01 IPCS Prelims 1. - Pharmaceutical Press...4 Central nervous system cases " 113 INTRODUCTION " 113 1 Types of anxiety, their treatment and associated issues " 116 2 Treatment options

Contents

Foreword by Catherine Duggan " vii

Acknowledgements " viii

About the editors " ix

List of contributors " x

Abbreviations " xiii

Introduction " xvii

1 Gastrointestinal, liver and renalcases " 1

INTRODUCTION " 11 Uninvestigated dyspepsia " 32 Inflammatory bowel disease " 73 Treatment of threadworm " 104 Liver disease in an elderly patient " 135 Alcoholic liver cirrhosis " 156 Liver disease with ascites " 197 Management of paracetamol overdose with

acetylcysteine " 228 Chronic kidney disease " 269 Haemofiltration " 3110 Renal replacement therapy " 35

2 Cardiovascular cases " 39

INTRODUCTION " 391 Atrial fibrillation " 432 Angina management " 493 Heart failure " 524 Acute coronary syndromes " 565 Management of hypertension in black

patients " 616 Cardiovascular (blood pressure) support in

an elderly hypotensive patient " 667 Deep vein thrombosis and warfarin " 708 Treatment of acute ischaemic stroke " 759 Secondary stroke prevention " 7810 Drug interactions " 82

3 Respiratory cases " 87

INTRODUCTION " 871 Asthma " 892 Treating an acute severe asthma

exacerbation " 93

3 Nebulised therapy for chronic obstructivepulmonary disease " 97

4 Paediatric cystic fibrosis " 1015 Cough " 108

4 Central nervous system cases " 113

INTRODUCTION " 1131 Types of anxiety, their treatment and

associated issues " 1162 Treatment options in schizophrenia –

antipsychotics and side effects " 1183 Bipolar disorder and its treatment " 1224 Treatment-resistant depression in a patient

on haemodialysis " 1245 Self-medication of depression with St John’s

wort, a herbal remedy " 1286 Extemporaneous preparation of

methadone " 1317 Neuropathic pain " 1348 Differential indicators for migraine and

medication-overuse headache " 1389 Epilepsy " 14210 Phenytoin and acute therapeutics " 14611 Drug therapy of Parkinson’s disease " 14912 Smoking cessation in community

pharmacy " 15313 Dementia/Alzheimer’s disease " 15914 Dementia and its pharmacotherapy " 163

5 Infections cases " 169

INTRODUCTION " 1691 Cellulitis and MRSA " 1732 Typhoid " 1783 Community-acquired pneumonia " 1834 Urinary tract infection " 1875 Uncomplicated genital Chlamydia

trachomatis infection " 1896 Surgical antibiotic prophylaxis " 1937 Diarrhoea and antibiotic treatment " 1968 ‘Fever with no focus’ in a young infant " 1989 Management of tuberculosis and its

complications " 202— [continued over]

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Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015

10 Management of latent TB infection andpharmacy interventions " 205

11 Influenza " 20712 Chronic hepatitis C " 21013 Primary HIV Infection " 21514 Immunisations against infectious diseases

and malaria chemoprophylaxis " 221

6 Endocrinology cases " 225

INTRODUCTION " 2251 Insulin pump use in a child " 2282 Hypoglycaemia during insulin therapy " 2323 Type 2 diabetes mellitus " 2354 Serious lactic acidosis induced by

metformin " 2395 An unusual case of Cushing’s

syndrome " 2426 Addisonian crisis " 2487 Hypothyroidism " 2548 Osteoporosis in a younger woman " 2589 Osteoporosis in an elderly woman " 26210 Treatment for Hypercalcaemia " 266

7 Malignant disease,immunosuppression and haematologycases " 271

INTRODUCTION " 2711 Lung cancer " 2742 The use of antimetabolites in the treatment

of breast cancer " 2783 Clinical verification of prescriptions for oral

anticancer medicines " 2824 Thromboprophylaxis in a patient undergoing

surgery for cancer " 2875 Febrile neutropenia in paediatric

oncology " 2916 Managing chemotherapy-induced nausea and

vomiting in a patient with lung cancer " 2957 Drug therapy of multiple sclerosis " 2998 Management of vaso-occlusive crisis in sickle

cell disease " 304

8 Musculoskeletal and joint diseasecases " 309

INTRODUCTION " 3091 Gout " 311

2 Approaches to the effective treatment ofnon-specific, low back pain " 314

3 DMARDs and treatment for rheumatoidarthritis " 317

4 Glucosamine supplements for osteoarthritisand joint stiffness " 324

5 Treating juvenile idiopathic arthritis in youngpeople " 327

6 Systemic lupus erythematosus " 331

9 Eye, nose and throat cases " 335

INTRODUCTION " 3351 Conjunctivitis in pregnancy " 3372 Chronic open-angle glaucoma " 3413 Wet age-related macular degeneration " 3454 Sore throat " 3485 Hay fever " 352

10 Skin cases " 357

INTRODUCTION " 3571 Atopic eczema " 3592 Contact dermatitis " 3633 Management of an acute flare of

psoriasis " 3664 Acne " 3695 Antibacterial treatment of acne in young

people " 3726 Fungal infection of the foot " 3767 Treatment of head lice " 380

11 Special cases " 383

INTRODUCTION " 3831 Paediatric pharmacokinetics in a newborn

preterm infant " 3852 Falls and care of elderly people " 3893 Treating a patient with benign prostatic

hyperplasia " 3964 Pain management using strong opiates in

palliative care " 3995 Human papillomavirus and cervical

cancer " 4046 Black cohosh for menopausal

symptoms " 406

Index " 411

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List of contributors

BOTHAINA B JERAGH ALHADDAD, BSc, MSc, PhD | AssistantProfessor and Lecturer in Clinical Pharmacy, Department ofPharmaceutical Sciences, Public Authority for AppliedEducation and Training, Shwaikh, Kuwait

FATEMAH MOHAMMAD ALSALEH, BPharm, MSc, PhD | AssistantProfessor, Department of Pharmacy Practice, Faculty ofPharmacy, Kuwait University, Kuwait

SOTIRIS ANTONIOU, MRPharmS, MSc, DipMgt | Independentprescriber; Consultant Pharmacist, Cardiovascular Medicine,Bart’s Health NHS Trust, London, UK

ANA ARMSTRONG, BPharm, PgDipClinPharm | Lead Pharmacist,Medical Division, Surrey and Sussex Healthcare NHS Trust,UK

NELA RONČEVIĆ ASHTON, BSc, PgDip | Clinical Tutor, School ofPharmacy and Biomedical Sciences, University of CentralLancashire; Advanced Primary Care Pharmacist, Cumbriaand Lancashire Clinical Support Unit, UK

ZOE ASLANPOUR, BPharm, PhD | Member of UKPHR, FRSPH,Head of Pharmacy and Public Health Practice, University ofHertfordshire; Consultant in Public Health, NHSBedfordshire, UK

PAUL BAINS, DipClinPharm, MRPharmS | Independentprescriber; Senior Lead Pharmacist for Medicine, ImperialCollege Healthcare NHS Trust, Pharmacy Department,Hammersmith Hospital, London, UK

JOANNE BARTLETT, BPharm, ClinDipPharm | Specialist ClinicalPharmacist, End of Life Care, John Taylor Hospice,Birmingham, UK

GORDON BECKET, BPharm, PhD, MRPharmS, MRSC, FNZCP| Professor of Pharmacy Practice, School of Pharmacy andBiomedical Sciences, University of Central Lancashire,Preston, Lancashire, UK

SIÂN BENTLEY, BPharm, MRPharmS, DipClinPharm | SpecialistPharmacist, Paediatrics, Royal Brompton and Harefield NHSFoundation Trust, London, UK

RANIA BETMOUNI, BPharm, DipClinPharm | Independentprescriber; MSc Quality and Safety in Healthcare, ClinicalPharmacist – BUPA Cromwell Hospital, London, UK

ANNETT BLOCHBERGER, DipClinPharm | Independent prescriber;Lead Pharmacist, Neurosciences, St George’s NHSHealthcare Trust, London, UK

LISA BOATENG, BSc, MSc, MRPharmS, Certificate in ClinicalPharmacy | Independent prescriber; Highly SpecialisedPharmacist, Antimicrobials and Infection Control, London,UK

MARK BORTHWICK, MPharmS, MSc | Consultant Pharmacist,Critical Care, John Radcliffe Hospital, Oxford UniversityHospitals NHS Trust, Oxford, UK

SIMONE BRACKENBOROUGH, BSc, DipClinPharm | Independentprescriber; Senior Lead Pharmacist for Medicine at ImperialCollege Hospitals NHS Trust (St Mary’s Hospital Site),London, UK

NADIA BUKHARI, BPharm, MRPharmS, PgDipFHEA | ClinicalLecturer, MPharm Student Support Manager & PreRegistration Coordinator, UCL School of Pharmacy, London,UK

MEE-ONN CHAI, MSc, DipClinPharm, BPharm | ClinicalPharmacist, Team Leader – Renal Services, King’s CollegeHospital NHS Foundation, London, UK

BARBARA CLARK, MPharm(Hons), GPhC, ClinDip | Lead ClinicalPharmacist, London Bridge Hospital; Chair UKCPAHaemostasis, Anticoagulation and Thrombosis (HAT)Group, London, UK

JESSICA CLEMENTS, MPharm, CertPharm Pract, DipPharmPract,Cert Independent prescribing practice | Highly SpecialisedPharmacist HIV at Medway Maritime Hospital, Gillingham,Kent, UK

LOUISE COGAN, BSc, MRPharmS, PgDipFHEA | TeacherPractitioner, University of Central Lancashire, Preston,Lancashire, UK

ANDREW CONSTANTI, BSc, PhD, FBPharmacolS | Reader inPharmacology, UCL School of Pharmacy, London, UK

SHANI CORB, MRPharmS, MSc | Independent prescriber; LeadPharmacist, Paediatric Oncology, Royal Alexandra Children’sHospital, BSUH NHS Trust, Brighton, Sussex, UK

JOYETA DAS, MPharm, DipClinPharm | Independent prescriber;Lead Pharmacist, Hepatology, Imperial College London NHSTrust, London, UK

HALA M FADDA, MPharm, PhD | Assistant Professor, College ofPharmacy and Health Sciences, Butler University,Indianapolis, IN, USA

JOSEPHINE FOLASADE FALADE, BPharm, MSc, FHEA | HighlySpecialist Pharmacist, Bart’s Health NHS Trust; ClinicalLecturer, UCL School of Pharmacy, London, UK

SALLY-ANNE FRANCIS, BPharm, PhD, MRPharmS, FHEA| Honorary Senior Lecturer, UCL School of Pharmacy,London, UK

CLAIRE GOLIGHTLY, MPharm ClinDipHosp, PGCertEd| Lecturer in Professional Practice, Bradford School ofPharmacy, University of Bradford, Bradford, UK

LARRY GOODYER, PhD, MRPharmS, FFTMRCPS(Glas), FRGS| Professor, Head of the Leicester School of Pharmacy,Faculty of Health and Life Sciences, De Montfort University,Leicester, UK

NICOLA J GRAY, BSc, PhD, MRPharmS, FHEA, FSAHM(US)| Independent pharmacist researcher; Director, Green LineConsulting Limited, Manchester, UK

KATIE GREENWOOD, MRPharmS, PGCertTLHE, FHEA| Lecturer in Pharmacy Practice, Placement Co-ordinator andPre-Registration Facilitator, School of Pharmacy andBiomedical Sciences, University of Central Lancashire,Preston, Lancashire, UK

ELIZABETH HACKETT, BSc, MSc | Independent prescriber;Principal Pharmacist for Diabetes, University HospitalsLeicester, Leicester, UK

DELYTH HIGMAN JAMES, PhD, MSc, BPharm, MRPharmS,AMBPsS, FHEA | Senior Lecturer, Programme Director, MScin Pharmacy Clinical Practice (Community and PrimaryCare), Cardiff, South Wales, UK

