Essential Dental Therapeutics E-Book
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- Herausgeber: John Wiley & Sons
- Kategorie: Fachliteratur
- Serie: Essentials (Dentistry)
- Sprache: Englisch
Essential Dental Therapeutics is a practical guide to drugs and their effects on dental care. Covering both medical and dental prescribing, all major categories of prescription drugs, their possible side effects, and potential drug interactions are discussed. The medical section is succinct and easily understandable, providing busy dentists with the information they need about medical conditions and the drugs used to treat them. The dental section offers practical, straightforward information that is relevant to everyday dental prescribing.
All clinical contributing authors are medically and dentally trained, and both strands are fully integrated throughout the text. Readers can test their knowledge by using the key topics and learning objectives at the start of each chapter, and by accessing the companion website featuring self-assessment questions. Essential Dental Therapeutics is a practical reference for dental students and practitioners, ensuring they are safe and informed in everyday practice.
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Veröffentlichungsjahr: 2017
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Table of Contents
Cover
Title Page
Copyright
List of contributors
Preface
About the companion website
Chapter 1: Introduction to pharmacology and therapeutics – pharmacodynamics
Introduction
History of therapeutics
Targets for drug actions
Selective toxicity
Conclusion
Chapter 2: Introduction to pharmacology and therapeutics – pharmacokinetics
Introduction
Introduction to pharmacokinetics
Chapter 3: Introduction to pharmacology and therapeutics – drug safety
Introduction
Determining drug safety
Individual variations
Chapter 4: Antimicrobials – antiseptics and disinfectants
Introduction
Antiseptics
Disinfectants
Specific agents
Chapter 5: Antimicrobials – antibiotics
Introduction
Management of infection
Antibiotic prophylaxis
Prescribing considerations
Microbiological considerations
General aspects of antibiotic drugs
Mechanisms of action
Pharmacokinetics
Tuberculosis
Principles of treatment
Antituberculosis drugs
Chapter 6: Antimicrobials – antifungals
Introduction
Aspergillosis
Blastomycosis
Cryptococcosis
Histoplasmosis
Oral fungal infections
Skin and nail infections
Antifungal drug treatment
Implications for dental practioners
Chapter 7: Antimicrobials – antivirals
Introduction
Hepatitis (viral)
Herpesvirus infections
Human Immunodeficiency Virus (HIV)
Influenza
Respiratory syncytial virus (RSV)
Implications for dentistry
Chapter 8: Therapeutics of pain management
Introduction
Local anaesthesia
General anaesthesia
Sedation
Analgesics
Reference
Chapter 9: Corticosteroids
Introduction
Topical corticosteroids
Systemic corticosteroids
Chapter 10: Fluoride and toothpaste
Introduction
Water fluoridation
Fluoridated milk
Fluoridated salt
Toothpaste
Fluoridated mouth rinses
Fluoride gels and foams
Fluoride varnishes
Fluoride tablets
Chapter 11: Treatments for dry mouth
Introduction
Topical treatments for dry mouth
Systemic treatments for dry mouth
Chapter 12: Therapeutics for medical emergencies in dental practice
Introduction
Emergency drugs
Adrenal insufficiency
Anaphylaxis
Asthma
Cardiac emergencies
Choking and aspiration
Epileptic seizures
Hypoglycaemia
Syncope
Chapter 13: Central nervous system 1 – mood disorders
Introduction
Depression
Antidepressant drug treatment
Anxiety disorders
Chapter 14: Central nervous system 2 – neurodegenerative and acquired disorders
Introduction
Stroke
Neurodegenerative disorders
Chapter 15: Central nervous system 3 – genetic and developmental disorders
Introduction
Seizures and epilepsy
Schizophrenia
Attention deficit/hyperactivity disorder
Cerebral palsy
Down syndrome
Chapter 16: Endocrine disorders 1
Introduction
Pituitary gland
Thyroid gland
Parathyroid glands
Adrenal glands
Reproductive hormones
Chapter 17: Endocrine disorders 2 – diabetes mellitus
Introduction
Diabetes mellitus
Signs and symptoms of diabetes
Diagnosis of diabetes
Management of diabetes mellitus
Management of the diabetic patient in the dental chair
Chapter 18: Cardiovascular therapeutics
Introduction
Cardiovascular physiology
Cardiovascular pathology
Drugs used in cardiovascular disease
Efects of cardiovascular medications of relevance to dentistry
Chapter 19: The respiratory system
Introduction
Respiratory physiology
Asthma
Chronic obstructive pulmonary disease (COPD)
Rhinitis
Cough
Drugs used in respiratory disease
Implications for dentistry
Chapter 20: Coagulation
Introduction
Normal haemostasis
Haemostasis and platelets
Coagulation cascade and haemostasis
Local haemostatic measures
Anti-coagulant medications
Chapter 21: Gastrointestinal pharmacology
Introduction
Gastric acid-related conditions
Medications used in gastric acid-related conditions
Nausea and vomiting
Anti-emetics
Constipation
Diarrhoea
Irritable bowel syndrome
Inflammatory bowel disease
Gallstones
Chapter 22: Antineoplastic therapeutics
Introduction
Chemotherapy (cytotoxic therapeutics)
Hormone therapy
Biological therapy
Transplants
Bisphosphonates
Other treatments
Dental management of the patient undergoing treatment for cancer
Chapter 23: Vitamins and minerals
Introduction
Fat-soluble vitamins
Water-soluble vitamins
Minerals and trace elements
Chapter 24: Musculoskeletal therapeutics
Introduction
Musculoskeletal disorders
Drugs used for musculoskeletal disorders
Dental relevance
Index
End User License Agreement
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Guide
Cover
Table of Contents
Preface
Begin Reading
List of Illustrations
Chapter 8: Therapeutics of pain management
Figure 8.1 The physiological processing of pain.
