Medical Sciences [3rd Edition] 9780702073380, 9780702073397

Table of contents :
Medical Sciences, 3rd Edition [Jeannette Naish]......Page 1
Half Title......Page 3
Title Page......Page 5
Copyright......Page 6
Contents......Page 7
Preface......Page 8
Contributors......Page 9
Acknowledgements......Page 11
Chapter 1 Introduction and homeostasis......Page 13
Chapter 2 Biochemistry and cell biology......Page 27
Chapter 3 Energy metabolism......Page 69
Chapter 4 Pharmacology......Page 115
Chapter 5 Human genetics......Page 165
Chapter 6 Infection, immunology and pathology......Page 221
Chapter 7 Epidemiology: science for the art of medicine......Page 283
Chapter 8 The nervous system......Page 339
Chapter 9 Bone, muscle, skin and connective tissue......Page 405
Chapter 10 Endocrinology and the reproductive system......Page 453
Chapter 11 The cardiovascular system......Page 495
Chapter 12 Haematology......Page 569
Chapter 13 The respiratory system......Page 615
Chapter 14 The renal system......Page 655
Chapter 15 The alimentary system......Page 699
Chapter 16 Diet and nutrition......Page 749
Index......Page 783

Citation preview

Medical Sciences

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3rd

Edition

edical Sciences Edited by

Jeannette Naish, MBBS MSc FRCGP Clinical Senior Lecturer, Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine and Dentistry, London, UK AND

Denise Syndercombe Court, CBiol MRSB CSci FIBMS DMedT MCSFS PhD Professor of Forensic Genetics, King's College London, London, UK For additional online content visit StudentConsult.com

ELSEVIER Edinburgh

London

New York

Oxford

Philadelphia

St Louis

Sydney

2019

ELSEVIER C 2019, Elsevier Umited All rights reserved. First edition 2009 Second edition 2015 Third edition 2019

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 Ucensing 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 Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds or experiments described herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. To the fullest extent of the law, no responsibility is assumed by Elsevier, authors, editors or contributors 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.

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Contents Preface ..............................................................................................................................vi Contributors................................................................................................................vii Acknowledgements ............................................................................................ ix Dedication ...................................................................................................................... ix 1. 2.

3. 4. 5. 6. 7.

8.

Introduction and homeostasis ................................................ 1 Jeannette Naish Biochemistry and cell biology..............................................15 Marek H. Dominiczak Energy metabolism .............................................................................57 Despo Papachristodoulou Phannacology ........................................................................................103 Clive Page Human genetics...................................................................................153 Denise Syndercombe Court Infection, immunology and pathology ....................209 Denise Syndercombe Court, Armine Sefton Epidemiology: science for the art of medicine ................................................................................................271 Jeannette Naish, Denise Syndercombe Court The nervous system .......................................................................327 Brian Pentland

lndex................................................................................................................................771 Videos (www.studentconsult.com) • Nerve Impulse Transmission Made Easy Shafiq Pradhan • Cardiac Physiology Made Easy Shafiq Pradhan • Renal Filtration Made Easy Shafiq Pradhan

9. 10.

11. 12. 13. 14. 15. 16.

Bone, muscle, skin and connective tissue .......393 Lesley Robson, Denise Syndercombe Court Endocrinology and the reproductive system ..............................................................................................................441 Joy Hinson, Peter Raven The cardiovascular system ...................................................483 Andrew Archbold, Jeannette Naish Haematology............................................................................................557 Adrian C. Newland, Peter MacCallum, Jeff Davies The respiratory system ..............................................................603 Gavin Donaldson The renal system ................................................................................643 Girish Namagondlu, Alistair Chesser The alimentary system ................................................................687 John Wilkinson Diet and nutrition ...............................................................................737 Amrutha Ramu, Penny Neild

Preface We were delighted to be offered the opportunity to compile a third edition of Medical Sciences. This book was envisaged as a comprehensive introduction to medical studies, focussed on explaining the scientific foundation of core facts that are important to clinical medicine. It is unique in providing a text that integrates information across the diverse branches of medical science, focussing on body systems in health and linking to clinical phenomena. Accompanying the system chapters are more broadly ranging chapters that introduce the reader to concepts important to all students of medicine: homeostasis; biochemistry and cell biology; energy and metabolism; diet and nubition; pharmacology; genetics; epidemiology and statistics. Many aspects of medical science have developed or changed over the last few years and this new edition has provided us with the opportunity to update the material. Some chapters have been

substantially rewritten. We have tried to avoid chemical formulae and mathematical equations that many students will not require, while maintaining an understanding of the processes that these relate to. Some chapters include more clinical content than others, as clinical and information boxes. This is because these areas relate to more common, and therefore, important, clinical conditions. The student must, however, never forget that uncommon or rare conditions do exist and are, therefore, equally important. It is never easy to get the balance right between basic and clinical sciences. We therefore welcome your feedback. We sincerely hope that you will enjoy reading this book and find it useful throughout your studies. Jeannette Naish Denise Syndercombe Court

Contributors Andrew Archbold MD FRCP

Jeannette Naish MBBS MSc FRCGP

Brian Pentland BSc MB ChB FRCP(Ed) FRCSLT

Clinical Senior Lecturer, Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine and Dentistry, London, UK

Girish Namagondlu MBBS, MRCP

Head of Rehabilitation Studies (retired), University of Edinburgh; Professor (Honorary), Queen Margaret University, Edinburgh, UK Consultant Neurologist (retired), Astley Ainslie Hospital, Edinburgh

Consultant Nephrologist, Barts Health NHS Trust, Royal London Hospital, Whitechapel, London, UK

Amrutha Ramu MBBS BSc MRCP MRCPGastro MSc

Jeff Davies MA MRCP FRCPath PhD

Penny Neild MD FRCP

Consultant Gastroenterologist, Frimley Park Hospital, Portsmouth, UK

Clinical Senior Lecturer, Department of Haematology, Barts and the London School of Medicine and Dentistry, London, UK

Consultant Gastroenterologist and Honorary Senior Lecturer, StGeorge's Hospital, St. George's University of London, London, UK

Marek H. Dominiczak dr hab med FRCPath FRCP (Gias)

Adrian C. Newland BA MB BCh MA FRCP(UK) FRCPath

Consultant Biochemist, NHS Greater Glasgow and Clyde, Department of Biochemistry, Gartnavel General Hospital, Glasgow, UK Honorary Professor of Clinical Biochemistry and Medical Humanities, University of Glasgow

Department of Haematology, Royal London Hospital, Whitechapel, London, UK Professor of Haematology, Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

Consultant Cardiologist, Barts Heart Centre, Barts Health NHS Trust, London, UK

Alistair Chesser MB BChir FRCP PhD Consultant Nephrologist, Barts Health NHS Trust, The Royal London Hospital, Whitechapel, London, UK

Gavin Donaldson BSc PhD Reader in Respiratory Medicine, National Heart and Lung Institute, Faculty of Medicine, Imperial College London, London, UK

Clive Page BSc PhD OBE Professor of Pharmacology, Head of Sackler Institute of Pulmonary Pharmacology, King's College London, London, UK

Joy Hinson BSc PhD DSc FHEA Professor of Endocrine Science, Dean for Postgraduate Studies, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, UK

Peter MacCallum BMedSci MB ChB MD FRCP FRCPath Senior Lecturer, Department of Haematology, Barts and the London School of Medicine and Dentistry, London, UK

Peter Raven BSc PhD MBBS MRCP MRCPsych FHEA Honorary Consultant Psychiatrist, Camden and Islington Mental Health Trust, London, UK Faculty Tutor, Faculty of Medical Sciences, UCL

Lesley Robson BSc PhD Reader, Institute of Health Sciences Education, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, UK

Armine M. Sefton MBBS MSc MD FRCP FRCPath FHEA Emerita Professor of Clinical Microbiology, Centre of Immunology and Infectious Disease, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK

Despo Papachristodoulou MD Reader in Biochemistry and Medical Education, Lead for the MBBS Graduate/ Professional Entry Programme, GPEP admissions tutor/MBBS senior tutor, GKT School of Medical Education, Faculty of Life Sciences and Medicine, King's College London, London, UK

Denise Syndercombe Court CBiol MRSB CSci FIBMS DMedT MCSFS PhD Professor of Forensic Genetics, King's College London, UK

John Wilkinson BSc (Hens) PhD Academic Manager (Retired), School of Life Sciences, University of Hertfordshire, Hatfield, UK

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Acknowledgements We thank all the contributors to this third edition of Medical Sciences; in particular our new contributors, as we recognise that joining an established writing team is often as difficult as to undertake an entirely new commission. We would like to thank Elsevier for giving us the opportunity to update information in the previous edition as in some subjects especially, scientific development is fast moving. As Editors we have been supported through the project, in particular by Carole McMurray, Content Development Specialist. Pauline Graham, Senior Content Strategist, has been instrumental in commissioning this third edition and we would like to thank her for her encouragement and support through this process. We also thank the whole production team have been wonderfully efficient and thorough, providing the clarity necessary to communicate complex information through text and clear illustrations across the book pages to increase accessibility. We would also like to thank Shafiq Pradhan for creating the video animations which are a valuable addition to this third edition.

We would finally like to thank those contributors to the second edition who do not appear in the new addition, and acknowledge here, especially, the contribution of the late Patricia Revest, editor of the first edition. Without their contributions we would not be where we are today. • Paola Domizio • Mark Holness • David Kelsall • Drew Provan • Mary Sugden • Walter Wieczorek

Dedication We would like to dedicate this book to all students of medicine and the medical sciences, past and future and hope that its contents will continue to provide knowledge for medical professionals in the future. We believe that you have to know the science in order to understand the practice of medicine.

Jeannette Naish Denise Syndercombe Court

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Introduction and homeostasis Jeannette Naish

Chapter 2 Biochemistry and cell biology

1

Chapter 16 Diet and nutrition

3

Chapter 3 Energy and metabolism

1

Homeostasis

3

Chapter 4 Pharmacology

1

3

Chapter 5 Human genetics

2

Chapter 6 Pathology and immunology

2

Chapter 7 Epidemiology

2

Homeostatic regulation mechanisms Water and electrolytes: homeostatic control of body fluids Acid-base balance: homeostatic control of hydrogen ions

Systems of the body

2

Disease ensues when normal physiological mechanisms and processes are disrupted . These processes take place in the basic unit of living organisms: the cell. It is therefore essential that all clinicians understand normal cellular and molecular mechanisms and processes in order to understand disease. The following chapters address specific mechanisms related to particular areas of human function and systems of the body. The basic science concepts that attempt to explain disease processes cannot be undervalued . The best diagnostic and most effective therapeutic decisions made by clinicians have to be underpinned by sound scientific principles. The inclusion of all the relevant basic sciences in one book will , hopefully, be useful.

CHAPTER 2 BIOCHEMISTRY AND CELL BIOLOGY This chapter gives an overview of the principles of mechanisms that enable the body to work as a biochemical system. The functional unit of the human organism is the cell (Ch. 2, Fig. 2.39) . All cells are surrounded by a cell membrane, also known as the plasma membrane. Other cell components are contained in the cytoplasm in which the cellular elements (organelles), including the nucleus, are suspended in the cytosol (intracellular fluid (ICF) or cytoplasmic matrix). Cells are suspended in fluid composed of water and a variety of biologically active molecules. Movement of these molecules into and out of cells, involving both active and passive transport, triggers the physiological mechanisms that enable the cells to perform their normal physiological functions . Examples include protein synthesis, regulation of cell function (signalling), cell movement, metabolism (glucose and respiration), cell division and death (apoptosis), skeletal and cardiac muscle contraction, the transmission of signals along nerve fibres, the digestion and absorption of nutrients in the alimentary system, the synthesis and secretion of hormones by the endocrine system , transport of oxygen and carbon dioxide by blood , the exchange of respiratory gases and the important functions performed by the renal system. These cells perform different functions , and therefore possess different properties, described in detail in the

6

10

ensuing chapters on the systems of the body. Understanding cell and molecular biology - the similarities and differences between cell types, their components and functions - is essential to understanding the clinical sciences because disease results from the disruption of normal mechanisms. These principles underpin the development of disease, therapeutics and , in particular, the understanding of cancers and their treatment.

CHAPTER 3 ENERGY AND METABOLISM Chapter 3 discusses the cellular mechanisms that enable human beings to produce the energy needed to survive, maintain body temperature and work. Most biological processes are driven by energy in the form of adenosine triphosphate (ATP), produced through metabolism of the food that we eat. The main metabolic fuels are carbohydrate, protein and fat. The most important source of energy is glucose, but the body has intricate and dynamic adaptive mechanisms for using alternate fuels under particular physiological conditions. Metabolism occurs in cells. It is tightly regulated by the actions of enzymes, gene expression and transcription in response to changing demands on the need for energy and by the action of hormones, which may take place rapidly or gradually. Energy metabolism is essential for life, and disturbances can lead to important diseases, such as diabetes mellitus.

CHAPTER 4 PHARMACOLOGY This chapter describes how drugs work (pharmacodynamics) and how they are absorbed, distributed around the body (pharmacokinetics), metabolised and then eliminated . Knowledge of cell and molecular biology underpins the understanding of pharmacology and therapeutics. The pharmacokinetics and pharmacodynamics of synthetic drugs depend on their individual properties. Specific

2

Introduction and homeostasis

classes of drugs share common properties, but there are variations between individual drugs. It is also important to remember that how a drug performs in the laboratory On vitro) is not necessarily how it performs in the body On vivo), which is important for the safety and effectiveness of drugs. Generally, pharmacokinetics follows the principles of cell biology. In pharmacodynamics, drugs work by targeting cellular processes to either enhance or inhibit the process. Examples include the targeting of enzymes, transport processes and receptors on cell surfaces. Here, understanding of the autonomic nervous system is essential because most drugs are designed to target elements of this system.

CHAPTER 5 HUMAN GENETICS The understanding of genetics dates back to Charles Darwin's (1809-1882) On the Origin of Species (1859), later further explained by Gregor Mendel's (1822-1884) principles of inheritance and mutations. The most exciting modem development in genetics was the Human Genome Project, which mapped the complete set of genetic codes stored as DNA sequences in the whole 23 chromosomes of the human cell nucleus and took place between 1990 and 2003. The Human Genome Project published the working draft of the human genome in 2000; the complete genome was published in 2003. Taking advantage of the multiplexing capabilities of new sequencing technologies, the 1000 Genomes Project ran from 2008 until 2015, targeting sequence variation in five continental regions. In 2015 Nature published this work, which mapped population genetic variation from more than 2500 human genomes, providing publically available data for research. In the UK the 100,000 Genomes Project was launched by Genomics England at the end of 2012. Its aim was to provide sequence data from NHS patients diagnosed with cancer or a rare disease with the aim of stimulating the UK genomics industry. With its medicine-focussed approach the 100,000 Genomes Project is currently planned to run until the end of 2018 and has been expanded to include infectious disease. By mid-2017 the project had sequenced more than 36,000 genomes, putting the UK at the forefront of using genomic technology to transform patient care. The importance of partnering with industry is crucial to the project so that frontline clinicians of the Mure will be provided with the necessary infrastructure to benefit from this exciting Mure so that we can better understand disease processes and the development of preventive measures, diagnosis, prognosis and therapeutic strategies as genomic medicine moves into the mainstream.

CHAPTER 6 PATHOLOGY AND IMMUNOLOGY Pathology and immunology are essential for understanding disease processes to enable the clinician to formulate sensible diagnostic and therapeutic decisions. Infectious diseases and the body's response to them, immunology, are discussed. Disorders of the immune system, including autoimmunity and hypersensitivity, are also discussed. In these conditions, it is thought that there is a defect in the genetic regulation of the immune response. The inflammatory response underpins the body's defence mechanisms and needs to be fully understood. This is followed by the pathology of neoplasia; cancers,

which cause about 25% of all deaths in the UK. The pathology of common degenerative diseases is discussed in the chapters on systems of the body. Once again, molecular and cellular biology and medical genomics form the basis for understanding these processes.

CHAPTER 7 EPIDEMIOLOGY Chapter 7 is about the epidemiological principles that underpin the discovery of patterns of diseases and their occurrence in populations, and how the effectiveness of therapeutic interventions is evaluated. It is, pemaps, unusual to consider this as a basic science. Epidemiology and the epidemiological approach, however, is the science that underpins the art of clinical medicine. Observational studies form the cornerstone of clinical medicine. For example, how do we know how to diagnose disease from patient descriptions of symptoms? Our understanding of how disease presents and progresses clinically is based on repeated, multiple observations by many doctors and the sharing of their observations; e.g. whooping cough, which starts like a common cold, before the cough develops and continues for up to 100 days. The cough is characteristic in being spasmodic and prolonged, often ending in a sharp intake of breath - the 'whoop'. In the example of John Snow and the Broad Street Pump, Snow found the association between the water from the Broad Street Pump and the cholera epidemic. The actual cause of cholera, the organism Vibrio choleras, was not discovered until later by Filippo Pacini, an Italian anatomist, and was not widely known until published by Robert Koch some 30 years thereafter. Until the comma-shaped bacterium was identified, treatment and prevention could not be formulated. Careful and systematic observation thus formed the basis for further research into the cause of this disease. Moreover, how do we select therapeutic interventions, whether pharmacological or surgical? How do we know that this intervention is effective, or more effective than another one? Here, the methodology for experimental studies, e.g. randomised controlled trials, and the statistical concepts that underpin the proof for the likelihood of a positive effect need to be understood. The mathematics might be daunting, but understanding the principles is essential. These principles also apply to diagnostic and screening tests.

SYSTEMS OF THE BODY The next eight chapters are about all the systems of the body and discuss the cellular makeup of different organs, their functions, normal metabolic processes in health and the biological basis for disturbance leading to disease. Understanding these processes forms the rationale for diagnostic and therapeutic decisions. Despite their separation, the systems interconnect so that the body functions as a whole. Rather than describe each chapter in detail, it might be more helpful to think about the cellular mechanisms that ensure normal physiological function. These basic mechanisms are common to all living organisms, including Homo sapiens. As mentioned previously, the basic unit of the human organism is the cell. Normal biological functioning is determined by molecular and cellular processes and controlled by human genomics and epigenetic modification, as outlined in Chapter 5. The cells in each system vary according to their physiological function. For example,

Homeostasis 3 hepatic Qiver) and muscle cells both store glycogen, but the primary function of the liver is to release glucose converted from glycogen (glycogenolysis) into the circulation when there is a shortage of glucose, whereas muscle cells (myocytes) are primarily need to break down the stored glycogen for generating ATP for muscle contraction. Skeletal muscle lacks the enzyme glucose-6-phosphatase (G6Pase); giUC099-6-phosphate generated from muscle in glycogenolysis instead enters the glycolytic pathway after glucose, preserving one of the ATP molecules consumed at the start of glycolysis. A more obvious example of the influence of genomics is sickle cell disease (SCD). This is a condition where there is a mutation in the haemoglobin gene (13-globin gene), leading to the red cells assuming a sickle shape and becoming rigid. Sickle cells confer a resistance to malarial infection, and the mutation arose historically among populations in tropical and subtropical regions where malaria is endemic. The disadvantage is that, under conditions of reduced oxygenation, infection, cold or dehydration, the sickle haemoglobin elongates and cannot flow smoothly through small blood vessels. It sticks to the vessel lining, leading to occlusion of the vessels and causing sickle cell crises, which may be life-threatening. An understanding of molecular and cell biology and human genomics for the cells in each system is therefore necessary for understanding disease processes.

CHAPTER 16 DIET AND NUTRITION Chapter 16 is about the nutritional needs for humans to stay alive and, more importantly, the principles for assessing these needs in health and disease. What makes a human being eat or not eat is also addressed, with implications for dietary control of conditions such as obesity and some therapeutic diets for chronic conditions such as inflammatory bowel disease. The association between diet and disease is also discussed. Nutritional support during severe illness, artificial nutrition, and associated complications are discussed. Artificial nutrition includes enteral feeding, i.e. putting feeding liquid directly into the stomach or small intestine, and parenteral nutrition, which is intravenous feeding. The makeup of the feeding fluid will depend on the nutritional needs of the patient. These principles are important, especially during the foundation years. Inclusion of nutrition as a basic science in this book is perhaps unusual, but clinicians need to know about these principles for sustaining life.

HOMEOSTASIS To maintain the normal physiological processes for sustaining life, all living organisms and cells have to maintain a stable internal environment in response to changes in external conditions. Physiologists have called this function homeostasis, from the Greek homeo meaning same or unchanging, and stasis meaning standing still. When an attribute of the organism or cell (such as pH or temperature) changes for any reason, this complex system of processes adjusts the attribute back to the set constant level needed for physiological functioning. Such an attribute is labelled a variable, something that is changeable. Homeostatic systems are multiple, dynamic mechanisms that are regulated (or controlled) for making the adjustments necessary for a stable internal environment; this is unlike simple dynamic equilibrium

or steady states that are not regulated. Many examples of human homeostasis are discussed in the following chapters. Disease ensues when homeostatic mechanisms break down and the body exhibits symptoms (what the patient experiences) and signs (what the clinician finds on clinical examination). Many physiological parameters, such as blood glucose level (discussed in detail in Ch. 3, Energy and metabolism), water and electrolyte (sodium, potassium, calcium, etc.) balance and body temperature, are examples of precise control by homeostatic mechanisms. Of the homeostatic mechanisms that control body fluids, fluid balance (the control of fluid volumes) and acid-base balance (the control of acidity [W ionsD are important to understand.

Homeostatic regulation mechanisms Homeostatic control mechanisms have three (sometimes more) interdependent components for the variable being regulated. 1. A receptor that detects, monitors and responds to changes (sometimes wide variation) in a variable in the external environment; known as the sensor. 2. The sensor sends information to a control centra that sets the physiological range for the variable, and determines the necessary response for bringing the variable back to the set point. In humans, the control centre is usually in the brain. Many examples are discussed in Chapter 8. 3. The control centre sends signals to the tissues and organs, known as the effectors, that have to effect, i.e. make the adjustment, to changes in the relevant variable to bring it back to its set point. A simplistic analogy would be ambient temperature control in air-conditioning systems, where the thermostat is the sensor responding to changes in environmental temperature, set at a comfortable level. It also acts as the control system that switches heating or cooling systems on and off. The effector would be the heating and cooling systems with their own, separate mechanisms. Once the control centre receives the stimulus that a variable has changed from the set point, it sends signals to effectors to correct the change by: • Negative feedback to depress the change if the variable level has increased beyond the narrow, set range. This is the commonest mechanism. • Positive feedback to affect an increase or acceleration in the output variable that has already been triggered. The result is to push the level beyond the physiological range. • Feedforward control to either depress or enhance the level of a variable before the change is needed, i.e. anticipatory (or open loop). Open-loop systems have no way to calibrate against the set point and so always need an accompanying closed-loop negative feedback to correct any over- or underanticipation.

Negative feedback Negative feedback mechanisms can either increase or reduce the activity of tissues or organs back to normal, set levels, and the system is sometimes called a negative feedback loop (Rg. 1.1). Numerous examples of negative feedback exist in the metabolic processes of all physiological systems.

Homeostatic control of glucose metabolism An example of a negative feedback system is the homeostatic control of blood glucose. Among the tissues of the body, red blood cells and the brain (under normal conditions) can only use glucose to

4

Introduction and homeostasis

generate the energy needed to drive metabolic processes. Glucose is essential to ensure an adequate supply of energy for the vital functions performed by these and other tissues. Blood glucose concentration (measured as fasting blood glucose) is therefore tightly maintained within a narrow range (3.5--8.0 mmoi/L.) normally. Here, the sensor is specialised pancreatic cells that receive blood from the portal circulation. The control is the autonomic nervous system, and the effectors are the a (secreting glucagon) and ~ (secreting insulin) pancreatic cells in the islets of L.angerhans. A simplified explanation of glucose homeostasis is shown in Fig. 1.2. • When blood glucose concentration is too high (hyperglycaemia), e.g. following a high-carbohydrate meal or the ingestion of excessive amounts of alcohol, increased secretion of the hormone insulin causes increased uptake of glucose into cells and inhibition of the glucagon-secreting a cells, thus reducing blood glucose concentration towards normal. These processes are described in detail in Chapters 3 and 16.