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TIM HILLS, MRPharmS, DipClin | Independent prescriber; LeadPharmacist Antimicrobials and Infection Control,Nottingham University Hospitals NHS Trust, Nottingham,UK

STEPHEN HUGHES, MPharm | Specialist Renal Pharmacist,Central Manchester Foundation Trust, Manchester, UK

LYNN HUMPHREY, BPharm, DipPharmPrac, IPP | Senior LeadPharmacist – Cardiovascular, Imperial College HealthcareNHS Trust, London, UK

ANDY HUSBAND, DProf, MSc, BPharm, MRPharmS | Dean ofPharmacy, Durham University, Durham, UK

MATTHEW D JONES, MPharm, PhD, MRPharmS | SeniorPharmacist – Medicines Information, Royal United HospitalBath NHS Trust, Bath, UK

SARAH C JONES, MPharm, MSc, MRPharmS | Locality LeadPharmacist, Avon and Wiltshire Mental Health PartnershipNHS Trust, Bath, UK

NAVEED IQBAL, MPharm, PGClinDip, MSc | Teaching Fellow,Aston University; Prescribing Support Pharmacist for NHS,Birmingham Cross City CCG; community pharmacist

KUMUD KANTILAL, BSc(Pharm), DipPharmPract, Postgraduateaward in clinical oncology | Macmillan Principal Pharmacist,Lead for Cancer Education and Training, Guy’s and StThomas’ NHS Foundation Trust, London, UK

NAZANIN KHORSHIDI, MPharm, PGDip | Highly SpecialistPharmacist; Orthopaedics and Plastics at Guy’s and StThomas’ NHS Foundation Trust, London, UK

STEPHANIE KIRSCHKE, PhD | Senior Lead PharmacistHaematology, Imperial College Healthcare NHS Trust,London, UK

ROGER DAVID KNAGGS, BSc, BMedSci, PhD, MRPharmS| Associate Professor in Clinical Pharmacy Practice,University of Nottingham; Advanced Pharmacy Practitioner– Pain Management, Nottingham University Hospitals NHSTrust, Nottingham, UK

SARAH KNIGHTON, MPharm, MPharmS | Independentprescriber; Clinical Pharmacy Team Leader, Liver and PrivatePatient Services, King’s College Hospital NHS FoundationTrust, London, UK

ROMAN LANDOWSKI, BSc(Pharm), DipClinPharm | WardPharmacist, Maternity Care Unit, University CollegeHospital, London, UK

JEREMY LEVY, MBBChir, PhD, FHEA, FRCP | ConsultantNephrologist, Imperial College Healthcare NHS Trust,London, UK

NATALIE LEWIS, MPharm, ClinDipPharm, PGCertEd | SeniorPharmacist – Teacher Practitioner, Aston University andUniversity Hospitals Birmingham NHS Foundation Trust,Birmingham, UK

TRACY LYONS, BSc(Pharm), MSc | Lead Pharmacist, Infection,Imperial College Healthcare NHS Trust, London, UK

FIONA MACLEAN, MSc, MRPharmS | Independent prescriber;Lead Clinical Pharmacist, Cancer and Neurosciences, NHSGreater Glasgow and Clyde, Glasgow, UK

JANET E MCDONAGH, MB BS, MD, FRCP | Clinical SeniorLecturer in Paediatric and Adolescent Rheumatology,University of Birmingham and Birmingham Children’sHospital NHS Foundation Trust, Birmingham, UK

DUNCAN MCROBBIE, MSc, FRPharmS | Associate ChiefPharmacist, Guy’s and St Thomas’ NHS Hospital Trust;Clinical Reader, Kings College London, London, UK; VisitingProfessor, UCL, UK

CARL MARTIN, PhD, GPhC registrant, MRPharmS, PGCHE| Senior Clinical Teacher, Department of Practice and Policy,UCL School of Pharmacy, London, UK

JAYMI MISTRY, MPharm, DipGPP | Highly Specialist Pharmacist– Acute Medicine (general medicine) and Medicines Safety,London, UK

SANDEEP SINGH NIJJER, MPharm, MBA, GPhC | Pharmacist, UKLELLY OBOH, BPharm, DipClinPharm | Independent prescriber;Consultant Pharmacist, Care of Older People, Guy’s and StThomas’ Community Health Services, London, UK

JIGNESH PATEL, PhD, MRPharmS | Clinical Senior Lecturer/Honorary Consultant Pharmacist, Anticoagulation, King’sCollege London/King’s College Hospital, London, UK

NEIL POWELL, MPharm, ClinDip, MRPharmS | Antibiotic andHIV Pharmacist, Royal Cornwall Hospital Trust, Truro, UK

ANNA PRYOR, MPharm, MRPharmS | Lead Pharmacist, A&Eand Admissions, Imperial College Healthcare NHS Trust (StMary’s site), London, UK

GEMMA QUINN, PGDip, MRPharmS | Course Director MScClinical Pharmacy (Hospital) and MPharm Stage Tutor(Stage 4), University of Bradford, Bradford, UK

TIMOTHY RENNIE, MPharm, PhD | Head of School of Pharmacy(Associate Dean), University of Namibia, Namibia, Africa

IAN ROWLANDS, MRPharmS, DipClinPharm | Independentprescriber; Lead Pharmacist Stroke Services, Imperial CollegeHealthcare NHS Trust, London, UK

IMOGEN SAVAGE, BPharm, PhD, MRPharmS | Senior Lecturer(retired), UCL School of Pharmacy, London, UK

JENNY SCOTT, BSc, PhD, MRPharmS | Independent prescriber;Senior Lecturer in Pharmacy Practice, University of Bath,Bath, UK

LOUISE SEAGER, BPharm, ClinDipPharm, MRPharmS | SeniorSpecialist Clinical Pharmacist End of Life Care, John TaylorHospice, Birmingham, UK

RITA SHAH, BPharm, MRPharmS, MSc | Senior ClinicalPharmacist, Critical Care, King’s College Hospital NHSFoundation Trust, London, UK

KATE SHARDLOW, MBBS, BPharm, MRCGP | GP and specialitydoctor in genitourinary medicine, Chelmsford, Essex, UK

NEELAM SHARMA, BA, PGCert Psychiatric Therapeutics| Registered Pharmacy Technician, Chief PharmacyTechnician, Medicines Management and E&T, South Londonand Maudsley NHS Foundation Trust, London, UK

ROB SHULMAN, BScPharm, MRPharmS, DipClinPharm, DHC(Pharm) | Lead Pharmacist – Critical Care, PharmacyDepartment, University College Hospital; Honorary AssociateProfessor in Clinical Pharmacy Practice, UCL School ofPharmacy; Honorary Lecturer, Department of Medicine,University College London, London, UK

MERVYN SINGER, MBBS MD MRCP | Professor of IntensiveCare Medicine; Head, Research Department of ClinicalPhysiology, Division of Medicine, University College London,UK

TIMOTHY J SNAPE, PhD MSci MRSC, CChemCSci | Lecturer inMedicinal Chemistry, University of Central Lancashire,Preston, Lancashire, UK

NUTTAN KANTILAL TANNA, MRPharmS, DComP, PhD| Pharmacist Consultant, Women’s Health and Older People,Women’s Services and affiliated with the Arthritis Centre,NW London Hospitals NHS Trust, London, UK

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NEIL TICKNER, MPharm, MRPharmS, PGDipClinPharm | LeadPharmacist Paediatrics, St Mary’s Hospital, Imperial CollegeHealthcare NHS Trust, London, UK

ADAM TODD, MPharm, PhD, MPharmS, MRSC | Lecturer inPharmacy Practice, Division of Pharmacy, DurhamUniversity, Durham, UK

MARK TOMLIN, PhD, FRPharmS | Independent prescriber;Consultant Pharmacist Critical Care, Southampton GeneralHospital, Southampton, UK

STEPHEN TOMLIN, BPharm, FRPharmS | Consultant Pharmacist– Children’s Services, London, UK

CHARLES TUGWELL, BPharm, MSc, MRPharmS, MCLIP| Specialist Clinical Pharmacist, Neurology/Neurosurgery,Royal London Hospital, Bart’s Health NHS Trust, London,UK

SINEAD TYNAN, MPharm, IP, ClinDip, MSc, MRPharmS | SeniorClinical Pharmacist – Liver Services, King’s College Hospital,London, UK

SAMIR VOHRA, BPharm | Lecturer in Clinical Pharmacy Practice,School of Pharmacy and Biomedical Science, University ofCentral Lancashire, Preston, Lancashire, UK

PETER S WHITTON, BSc, MSc, PhD | Senior Lecturer inPharmacology, UCL School of Pharmacy, London, UK

HELEN WILLIAMS, BPharm, PGDip(Cardiol), MRPharmS| Independent prescriber; Consultant Pharmacist forCardiovascular Disease, South London, hosted by SouthwarkCCG, London, UK

ELIZABETH M WILLIAMSON, BSc, PhD, MRPharmS, PhD, FLS| Professor of Pharmacy and Director of Practice, Universityof Reading School of Pharmacy, Reading, UK

KEITH A WILSON, BSc, PhD | Professor, Aston University,Birmingham, UK

STEWART WILSON, BPharm, ClinDipPharm | Lead PharmacistCardiology, Imperial College NHS Healthcare Trust, London,UK

KAY WOOD, BSc, DipClinPharm, PhD, MRPharmS, PGPCTL| Senior Lecturer in Clinical Pharmacy, Birmingham, UK

KIRSTY WORRALL, BSc, MRPharmS | Teacher Practitionerworking with Boots and UCL School of Pharmacy, London,UK

PAUL WRIGHT, MRPharmS, MSc | Specialist Cardiac Pharmacist,Bart’s Health NHS Trust, London, UK

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Introduction

An integrated approach to learningWithin the healthcare team, pharmacists are therecognised medicines experts. They have a breadthand depth of understanding about all aspects ofmedicines that set them apart from other healthprofessionals. As a result of their extensive,specialist education and training, pharmacists canconceptualise a drug molecule, together with itsformulation and delivery, as a medicine, and canensure its safe and effective use by patients.Pharmacists also have a deep understanding ofpharmacology and therapeutics, thephysicochemical properties of drugs andexcipients, biopharmacy and pharmacokinetics,side effects, contraindications and druginteractions. This is combined with knowledge ofthe legal and ethical framework in whichmedicines are supplied, as well as biological causesof disease, and the social and behavioural factorsthat determine whether a patient will obtainoptimal benefit from their medication. This hugelyvaried, complex, integrated, expert knowledgeallows pharmacists to make professionaljudgements relating to medicines, giving them anunchallengeable sphere of expertise, which, whenutilised for patient benefit, legitimises pharmacists’professional status.To be effective, pharmacists’ education must

prepare them to be scholars, scientists,practitioners and professionals – no mean feat. Amodern undergraduate Masters pharmacycurriculum recognises the importance of bothpharmaceutical science and pharmacy practice,which, when seamlessly integrated, preparesgraduates for the many professional roles andactivities that they will be called upon toundertake now and in the future. Nowadays,pharmacy programmes aim to achieve thisintegration during a student’s studies, increasinglyincorporating opportunities for workplace learningto provide a context in which they learn and applytheir scientific knowledge.In the UK, the General Pharmaceutical Council

(GPhC) regulates the education and training ofpharmacists. The GPhC is responsible foraccrediting pharmacy degrees and ensuring that

they are fit for purpose. It has published adocument containing a comprehensive set ofstandards and outcomes against whichprogrammes are accredited and reaccredited(GPhC, 2011). This document highlights:‘Curricula must be integrated .. . the componentparts of education and training must be linked in acoherent way’ and ‘Learning opportunities must bestructured to provide an integrated experience ofrelevant science and pharmacy practice’.

