Instant digital products (PDF, ePub, MOBI) ready for you
Download now and discover formats that fit your needs...
Goodman and Gilman’s The Pharmacological Basis of Therapeutics, 13th Edition (Goodman and Gilman’S the Pharmacological Basis of Therapeutics) 13th Edition, (Ebook PDF)
No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions
This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).
Notices
Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary.
Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility.
To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein.
Library of Congress Cataloging-in-Publication Data
A catalog record for this book is available from the Library of Congress
British Library Cataloguing-in-Publication Data
A catalogue record for this book is available from the British Library
ISBN: 978-0-323-90903-7
For information on all Academic Press publications visit our website at https://www.elsevier.com/books-and-journals
Publisher: Stacy Masucci
Acquisitions Editor: Katie Chan
Editorial Project Manager: Sara Pianavilla
Production Project Manager: Punithavathy Govindaradjane
Cover Designer: Christian Bilbow
Typeset by STRAIVE, India
The illustration shows three legendary figures in medicine (from left to right): Apollo holding a bow, Aesculapius holding a serpent-entwined staff, and Hippocrates holding a skull and all three examining a poppy plant. Putti at the steps hold Materia Medica and a box of various chemicals, while the section on the right shows drugs being produced in the laboratory. Oil painting by Johannes Prey (c. 1791 CE) from Wellcome Collection. https://wellcomecollection.org/works/ju4rytva
Dedication
To my parents, Sara and Kay, for the trail
To my wife Jo and son Barrett for the journey
9.
Opioids
9.1
9.1.2
6.
6.1
6.2
7.
7.1
7.2
8.1
9.3.7 Buprenorphine
9.3.8 Nalorphine
9.3.9 Naloxone
9.3.10 Naltrexone
9.4.1 Extended release
9.4.2 Abuse deterrent
9.4.3 PAMORA
9.4.4 Novel synthetics
9.5 Milestones in opioid synthesis
9.6 Synopsis
Part V Molecular basics
10. Receptors
10.1 Overview
10.1.1 Discovery
10.1.2 Receptor diversity
10.1.3 Opioid genes
10.2 Endogenous opioid peptides
10.3 Opioid receptor terminology
10.4 Ligand characteristics
10.4.1 Message-address sequence
10.4.2 Agonist/antagonist
10.5 Receptor structure
10.5.1 Structural basics
10.5.2 Binding pocket
10.5.3 Orthosteric and allosteric sites
10.6 Kinetics of conformational changes
10.7 Distribution of opioid receptors
10.7.1 Central distribution
10.7.2 Peripheral distribution
10.8 Milestones
11. Effectors
11.1 Overview 125
11.2 Heterotrimeric G proteins 125
11.2.1 Structure 125
11.2.2 Basal coupling with GPCR 126
11.3 G protein/GPCR complex 126
11.3.1 Activation 126
11.3.2 Termination of action 127
11.4 G protein-dependent pathways 127
11.4.1 Adenylyl cyclase and Gα pathways 128
11.4.2 Effectors of Gβγ subunit 129
11.5 G protein-independent pathways 130
11.5.1 Structure of arrestins 130
11.5.2 Arrestin-mediated pathways 131
11.5.3 Receptor trafficking 132
11.6 Molecular mechanisms of opioid effects 132
11.6.1 Gα effects 133
11.6.2 Gβγ effects 133
11.6.3 Arrestin effects 133
11.6.4 Heterologous sensitization 133
11.6.5 Effector pathways database 134
14. Adverse effects
Part VI
12. Metabolism
12.1 Overview
12.1.1 Receptor-specific functions
12.1.2 Systemic effects
12.1.3 Supraspinal effects
12.1.4 Spinal and peripheral effects
12.2 Opioid metabolism
12.2.1 Absorption
12.2.2 Distribution
12.2.3 Metabolism
13. Analgesia
16. Advances and prospects
Part VII
Therapeutic utility
15. Uses and issues
15.1 Opioids in therapeutics
15.2 Therapeutic principles
15.2.1
15.2.2
15.4.1 Perioperative use
15.4.2 Nonsurgical use
15.5 Chronic pain
15.5.1 Taxonomy
15.5.2
15.5.3 Chronic noncancer pain
15.6 Opioid use disorder
15.6.1 Taxonomy
15.6.2 Medical use of opioids
15.6.3 Nonmedical use of opioids
15.6.4 Treatment of dependence
15.6.5 Guidelines
16.5.2 Modification of endogenous opioids
16.5.3 Multifunctional ligands
16.5.4 Allosteric modulation
16.5.5 Biased agonism
16.5.6 Nonopioid receptor targets
16.5.7 Receptor-independent selective
About the Author
Vasantha K. Kumar, MD, completed medical school at Madurai Medical College, Madurai, India, and served for five years as Captain in Army Medical Corps. After this tenure, he earned MD in Aerospace Medicine in 1986 from the Indian Air Force Institute of Aerospace Medicine, Bangalore, India. He was National Research Council Research Fellow at NASA Johnson Space Center, Houston, Texas, from 1988 to 1990 and conducted human trials on decompression sickness supporting extravehicular activities for the Space Shuttle program. He continued this research as Supervisor of Environmental Physiology Laboratory with a subcontractor at NASA Johnson Space Center, Houston, Texas, until 1996. He later completed an anesthesiology residency at the University of Texas, Galveston, Texas, in 2000 and a pain medicine fellowship
at the University of Cincinnati, Cincinnati, Ohio, in 2001. Since then, he has practiced comprehensive pain care in various clinical settings.