Efledor

I

Fig. 1.1

Negative feedback loop. An increase in the variable produces an effector response to decrease it and a reduction in the variable leads to an effector response to increase it with the aim of returning to equilibrium.

Rise in blood glucose concentration

?

Another example of a physiological homeostatic negative feedback system, addressed elsewhere in Chapter 8, is the control of body temperature: thennoregulation. Ambient environmental temperature can vary widely (-50°C to +50°C), but human body temperature has to be set at about 37"C (range 36°C to 38°C) for normal physiological functioning. For example, some mechanisms in glucose metabolism require energy, and if body temperature falls below a certain level, there will not be enough energy to drive the process. Rg. 1.3 shows the mechanisms for controlling body temperature by negative feedback. Body temperatures outside the normal range are defined as: • Hyperthermia, when core temperature rises above 40°C • Hypothermia, when core temperature falls below 35•c. Prolonged and significant elevation (as in hyperthermia) or depression (as in hypothermia) in core body temperature (see below) can have fatal consequences.

As mentioned above, human body temperature is set at about 37"C.

vanable

Insulin release

Thennoregulation

Human body temperature (Clinical box 1.1)

~-"q. ~~-.

• When blood glucose concentration is abnormally low (hypoglycaemia), as in prolonged fasting, glucagon is released from the pancreas to trigger alternative metabolic pathways to bring the level up: glycogenolysis, the process in which glucose stored in the form of glycogen is broken down to glucose; gluconeogenesis, in which, when glycogen stores are depleted, other metabolic fuels such as fat and protein are converted to glucose, and alternative fuels, such as fatty acids and ketone bodies, are used for generating energy.

~

This can be measured through different anatomical orifices, such as the oral, rectal or vaginal orifice and the external auditory meatus. These are measurements of peripheral temperature and will vary between healthy subjects depending on where the measurement is taken. The core temperature (or core body temperature) is the temperature needed for normal physiological functions in deep organs such as the liver or brain, and is different from peripheral

Increase: • rate of glucose entry into cells • glycolysis • glycogenesis To decrease blood glucose concentration Normal blood glucose concentration (norrnoglycaemia)

Normal blood glucose concentration (norrnoglycaemia)

'

Fall in blood glucose concentration (hypoglycaemia)

Fig. 1.2

Glucagon release

~

Increase: • rate of glycogenolysis and glucose release from liver • rate of gluconeogenesis • ketone bodies used as alternative metabolic fuel

/

To increase blood glucose concentration

Simplified scheme for glucose homeostasis. Increased blood glucose concentration leads to increased insulin secretion to lower blood glucose concentration back to normal, and a reduction in blood glucose concentration leads to the release of glucagon to raise blood glucose concentration to normal.

Homeostasis 5

I

Senso~

I

~

Skin (peripheral) Hypothalamus (cenlraQ

Rar

\

1,-Con-lrol_:_cenlre_---. 1

Body temperatura

Hs1oss

Hypothalamus

~

j

Vaooon•oo .

~g

I """"' I/

~Smooth muscle in walls of

blood vessels supplying skin

........___SWeat glands

® I

~

I

~

Skin (peripheral) Hypothalamus (centraQ

\

I Control centra I Body temperature

+

Heat gain Shivering

I

-1/MO'

'

vasoconstriction Skeletal muscle Fat burning"'--. Smooth muscle in walls of ~ blood vessels supplying skin Insulation · ,........___ Brown and adipose tissue (brown fat)

~Piloerection

Fig. 1.3

Control of body temperature by negative feedback. (A) Responses to an increase in body temperature; (B) responses to a decrease in body temperature.

0

Clinical box 1.1 Fever The set point for temperabJre control is nut always fixed. In infection, toxins released from bacteria and chemicals produced by cells of the immune system change the set point upwards (see Ch. 6). The normal mechanisms to generate heat, such as shivering, are triggered, leading to an increase in body temperature known as fever or pyrexia. The cause for this fever is thought to be a mechanism to activate certain immune cells and to limit bacterial growth. A higher rate of metabolism will also produce a faster rate of healing and more rapid induction of defence mechanisms. If the temperature becomes too high, however, the proteins inside the cells may be damaged.

temperatures. Core temperatures have to be measured by inserting a deep probe, which is not always possible, so that rectal or vaginal temperatures are taken as an accurate reflection of core temperature. Body temperature also varies according to the time of day, known as the circadian rhythm, an endogenous biological process driven by light and dari7.45: alkalosis

2. Measure arterial pCO. and [HC0.1 (etandard bicarbonate). Normal valuea: pCO, 35-15 mmHa (4.8-8.1 kPa), [HC0.1 22-28 mM. The following ahowa the valuee for the clfferent type& of aci~- clatumance

pCO. > 45 I'TVTlHg (6.1 kPa): respinrtory acidosis

[HCO,-) < 22 mM: metabolic acidosis

peo. < 35 mmHg (4.8 kPa): respiratory alkalosis

[HCO.-] > 28 mM: metabolic akalosis

3. Interpret the two meaaurementa together

3. Interpret the two mea11.1rementa together

[HCO,-] > 28 mM:

[HCO.-1 < 22 mM: respiratory

pCO. > 45 mmHg (6.1 kPa):

alkalosis with renal compensation

metabolic acidosis with respiratory compensation

respinrtory acidosis with

pCO. < 35 mmHg (4.8 kPa): metabolic acidosis with

renal compensation

respiratory compensation

the surface of the tubule cells, carbonic anhydrase converts H2COa to H20 and C02• The C02 diffuses freely into the tubule cells where intracellular carbonic anhydrase catalyses the reverse reaction to produce H2COa. This then dissociates into HCOa- and W. The H" is secreted into the urine and the HCQ3- diffuses into the blood. The net result is the transfer of one molecule of HC03 - from the urine to the blood. When a mechanism fails, for example in respiratory acidosis, a compensatory renal mechanism may operate to retain bicarbonate

and [W] could return to nonnal. In respiratory alkalosis, when C02 levels are persistently low a compensatory metabolic acidosis may occur, although the response is usually slight (Clinical box 1 .1 0 and Table 1.3). Respiratory compensation of metabolic acidosis also occurs, when respiration increases to 'blow off' C02 and allows [W] to rise in a respiratory alkalosis. There is usually a delay in this respiratory compensatory mechanism. Similarly, respiratory compensation for metabolic alkalosis, although slight, can occur.

Biochemistry and cell biology Marek H. Dominiczak

Principles of molecular interactions

15 16

Atoms Ions Acids and bases Chemical bonds Organic compounds Chemical reactions Energy in biological systems

16 17 17 17 18 18 19

Chemical composition of the human body

20

Introduction

Chemical elements Water content and the main fluid compartments The role of vitamins Organic biomolecules

20

Carbohydrates Lipids

22 24 24

Fatty acids Cholesterol and steroids Complex lipids

24 25 26

Purines and pyrimidines Nucleic acids

26 29

Deoxyribonucleic acid Ribonucleic acids

29 31

Amino acids Proteins

32 34

Structure of proteins Protein synthesis and processing Functions of proteins Structural proteins Catalytic proteins: enzymes

34 36 39 39 40

Complex carbohydrates

21 21 22

INTRODUCTION Cell biology tells us about the structure and functions of the cell and its organelles, whereas biochemistry addresses the chemical basis of the composition of the human body, its structure and its functions, and also the preservation and continuity of the structure and function through generations. The body is an open system and, thus, there are the interfaces with surroundings that are both sensory and metabolic, the latter through nutrition and excretion of metabolic products. The function of the organism may become disrupted during both the lack of nutrients (starvation, malnutrition) and their excessive intake (the diseases of excess: obesity, cardiovascular disease and diabetes). Central to metabolism and homeostasis is the energy flow: metabolism includes reactions that are energy requiring (endergonic)

Signalling proteins and cell signalling systems Hormone receptors Proteins involved in cell adhesionin and recognition Membrane transport proteins and membrane transport systems Passive diffusion Carrier-mediated transport Coordinated action of cellular transport systems

42 43

The cell

46

Cytoplasm Cytoskeleton Nucleus Endoplasmic reticulum Golgi apparatus (golgi complex) Mitochondria Lysosomes Proteasomes Peroxisomes Cell junctions Cell adhesion and recognition

47 48 48 48 49 49 49 49 49 49 50

Transport within cells

50

44 44 44 44 45

Endocytosis

50

Intracellular and transcellular transport

51

Exocytosis Transcytosis Receptor-mediated endocytosis

51 51 51

Organs and tissues

51

Epithelial tissues Connective tissue Muscle Nervous tissue Integrated learning: the systemic approach

52 52 54 55 56

and the ones that yield energy (exergonic). Some chains of reactions (pathways) accumulate energy in a range of biosynthetic products (anabolic pathways), and others release energy (catabolic pathways). Reactions take place in an aqueous environment, and electrolytes and ions are both bystanders and participants in chemical reactions. Most reactions happen at physiological temperature within a narrow range of pH , thanks to the action of biocatalysts (enzymes) . There has been an enormous acceleration in our understanding of the chemical aspects of body structure and function. Perhaps the most significant development in biochemistry in the last few years was the expansion of knowledge concerning cellular signalling systems and their links to the control of gene expression (Fig. 2.1). It is so important because the aim of a large number of medical therapies is to control these processes when the normal regulatory mechanisms fail.

16 Biochemistry and cell biology In this chapter, we will first consider the fundamentals of the atomic structure, chemical bonds and chemical reactions, highlighting the energy flow in biological systems. We will go on to discuss the chemical composition of the human body and the most important classes of biological compounds: carbohydrates, fats, proteins, nucleic acids and a range of 'hybrid' molecules, such as glycolipids or proteoglycans. We will then discuss the cell and its organelles, highlighting the function of cell structures that enable cells to communicate, transport nutrients and interact with each other.

PRINCIPLES OF MOLECULAR INTERACTIONS Atoms All atoms have a nucleus surrounded by shells of electrons. Each of these shells is characterised by a different energy level. Subshells (orbitals) exist within each shell. Atomic orbitals are described by quantum numbers. The principal quantum number (X) corresponds to the energy level, and the angular quantum number I (type, denoted by a small letter) describes the shape of the subshell. The superscript (y) in the convention Xtype Y describes the number of electrons in an orbital. The orbitals are designated as 1s, 2s, 2p, 3s, 3p and 4s. The 1s orbital is closest to the nucleus. Each orbital can be occupied by a maximum of two electrons, each of them having a different spin. The order in which the atomic orbitals are filled goes from the lowest energy level (closest to the nucleus) to the higher levels. The order (from first to last) is 1s, 2s, 2p, 3s, 3p, 4s, 3d, 4p, 5s, 4d, 5p, 6s, 4f, 5d, 6p, 7s, 5f, 6d and 7p. When orbitals of the same energy are available, the electrons fill them singly first (this is known as the Hund rule).

Each of the electron shells contains a defined number of electrons in their orbitals: • The first Onnermost) shell can have one orbital (1 s) and a maximum of 2 electrons. • The second shell 2s2p has 4 orbitals and a maximum of 8 electrons. • The third shell can have 3 orbitals (3s3p3d), which together makes 9 orbitals and up to 18 electrons. • The fourth shell has 16 orbitals and up to 32 electrons. Electrons always occupy orbitals of the lower energy first. Note the anomaly that occurs between the third and the fourth shell. The 4s orbital is filled before 3d (contravening the general rule, it has a lower than 3d energy level). A fully occupied shell makes an atom chemically inert (examples are the noble gases such as helium and neon). Atoms that have incompletely filled outer shells can react until their shells become fully occupied. The outermost orbital of the atom contains the so-called valence electrons that participate in fonning chemical bonds. The configuration of eight electrons (octet) in the outer shell is the most stable one (Fig. 2.2). Atoms that possess an unpaired electron that is not shared with other atoms are known as free radicals and are highly reactive. The nucleus contains protons and neutrons (the hydrogen atom has only a single proton as a nucleus). The number of protons is the atomic number of an element. The sum of the protons and neutrons is the atomic mass. Different isotopes of a given element differ with respect to the atomic mass (Information box 2.1 ).

0

Information box 2.1 The carbon atom

cart:Jon is the element present in all organic molecules. The carbon atom is assigned an atomic number of 6 because it has 6 protons. However, it can have 6, 7 or B neutrons, forming different isotopes with different atomic masses. Carbon isotopes show no differences in chemical reactivity (fable 2.1 ).

Fig. 2.1 Metabolism and its genetic control. Supply of nutrients (reduced compounds) and their oxidation yields energy that is conserved in the form of adenosine triphosphate (ATP). ATP is subsequently used in energy-requiring biosyntheses (predominantly reductions again). The wort< of the entire system is controlled by information contained in the genetic code, which also utilizes the metabolic machinery to preserve its continuity. ETC, electron transport chain.

0 Electrons

0

Empty orbitals

Fig. 2.2 The carbon atom. The carbon atom contains 2 shells and 5 subshells (orbitals). Note that the 2 orbitals in shell 2 are filled by 1 electron each. Sharing of 4 electrons in shell 2 with another atom would fonn an octet - a stable configuration.

Principles of molecular interactions groupe and cluee8

Table 2.1 Common of Group

Formula

Class

Hydroxyl

R-OH

Alcohols

Aldehyde

R-coH

Aldehydes

Ketone

A-coR'

Ketonee

Carboxy

R-cooH

Carboxylic acids

Ester

A-coo-A'

Esters

Amino

R-NH2

Amlnes

Imino

R-NH

Imines

Sulphydryl

R..SH

Thiols

Ions In an atom, there is normally a balance between the positive charge of the protons and the negative charge of the electrons, rendering the atom electrically neutral. Consequently, when it gains or loses electrons, it acquires an electrical charge: such an atom is called an ion. The charge can also be associated with groups of atoms, forming ionised (functional) groups. Thus, • • •

n

17

Information box 2.2 Strength of acids

The strength of an acid is the ease with which it donates proton or accepts electrons. Strong acids dissociate completely, whereas weak acids dissociate to a limited extent. This tendency is described by the acid's dissociation constant (IQ, which is a ratio between its undissociated and dissociated forms:

The derivative of the dissociation constant is its negative logarithm, the pi(,. The lower the pi(, is, the more active a molecule is as a proton donor (a stronger acid). Examples of strong acids are inorganic acids such as hydrochloric or sulphuric acid. The weak acids are carbonic acid (an Important blood buffe~ and the carboxylic acids. Conversely, increasing pi(, means an increase in the alkalinity- of the conjugate base.

The acidity or alkalinity of a solution also relates to the concentration of hydrogen Ions (H') meuured as Ill negative logarithm, the pH. The neutral pH of pure water Is close to 7.0. Solutions with a pH of less than 7.0 are acidic, and solutions with a pH of greater than 7.0 are alkaline. The normal range of human blood pH is 7.35-7.45. The maintenance of stable pH of the body fluids is necessary for survival (Ch. 1).

Ionic bonds

Anions are negatively charged ions and are generated by the gain of electrons. Cations are positively charged ions and are generated by the loss of electrons. Metals tend to form cations, and non-metals form anions. Formation of ionic bonds between atoms is one of the principal mechanisms of chemical reactions.

®

Cavalanl bonds

Acids and bases The concept of an acid and a base is associated with the movement of protons and electrons in aqueous solutions. According to the Br6nsteci-Lowry definition, an acid is a molecule that can donate protons and a base is a molecule that accepts protons. Therefore, an acid in a sense 'contains' a base: when an acid loses a proton, the remaining species (now negatively charged) is its conjugate base. Another definition of an acid, the Lewis definition, defines it as a molecule that accepts a pair of electrons and a base as a molecule that donates a pair of electrons (Information box 2.2)

Methane(~

@

Oxygen(~

Hydrogen bonds

Chemical bonds Chemical bonds determine how molecules join together. Atoms can form chemical bonds with other atoms of the same or different kind (Fig. 2.3). Bonds differ in their strength and stability, and are also determine the spatial conformation of molecules. The bonds most relevant to biomolecules are the following: • Ionic bonds • Covalent bonds • Hydrogen bonds.

Ionic bonds Ionic bonds form when ions are attracted to each other by their opposite electrical charge. An electron(s) from one atom move(s) closer to the nucleus of another, forming a molecule. Importantly, such molecules dissociate into their component ions in an aqueous solution. For instance, sodium chloride (table salt} is formed when sodium (Na) and chlorine (CI) atoms attract each other. In this

-

Covall!ll! bond

• · · Hydrogen bond

Fig. 2.3

Different types of chemical bond. (A) Ionic bonds. (B) covalent bonds, (C) hydrogen bonds. In (C}, 8" and a- denote

partial positive and partial negative charges, respectively. reaction, Na loses an electron, becoming a cation, Na+, whereas Cl acquires the electron, forming an anion, Ct'. A strong ionic bond forms sodium chloride (NaCI). When the water is removed, salt crystals consisting of Na+ and Ct' held together by ionic bonds are formed (see Fig. UA).

Covalent bonds The principle behind covalent bonds is electron sharing. A pair of electrons is shared between two atoms, making both atomic shells

18 Biochemistry and cell biology bonds are weaker than covalent and ionic bonds, and are easily disrupted by pH and temperature changes. They are important in stabilising the spatial structures of proteins and nucleic acids. Many large molecules contain numerous hydrogen bonds.

Non-polar molecular interactions

0 Ammlcn~dllll /::,. Clnlorofpoollw "'--I• 0 Clnlorofnogollooo"'-llo

Fig. 2.4 Polar and non-polar covalent bonds. (A) Covalent bonds formed between atoms of the same kind are usually non-polar, and the shared electrons are equidistant from both atomic nuclei. (B) A polar covalent bond may form between atoms of different elements, where the electrons are closer to the nucleus of one element than to that of the other. Such a molecule acquires a partial electric charge. (C) Water is a dipolar molecule. Oxygen has a higher electronegatMty than hydrogen and results in a charged molecule. Dipole-dipole interactions are the basis of attraction between many molecules known as hydrogen bonding (see Rg. 2.3C).

complete. This may occur between atoms of the same or different elements. Examples include oxygen (02}, where two oxygen atoms form a double bond (0=0); hydrogen atoms sharing electrons with a single bond (H-H); and carbon and hydrogen atoms sharing electrons to form methane (CH4) (see Rg. 2.36).

Polar covalent bonds A covalent bond is electrically neutral when the electrons remain equidistant from the two participating atoms (Rg. 2.4A). However, when the nuclei of two atoms differ in their positive charge, this distance becomes unequal, creating partial elecbic charges across the covalent bond. Such a bond becomes a polar covalent bond (see Rg. 2.~ and the resulting molecule becomes a dipole. The water molecule (H20) is an example of a dipole (see Rg. 2.4C). The strongly negative oxygen atom attracts electrons away from the two hydrogen atoms, which become positive. Because of this, they keep at a distance from each other. The water dipole can form hydrogen bonds with non-water molecules: this is the principle behind the solubilisation of substances by water. The hydrogen ions can also associate with other water molecules. This results in water dissociation into the hydronium ion (H30') and the hydroxide ion (OH1:

H20 + H:!O ~ ~o+ +OW We normally simplify this in our notation and show water dissociation as

Non-polar molecules are water-insoluble (hydrophobic). Such molecules tend to aggregate in polar solvents; this is known as hydrophobic interaction. An example is the behaviour of lipid molecules in the plasma membrane. Another type of weak interaction, the Van der Waals force, makes molecules align in an energetically optimal conformation. Van der Waals forces are effective at a relatively long range (up to 50 nm) and are easily reversible. For example, they contribute to the binding of substrates to enzyme molecules and to the binding of antibodies to antigens.

Organic compounds An organic compound is a compound containing carbon atoms linked by covalent bonds. This definition usually excludes some small molecules, such as carbon dioxide. Organic compounds may also contain oxygen, nitrogen and sulphur. The carbon atoms commonly bond with each other and with hydrogen, forming hydrocarbon chains. The hydrogen atoms in hydrocarbons may be replaced by other atoms or functional groups. In addition, carbon atoms can share more than one electron with another atom, forming double or triple covalent bonds. Talble 2.1 shows examples of the chemical groups that occur in different classes of organic compounds. The carbon atoms may share four electrons with other atoms, including carbon (see Rg 2.2). For example, in methane (CH.J, the carbon atom links covalently with four hydrogen atoms. Importantly, the carbon can form long chains (e.g. in some fatty acids), which can also branch, or form rings (e.g. the steroids), containing either carbon only or carbon linked to other atoms, such as nitrogen.

Spatial arrangement of organic molecules Within an organic molecule, a carbon atom that shares its four availalble electrons with four different atoms (or groups) is known as the chirality centre or stereocentre. The chiral compound cannot be superimposed on its mirror image. Such a molecule can exist as variants that, while having the same formula, have different spatial orientations (known as stereoisomers). Stereoisomers are identified by the way they rotate the plane of polarised light. Those that rotate the compound arrticlockwise (to the left) are called L-isomers, whereas those that rotate it clockwise (to the right) are called D-isomers. Another type of isomerism is ci&-4rans isomerism, which relates to the arrangement of atoms across the carbon-carbon double bonds. The cis configuration is when two linked atoms reside on the same side of the double bond, whereas the trans one is when they reside on the opposite sides. Cis-trans isomerism is particularly important in lipid chemistry.

Chemical reactions Hydrogen bonds The hydrogen atom has a single proton as the nucleus, and only one electron shell, occupied by a single electron. When this electron is lost, a cation (H"') forms. Such a cation can attract the negative pole of a dipolar molecule, forming a hydrogen bond (see Rg. 2.3C). These

Chemical reactions are exchanges of protons and electrons. They result in the formation, or breakage, of chemical bonds between atoms and molecules. Chemical reactions are associated with energy transfer - some require energy to proceed, whereas others release energy. The strength (potential energy) of different chemical bonds is shown in Table 2.2.

Principles of molecular interactions of eome chemical bondlln E.._ (lrJ/mol)

Type of bond Ionic

12.649.3

Covalent (sngle)

21Q-160

Covalent (double)

SOQ-710

Covalent (triple)

815

Hydrogen

4.2-3.4

Van der Waals Interactions

4.2

I

A-A•+e

Oxidation

e• +e-- B

Reduction

A~e·

Raducln11

\

Oxldlsln11

·u~ Redox couple

Fig. 2.5

Oxidation-reduction reaction. Note: The reducing agent becomes oxidised by donating electrons. The oxidising agent becomes reduced by accepting electrons.

• • •

The main types of chemical reactions are the following: Syntheais, when a larger molecule is formed from smaller substrates Lysis, when a molecule is broken down into smaller compounds Exchange reactions, where atoms, or groups of atoms, are exchanged between molecules (e.g. transamination reactions, where the amino group is transferred between molecules).

Electrophiles and nucleophiles During a chemical reaction, atomic structures of reacting molecules are modified by the transfer of electrons (or protons). The excess electrons from one atom may 'invade' the orbitals of another, forming new shared orbitals. The relevant terminology is as follows: • Nucleophiles are negatively charged atoms that are electron-rich. They tend to lose pairs of electrons. • Elecb'Ophiles are positively charged atoms that are electron-poor. They accept electrons. • A nucleophilic attack is a situation where the electrons from a nuclaophila move into an electrophilic atom. Nucleophilic attack underpins, for instance, very common reactions of hydrolysis.

Oxidation-reduction (redox) reactions Oxidation-reduction (redox) reactions are paired reactions in which electrons pass from one molecule to another (Fig. 2.5}. In the process, the energy trapped in the chemical bonds in the molecule being oxidised is transferred to the molecule being reduced. Oxidation is a net loss of electrons with an increase in oxidation state by a molecule (the complete oxidation state is when an atom

19

is maximally charged after all its electrons have participated in ionic bonds). Reduction is a net gain of electrons (or protons - hydrogen ions) with a deCf98S9 in oxidation state by a molecule. Oxidation has also been defined as a loss of a hydrogen atom from a compound, and reduction as an addition of a hydrogen ion to a compound. The oxidation-reduction (redox) reactions are key to the cellular flow of energy. In redox reactions, electrons will flow from carrier A to carrier 8, which has the higher redox potential (a tendency to be reduced or to accept electrons). An electron added to an atom (a reductant) traps the energy. Reduced molecules possessing such trapped energy are more stable. The energy can then be released during oxidations. Specific compounds in the cell transfer protons and electrons. The coenzyme nicotinamide adenine dinucleotide (NAD') is the most important electron acceptor. Another one is flavin adenine dinucleotide (FAD), which is an integral part (the prosthetic group) of several enzymes. Both are also hydrogen ion caniers. The structurally almost identical nicotinamide adenine dinucleotide phosphate (NADP) is a reductant that participates in many biosynthetic reactions.