Figure 8.2 The WHO pain relief ladder.
Figure 8.3 Local anaesthetic – mechanism of action on peripheral sensory nerves.
Chapter 18: Cardiovascular therapeutics
Figure 18.1 The human cardiovascular system.
Figure 18.2 The renin-angiotensin-aldosterone system.
Chapter 19: The respiratory system
Figure 19.1 The British Thoracic Society/Scottish Intercollegiate Guideline Network five-step asthma management plan.
Chapter 20: Coagulation
Figure 20.1 The coagulation cascade.
List of Tables
Chapter 4: Antimicrobials – antiseptics and disinfectants
Table 4.1 Ideal properties of an antiseptic
Table 4.2 Hand hygiene in dental practice
Table 4.3 The ideal properties of a disinfectant
Chapter 5: Antimicrobials – antibiotics
Table 5.1 Antimicrobials for which dose modification is required in mild, moderate or severe renal failure and in liver disease
Chapter 6: Antimicrobials – antifungals
Table 6.1 Key topics
Table 6.2 Risk factors for oral candidosis
Table 6.3 Clinical presentations of Tinea
Table 6.4 Oral side effects of antifungal medications
Chapter 7: Antimicrobials – antivirals
Table 7.1 Viral infections
Table 7.2 Viruses in the human herpesvirus (HHV) group
Chapter 8: Therapeutics of pain management
Table 8.1 Converting concentration to dose
Table 8.2 Maximum dosages of local anaesthetics in dentistry/oral surgery
Chapter 9: Corticosteroids
Table 9.1 Equivalent anti-inflammatory doses of different oral corticosteroids
*
Table 9.2 Potential side effects of corticosteroids
Table 9.3 Procedures requiring steroid cover
Chapter 10: Fluoride and toothpaste
Table 10.1 Recommended use of fluoridated toothpastes
Chapter 11: Treatments for dry mouth
Table 11.1 Key points for the management of patients with a dry mouth
Table 11.2 Dry mouth management
Chapter 12: Therapeutics for medical emergencies in dental practice
Table 12.1 The ‘ABCDE’ approach to assessing any patient who is unwell
Table 12.2 The underlying principles of managing medical emergencies
Table 12.3 Medical emergencies in dental practice
Table 12.4 Emergency drugs
Chapter 13: Central nervous system 1 – mood disorders
Table 13.1 A simple classification of psychological disease
Table 13.2 The defining symptoms of depression
Table 13.3 Practice points – depression
Chapter 17: Endocrine disorders 2 – diabetes mellitus
Table 17.1 Systemic and oral signs of diabetes
Chapter 18: Cardiovascular therapeutics
Table 18.1 Drugs used in the management of cardiovascular disease
Chapter 19: The respiratory system
Table 19.1 Chapter key sections
Chapter 21: Gastrointestinal pharmacology
Table 21.1 Gastrointestinal conditions requiring medical management
Chapter 22: Antineoplastic therapeutics
Table 22.1 The currently known therapeutics available for cancer
Table 22.2 Generic side effects of cytotoxic drugs
Table 22.3 Therapeutics used to prevent and treat the side effects of cytotoxic drugs
Table 22.4 Cytotoxic therapeutics
Table 22.5 Alkylating drugs
Table 22.6 Cytotoxic and Anthracycline antibiotics
Table 22.7 Antimetabolites
Table 22.8 Vinca alkaloids
Table 22.9 Hormone therapies
Table 22.10 Examples of anti-angiogenesis inhibitors
Chapter 23: Vitamins and minerals
Table 23.1 Summary of fat-soluble vitamins
Table 23.2 Summary of water-soluble vitamins
Essential Dental Therapeutics
Edited by
David Wray
University of Glasgow UK
This edition first published 2018
© 2018 John Wiley & Sons Ltd
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions.
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Library of Congress Cataloging-in-Publication Data
Names: Wray, David, author.
Title: Essential dental therapeutics / by David Wray.
Description: First edition. | Chichester, West Sussex ; Hoboken : Wiley, 2018. | Series: Essentials | Includes index. |
Identifiers: LCCN 2017014504 (print) | LCCN 2017015962 (ebook) | ISBN 9781119057413 (pdf) | ISBN 9781119057420 (epub) | ISBN 9781119057390 (pbk.)