Dr. Kumar has authored or presented more than 70 papers on topics such as decompression sickness, historical perspectives, and chronic pain. He was awarded the “Silver Snoopy” medal in 1996 by NASA astronauts for his contribution to the Space Shuttle program. He also served on the Editorial Board of the journal Aviation, Space, and Environmental Medicine between 1996 and 1998. He is Board Certified in Anesthesiology and Pain Medicine from the American Board of Anesthesiology and a member of several professional organizations. In addition to his professional activities, Dr. Kumar has a special interest in historical biographies and epistemology.
Preface
Those about to study medicine, and the younger Physicians, should light their torches at the fires of the Ancients.
Carl von Rokitansky (c. 1846 CE)
Opium has always held a polysemic relationship and significance in society. One of the earliest known drugs in the history of humanity, its use has spanned contexts, cultures, and continents across the globe. From the earliest find in the funerary sites of Europe, it has proven to be a dominant sociocultural factor in medicine, geopolitics, and economy. Cautiously advocated by Hippocrates and ardently favored by great minds such as Galen, Avicenna, and Paracelsus, and commodified by colonial interests, opium has always evoked dualistic attributes of remedy and poison in history.
After Serturner’s discovery of morphine almost 200 years ago, unbridled enthusiasm and use resulted in the first opioid epidemic during the Industrial Age. Global antiopium movement of this period assigned stricter controls and limited use of opioids in medicine. Since then, a quest for enhancing remedial effects of opium poppy has thrust research on poppy and its products to a higher level, unimagined by polymaths of the bygone era. Our comprehension of the plant and its potential has grown leaps and bounds over the past century, and it is difficult to keep pace with the flood of information. However, the use of opioids for chronic pain in the 20th century, in its characteristic dualism, has either endorsed or queried its use during the current opioid epidemic.
Aware of public health emergency during the current opioid epidemic, I focused on doing the right thing by implementing guidelines proffered by medical societies and regulatory bodies that I only vaguely acknowledged historical events. About 5 years ago, I stumbled upon a book that was tucked behind the counter in a dingy little bookstore at the airport, where I was waiting for my flight home. The book that piqued my interest, A Concise History of Hong Kong by John Carroll (Rowman & Littlefield Publishers, Inc., 2007), recounts the history of Hong Kong Island from its tumultuous founding to its emergence as a major financial center of the East. I was thrilled with what the book had
to offer and sat wide-eyed through the long flight. I was fascinated, but nescient, about the turn of events in the glorious age of sail and the ignominious basis for this critical piece of history—opium. It was a fortuitous moment, as it set me on a quest to learn and retell the history of poppy as it was scripted over the years.
Many therapeutic dilemmas posed by opioid use during the current epidemic are not new, as these issues have challenged physicians for centuries. Ironically, several factors that led to the first opioid epidemic of the Industrial Age share common features with the second opioid epidemic of modern times. However, we missed the opportunity to learn from historical works and events while getting mired in details of the current opioid epidemic. As I waded through historical documents on opium, I realized that history has the answers to provide perspectives for research, therapeutics, and policy-making for the future.