Energy in biological systems Energy is the capacity to do work. There is potential energy and kinetic energy. Potential energy is the capacity of an object to do work (e.g. because of its position in space), whereas kinetic energy is the capacity to do work associated with the movement of an object. Each chemical reaction is associated with a change in free energy (4G). Exergonic reactions are reactions that release energy and are characterised by a negative change in free anergy (-~G). Endergonic reactions are reactions that require energy to proceed (positive change in free energy (+~G).

Energy cycle in biology The energy required by living organisms is trapped in foodstuffs by plant photosynthesis, which consumes carbon dioxide and generates oxygen. Organic molecules thus produced then become metabolic fuel for animals. Their absorption and digestion by IMng organisms provide the energy necessary for their survival. This energy is released in a highly controlled, stepwise manner during biological oxidations, resulting finally in the production of carbon dioxide and water. The released energy is used for the building up of sophisticated biological structures. It is also used to support cellular transport, neural transmission and mobility, as well as growth, reproduction, defence and repair.

Potential energy of chemical bonds Formation of a chemical bond requires energy input, and some potential energy accumulates in the formed bond (see Table 2.2). This energy can be recovered when the bond is broken. An analogy is putting a bucket of water on a high shelf (inputting energy) and recovering the energy when the water is poured down to drive a wheel. The biologically important bonds that have a particularly high potential energy are the phosphoanhydride bonds formed between phosphate groups in molecules such as adenosine triphosphate (ATP). Another mechanism of energy trapping is building up an ion gradient across a biological membrane. Energy input is required to create such a gradient; it is released when the ions 'return' across the barrier.

20 Biochemistry and cell biology Energy flow in chemical reactions The content of free energy (G) changes during chemical reactions. We describe the energetics of reactions in relative terms, indicating free energy change ~. which is negative when the energy content decreases or positive when it increases. If a reaction relee.9es energy, it is exergonic, and when it requires energy input to proceed, it is endergonlc. The products of exergonic reactions have a lower potential energy than their substrates, and the products of endergonic reactions have a higher potential energy. Reactions where products have less potential energy than the substrates tend to occur spontaneously, whereas those where the potential energy of substrates increases require energy Input. The key concept in biochemistry is that the energetically favourable reactions are used to drive the unfavourable ones. Let us Imagine two reactions: 1. A + B -t X and (endergonic reaction) 2. X+ Y -t Z (exergonic reaction). Reaction 1 is energetically unfavourable. It occurs only very slowly, yielding small amOll'lts of the product X, according to its equilibrium. Reaction 2, on the other hand, proceeds spontaneously. As its substrate is X, it depletes it, shifting the equilibrium of reaction 1 and 'forcing' it to proceed. This is a common pattem in various metabolic pathways. Note that the hydrolysis of ATP has a highly negative G. Thus, ATP can drive the otherwise energetically unfavourable reactions.

Anabolic and catabolic pathways Metabolic pathways are chains of chemical reactions, classed according to their purpose. The anabolic pathways use energy In order to build up large molecules and are usually associated with reductions; the catabolic pathways, on the other hand, break down large reduced precursor molecules. They are associated with oxidations.

Generation of metabolic energy Metabolism generates energy to support body functions, growth and regeneration. The required energy is acqlired from nutrients. Cellular energy flow depends on biological oxidations. The overall oxidation process In living organisms is the multistep conversion of highly reduced organic compounds, in the presence of oxygen, to carbon dioxide and water. It is analogous to the combustion reaction, but In biology this 'combustion' proceeds by minute, carefully controlled, stages and under physiological conditions. The substrates for oxidation are highly reduced compounds, mainly carbohydrates and fats. We call them metabolic fuels (Information box 2.3). A substantial part of the released energy Is chemically trapped for subsequent use. The major stages in this process are as follows: 1. Ingestion of nutrients and their digestion in the gut, which results In the liberation of the molecules of metabolic fuels from more complex compounds. These are absorbed Into plasma. 2. Conversion of the fuel molecules. Metabolic fuels are then oxidised. The electrons (and protons) are fi'st transferred to intracellular coenzymes, such as NAD and NADP, forming the reduced NADH and NADPH, respectively (the NADPH Is used in biosynthetic reactions). The NADH then carries the electrons, accompanied by protons, to the mitochondria and transfers them to the electron transport chain (ETC; Ch. 3). 3. In the ETC, electrons and protons are transferred along the chain, participating in the sequence of redox reactions involving ferric iron complexes, cytochromes and other electron carrier

0

Information box 2.3 Metabolic fuels Metabole fuels are highly re IF~

!

~ Parallel dimerforms

Triple!

ff Fig. 2.42 filament.

during cell division. The microtubules are used as tracks along which organelles can be moved. An example of the function of microtubules is the transport of substances in the neurons. There, proteins required by the synapse are manufactured in the cell body and transported along the microtubules. This is known as fast axonal transport. It occurs in both directions along the same microtubule. The anterograde transport carries new materials from the cell body to the synapse and is performed by kinnins. The retrograde transport carries materials back to the cell body for destruction in the lysosomes and is performed by dyneins. Kinesins and dyneins, similar to myosin and actin, are molecular motors that perform movements using energy derived from ATP. A number of proteins known as microtubule-associated proteins are attached to the microtubules. They cross-link microtubules in the cytoplasm or bind to the intermediate filaments. One of such proteins found in nerve cells is called tau. Its accumulation and cross-linking can lead to the formation of so-called neurofibrillary tangles found In the brains of many people with Alzheimer disease. Ci&a and flageDa are mobile projections of the plasma membrane composed of microtubules. They are anchored to the basal body just underneath the membrane. They are moved by dyneins. Cilia are up to 10 )l.m long and move fluids or particles across the cell surface. For instance, cells that line larger airways have cilia that move mucus and small particles out of the lungs. Flagella are much longer; the only human cells that have flagella are sperm. Intermediate filaments are made from a variety of proteins. They form a-helical dimers that twist around one another (see Fig. 2.42Bj. They fulfil a structural role, forming the most stable element of the cytoskeleton and provide support to the nucleus and the plasma membrane. Depending on the tissue, they contain proteins known as vimentin, desmin, and also lamlns and keratins.

Nucleus

a.nelix

Doublet

nucleus and are the centre of the outward growth of the cytoplasmic microtubules. A ca rtroeome contans two centrtolee, also constructed of microtubules, that direct the movement of the chromosomes

Structure of cytoskeletal elements. IF, intermediate

Most eukaryotic cells possess a nucleus. Some cells have more than one nucleus, whereas mammalian red blood cells lose their nucleus as they mature (Ch. 12). The nucleus Is the only organelle that can be seen under a light microscope without staining. The nucleus is surrounded by a double layer of membrane called the nuclear envelope. The inner nuclear membrane is smooth, whereas the outer membrane may be confluent with the ER. The nuclear envelope is studded with pores approximately 9 nm in diameter through which proteins and RNA can pass. The nucleus contains chromatin, which is not normally visible as an organised structure. Inside the nucleus Is one or more dar1~~----~~n:-----tt~~d~ ...... __ .. _ synthase .. ________ .. __ _ .. malate de~ Lr-c~ -=o::-5.-..-.. J

Mitochondrion

1....,~ ~----sc--.tl

@~®

~·---------------------~'

Fig. 3.28

The malate shuttle. Acetyl-GoA and oxaloacetate do not easily cross the mitochondrial membrane and are transported between the mitochondrion and cytosol via the malate-citrate antiporter. The malate shuttle is a method of transporting electrons (and reducing equivalents) from the cytosol to the mitochondrion. ACC, acatyi-CoA carboxylase; PC, pyruvate carboxylase; PDC, pyruvate dehydrogenase complex.

100 Energy metabolism is converted to malate by cytosolic malate dehydrogenase. Malate is then transported back into the mitochondrion, via the malate-citrate antiporter, to be reconverted to oxaloacetate by mitochondrial malate dehydrogenase. In starvation, malate is converted to pyruvate to enter gluconeogenesis.

Fine-tuning of fatty acid synthesis, oxidation and ketogenesis In the liver, as mentioned previously, inhibition of mitochondrial CPT-I by malonyi-CoA, the product of ACC reaction, prevents the catabolism of newly synthesised fatty acids, favouring their esterification to TAG, which is subsequently exported as VLDL. With carbohydrate feeding (high insulin/low glucagon), the liver is actively engaged in fatty acid synthesis. lissue malonyl-coA content is high, and the capacity for mitochondrial long-chain fatty acid oxidation (and consequently ketogenesis) is depressed. Conversely, in starvation and uncontrolled diabetes mellitus, malonyi-CoA levels fall. Hepatic fatty acid synthesis is attenuated, and fatty acids reaching the liver from adipose tissue are efficiently oxidised. The transition between normal and ketotic states is accompanied by marked shifts in the sensitivity of CPT-1 to inhibition by malonyl-coA. As a result, the liver continues to oxidise fat immediately on re-feeding after starvation, enabling gluconeogenesis to continue, and thereby allows glycogen formation via the indirect pathway. The suppressive effect of malonyi-CoA on CPT-1 is not restricted to liver. Regulation of CPT-I in muscle, which is not a major site of fatty acid synthesis, appears to be an important aspect of metabolic fuel selection in muscle. Muscle malonyl-coA concentrations fall with starvation and also acutely in response to exercise, both conditions being associated with increased jk)xidation (when fatty acids become a major source of metabolic energy, ATP).

Regulation of fat metabolism Fat metabolism is controlled by the coordinated action of insulin, glucagon, adrenaline, cortisol and human growth hormone, and interacts with the regulation of carbohydrate metabolism. Insulin stimulates and regulates fatty acid synthesis and storage, promoting glucose uptake in both liver and adipose tissue. The rate of fat catabolism is controlled by the rate of TAG hydrolysis in adipose tissue, activated by rising concentrations of glucagon.

In the fasting (post-absorptive) state As blood glucose concentration falls, glucagon activates hepatic gluconeogenesis, coordinating the release of amino acids and TAG hydrolysis. This results in increasing plasma concentrations of: • Fatty acids • Glycerol • Ketone bodies. Adrenaline secretion, in response to physiological or psychological stress, has a similar effect. Cortisol has a more long-term effect (over weeks) and may cause insulin resistance (Clinical box 3.23).

In the fed (absorptive) state When there is excessive energy intake, especially excessive dietary carbohydrate, the pathways for de novo fatty acid synthesis Oipogenesis) are activated by insulin. The carbohydrate is converted into fatty acids in the liver, then stored as TAG in adipose tissue. In fact, the liver is carrying out gluconeogenesis at all times except

n

Clinical box 3.23 Cushing syndrome

Increased cortisol secretion in Cushing syndrome has a major long-term influence on fat metabolism by: • Increasing gluconeogenesis • Inhibiting glucose uptake and metabolism in peripheral tissues ~nsulin resistance) • Stimulating glycogen degradation and lipolysis. High plasma cortisol concentrations result in: • Hyperglycemia, which may lead to diabetes mellitus • Muscle wasting • Redistribution of adipose tissue from glucagon-sensitive depots to areas such the face, upper back and abdomen, giving the typical appearance of central obesity (apple versus pear shape, see Ch. 16) • Osteoporosis. The character1s11c moon face and 'dowager's hump' In Cushing syndrome is the result of facial fat deposition and thoracic spinal vertebral collapse from osteoporosis leading to kyphosis. Although Cushing syndrome can be the result of advanced adrenal or pituitary disease, it occurs more commonly because of long-term administration of therapeutic steroids.

in the fed state when it performs glycolysis, unlike other tissues that use glycolysis for energy. The liver channels the resulting acetyl-GoA into fatty acid synthesis rather than the TCA cycle for oxidation.

SUMMARY This chapter has discussed the use of metabolic fuels, carbohydrate, fat and protein in different physiological (and some pathological) conditions. What follows is a summary of the use or storage of fuel by the main organs considered in this chapter: namely, the liver, brain, muscle, erythrocyte and adipose tissue. The fed state is characterised by a high insulin:glucagon ratio and the fasting state and starvation by high glucagon/insulin. In the figures that follow, processes taking place in the fed state are in blue and processes taking place in the fasting state are in red. Fig. 3.29 shows the pattern of metabolism in the liver. In the fed state, glucose enters the liver cells via the GLlJT2 transporter, which operates when blood glucose is high. Glucose is converted into glycogen and any excess is converted into TAG, which leaves the liver as very-low-density lipoprotein (VLDL) and is taken up by the adipose tissue for storage. In the fasting state, glycogen is degraded and glucose is released into the bloodstream for use by brain and erythrocyte. When glycogen stores are depleted, the liver carries out gluconeogenesis from muscle amino acids and the glucose is also released into the bloodstream. The liver also takes up FA released by the adipocytes in response to glucagon. The FAs are converted into ketone bodies, which are also released into the bloodstream and are used by brain and muscle as fuel. Fig. 3.30 shows the metabolism in the brain in the fed and fasting state. In both the fed and fasting state, the brain (and neural tissue) use glucose as fuel as FAs are unable to cross the blood-brain barrier. In the fed state, glucose is supplied by the diet and in the fasting state, from liver glycogen and then muscle amino acids. In prolonged starvation, the brain can use ketone bodies produced by the liver for more than 50% of its energy needs. This is important

Summary

Fig. 3.29 Pattern of metabolism in the liver. In the fed state, glucose enters the liver cells via the GLUT2 transporter, which operates when blood glucose is high. Glucose is converted into glycogen and any excess is converted into TAG, which leaves the liver as very-low-density lipoprotein (VL.DL) and is taken up by the adipose tissue for storage. In the fasting state, glycogen is degraded and glucose is released into the bloodstream for use by brain and erythrocyte. When glycogen stores are depleted, the liver carries out gluconeogenesis from muscle amino acids and the glucose is also released into the bloodstream. The liver also takes up FA released by the adipocytes in response to glucagon. The FAs are converted into ketone bodies, which are also released into the bloodstream and are used by brain and muscle as fuel.

101

Fig. 3.31 Metabolism in skeletal muscle in the fed and fasting states. In the fed state, muscle cells take up glucose via the GLUT4 transporter, which is insulin dependent. The glucose is converted into glycogen and stored. Glycogen will be used by the muscle cell only when energy is needed for contraction and is not released into the bloodstream. In fasting, glucose is not taken up by muscle cells because GLUT4 is no longer operating. This saves glucose for use by the brain and erythrocyte. The energy needs of muscle cells are covered by using FAs from adipocytes and ketone bodies produced in the liver.

Glucose from the diet

Gkl:ose from the clet To the IYerfor gluconeogenesis

Fig. 3.30 Metabolism in the brain in the fed and fasting states. In both the fed and fasting states, the brain (and neural tissue) use glucose as fuel because FAs are unable to cross the blood-brain barrier. In the fed state, glucose is supplied by the diet and in the fasting state, from liver glycogen and then muscle amino acids. In prolonged starvation, the brain can use ketone bodies produced by the liver for more than 50% of its energy needs. This is important because it means that glucose supply from muscle amino acids can be reduced, allowing survival for a longer time. Loss of approximately one-third of body protein results in death.

as it means that glucose supply from muscle amino acids can be reduced, allowing survival for a longer time. Loss of approximately one-third of body protein results in death. Rg. 3.31 shows metabolism in skeletal muscle in the fed and fasting state. In the fed state, muscle cells take up glucose via the GLUT4 transporter, which is insulin dependent. The glucose is converted into glycogen and stored. Glycogen will be used by the muscle cell only when energy is needed for contraction and is not released into the bloodstream. In fasting, glucose is not taken up by muscle cells as GLUT4 is no longer operating. This saves glucose for use by the brain and erythrocyte. The energy needs of muscle cells are covered by using FA from adipocytes and ketone bodies produced in the liver.

Fig. 3.32 Metabolism in the erythrocyte in the fed and fasting states. The erythrocyte can use no other fuel than glucose because it lacks mitochondria, which would be needed for FA oxidation. In the fed state, glucose is supplied by the diet. Glycolysis continues to the production of lactate, which allows NAo+ regeneration, which enables glycolysis to continue. The lactate is taken up by the liver for gluconeogenesis. In the fasting state, the erythrocyte is supplied with glucose from glycogen degradation and then by gluconeogenesis using muscle amino acids, both processes taking place in the liver.

Rg. 3.32 shows metabolism in the erythrocyte in the fed and fasting state. The erythrocyte can use no other fuel than glucose, as it lacks mitochondria which would be needed for FA oxidation. In the fed state, glucose is supplied by the diet. Glycolysis continues to the production of lactate which allows NAD+ regeneration, which enables glycolysis to continue. The lactate is taken up by the liver for gluconeogenesis. In the fasting state, the erythrocyte is supplied with glucose from glycogen degradation and then by gluconeogenesis using muscle amino acids, both processes taking place in the liver. Rg. 3.33 shows the metabolic pattern in the adipocyte in the fed and fasting state. In the fed state, dietary TAG derived from chylomicrons and endogenously synthesised TAG from VLDL are hydrolysed by lipoprotein lipase in the capillaries, stimulated by the presence of insulin. FAs from these lipoproteins enter the

102 Energy metabolism

Fig. 3.33 Metabolic pattern in the adipocyte in the fed and fasting states. In the fed state, dietary TAG derived from chylomicrons and endogenously synthesised TAG from VLDL are hydrolysed by lipoprotein lipase in the capillaries stimulated by the presence of insulin. FAs from these lipoproteins enter the adipocyte and are ra-esterified to TAG for storage. Re-esterification requires glycerol-3-phosphate, which is supplied by glycolysis using diet-dertved glucose. Glucose uptake by the adipocyte is possible via the insulin-dependent GLUT4. It is not possible in fasting. In fasting, the adipocyte hydrolyses TAG into FA as a result of hormone-sensitive lipase activation by glucagon. FAs are released into the circulation and are used by muscle as fuel. FAs also reach the liver, where they are converted into ketone bodies, which are also released into the bloodstream. Ketone bodies are used by muscle but, mora importantly, they can be used by the brain in prolonged starvation, thus reducing the need for precious muscle amino acids to be degraded to provide glucose. In this way, the brain is using a fat-derived fuel, which is possible because ketone bodies are small and can cross the blood-brain barrier and diffuse into brain cells. The glycerol released from TAG hydrolysis in the adipocyte is released into the bloodstream and is used for gluconeogenesis by the liver.

adipocyte and are re-esterified to TAG for storage. Re-esterification requires glycerol-3-phosphate, which is supplied by glycolysis using diet-derived glucose. Glucose uptake by the adipocyte is possible via the insulin-dependent GLUT4. It is not possible in fasting. In fasting, the adipocyte hydrolyses TAG into FA as a result of hormone-sensitive lipase activation by glucagon. FAs are released into the circulation and are used by muscle as fuel. FAs also reach the liver, where they are converted into ketone bodies, which are also released into the bloodstream. Ketone bodies are used by muscle but, more importantly, they can be used by brain in prolonged starvation, thus reducing the need for precious muscle amino acids to be degraded to provide glucose. In this way, the brain is using a fat-derived fuel, which is possible as ketone bodies are small and can cross the blood-brain barrier and diffuse into brain cells. The glycerol released from TAG hydrolysis in the adipocyte is released into the bloodstream and is used for gluconeogenesis by the liver. We add a short note here about metabolism in untreated diabetes mellitus type 1. There are similarities to starvation, and diabetes mellitus has been described as starvation in the midst of plenty. The hallmarks are hyperglycaemia and ketoacidosis. Why? In fasting and starvation, the insulin:glucagon ratio is low. In diabetes, there is negligible insulin, so glucagon is acting unopposed and there is no fine-tuning of metabolism. Gluconeogenesis in the liver is proceeding regardless of the fact that blood glucose is high, as there is no insulin to halt it. Lipogenesis is similarly proceeding unopposed and ketone body production does not match the use by muscle and brain to the point that it causes ketoacidosis. Proteolysis is also continuing unchecked because there is no insulin to inhibit it. This provides further material for gluconeogenesis and exacerbation of hyperglycaemia. Uptake of glucose and fat by the periphery is impaired due to lack of insulin, so glycogen synthesis and lipogenesis are compromised as well. Diabetic ketoacidosis is a medical emergency.

Pharmacology Clive Page

Introduction

103

Pharmacodynamics

122

Tenns used in pharmacology

103

Routes of administration of drugs

122 132

Pharmacokinetics

103 106

Drug targets The safety and effectiveness of drugs

The autonomic nervous system

137

Absorption - transfer of drugs across cell membranes Drug distribution Drug metabolism Excretion of drugs and metabolites The mathematics of pharmacokinetics

107 110 113 116 119

Neurotransmitters Functions of the autonomic nervous system Overview of the autonomic nervous system Anatomy of the autonomic nervous system Neurotransmitters and receptors of the autonomic nervous system

137 137 138 139

INTRODUCTION Pharmacology is the science that covers the actions, mechanisms of action, uses, adverse effects and fate of drugs in animals and man. The word 'pharmacology' comes from the ancient Greek word 'pharmakon' and is the science of what drugs do to the body and how the body reacts to xenobiotics, which covers any biologically active substance that is taken with the intent of producing a change in the body. This includes drugs for medicinal use, familiar substances such as caffeine, nicotine and alcohol, drugs of abuse such as cannabis, heroin and cocaine, food constituents such as vitamins, amino acids and proteins, and also cosmetics. Pharmacology is concerned with the investigation of drugs on living systems or their constituent components such as cells, cell membranes, organelles, DNA and lipids. Drugs are routinely investigated at different levels of biological complexity from cloned receptors, cell membranes incorporating drug targets such as receptors or ion channels, cultured cells, isolated tissues or organs and in whole animals or people. A proper understanding of drug action usually requires integrating information across many of these approaches, including investigating unwanted effects of drugs, both at doses considered to be beneficial (safety pharmacology) and when used at higher than recommended doses (toxicology}. The core of pharmacology is to determine the so-called 'therapeutic window', which is the difference in dose between the effective dose and the dose where unwanted side effects arise (Fig. 4.9). This clearly should be as wide as possible, but there is no set number for this window, and the window that might be acceptable for a drug to be used in a life-threatening condition such as cancer might not be acceptable for the treatment of another clinical condition such as rhinitis. In some cases, the therapeutic window of a drug can be improved by altering the route of administration. For example, glucocorticosteroids are very effective drugs for the treatment of a range of inflammatory diseases, but when given orally (e.g. prednisone) have many unwanted side effects at similar doses that are effective at reducing inflammation. However, we now have glucocorticosteroids that can be administered topically as, for example, a cream on the

139

skin, as a spray into the nose or by inhalation to the lung that provide a highly effective anti-inflammatory effect locally in the relevant organ, whilst not being able to readily enter the blood and therefore having far less unwanted effects on other organs.

Terms used in phannacology • •

• •

• •

Pharmacodynamics is the study of what drugs do to the body (or components of the body) Pharmacokinetics is the study of how the body deals with the drug, i.e. how the body absorbs, distributes, metabolises and excretes drugs Therapeutics is the study of the clinical use of drugs to treat diseases in human and veterinary medicine Pharmacogenetics is the study of how the genetic make-up of individuals determines their response to drugs, e.g. in drug metabolism Pharmacoepldemlology is the study of the effect of drugs on populations Pharmacoeconomics is the increasingly important area studying the cost-effectiveness of drugs.