Subjects: | MESH: Dental Care | Drug Therapy
Classification: LCC RK51.5 (ebook) | LCC RK51.5 (print) | NLM WU 29 | DDC 617.6-dc23
LC record available at https://lccn.loc.gov/2017014504
Cover design: Wiley
Cover image: © Vstock LLC/ Gettyimages
List of contributors
Dr. Esther A. Hullah,
BDS, MB ChB, MFDS RCS Eng, FDS (OM) RCS Eng, FHEA., Consultant and Specialist in Oral Medicine, Department of Oral Medicine, Guy's and St Thomas' NHS Foundation Trust & Honorary Lecturer in Oral Medicine, Kings College London Dental Institute, Guy's Hospital, London, United Kingdom
Dr Sabine Jurge,
DDS, MSc, MBBS, MFDS RCS Eng, FDS (OM) RCPS, FHEA., Consultant and Specialist in Oral Medicine, Charles Clifford Dental Hospital, Sheffield Teaching Hospitals NHS Foundation Trust & Honorary Senior Clinical Lecturer in Oral Medicine, The School of Clinical Dentistry University of Sheffield, London, United Kingdom
Dr. Roddy McMillan,
BDS, MB ChB, MFDS RCS Eng, FDS (OM) RCPS, FHEA., Consultant & Specialist in Oral Medicine, Eastman Dental Hospital, University College London Hospitals NHS Trust & Honorary Clinical Teaching Fellow in Oral Medicine and Facial Pain, Eastman Dental Institute, University College London, London, United Kingdom
Professor Alan J. Nimmo,
PhD, BSc(Hons)., Professor of Medical Science, College of Medicine and Dentistry, James Cook University, Smithfield Campus, Cairns, Australia
Dr. Martyn Ormond,
BDS, MBBS, MFDS RCS Ed., Specialty Registrar in Oral Medicine, Department of Oral Medicine, Guy's and St Thomas' NHS Foundation Trust & Honorary Lecturer in Oral Medicine, Department of Oral Medicine, Kings College London Dental Institute, Guy's Hospital, London, United Kingdom
Dr. Martina K. Shephard,
BDent(Hons), MBBS(Hons), FRACDS, FDS (OM) RCS Eng., Consultant & Specialist in Oral Medicine, Eastman Dental Hospital, University College London Hospitals NHS Trust, London, United Kingdom
Dr. John C. Steele,
BDS, MB ChB, MFDS RCS Ed, FDS (OM) RCS Ed, Dip OM, PGCTLCP, FHEA., Consultant & Specialist in Oral Medicine, The Leeds Teaching Hospitals NHS Trust & Honorary Senior Lecturer in Oral Medicine, Leeds Dental Institute, Faculty of Medicine & Health, University of Leeds, London, United Kingdom
Dr Jennifer Taylor,
BDS, MB ChB, MFDS RCS Ed, FDS (OM) RCPS., Consultant and Specialist in Oral Medicine, Greater Glasgow and Clyde NHS Trust, &, Honorary Senior Lecturer in Oral Medicine, University of Glasgow, Glasgow Dental Hospital and School, 378 Sauchiehall Street, Glasgow, United Kingdom
Professor David Wray,
MD(Hons), BDS, MB ChB, FDS RCPS, FDS RCS Ed, F Med Sci., Emeritus Professor, University of Glasgow, University Avenue, Glasgow, United Kingdom
Preface
Dentists, along with medical practitioners, are allowed to prescribe all medications although dentists must prescribe only within their competence as part of their clinical practice. Dentists, working within the National Health Service, are restricted to prescribing only those drugs included in the dental list and they must only prescribe generically.
Although the range of medications prescribed by dentists is narrower than their medical counterparts, dentists prescribe drugs to patients with a wide range of medical conditions who may be taking a number of other medications, which will influence dental practice as well as potentially causing interactions among the prescribed drugs.
For these reasons dentists must not only be familiar with the conditions they prescribe for and the drugs they prescribe but also they must be knowledgeable about general medical conditions affecting their patients and have knowledge of the drugs these patients may be concurrently taking.
To this end this textbook, designed to inform both dental students and dental practitioners, aims to provide information about dental prescribing and also general medical conditions, the drugs used to treat them, and their impact on dental practice.
This text does not cover the competencies required by the prescriber since these are detailed in the recently published Prescribing Competency Framework, produced the Royal Pharmaceutical Society under the aegis of NICE. The competencies contained in this Framework should be accomplished by all practitioners seeking to prescribe safely.
Similarly, this text does not detail specific prescribing details. These are comprehensively included in the British National Formulary and the British National Formulary for Children which are updated electronically, monthly and published in hard copy bi-annually and annually respectively. All prescribers should make reference to these sources when prescribing.
A specific, abridged text, Drug Prescribing for Dentistry, is produced by the Scottish Dental Clinical Effectiveness Programme (SDCEP.org.uk), which is also available as an iPhone app (https://itunes.apple.com/gb/app/sdcep-dental-prescribing/id509188306?mt=8). This provides explicit prescribing information for all drugs on the dental list and is designed to help dentists in primary care practice.
About the companion website
This book is accompanied by a companion website:
www.wiley.com/go/wray/dental-therapeutics
This website contains a set of multiple-choice questions for every chapter for students' use.
Chapter 1Introduction to pharmacology and therapeutics – pharmacodynamics
Alan Nimmo
Key Topics
•
Introduction to therapeutics – pharmacodynamics and the basis for drug action
•
Molecular targets for drug action – receptors, enzymes, ion channels and carrier proteins
•
Selective toxicity – the basis of antibacterial, antiviral and antifungal drug action, and cancer chemotherapy
Learning Objectives
•
Be familiar with the main types of functional protein that serve as the molecular targets for drug action
•
Be aware that in most cases, altering the activity of these proteins alters chemical signaling in the body, and hence control of body function
•
Be familiar with how drugs, such as antibiotics, are able to exert a selectively toxic effect
•
Be aware of the challenges posed in developing antiviral drugs and drugs for the treatment of cancer
Introduction
Therapeutics has its roots in the historical use of herbal remedies and natural potions. However, the modern practice of therapeutics really began in the twentieth century. The herald for this new era was the German physician, Paul Ehrlich. Ehrlich sowed the seeds for transforming therapeutics into a science by insisting that drug action could be explained in terms of chemical and physical reactions. The understanding of how drugs produce their effects represents the area of therapeutics known as pharmacodynamics.