The conception and design of thisbookIntegration of science with practice, together withits practical application, is at the core of modernpharmacy programmes. The need for pharmacystudents to integrate their learning has been aguiding principle in the design and production ofthis book. True integration of all the elements thatcontribute to pharmacists’ knowledge is difficult.This text aims to present the fundamental aspectsof pharmaceutical chemistry, pharmacology,pharmaceutics and therapeutics within a patient-care context. Traditional attempts at integrationcommonly begin with sections of ‘underpinning’science, and then build clinical and professionalelements onto it. This approach can be superficialand undermines the credibility of any resultantlearning exercise. By contrast, in this text, with thehelp of many experienced practitioner colleagues,each case study is grounded in a real-life clinicalsetting, which has then been used as a startingpoint to illustrate how pharmacists’ practice anddecision-making are informed by pharmaceuticalscience.Thus, the case studies in this book were initially

written by pharmacist practitioners, based on theirown practice and experience, with additionalscience content being incorporated later throughcollaboration with the editorial team. In this way,the science concepts included have a directrelevance to contemporary practice. In particularthe science is included in the case because it helpsinform understanding and decision-making inreal-life practice settings: it has earned the right tobe there!

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The cases have been organised into sections,broadly based on the British National Formulary,the most widely used reference source inpharmacy, where the chapters relate to particularsystems of the body (e.g. the cardiovascularsystem) or to aspects of medical care (e.g.infections). Although this has allowed us toimpose some structure, our cases are very diverseand reflect the fact that real patients experiencemultiple pathologies. They include materialrelevant to the wider clinical picture.We have striven to include cases covering the

broadest range of clinical conditions, from bothcommunity and hospital practice. All the casestudies have a similar structure. Within each casewe have integrated a significant sciencecomponent from one or more of pharmaceuticalchemistry, pharmacology or pharmaceutics, and inmany cases all three. We have included what webelieve are the key science concepts. However, itwould be impossible to cover in a single set of casestudies all the pharmaceutical, clinical andbehavioural science that appears in anundergraduate pharmacy programme. The goalhere is to demonstrate the potential diversity ofclinical scenarios and the relevance of scienceacross all.Most cases describe the use of many drugs in a

particular clinical setting. Again it has not beenpossible to detail the chemistry, pharmacology,indications, posology, contraindications, sideeffects and formulations for every drug. However,these case studies can be used as a starting pointto expand learning and application of knowledgeacross the science and practice disciplines. Eachcase ends with references/further reading andextended learning points, designed to take thereader’s learning beyond the specific case;highlighting other relevant, tangential areas ofscience and practice.

How to use this bookThis book has been designed primarily for use byundergraduate pharmacy students and pre-registration trainees. However, it may also beuseful for qualified pharmacists, pharmacytechnicians and other health professionals. It willalso provide a resource for tutors and lecturers toplan and use in learning activities.We intend this book to be free standing: a

learning and teaching aid to promote integrationand contextualisation of material learned during

undergraduate studies. It is not a textbook. Thereare plenty of excellent textbooks that will providea detailed understanding of the subjects that areintroduced here. The case studies provided are ofvarying complexity, independent of each other andnot intended to be read sequentially.Each case begins with a set of Learning

outcomes which provides an overview of what iscontained in the case study and highlights whatthe reader should be able to do having studied thecase.Each, detailed Case study begins with

contextual information about a patient, includingthe medical and drug histories. This equates to thelevel of information likely to be available to apharmacist on consulting medical notes, or talkingwith other members of the healthcare team or tothe patient and/or their carer. The cases areinterspersed with, and followed by, a series ofquestions. These are the sort of questions thatpharmacists will ask themselves whenencountering such a case in practice, or questionsthat might be asked of pharmacists by patients orother health professionals. We recommend thatreaders consider each question based initially ontheir current knowledge, before accessingadditional sources such as the current BritishNational Formulary, lecture notes, NICE guidance,websites and textbooks. At times, supplementaryinformation may be revealed as the caseprogresses, which may take readers in a differentdirection or cause them to reflect and re-evaluatetheir previous responses and recommendations.The cases and questions are followed by a

section entitled Case discussion. We have chosennot to supply discrete answers for each question.Such an approach gives the impression that adefinite answer is possible; that all questions haveright and wrong answers. Professional practicedemonstrates that real-life issues cannot beconsidered in such a black-and-white manner, andwhat demarcates the professional is theirappreciation and acceptance of uncertainty andtheir ability to make judgements based on theavailable evidence. ‘Answers’ to the questions canbe found in this section, but there is much morebesides, because the case is considered in itsclinical, practice and science context. Having readthis section, refer back to the questions posed inthe case, consider how you might answer them inlight of this information, and think of whatadditional questions you might now ask and what

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further information you would like. This is thespur to References and further reading. We havealso provided some Extended learning questions,representing our own thoughts for how this casemight encourage useful further study. Hopefully,you will also have formulated your own questions.Finally, although all the cases are ‘practice’focused, in some instances we have includedAdditional practice points, highlightingsupplementary practice issues that may betangentially linked to the substance of the casestudy, or alluding to pertinent debates andconcerns within pharmacy.The cases have been written by practitioners

with academic input, representing current clinicaland scientific knowledge, and are informed by theexperience, expertise and opinions of the authors.They should not be taken as a template forprofessional practice. Readers are reminded thatknowledge, pharmacotherapy and treatmentguidelines are continually changing and thatpharmacists are called on to make judgementsbased on their own knowledge and experience. Beprepared, at times, to disagree with what you read!

Conventions used in the textWith the widely different backgrounds of thecontributing authors, there were inevitablydifferences in terminologies, units ofmeasurement, etc., between cases. Also clinicaland science conventions often diverge. Thus, inthis text we express drug doses as mg, micrograms(written in full), etc., as is accepted in clinicalpractice (to minimise the risk of prescribingerrors), but follow scientific conventions forclinical data and other measurements, e.g. we haveused mg throughout (rather than microgram ormcg) to express 10-6 grams.Most cases include medicines that are currently

being used or are to be used by a patient. Notethat all doses are for the oral route (p.o.), unlessotherwise stated; dosing instructions are indicatedas standard Latin abbreviations, e.g. t.d.s. We haveensured that the names of the medicines referredto in the case studies are as found in the mostcurrent version of the British National Formulary(BNF 68, September 2014) at the time of writing.Occasionally, the proprietary name of a product

has also been included, where this is appropriateto the context of the case.

The editorial team and the case studyauthorsThe authors of the cases were chosen because oftheir experience as practising pharmacists, theirunique knowledge of a particular area of practiceor therapeutics, and their ability to communicateto early years pharmacists. The large majority ofthe authors currently practise as pharmacists inthe community and hospitals, and the cases reflectthat contemporary practice. Their enormous,learned contributions to this text are testament tothe vast expertise that UK clinical pharmacistsnow possess and use daily for patient benefit.The editorial team, all with pharmacy degrees,

has extensive experience in teachingundergraduate and postgraduate pharmacists, aswell as pharmacy technicians. Between them, theyconduct research and teach in the core disciplinesof pharmacy, namely pharmacy practice,pharmaceutics, chemistry and pharmacology. Theyhave worked together building up the case studiessupplied by the authors to ensure that each caseintegrates current science and practice, iscoherent, and provides a tool for effective learning.The authors and editors have worked together

with the shared belief that this is a valuable andworthwhile project. The collaboration has led toan innovative learning resource, which has drawnon the collective knowledge and experience of avery diverse group.This collection of case studies has been a great

pleasure to produce. In the process, we haverealised the enormous range of subjects of whichpharmacists require a deep knowledge andunderstanding, in order to make their uniquecontribution to healthcare. We hope that readerswill derive the same enjoyment, and that this bookclearly illustrates how the various disciplines thatcomprise pharmacy can complement, support andinform each other, such that pharmacists truly aremedicines experts.

ReferenceGeneral Pharmaceutical Council. Future Pharmacists:

Standards for the initial education and training ofpharmacists. London: GPhC, 2011.

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3Respiratory cases

INTRODUCTION

This section contains five cases centred onpatients with respiratory diseases, namely:asthma, chronic obstructive pulmonary disease(COPD), cystic fibrosis and cough.

Case 1Asthma " 89

This case is based on a patient with asthma who isreceiving regular treatment with a salbutamolpressurised metered-dose inhaler (pMDI). Thepathophysiology, signs and symptoms of asthmaare outlined, then the treatment options in asthmaare described, particularly in relation to steppingup and stepping down therapy. The mainstays ofasthma therapy are inhaled b2-adrenoreceptoragonists and glucocorticoids, and the chemistry ofthese agents is briefly outlined. The mostfrequently prescribed inhalation devices, pMDIs,are described and their formulation considered. Toenhance the efficiency of drug delivery in theairways, and ease of use by patients whoexperience difficulties with pMDIs, they may beused with spacer devices. Alternatively dry powderinhalers may be prescribed as a means ofdelivering drugs to the lungs. The formulation anduse of these devices are outlined. Ultimately, as thecase illustrates, the benefit that patients receivefrom prescribed medicines will depend on theiradherence to the prescribed regimen and theability to use their inhalation device correctly.

Case 2Treating an acute severe asthmaexacerbation " 93

This case continues the theme of asthma, with anacute exacerbation as the focus. It considers thepathophysiology and classifications of acuteasthma, and the signs and symptoms of acuteasthma exacerbations. Common triggers of an

exacerbation, such as medicines, allergens,exercise, non-compliance and infection, areidentified. The chemistry and delivery ofbeclometasone dipropionate are considered, beforethe various treatment options in asthmaexacerbations, such as high-flow oxygen, nebulisedb2-adrenergic receptor agonists, oral steroids andnebulised ipratropium bromide, are outlined. Thepharmaceutical monitoring, follow-up andtreatment are described. The case also allows for acomparison of the key features of various types ofinhalation device (pMDIs, dry powder inhalers,nebulisers) and emphasises the need for patientcounselling in the use of these devices.

Case 3Nebulised therapy for chronic obstructivepulmonary disease " 97

This case describes an elderly ex-smoker,previously diagnosed with, and treated for, COPD,requiring hospitalisation for an exacerbation. Thepathophysiology, symptoms, signs and diagnosis ofCOPD are outlined, followed by the treatmentoptions, particularly in relation to exacerbations.The chemistry and pharmacology of long- andshort-acting b2-adrenergic receptor agonists,particularly salbutamol and salmeterol, aredescribed, and related to their clinical use andadverse effects. The place of nebuliser therapy inCOPD is described, together with the operatingprinciples and designs of commercially availablenebulisers (air-jet, ultrasonic and mesh). Practicalconsiderations relating to patients’ use andmaintenance of nebulisers are considered.

Case 4Paediatric cystic fibrosis " 101

This case describes the treatment of allergicbronchopulmonary aspergillosis (ABPA) in a childwith cystic fibrosis (CF). The aetiology of CF andthe role of different medications routinely

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prescribed for a patient with CF are outlined. Thechemistry and mode of action of the proton pumpinhibitor (PPI), omeprazole, used to treat gastro-oesophageal reflux, frequently presenting in CFpatients, are described. Itraconazole is used totreat patients with ABPA. The formulationstrategies to enhance this water-insoluble drug’sbioavailability are outlined. The clinical use anddelivery of nebulised antibiotics and dornase alfa(DNase), an enzyme that cleaves extracellularDNA in the sputum, aiding its removal, aredescribed. The case ends with a discussion of theuse of shared-care protocols to ensure consistencyof care across the primary care–secondary careinterface, and consideration of medicinesmanagement in the home, which can be a complextask for this patient group.

Case 5Cough " 108

This case describes the treatment of cough in ayoung person, which is, possibly, smoking related.The case starts by considering thepathophysiology, signs, symptoms and diagnosis ofdifferent types of cough and the appropriatetreatment. The use of mnemonics such asWWHAM is outlined, to ensure effectivequestioning of a patient when determining adiagnosis. The chemistry and mechanism of actionof expectorants and opiate antitussives, widelyused to treat coughs, are considered. Symptomsindicating that a patient with a cough should bereferred to another healthcare professional aredescribed. The opportunity for a pharmacist tooffer lifestyle advice, particularly in relation tosmoking cessation, is highlighted.