I must admit that I am neither a historian nor a linguist, and my medical training stopped short of educating me on drugs, “guidelines,” and how to use them in practice. This book is an effort to bridge history and therapeutics. This book trails poppy from prehistory to present history, as advocated, analyzed, and advanced by the great minds in medicine. As such, it is a synthesis of botany, chemistry, physiology, and molecular biology interlaced with historical vignettes in the spirit of great encyclopedists before me.
What started as a venture of self-education in history led to a more complex palimpsest that poppy truly is. I have attempted to present readers with a comprehensive knowledge base on opium poppy, starting with the plant, its history, commerce, medical use, current status, and future perspectives. It is my fervent hope that this endeavor serves as a resource for anyone wishing to explore the world of opium poppy or at least awakens interest in history as it has done for me.
Proceed then as you have begun.
Robert Brady (c. 1670 CE) in “Epistle to Thomas Sydenham”
Vasantha K. Kumar Columbus, OH, United States
Acknowledgments
This work is a tribute to the deliberations of numerous protagonists and adversaries, struggles of transcribers and glossators, and trials and labors of those researchers on opium throughout history. Pictures tell stories better than words, and I would like to acknowledge the contribution by public domain figures and open source articles from the United States National Library of Medicine, RCSB Protein Data Bank, GPCRdb, Reactome, Wikimedia,
Wellcome Collection, and numerous other institutions. All illustrations in this book are by the author, unless otherwise indicated. This compilation is a work of passion and personal endeavor, and the author received no financial support for research, authorship, graphics, drafting, and/or publication of this book. Particular thanks are due to my team at Elsevier for bringing this project to fruition.
Plant Part I
Chapter 1
Botanical aspects
And he bowed his head to one side like a poppy that in a garden is laden with its fruit and the rains of spring.
Homer in Iliad (c. 630 BCE)
1.1 Plant
1.1.1
Overview
Plants included in the family Papaveraceae are a group of herbaceous flowering plants found primarily in the Northern Hemisphere, which prefer a temperate climate and have more than 100 subspecies. However, Papaver (Latin: poppy) is also cultivated in some tropical areas in the Southern Hemisphere. Many varieties grow in the wild, including Poppy of Troy, Papaver setigerum (Latin: bristly), some plants like Papaver rhoeas (Greek: red or to fall) are grown for ornamental purposes, and Papaver somniferum (Greek: to induce sleep) is the only species acclaimed as a distinctive medicinal plant for pain relief and maligned as the source of addictive drug all over the world.
1.1.2 Cultivation
Papaver is a self-pollinating, multipurpose species. It is a valuable food source for humans and also serves as animal fodder (Bernath, 1998; Duke, 1983; Kapoor, 1995; Lim, 2013). It has a glaucous stem, sessile leaves with dentate margins with peduncle, and drooping buds (Fig. 1.1). Poppy flowers come in various shades of color, including white, pink, violet, and red.
After poppy blooms, leaves fall within a week, and a poppy pod or a capsule with its characteristic calyces forms a prominent part of the plant (Fig. 1.2). The capsule size may vary depending on the cultivar and geographical distribution, from broad oval to cylindrical.
Poppy seeds are the most edible part of the plant and kidney shaped and also vary in color from gray, white to blue. They are usually harvested after the poppy capsule has dried out, and they are used as a food additive to
provide texture, flavor, and caloric value (100 g of poppy seeds provides approximately 500 cal). The seeds contain linoleic acid (up to 60%) and are a great source of calcium, niacin, thiamine, and tocopherols (Knutsen et al., 2018). Poppy seed oil can be used without refining for cooking, lubrication, or lamps, where they burn longer and cleaner than olive oil. Poppy seed oil is expensive; its production slowly reduced in the late 18th century, after which it was completely stopped.
The vegetation period of cultivated poppy varies from region to region, from 120 to 250 days, based on agrotechnical methods used and whether sown in spring or fall. It is usually cultivated by the end of the rainy season in Southeast Asia (Fig. 1.3). Usually, about a pound of poppy seeds is required to sow one acre of land (Drug Enforcement Administration (DEA), 1992)
Six distinct developmental stages are observed in the growth of poppy (Bernath, 1998; Duke, 1983; Lim, 2013):
Phase 1: Embryo phase, when seeds are in the soil or dormant (for up to 6 years).
Phase 2: Germination phase, when first leaves appear (15–20 days).
Phase 3: Leaf rosette phase, the longest stage of leaf formation (50–60 days for summer varieties and 180–220 days for winter varieties).