During the twentieth century, the advent of many effective therapeutic agents began to deliver immeasurable benefits to society. Perhaps the biggest single advance in medicine was the development of antibiotic therapies, exemplified by the work of Florey, Chain and Fleming on penicillin. The introduction of these novel treatments transformed what had previously been fatal or life-devastating diseases into manageable conditions.
However, we cannot be complacent. There are still many areas of practice where our current therapies have limited efficacy, or are associated with unwanted, or side, effects. For example, many cancer therapies come with significant side effects. In dental practice you'll see some of the most severe side effects associated with cancer treatment, such as stomatitis. It will only be through making cancer treatments more specific in the way they target cancerous cells, that we will be able to overcome many of these issues. Another challenge we face is the ability of bacteria to develop resistance to antibiotic therapy. In developed countries, antibiotic-resistant bacteria are now responsible for more deaths than HIV/AIDS. If we do not respond appropriately to these issues, we could return to an era where bacterial infections are no longer treatable. Hence therapeutics is, and needs to be, a constantly evolving science.
In dentistry, therapeutics may not be such a major component of daily practice as compared to general medical practice. However, an understanding of therapeutics is one of the cornerstones of good clinical dental practice. Pain-free dentistry would not be possible without the use of local anaesthetics, while analgesics are used to manage peri- and post-operative pain. In dental practice, the primary approach to managing microbial infection is surgical, however antibiotics do provide an important adjunct therapy, particularly in the case of a spreading infection. Dental practitioners also rely on drugs to manage fungal and viral infections, and inflammation. Other common uses of drugs in the dental clinic are to manage patient anxiety and to provide sedation for patients. However, this is only one side of the coin. Being aware of patients' general medical conditions, and their associated medications, is central to providing safe and effective treatment. Patients' medications may impact directly upon their oral health, for example many common medications cause the problem of xerostomia. In addition, medications may impact upon how a dentist manages a patient within the dental clinic. A significant number of patients may be receiving anticoagulant therapy in order to reduce their risk of a thrombotic event, such as a heart attack. However, a direct consequence of this is these patients will have a tendency to increased bleeding with surgical procedures, and this must be controlled with effective, local measures. Hence, good dental practice relies on a good understanding of therapeutics.
History of therapeutics
The practice of therapeutics is as old as history, and was well documented in ancient Greek and Egyptian civilizations. Throughout history there have been two opposing approaches to therapeutics, a magico-religious approach and an empirico-rational approach. The magico-religious approach is based upon the belief that disease is a supernatural event, and therefore should be managed by such forces, while the empirico-rational approach assumes that disease is a natural process that is best managed by a scientific approach, and evolving treatments in response to careful observation and evaluation of patient outcomes. It is this latter approach that forms the basis of current evidence-based practice.
In itself, the empirico-rational approach is not new. The father of modern medicine was the Ancient Greek physician, Hippocrates (circa 460–370 bce). Hippocrates is accredited with insisting that disease is a natural process, and should be managed in a judicious manner. Some of the most basic principles of clinical practice, such as the importance of hygiene, can be traced back to the Hippocratic Works. Hippocrates even suggested that sometimes, ‘to do nothing was the best remedy’, recognition of the capacity of the human body to fight disease and initiate repair. However, for most of the intervening period between Hippocrates and the twentieth century, the practice of therapeutics was not based upon a scientific rationale. Common practices have included treatments such as bleeding patients, not only through the use of leeches, but also by severing blood vessels. Needless to say, many of these treatments did more harm than good. In fairness, though, a key underlying issue was that the function of the human body, and the basis of disease, was so poorly understood that it impeded a more scientific approach to medicine. It was the Russian physician, Virchow, who indicated that a scientific approach to therapeutics would come through its combination with physiology, and with it an improved understanding of normal body function.
As mentioned earlier, the historical basis of therapeutics lay in the use of natural potions, normally of plant origin. Some of these natural agents were actually very potent and effective. Indeed, there are a number of agents in current, clinical use, which have been used, in crude form, for hundreds, and even thousands of years. Some notable examples include the analgesic, morphine, which comes from the opium poppy, and the muscarinic antagonist, atropine, which comes from the plant, deadly nightshade. Indeed, the first local anaesthetic was cocaine, which comes from the leaves of the cocoa plant. One might assume that the existence of such effective medicinal agents would facilitate a scientific approach to therapeutics but, if anything, they tended to work against it. The issue was that those agents that were effective, produced their effects in such a specific and potent manner, that it was believed their actions could not be explained in terms of physical or chemical reactions. Instead, it was assumed that they must be imbued with some kind of magical, or vital forces. It was Paul Ehrlich, at the beginning of the twentieth century, who insisted that drug action should be understood in terms of normal chemical and physical reactions. In particular, he suggested that drugs are able to produce their specific and selective effects because they bind to specific targets within the body. It is an understanding of these targets, and how drugs interact with them, that underpins modern pharmacology.
Targets for drug actions
Although there are hundreds of different drugs in clinical use, the way in which these drugs are able to produce their effects within the body is limited to a few basic mechanisms. Ehrlich suggested that drugs bind to specific target molecules, and we now recognize that these molecules are primarily key functional proteins, particularly proteins associated with communication within the body. The normal function of the body is under the control of the nervous, endocrine and paracrine systems. These systems use chemical mediators, such as neurotransmitters and hormones, to affect their control. In the same way, many drugs produce their effect by modulating this natural chemical signalling through targeting the functional proteins associated with chemical communication. The other, major way in which drugs act is by being selectively toxic, in other words they are toxic to particular cells or organisms, but are relatively innocuous to healthy human cells.