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Case 1AsthmaGEMMA QUINN

LEARNING OUTCOMES

At the end of this case, you will be able to:

. Outline the pathophysiology, and signs andsymptoms of asthma

. Describe the treatment options in asthma,particularly in relation to stepping up andstepping down therapy

. Outline the chemistry of glucocorticoidsand b2-adrenoreceptor agonists used in thetreatment of asthma

. Outline the formulation of pressurisedmetered-dose inhalers

. Describe the use of spacers withpressurised metered-dose inhalers

. Outline the formulation of dry powderinhalers

. Consider the issues that may affectadherence in asthma, and make appropriatetreatment recommendations to improvethis

Case studyMiss GN is a 19-year-old young woman who iscurrently studying for a degree in English at thelocal university. She was diagnosed with asthmawhen she was 7 years old and her regularprescription is for salbutamol pMDI200 micrograms when required.

.? What is asthma?

.? What are the most common signs andsymptoms of asthma?

.? How is a diagnosis made?

.? What non-pharmacological treatment optionsare available?

.? What is the first-line pharmacologicaltreatment in asthma?

Miss GN came to the pharmacy to collect her thirdprescription for a salbutamol pMDI in 4 weeks.The pharmacist asked to speak to her anddiscovered that she was currently using her inhalerfive to six times a day. Miss GN was referred to herGP and returned a few days later with a

prescription for beclometasone (Clenil)200 micrograms twice daily, via a spacer.

.? When is it appropriate to start treatment withinhaled corticosteroids?

.? What is a pMDI and what are the benefits ofusing a spacer?

Miss GN continued to collect her prescriptions forsalbutamol and beclometasone, but after a fewmonths she complained that she was still using hersalbutamol up to four times a week and waswaking at night. She also found it difficult to carrythe spacer and two inhalers around with her,meaning that she sometimes missed doses. Thepharmacist suggested seeing her GP again for areview. Miss GN subsequently presented with aprescription for budesonide/formoterol (Symbicort100/6 Turbohaler), two puffs twice daily and onepuff when required (SMART regimen: singleinhaler maintenance and reliever therapy).

.? What sort of inhalation device is a Turbohaler,and how does it differ from a pMDI?

.? Draw the structures of budesonide andformoterol. How are they related to othersteroids and b2-adrenergic receptor agonistsused in asthma?

.? What issues may affect adherence with asthmatreatments, particularly in Miss GN’s case?

.? What is the SMART regimen and when is itrecommended?

Miss GN asks you whether she might be able toreduce her inhalers in the future.

.? When should inhaler therapy be stepped down?

Case discussion— Asthma and its pathophysiologyAsthma is one of the most common respiratorydiseases in the UK, with about a fifth of children(21%) and 15% of adults affected. It ischaracterised by ‘reversible’ obstruction of theairways, caused by a combination of bronchialhyper-responsiveness, inflammatory changes in theairways, and increased numbers of eosinophils andactivated T cells. It is usually an allergic condition,with common triggers including pollen, dust,

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animal dander, respiratory infections, medicines(e.g. b-blockers and non-steroidalanti-inflammatory drugs [NSAIDs]), cold air,strong emotions and exercise.

— Signs and symptoms of asthmaSymptoms characteristic of asthma includewheeze, breathlessness, chest tightness and cough.Symptoms usually occur in response to a triggerand are often worse at night and early in themorning. There is also frequently a family historyof asthma or atopic (hyperallergic) disorders.There is no agreed definition of asthma, so a

diagnosis is made based on the pattern of signsand symptoms, where there is no probablealternative diagnosis. Spirometry is the preferredmethod of demonstrating fluctuating airflowobstruction in asthma, although a normalspirogram does not exclude a diagnosis of asthma.

— Pharmacological and non-pharmacologicaltreatment options for asthma

Many patients can identify triggers for theirasthma and, where possible, these should beavoided, particularly where they include dust mitesand passive smoking. Where dust mites are felt tobe a trigger, patients can try methods such asmattress barrier systems and high temperaturewashing of bed linen. However, this can beexpensive and is not of proven benefit.Management of asthma is mainly

pharmacological, with the aim of achieving‘complete control’. This can be defined as:

. No daytime symptoms

. No night-time awakening due to asthma

. No need for rescue medication (b2-agonist)

. No exacerbations

. No limitations on activity, including exercise

. Normal lung function (FEV1 and/or PEF >80%of predicted or best)

. Minimal side effects of medication.

Mild asthma may be managed with a b2-adrenoreceptor agonist taken only when required.The British Thoracic Society/ScottishIntercollegiate Guidelines Network (BTS/SIGN)guidelines do not recommend one drug over anyother, but in practice salbutamol is the usualchoice.

— Stepping up treatment: initiating inhaledcorticosteroids

Patients should be considered for inhaledcorticosteroids if they are symptomatic and/or

need to use their b2 agonist three times a week ormore, if their symptoms wake them at least once aweek or if they have had an exacerbation in thelast 2 years. The use of two or more canisters of b2agonist a month, or 10–12 puffs per day, indicatesthat patients are poorly controlled and at risk offatal or near-fatal asthma.Adults are usually started on the equivalent of

200 micrograms beclometasone twice daily,whereas 100 micrograms twice daily is usuallyprescribed for children. It is important to note thatdifferent formulations of beclometasone are notbioequivalent; some pMDI products are solutionformulations in hydrofluoroalkane (HFA)propellants and others are suspensionformulations producing different drug depositionprofiles within the lung. Consequently,preparations should always be prescribed by brandproprietary name.

— Chemical properties of glucocorticoids andb2-adrenoreceptor agonists

Budesonide is a glucocorticoid that is closelyrelated to beclometasone dipropionate, and bothdrugs have essentially the same steroid skeleton.The principal difference is that beclometasone isprepared as the dipropionate ester, whereasbudesonide contains an acetal group.Beclometasone dipropionate is a prodrug: the less-hindered ester (at carbon-21) is hydrolysed to givethe more active monopropionate metabolite.Budesonide already has a free primary hydroxyl atcarbon-21 so is not a prodrug.Formoterol is structurally similar to other long-

acting b2-adrenoreceptor agonists such assalmeterol. Formoterol has an extended lipophilicsubstituent on the secondary amine nitrogen. Thisresults in a greater affinity for, and longerresidence time, on the b2-receptor, therebyprolonging its duration of action. Only the (R,R)stereoisomer of formoterol is biologically active.

— Pressurised metered-dose inhalersThe pMDIs comprise an aluminium container/canister containing a liquefied aerosol propellant(HFA 134a or 227). The drug is either dissolved ordispersed as micronised particles (usually 2–5 mm)in the propellant liquid within the canister.Evaporation of propellant within the headspace ofthe canister provides a pressure (the saturationvapour pressure of the propellant gas), whichexpels liquid from the canister, via a meteringvalve; this sits in a plastic actuator. Excipients in

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the formulation may include a surfactant, such assorbitan ester, lecithin or oleic acid, which acts asa suspending agent in suspension formulations,and ethanol as a co-solvent to aid in thedissolution of drug or surfactant.

— Use of spacersMany patients find using a pMDI very difficult anduse it incorrectly. One study found that only 23–43% of patients can use a pMDI correctly; thisfigure was 55–57% for patients using a pMDI witha spacer.Spacers are plastic devices used by some

patients together with a pMDI. They reduce thevelocity of the aerosol emitted from the pMDI,remove large droplets by impaction with thespacer walls, provide time and space for propellantto evaporate from droplets, allowing a fineaerosol to be produced, and remove the need forpatients to inhale at the same time as actuatingthe pMDI.The use of a b2-adrenoreceptor agonist with a

spacer in mild and moderate exacerbations hasbeen shown to be as effective as treatment with anebuliser, making a spacer a vital part of anasthma personal management plan. It is importantto note that spacers should be cleaned monthlyand changed at least every 6–12 months.The use of a spacer with inhaled corticosteroids

may also reduce the risk of oral candidiasis.Rinsing the mouth with water or brushing theteeth after inhaling the dose are also sometimes

tried, but there is little evidence to confirm theeffectiveness of any of these interventions.

— Dry powder inhalersThe Symbicort Turbohaler is a dry powder inhaler(DPI) from which drug is inhaled as a cloud of fineparticles. DPIs have several advantages overpMDIs. They are propellant free and usually donot contain any excipients, other than a carrier(see below). They are breath actuated, so theproblems for patients of coordinating actuationand inhalation are removed.The drug (with a particle size usually <5 mm)

and excipients (if present) is either preloaded in aninhalation device (e.g. Turbohaler, Accuhaler), orput into hard gelatin capsules (e.g. Handihaler),which are loaded into a device before use.The small drug particles produced by

micronisation (milling) have poor flow properties,due to their high surface energy. To improve theirflow, and aid device manufacture and delivery ofdrug from the device, particles are generally mixedwith larger ‘carrier’ particles (30–150 mm) of anexcipient, usually lactose. Some formulations alsocontain fine lactose particles or magnesiumstearate to optimise the formulation properties.During inhalation, the turbulent airflow generatedwithin the inhalation device should be sufficientfor the deaggregation of the drug/carrieraggregates, with drug particles carried in theinhaled air deep into the airways. Most DPIformulations contain a carrier; some Turbohaler

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formulations do not. Instead, drug particles areloosely aggregated, and these aggregates arebroken up by turbulent airflow created in thedevice during inhalation by patients.

— Factors affecting adherence with asthmatreatments

Patients may find it difficult to adhere totreatments for asthma. This may be intentional orunintentional. As already discussed, achievingcorrect inhaler technique is very difficult. DPIsmay be preferable (53–59% of patients use correctinhaler technique), although alternative devices toa pMDI should be prescribed according to patientpreference and local cost. The type of device maybe limited by the drug, so it may be appropriate tochange the drug, e.g. beclometasone is notavailable as a Turbohaler, whereas budesonide is.There are also devices available to measurepatients’ inspiratory flow and match this to themost appropriate device.The side effects of inhaled corticosteroids may

discourage patients from adhering to theirprescribed regimen, as may lifestyle issues. As astudent Miss GN may have a busy social life andlive away from home; this may impact on herability to have inhalers with her when needed andshe may benefit from having more than one ofeach inhaler available, e.g. one to keep at both herstudent and her home addresses.Pharmacists can make a huge impact by

teaching patients how to use their inhalerscorrectly, recommending changes to alternativedevices when appropriate and making otherpractical suggestions that may help withadherence.

— The SMART regimenStudies have shown that the SMART (singleinhaler maintenance and reliever therapy)combination of budesonide/formoterol can safelyand effectively be used as an asthma reliever aswell as a preventer in primary care asthmamanagement, with formoterol acting as quickly assalbutamol. This can be prescribed if control is notachieved with standard dose inhaledcorticosteroids. When this regimen is prescribed,the total daily dose of inhaled steroid should notbe decreased, and patients should be advised that

the regimen will require review if they need to usethe reliever once a day or more on a regular basis.This may aid adherence because the patient

requires only one dry powder inhaler (andtherefore no spacer).

— Stepping down treatmentOnce a patient’s asthma has been controlled,‘stepping down’ should be considered. The mostappropriate drug to be reduced should beconsidered in view of current dose, side effects andbeneficial effects of the current dose, as well as theseverity of asthma and patient preference.If stepping down inhaled steroids, reductions

should be considered every 3 months, with a dosereduction of 25–50% at a time.

EXTENDED LEARNING

. How are inhalation products formulatedand manufactured?

. What are the mechanisms whereby inhaledparticles are deposited in and cleared fromthe airways?

. Why is particle size such an importantproperty of inhalation aerosols?

. What methods are used to reduce the sizeof particles and to measure the sizedistribution of particles?

ADDITIONAL PRACTICE POINT

. How will you counsel a patient to use apMDI, pMDI with spacer or DPI?

Further readingBritish Thoracic Society/Scottish Intercollegiate GuidelinesNetwork (2012). British Guidelines on the Management ofAsthma. London: BTS/SIGN, May 2008, updated January2012.

Murphy A (2010). Asthma: The condition and its diagnosis.Clin Pharmacist 2:203–07.