ROUTES OF ADMINISTRATION OF DRUGS Drugs can be administered via a variety of different routes. By far the most common route of administration for many drugs is the oral route as this is often the most convenient for patients, although it also means that if the drug is absorbed into the bloodstream, it has the potential to be distributed throughout the body and thus produce unwanted side effects. However, some drugs may not be readily absorbed or could be metabolised in the gastrointestinal system, meaning that other routes of administration have to be used. For example, insulin (widely used in the treatment of patients with diabetes) is a peptide subject to degradation by protease enzymes in

104 Pharmacology the stomach and has to be administered by subcutaneous injection. Many of the new so-called 'biologics' that are often monoclonal antibodies (proteins) used ina'eaSingly for the treatment of cancer and inflammatory conditions such as rheumatoid arthritis and psoriasis, can also not be administered by mouth and are usually injected subcutaneously or administered intravenously. The intravenous route is also used for the administration of drugs where a rapid onset of action is required: for example, in the induction of general anaesthesia (e.g. thiopentaO or drugs used to influence cardiac arrhythmias (e.g. vernakalant). Drugs that are poorly absorbed are often administered topically/ locally to the organ or tissue of interest such as local anaesthetics (e.g. lidocaine), creams and ointments for the treatment of skin diseases and drugs administered by inhalation to the lungs for the treatment of asthma and chronic obstructive pulmonary disease (COPD) {e.g. bronchodilators such as the 132 agonist salbutamol and anti-inflammatory glucocorticosteroids such as beclometasone diproprionate). Other routes of administration include buccal, sublingual, intranasal, intrathecal, vaginal, rectal, ocular and intramuscular. The different routes of administration will now be discussed in more detail.

Oral administration Oral drug administration is the most commonly used route. It is also the cheapest and most convenient. Its suitability for a specific drug depends on how well the drug is absorbed into the systemic circulation from the gastrointestinal lumen and on how it is metabolised. Oral administration may be used to produce local effects within the gastrointestinal tract or if the drug is absorbed for systemic effects.

Factors affecting gastrointestinal absorption of a drug The factors that affect absorption of a drug from the gastrointestinal lumen into the systemic circulation are: • Drug formulation • Physico-chemical properties • Rate of passage through the gastrointestinal tract.

with neutral pH at the interface of the stomach contents and the gastric mucosa, which acts as a barrier that limits drug absorption.

Surface area for absorption The surface area over which absorption can take place in the stomach is relatively small compared with the small intestine. The surface area in the small intestine is increased 600-fold by the presence of villi and microvilli so that the small intestine is the major site for absorption. This large area allows even ionised drugs to be absorbed. The time taken for the drug to pass through the small intestine also influences absorption. Absorption increases the longer the drug stays in contact with the mucosal surface. Increased gastrointestinal motility, as in diarrhoea, will reduce absorption. Inflammatory bowel disease that destroys the villi will also prevent or reduce absorption.

Fate of drugs in the stomach Apart from the high acidity of the gastric juices, the presence of food, grapefruit juice and other drugs can affect the absorption of certain drugs (Clinical box 4.7): •

Formation of complexes with ions (tetracycline antibiotics and Ca2"') or with food reduces absorption. • Gastric emptying determines the time that it takes for an oral dose of a drug to reach the small intestine where absorption takes place. • Drug formulation: - The active drug in an oral preparation (tablet, capsule, etc.) is only a small proportion of the preparation's constituents. The rest is made up of ingredients that influence the speed and site of absorption: excipients, disintegrating agents, diluents, lubricants, etc. These ingredients and their proportions - the fonnulation - can vary among products containing the same active ingredient, but with the aim of ensuring similar effects, if the product is to be considered

-

Physicochemical properties of the drug, the medium and surface area Absorption of an orally administered drug is influenced by: • Its solubility in water and/or lipids • The characteristics {e.g. pH) of gastrointestinal contents {e.g. from stomach, small intestine, or colon) from which it has to be absorbed into the systemic circulation • The available surface where absorption takes place.

Drug solubility Orally administered drugs have to cross cell membranes in the gastrointestinal tract to be absorbed into the systemic circulation. As drugs exist in the ionised and non-ionised forms, the non-ionised lipid-soluble form moves across cell membranes much more readily than the water-soluble, ionised form. Highly acidic Qonised) and basic drugs are poorly absorbed from the gastrointestinal tract, and most of the dose is excreted in the faeces.

Acid-base considerations As most drugs are weak acids or weak bases, they undergo pH partitioning between the lumen of the gastrointestinal tract and the mucosal cells. Acid drugs are least ionised in the stomach so that they are best absorbed there. Basic drugs are better absorbed in the small intestine, where the pH is higher. There is also a zone

-

'bioequivalent' as a generic version of our innovator product. The formulation determines the rate at which a tablet or capsule disintegrates and dissolves. A drug cannot be absorbed until it is liberated into the gastrointestinal fluid to form a solution. Usually, this occurs rapidly, but there are special modified-release formulations that disintegrate more slowly to control the amount of drug available for absorption over time. Drugs may be affected by the acid gastric juices and need to be protected by having a special acid-resistant coating on the tablet/capsule {enteric coated). For example, mesalazine, used in the treatment of inflammatory bowel disease, is enteric coated to protect the drug from the action of acid gastric juices and is transported to the colon where it is released.

Metabolism of drugs in the gastrointestinal tract How much of an orally administered drug actually enters the systemic circulation and exerts a therapeutic effect is called bioavailability. Because most drugs are, to some extent, metabolised in the gut and liver before reaching the systemic circulation, so-called 'first pass' metabolism in the hepato-portal circulation, bioavailability is not the same as the amount administered. It is calculated by comparison with an intravenously administered equivalent dose that is considered to have 1 00% bioavailability. • The lumen of the intestine contains digestive enzymes that can split amides and esters; proteases can also breakdown

Routes of administration of drugs peptides and proteins, preventing them from being administered by this route of administration • The colon contains a large number of aerobic and anaerobic bacteria that possess enzymes capable of catalysing a number of reactions, including hydroxylation (hydrolysis) and reduction • Phase I hydroxylation and phase II sulphate conjugation enzymes are also present in the intestines (see Drug metabolism, later) • P-glycoproteins 'block' absorption by extruding drug molecules into the intestinal lumen, and may be part of the 'first pass' mechanism (see earlier). Drug metabolism in the intestines reduces bioavailability. A normal oral dose of drug may not be therapeutically effective if much of the dose were inactivated in the intestine or first metabolised by the liver before reaching the systemic circulation via first pass metabolism and thus drugs subjected to this type of effect have to be administered orally at higher doses.

Bioavailability and bioequivalence Although bioavailability indicates the proportion of orally administered drug that reaches the blood, it does not indicate the extent of absorption. Regulatory authorities that approve the use of drugs on humans use the concept of bioequivalence, which is a comparison of the generic drug formulation with the proprietary product to ensure that the new product has a similar pharmacokinetic profile to the originator drug as a proxy for equivalent effectiveness and safety.

First pass metabolism Even if an orally administered drug is absorbed intact, first pass metabolism in the liver reduces bioavailability to a greater or lesser extent. • Some drugs are completely inactivated by first pass metabolism and therefore cannot be administered orally (e.g. glyceryl trinitrate, which has to be administered sublingually for buccal absorption). An alternative route, or a specific drug design, e.g. pro-drug, may be needed to bypass first pass metabolism. • A larger dose of drug may be needed for drugs that are not entirely inactivated by first pass metabolism to achieve a therapeutic effect (e.g. propranolol, aspirin, morphine).

Impact of liver disease on first pass metabolism Extra caution needs to be taken in patients needing long-term medication who have coexisting impaired liver function or in the elderly as: • The drug will not be metabolised as extensively by the liver before entering the systemic circulation • The usual dose of the drug could therefore become an overdose or toxic dose

105

denatured by proteolytic digestive enzymes (e.g. insulin) and other peptides.

Intravenous The intravenous administration of a drug produces a rapid onset of action. A known concentration of drug is administered into the bloodstream, either as a bolus when the whole amount of drug is given as one dose, or by infusion when the total dose is given slowly over a longer period of time. Drugs that would otherwise act as irritants can be administered intravenously, because veins are insensitive and the drug is rapidly diluted by plasma, particularly if injected into a large forearm vein. Factors that determine the rate of systemic absorption after intravenous injection are the solubility of the drug in interstitial fluid and intercellular pores (gap junctions) in the vascular endothelium that promote rapid diffusion, independent of the lipid solubility of the drug. Toxic:ily can be a problem because of the rapidity of drug administration and onset of therapeutic effect. However, intravenous administration of drugs requires trained personnel and is expensive because of sterilisation requirements and storage costs.

Subcutaneous Subcutaneous injection is when the drug is injected just under the skin (e.g. insulin). Absorption is relatively slow, but usually complete and can be improved by massage or heat at the site of injection. Highly ionised or high molecular weight drugs are absorbed by diffusion through large intercellular pores in the capillary endothelium. A vasoconstrictor may be co-administered to delay the absorption of a drug (e.g. epinephrine (adrenaline) with a local anaesthetic agent), thereby prolonging its effect at the site of injection. Drugs that have irritant properties can cause local tissue damage if administered subcutaneously (e.g. thiopental).

Intramuscular Drugs administered intramuscularly are either specialised depot formulations (the drug is in a solvent, or vehicle, that keeps it at the site of injection, to be absorbed gradually over days or weeks), or sustained release preparations. These are a suspension of the drug in a non-aqueous preparation called the vehicle; for example, fluphenazine decanoate used in the treatment of schizophrenia, or depot progestogens used as a long-acting contraceptive. Absorption from injected depot formulations is sometimes erratic, especially for poorly soluble drugs. Additionally, the vehicle may be absorbed faster than the drug, causing precipitation of the drug at the injection site.

Other forms of injection Other forms of injection are used to deliver drugs to their precise site of action, although again trained personnel are needed to perform these techniques.

Parenteral administration

Intrathecal

Parenteral administration is to give a drug by injection. This could be through a variety of methods including intravenous, intramuscular, subcutaneous or intrathecal Onto the cerebrospinal fluid (CSF)) routes. Drugs are administered by injection: • When effective plasma concentrations are needed rapidly. • To bypass first pass metabolism. • When administration by the oral route is not possible, as in severe vomiting. In addition, some drugs are acid labile and are destroyed by the low pH of the stomach contents or

Some drugs have to be delivered directly into the CSF because the blood-brain barrier prevents entry from the systemic circulation. This is done via an intrathecal injection where the drug is injected through the theca of the spinal cord directly into the CSF in the arachnoid space via a lumbar puncture performed under local anaesthesia.

Epidural Epidural injections are delivered into the space surrounding the meninges (dura) and therefore not into the CSF. They are used as

106 Pharmacology a form of local anaesthesia, producing selective nerve block. This can be temporary, using a local anaesthetic, for surgical procedures such as inguinal herniorrhaphy, childbirth and caesarean sections. A more permanent nerve block, using phenol (which destroys the nerves), is sometimes used to relieve intractable pain.

Local injections into tendons/bursae Cortisone injection directly into tendon insertions (for the treatment of tennis elbow and golfer's elbow) and bursae sometimes help to relieve pain, but delays healing.

Buccal/sublingual administration Some drugs are taken as small tablets that are held in the mouth, in contact with the buccal mucosa (buccaO or under the tongue (sublinguaQ (Clinical box 4.8). This route facilitates rapid absorption of lipid-soluble drugs into the systemic circulation across the mucous membranes, thus avoiding first pass metabolism. The delivery of organic nitrate drugs to treat the symptoms of angina are via this route to provide rapid relief of symptoms. It is also used as an alternative to subcutaneous injection for the delivery of allergens to allergic patients undergoing 'immunotherapy'.

Rectal The rectal route is useful for patients who are unable to take drugs orally because of vomiting and for younger children. When given as a suppository or enema, more than 50% of the drug absorbed via the rectum bypasses the liver and so the effect of first pass metabolism is reduced. However, absorption is often incomplete and erratic, and it may also cause irritation of the rectal mucosa.

TopicaVtransdennal Some drugs are formulated for direct application to the skin for topical cutaneous application when a local effect is needed. Some absorption through the skin (transdermal absorption) can, however, take place to give systemic effects. To produce local effects, some drugs are applied directly (topical application) to the mucous membranes of the conjunctiva, or vagina. Lipid-soluble drugs can be formulated as skin patches to allow absorption through the skin (dermis) for systemic effects, known as the transdennal route. Nicotine patches are an example of this route of administration to help reduce smoking. The topical and transdermal routes of administration bypass first pass metabolism. Some drugs are formulated for topical application so that they can be absorbed through the skin to bypass possible adverse side effects on the gastrointestinal tract {see Clinical box 4.8).

is rapid because of the large surface area of the alveolar regions in close proximity to the pulmonary vascular bed. In the treatment of lung disorders (e.g. asthma and COPD), drugs can be inhaled as a powder or an atomised solution of a drug, which enables a high concentration of drug to be delivered directly to the target structures, for example airway smooth muscle, whilst minimising significant systemic side effects. Drugs can also be formulated for inhalation in a way that deliberately increases lung retention and by reducing their absorption across cell membranes, to reduce unwanted systemic side effects. Thus, the physical characteristics of the formulation, i.e. size of the particle, play an important role in determining the effectiveness of the drug. Particles greater than 20 IJll1 in diameter stay in the mouth and throat and are swallowed, but 2-61Jll1 diameter particles penetrate deep into the lungs to produce a rapid local effect in the lung or, depending on the drug, to be absorbed into the bloodstream to produce a systemic effect. Examples of the latter approach are the recent inhaled formulations of insulin as an alternative to injections for the treatment of diabetes.

PHARMACOKINETICS Pharmacokinetics is the study of how the body deals with drugs once they have been administered. It is necessary to understand how a drug is absorbed (or not) and the fate of the drug once in contact with the body, i.e. how it is distributed, metabolised and eliminated, as these factors will determine the speed of onset, intensity and duration of drug action, and thus, for a drug to be used chronically, the dosing regimen. The formulation and route of administration of a drug are also other important factors to be considered (see later) (Fig. 4.1f. • Absorption, into the body and into cells • Distribution, around the different compartments of the body

Route of administration

I

(

Intravenous

Intranasal administration Some drugs are administered as a nasal spray, to be absorbed through the mucous membrane to act directly on the nasal mucosa or to target the pituitary gland. Examples include: • Vasopressin used in the treatment of diabetes insipidus • Calcitonin as a treatment of bone disease • Bromocriptine used for the suppression of lactation, hyperprolactinaemic disorders and the downregulation of menstrual cycles in the treatment of infertility • Glucocorticosteroids for the treatment of allergic rhinitis (hay fever).

Inhalation Gaseous and volatile drugs (e.g. the general anaesthetics nitrous oxide (N20) and halothane, respectively) are administered by inhalation. Absorption of these drugs into the systemic circulation from the lungs

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Fig. 4.1 The relationship between absorption, distribution, metabolism and excretion of a drug. The route of administration determines the degree of absorption , and thus the dose required for sufficient drug to enter plasma in the systemic circulation. The drug leaves the plasma to be distributed to its site of action and to storage sites (fat deposits). Finally, the majority of drugs are metabolised before excretion.

Pharmacokinetics •

Metabolism, when the drug is broken down and inactivated, or sometimes transformed into an active form • Elimination or excretion from the body. To produce a pharmacological response, a drug needs to achieve an adequate concentration at the site of action. The two fundamental processes that determine the concentration of a drug in any given part of the body are: • Absorption, the process of transfer of a drug from its site of administration into the systemic circulation, and into tissues where the drug exerts its therapeutic effect. Both necessitate the transfer of a drug across cell membranes. • Distribution of drug molecules from the site of administration to other parts of the body and ultimately organs involved in metabolism or excretion of the drug from the body.

II

107

Information box 4.1 1he relative ease with which drugs permeate cell membranes

The lipid solubility of a drug determines whether it can permeate cell membranes through passive diffusion. • Aminoglycoside antibiotics are suflicienUy lipid soluble for the whole molecule to permeate cell membranes. • Thiopental, a general anaesthetic, Is highly lipid soluble and can rapidly permeate cell membranes in the central nervous system (CNS) and therefore has a rapid onset of action, making it useful as a general anaesthetic. • Phenobarbital, of the same family of barbiturates as thiopental, used for its sedative and anti-epileptic action, is much less lipid soluble. Phenobarbital enters the CNS much more slowly, and is used in more long-term treatment.

Absorption - transfer of drugs across cell membranes T...._ 4.1 Varlllllon In piC., of druga and pH of body tlulda Absorption is important for all routes of drug administration except intravenous injection. The degree of absorption depends on the route chosen and the physicochemical properties of the drug. Cell membranes form barriers between intracellular and extracellular aqueous compartments in the body. A drug must cross at least one cell membrane to be absorbed, reach its site of action and eventually be eliminated. The ways that drugs, nutrients and other substances (solutes) in aqueous solution cross a membrane barrier are by: • Passive diffusion through cell membranes • Carrier-mediated transport • Endocytosis and exocytosis • Diffusion through aqueous pores and intracellular pores.

Passive diffusion through lipid membranes The majority of drugs pass through cell membranes by passive diffusion of molecules down a concentration gradient, a process which does not involve energy expenditure (see Ch. 2) and is not saturable. As cell membranes are composed of a double layer of phospholipid molecules, the drug has to be lipid soluble to diffuse across them. The rate of diffusion across the membrane depends on: • The lipid solubility of the drug • The area over which absorption occurs • The concentration gradient across the membrane. Molecular size has little effect on diffusion because most drugs have a molecular mass of below 1000 daltons.

Lipid solubility The human body largely consists of water, which forms the major part of extracellular and intracellular fluids (see Ch. 2). A drug must be water soluble to be distributed throughout the body. However, cell membranes that separate the extracellular from the intracellular compartments are mostly composed of lipids. The ability of a drug to enter or exit cells will depend on its lipid solubility. Some drugs are sufficiently lipid soluble to permeate the lipid membrane. Drugs that are not lipid soluble need to be transported across the cell membrane (Information box 4.1}.

Ionised and non-ionised forms of a drug Most drug molecules exist in solution as a mixture of ionised and non-ionised forms. The ionised form carries an electrical charge, has very low lipid solubility and cannot easily permeate lipid membranes. Most ionised drugs are weak organic acids. The

Variation 1n pK. or c~n~ge

YMatlon In pH of body fluld8 Normal pH

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Adenosine Adenosine triphosphate (AlP)

Substance P Met-en kephalin ~Endorphin

Dynorphlns Somatostatin Cholecystokinin

Many classical transmitters have both ionotropic and metabotropic receptors and hence are both fast and slow transmitters. When a neurotransmitter binds to an ionotropic receptor, ion channels open, permitting ions to flow in. This produces a postsynaptic current that changes the membrane potential, generating a postsynaptic potential, which is either excitatory or inhibitory. If activation of a receptor causes a net inward current, the postsynaptic membrane depolarises. This is an excitatory postsynaptic potential (EPSP) as it brings the cell closer to the threshold for firing action potentials. Glutamate and acetylcholine produce EPSPs via non-selective cation channels (Rg. 8.29A). Conversely, receptor activation that results in a net outward current makes the membrane potential become more negative and produces an Inhibitory postsynaptic polanllal (IPSP), so reducing the probability of the postsynaptic neuron firing. GABA ("f'aminobutyrate) and glycine are the principal inhibitory neurotransmitters and act on ion channels selective for chloride or potassium (Fig. ~ .

Summation In contrast to action potentials, which maintain their amplitude as they pass along the axon, postsynaptic potentials get smaller, or decay, both with time and distance. At any given instant one neuron may receive EPSPs and IPSPs from hundreds or thousands of neurons. However, postsynaptic potentials can combine together to form a larger potential. This is referred to as summation. Whether or not the postsynaptic neuron fires is dependent on the summed potential {i.e. the combined effects of EPSPs and IPSPs) arriving at its axon hillock. There are two types of summation, temporal and spatial (Rg. 8.30). If for simplicity we imagine only EPSPs: • Temporal summation occurs when EPSPs arrive rapidly one after the other at the same target cell, without the time to decay, bringing the membrane potential to threshold. • Spatial summation is when EPSPs from different sites on the neuron combine at the same time. If only IPSPs were summed, the membrane potential would move away from threshold.

Neurotransmitter inactivation The effect of the neurotransmitter is terminated in three main ways: • Reuptake of the transmitter by the presynaptic neuron or by glial cells. • Enzymatic destruction, for example of acetylcholine, which is broken down into acetate and choline by the enzyme acetylcholinesterase. Several drugs act on acetylcholinesterase (see Ch. 4). • Diffusion away from the synaptic cleft. This occurs slowly with peptide transmitters, explaining their long duration of action.

Transmission of neural signals 351

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(A) Glutamate and acetylcholine produce excitatory postsynaptic potentials (EPSPs); (B) y-aminobutyrate (GABA) and glycine produce inhibitory postsynaptic potentials (IPSPs). (Redrawn from Longstaff A 2005 Instant notes in neuroscience, 2nd edn. Taylor & Francis,

Abingdon, with permission.)

Stimuli in input 1

2mvL 2ms

Fig. 8.30 Summation. (A) Three inputs onto different regions of a cortical pyramidal cell: 1 and 2 are excitatory, 3 is inhibitory. (B) Postsynaptic potentials recorded from the cell body after stimulating each of the inputs indMdually. (C) Spatial summation: postsynaptic potentials caused by stimulating pairs of inputs at the same time. (D) Temporal summation: the postsynaptic potential generated by repeated stimulation of an excitatory input.

Presynaptic receptors Presynaptic receptors can regulate neurotransmitter synthesis and release in the CNS and peripheral nervous system. A presynaptic receptor that is stimulated by the same transmitter released by the neuron is known as an autoreceptor. These can be inhibitory or excitatory. When a transmitter different to that released by the neuron acts on the presynaptic receptor, it is termed a heteroceptor.

Types of neurotransmitters There are five main types of neurotransmitter: amino acids, acetylcholine, monoamines, purines and peptides (see Table 8.6) (see also Ch. 4).

Amino acids Excitatory amino acids The principal excitatory amino acid transmitter is glutamate. It is widespread throughout the CNS and most cells in the cerebral cortex respond to glutamate. Glutamate is synthesised in neurons from glutamine and is then pumped into vesicles. After release it is removed from the synaptic cleft by glutamate transporters in neurons and glia {Rg. 8.31A). In neurons the glutamate is probably metabolised, although some

352 The nervous system

n

@

Synaptic cleft

Cell death that occurs in the penumbra of a stroke infarct is caused by the excessive release of glutamate from neurons. This phenomenon is termed exciloloxicily. The sequence of events is as follows: 1. Hypoxia from the lack of blood flow causes failure of the Na+IK+-ATPase, leading to c:yto1DXIc oedema and a fall in the extracellular fluid (ECF) volume. 2. K+ ions accumulate in the ECF, depolarising neurons, opening voltage-gated ca2t channels, driving the release of glutamate. 3. Large-scale acllvaHon of AMPA receptors lifts the Mg2t block on NMDA receptors, allowing more ca2+ influx. 4. In the absence of energy to power them, transport mechanisms that keep cytoplasmic concentrations low are overloaded. 5. High intracellular Ca2+ triggers apoptosis or cell death.

n

®

gin Glia Giutamine synthase gluGABA GABA

l

transaminase

GliaiGABA transporter

Synaptic cleft

Fig. 8.31 Metabolism of (A) glutamate and (B) "t'aminobutyrate (GABA). gin, glutamine; glu, glutamate. may be reused as a transmitter, but in glial cells it is converted to glutamine, which is taken up by neurons. Glutamate acts at both ionotropic and metabotropic receptors, responsible for fast and slow transmission, respectively. Two populations of ionotropic receptors mediate glutamate fast transmission: • AMPA receptors: when glutamate binds, a conformation shift allows an influx of Na+ ions. A less common subtype, AMPA-kainate receptors, are also permeable to ca2+. • NMDA receptors: these are ion channels particularly permeable to Ccf+. These channels need to bind not only to glutamate but also to glycine, as a co-agonist, to open. In addition, at normal resting membrane potentials, the ion channel is blocked by Mg2+ ions, which must be removed by depolarisation to allow Ca2+ to enter. NMDA receptors have a role in the rewiring of neural circuits during development and are involved in learning. In high concentration, glutamate is toxic to the brain. It may be responsible for cell death in stroke Onformation box 8.7) and in status epilepticus. Reduced reuptake by glial glutamate transporter may underlie the excitotoxicity seen in motor neuron disease, a condition characterised by loss of motor neurons.