Phase 4: Branching phase, lasts until blossoming (20–30 days).
Phase 5: Blossoming and capsule formation phase, when flowers bloom briefly for a day and green capsules take another 10 days to mature (20–30 days).
Phase 6: Capsule ripening is the final phase when dry, rattling poppy capsules are ready for seed harvesting (15–25 days).
All phases of growth require careful tendering to ensure good capsule formation and may be adversely affected at any stage by environmental factors such as light, temperature, and moisture (Bernath, 1998). However, it is labor-intensive once the capsule forms and is ready for tapping.
Handbook on Opium. https://doi.org/10.1016/B978-0-323-90903-7.00018-1
FIG. 1.1 Poppy plant. Parts of Papaver somniferum by Otto Thome (c. 1885 CE) including A, leaves; 1, longitudinal section of flower; 2, stamen; 3, pistil; 4, cross-section of ovary; 5, poppy capsule; 6, poppy seeds. (Credit: Thome, O. W. (1885) from Wikimedia. https://commons. wikimedia.org/wiki/File:Illustration_Papaver_somniferum0.jpg.)
FIG. 1.2 Green poppy capsule. Capsules may vary from oval to cylindrical in shape. (Credit: Pixabay. https://pixabay.com/photos/ poppy-poppy-capsules-seeds-2502046/.)
1.2 Latex
1.2.1 Laticifers
Laticifers are an elongated, anastomosing network of cells found in the cortex of the entire poppy plant from roots to the capsule (Bird, Franceschi, & Facchini, 2003; Liscombe & Facchini, 2008; Mahlberg, 1993). In the capsule, laticifers are found within 2–4 cm of capsular surface (Fig. 1.4). These laticifers are formed by resorption and coalescence of cell walls, resulting in an elongated tubular system running throughout the plant.
It has been shown that biosynthetic enzymes are synthesized in companion cells. They are then transported to sieve elements where alkaloid biosynthesis occurs. Alkaloids of poppy are stored as latex in vacuoles (Fig. 1.5), formed from localized dilatation of endoplasmic reticulum within the laticifer networks (Bercu, 2012; Lee, Hagel, & Facchini, 2013; Liscombe & Facchini, 2008). Latex particles of opium alkaloids are suspended in these vacuoles (Fig. 1.6) and located just below the capsular surface (Beaudoin & Facchini, 2014; Griffing & Nessler, 1989; Nessler, Allen, & Galewsky, 1985; Nessler & Mahlberg, 1976).
Modern techniques, such as immunofluorescent labeling, have enabled us to identify key enzymes in the biosynthesis of opium alkaloids. Furthermore, molecular genetic techniques have aided in cell-specific localization of alkaloid synthesis in Papaver somniferum (Beaudoin & Facchini, 2014; Chalise, 2015; Liscombe & Facchini, 2008).
Results of these studies showed that synthesis of alkaloids of poppy occurs in the adjacent companion cells and sieve elements and then they accumulate in laticifers (Bird et al., 2003; Harvest, 2011; Weid, Ziegler, & Kutchan, 2004). It is difficult to produce morphine in Papaver somniferum cell cultures, possibly due to the absence of a naturally occurring laticifer system in cultured cells (Bird et al., 2003). Multiple levels of regulation exist in the synthesis of alkaloids from naturally occurring amino acid l-tyrosine in the plant. Details of morphine synthesis are dealt with in another section (please refer to Section 8.3).
Box 1.1 Laticifer
Marcello Malpighi (1628–1694 CE), a renowned Italian physician biologist (Fig. 1.7), called the milky latex exudate of plants “vasa propria.” His contemporary Nehemiah Grew (1641–1712 CE), an English physician and the “Father of Plant Anatomy” (Fig. 1.8), used a microscope to describe the structure of the laticiferous system in plants, which contain the milky sap, and also noted that this exudate coagulated (like blood) after extraction from the plant (Arber, 1941).
Land Prep Ger mina tion 15 days
RAINY SEASON
COLD SEASON
Leaf Rosette 60 days Branching 30 days Flowering 30 days Capsule forma tion & ripening 30 days
FIG. 1.3 From cotyledons to capsules. Duration of each stage of growth varies depending on the subspecies, region, and environmental factors.
FIG. 1.4 Laticifers in poppy plant. Cross section of phloem shows pairing of laticifers (yellow), sieve elements, and companion cells (red) in aerial parts, compared with roots of poppy. (With permission from Liscombe, D., & Facchini, P. (2008). Elsevier. https://doi.org/10.1016/j.copbio.2008.02.012.)