Murphy A (2010). Asthma: Treatment and monitoring. ClinPharmacist 2:209–14.

Taylor KMG (2013). Pulmonary drug delivery. In: Aulton ME,Taylor KMG (eds), Aulton’s Pharmaceutics: The design andmanufacture of medicines, 4th edn, Elsevier: London, 638–56.

Thomas M, Pavord I (2012). Single inhaler maintenance andreliever therapy (SMART) in general practice asthmamanagement: where are we? Primary Care Respir J 21:8–10.

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Case 2Treating an acute severe asthma exacerbationANNA PRYOR

LEARNING OUTCOMES


. Outline the pathophysiology of asthma

. Explain the signs, symptoms and commontriggers of acute asthma exacerbations

. Outline the different classifications of acuteasthma

. Discuss the treatment options in asthmaexacerbations

. Outline the key features of the variousinhalation devices (pressurised metereddose inhalers, dry powder inhalers,nebulisers)

. Outline the pharmaceutical monitoringrequired when looking after asthmapatients and be able to makerecommendations on therapy

Case studyMiss SA is a 19-year-old white young woman whohas had asthma since the age of 5. She has beenbrought to the A&E by ambulance suffering withan asthma attack after collapsing during a localcharity summer fun run.

Her mother tells you that her regular medicationsare as follows:

Beclometasone pMDI 100 micrograms two puffs b.d.Salbutamol pMDI 100 micrograms two puffs p.r.n.

Past medical history: hay fever

Miss SA has recently been taking ibuprofen 400 mgwhich she purchased over the counter (OTC) for aknee sprain she sustained while training for the funrun.

She has been admitted to hospital with her asthmabefore, as a child, but hasn’t had any problems fora long time and ‘hasn’t been using her browninhaler much lately’.

On admission, she is severely short of breath andunable to speak in full sentences; she is holding onto the sides of the trolley, leaning forward andgasping for breath. Her observations are as shownin the box.

On examination. Blood pressure (BP) 95/75 mmHg. Heart rate (HR) 120 beats/min. Respiratory rate (RR) 30 breaths/min. Widespread expiratory polyphonic wheeze. Oxygen saturations PaO2 = 59 mmHg

(7.8 kPa) (normal 80–100 mmHg [10–

13 kPa]); SpO2 = 92% on air (normal >92%). arterial blood pH 7.3. Peak expiratory flow (PEF) = 200 L/min

(best = 450 L/min)

.? What is the underlying pathophysiology ofasthma?

.? What factors could have contributed to MissSA’s asthma exacerbation?

.? Beclometasone is administered as thedipropionate ester. How is beclometasonemetabolised in lung tissue to give its activemetabolite?

.? What is the fate of the beclometasonedipropionate that is NOT deposited in therespiratory tract?

.? What other investigations should be performedon Miss SA and why?

.? How would you classify the severity of herasthma attack? What features of her history andpresentation give cause for concern?

.? What treatment should she be givenimmediately?

She does not respond to initial treatment..? What further therapy could you recommend?.? What are the key differences between thevarious types of inhaler devices available?

Once she has been stabilised, she is taken to theadmissions ward..? What recommendations would you make forher further treatment and which specificparameters should you monitor as apharmacist?

Case discussion— Pathophysiology of asthmaAsthma is a chronic inflammatory disorder of theairways, characterised by bronchoconstriction,

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increased vascular permeability, excess mucusproduction and impaired mucociliary clearance(the process whereby the cilia of the cells liningthe airways propel mucus, and deposited materials,upwards towards the throat). Due to airwayhyper-responsiveness, both specific andnon-specific stimuli can trigger the complexinflammatory response in people with asthma,which is mediated by eosinophils, mast cellslymphocytes and neutrophils.

— Possible trigger factors for an exacerbation inthis case

. Medicines: NSAIDs, such as ibuprofen, caninduce bronchospasm in people with asthma.This is due to the drug’s effect on arachidonicacid metabolism: production of prostaglandinsis blocked, causing increased production ofleukotrienes which cause bronchoconstriction.

. Allergens: grass pollen is prevalent in June andJuly and mould spores (Cladosporium andAlternaria spp.) are common in late summer.Given that Miss SA is known to have hay feverand was outside participating in the ‘fun run’,this could have been a contributory factor. Noantihistamine medication is mentioned. Ofnote, in the UK there is a peak of asthmadeaths in people aged up to 44 years in July andAugust.

. Running: vigorous exercise causes narrowing ofthe airways in most people with asthma.

. Non-compliance with medication: Miss SAmentioned that she has not been using hersteroid inhaler as prescribed.

. Infection: respiratory tract infections canprovoke a transient increase in airwayresponsiveness in normal individuals, as well aspeople with asthma. Upper respiratory tractinfections, principally of viral aetiology, are themost common trigger factor for acute asthma.

— Less likely triggers in this case

. Changes in weather, particularly high humidity

. Possible premenstrual component

. Psychological stimuli, such as stress or anxiety.

— Beclometasone dipropionateBeclometasone is a potent glucocorticoid steroid.In the management of asthma, beclometasone isadministered as a diester – the hydroxyl groups atcarbon-17 and carbon-21 are both esterified as thepropionate (propanoate) esters. After inhalation,the more accessible ester at carbon-21 is rapidly

cleaved by lung esterases to give the highly activebeclometasone 17-monopropionate (17-BMP)metabolite. After absorption from the lungs, the17-BMP is rapidly cleared to inactive metabolitesin the liver.

Only around 10–30% of an inhaled dose isdeposited in the respiratory tract, the remainderbeing deposited in the oral mucosa andsubsequently swallowed. Very little beclometasonedipropionate is absorbed from the gastrointestinal(GI) tract due to its very low polarity and verypoor water solubility; most is simply eliminatedunchanged in the faeces. Any small fraction that isabsorbed undergoes significant first-passmetabolism in the liver, minimising systemicavailability.

— Recommended further investigations

. Chest radiograph: although not recommendedas routine, radiography is useful to rule outother causes for breathlessness, such aspneumothorax or pneumonia.

. Arterial blood gas (ABG): this will helpdetermine the severity of Miss SA’s asthma. Alow PaO2 (partial pressure of oxygen dissolvedin arterial blood) could be indicative of life-threatening asthma and an SpO2 (blood oxygensaturation: percentage of Hb molecules boundto oxygen) <92% is associated with a risk ofhypercapnia (elevated arterial CO2; normalPaCO2 = 40 mmHg [5.3 kPa]).

. Blood tests: including CRP (C-reactive protein,produced by the liver as a measure of generallevel of inflammation in the body) and fullblood count (FBC) to look for evidence ofinfection.

. Temperature: to diagnose or exclude infection.

. Echocardiogram (ECoG): to exclude a cardiaccause or complication for her symptoms.

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— Signs of acute severe asthma: considerationsin this case

In this case, Miss SA’s PEF is <50% of her best,and both her heart rate (HR) and respiratory rate(RR) are elevated. She is unable to completesentences and is having to use her accessorymuscles to breathe (note: ‘holding on to the sidesof the trolley, leaning forward and gasping forbreath’).

FEATURES OF ACUTE ASTHMA

. Peak expiratory flow (PEF) 33–50% of best(use percentage predicted if recent bestunknown)

. Cannot complete sentences in one breath

. Respirations �25 breaths/min

. Pulse �110 beats/minMiss SA is also exhibiting worrying signs that

could indicate that she is close to progression tolife-threatening asthma, including hypotension anddangerously low oxygen saturation. A blood gasreading would be essential at this stage todetermine her risk and plan her treatment.

LIFE-THREATENING FEATURES OFASTHMA

. PEF <33% of best or predicted

. PaO2 <8 kPa and/or low pHa on ABG

. SpO2 <92%

. Silent chest, cyanosis or feeble respiratoryeffort

. Hypotension

. Exhaustion

. Altered conscious level, confusion or coma

. Arrhythmias

aNormal arterial pH = 7.35–7.45

— Immediate treatment of an asthmaexacerbation

High-flow oxygen is the most importantimmediate treatment and should be the firstintervention, because hypoxia can put the patientat risk of cell injury and death. Give 15 L O2 via are-breathe mask, aiming for an arterial SpO2 94–98%.High-dose nebulised b2-agonist, either salbutamol5 mg or terbutaline 10 mg: there is no evidence tosuggest superior efficacy of either agent. This must

be delivered via an oxygen-driven nebuliser with aminimum flow rate of at least 6 L/min because ofthe risk of desaturation with air-driven devices.Back-to-back nebulisation is recommended, e.g.salbutamol 5–10 mg/h.Steroids: early administration of steroids isimperative. Their use has been shown to reducemortality and lower requirements of b2-agonisttherapy. Oral steroids are as effective as parenteraltherapy, provided that the patient is able toswallow and retain the tablets. Recommendeddoses are prednisolone 40–50 mg daily,hydrocortisone 100 mg 6-hourly ormethylprednisolone 160 mg intramuscularly.Nebulised ipratropium bromide (anticholinergic)500 micrograms 4- to 6-hourly via an oxygen-driven nebuliser: combining an anticholinergicwith the nebulised b2-agonist will producesignificantly greater bronchodilatation than the b2-agonist alone.

— Possible add-on therapyMagnesium sulfate: there is some evidence that, inadults, magnesium sulfate has bronchodilatoreffects. A single dose has been shown to be safeand effective in acute severe asthma unresponsiveto initial therapy. The recommended dosage is1.2–2 g intravenous infusion administered over 20minutes.Intravenous fluid rehydration: patients with acuteasthma tend to be dehydrated because they are toobreathless to drink adequate amounts of fluid, inaddition to experiencing increased fluid loss fromthe respiratory tract. Dehydration causes theproduction of more viscous mucus, makingclearance more difficult and risking mucusplugging. Consider potassium supplementation tocompensate for the hypokalaemic effect ofsalbutamol and corticosteroids.Antibiotics: routine prescribing of antibiotics is notindicated in asthma exacerbations. Most infectiveprecipitants are viral in origin. Only if there isobjective evidence of bacterial infection, e.g.elevated white cell and neutrophil counts, hightemperature and radiological changes, shouldbroad-spectrum antibiotics, such as amoxicillin, beinitiated.Intravenous aminophylline: some patients mayderive benefit from the addition of an infusion ofintravenous (i.v.) aminophylline; however, it is nolonger considered routine therapy. The loadingdose is 5 mg/kg over 20 min followed by

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continuous infusion of 500 micrograms/kg perhour (maximum concentration 25 mg/mL). Besure to check the drug history and for interactions.Therapeutic drug monitoring will be required ifthe infusion is continued for more than 24 hours.Parenteral b2-agonist: intravenous salbutamol maybe beneficial in addition to the nebulised route insevere cases, or for patients who are ventilated,although there is limited evidence to support this.Recommend prescribing: 5 mg salbutamol1 mg/mL diluted in 500 mL 5% glucose or 0.9%sodium chloride and infusing at 0.3–2 mL/min (3–20 micrograms/min) and titrating to response.

— Recommended pharmaceutical monitoring,follow-up and treatment

. PEF: PEF readings should improve, but becareful to watch out for any diurnal variation –asthmatics typically dip first thing in themorning and failure to consider this could leadto inappropriately hasty step-down of treatmentand discharge.

. Electrolytes: watch for hypokalaemia in view ofthe high dose steroid and salbutamol therapy.

. Side effects: monitor for side effects from alldrugs, e.g.:. Salbutamol: tremor, tachycardia, headaches,palpitations

. Ipratropium: dry mouth, urinary retention,nausea, headache

. Steroids: hyperglycaemia, hypertension.. Switch steroids to oral prednisolone 40 mgdaily and continue for at least 5 days. At thisdose, they can be stopped abruptly on dischargewith no need for weaning. Tapering is necessaryonly if the patient has had repeated courses,doses >40 mg prednisolone or received over 3weeks of treatment.

. Step-up inhaler therapy: suggest switching to acombination inhaler containing a long-acting b-agonist + corticosteroid, e.g. Symbicort 200/6or Seretide 125/25 (step 3 of BTS guidelines);this can be stepped down at a later date ascontrol is maintained.