Inhibitory amino acids The main inhibitory amino acid throughout the CNS is GABA, whilst glycine has a major inhibitory role in the brainstem and spinal cord.

lnfonnation box 8.7 Excitotoxicity and strokes

lnfonnatlon box 8.8 Drugs acting at

~ receptor&

Several drugs act at y-aminobutyrate (GABA)A receptors, particularly barbiturates and benzodiazepines. The barbiturates (e.g. phenobar1bital) and benzodiazepines (e.g. diazepam) both bind to separate sites, which allosterically alter the affinity for GABA binding. Binding of the drug and GABA produces a greater flux of cl- through the ~ receptor than does GABA alone, thereby enhancing inhibition. Both these drug groups cause sedation. Highly lipophilic barbiturates (e.g. thiopentaQ cnoss the bloocl-brain barrier very easily and are used Intravenously for rapid Induction of anaesthesia. Benzodlazeplnes can be used intravenously to provide sedation for minor procedures and are used to terminate seizures in status epilepticus. Some are used orally in epilepsy treatment (e.g. clonazepam) but sedation limits their usefulness. Some bar1biturates (e.g. phenobar1bitaQ have a specific anticonvulsant acHon and are used In the long-term management of epilepsy. Oral benzodiazepines are sometimes used short-tenn as anxiolytics (i.e. anxietyreducing agents). Elhlnol acts on ~ receptors and this contributes to the lntoxlcaHon and ataxia of drunkenness. Flumazenil, an antagonist of the benzodiazepine binding site on the GABA,. receptor, reverses the effects of benzodiazepine overdose and the central nervous system effects of acute ethanol intoxication. There are compounds that bind to the G~ benzodiazepine site which reduce the GABA·evoked chloride flux. These 111¥8118 qoniiiB have the opposite pharmacological profile to the usual agonist benzodiazepines; they are procorMJisants and anxiety-producing.

GABA is a synthesised from glutamate; after release, GABA is taken up by specific transporters into both neurons and glia, and is then catabolised to succinic semialdehyde by the mitochondrial enzyme GABA transaminase (Rg. 8.3111). The GABA analogue anticonvulsant vigabatrin is an irreversible competitive inhibitor of GABA transaminase and is thought to act by increasing the neurotransmitter pool of GABA There are both ionotropic (GABA,J receptors Onformation box 8.8) and metabotropic (GABAa) receptors. Binding of GABA to GABA,. receptors allows the influx of Cl- ions, causing hyperpolarisation of cells and taking the neuron further from its threshold potential. Glycine receptors have a similar mode of action to GABA,. receptors. GABAergic neurons represent the sole output of the cerebellar cortex and play a major role in basal ganglia pathways. Both GABA and glycine are used by many intemeurons, including those involved in regulation of muscle tone (see later).

Transmission of neural signals 353

----

iii Tlble 8.7 MaJor cholinergic palhwayl Ortgln

Dednatlon

Pontine reticular formation

Tlble 8.1 MaJor dop8mlnerglc pathways

Role

Ortgln

Dednatlon

Role

Forebrail {thalamus) and spinal cord

Sleep and wakefukless

Substantia nigra (nigrostriatal)

Striatum

Intentional movement

Tegmentum (masolimbic)

Umble system

Reward, motivation

Tegmentum (mesocortical)

Prefrontal cortex

Working memory Cognitive tasks

Hypothalamus (tuberolnfundlbular)

Median eminence

PitUitary secretion of prolactin

Hypothalamus

Spinal grey matlllr

Sympathetic

Forebrain

Cerebral cortex

Cortical arousal

Septum

Hippocampus

Learning and memory

Ventral hom of spinal grey matter

Skeletal muscle

Movement

EEE Tlble 8.8 Norachnerglc Mel ad~ palhwayll Ortgln

DMtlnatlon

Role

Locus coeruleus (dorsal pons)

Widely throughout

Sleep and arousal

brain but especially

8.10 Major ..-otanerglc palhwayll

cersbral cortex Nucleus ambiguus (ventral medulla) Nucleus of the solitary tract

Hypothalamus

Hypothalamus

Parabrachial nucleus

Spinal cord

Deatlnetlon

Role

Medulla and

Spinal cord

Pain perception Autonomic modulation Modulation of motor output

and midbrain

Mecial forebrain bundle, especialy hypothalamus

Cardiovascular and thermoregulatory homeostasis

Dorsal pons

Cerebral cortex

Cortical modulation

Dol$81 pons

Pons (cholinergic naurons)

Termlnatlon of rapid f1Y8 movement (REM) sleep

Several raphe nuclei

Cersbral blood

Regulation of cersbral blood flow

ventral pons

Effects on visceral and ventilatory networks

Dorsal pons

Motor nucleus of vagus nerve (dorsal medulla) Pons

Origin

Endocrine and cardiovascular functions

and midbrain

Pain perception (AD) Tonic vasoconstriction (NA)

Acetylcholine

VBIIseiS

Choroid plexus

Secretion of cersbrospinal fluid

The metabolism and receptors for acetylcholine (ACh) are described in Chapter 4 and at the neuromuscular junction in Chapter 9. There are four major cholinergic pathways in the CNS (Table 8.7). In the brain, systems (see Fig. B.61 1ater). Others are involved via the hypothalamus with endocrine and autonomic function, and

cholinergic pathways are thought important in memory formation. Loss of cholinergic neurons occurs in Alzheimer disease, in which symptoms are aggravated by anticholinergic drugs.

Monoamines

those to the spinal cord modulate pain transmission. •

The major brain monoamines are: • •

Loss of these neurons occurs in Parkinson disease (PD). The mesolimbic and mesocortical pathways are involved in reward,

The catecholamines: norepinephrine (noradrenaline) and epinephrine (adrenaline), dopamine Serotonin (5-hydroxytryptarnine, 5-HT)

motivation and cognitive pathways. 0 1 agonists are used in PD and in some endocrine disorders (see Ch. 1 0). 0 2 antagonists are used in schizophrenia, which is associated with defects

• Histamine. The metabolism and receptors for norepinephrine and epinephrine and the metabolism of dopamine are dealt with in Chapter 4 . Dopamine receptors are G-protein-coupled receptors and fall into two families:

Dopamine: the largest concentration of dopaminergic neurons is in the nigrostriatal pathway in the basal ganglia system.

in dopamine neurotransmission in the mesolimbic and mesocortical systems. •

Dt family (01 and 05) act through G., increasing cAMP levels, causing

Serotonin: there are multiple serotonergic pathways; ascending pathways participate in regulation of temperature,

excitation; and 0 2 family (02 , 0 3 and D,J, which are G1 linked, reduce cAMP and are inhibitory.

sleep, eating, and in emotional responses. The latter explains the probable relation between reduced serotonergic

Serotonin is synthesised from tryptophan first by hydroxylation,

transmission and depression and the use of selective

then decarboxylation. Serotonin is removed from the synaptic cleft by a specific transport system. The synthesis and release of transmitter

serotonin reuptake inhibitors (SSRis) in its treatment. The recreational drug 'Ecstasy' (3,4-methylene-

from many catecholaminergic neurons and serotonergic neurons is regulated by autoreceptors. Histamine receptors are discussed

dioxymethamphetarnine, MOMA) reduces anxiety and produces euphoria by competing with serotonin for the

in Chapter 6. The cell bodies of neurons containing monoaminergic transmitters

reuptake system, thus increasing cytoplasmic serotonin levels Onformation box 8.9).

are mainly found in the brainstem, but their axons are widely distributed throughout the CNS. Tables 8.8-8.10 summarise the main pathways; brief notes on each follow. • Norepinephrine and epinephrine: noradrenergic neurons in the locus coeruleus are important in sleep and brain arousal

•

Histamine: concentrated in the tuberomammillary nucleus, histaminergic neurons project widely in the CNS. They are involved in sleep and arousal system. Antihistamines (H2 antagonists) that cross the blood-brain barrier may cause drowsiness as a side effect.

354 The nervous system

n

lnfonnation box 8.9 Serotonin, GABA and anxiety

Serotonin neurotransmission is implicated in anxiety: • In animal experiments, destruction of serutonergic neurons reduces behaviours associated with anxiety. • There is an association between anxiety and a long version of the gene for the serutonin transporter that clears serutonin from the synaptic cleft faster than the short version. • Serotonin 5-HT1A receptors are inhibitory metabotropic autoreceptors of serotonergic nerve terminals which decrease serotonin secretion. Partial agonlsts of 5-KT,A receptors (e.g. busplrone) - which reduce serotonin release - have proved to be clinically potent anxlolyllc (anxiety-reducing) agents. GABA (y-aminobutyrate) transmission is implicated in anxiety because high numbers of GABA,., receptors are found in the limbic system, parUcular1y In the amygdala, and benzodlazeplnes (see Information box 8.8) are anxiolytic. Benzodiazepine inverse agonists are actually anxiogenic (anxiety-generating) agents. It is possible that there are endogenous inverse agonists that are mediators of anxiety. Serotonergic neurons are inhibited by GABAergic neurons, so indirect actlons on serotonin transmission may contribute to the anxlolytlc actions of benzodiazepines.

iii T...._ 8.11 Rec:eplcn for purine neu~ "-Ptor

TIWI8duc:llon

Endogenoua agoniats

G-protein-coupled

Adenosine

receptor, lnct'118S11S

Caffeine, theophylline

cAMP G-protein-coupled receptor, decreases cAMP

Adenosine

Ugand-gated cation channel

Adenosine triphosphate (ATP)

G-protein-coupled

ATP, adenosine diphosphate (ADP)

receptor

Purines The purine neurotransmitters are ATP and adenosine. A number of receptors have been identified (Table 8.11) at sites in both the CNS and PNS. Their function is not fully understood. ATP is co-released with classical transmitters fnom postganglionic autonomic fibres and some central synapses. Thus, it acts as a co-transmitter with norepinephrine in some sympathetic pathways and with acetylcholine in certain postganglionic parasympathetic synapses. There is also evidence of its release from sensory afferents in the spinal cord. Adenosine acts at ~ presynaptic receptors, reducing the release of a number of transmitters in the peripheral and CNS, particularly excitatory glutamate. Adenosine levels rise when brain metabolism is very high (e.g. during an epileptic seizure), or during ischaemia. By inhibiting glutamate release, adenosine may naturally curtail seizure actMty and be neuroprotective in ischaemia. ~ receptors are located in nociceptors in the heart. Adenosine levels rise in cardiac ischaemia and these receptors may help mediate the pain of angina.

Peptides There are a large number of neuropeptides. They include some originally identified in the gastrointestinal tract and so are sometimes termed gut-brain peptides. These include cholecystokinin, vasoactive intestinal peptide, somatostatin and substance P. Substance P

=== T..,._ 8.12 Oplold raceptor1

Ill

RecepiDr

Location

Endogenoua ligand

Prehnntlal agonla'la.

J4

Ubiquitous

!!-Endorphin, dynorphin

Morphine and analogues (e.g. fentanyl)

li

Spinal cord

~-Endorphin ,

enkephalins 1:

Peripheral nervous system

IJ-Endorphln, dynorphln

Benzomorphans (e.g. pentazocine)

•Au receptors are blocked by oplold antagonists (e.g. naloxone).

belongs to a family of peptides called tachyklnlns. The other major family is the opioids. • Tachykinins: substance P is an excitatory transmitter in several brain regions including the cerebral cortex, striatum and substantia nigra. It is released by both central and peripheral terminals of C fibre primary afferents. The central terminals carry pain and temperature information to dorsal horn cells, while release from peripheral terminals causes neurogenic inflammation (see late~. Other members of the tachykinin family include substance K and neurokinins A and B. • Opioids: act on opioid receptors, the targets for opiate drugs such as morphine. Opioids make up an entire class of transmitters. They include enkephalin, met-enkephalin and leu-enkephalin, j}-endorphin and dynorphin. They are generally inhibitory and co-released with classical transmitters, e.g. GABA and serotonin. They are widely distributed, including in the basal ganglia, limbic system and hypothalamus. Opioid transmission is thought to be important in analgesia pathways in the CNS and is also implicated in emotion and behavioural pathways. The properties of opioid receptors are summarised in Table 8.12. There are three populations - all are G-protein-coupled receptors. The euphoria, dependence and respiratory depression of opiate drugs relate to the 11 opioid receptors. The symptoms of opiate drug overdose may be treated with opiate antagonists (e.g. naloxone).

MOTOR CONTROL AND PATHWAYS The control of motor activities involves a multiplicity of systems and pathways. It is useful to consider a hierarchy of motor systems that are interconnected with sensory input at all levels. Beginning at the highest level of motor function the hierarchy is as follows: • The motor cortex in the fnontal lobe is where voluntary movements are planned and executed from. Signals are sent fnom here by descending pathways to motor nuclei in the brainstem and spinal cord. • The basal ganglia are also involved in the initiation and scaling of motor actions through connections with the motor cortex. • The cerebellum also influences activity in the motor cortex and is important in the timing, coordination and accuracy of movements. • At an intermediate level, a number of nuclei in the brainstem (e.g. reticular, vestibular and red nucleO provide descending tracts that influence lower motor neurons particularly involved in postural mechanisms.

Motor control and pathways 355 •

The lowest level of the hierarchy is represented by the motor neurons of cranial nerves in the brainstem and the a motor neurons in the spinal cord, which are the targets of the descending motor pathways. These neurons and their axons to muscles are described as the final common pathway for motor action. Voluntary, goal-directed motor sequences require the involvement of the highest levels, while some coordinated, largely automatic movements, such as walking or the maintenance of posture, rely on intermediate levels of function. Many reflexes, however, occur at the lowest level only, involving sensory input and the action of cranial nerve and spinal cord motor neurons. Sensory input is important at all levels of the hierarchy and plays an important role in feedback and feedforward controls of voluntary movements: • Feedback control: when a voluntary movement is made, sensory signals in the form of proprioception (which provides information about the position of joints and muscles and muscle movement) are sent to the cerebrum and cerebellum. If there is a difference between the desired position and actual position, it is termed an en-or signal. This allows a correction to be made to the movement. • Feedforward control: sensory information gives advance information so the required movement can be anticipated and directed to the target (e.g. picking up a pencil).

Premotor and supplementary motor cortices Immediately anterior to the primary motor cortex is the premotor cortex (Brodmann area 6) and anterior to it is the supplementary motor cortex. These are thought to plan movements because functional imaging shows increased activity in these areas when subjects are asked to think about a motor activity without actually doing it. The premotor cortex receives input from sensory and visual cortices and from the basal ganglia and cerebellum via the thalamus. It projects to the corticospinal and reticulospinal tracts. The supplementary motor area also receives input from the basal ganglia and from the contralateral motor cortex. It appears to have a role in integrating movements performed simultaneously by both sides of the body.

Lateral motor pathways There are two lateral motor pathways. The major tract and principal controller of muscle activity is the corticospinal tract. The other, the rubrospinal bact, originates in the same motor cortex areas as the corticospinal tract and runs in the corticorubral tract to the red nucleus in the midbrain. The rubrospinal tract is functionally similar to the corticospinal tract and is not discussed further in this chapter. The corticospinal (or pyramidaQ tract (Rg. 8.33} arises from neurons in the motor cortex, and fibres descend as the corona raclala and internal capsula (Clinical box 8.13) to enter the brainstem.

Motor cortex The motor cortex is the part of the cerebral cortex where voluntary movements are planned, controlled and executed. It is composed of the primary motor cortex and the premotor and supplementary motor cortices. Its principal output is by the lateral motor pathways.

Primary motor cortex Immediately anterior to the central sulcus is the precentral gyrus of the frontal lobe (see Fig. 8.8). This is the site of the primary motor cortex {M1 or motor strtp), Brodmann area 4. Each motor strip controls movement of the opposite (contralateraO side of the body. It has a somatotopic map of body movements in which areas such as those controlling hand, tongue and larynx are disproportionately large, reflecting the complexity of movement associated with these structures. The map is termed the motor homunculus (Fig. 8.32}. Lesions, particularly tumours, affecting particular parts of the primary motor cortex can lead to a disturbance of function in individual parts of the head or body (Clinical box 8.12). The map also helps explain the way in which partial motor seizures Oacksonian epilepsy) start with clonic movements in one area, which may spread (e.g. begins in fingers and can spread to arms and then becomes more generalised). The motor cortex controls movements rather than the activation of single muscles. Populations of cortical neurons act together to determine the direction and force of movements. The main function of the primary motor cortex is the execution of movements with projections to brainstem and spinal motor neurons principally in the corticospinal tract.

n

Clinical box 8.12 Parasagittal meningioma

Meningiomas are slow-gruwing tumours that arise from arachnoid granulations. When they develop in the midline near the vertex they can extend through the falx and, by causing pressure on both motor homunculi, lead to bilateral leg weakness, which might be misinterpreted as arising from a spinal cord lesion.

Fig. 8.32

Somatotopic map of the primary motor cortex. Compare it with the somatosensory map in Rg. 8.43. {Redrawn from

Penfield

w, Rasmussen T 1952 The cerebral cortex of man.

Macmillan Press, New YOlk, with permission.)

n

Clinical box 8.13 Internal capsule

All the corticospinal tract fibres are packed close together in the internal capsule, which receives its blood supply from the lenticulostriate branches of the middle cerebral artery. When these branches, or the middle cerebral artery itself, are occluded in a stroke, the result is paralysis of the lower part of the face and of the arm and leg on the opposite side of the body o.e. a contralateral hemiplegia).

356 The nervous system Motor cortex Caudate nucleus Thalamus

Corona radiata

Internal capsule

MIDBRAIN

MIDBRAIN Pontine reticular nuclei--+--------
4 g. Rates of acute renal failure, 49%~5%, 15%: haemodialysis. However, liposomal formulations (AmBisome) have rendered it safe and reduced risk of nephrotoxicity. Heavy metals such as lead, cadmium, mercury, lithium, arsenic and bismuth are well recognised causes of renal impairment. Discussion of this topic is beyond the scope of this chapter.

•

Proton pump inhibitors PPis such as omeprazole have been used since the late 1980s as an effective treatment for numerous gastrointestinal disorders such as gastroesophageal reflux disease (GORD) and peptic ulcer disease. Recently, several observational studies have raised concerns regarding increased incidence of AIN, AKI and CKD in patients using PPis. There is increasing evidence that PPis can cause renal impairment. Studies also show that the risk appears to be related to PPI use itself and not to the underlying problems; histamine-2 receptor antagonists, which are also used to treat gastroesophageal reflux, did not show a similar association. We would advise caution regarding the use of PPis in patients at risk of AKI or CKD. An alternative agent such as a histamine-2 receptor blocker seems a better option in such cases.

682 The renal system Metformin

iii T8ble 14.7 Clullftcldlon of chronic kidney dlleele

Metformin is often falsely considered to be harmful to the kidneys. In fact, nephrotoxicity due to metformin is a myth; the actual fact is that it is not a nephrotoxic drug. Theoretically it can accumulate in renal failure and increase the risk of lactic acidosis. However, all the available evidence, including Cochrane reviews, has shown no significant increase in incidence of lactic acidosis.

Staaee &tlrnated glomerular filtmlonndll 90+

Nonnal kidney function but urine findings or structural abnormalities or g~ic trait point to kidney disease

~9

Mildly reduced kidney fooction, and other findings (as for stage 1) point to kidney disease

3A

45-{)9

Moderately reduced kidney function

3B

30-44

2

Drugs and the elderly In the elderly and those with pre-existing renal dysfunction, great care must be taken if drugs with known nephrotoxicity are used. Poor renal function results in the patient being exposed to a higher, potentially toxic level as it takes longer for the drug to be cleared from the tubule cells than in those with normal renal function. Digoxin is a case in point and the failing heart impairs the renal excretion, thus leading to digoxin toxicity. Although the values of plasma creatinine and creatinine clearance give earty warning of renal impairment in most patients, this can be misleading in the elderly with a low muscle mass, as the creatinine values may be only slightly elevated while renal function is depressed. In addition, if the patient is volume depleted, the conservation of sodium and water can over-ride the normal expected response and may lead to a poor clearance of drugs by tubular secretion. Even if the treatment is terminated, the retention of the drugs in the tubular cells can lead to continued damage. Treatment consists initially of fluid maintenance and electrolyte balance. The use of diuretics such as furosemide and matolazone can help but great care must be taken in monitoring renal function.

Chronic kidney disease CKD is a clinical syndrome caused by irreversible and progressive renal injury which is persistent for at least 3 months. This condition leads to a rise in plasma creatinine and in blood urea nitrogen (BUN), which is caused by a fall in GFR. In addition, other functions of the kidney are also impaired, such as the failure to secrete hormones such as erythropoietin and calcitriol, which can lead to anaemia and hypocalcaemia. The elevation of plasma urea is referred to as uraemia or azotaemia, and is seen in both chronic and acute renal failure. A new classification of CKD (Table 14.7) is clinically used and the stages of CKD are mainly based on measured or estimated GFR calculated by the modification of diet in renal disease (MDRD} equation. This staging is an important tool in early identification and management of CKD.

Causes of chronic kidney disease CKD can be caused by a wide variety of conditions: • Diabetes mellitus is the commonest, which accounts for some 30%-40% of the cases needing dialysis. Type 1 diabetes leads to chronic renal failure after approximately 10 years, the first signs being microalbuminuria accompanied by diabetic neuropathy and retinopathy. It can also occur in type 2 dialbetes, which is also dependent on the duration of the condition and on good glucose control. The mechanisms underlying diabetic nephropathy are discussed in detail in Chapter3. • Hypertension is also a major cause of chronic renal failure, which causes thickening of the arterioles and nephrosclerosis, and is limited by reducing the blood pressure. • The third most common cause of CKD is glomerulonephritis, which includes conditions such as membranous nephropathy,

4

15-29

Severely reduced kidney function

5

300 mglg

~OOmg/g

...---------.·

~TW~agement

of ctvonlc kidney disease. Nefrolog/a 2014;34{2):243-62.

Clinical box 14.22 Dialysis

Once a patient is oliguric and fails to respond to diuretic treatment, it is better to Initiate dialysis at an earty stage than walt until hyper1 6.5 mEqil) with oligo-anuria • Pulmonary oedema (diuretic resistant or with oligo-anuria) • Severe metabolic acidosis • Uraemic pericarditis (pericardia! rub) Humotlltnllon A continuous (usually 24--48 hours) and gentle form of dialysis, which Is performed in haemodynamically unstable patients, exclusively in an intensive care setting.

Renal diseases 685

n

Clinical box 14.22 Dialysis - cont'd

Skin---

Dialysate ports

®

Hollow fibre dialyar

Blood

Blood

port out

port in

Fibre bundle (8000--10000 fibres) 200 llllli/D, wall 11 11m thick

Counter-current flow

Fill: ftbra dlaly&ar Single layer flit plata

Counter-current flow

Blood compartment------' Grooves for dialysate----"

support board

•1111!!••••··~~------ Dialysate ....,___

....,___ ---Blood ftow

iiiiilllllliiiiii•iiiii------- Dialysate Fig. 14.24 Haemodialysis. Diagrams of ftat plate and hollow fibre dialysers. Note the arrangements for increasing the surface area of the dialyser membrane.