Receptors
As indicated, the key communication and control systems in the body exert their effects through the release of chemical mediators, such as neurotransmitters and hormones. These mediators are able to produce their effects on their target cells because those cells have receptors, that are not only capable of detecting chemical messages, but are also able to transduce and amplifying that signal to bring about a meaningful response within that cell. In terms of the way in which natural mediators act on these receptors, there are two components to their action. First, they bind to the receptor in question, but coupled to that, they also stimulate that receptor, to bring about a response. The ability of a messenger to bind to a particular receptor is referred to as its affinity, while the ability of the messenger to actually stimulate a receptor, and bring about a response, is referred to as efficacy. An analogy that is commonly used to describe this mechanism is the ‘lock and key’ effect. A key must not only have the correct shape to fit into a particular lock (affinity), but it must also have the precise shape that enables it to turn in the lock, and open that particular lock.
In terms of drugs, a number of drugs produce their effects by acting upon receptors, and thereby altering chemical signalling, and with it, control function within the body. Some drugs will produce their effect by mimicking the actions of the natural chemical messengers, in other words they will bind to, and stimulate the specific receptor. Those drugs, which have both affinity and efficacy for a particular receptor, are referred to as agonists. An example of a drug which acts as an agonist is salbutamol, which is used for the management of asthma. Salbutamol is an agonist for the beta2-adrenergic receptor. It mimics the natural actions of adrenaline on the beta2-receptors of airway smooth muscle, relaxing the airways, and thereby relieving an asthmatic attack.
Another way in which drugs can alter chemical signalling at receptors, is to block that receptor. If a drug binds to a receptor, but does not stimulate it, it has in itself no direct action. However, by binding to, and occupying the binding site, it can prevent the natural messenger from producing its effects at that receptor, and hence the drug can prevent a particular, unwanted response. Such drugs, which possess affinity for a receptor, but no efficacy, are referred to as antagonists. Such drugs are often identified by the prefix “anti” or the suffix “blocker”, for example antihistamines or beta-blockers. Antihistamines can be used to manage some allergic reactions, such as allergic rhinitis, or hay fever, through blocking the unwanted actions of histamine.
Enzymes
The second class of functional protein that drugs may act upon, is enzymes. Enzymes are obviously essential for catalysing metabolic reactions within the body. However, a number of enzymes are responsible for the synthesis of, and degradation of, chemical messengers. It is particularly this kind of enzyme that serves as a target for drug activity.
The eicosanoids are a family of chemical messengers that are derived from membrane phospholipids. The synthesis of these mediators begins with the liberation of arachidonic acid from membrane phospholipids by the enzyme phospholipase A2. The arachidonic acid is then metabolized by another enzyme, cyclooxygenase, to give rise to the prostanoids (prostaglandins and thromboxanes). These lipid mediators regulate a number of physiological processes, but are also important inflammatory mediators. The most widely used anti-inflammatory drugs are the non-steroidal anti-inflammatory drugs (NSAIDs), like ibuprofen. They produce their anti-inflammatory effects by inhibiting the cyclooxygenase enzyme, thereby inhibiting the production of the prostanoids.
Drugs that inhibit enzyme activity can also be used to enhance chemical signalling. Currently, the main agents used to manage Alzheimer's disease are acetylcholinesterase inhibitors. These drugs reduce the breakdown of acetylcholine, thereby increasing its activity in the brain.
Ion channels
The function of nerve and muscle cells is related to the electrical excitability of their cell membranes. For example, the ability of a nerve cell to send signals along the nerve axon is dependent upon its ability to generate action potentials. Membrane excitability is related to the presence of ion channels in the cell membrane. Drugs are able to modify the electrical activity of target cells by altering ion channel activity.
Local anaesthetics, like lignocaine, are the most widely used drugs within the dental clinic. Local anaesthetics produce their effects by blocking voltage-gated sodium ion channels. The opening of voltage-gated ion channels is central to the ability of a nerve to generate action potentials and, consequently, the ability of a nerve to signal. By blocking the transmembrane pore of the sodium ion channel, local anaesthetics inhibit the inward sodium current required to generate action potentials. As such, nociceptive nerves cannot send signals regarding a painful stimulus to the brain, and hence, pain sensations are abolished.
Drugs can also produce their effect by enhancing the opening of ion channels. For example, benzodiazepines, such as diazepam, which may be used as sedatives within the dental clinic, produce their effect by facilitating the opening of chloride ion channels associated with the GABAA receptor. GABA (γ-amino butyric acid) is the main inhibitory neurotransmitter in the brain, and its inhibitory effects are enhanced by benzodiazepines, which increase chloride ion channel opening, leading to hyperpolarization of neuronal cell membranes, and hence decreased excitability.
Carrier proteins
The fourth group of functional proteins that serve as a target for drugs are the carrier proteins associated with transmembrane transport. Again, for drugs that act on these targets, their main impact is on cell signalling and chemical communication.
In terms of nerve signalling, once a neurotransmitter has been released from a nerve terminal, there must be some mechanism to terminate the activity of the released neurotransmitter. This primarily happens in one of two ways. There may be enzymic breakdown of the released transmitter, as seen with acetylcholinesterase breaking down acetylcholine. Alternatively, a released neurotransmitter can be ‘recycled’ through neuronal reuptake involving a specific carrier protein. Such carrier proteins are responsible for the reuptake of catecholamines, such as noradrenaline and serotonin, following release. These carrier proteins serve as an important target for a number of anti-depressant medications. For example, drugs that inhibit the re-uptake of serotonin (selective serotonin reuptake inhibitors (SSRIs), e.g. fluoxetine), increase serotonin activity in the brain, and help enhance mood.