— The key difference between types of inhalerdevice

See Table 3.1.

— CounsellingIt is important to reinforce the need forcompliance with treatment, and to ensure thatinhalers are used correctly with the optimaldevices prescribed. Using these devices to achieveoptimum effect is not easy. In particular, pMDIsrequire coordination of inhaling and actuation, aspart of a routine with a number of steps topromote effective drug delivery to the lungs.Patients should be assisted to ensure that they

! TABLE 3.1

Comparison of inhaler devices

Device A pMDI DPI Nebuliser

Principle of operation Pressurised gas, e.g. HFA Powder particles dispersed bypatient’s inhalation

Compressed air/oxygen, or:UltrasonicMesh

Drug presentation Drug dissolved or suspendedin liquid propellant

Micrometre-sized drugparticles as powder

Drug dissolved or suspendedin water

Possible excipients Propellant, surfactant,co-solvent

Carrier particles, e.g. lactose Tonicity and pH modifiers

Storage of medication In inhaler In inhaler or capsules As unit-dose ‘nebules’,independent of device (rarelymultidose in vials)

Treatment time <1 s One breath Up to 20 min

Advantages Small, portable, nopreparation

Small, portable, minimalpreparation

Ease of use, potential fordelivering large doses

Disadvantages Poor patient compliance Inspiratory effort required Relatively large, cost, durationof treatment, non-availabilityof devices on NHS

DPI, dry powder inhaler; HFA, hydrofluoroalkane; pMDI, pressurised metered-dose inhaler.

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sustain a good technique in the operation ofdevices.A personalised self-management plan should be

devised and a written plan issued to the patient ondischarge. These, together with self-managementeducation, have been shown to reducehospitalisation and A&E attendance, particularly inpeople with asthma who have had recentexacerbations.The plan should include:

. Structured education, with specific advice aboutrecognising loss of asthma control assessed bysymptoms and/or PEF monitoring

. What to do if asthma deteriorates, such asseeking medical attention, increasing inhaledsteroids or starting oral steroids, depending onseverity.

Consider the need for supplementarytreatments such as non-sedating antihistamines,e.g. cetirizine 10 mg daily.

EXTENDED LEARNING

. Outline the British Thoracic Societyguidelines for treatment of asthma.

. Describe the pharmacology of long- andshort-acting b2-agonists.

. Describe the anatomy of the lung – howdoes this impact on the way in whichtherapeutic aerosols are deposited andcleared from the airways?

. Describe how particles delivered frominhaler devices deposit in the airways, andoutline the importance of particle size anddensity in these mechanisms.

Further readingTaylor KMG (2013). Pulmonary drug delivery. In: Aulton ME,Taylor, KMG (eds), Aulton’s Pharmaceutics: The design andmanufacture of medicines, 4th edn. London: Elsevier, 638–56.

Case 3Nebulised therapy for chronic obstructive pulmonary diseaseBOTHAINA ALHADDAD

LEARNING OUTCOMES


. Outline the pathophysiology, symptoms,signs and diagnosis of COPD

. Describe the treatment options in COPD,particularly in relation to exacerbations

. Outline the place of nebuliser therapy inCOPD, and describe the variations inoperating principles and designs ofavailable nebulisers

. Describe the practical aspects relating topatients’ use and maintenance of nebulisers

. Outline the pharmacological mechanism ofaction of b2-adrenergic receptor agonistson bronchial smooth muscle

. Outline the common side effects of b2-adrenergic receptor agonists

. Appreciate the structural characteristics oflong- and short-acting b2-adrenergicreceptor agonists that are important in theirpharmacological activity and clinical use

Case studyMrs MM is a 75-year-old white woman, who hassmoked for the previous 40 years. She wasdiagnosed with COPD 5 years ago, and has sincebeen prescribed bronchodilators, includingsalmeterol, delivered from a pMDI to relieve herbreathlessness. Salmeterol is a long-acting b2-adrenergic receptor agonist.

.? What is COPD?

.? What are the classic symptoms of COPD?

.? How is a diagnosis of COPD confirmed?

.? How is stable COPD managed?Mrs MM began to feel unwell on Christmas Eve.She was increasingly breathless despite using herinhalers and had just managed to call for anambulance. The paramedics noted that Mrs MMwas out of breath and her PaO2 was markedly low.She was given oxygen as well as nebulisedbronchodilators. During her stay in hospital, MrsMM was started on an antibiotic and a course oforal steroids. On discharge, she was lent anebuliser by the hospital for use with prescribed

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salbutamol nebules. Salbutamol is a short-actingb2-adrenergic receptor agonist.

.? What is an exacerbation of COPD?

.? How is it managed?

.? What is the mechanism of action of salbutamoland salmeterol in the treatment of respiratorydisease?

.? What structural characteristics of thesalmeterol molecule result in a longer durationof action compared with shorter-acting b2-agonists, such as salbutamol?

.? What other structural features are important inthe clinical use of these agents?

.? What is the rationale for using a nebuliser inthe management of COPD?

.? What are the advantages of using a nebuliserrather than a dry powder or pressurisedmetered-dose inhaler in this case?

Mrs MM’s condition improved and she wasstabilised after 14 days. She visited her GP whorecommended that she continue to use a nebuliserbecause her COPD had not been adequatelycontrolled with her previous medication; she hadincreased breathlessness, which limited her dailyactivities, a productive cough with purulentsputum, and a history of recurrent respiratoryinfections in the last few years.

Mrs MM is very keen on controlling her symptomsand wanted the GP to help her choose the ‘best’nebuliser available.

.? What are the different types of nebulisersystems available?

.? Given the variation between different availablenebuliser systems, what factors should influencethe choice of the doctor/patient?

.? What factors will determine the proportion ofdrug in the prescribed salbutamol nebules thatwill reach the deep lung of a patient using anebuliser?

Mrs MM comes to the pharmacy and asks you forguidance on the use of her nebuliser.

.? Can you explain when and how the nebulisershould be used, giving clear instructions oncleaning and maintenance?

Case discussion— COPD and its pathophysiologyChronic obstructive pulmonary disease,characterised by airflow obstruction that is notfully reversible and does not change over severalmonths, is usually progressive and frequently

caused by smoking. COPD is an umbrella termused to describe a range of different overlappingconditions affecting the airways, such as chronicbronchitis, emphysema, long-standing asthma andsmall airway disease. In COPD, the airwaysbecome inflamed as a result of an exogenousfactor, often smoking, and produce elastaseswhich, over time, result in disruption of theelastin/elastase balance in the lung. This, coupledwith inactivation of the protective anti-elastases inthe lung (as a result of the oxidants in cigarettesmoke), leads to loss of lung elastin, destruction oflung tissue and emphysema. Loss of elastin alsocauses the lungs to become hyperinflated due toair being trapped in the small airways. In addition,smoking causes inflammation and mucusproduction, which accelerate the decline in lungfunction and predispose patients to infections. Theconsequences of this are breathlessness onexertion, hypoxia, pulmonary hypertension andperipheral oedema.

— Symptoms, signs and diagnosis of COPDPatients with COPD often experience symptoms ofbreathlessness on exertion, coughing, sputumproduction and wheezing. However, clinical signssuch as barrel chest, prominent accessory muscleof respiration, recession of lower costal margins,abdominal breathing, weight loss, central cyanosis,peripheral oedema and raised jugular venouspressure (JVP) are seen only when the disease is inthe severe stage. Diagnosis of COPD oftenincludes full clinical assessments for symptomsand the presence of any clinical signs, as well ascomplete history taking. Measurement of lungfunction by spirometry is essential in making adiagnosis of COPD. However, in uncertain cases,bronchodilator or steroid reversibility testing maybe useful.Spirometry is a standardised measure of a

forced expiration (and sometimes inspiration) intoa spirometer (a calibrated measuring device).Spirometers usually measure flow and thencalculate volume with respect to time. The mostcommon measurements are:

. FEV1: the forced expiratory volume in 1 s,which is the amount of air blown out in 1 s.

. FVC: the forced vital capacity, which is the totalamount of air blown out in one breath.

. A FEV1 : FVC ratio is then calculated.

There are several manufacturers of equipment,and all spirometers need, as a minimum, to meet

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the standards of measuring and recording asspecified in international guidelines. To performquality-assured spirometry testing and providevalid results for patients, a systematic approachwould need to be employed by trained staffaccording to local standards.

— Treatment options for stable COPD, andduring an exacerbation

COPD is mainly managed in primary care withpharmacological and non-pharmacologicaloptions. Drug options include inhaledbronchodilators, theophylline, oral or inhaledcorticosteroids, and combination therapy of morethan one of these. Non-pharmacological optionsinclude smoking cessation, pulmonaryrehabilitation programmes and oxygen therapy.Exacerbations are common health problems in thenatural development of COPD. The NationalInstitute for Health and Care Excellence (NICE)defines an exacerbation as ‘a sustained worseningof the patient’s symptoms from his or her usualstable state that is beyond normal day-to-dayvariations, and is acute in onset. Commonlyreported symptoms are worsening breathlessness,cough, increased sputum production and changein sputum colour. The change in these symptomsoften necessitates a change in medication.’Treatment of an exacerbation includes large dosesof inhaled bronchodilators, systemiccorticosteroids, antibiotics, intravenoustheophylline and oxygen.

— Pharmacology of b2-adrenergic receptoragonists

The clinical usefulness of drugs such as salbutamoland salmeterol as bronchodilators relies on theirability to ‘select’ for the b2-subtype of adrenergicreceptor that is present on bronchial smoothmuscle cells. Salbutamol was originally introducedinto practice for bronchodilatation in 1968 andimmediately became successful in asthma andCOPD treatment, because it produced fewerserious (particularly cardiac) side effects. (Themost common side effects reported for inhaled b2-adrenergic receptor agonists in the BNF are: finetremor in the hands, nervous anxiety, dizziness,headache, muscle cramps, dry mouth andpalpitations/cardiac arrhythmias.)Up to that time, the less-selective b-adrenergic

agonist drugs isoprenaline and orciprenaline werecommonly used for such conditions, but theircardiovascular, central nervous system (CNS) and

gastrointestinal (GI) side effects were consideredtoo significant and potentially life threatening, andso were withdrawn. The main pharmacologiceffects of b2-adrenergic receptor agonists onbronchial smooth muscle are mediated through acoupling of the b2-adrenergic receptor with a so-called stimulatory G-protein (Gs), which thenactivates intracellular adenylyl cyclase, the enzymeresponsible for catalysing the conversion ofintracellular adenosine triphosphate (ATP) tocyclic adenosine monophosphate (cAMP). Theincreased intracellular cAMP levels, via activationof protein kinase A, lead to a decrease inintracellular Ca2+ concentration and myosin lightchain kinase activity, which ultimately causessmooth muscle relaxation (bronchodilatation). Inaddition, b2-agonists directly open large (size)conductance Ca2+-activated potassium [BK(Ca)]channels in the cell membrane, leading tohyperpolarisation and relaxation of airway smoothmuscle cells. The combination of all these effectsis responsible for the beneficial bronchodilatoraction.

— Chemistry of salbutamol and salmeterolSalmeterol is considerably more lipophilic thansalbutamol due to the extended lipophilicsubstituent on the nitrogen atom. This extendedlipophilic group makes a specific non-covalenthydrophobic interaction with part of the b2-adrenergic receptor resulting in a higher (10-fold)potency, and localises the drug in the active sitefor longer.The secondary amino group nitrogen atom

present in both b2-agonists is basic, with a pKavalue of around 9.0 for the conjugate acid. Atphysiological pH 7.4, the amino group isprotonated and therefore positively charged. Thispositive charge is essential in making anelectrostatic force of attraction with a negativelycharged part of the receptor. The basic aminogroup also means that both agonists can beformulated as salts, which have improved watersolubility and dissolution. Hence, salbutamolnebules contain an aqueous solution of salbutamolas the salbutamol sulphate salt.The carbon atom bonded to the hydroxyl group

(-OH) is a chiral centre. Although both salmeteroland salbutamol are manufactured as racemicmixtures (50 : 50 mixtures of R- and S-enantiomers),only the R-enantiomer has the correct shape tobind to the b2-receptor, because the R-enantiomer

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has the same relative configuration as theneurotransmitter noradrenaline and thecirculating hormone adrenaline.A bulky substituent on the nitrogen atom and a

hydroxymethyl (-CH2OH) substituent on thearomatic ring are important for b2 selectivity. Thehydroxymethyl group also hydrogen bonds withthe receptor-binding site and prevents the drug’smetabolism by COMT (catechol-O-methyltransferase – the enzyme responsible formetabolising noradrenaline).