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The alimentary system John Wilkinson

Introduction Basic functions and structure of the alimentary system Blood supply to the gastrointestinal tract

687

Overview of digestion and absorption Physical digestion Chemical digestion Absorption

689

Surface anatomy of the abdomen Abdominal regions Quadrants

697

Microanatomy of the gastrointestinal tract Innervation of the alimentary canal

887 888 689 889 692 698 699 699

701

Mouth Teeth Tongue Mastication

701

Salivary glands Functions of saliva Composition of saliva Secretory mechanisms Control of salivary secretion

Inhibition of gastric acid secretion Stimulation of pepsinogen secretion Cellular mechanisms of gastric acid secretion Gastric mucosal protection Gastric motility Gastric musculature Electrical and contractile activity of gastric smooth muscle Gastric motility during the interdigestive period Gastric motility during a meal Nausea, retching and vomiting Exocrine pancreas Pancreatic enzymes Control of pancreatic juice secretion

710 712 712 714 714 714 715 715 716 717 718 718 720

722

701

The liver and biliary system Anatomy of the liver Functions of the liver Some diseases of the liver Gall bladder

703 703 703 705

Small intestine Structure of the small intestine Small intestinal fluid secretion Small intestinal motility

731

Pharynx and oesophagus Swallowing

706

733

Stomach and duodenum Anatomy of the stomach

707

Large intestine Large intestinal fluid secretion Musculature of the large intestine Large intestinal motility Motility of the rectum and anal canal Defecation

Control of gastric secretions Stimulation of gastric acid secretion

701 701 701

706 707 710 710

INTRODUCTION The chemical composition of food is complex and little of it is water soluble; therefore, it cannot enter the body fluids unaltered. A series of digestive processes enables food to be broken down and absorbed. These processes take place in the alimentary canal, which consists of the mouth, oesophagus and gastrointestinal tract, and associated exocrine glands producing secretions that act on food.

Basic functions and structure of the alimentary system The functions of the alimentary canal are concerned with storage, digestion and absorption of food together with the excretion of undigested food and waste products. Digestion is the process of breaking down complex food molecules, by mechanical and chemical methods, into simple ones that can be absorbed. The digestion products, together with salts and water, are absorbed

722 723 728 730 731 732 732 733 734 734 734 734

into the blood and lymphatic systems. In addition, the alimentary canal serves to host microorganisms {microbiota) that contribute to health and disease and also protects the body from bacterial toxins and swallowed noxious chemicals. Four activities of the alimentary canal can be identified. These are • Motility • Secretion • Digestion • Absorption. Motility is the term used to describe movements of the alimentary canal that are responsible for propelling partly digested food along the canal and for mixing the food with the digestive secretions so that digestion and absorption can take place in a regulated manner. These actMties are inter-related. In health there is a balance, and we pay little attention to alimentary function. Disruption of one activity in disease leads to an imbalance, and we become conscious of gastrointestinal function, e.g. pain and peptic ulceration, diarrhoea, constipation, etc. Coordination of alimentary function depends on the combined action of the nervous, endocrine {circulating hormones) and

688 The alimentary system

Buccal cavity-

---..

rl!::lr-----"'....,..---

- - - Upper oeaophageal sphinct&r

+--- -- ____..,.c--- Oesophagus

-+l!H--

Liver-----'1---+-

Gall bladder-

-1--t-f

-Stomach

~V>-:7"---+-+---Pylork: sphincter

~um--~-~~~~~~-+---P~

~~R~~+---Transverse colon Jejunum

Asc:enOOg colon- -f--ir:-! i leum--H~+

llecH:aecal sphincter--+--->,;::::¥'~"'--/

Appendix- - t - - . r Redum --1----~

and external sphincters

~----f.-- I nternal

Anus- - 1 - - - -./l

Fig. 15.1

The alimentary canal and its associated glands.

paracrlne Oocal hormones) systems. The anatomy of the alimentary system and associated glands is shown in Rg. tS.t. • The mouth or oral cavity consists of the lips, tongue, gums, teeth, hard and soft pala1e and the pharynx, together with the salivary glands. Food is ingested, mixed with saliva, chewed and swallowed. • The oesophag.._. is a muscular tube lying in the thorax and abdomen that connects the pharynx to the stomach. It is separated from the pharynx by the upper oesophageal sphincter. Food and drink are propelled to the stomach by the action of the oesophageal muscles. • The stomach lies in the abdomen below the diaphragm. It Is separated from the oesophagus and small intestine by the lower oesophageal (cardiac) and pyloric sphincters, respectively. • The duodenum forms the first part of the small intestine. It receives the pancreatic and biliary ducts from the pancreas and liver, respectively. • The JeJooum and Ileum are a continuation of the small Intestine. The ilam terminates at the ileo-caecal junction. • The large intestine consists of the caecum with the appendix, the colon (divided into three sections: ascending, transverse and descending) and the rectum. • The an... is the opening at the end of the large intestine. An Internal and an external anal sphincter control the opening.

Vena cava (

..

Aorta

Hepatic vein Hepatic artery

Abdominal aorta

SIDmach

Coeliac artery

Superior

mesenteric artery

Inferior mesenteric artery

Blood supply to the gastrointestinal tract The gastrointestinal tract, liver, gall bladder, pancreas and spleen are supplied with blood from the splanchnic circulation In a number of parallel circuits (Rfl. 15.2). Blood is delivered via three major arteries:

Fig. 15.2

The splanchnic circulation.

Overview of digestion and absorption 689 •

Coeliac artery to the liver, gall bladder, pancreas, stomach

and spleen • Superior 11'10Wf1teric artery to the pancreas, small intestine and most of the large intestine • Inferior mesenteric artery to the terminal portions of the large Intestine and rectum. The arterial supply divides into a capillay network within the digestive organs that subsequently drains into the hepatic portal vein, which enters the liver. The blood from the hepatic portal vein flows through liver slnusolds before being returned to the heart by the Inferior vena cava. The liver also receives approximately 20%-25% of its blood supply from the hepatic branch of the coeliac artery. Blood flow through the splanchnic circulation is enhanced during feeding. The control of blood flow to the different mucosal and muscle layers of the gastrointestinal tract is regulated independently. The neural, endocrine and paracrine mechanisms controlling gastrointestinal blood flow are shown in Table 15.1. Mucosal blood flow is required to • Mai1taln the viability of the mucosa • Provide the precursors for secretory products • Deliver hormones to their target cells • Remove absorbed digestion products, toxins and drugs from the mucosa.

OVERVIEW OF DIGESTION AND ABSORPTION Before nutrients can be absorbed, ingested carbohydrates, protein and fat have to be digested. Disruption of the normal mechanisms for either digestion or absorption (malabsorption), or both, leads to disease. Two mechanisms for the digestion of ingested food can be identified. These are • Physical digestion • Chemical digestion.

11.1 Conbal flllllllllw•.... lll blood tow YMOdlator action

t-cAJa••ll....flt PBI'IIIIYITip&thetlc

ACh, VIP

net'Vllll Sympathetic nerves

NE via a adrenocept01'9

NE via Jlt

adrenoceptors CGRP, SP, NKA

Sensory n81Vea Enteric nervea Hormonal

meot.ni&M

ACh, VIP, NO CatecholsnQs (mUlly epinephrine (adrenaline))

Gastrin

Angiotansin II

~

Vasopressin

Seaetin

Somatostam Endothelin 1

Adenosine LowpO.

Histamine Prostacyclln (PGit)

Prostaglandin E1 ACh, aoetylcholne; CGRP, calcitonin gene-related peptide; NE, norepinephrine (noradrenaline); NKA, neurokinin A; NO, nitric oxide; SP, llllbstance P; VIP, vllliOIIC!Ive Intestinal polypeptide.

Physical digestion Physical digestion is produced by the mechanical activity of the alimentary canal, bnlaking down pieces of food into smaller particles. The food retains its complex chemical stnucture, but its surface area is increased to expose more sites to enzymic action. Physical digestion takes place in the • Mouth • Antrum and pylorus of the stomach • Small intestine. It is dependent upon muscular contractions squeezing and grinding the food, and mixing it with secretions. In addition, bile salts and lecithin act as detergents to emulsify fat globules. These actions are produced by the physical properties of bile salts and lecithin, having fat- and water-soluble components In the molecules (Clinical box 15.1).

Chemical digestion Enzymes are responsible for chemical digestion. This involves the hydrolysis of the complex food molecules, I.e. being broken down into their simpler constituents, which are capable of being abso!bed. Chemical digestion may OCCU" by means of enzyme activity present in the lumen of the alimentary canal or on the luminal-facing membrane of the epithelial cells (enterocytes) In the small intestine.

Carbohydrate digestion The predominant carbohydrates in the diet are • Starch and glycogen (polysaccharides) • Sucrose and lactose (disaccharides) • Fructose (monosaccharide).

II

Clinical box 15.1 Clinical c:oncltlon8 8880Ciated with Impaired physical digestion

Begi'flllg in the mouth, pain from diseased mucous membranes or denial

prttlems intarferes with chewing (mastication), the first step in the process of breaking OOwr1 ia"ge food pa'tlcles. Arunber of systemic diseases are associated with oral manifestations. Common COidtions include the following: • Oral candidiasis (thrush) may be associated with either diabetes mellitus, debilitating Illness such as human Immunodeficiency virus (HIV)Iacquired immune deficiency syndrome (AIDS), cancer and blood dyscrasias, or chemotherapy. • Mouth ulcers may be due to infections, e.g. herpes simplex, erythema mulmorme (Steven-Johnson syndrome), etc.; other ulcerations of the gastrointestinal tract, e.g. coeliac disease, regional Ileitis (Crohn disease), ulcerative colitis, disseminated (or systemic) lupus erythematosus, Beh~;et disease, etc.; squamous cell carcinoma and other less common tumours; and trauma Including ill-fitting dentures. • Absence of teeth or neuromuscular defects in old age (e.g. after a strdal) can klterfere with mastk:atlon. • Physical digestion in the stomach, i.e. storage of ingested food, mixing the cootents to promote fat enusiflcation, enzyme and acid action, may be impaired throtVI infiltration of gastrtc musruature by tumotl' ('leather bottle stomach'), affecting motility. P)1orlc stenosis from peptic ulceration or tumotl' delays gastric emptying. &.gical resection (partial gastrectomy) increases the rate of gastJ1c emptying (see Clinical box 15.10). • ConditiOns that affect small intestine motility are usually manifested by Increased motility and may lead to dlarmoea, abdominal pain and discomfort. Irritable bowel syndrome OBS) is an example. Other causes include infection, food sensitivities, endocrine disease and radiation enteritis.

690 The alimentary system Starch and glycogen are polymers comprising chains of glucose molecules joined together by a-1 ,4 glycosidic bonds and, at branch points, by a-1,6 glycosidic bonds. Salivary and pancreatic amylases catalyse the hydrolysis of the interior a-1 ,4 bonds but do not split either the terminal a-1 ,4 glycosidic bonds or the a-1,6 glycosidic bonds at the branches of starch and glycogen. The products of amylase action are maltose (a disaccharide), maltotriose (a trisaccharide) and a-limit dextrins (branched oligosaccharides) (Rg. 15.3). However, there are no transport systems for the absorption of these carbohydrates in the intestine. The oligosaccharides derived from starch, together with maltose, sucrose and lactose, are further digested by enzymes present on the brush border of enterocytes to their monosaccharides -glucose, galactose and fructose (Table 15.2 and Clinical box 15.2).

Protein digestion The various sources of protein for digestion are from food and also desquamated gastrointestinal cells and digestive secretions. Proteins and polypeptides consist of amino acids linked together by a peptide bond formed between the amino terminal of one amino acid and the carboxy terminal of another (see Ch. 2). Protein digestion is accomplished by enzymes (protease or peptidase) hydrolysing peptide bonds either within a polypeptide chain or protein (endopeptidase) or at the free ends (exopeptidase). Thus, a protein may be broken down to a mixture of small polypeptides and amino acids.

Protein digestion in the stomach Peptic cells in the stomach secrete pepsinogens, the precursor of a family of enzymes known as pepsins. The acid contents of the stomach activate pepsinogens to pepsins and denature the structure of proteins. Pepsin is an endopeptidase and specifically hydrolyses peptide bonds, containing an aromatic L-amino acid such

Tllble 11.2 Acllon of dleacc~ In the brulh bord• of enterocyllals

as phenylalanine or tyrosine. Pepsin is inactivated by the alkaline pH found in the duodenum (Clinical box 15.3).

Protein digestion in the small intestine Protein digestion in the small intestine occurs owing to the presence of pancreatic proteases (Table 15.3). The most important are trypsin, chymotrypsin and carboxypeptidase. These are secreted as precursors into the duodenum and activated by enteropeptidase (enterokinase) secreted by the duodenal and jejunal mucosa. Enteropeptidase activates trypsinogen to trypsin. Once some trypsin is formed, it acts autocatalytically to convert more trypsinogen to trypsin and also activates chymotrypsinogen to chymotrypsin. Trypsin, chymotrypsin and elastase are endopeptidases and convert protein into polypeptides. Carboxypeptidases release single amino acids from the carboxyl end of polypeptides. The pancreatic proteases active in the lumen of the intestine produce small peptides and some amino acids before being inactivated by autodigestion. The next stage of protein digestion occurs at the brush border of the enterocytes by the action of peptidases present in the luminal membranes to produce small peptides (di-, tri- and tetrapeptides) and single amino acids. Finally, small peptides (usually di- and tri-) are hydrolysed to single amino acids after they have been absorbed into the enterocyte (see rig. 15.3).

Fat digestion The majority of the fats in the diet are triacy1glycerols (triglycerides), consisting of glycerol to which three fatty acids are attached (see Ch. 2). Fats separate from the water phase of the partly digested food in the stomach and empty slowly. The contractile action of the stomach breaks the fat into small droplets and mixes them with the water phase. The nature of fats and their insolubility in the water create difficulties for their digestion by water-soluble lipases. There are three lipases: • Lingual • Gastric • Pancreatic.

Enzyme

Substme

Products

GluCClllfT1Yiase

Maltose Maltotriose

Glucose Glucose

a-Umlt dextrlns

Glucose

Pr8cursor

Activator

a-Umit dextrins

Glucose

Pepsinogen&

Acid

Pepsins

Trypsinogen

Errteropeptidas

Trypsin

Chymotrypsinogen

Trypsin

Chymotrypsn

ProcaiJoxypepllase

Trypsin

Caboxypeplldase

Proelastase

Trypsin

Elastase

(maltase)

lsomaltase (a-dextrlnase)

Sucrase

Sucrose

Glucose and fructose

Maltose

Glucose

Maltotriose

Glucose

Lactose

n

Glucose and galactose

Clinical box 15.2 Enzyme deficiency

Deficiencies in enzymes concerned with carbohydrate digestion prevent the breakdown of oligo- and di-saccharides to monosaccharides that can be absorbed; therefore, these are excreted undigested Instead. This gives rise to diarrhoea after ingesting foods rich in these particular carbohydrates. A common example is milk intolerance due to lactase deficiency, a condition more common in some Asian and Mediterranean countries. It is not a major clinical problem, as most people with lactase deficiency simply avoid milk. A lactose tolerance test is available, but rarely used for adults.

iii Tllble 1U Gasblc and pancr.tlc prcauee

n

Protllae

Clinical box 15.3 Enzyme defects In protein digestion

Deficiency in pancreatic enzyme secretion, notably of trypsinogen and chymotrypsinogen, prevents the conversion of dietary protein into polypeptides for absorption. This can occur in chronic pancreatitis, mainly related to sustained alcohol overuse. Cystic ftbrosls sufferers have the same enzyme deficiency. The inability of children with cystic fibrosis to digest protein and fat because of the lack of pancreatic enzymes, trypsin and lipase, leads to nutritional deficiencies in essential amino acids, fatty acids and fat-soluble vitamins. High-dose pancreatic enzyme supplements to treat the resulting steatorrhoea, as well as nutritional supplementation, will be necesSIII)'.

Overview of digestion and absorption @

691

luminal digestion of starch

Glucose residua

I Interstitial fluid

Enterocyte

GLUT5

GLUT5 GlUT2?

Fructose..._ GlucoseSGlT1

Galactose~

Gluooamylase Glucose Galactose

Q

lactose~S£

SGLT1 H~

Lactase

@

luminal digestion of protein by gastric and pancreatic proteases

H+

Na+ K+

@

c~

Na•, Cr and water transport in the small intestine

Na+

Na+

Na+

Cl-

cr

K+

Fig. 15.3 Digestion and absorption of carbohydrates and protein from the small intestine. (A) Carbohydrate. (8} Protein. (C} Electrolytes and water. GLlJT2, GLUTS, membrane glucose transporters; PepT1, peptide membrane transporter; SGLT1, sodium/glucose-linked transporter.

692 The alimentary system The lingual and gastric lipases have acidic pH optima and function in the stomach, producing fatty acids and diacylglycerols (diglycerides) by attacking the outer ester linkages between glycerol and the fatty acids. The major site of fat digestion is in the small intestine Onformation box 15.1). Fat enters the duodenum relatively slowly so that there is time for the process of emulsification and fat hydrolysis. Fat is emulsified into droplets approximately 5Q0-1000 nm in diameter by the action of bile salts, with their hydrophobic side (fat soluble) dissolving in the fat and their hydrophilic side (water soluble) facing outwards in the water of the intestinal fluid. This process is aided by lecithin and cholesterol, which are also found in bile. The emulsifying agents reduce the surface tension of the fat droplets and keep them apart. These actions increase the surface area of the ingested fat. An additional pancreatic enzyme, colipase, anchors pancreatic lipase to the fat/water interface and activates it. This allows an interaction between the water-soluble pancreatic lipase and the ingested fat. Pancreatic lipase (optimum pH 8.0) preferentially hydrolyses the bonds between glycerol and the fatty acid residues at positions 1 and 3 to produce 2-monoacytglycerols (monoglycerides) and free fatty acids. A small quantity of the 2-monoacylglycerols is hydrolysed to glycerol and a free fatty acid. The presence of fat digestion products, bile salts, cholesterol and phospholipids causes the emulsion to break up into smaller particles, known as mixed micelles, with diameters of up to 5 nm. The bile salts form an outer coat, with the fatty digestion products in the centre. The micelles are small enough to diffuse between the microvilli of the enterocytes.

Absorption Absorption is the term used to describe the transfer of nutrients or their digestion products from the lumen of the alimentary canal to either the blood or the lymph. The small intestine possesses efficient mechanisms for the absorption of nutrients and prevents their passage to the large intestine. The presence of nutrients in the large intestine produces diarrhoea resulting from water being drawn into the lumen by osmosis or by bacterial overgrowth. The absorbed molecules have to overcome a barrier (Rg. 15.4) made up of the • Unstirred layer of fluid covering the microvilli • Glycocalyx covering the microvilli • Luminal plasma membrane • Cytoplasm • Basal or lateral border of the cell • Intercellular space • Basement membrane (basal and reticular lamina) • Plasma membrane of the capillary or lymph vessel.

0

lnfonnatlon box 15.1 Def8cts in cllamlcal fat digestion

Failure of secretion of pancreatic lipase and deficiency in bile salts affect fat digestion in the small intestine. Pancreatic lipase deficiency occurs in many conditions, including chronic pancreatitis, carcinoma of the pancreas and cystic fibrosis. Deficiency in bile salts is usually due to obstruction, which may be Intra-hepatic, as In cirrhosis of the liver, or extra-hepatic due to gall bladder disease, stones in the bililll)' tree or tumours. The resulting failure to digest fat leads to the excretion of undigested fat globules in the form of pale, bulky, otrensive and sometimes frothy stools that float (steatormoea). Steatormoea may be confirmed by measuring the fat content of stools. The absorption of fat-soluble vitamins may also be impaired (see late~.

General principles of absorption Most carbohydrate, protein and lipid absorption occurs in the small intestine, the duodenum, the jejunum and the early sections of the ileum. These sites, together with the stomach, are also where orally administered drugs are absorbed. Disease of the membranes through which absorption takes place, and defects in the normal mechanisms for absorption, leads to nutritional deficiencies and also adverse or toxic drug effects. Absorption of solutes may occur by either passive or active processes (Clinical box 15.4). There are two types of passive diffusion. These are simple diffusion, where small molecules, such as 0:! and CO:!, and fat-soluble molecules diffuse through the lipid bilayer of the cell membrane, and facilitated diffusion, where the transported molecule moves through the membrane by means of a protein carrier. In a passive process, the absorbed solute will move from a high to a low concentration. Passive processes do not require the use of energy from cellular metabolism. Water and some solutes pass through membranes at a faster rate than would be expected from a knowledge of the lipid solubility. This suggests that there are routes through the membrane for water and small hydrophilic solutes. These may be in the spaces between the membrane phospholipids and through specific membrane proteins called aquaporins. Ions can diffuse through specific protein ion channels that span the membrane. In contrast, an active process involves cellular energy to drive an absorbed solute against either a concentration gradient or an electrical gradient, i.e. an 'uphill' movement from a low to a high concentration or for a charged solute moving to a region of the same charge, e.g. Na+ ions being transported out of cells. The two types of active transport use adenosine triphosphate (ATP) either directly, as in the Na+JK+-ATPase pump, or indirectly as a source of energy to power secondary active transport. For the absorption of many solutes in the alimentary canal, there are carrier-mediated mechanisms that use the concentration gradient built up as a result of the primary active transport of Na+. This

0

Clinical box 15.4 Diarrhoea Disease of the gastrointestinal tract prevents efficient absorption by compromising the transfer of nutrients across the intestinal epithelium. This can be caused by inflammatory processes through infection (gastroenteritis, dysentery and parasitic Infestations), Immune responses (Crohn disease, ulcerative colitis, coeliac disease, etc.), antibiotic use, hereditary digestive enzyme deficiency, the presence of defective Na+/ glucose transporter (SGLTl) or a reduction in surface area after surgical resection. Clinically, diarrhoea occurs when there is an increase in daily stool weight to more than 300 g, increased fluid content and stool volume, and there is usually an associated increase in frequency of bowel action. Steatorrhoea occurs when there is impaired fat absorption and the stools have a high fat content. Diarrhoea may be • Osmotic -when the presence of undigested hypertonic substances draws fluid into the large bowel by osmosis • Secretory- usually after intestinal resection, in the presence of toxins or laxative use, when fluid and electrolyte absorption is decreased at the same lime as an Increase In secretion occurs • Inflammatory- due to damage of the intestinal mucosa through infection or inflammation. There is increased fluid and electrolyte loss as well as reduced absorption. The fluid and electrolyte loss can lead to severe dehydration and metabolic imbalance. Diarrhoea is one of the leading causes of death among children in developing countries.