Selective toxicity
The other main way that drugs exert their beneficial effects is by being selectively toxic. As the name suggests, the drug should be toxic to a particular invading organism, but innocuous to healthy human cells. Selectively toxic agents form the basis for antibacterial, antiviral and antifungal drug treatments, as well as the treatment of cancer. The development of selectively toxic treatments relies on exploiting the biochemical differences between particular organisms and cells. This may be ‘relatively’ easy when one is trying to deal with bacterial and fungal infections within a human, where there are significant differences between the organisms, but it becomes much more difficult when one tries to deal with viral infections and cancer.
Antibacterial drugs
There are significant biochemical differences between prokaryotic cells (bacteria) and mammalian, eukaryotic cells. A number of these serve as effective targets for antibacterial agents. Although not the first antibiotic, penicillin represented a major step forward in terms of being a very effective bactericidal agent. Penicillin, and all β-lactam antibiotics, such as amoxicillin, produce their effects by interfering with the synthesis and integrity of the bacterial cell wall. Because the main component of the bacterial cell wall, peptidoglycan, is not found in human cells, β-lactam antibiotics have a very low toxicity. However, some individuals may develop allergic reactions to penicillins. While severe allergic reactions and anaphylactic shock are rare, they may potentially be fatal.
There are other biochemical targets for antibiotic drugs. Some drugs, such as sulfonamides, can interfere with folic acid synthesis, which subsequently impacts upon nucleotide synthesis in bacterial cells, conferring a bacteriostatic effect. Other antibacterial agents, such as the tetracyclines, target protein synthesis, and in particular the differences between bacterial and mammalian ribosomes. The quinolones, such as ciprofloxacin, target a bacterial enzyme, known as topoisomerase II. These agents have become important in dealing with bacteria that are resistant to agents such as the penicillins.
Antifungal agents
There are a number of agents that can be used to manage fungal infections. Some of these agents, such as amphotericin and nystatin, are naturally occurring, while others, such as clotrimazole and fluconazole, are synthetic. Antifungal agents primarily target the fact that the fungal cell membrane contains the sterol, ergosterol, while animal cells, including humans, contains cholesterol. Amphotericin and nystatin will preferentially bind to fungal cell membranes and form a transmembrane pore, disrupting the fungal cell. In contrast, the synthetic azoles still target ergosterol, but do so by inhibiting a fungal cytochrome enzyme responsible for ergosterol synthesis.
As a generalization, antifungal agents are safe and effective for use on topical, including oral infections, but require careful management when used for systemic infections in order to manage potential side effects.
Antiviral drugs
Historically, viral infections have been difficult to target with drug treatment. In themselves, viruses just consist of nucleic acid (either DNA or RNA) enclosed in a protein coat, or capsid. In order to replicate, viruses have to attach to, and enter a living, host cell. Having infected a host cell, the virus then uses the host cell's metabolic machinery to replicate. As such, there are very few biochemical differences between healthy human cells and those that are infected with a virus. However, in recent years, there has been a significant increase in the number of effective antiviral agents. This has occurred following the recognition that infected cells may contain virus-specific enzymes that are required for the replication and release of the virus particles. Aciclovir (zovirax) represented a major step forward in terms of developing effective antiviral agents. The drug itself is activated by one viral enzyme, viral thymidine kinase, and it subsequently inhibits another viral enzyme, viral DNA polymerase, that is required for viral replication. This two-step process gives aciclovir a high degree of selectivity in terms of inhibiting viral as opposed to human DNA polymerase. It is effective against infections caused by the herpes simplex and zoster viruses, including cold sores.
Cancer chemotherapy and treatment
Perhaps the hardest cells to target through a selectively toxic action are cancerous cells, since the biochemical differences between healthy and cancerous human cells are minimal. Historically, cancer treatments have primarily exerted a cytotoxic effect, targeting cells that are actively dividing. However, this does not represent a target that is selective for cancer, since many cells in the body are actively dividing in order to replace cells that have a high turnover rate. It is this, non-selective action that accounts for the many, significant side effects seen with cancer chemotherapy. Indeed, the epithelial cells that line the oral cavity have one of the highest turnover rates in the body, and as such, cancer chemotherapy can have marked effects in the oral cavity, causing problems such as stomatitis.
There is a constant drive to develop more selective drug treatments for cancer. Some success has been achieved by targeting growth-promoting signals that are overactive in some cancers. For example, in approximately 25% of breast cancers, the human epidermal growth factor receptor 2 is overexpressed, giving an increased growth-promoting stimulus (HER2+ve breast cancer). Trastuzumab (Herceptin) is a monoclonal antibody that binds to the HER2 receptor, and interferes with the growth stimulus produced by epidermal growth factor. However, perhaps the biggest conceptual breakthrough has come with the development of imatinib (Gleevec). Imatinib is a tyrosine-kinase inhibitor that is used in the treatment of a number of cancers, including chronic myelogenous leukemia. Imatinib inhibits a specific form of tyrosine kinase, BCR-Abl, which activates the signalling pathway responsible for the cancerous cells' growth. Because this tyrosine kinase is only found in certain cancerous cells, imatinib has a truly selectively toxic action against cancerous cells. As a result, imatinib is devoid of the significant side effects commonly associated with cancer treatment.
