorothiazide, chlorthalidone ! High ceiling: Furosemide ! K+ sparing: Spironolactone,eplerenone, triamterene and amiloride MOA: Acts on Kidneys to increase excretion of Na and H2O – decrease in blood volume – decreased BP ! Angiotensin-converting Enzyme (ACE) inhibitors: ! Captopril, lisinopril., enalapril, ramipril, fosinopril etc MOA: Inhibit synthesis of Angiotensin II – decrease in peripheral resistance and blood volume ! Angiotensin (AT1) blockers: ! Losartan, candesartan, valsartan, telmisartan etc MOA: Blocks binding of Angiotensin II to its receptors Antihypertensive
    [Show full text]
  • AHRQ%Systematic%Review%Surveillance% Program%
    AHRQ%Systematic%Review%Surveillance% Program% " CER$#34:$Angiotensin"Converting"Enzyme"Inhibitors" (ACEIs),"Angiotensin"II"Receptor"Antagonists"(ARBs)," and"Direct"Renin"Inhibitors"for"Treating"Essential" Hypertension"–"An"Update"" $ $ Original$Release$Date:$June"2011""" Surveillance$Report$Date:$March"2016"" $ Summary$of$Key$Findings$from$Surveillance$ Report:$ 1)" Key"Question"1:"Conclusions"on"the"effectiveness"of"the"ACEIs" and"ARBs"included"in"the"original"systematic"review"are"likely" current."However,"one"new"RCT"found"that"the"ARB"azilsartan"–" approved"after"the"original"systematic"review"was"published,"may" be"more"effective"than"ramipril"(ACEI)"at"improving"systolic"BP."In" addition,"one"new"RCT"found"that"aliskiren"(DRI)"and"irbesartan" (ARB)"had"similar"effects"on"glucose"and"lipid"profiles."No" evidence"had"previously"been"identified."Finally,"while"the"original" review"found"no"evidence"comparing"ACEIs"or"ARBs"on" progression"to"type"II"diabetes,"we"identified"one"retrospective" cohort"study"which"found"a"lower"risk"of"type"II"diabetes"onset" associated"with"candesartan"(ARB)"as"compared"to"enalapril" (ACEI)."All"other"conclusions"are"likely"current.""" 2)" Key"Question"2:"Conclusions"on"withdrawal"rates"due"to"adverse" events"associated"with"the"ACEIs"and"ARBs"included"in"the" original"systematic"review"are"likely"current."However,"we" identified"an"RCT"examining"the"new"ARB"azilsartan,"which"found" lower"withdrawal"rates"associated"with"azilsartan"as"compared"to" ramipril"(ACEI)."All"other"conclusions"are"likely"current."Of"note,"
    [Show full text]
  • Beta Blockers and Blood Pressure Medication Guidelines 11/2014
    Beta Blocker and Blood Pressure Medication Guidelines Beta Blockers Please take this medication as normally scheduled, even on the morning of surgery with a small sip of water, unless otherwise instructed by your surgeon. Acebutolol Bystolic InnoPran XL Metoprolol Tartrate/HTZ Propranolol/HTZ Toprol Atenolol Carteolol Kerlone Nadolol Sectral Toprol XL Atenolol/chlorthalidone Cartrol Labetalol Nadolol/bendroflumethiazide Sorine Trandate Betagan Carvediolol Levatol Nebivolol Sotalol Trandate HCL Betapace Coreg Levobetaxolol Nebivolol HCL Sotalol HCL Visken Betapace AF Corgard Levobunolol Nebivolol Hydrochloride Tenoretic Zebeta Betaxolol Corzide Lopressor Normodyne Tenormin Ziac Bisoprolol Esmolol Lopressor HCT Penbutolol Tenormin IV Bisoprolol/fumurate Inderal Lopressor HTZ Pindolol Timolide Bisoprolol/HTZ Inderal LA Metapranolol Propranolol Timolol Blocardren Inderide Metoprolol Propranolol HCL Timolol Maleate/HTZ Brevibloc Inderide LA Metoprolol/HTZ Propranolol Hydrochloride Timolol/ HTZ Ace Inhibitors (ACEI) Please DO NOT take this medication on the morning of surgery unless otherwise instructed by your surgeon. Accupril Enalapril maleate/diltiazem Lotensin HCT Prinzide Uniretic Accuretic Enalapril maleate/HCT Lotrel Quinapril Univasc Aceon Enalapril diltiazem Mavik Quinapril HCL Vaseretic Altace Enalapril/felodipine Moexipril Quinapril HCL/HCT Vasotec Benazepril Enalapril/HCT Moexipril HCL Quinapril HCT Zestoretic Benazepril/amlodipine Enalaprilat Moexipril HCL/HCT Quinaretic Zestril Benazepril HCL Fosinopril Moexipril HCT Ramipril
    [Show full text]