Overview of digestion and absorption

693

Emulsification by bile Bile salts Lecithin Cholesterol

~~~

Luman

T

0 Bulk phase of -

intestinal fluid

is alkaline ~

-~ F~1~ M~:lroi(Short~~~~~adds Ileum

~rrr~Choleslerol ~ ~

Bile salts

c;

~

Unstirred layer: acidified region where prolonation of free fatly acids enhances their absorption

. . ------ Lecithin

Microvillus

I Fatly acid bindng prolsin I

f

.

Smooth enaaplasm1c reticulum

+

Entarocyta

Triglyceride reaynlheais by acyt.CaA synthetale and acyllransfelase

Cllylomiaons are tnnpalted ta the baaolaten!l membrane, then dlecl1arged by emcytosll inlo the irierstitial flLid

+

Galgi apparalus S/lolt~hail fatly acidl.,d

Chalesteroi-®PhCllpholipid Chylomicron Lipoprotein coat

Protein -

Lacteal

Fig. 15.4

glyoelol are absorbed independenUy of bile salla and micela fonnllllion, and dilfule into the capillary network

Capillary

Digestion and absorption of triglycerides.

process is known as secondary active transport. The carriers have binding sites for the organic molecules and for Na+. The movement of Na+ down its concentration gradient can lead to the simultaneous transfer of the organic molecule into the cell against its concentration gradient. Metabolic inhibitors that block the primary active transport system will lead to inhibition of the secondary active transport system once the potential energy stored in the Na+ concentration gradient across the cell membrane has run down.

Carbohydrate absorption The carbohydrate digestion products are glucose, galactose and fructose. A small quantity of these sugars is albsorbed by passive diffusion through aqueous channels between enterocytes and in the cell membranes. The main transport mechanisms involve carrier proteins in the brush and basolateral borders of enterocytes. All the sugars enter the hepatic portal vein for delivery to the liver.

Glucose and galactose absorption Glucose and galactose are absorbed by secondary active transport involving a sodium-dependent glucose and galactose transporter (sodium/glucose-linked transporter, SGLT1) in the bnush border membrane of the enterocyte (see Rg. 15.3}. The glucose and galactose compete for the sugar site on the transporter, which also binds two Na+ ions at a different site. Once loaded, the transporter moves the Na+ down its electrochemical gradient into the cell together with either the glucose or the galactose. The Na+ diffuses into the intracellular ftuid and is transported out of the cell by the Na+fK"-ATPase (sodium pump) on the basolateral membrane. The glucose and galactose accumulate in the cell until they are removed by simple diffusion and facilitated diffusion involving GLUT2, a transporter found in the basolateral borders of the enterocyte. The importance of GLUT2 has been questioned because patients with the rare Fanconi-Bickel syndrome in which GUJT2 transporters are defective albsorb glucose

694 The alimentary system from the intestine but not from the kidney tubules, which also have GLUT2 transporters located on the basolateral borders of the tubular cells.

iii Table 15.4 Site and sptem

Amino acid transport systems In enterocyles

Amino acid transporter

Co-transported lon

Fructose absorption

Apical membrane

Fructose enters the enterocyte by facilitated diffusion using the specific fructose transporter GLUT5, which does not require the co-transport of Na+ to function (see Rg. 15.3). Young children may have difficulty in absorbing fructose in fruit juices owing to a less developed transport system compared with adults, leading to the production of gas and diarrhoea. As with glucose and galactose, GLUT2 is believed to transport fructose across the basolateral border of the enterocyte to the tissue fluid; however, patients with Fanconi-Bickel syndrome are able to absorb fructose. GLUT5 has been identified in the basolateral border of human enterocytes and will provide a route for fructose transport to the tissue fluid.

8

Neut ral amino acids, e.g. alanine

e•

Neut ral and cationic (basic) amino acids, e.g. lysine and also cystine

b"'

Neut ral and cationic amino ac ids

None

x:.o

Anionic (acidic) amino acids, e.g. glutamate, aspartate

2 Na•, 1 W, inward; 1 K+, outward

y+

Cationic (basic) amino acids, e.g. arginine, lysine

None, but will also co-transport small neutral amino acids with Na+

Protein absorption

Imino

Proline and hydroxyproline

Na+and CI-

p

13 amino acids: p-alanine

Na+and Cl-

The proteases in the gastrointestinal tract produce a variety of peptides and free amino acids for absorption. The enterocytes have a relatively high cytosolic concentration of free amino acids for protein synthesis that, in turn, can make amino acid absorption more difficult. This difficulty is overcome by the absorption of diand tripeptides that are subsequently hydrolysed by peptidases to release free amino acids within the cell. This hydrolysis maintains a concentration gradient for peptides across the luminal cell membrane. After passing across the basolateral membrane, the absorbed amino acids enter the hepatic portal vein for delivery to the liver.

Di- and tripeptide absorption Di- and tripeptides are absorbed into the enterocyte by means of a brush border carrier, PepT1. The transport of di- and tripeptides is a secondary active transport process. The movement of Na+ down its concentration gradient, to enter an enterocyte in exchange for a proton moving into the lumen, provides the electrochemical energy for absorbing the peptides (see Rg. 15.3). The PepT1 transporter co-transports W from the lumen and peptides into the cell down an electrochemical gradient for W. It is interesting to note that the absorption of IJ-Iactam antibiotics (penicillins) and angiotensin-converting enzyme inhibitors (captopril) is by means of the PepT1 transporter.

Amino acid absorption There are a number of transport systems (Table 15.4) for L-amino acids in the brush border of enterocytes that require the co-transport of Na+ to allow the transfer of amino acids against a concentration gradient by means of secondary active transport. Facilitated diffusion of some amino acids also occurs. The presence of carrier systems working in parallel for single amino acids and small peptides in the intestine enhances the overall absorption of amino acids by allowing the uptake of the same amino acid, e.g. glycine in peptide form, as well as of free amino acid. Five carrier mechanisms are present in the basolateral borders of enterocytes. Three amino acid carriers not requiring Na+ to function transport the intracellular amino acids to the extracellular fluid for diffusion into the blood. The Na+-requiring carriers provide amino acids from the circulation for protein synthesis in crypt cells.

Fat absorption The process of fat absorption (see Rg. 15.4) differs from that of carbohydrate and proteins. Short- and medium-chain fatty acids

and taurine

Basolateral membrane A

Most neutral and imino acids

Na+

ASC

Neut ral amino acids with 3-4 carbons

Na+

b"'

Neut ral and cationic amino acids

None

L

Neut ral amino acids with hydrophobic side chain

None

y+

Cationic (basic) amino acids, e.g. arginine, lysine

None but will also co-transport small neutral amino acids with Na•

(CS--14) and glycerol are water soluble and diffuse directly through the luminal and basolateral membranes of the enterocyte to enter the capillaries. The micelles, containing 2-monoacylglycerols and larger free fatty acids (chain length greater than 14 carbon atoms) in their cores, being water soluble, diffuse through the unstirred layer of water at the surface of the enterocyte at a faster rete than can be achieved by fat digestion products alone. The hydrophobic 2-monoglycerides and free fatty acids are delivered by this mechanism to the enterocytes of the jejunum, where they are absorbed by diffusion through the lipid portions of the surface of the cell membrane. The absorbed long-chain fatty acids and 2-monoglycerides bind to a fatty acid-binding protein within the enterocyte, thus maintaining the concentration gradient across the cell membrane for these products. The fatty acid-binding protein transfers the fatty acids and 2-monoglycerides to the smooth endoplasmic reticulum for the resynthesis of triglyceride by acyi-CoA synthetase and acyltransferase. The triglyceride is coated with lipoprotein, derived from cholesterol, phospholipid and apoprotein B in the rough endoplasmic re1iculum, to form a chylomicron that is transferred to the Golgi apparatus where the protein coat is glycosylated prior to exocytosis across the basolateral membrane. Chylomicrons (diameter 75-600 nm) are too large to enter the capillaries, but can diffuse through spaces in the walls of lacteals (lymphatic vessels) in the villi. The lacteals drain into larger lymphatic vessels, leading to the thoracic lymphatic duct, which, in tum, distributes the lymph to the venous system at the junction of the left subclavian vein and left jugular vein. In contrast to other nutrients, the absorbed lipids are available for

Overview of digestion and absorption either energy production or storage in all organs of the body before 1118Ching the liver.

0

The bile salts are ionised at intestinal pH and require a carrier mechanism for their absorption. The sodium-dependent carrier Is present in the enterocytes of the terminal ileum. Absorption is by means of secondary active transport similar to that descr1bed for glucose or amino acid transport. The absorbed bile salts enter the venous system draining the ileum and are transported to the liver in the enterohepatlc circulation. The liver extracts the bile salts and secretes them Into the bile. The bile salt pool may recirculate two or three times during a large meal.

Vitamins

Water-soluble vitamins The water-soluble vitamins (B group and C) are absorbed by passive diffusion and, in some cases, by secondary active transport. Specialised sodium-dependent transport systems exist for thiamine (B,), niacin, folate and vitamin C in the apical membrane of enterocytes. A facilitated transport system is responsible for the exit of niacin, folate and thiamine across the basolateral border.

Vitamin

812

The absorption of vitamin 8 12 (cobalamin) involves a complex ser1es of events. Vitamin B 12 in food is bound to proteins. The action of acid and pepsins in the stomach releases the vitamin 812· The free vitamin 8 12 binds to glycoproteins, known as R proteins, that are present in the stomach contents derived from saliva and gastric juice. Another glycoprotein capable of binding vitamin 812 Is lntr1nslc factor secreted by parietal cells. The affinity of intr1nslc factor for ingested 8 12 is less than that of R proteins; therefore, most of the vitamin 8 12 In the chyme leaving the stomach and enter1ng the intestine is bound to R protein. Once in the intestine, the pancreatic proteases digest the R protein and vitamin 8 12 is free once again. It binds to lntr1nslc factor, which is resistant to digestion by pancreatic proteases. The vitamin B1rintrinsic factor complex passes along the small intestine to the terminal ileum where there are receptors in the brush borders of the enterocytes for the vitamin B1rlntrinslc factor complex. Binding of the vitamin B1rintrinsic factor complex to the membrane receptor triggers endocytosis (receptor-mediated endocytosis) of the complex into the cell. Vitamin 8 12 Is released from the complex within the cell and exported across the basolateral border and diffuses Into the blood where it binds to transcobalamin II, a transport protein (Information box 15.2).

Fat-soluble vitamins The fat-soluble vitamins A, 0, E and K enter1ng the small intestine .., solubilised by diffusion into micelles containing bile salts a'1d fat digestion products (see Ch. 16). Absorption of these vitamins occurs by diffusion across the brush border of the enterocyte together with fatty acids n monoglycerides. The fat-soluble vitamins are exported to the lymphatic system In chylomicrons (Information box 15.3).

Absorption of electrolytes and water Each day, approximately 9 L of fluid enters the alimentary canal. This Is derived from the diet (2 L) and the digestive secretions (7 L)

Information box 15.2 vtt.nln 8,2 malabsorption Vrtamil B, 2 defiCiency is caused by the rnalabsorpllon of vitamin B12· The commooest cause is pemiciDus INifltlia. There is atrophic gastritis leading to a failure in the production of inbtnllc flciDr. This is an autoimmune condition and is associated wilh olher autoimmune clseases, such as thyroid disease and vitiligo. It is sometimes also associated with gastric carcinoma. Intrinsic factor antibodies are present, inhibiting lhe binding of intrinsic factor to B12 in lhe stomach and also blocking lhe vitamin B,rinllinsic factor complex coupling to receptors in lhe terminal Ileum, where B12 would normally be absorbed. A 3-6-year store of vitamin B12 is present in lhe liver, and, lherefore, patients wilh pernicious anaemia may take years to develop symptoms of anaemia. Treatment is by intramuscular injet:tions of vitamin B12 • Olher causes of vitamin B1 2 malabsorption include coeliac disease, surgical resection of the stomach or Ileum, and lhe long-term use of drugs such as proton pump Inhibitors.

Bile salt absorption

Vitamins (A, B, C, 0, E and K) are organic compounds that the body is unable to synthesise; therefore, they must be absorbed from the small Intestine (see Ch. 16).

695

0

lnformallon box 15.3 vtt.nln 0 deficiency Olronic sl8atonhoea coukllead to malabsorption of fat·soluble vitamins. Allhough lhls coukl be the cause of vttarnkl D deflcleocy (ltclcatl, adllonlllacla), ~factors are anticonvulsant lherapy and renal failure, which irterfere with vitamiJ D metabolism.

{RJ. 15.5). In health, approximately 99% of the water and electrolytes

are absorbed into the blood as the fluid passes along the small and large intestine. The major site of fluid absorption Is the jejunum and Ileum (8.5 L), with a relatively small quantity being absorbed from the colon (0.4 L). The faeces contain approximately 0.1 L of water. The absorption of water is secondary to the uptake of electrolytes, in particular Na+ and Ct', sugars and amino acids.

Pathways for electrolyte and water absorption The electrolytes and water may be absorbed by passing between the enterocytes (paracellular route) via aqueous channels, through the tiglt junctions linking the cells together. The alternative route is by passing through the cells (tra.nscellular route). This may involve both carrier-mediated mechanisms and passage through water-permeable channels (Table 15.5). Water movement from the lumen of the intestine may occur via membrane proteins, including the SGLT1 , sodium/glucose ~transporla' and channels named aquapor1ns that allo w the passage of water. The unstimulated SGLT1 acts as a water-permeable protein channel. When stimulated by the presence of Na+ and glucose in the intestinal lumen, it co-transports water together with Na+ and glucose into the intestinal mucosal cell. In addition, the absorption of water is secondary to organic and Ionic solute movement. The transfer of solutes across the intestinal epithelium creates an osmotic gradient between the k.men n the interstitial ftuld and blood. Water is absorbed by osmosis via paracellular and transcellula' routes (see Fig. 1~ . The principle of oral rehydration therapy, used to treat diMhoea, is based on promoting water albsorption, either by means of ~tralsport or by osmosis, following an isotonic dr1nk containing glucose and electrolytes, including sodium chloride.

Calcium absorption Dietary calcium is found in a variety of foods Including dairy products. Calcium may exist bound to oxalates, phosphates and phytates or in the ionised form (Ca~ in the Intestine. Ionised calcium is available for absorption by enterocytes In the upper small intestine. The free Ca2+ concentration in the cell Is low, giving r1se to a steep

696 The alimentary system Secretions

Absorption

Saliva 1.5 Uday NaHC03

pH5.5-7

Gastric secretions 2 Uday HCI

Stomach pH2

Moulh

Liver Bile 1 Uday

Auid Duodenum

Pancreas Pancreatic juice 1.5 Uday NaHC03

pH2~

Calcium Magnesium Iron

------

Glucose Galactose Fructose

Na+ lntesonal juice 1 Uday NaHCOs

Jejunum pH4-7

~

cr

Ileum pH 6-7.5 Bile salts Vitamin B12 Na+

cr

Colon pH8

0.4Uday

------------ t ------------Anus

Faeces 0.1 Uday

Fig. 15.5

Fluid and electrolyte movements into and out of the alimentary canal.

concentration gradient between the lumen and the cytoplasm. Ca2+ions bind to a protein in the brush border and are transported down their concentration gradient into the cell. The free Ca2+ concentration in the cytoplasm is kept low by ca2+ binding to calcium-binding proteins that are sequestered in intracellular organelles such as the endoplasmic reticulum. Ca2+ ions are exported across the basolateral border of the cell against an electrochemical gradient by active transport. There are two mechanisms: • ca2+-ATPase, which uses energy derived from the hydrolysis of ATP to transfer Ca2+ out of the cell • Na+/Ca2+ exchanger, in which Na+ moving down its electrochemical gradient into the cell drives Ca2+ extrusion. The ca2+-ATPase mechanism is the more important one. calcium absorption is regulated by 1,25-dihydroxycholecalciferol, the active form of vitamin D, which stimulates the synthesis of both calcium-binding proteins and ca2+-ATPase (see Ch. 10). Note: a high dietary phytate content, as in chapatti flour, may inhibit calcium absorption.

Iron absorption Dietary iron is present in two forms: • The haem portion of haemoglobin, myoglobin and cytochromes • An insoluble, non-absorbable state complexed with phytate, tannins and plant fibres. Insoluble iron salts may also form with hydroxide, phosphate and bicarbonate found in digestive secretions. The acidic conditions of the stomach mobilise the iron compounds by converting the ions from the ferric (F~ to the ferrous (Fif') state. Similarly, vitamin C reduces iron to the ferrous state and also forms soluble complexes with it that enhance absorption. Ferric ions are reduced to ferrous ions by duodenal cytochrome b ferric reductase in the brush border of the duodenal enterocyte. The enterocytes of the duodenum absorb haem and ferrous ions by two separate mechanisms: 1. Haem is absorbed by endocytosis and digested in the enterocyte by haem oxidase to release ferric ions, carbon

Surface anatomy of the abdomen iii

Table 15.5 Electrot,ile transport In the smell

697

and lalge Intestine K•

Intestinal region Duodenum and jejunum

Actively absort:led • Co-transport with glucose, galactose, amino acids • Co-transport with Cl• Counter transport exchange for W • Diffusion through aqueous channels

Passively absorbed by diffusion through paracellular pathways as the luminal concentration rises after water absorption

Passively absorbed • Co-transport with Na+ • Counter transport exchange for HCO;; • Diffusion through paracellular channels

Absortled as C02 following neutralisation of secreted W

Ileum

Actively absort:led as above but reduced importance of co-transport with organic solutes

Passively absorbed as above

Passively absorbed • Counter transport exchange for HCOi • Diffusion through paracellular channels

Passively absorbed • Counter transport in exchange for Ct' • Diffusion

Colon

Actively absorbed • Via Na• channels • Co-transport with cl• Counter transport exchange for W

Secretion Passive leakage from enterocytes through K• channels in their apical membranes when luminal concentration is 1 02 em and in women > 88 em.

Underweight

23.00-24.99

32.50-34.99 35.00-37.49 37.50-39.99 >40.00

BM I vaiUIIS, being ratios, ant the same for males and females, and vary with age. Overweight and obesity may impar health, but the degrees of excessive fat accumulation vary between populations. Therefore, the health risk associated with increasing BMI differs for different populations. Adapted from \1\/HO (1995, 2000, 2004).

can occur with effective refeeding of malnourished children (catch up growth). An example of a growth chart used in the UK is shown in Fig. 10.13. They are adapted for age and gender.

Measures of body composition: adults Measures of body composition are important in a clinical setting. They allow not only initial assessment but also monitoring of any change in body composition that may be due to disease. For measurement of body composition, the body is usually divided into compartments consisting of fat mass Oipids) and fat-free mass. There are a number of methods used to estimate body composition, depending on which measurements need to be obtained. They differ in their advantages, cost, complexity and availability, some being used only in the research environment.

Estimating body fat There are several methods of estimating body fat, which range from simple to more complex. One commonly employed is anthropometry, where, by using simple tools, the percentage of body fat can be estimated by measurements taken at selected anatomical sites where fat is deposited: • Skinfold thickness • Arm circumference • Waist circumference and waist/hip ratio.

Skinfold thickness Skinfold measurement, also called the 'pinch test', assesses the thickness of a fold of skin at selected body sites where adipose tissue

Other measurements of nutritional status Plasma proteins Serum albumin is often incorrectly used as an indicator of nutritional status, with levels often remaining normal in undernutrition that is uncomplicated by disease. The decrease in serum albumin concentration during infection, cancer, bums and after trauma or surgery is related primarily to increased vascular permeability. Although undernutrition may exacerbate disease-related hypoalbuminaemia, albumin concentration primarily reflects a disease process, and it is better considered as an 'index of disease severity' rather than a nutritional indicator. Serum albumin can also be depressed by dilution during refeeding or excessive rehydration. It should be interpreted in combination with some other estimate of the acute-phase response, such as C-reactive protein or the erythrocyte sedimentation rate. The same problems apply to other plasma proteins that are used as nutritional indicators, such as pre-albumin, transferrin and retinol-binding protein. However, these may be more sensitive as nutritional indicators because they have a shorter half-life in the circulation and can respond to dietary change more quickly.

Vitamin status Vitamin deficiencies can be detected either by biochemical assays or by physical symptoms (see later). The detailed assessment of vitamin status is beyond the scope of this chapter. The relatively common presentation of macrocytic anaemias necessitates vitamin 8 12 and folate assays, but other vitamin deficiencies are unmeasured and often overlooked. Specific deficiency syndromes are outlined later.

Muscle strength Studies have shown that malnutrition leads to impaired muscle strength, and nutritional support may rectify this before improvements in weight are seen.

Nutritional status

743

Immunological skin testing

Energy balance

Adequate nutrition is essential for the maintenance of a normal immune system. A reduced blood total lymphocyte count may be indicative of protein calorie malnutrition. Delayed hypersensitivity is particularly affected by undernutrition.

Positive energy balance results in weight gain and the deposition of fat and glycogen, whereas a negative energy balance leads to weight loss and the depletion of glycogen and fat stores and ultimately muscle loss. The chemical energy content of food (measured in calories or joules) is the amount of energy that would be released from food if it was burned in oxygen in a fixed volume. This can be undertaken experimentally using a bomb calorimeter, which measures the heat produced per unit of food. In healthy people, most of the energy in food is absorbed approximately 97% of the energy in carbohydrate, 95% in fat and 92% in protein. Less energy is absorbed from protein because nitrogen is metabolised to urea and not fully oxidised, so that some of the energy from protein is not available to the body (see Ch. 3).

Malnutrition screening tools Research has shown that not only are a significant number of patients already malnourished on entry to hospital, but that hospital admissions are also often associated with a deterioration in nutritional state. The causes of this are invariably multifactorial, but the associated effects on morbidity and mortality are reflected in the high rates of readmission, lengthier hospital stays, susceptibility to infection and impaired wound healing in such patients. This has prompted some countries to develop national guidelines that recommend mandatory assessment of the nutritional status of all patients in hospital, as well as those who are at risk in the community, in order to identify those who may require nutritional support. In the UK, these have been developed by the National Institute for Health and Care Excellence (NICE). Many hospitals and other healthcare settings will have their own screening tools that combine features from the history and clinical examination, which are then ranked and combined to produce a score indicating malnutrition risk. In the UK, the Malnutrition Universal Screening Tool (MUSl) is a five-step process based on BMI and weight loss designed to identify patients who are at risk of malnutrition or obesity, and includes management guidelines. In other parts of Europe, the nutritional risk screening (NRS-2002} is often employed, whereas the Mini Nutritional Assessment (MNA) and more complex Subjective Global Assessment (SGA) are used more commonly in the United States and Canada.

Energy and nitrogen balance Energy is required for metabolic processes such as active transport of molecules and ions, synthesis of tissue, thermoregulation, and voluntary and involuntary muscle movement. Dietary intake of food provides the body with the macronutrients - carbohydrates, fats and proteins- that are converted to energy. Each one of these has a slightly different energy content, the approximations of which are shown in Table 16.4.

Basal metabolic rate (BMR) and resting energy expenditure BMR is the energy that is used by the body to maintain basic physiological functions, including metabolic processes, cell membrane pumps and intracellular pumps. Resting energy expenditure (REE) is the energy used by a normal, post-absorptive (approximately 12 hours fasting) indMdual at rest, but not asleep, under thermoneutral conditions. Measurements of REE are used as surrogates for BMR, though in reality are approximately 10% greater than BMR. Although BMR varies among people of equal height and weight, owing to ethnic and geographical differences, individual BMRs remain relatively constant over a number of years. There are a number of factors that can affect BMR, including age, sex, obesity, climate, medications and disease. In the acutely unwell patient, even in the absence of fever, metabolic demands may increase significantly. The measurement of these stress factors can be difficult, but accurate clinical assessment is required in order to ensure the individual obtains sufficient calories.