Conclusion
Antibiotic drugs, like penicillin helped revolutionize clinical practice, enabling the safe and effective management of conditions that had been previously fatal. Now, new antiviral and anticancer agents are showing that it is possible to achieve a similar, effective medical management of these conditions. However, we cannot be complacent, and we need strategies to manage problems like increasing antibiotic resistance in order to maintain the effectiveness of therapeutics.
Chapter 2Introduction to pharmacology and therapeutics – pharmacokinetics
Alan Nimmo
Key Topics
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Introduction to pharmacokinetics and the factors that affect drug concentration within the body
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Drug diffusion and partitioning within the body
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Elimination of drugs from the body – metabolism and excretion
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Routes of drug administration
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Quantifying drug kinetics
Learning Objectives
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Be familiar with the factors that influence the concentration of a drug within the body
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Be aware of factors, such as regional differences in pH, which may influence the distribution of drugs within the body
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Be aware of the mechanisms involved in eliminating drugs from the body, and the potential for drug interactions and toxicity
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Be familiar with the main routes of drug administration
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Be aware of some of the basic approaches used to quantify drug kinetics
Introduction
While the science of pharmacodynamics helps explain how drugs produce their effects within the body, safe clinical practice is equally dependent upon a knowledge of pharmacokinetics. By definition, pharmacokinetics studies the movement of drugs, and in particular their ability to move from their site of administration to their site of action. However, it is also the science that determines the correct dose and route of administration of a particular drug in order to ensure that one achieves the required concentration of the drug at its target site.
The importance of correct dosing cannot be overstated. Drugs will only produce their beneficial effects within their ‘therapeutic range’. If the drug concentration is too low, then the required, beneficial effects will not be achieved, while if the dose is too high, unwanted or toxic effects of the drug will start to predominate. For some drugs, their therapeutic range may be quite wide, making them both easy and safe to use in clinical practice. However, other drugs may have a narrow therapeutic range, requiring careful management and monitoring in order to avoid adverse reactions. In the words of the Swiss-German physician Paracelsus (1493–1541), who has been credited as the founder of modern toxicology, ‘Solely the dose determines that a thing is not a poison’.
There is a whole range of factors that will influence the concentration of a drug at its target site and, in general, they are all interdependent. These factors are commonly divided into four components, referred to as the phases of drug disposition, these being absorption, distribution, metabolism and excretion, commonly abbreviated to ADME. When one thinks about administering a local anaesthetic in the dental clinic, one may feel that these factors are of little importance, since the drug is being ‘placed’ near the nerve you want to block. However, you will find it is much more difficult to achieve effective anaesthesia in an area where there is significant inflammation, as compared to non-inflamed tissue. One potential explanation for this lies in an understanding of basic pharmacokinetics.
Introduction to pharmacokinetics
While absorption is considered the first phase of drug disposition, it is perhaps worth considering the factors that affect drug distribution first of all, since these can have broad ramifications, including influencing the route of administration.
Distribution
For many drugs, following administration, they are transported around the body via the bloodstream. Drugs may be either injected directly into the circulation (i.e. intravenous injection), or they may enter the circulation, for example following absorption from the gastrointestinal tract. Once in the bloodstream, almost all drugs are transported in exactly the same way, by what is referred to as bulk-flow transfer, where the drug is transported rapidly around the body. Because most drugs are transported in the same way, this does not have a major influence on the pharmacokinetic characteristics of an individual drug. The one caveat to that is that within the bloodstream, many drugs will bind to the plasma proteins, which will influence their movement, but we will discuss this aspect separately. However, for a drug to produce its effects within the body, it will have to leave the bloodstream and diffuse to its target site. It is this ability of a drug to diffuse within the body that is a key factor in determining an individual drug's pharmacokinetic properties.
In order to understand the way a drug is able to move around the body, perhaps the first thing that needs to be considered is the nature of the body itself. Our body does not consist of one single compartment, but instead is made up of a number of different compartments, each with its own physicochemical characteristics. The barriers that separate these various compartments are composed of our body's cells, for example epithelial cells lining the gastrointestinal tract. With these cellular barriers, it is the phospholipid membrane of the cell that forms the actual barrier. For a drug to pass through such a barrier, there are two possibilities.
On the one hand, a drug may pass between the cells if there are gaps between neighbouring cells forming the barrier (paracellular movement). This is seen in many capillaries, where there are small pores, or intercellular clefts, between the vascular endothelial cells. These pores allow for the passage of small, water-soluble molecules through the barrier. However, larger molecules, such as plasma proteins, are too big to pass through these pores, and will be retained in the circulation.
However, other barriers, such as the blood-brain barrier, serve a protective function, and here there are tight junctions between neighbouring cells, giving the barrier more functional integrity. For a drug to cross such a barrier, it has to be able to pass through the cells (transcellular movement), rather than between them. The blood-brain barrier represents the most robust barrier within the body, with astrocyte foot processes providing an extra cell layer around the vascular endothelium to both restrict and regulate the movement of solutes.
There are four basic ways in which a drug molecule may diffuse through an epithelial or endothelial cell barrier. If the drug molecule is neither ionized nor polar, then the molecule will have sufficient lipid solubility to diffuse directly through the cell membrane. However, many drugs are either weak acids or bases, and hence, at any one time, exist in both an ionized and non-ionized form. The actual proportion of these forms, and therefore the overall lipid solubility of the drug, will depend upon the pH of the solution in which the drug is dissolved. We will revisit this concept in considering pH partitioning.