— Nebulisers and their modes of operationA nebuliser is a device that converts a drugsolution or, less frequently, a suspension into afine aerosol for inhalation. The nebuliser systemconsists of a nebuliser chamber and a driving/energy source. Broadly speaking, there are threetypes of nebuliser:

1 Air-jet nebulisers, which are most commonlyused in practice and comprise a nebuliserchamber and a compressor that generates airat high pressure to atomise the nebuliserliquid

2 Ultrasonic nebulisers, which use high-frequencysound waves to agitate the fluid and cause thedrug-containing droplets to be generated fromthe surface

3 Mesh nebulisers, in which fluid is forcedthrough a mesh with micrometre-sized holes toform droplets.

Each of these devices has advantages anddisadvantages. The proportion of available drugthat reaches the deep airways depends on thedesign and mode of operation of the nebuliser,duration of nebulisation, fluid volume (which canbe increased by diluting the contents of thenebule) and fluid physicochemical properties, suchas viscosity and surface tension. In addition to thedevice/fluid characteristics, patient technique andbreathing pattern are important factors thatdetermine the proportion of drug that reaches thesite of action and hence the effectiveness oftherapy and clinical outcomes.

— Rationale for using a nebuliser to inhalebronchodilators during an exacerbation

The mode of bronchodilator delivery is changedfrom regular hand-held inhalers to a nebuliserduring an exacerbation. A nebuliser is preferred inthis situation as higher doses can be administeredto the patient more easily. It is also convenient forhealthcare staff to administer, as less patienteducation and cooperation are required, since thedrug is administered during normal tidalbreathing, via a mouthpiece or facemask. This isparticularly helpful if the patient is distressed.Additionally, the nebulised medication may reducethe viscosity of the mucus and assist in itsexpectoration from the airways.

— Prescribing nebuliser therapyNebulisers are indicated when a patient has severe,distressing breathlessness, despite optimal therapywith pMDIs or DPIs, or is too ill or incapable ofusing a hand-held inhaler. Domiciliary nebulisertherapy is prescribed after assessment of COPDpatients in hospital or general practice.Components of the assessment should include areview of the diagnosis, peak flow rate monitoringat home, and sequential testing of differenttreatment regimens using peak flow and subjectiveresponses. Only patients who have a clearsubjective and peak flow response to domiciliarynebuliser treatment should be advised to continue.If there is a subjective response with <15%improvement over baseline peak flow, a physicianshould make a clinical judgement, whereas all otheroutcomes should not result in continued treatment.

— Use and maintenance of nebulisersWhen a nebuliser is prescribed, patients (and/orcarers) should be provided with the equipment,servicing, advice and support, and should haveregular reviews. They are given clear instructionson how and when to use the nebuliser, how toclean it, when to replace parts and when to servicethe equipment. The nebuliser chamber and themouthpiece or facemask should be washed inwarm soapy water and dried after each use.

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Tubing should not be washed because it is difficultto dry. It is advised that air be blown throughtubing by running the compressor for a fewseconds to dry it out, after the nebulisation sessionis complete and the chamber is detached fromtubing. The chambers should be replaced after 3months of regular use and the compressor shouldbe serviced regularly according to themanufacturer’s recommendations.

EXTENDED LEARNING

. How are COPD and asthma distinguished?

. What are the latest developments innebuliser design and therapy?

. What conditions other than COPD andasthma may be treated by nebulisedtherapy?

. What is the place and operation ofsmoking cessation programmes in theprevention of chronic disease?

ADDITIONAL PRACTICE POINTS

. Familiarise yourself with a nebuliser and itscomponent parts

. Topical use of b-adrenergic receptorblockers such as timolol, betaxolol,levobunolol or carteolol in the treatment ofglaucoma may lead to sufficient drug beingabsorbed systemically to pose a threat to

patients with asthma or COPD, due tobronchial b2-receptor blockade andconsequent bronchospastic complicationsand risk of respiratory failure/death.Practitioners reviewing asthma or COPDtherapy should therefore routinelyinvestigate whether there is any ongoingocular (or systemic) use of b-blockersbefore formulating a treatment plan

References and further readingBellamy D, Booker R (2004). Chronic Obstructive Pulmonary

Disease in Primary Care. London: Class Publishing Ltd.Boe, J, Dennis JH, O’Driscoll BR, Bauer TT et al. (2001).European Respiratory Society Guidelines on the use ofnebulizers. Eur Respir J 18:228–42.

Boe, J, O’Driscoll BR, Dennis JH (2004). Practical Handbook ofNebulizer Therapy. London: Martin Dunitz, Taylor &Francis Group plc.

British Thoracic Society (1997). Current best practice fornebuliser treatment. Thorax 52(Suppl 2):S1–106.

Levy ML, Quanjer PH, Booker R, Cooper BG, Holmes S, SmallIR (2009). Diagnostic spirometry in primary care: proposedstandards for general practice compliant with AmericanThoracic Society and European Respiratory Society. PrimaryCare Respir J 18:130–47.

National Institute for Health and Clinical Excellence (2004).Chronic Obstructive Pulmonary Disease: National guidelinefor management of COPD in adults in primary andsecondary care. Thorax 59:(Suppl I).

Primary Care Commissioning (2013). A guide to performingquality assured diagnostic spirometry. Available at: www.pcc-cic.org.uk (accessed 25 May 2013).

Case 4Paediatric cystic fibrosisSIÂN BENTLEY

LEARNING OUTCOMES


. Outline current knowledge of the aetiologyof cystic fibrosis (CF)

. Explain the role of different medicationsroutinely prescribed for a patient with CF

. Describe the presentation and managementof allergic bronchopulmonary aspergillosisin a CF patient

. Outline the chemistry and mode of actionof omeprazole

. Describe the properties of itraconazole andoutline formulation strategies to enhanceits bioavailability

. Understand the application of shared-careprotocols in prescribing of specialistmedication outside the hospital setting

Case studyCharlotte, a 7-year-old girl weighing 21 kg, isadmitted to the ward after presenting at heroutpatient clinic with increased shortness of breath,increased sputum production (sputum darker than

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normal), tiredness and generally feeling unwell forthe last 3 days.

CASE NOTES~Past medical history. Cystic fibrosis (CF). Pancreatic insufficiency

Allergies. No known drug allergy (NKDA)

Drug history. Creon 10 000 with snacks and meals. Dalivit multivitamin drops 1.2 mL o.d.. Tocopheryl acetate 100 mg o.d.. Omeprazole MUPS 20 mg o.d.. Flucloxacillin 250 mg b.d.. Colistin (Polymyxin E) 1000 000 units b.d.

nebuliser solution. Salbutamol 100 pMDI two puffs inhaled via a

spacer p.r.n. and pre-physiotherapy

On examination. Temperature 38.58C

A diagnosis of an infective exacerbation of CF ismade. A new sputum sample is taken and sent tomicrobiology for culture and sensitivity testing.Charlotte is empirically prescribed ceftazidime andgentamicin. The flucloxacillin is increased to atreatment dose:

Ceftazidime: 1000 mg t.d.s. i.v.Tobramycin: 210 mg o.d. i.v.Flucloxacillin: 500 mg q.d.s.

.? What is CF? Outline the current understandingof its aetiology and symptoms

.? Explain what each of Charlotte’s medicines onadmission are being used for and how theywould be administered. Charlotte is unable totake capsules/tablets (Hint: also think abouttiming with physiotherapy)

.? What organisms, common in CF, are theintravenous (i.v.) antibiotics covering?

.? Are the doses of the i.v. antibiotics appropriate,and how do they relate to alteredpharmacokinetics in CF patients?

.? How should the i.v. antibiotics be monitored?Charlotte receives these antibiotics for a week, butdoes not improve and becomes progressively more

wheezy. Her FEV1 (% predicted) falls from 65% to50%. Her blood results show an IgE of1054 units/mL and Aspergillus fumigatus RAST(radioallergosorbent test) of 19.8 units/mL, andAspergillus sp. is noted in her recent sputumsample. A diagnosis of ABPA is made andCharlotte is started on prednisolone 30 mg eachmorning and itraconazole liquid 100 mg twicedaily.

.? What does ABPA stand for? What is this? Isthe therapy appropriate?

.? Comment on the formulation and oralbioavailability of itraconazole in both capsuleand liquid form

! TABLE 3.2

Blood tests and sputum culture results

Na+ 136 mmol/L (normal: 134–145 mmol/L)

K+ 4.5 mmol/L (normal: 3.5–5.2 mmol/L)

Urea 3.3 mmol/L (normal: 2.5–6.5 mmol/L)

Creatinine 35 mmol/L (normal: 32–94 mmol/L)

WBC 17.46 109/L (normal: 4–13.56 109/L)

Most recent sputum culture results:

Pseudomonas aeruginosa sensitivity:

Azithromycin R

Ceftazidime S

Chloramphenicol S

Colistin S

Gentamicin S

Tobramicin S

Amikacin S

Temocillin S

Aztreonam R

Timentin S

Meropenem S

Ciprofloxacin R

Staphylococcus aureus sensitivity:

Flucloxacillin S

Penicillin S

Erythromycin R

Gentamicin S

R=resistant; S=sensitive.

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.? How would you counsel Charlotte and hercarer to take itraconazole?

.? How would you monitor itraconazole therapy?Charlotte responds well to the itraconazole andprednisolone. However, her sputum remainsdifficult to expectorate and she is started on DNase2.5 mg once daily pre-physiotherapy.

She continues to improve and is ready for dischargeafter 3 weeks. Her discharge medications are asfollows:

Creon 10 000: with snacks and mealsDalivit: 1.2 mL o.d.Tocopheryl: 100 mg o.d.Omeprazole: 20 mg o.d.Flucloxacillin: 250 mg b.d.Colistin: 1000 000 units b.d. nebuliser solutionSalbutamol 100 pMDI: two puffs via spacer p.r.n.and pre-physiotherapyItraconazole: 100 mg b.d.Prednisolone: 30 mg mane to be reviewed in clinicin 2 weeksDNase: 2.5 mg o.d. nebuliser solution

.? What is DNase (dornase alfa) and how does itwork?

The clinical nurse specialist for CF contactsCharlotte’s GP to explain the changes to herregimen, to be told that they are not able toprescribe the DNase under the new commissioningarrangements, and the hospital must provideongoing supplies. They ask if it can be provided aspart of a homecare scheme.

.? In the NHS, what is meant by ‘homecare’?What are the potential benefits of using such aservice?

Case discussion— Causes and symptoms of cystic fibrosisCystic fibrosis is an autosomal recessive, life-limiting disease caused by mutations in the cysticfibrosis transmembrane conductance regulator(CFTR) gene (discovered in 1989), which codes fora Cl� ion channel normally present in lungepithelial cells. More than 1900 mutations have sofar been found in the gene, but only a relativelysmall number of these mutations (so-called class I–V, with different biological outcomes) can accountfor most of the CF patients so far characterisedwith the condition. The most frequent mutation isa deletion of a phenylalanine amino acid residue atposition 508 (DF508) which results in misfolding of

the CFTR channel protein in the cell endoplasmicreticulum (ER), thus preventing it from beingtrafficked to the plasma membrane. The poorlyfunctioning CFTR channel in CF means that thereis an imbalance of chloride and subsequently wateracross the epithelial cell, leading to accumulationof thick mucus secretions at mucosal surfaces inthe lungs that are difficult to clear, and thereforeparticularly prone to bacterial infection andchronic inflammation. The CFTR mutations alsoaffect the exocrine functions of the pancreas,intestine, liver, bile duct, salivary and sweat glands.There has been extensive research in recent

years, with limited success, into the use of genetherapy for the treatment of CF, with delivery ofthe CFTR gene directly to the airways. Transfer ofgenes into the airway cells requires the use of avector, which may be viral (e.g. adenoviruses,adeno-associated viruses) or non-viral (e.g.liposomes).