Total energy expenditure Total energy expenditure (TEE) is composed of: • REE (approximately 60%-70% of TEE} • Exercise/ physical activity (10%-30%)

Conversion of macronutrients to energy After absorption, macronutrients may pass through a number of different pathways of metabolism, shown in Rg. 16.4, but ultimately the energy comes from the tricarboxylic acid (TCA) cycle and the mitochondrial process of oxidative phosphorylation (see in detail in Ch. 3}.

T.tlle 11A Energy valu. far macronublenbl and alcohol • maaa~rad bV Indirect calorlmeby_ __ Nutrient

kJ/g

kcallg

Carbohydrates

172

4.1

Protein

23.8

5.7

Fats

39.7

9.5

Alcohol

29.7

7.1

2COz

Fig. 16.4

Metabolic pathways for converting macronutrients to energy. ADP, adenosine diphosphate; ATP, adenosine triphosphate; TCA, tricarboxylic acid.

744 Diet and nutrition • • •

Food induced thermogenesis (up to 10%) Growth in children Disease processes.

Measuring energy expenditure BMR can be measured at rest by direct calorimetry (direct measurement of heat exchange in a chamber), or indirect calorimetry, which uses a canopy over the head to measure oxygen consumption and carbon dioxide generation from which energy consumption can be calculated. In practice, BMR is estimated from the Schofield (1985) predictive equations, which are based on the analysis of a large number of measurements of BMR and can predict individual BMR reasonably accurately. Oxygen consumption and carbon dioxide production can also be measured during exercise either by collecting exhaled gases in portable Douglas bags (an airtight bag, which collects expired gases via a one-way valve) or by studying the subject in a chamber calorimeter. Energy expenditure can alternatively be measured by administering a drink of doubly labelled radioactive water and monitoring the relative decay of 2H and 18Q from the body. The difference between the decay of 2H and 18Q allows estimation of C02 production and total energy consumption. This method has the advantage that the subject is free to move about.

Total energy expenditure and the effect of physical activity The total amount of energy used up in a day will depend on the individual's BMR, the nature of their occupation (whether sedentary or labour intensive), and the amount of physical activity undertaken in leisure and the pursuit of sports. The heat derived from food is not measured separately, but is included in measurements or estimations of energy expenditure.

An EAR for energy can be calculated by multiplying the BMR by the appropriate PAL (see Table 16.5). The PAL index takes into consideration occupational as well as non-occupational activities because an individual with a sedentary occupation may undertake a lot of non-occupational activity, and vice versa. Physical activity makes a varialble contribution to the TEE, which, over average 24-hour periods, is nearly always less than the BMR. An individual at rest would be using energy for maintaining BMR only, i.e. a PAL of 1. Many people in the developed world have sedentary occupations Oight activity) and are non-active, or only moderately active, outside work. From the corresponding PAL of 1.4 and 1.5 (see Talble 16.5), it can be seen that their energy consumption is mainly due to BMR; only approximately a third of it (0.4-0.5) is due to physical activity. For example, for a woman who has a BMR of 6000 kJ, has a sedentary occupation and is moderately active outside of work, the total daily energy output is:

6000 kJ x 1.5"" 9000 kJ (4. 2 kJ is equivalent to 1kcal) Estimates of energy consumption for different types of activity More accurate estimates of energy consumption during a 24-hour period can be made by keeping a diary of each activity, then calculating the total by adding all the different components. The energy used during each activity is calculated by reference to physical activity ratios (PARs) for different activities. PAR is an index of the energy expenditure for the duration of a particular actMty compared with a reference activity, such as BMR, expressed as the estimated energy cost per minute for the specific activity relative to the measured energy cost per minute for the reference activity. This index is used to compare the energy consumption of various activities by different people {Table 16.6).

Energy expenditure during daily living Daily energy output for the activities of daily living can be estimated from the BMR and the individual's physical activity level (PAL), an index derived from experimental studies of energy expenditure for physical activity over 24 hours. Energy expenditure during activities of daily living is best measured by the doubly labelled water method, which allows measurements to be made over periods of days or weeks. PAL is expressed as a ratio of TEE and the REE (BMR). Total daily energy requirement can be calculated from a talble of PAL, calibrated for the subject's leisure and work occupation, which provides a multiple by which the estimated BMR can be multiplied. For any one individual, these values are obtained from reference tables {Table 16.5). The most commonly used units are kcal/24 h or kJ/24 h.

Energy expenditure during exercise Energy needs during exercise vary depending on whether it is intense, over a short period (e.g. 100 m sprint), or sustained endurance exercise, such as running a marathon (Clinical box 16.2).

Anaerobic carbohydrate metabolism During short bursts of intense activity (e.g. sprinting, weight lifting), close to maximum oxygen consumption (V02moxl takes place when the exercising muscles depend on their own individual stores of adenosine triphosphate (ATP), supported by glucose from the muscle's own store of glycogen. This allows for brief periods when energy consumption is substantially greater than can be supplied by circulating substrates and oxygen. This is called 'anaerobic' metabolism. It builds up lactate and an oxygen debt, which have

m Table 1u Physical activity level8 (PAL.a) Non-oocupdon.l

Oooupmlon.. •atlvlty

activity Light

Moderate

ll.txBat&' heavy

M

F

M

F

M

F

1.4

1.4

1.6

1.5

1.7

1.5

Moderately active

1.5

1.5

1.7

1.6

1.8

1.6

Very active

1.6

1.6

1.8

1.7

1.9

1.7

Non-active

Department of Health 1991 Dietary reference values for food energy and nutrients for the United Kingdom. HMSO, London (Report on Health and Social Subjects, No. 41).

I

Clinical box 16.2 Energy needs for sport: advice for sportsmen and sportswomen for optimising performance Tile advice on energy intake is aimed at enabling individuals to: • Compensate for the high energy consumption produced by training and competition to maintain an optimal body weight (Water, protein and fa~ • Ensure that the muscles and the liver contain plenty of stored glycogen prior to the event • Replace glycogen quickly and optimally after sport or between events • Maintain hydration during the sporting activity and salt replacement during prolonged endurance exercise.

Nutritional status ratloe (PARI) for different

PAR 1.2 (range 1.o-1.4)

Lying at

rest

Sitting at rest

Tlble 11.7 Adul nitrogen blllnce Nitrogen Intake (d'-1)

NtlrQgen output (excmlon)

62.5 g protein

Urine

6.50 g {7 g as urea)

Reading

Faeces

0.75 g

Watching television, 1'"88ding, eating

Other

0.75 g

Total

10.0 g

Example Ktlvltr

PAR

Standing at rest PAR 1.6 (range 1 .5-1.8)

Sitting

Sewing, playing piano, driving

Standing

Light kitchen work, ironing, office or laboratory work

PAR 2.1 (range 1 .9-2.4)

Standing

Household chores, cooking

PAR 2.8 (range 2.5-3.3)

Standing

Vacuuming, making beds, showering

Walking

3-4 kmlh, cricket

Industrial

Painting and decorating, machine

tool, tailoring PAR 3.7 (range 3.4--4.4)

PAR 4.8 (range 4.4-5.9)

PAR 6.9 (range a.o-7.9)

745

Standing

Gardening, sailing

Walking

4-6 kmlh, golf

Industrial

Motor vehicle r&pairs, bricklaying

Standing

Chopping wood, heavy gardening, volleyball

Walking

6-7 kmlh

Exercise

Moderate swimming, gentle cycling, slow jogging

Occupational

Labou"lng, digging/shoveling, fellng trees

Walking

Uphill with load, cross-country, climbing stairs

Exercise

Average jogging, cycling

Sports

Football, tennis, mora -rgatic swimming, skiing

Dietary nitrogen Nitrogen makes up approximately 16% of the weight of most proteins, i.e. 6.25 g protein contains 1 g nitrogen. Table 16.7 shows how a (numerically convenient) intake of 62.5 g protein, which equates with 10 g nitrogen, is balanced quantitatively by nitrogen excretion. Healthy adults have a net zero nitrogen balance, with ingestion of food by day balancing losses of nitrogen by day and night. Nitrogen balance is positive during growth, weight regain and pregnancy, and negative during starvation, protein deprivation, nutrient imbalance, trauma and sepsis. In clinical practice, true nitrogen balance is seldom assessed. However, it should be remembered that, whereas in the normal individual a high nitrogen intake is balanced by a higher resulting output, it may not be possible, or indeed desirable, to achieve such balance in a patient in a catabolic state, who is losing excessive amounts of protein due to sepsis or trauma, even with significantly increased nitrogen intake.

Protein requirements A positive nitrogen balance is seen during growth (nitrogen intake exceeds excretion), and sufficient nitrogen intake is required for cell renewal and to replace nitrogen excretion in adults. Adults in the developed world tend to eat more protein than they need: often more than the RNI of approximately 45 g/day for a non-pregnant woman and 55 g/day for a man.

to be compensated for later. Lactate is recycled to the liver for

Essential and non-essential amino acids

gluconeogenesis (Cori cycle) (see Ch. 3).

Twenty amino acids are needed for the manufacture of proteins in humans. These are traditionally categorised into essential/ indispensible and non-essentiaVdispensible, although it should be noted that in metabolic terms there is an essential need for all the amino acids, as all are required within metabolic pathways. The essential amino acids cannot be synthesised endogenously and thus must be taken from the diet. Some amino acids are 'conditionally' essential; their rate of synthesis may not be sufficient to meet demand under all conditions and so they may need to be taken by the diet. Non-essential amino acids are those that can be synthesised from other amino acids or precursors. These are listed in Table 16.8.

Aerobic carbohydrate metabolism During more prolonged exercise, 'aerobic' metabolism takes place, in which muscle stores of ATP run out very quickly if they cannot be replenished. Energy during prolonged exercise can be provided by: • The exercising muscle's glycogen stores • Circulating energy substrate - glucose derived from hepatic glycogenolysis and gluconeogenesis • Fatty acids derived from adipose tissue. Training increases the capacity of the muscle mitochondria to oxidise circulating substrate, especially tatty acids, to produce ATP (see later, TCA cycle). This delays the time at which the relevant muscle's glycogen runs out and the athlete becomes especially fatigued ('hits the wall').

Nitrogen balance and protein requirements Nitrogen balance is the difference between the amount of nitrogen that is ingested and the amount lost from the body. It indicates whether the body is anabolic or catabolic in terms of net protein metabolism: whether the lean tissue is increasing (positive nitrogen balance) or decreasing (negative nitrogen balance). Nitrogen is ingested in the form of dietary proteins, which are metabolised in the liver and excreted, mainly as urea, in the urine.

Obligatory nitrogen loss Obligatory nitrogen loss is the amount of nitrogen excreted when protein is excluded from a diet otherwise adequate in energy, electrolytes, minerals, vitamins and trace elements. In this highly artificial situation, the daily excretion of nitrogen in the urine and faeces declines over a few days to a minimum (Fig. 16.5).

Minimum nitrogen requirement In the absence of growth, nitrogen requirement is estimated by summing the obligatory loss in urine to faecal and other (e.g. skin, sweat) excretions on a protein-free diet (the so-called factorial method). However, an otherwise adequate diet providing only this

746 Diet and nutrition iii T8ble 1U Clullftcldlon of Imino acids

=== T8ble 1U Fuel stoNe In In aven~ge peNOn

Ill

In W8lght (g)

lnenergv(kJ)

Euentlel

NorHIMnllal

Conditionally eeeentlal

Fuel....ce

Isoleucine

Alanine

Arginine

Fat

Leucine

Asp«tic acid

Glutamine

Plasma free fatty acids

0.4

16

Valine

Aspa11gine

Histidine

Plasma triacylglycerols

4.0

156

Lysine

Cysteine

lntrarnyocellular triacylglycerol

Melhionine

Glutamic acid

Adipose tissue

Threonine

Glycine

Carbohydrate

Phenylalanine

Proline

Plasma glucose

20

360

Tryptophan

Serine

LJver glycogen

100

1800

Tyrosine

Muscle glycogen

350

6300

10000

168 000

Whole body protein

300

11700

12000

468000

Note: The principal component of body weight {wat~ provides no energy. Protein is structural and therefore not all is available for energy production. Glycogen and protein in the body are in the hydrated state and so weigh much more, kilojoule for kilojoule, than fat, which is stored in adipose tissue. Adipose tissue contains relatively little water. Adapted from Geissler C, Powers HJ (eds) 2005 Human nutrition, 11th edn. Elsevier, Edinburgh.

10

&::: Q)

I

&:::

5

.~

ll

:::;) -2.5

0

2

3

4

5

6

7

Days on protein-free diet

Fig. 16.5

Obligatory nitrogen loss: minimum urinary nitrogen excretion - protein-free diet. Urine nitrogen loss on a protein-free, otherwise adequate diet reaches equilibrium of approximately 2.5 g by approximately day 5-7. However, if only 2.5 g of nitrogen are supplied in the otherwise protein-free diet, nitrogen losses will increase marginally because of increased ureagenesis, and nitrogen balance is not quite achieved. Slightly more is required for balance.

amount of nitrogen (even as high-quality or first-class protein) does not achieve zero balance; the balance remains slightly negative because ureagenesis increases. A better way of finding minimum requirements in adults is by balance studies in which high-quality protein is gradually added to an otherwise complete diet until zero balance is obtained. In children, growth rates must be taken into account. Adults can maintain nitrogen balance on 96 mg Nlkg per day.

lnfonnatlon box 18.1 Effect of Insulin in the fed and fasted states

During the red state, the active metabolic pathways are for fuel breakdown, storage of excess fuel thruugh glycogen and lipid synthesis, and protein synthesis (anabolism) (see also Ch. 3). These processes are Induced by Insulin, an anabolic hormone, to: • Increase glycogen synthesis in the liver and muscle • Increase hepatic glycolysis • Increase glucose uptake into muscle • Increase lipogenesis and decrease lipolysis • Increase cellular uptake of amino acids and net protein synthesis. In fasting, which can begin a few hours after the last meal, the direction of the metabolic pathways is reversed to break down stored fuels to produce energy. Protein synthesis also slows down. The level of circulating Insulin falls. On the stress of disease or trauma, the acHon of insulin is opposed by increased levels of glucagon, epinephrine, cortisol and growth hormone.) Glycogenolysis, lipolysis, ketogenesis and gluconeogenesis are prumored.

mobilised for gluconeogenesis, and the metabolic pathways reverse during feeding towards protein synthesis. During feeding, as more protein is eaten, more amino acids are metabolised and more urea nitrogen is excreted so that nitrogen balance is maintained. Losses of nitrogen in the faeces approximate 1 glday and are relatively constant.

Nitrogen excretion Unlike glucose and fatty acids, amino acids do not have storage depots, so amino acids are stored in structural and functional protein. Most nitrogen is excreted in the urine as urea, with smaller amounts as creatinine and uric acid, for example. The nitrogen-containing amino group is removed from the amino acid, and the remaining carbon skeleton is then metabolised for gluconeogenesis and protein synthesis (see Ch. 3). The waste product is ammonia, NH3, which is highly toxic and rapidly converted to urea. Urea is excreted principally through the kidneys. The breakdown of amino acids for use in gluconeogenesis is the main source of urea, and plays a major part in nitrogen balance. When fasting, more amino acids are

Energy and protein metabolism during fasting and feeding In healthy people, intracellular metabolism to produce energy is regulated by hormones (see Ch. 3). During the fed state, energy stores are laid down for use during periods of fasting (Table 16.9). It is nonmal to fast overnight or for short periods during the day, but the body adapts if longer periods of fasting occur. The honmones insulin, glucagon, epinephrine (adrenaline), cortisol and growth honmone are involved in the regulation of energy metabolism, exerting short-tenm effects on the direction of metabolic pathways Onfonmation box 16.1 , Fig. 16.8; see also Ch. 3).

Nutritional status

Gl=

Area LRier curve test food (50 g carbohydrate) X

747

100

Area under curve glucose (50 g glucose)

Fed: Insulin Fast: low ina*!

12 11 10 ~9

Portal

~ 8

Glucose

7 .S.s E

~ 5 -+-----~....3ioc:,......;~4 .,3 ~ 2

..:!

a:l

Food under

test

1

0~----,-----,----,-----,--·

+-----

Glutann

______.

Alanine

0

liver

Ci'IUrtion Glucose Amino adds

Fig. 16.7

2 Time(h)

3

4

Glycaemic index (GI).

Laclal:e Urea

Tllble 11.10 Cluelllcallon of foods by glyoaemlc lndax Qlycaemlc Index

!

Ammonium

Fig. 16.6 Carbohydrate and amino acid metabolism during fasting and feeding.

The anabolic, fed, high-insulin state results in net storage of protein and glycogen. The catabolic, fasted, low-insulin state results in mobilisation of, firstly, glycogen for maintenance of blood glucose, and, subsequently, amino acids (especially 3C alanine) as substrate to make 6C glucose (gluconeogenesis-alanine cycle). 5C glutamine is an amino acid and is metabolised by rapidly dividing cells, for example enterocytes and lymphocytes, to 3C alanine which is then returns to the liver. During brisk exercise, when a low-insulin state prevails, the exercising muscles take up glucose, which may not be fully oxidised. Lactate is produced and recycled, after anaerobic glycolysis, back to the liver for gluconeogenesis (Cori cycle) (see Ch. 3.)

Fed state When nutrients are abundant, metabolic processes are geared to the catabolism of macronutrients and anabolism of the excess products for storage against lean times.

Absorbed carbohydrate in the fed state After a meal, blood glucose rises, as shown in the blood glucose response curves in Rg. 16.7. Some foods produce a blood glucose response very similar to that of glucose, the reference food; others produce a much flatter curve. Glucose is made available for: • Metabolism • Storage as glycogen (principally in muscle and liver) • In more extreme excess, lipogenesis. Many physical and chemical characteristics of carbohydrates affect how quickly they are absorbed and are reflected in how quickly blood sugar rises and falls after they are eaten. The glycaemlc Index (GQ describes this response in relation to glucose (see Rg. 16.1'), and foods can be classified as having low, intermediate or high Gl

High (70-100)

Bread (white or wholemea~, glucose, fruit juices, honey, mashed potatoes

Intermediate (5EHl9)

Grw~ary

Low (-136 clinical application of, 138b Drug clearance, 120 Drug detoxification, 115 Drug distribution, 110-113 aocumulation in fat and redlstl1butlon In other tissues, 110 apparent volume of distribution, 112-113 into aqueous compar1m&nts, 112 binding of drugs to proteins, 111, 111t blood flow, 110 In the body, 111-113 capillary permeability, 110 gap junctlone, 11 0 to special organs, 11 0 Drug excretion, 116-119 glomerular fiBration, 117 hepatobiliary excration and enterohepetlc circulation, 119 renal syfllem, 117-119, 117f tubular 11111bsorption, 117-119 tubular secretion, 117, 117b Drug Interactions, 41

Drug metabolism, 113-118 aasocllll&d with gene tralt!l, 205b conversion of Inactive pn:t-drug to active metabolite, 118, 118b detoxification, 115 factors .rtac:ting, 115-118 ftrat pssa, 105 in gastrointestinal tract, 104-105 hydrolysis, 11-4-115 liver and, 727 phase I metabolic reactions (pre-conjugation reactions), 113-115 phaee II metabolic reactions (conjugation reactions), 115 reduction, 114 Drug targ&tll, 122--132 cerrier proteins, 124 enzymes, 123 ion channels, 124-125 receptors, 125-126 Drug-receptor binding, strength of, 135 Drug-receptor interaction, alloateric modulation of, 135 Drugs abeorptlon. see Drug absorption acid labile, 105 bioavailability of, 105 bloequlvalence of, 105 classification of, according to performance, 133 distribution. see Drug dlst~butlon

dosage of, pars~inohippuric acid and, 657 sfflux 1ranaporters and, 657 elderly and, 682 haW-life, 120 injection of, 105-106 bucc:aVsubllngual administration and, 106 epidural, 105-106 intrathecal, 105 local, Into tandonalbursas, 106 rectal, 106 toplcalltransdermal, 106, 118b metabolism. see Drug metabolism parent91111 administration of, 105 Intramuscular. 105 intravenous, 105 subcutaneous, 105 performance of, factors that affect, 135-136 potency, 133, 134f routes of administration, 103-106 safety and aff&cliv&ness of, 132--136 selactivity, 133, 133b ~uesbatlon ,135

specificity, 133 In stomach, 104, 118b targets. see Drug targets tolerance, 138 Dry chemistry, urine testing and, 658 Dual-energy X-ray abeorptlomstry (OEXA scanning), 394 Duchenne muscular dyatrophy, 207, 432b Ductus arteriosus, 498, 499f Ductus venosus, 498, 499f Duffy amlgen receptor for chemokines (DARC), 173, 174f Duffy blood groups, 597 Duke& system, 266 Dumping syndrome, 717b Duodenal contents, 717 Duodenal Jejunal bypBBS liner, for obesity, 787 Duodenum, 688, 707-710 musculature of, 708-709 structural featul'98 of, 7311 Duplications, 162 Dura mater, 339

Dwarfism, 464b Dynelns, 48 Dysdiadochokinesia, 361b Dyagenesls, 257 Dyslipidaemias, 89b Dysplasia, 204, 255456, 256f Dyspnoea, 625, 632b Dystrophin gene, 199

E Eadle-Hofstee plot, 41f Early diastolic murmur, 488b Early l'nlgnancy Factor (EPF), 478 Eating. see Food intake Eccentric contractions, 426 Eccrine glands, 436 Ectoderm, 51 Ectopic beats, 507-509 Ectopic pregnancy, 477b Edinger-Westphal nucleus, 336 Edrophonium, 141 Elfector domain, 125 Elfectors, 3 Efferent lymph vae&Bis, 253 Efferent neurons, 342 Emux transporters, 657 eHAND, 169 Ehlers-Danlos syndrome, 38b Elcosanolda, 25, 130 Eicosapentaenoic acid, 24 ElnthOV9n's triangle, 505, 506f Eisenmenger syndrome, 4117b Ejection click, 488b Ejection systolic murmur, 488b Elastic (yellow) cartilage, 52, 394-3115 Elastin, 39, 438 Elbow joint, 413b, 413f dislocation of, 413b tennis elbow, 414b Electrical foro&, 347 Electrical synapses, 349 Electrocardiogram (ECG), 505 12-lesd, 505t deflections, detenminants of, 506t normal, 50EH;07, 5061, 507t Electrocardiography, 505-507 Electrochemical gradient, 109 Electroencephalography, 366b Electrolyte balenca, laboratory assessment of, 21 b Electrolytes, 754-755 absorption of, 695 depletion of, 755 transport of, in small and large Intestine, 697t Electron sharing, 17-18 Electron transport chain, 58, 60, 60f

coupling of, 81 inhibition of, 61 uncoupling of, 61 Electrophlles, 19 Electrophoresis, 194 haemoglobin, 577-078, 578b, 578f Elevation, dsllnltlon of, 415b Embryonal neoplasms, nomenclature of, 260t Embryonic stem cell transplantation, 207 Embryonic stem cells, 206 Emesis. sea Vomiting Emotion, 386-389, 387f expression, 387. 366b recognition, 387 Emphysema, 805b as respiratory !allure, 6311-&9 Empyema, 246b, 611 Enalaprtl, 116b Enamel, 52 Encephalopathy NH,-Induced, 87b porto-systemic, 730 End-diastolic volume (EDV), 515 Endergonic reactions, 20 Endocardial cuahlons, 496-497 Endochondral ossification, 401-402, 402f Endocrine activity, 231 Endocrine BXB, 446b Endocrine disease, 445-449 Endocrine effect, 441-442 Endocrine glands, 52, 441, 442f Endocrine hypertension, 554

system, 441-445 oomparison of nervous system and, 441b Endocrine testing, 448--447 Endoc~nology, 441-482 ageing, 481-482 concepts In, 445-448 control of blood calcium, 485-486 calcium homeostasis, 485-486 and phosphflle concentration, 466 control of glucoea metabolism, 48D-485 endoc~ne pancl'&llll, 462-465 plasma glucose concentration, 460--461 endoc~ne homeoataslll, 454-466 endocrine regulation, 448-451 endoc~ne system, 441-445, 442f growth honnone, 451-454 pregnancy, 47o4-481 reproductive physiology, 468-482 Endocytosis, 50, 50f, 109 Endoderm, 51 Endomysium, 432 Endoneurium, 338 Endoplasmic reticulum (ER), Endoc~ne

48--49

in hepatocytes, 49b Endoscopic barrier, 766f Endospores, becterla, 212-213 Endosteum, 400 Endothelial cells in haemostaais, 587 In lnnammatory response, 247 Endothelial damage, 522 Endothelium, In haemoatasls, 587, 587f Endotoxlns, 226 End-product inhibition, 144 End-i!YS~ollc volume (ESV), 515 Energy balance of, 743-746, 756f in biological systems, 19-20 coneumptlon of, 635 for diffen!nt types of activity, 744 converalon of macronutrlents to, 743, 743f, 7431 expenditure of during daily living, 744 during exercise, 744-745, 744b measurement of, 744 total, 743-744 for gluconeogenesis, 80 metabolism, 1, 57-102 during fasting and feeding, 746-747, 746t during illness, 749, 750b In muscles, 75b restrictions, in renal disease, 761 Energy cycle, in biology, 19 Energy flow, In chemical reactions, 20 Energy output, 61-62 Energy substrates dil'ferllnt tiasu. metabolise different, 63 metabolic pathways of, 748b, 748f Energy-coupling agent, 57-58 Englyat method, 738 Enhancers, in transcription, 185 Enkephallns, 7021 Enlenll nutrition, 762, 762b Enterochromemn-llke cells (ECL. cella), 710 Enterocytes, transport of sugars ~. 46f

EntenHndocrine cells, 731 Entemglucagona, 7021 Ent&roh&patic circulation, 119 of bile acids, 26 Enlhesis, 421 Entrainment, 5 Environmental contaminants, drugs and, 118 Enzyme activity, regulation of, 41-42

Enzyme cofactol3, 42 Enzyme hlstochemlstJy, 46b Enzyme induction, 114t, 116, 727 Enzyme lnhlbiUon, 41, 116 Enzyme inhibitors, 123, 123b Enzyme kinetics, 40-41 Enzyme-linked lmmunoeorbant assay, 449b Enzyme-linked receptors, 13[)-131 Enzymes, 40-42 binding of allosteric effectors, 62 as biornar1