1.2.2 Capsule
Latex juice is found in all parts of the poppy plant, with the highest concentration in the capsule, while its presence is negligible or absent in seeds (Knutsen et al., 2018). Latex juice containing psychoactive alkaloids increases in concentration as the capsule matures in the final phase (Fig. 1.9). Final alkaloid concentration is influenced by a host of environmental factors, including ambient light, water supply, temperature after flowering, nutrients, infection by fungi, and enzymatic degradation (Bernath, 1998).
phloem xylem phloem
xylem
Cur rent Opinion in Biotechnology
FIG. 1.5 Cross section of laticifer in poppy. Enzymes are synthesized in companion cells (cc), transported to sieve elements (se) for alkaloid synthesis and stored in laticifers (la) in phloem parenchyma (pp). Other structures shown include vascular cambium (vc) and xylem vessels (xy) in xylem parenchyma (xp). (From Lee, E., Hagel, J. M., & Facchini, P. J. (2013). https://doi.org/10.3389/fpls.2013.00182.)
FIG. 1.6 Electron micrograph of laticifer. Alkaloids of poppy are seen suspended within vesicles (v) in the sieve (s) tubules. (With permission from Nessler, C. L., Allen, R. D., & Galewsky, S. (1985). https://doi. org/10.1104/pp.79.2.499 )
FIG. 1.7 Marcello Malpighi. He was the first to describe the milky sap of plants. (Credit: Wellcome Collection. https://wellcomecollection.org/ works/svekkc2e.)
FIG. 1.8 Nehemiah Grew. He demonstrated the laticiferous system in plants by microscopy. (Credit: Wellcome Collection. https://wellcomecollection.org/works/axt8asec.)
FIG. 1.9 Alkaloid content in poppy capsule. With maturation, the alkaloid content of poppy increases after 3 weeks and starts to decrease by 4 weeks. (Data from Bernath, J. (1998). Cultivation of poppy under tropical conditions. In J. Bernath (Ed.), Poppy: The Genus Papaver (pp. 237–248). Harwood Academic Publishers.)
1.2.3 Extraction of opium
Opium alkaloids may be extracted from green poppy capsules by excoriating superficially with a sharp and shallow blade by hand, vertically or horizontally, so its milky white sap is extruded (Fig. 1.10). The sap is allowed to dry for a day or two, after which it is carefully scraped off the pods and collected into wooden bowls (Fig. 1.11). Then, the pod is ready for its next round of excoriation (Krikorian & Ledbetter, 1975).
The green poppy pod secretes for about 10 days of its annual cycle and may be tapped as much as six times during this period. The concentration of opium reduces if it is tapped more often. This process is labor-intensive, as the poppy capsule is individually tapped repeatedly over 10 days. On average, the yield is approximately 80 mg of raw opium per pod, and an acre of poppy provides
FIG. 1.10 Excoriation of poppy capsule. Each excoriation results in milky exudate over 1–2 days. (With permission from Couperfield@123rf.com https://www.123rf.com/photo_81603489_ detail-of-cutting-poppy-heads-with-knife-to-harvest-opium-latex. html?downloaded=1.)
FIG. 1.11 Dried poppy latex. The dried milky sap containing opium is scrapped manually from each capsule. (With permission from Couperfield@123rf.com https://www.123rf.com/ photo_81603467_detail-of-harvesting-of-raw-opium-on-poppy-field. html?downloaded=1 .)
less than 6 kg of raw opium (DEA, 1992; Krikorian & Ledbetter, 1975).
The raw opium may be “cooked” in boiling water to remove all plant contaminants and then strained through cheesecloth. This liquid opium may be re-heated in low flame to yield a sticky brown paste (suitable for smoking or eating). The collected opium is then air-dried before being packaged into cubes or balls for shipment.
Another source of extracting opium is the naturally dried pods of poppy capsules after harvesting their seeds (Fig. 1.12). These dry capsules, called “poppy straw,” are a common source for commercial production of opium, which still contain opium alkaloids albeit at a lower concentration.
FIG. 1.12 Poppy straw. Dry poppy capsules with seeds constitute the “straw.” (Credit: Pixabay.com https://pixabay.com/photos/ seeds-dried-poppy-poppies-flower-4461737/.)