The second mechanism by which drugs can cross a cell membrane is in combination with a carrier protein that either facilitates diffusion, or enables active transport. Such carriers naturally transport endogenous chemicals, such as nutrients, but may also facilitate drug movement. These carriers are mainly confined to specific organs, such as the gastrointestinal tract and kidney, and are also important in blood-brain barrier function.
Thirdly, drugs can transverse the cell membrane by the process of pinocytosis, or ‘cell drinking’, where the cell membrane invaginates around the molecule forming a vesicle, which is then transported into the cell. Pinocytosis may assist larger molecules, such as insulin, to cross the blood-brain barrier, but is unlikely to assist the transport of small drug molecules.
Finally, the presence of aqueous pores (aquaporins) and ion channels may potentially enable the movement of very small molecules or ions, such as lithium, to enter the intracellular fluid. However, in general, lipid diffusion and carrier-mediated transport are the more important mechanisms for the transcellular movement of drugs.
Partitioning:
As mentioned, the body not only contains a variety of compartments, but those compartments have different physicochemical properties. For example, the plasma of the bloodstream is a protein-rich aqueous solution, while adipose tissue represents a predominantly lipid environment. The pH of the plasma in the bloodstream is very slightly alkaline (pH 7.4), while gastric acid makes the lumen of the stomach highly acidic (∼pH 2). These different chemical environments can lead to an uneven distribution of a drug within the body because, depending upon the chemical nature of a drug, it may have a greater affinity for one environment over another. The main factors that give rise to an uneven drug distribution within the body are pH differences across a barrier (pH partitioning), protein binding and sequestration into lipid.
pH Partitioning:
For most drugs to diffuse through the barriers between compartments within the body, they must be in a non-ionized, and hence lipid soluble form. However, because many drugs are weak acids or bases, they exist in both an ionized and non-ionized state. The proportion of the two forms will vary depending upon the pH of the solution in which it is dissolved. For example, if a weak acid is dissolved in an acidic solution, it will be predominantly non-ionized, as compared to when it is in a basic solution, where it will be mostly ionized. The converse is the case for a weak base, which will be predominantly ionized in an acidic solution. If one knows the dissociation constant, or pKa, of the drug in question, the precise proportion of the two forms can be calculated using the Henderson-Hasselbach equation. It is worth keeping in mind that the pKa does not indicate whether a drug is a weak acid or base, but rather indicates its tendency to dissociate, depending upon the pH of its environment.
pH partitioning occurs when one has solutions of different pH on either side of a barrier. Within the human body, this occurs most markedly between the lumen of the stomach and the bloodstream. Keeping in mind that only the non-ionized form of the drug can diffuse through the barrier, the concentration gradients that drive diffusion only relate to the non-ionized form. Hence, if you have a weak acid in an acidic environment, the concentration of the non-ionized form is high, while in an alkaline environment, the non-ionized form has a low concentration. This provides a driving force for diffusion. As a result, weak acids tend to move from a relatively acidic environment to a more alkaline one. The opposite happens with weak bases, where they tend to diffuse from a more alkaline environment to an acidic one.
From a dentistry perspective, pH partitioning may impact upon local anaesthesia when there is significant, local inflammation. By nature, local anaesthetics are weak bases. It is the ionized form of the anaesthetic that interacts with the binding site in the transmembrane pore of the voltage-gated Na+ ion channel to produce the blockade. Access to the channel's binding site can occur either by direct diffusion through the neuronal membrane (hydrophobic pathway) or by first diffusing through the membrane into the cytoplasm, and then entering the active channel from the intracellular compartment (hydrophilic pathway). Both of these pathways rely on having a sufficient concentration of the non-ionized form of the anaesthetic outside the nerve, to drive diffusion through the neuronal membrane. Unfortunately, inflammation may cause the extracellular fluid to become more acid, reducing the concentration of the non-ionized form of the anaesthetic, thereby reducing diffusion of the anaesthetic into the nerve.
Protein binding:
In addition to acting on their target proteins, drugs may bind to other proteins, most notably the plasma protein, albumin. As a generalization, acidic drugs, such as NSAIDs, tend to bind more readily to plasma albumin than basic drugs, but there are a number of basic drugs, such as tricyclic antidepressants, that do bind. For some drugs, a significant proportion of the drug within the bloodstream may be bound to the plasma proteins (e.g. 99%), while only a small proportion is in free solution. This has a number of implications. Since the pores in the vascular endothelium are relatively small, plasma proteins, and with them the bound fraction of the drug, remain in the bloodstream, while only the drug in free solution is able to diffuse out of the circulation in order to produce its effects. For drugs with a high degree of protein binding, a significant proportion of the total drug within the body is retained in the circulation. In this way, plasma proteins can act as a ‘slow release’ mechanism for certain medications. The portion of a drug that is bound to the plasma proteins is also ‘protected’ from metabolism and excretion.
The other key aspect in relation to protein binding is it provides one mechanism by which drug–drug interactions can occur. Each albumin molecule has two drug-binding sites, and the concentration of albumin in the plasma is approximately 0.6 mmol/l. Given that most drugs produce their effects at relatively low concentrations (e.g. 1µM), there is an abundance of binding sites. However, for drugs that act at relatively high concentrations and exhibit a high degree of protein binding, there is the potential for competition for binding sites, and for one drug to displace another from plasma proteins. For drugs that are normally highly bound to plasma proteins, even the displacement of a relatively small proportion of the bound drug can have a huge impact on the concentration of the free drug, and with that, greatly increase the effects of the drug.