Pharmacological treatment in CF: considerationin this case

— Pancreatic insufficiencyApproximately 90% of CF patients in northernEurope are pancreatic insufficient because of thereduction of pancreatic secretions, which leads topoor digestion of fats and malabsorption ofproteins and carbohydrates. Patients havesteatorrhoea (fatty stools), decreased absorption offat-soluble vitamins (A, D, E and K), malnutritionand failure to thrive, and therefore requirepancreatic enzyme supplementation. Creon 10 000is usually administered as delayed-release capsules,which contain enteric-coated microspheres ofporcine-derived lipases, proteases and amylases.The microspheres are enteric coated to prevent thebreakdown of the enzymes in the acidicenvironment of the stomach. It is taken with allmeals and fat-containing snacks. The capsulesshould be swallowed whole at the start of a mealand the microspheres not chewed to ensure thatadequate enzyme levels reach the duodenum. Foryoung children/babies, capsules can be opened andthe microspheres mixed with acidic fluid or softfood. This could be apple sauce or yoghurt or anyfruit juice with a pH <5.5, e.g. apple, orange orpineapple juice. If the granules are mixed with fluidor food it is important that they are takenimmediately and the mixture not stored, otherwisedissolution of the enteric coating may result. Theymust not be mixed with the food that requires

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chewing, because this can cause a sore mouth andput children off eating, as well as reducing efficacyas described previously. The number of capsulestaken varies from patient to patient, and the doseand strength are adjusted according to the patient’sfat intake, stool consistency/frequency and weight.Dieticians usually advise on the enzymereplacement therapy for each patient. High-strength preparations such as Pancrease HL andNutrizym 22 are not recommended because oftheir association with colonic strictures in children.However, no association was found with Creon25 000. It was also recommended that the totaldaily dose of lipase should not usually exceed10 000 units/kg.It follows that all pancreatic-insufficient patients

require supplementation with the fat-solublevitamins A, D and E. Dalivit is a liquidmultivitamin preparation (containing mainlyvitamins A, B2, C and D) available in the form ofdrops, and tocopheryl acetate (vitamin E acetate:the ester form of tocopherol) is a 100 mg/mLliquid formulation. Levels of vitamins A, D and Eare usually checked every year at the annual reviewand supplement doses amended accordingly.

— Gastro-oesophageal refluxMany CF patients also have gastro-oesophagealreflux which is believed to be due to thehyperacidic gastric secretions and relaxed loweroesophageal sphincter tone. Symptom relief isusually obtained with proton pump inhibitors(PPIs) ± prokinetics such as domperidone andlow-dose erythromycin. Long-term treatment isusually required.PPIs (e.g. omeprazole) and histamine H2-

receptor blockers (e.g. ranitidine) may also beprescribed as adjuvant therapy to enhance theeffect of pancreatic enzyme replacement therapy,because pancreatic enzymes are inactivated bygastric acid; therefore, by decreasing acidity, theenzyme efficacy is increased.

— Omeprazole: mode of administration andmolecular properties

Omeprazole may be administered to Charlotte as aMUPS (multiple unit pellet system) tabletformulation. The tablets may be dispersed in10 mL non-carbonated water and then suspendedin a small amount of any fruit juice with a pH <5,e.g. apple, orange or pineapple juice, or in applesauce or yoghurt after gentle mixing. Milk orcarbonated water must not be used. The dispersion

should be taken immediately or within 30 min. Thedispersion is stirred just before drinking and rinseddown with half a glass of water. It is important thatthe tablets should not be crushed or chewed.

The omeprazole MUPS tablets consist ofmultiple enteric-coated pellets. The polymericcoating is specifically designed to dissolve only inthe higher pH environment of the small intestine,hence the need to disperse the tablets in a slightlyacidic medium before administration. On reachingthe small intestine, the omeprazole (which itself isinactive) is absorbed into the systemic circulation,from where it reaches the highly acidic environmentof the parietal cells, undergoing a pH-dependentchemical rearrangement to its active form. Thisactivated intermediate reacts with the thiol (-SH)group of a cysteine residue present on the H+/K+

ATPase (the proton pump), covalently modifyingand permanently inactivating it. If the omeprazolewere not formulated with an enteric coating, thisrearrangement would occur in the contents of thestomach, which would prevent the drug from everbeing absorbed and reaching the parietal cells.

— Staphylococcus aureus infectionsLong-term prophylaxis against Staphylococcusaureus is prescribed in order to reduce thefrequency of infective exacerbations caused by thisorganism. The use of anti-staphylococcalprophylaxis from diagnosis until 3 years of age wasshown by a Cochrane review to be effective inreducing the incidence of infection with S. aureus,although an improvement in clinical outcomes wasnot shown. Current guidance is to start it in all CFchildren identified by newborn screening ordiagnosed clinically, unless there is a compellingreason not to, i.e. not tolerated, or allergy. Onceaged 3 years, flucloxacillin prophylaxis is reviewed.Although policies vary from institution toinstitution, an example of such a policy is tocontinue only if S. aureus is repeatedly cultured,i.e. more than two isolates of S. aureus in a year.Cephalosporins are generally not used for long-term prophylaxis for S. aureus because of worriesabout increased pseudomonas isolation in a US

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cephalexin trial and also evidence from theEuropean database.In the case of Charlotte, flucloxacillin is

administered as the 250 mg/5 mL preparation,taken on an empty stomach to maximiseabsorption. As prophylaxis it is administered twicedaily to facilitate compliance and to fit better withCharlotte’s school day.

— Nebulised colistinNebulised antibiotics are prescribed for patientswho are chronically colonised with P. aeruginosa(grown on three or more isolates in a year) or foreradication of first growth. Long-term nebulisedtherapy has been shown to reduce the frequencyof infective exacerbations and the need forintravenous anti-pseudomonal antibiotics, and toimprove lung function. The most frequently usednebulised antibiotics are colistin (colistimethatesodium) and tobramycin. It is currentlyrecommended that colistin be used initially inpatients chronically colonised with P. aeruginosa.Nebulised colistin achieves low systemic and highlocal concentrations in the lung, which makes itvery useful for long-term therapy, because patientsdo not have the adverse effects associated with theuse of these antibiotics administered intravenously.Patients must have a bronchoconstriction trial

before starting therapy to ensure that thenebulised antibiotic does not causebronchoconstriction. Colistin nebulisers should beadministered post-physiotherapy. This enhancestheir effects because physiotherapy has removedmuch of the sputum, enabling better penetrationto the site of action.

— SalbutamolSome patients with CF also have asthma (smallairway disease) and therefore benefit from the useof bronchodilators, such as salbutamol (b2-adrenoreceptor agonist). Before starting treatment,patients should undergo a bronchodilator trial inwhich their lung function is measured before andafter treatment. In patients who demonstrate animprovement, bronchodilator treatment isinitiated. Nebulised or pMDI bronchodilators arealso used by some patients before nebulisingantibiotics, in order to preventbronchoconstriction.

— Intravenous antibiotics in CF: spectrum ofactivity, dose and monitoring

Ceftazidime is a third-generation cephalosporinand so has greater activity against Gram-negative

bacteria, particularly P. aeruginosa, compared withsecond-generation cephalosporins. However, it isless active against Gram-positive bacteria such asS. aureus compared with the second-generationcephalosporins.Tobramycin is an aminoglycoside that is

bactericidal and active against some Gram-positiveorganisms, including S. aureus and many Gram-negative organisms, including P. aeruginosa.Tobramycin is the aminoglycoside of choicebecause there is evidence that it is lessnephrotoxic than other aminoglycosides inpatients with CF.Larger doses of many antibiotics are used in CF

due to altered pharmacokinetics, notably anincreased volume of distribution and increasedclearance (renal and non-renal). It is not fullyunderstood why this occurs. In addition, due tothe severity of the disease, high concentrations ofantibiotics are needed at the site of action.Both ceftazidime and tobramycin have an

increased clearance in CF, so the high dosesprescribed are appropriate (ceftazidime 50 mg/kgthree times daily and tobramycin 10 mg/kg oncedaily). There is evidence, from a randomisedcontrolled trial of once versus three times dailytobramycin (the TOPIC study), that once-dailytreatment is equally efficacious and associated withless nephrotoxicity in children, although the studyshowed no difference in ototoxicity between thetwo regimens. In addition, less money is spent onequipment such as needles and syringes and,importantly for the child with CF, fewer bloodtests are needed because only trough serum levelsneed to be monitored. It also saves on nursingtime for drug administration.The antibiotic therapy must be monitored to

ensure that it is effective and not causing adverseeffects. Temperature and clinical response (generalwellbeing, sputum production and lung function)should be monitored to check efficacy.In this case, Charlotte’s trough serum

tobramycin level should be measured 23 hoursafter administration of the second dose (i.e. shortlybefore the third dose), 48 hours after anyadjustment and weekly thereafter, aiming for atrough level <1 mg/L. This will preventnephrotoxicity or ototoxicity associated withelevated levels of aminoglycosides. Serum urea andcreatinine should be measured at the time of firstcannula insertion, and with each trough level.

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Charlotte’s liver function and blood countshould also be monitored as ceftazidime can causedisturbances in LFTs (liver function tests) andblood disorders such as leukopenia.

Allergic bronchopulmonary aspergillosis

ABPA is an immune-mediated disease causingbronchiectasis (destruction and widening of thelarge airways) induced by Aspergillus fumigatus,and is not uncommon in CF (occurring inapproximately 1–11% of patients). The typicalpresentation is wheezing, new pulmonaryinfiltrates on chest radiograph, a rise in serumtotal IgE and specific IgE to A. fumigatus, with afall in lung function.The mainstay of treatment is oral corticosteroid

therapy to attenuate the inflammatory process, butthis may need to be continued for several monthsand is associated with significant adverse effects.Treatment is with oral prednisolone: an exampleregimen of 2 mg/kg in the morning (non-entericcoated due to difficulty in absorption of enteric-coated preparations in CF patients as a result ofpancreatic insufficiency) for 2 weeks, then 1 mg/kgper day for 2 weeks, and then 1 mg/kg onalternate days for 2 weeks. If an improvement inclinical symptoms, lung function and radiologicalchanges has occurred, and when the IgE levels fallappropriately, prednisolone dose should be taperedto zero over the next 8–12 weeks.

Itraconazole

Itraconazole is used to reduce the antigenicburden of A. fumigatus in the respiratory tract.Studies of itraconazole, initially in an uncontrolledsetting in CF, and recently in randomised trials inadults with asthma and ABPA, have shownevidence of benefit, including the ability to reducesteroid dosage. It should be given for 3–6 months.

— Formulation, pharmacokinetics andmonitoring of oral itraconazole preparations

Itraconazole is a water-insoluble, hydrophobicdrug with a log P value of 5.66. The poor solubilityresults in poor bioavailability, particularly from asolid dosage form, because the drug tends to passthrough the GI tract without dissolving, ultimatelybeing eliminated in the faeces. As a weakly basicdrug, however, dissolution is improved somewhatin acidic conditions. Once in solution, theproportion of drug in the deprotonated(unionised) form can be readily absorbed into

systemic circulation. Dissolution and absorptionare enhanced in the case of the capsules byforming a solid dispersion of the drug in therapidly dissolving polymer, hydroxypropylmethylcellulose (HPMC, hypromellose) coated onto sugar spheres. As dissolution requires an acidicenvironment for dissolution, acid-reducingtherapies should be stopped wherever possibleand, if not possible, administered at opposite endsof the day to minimise the effects on absorption.Bioavailability from solid dosage forms isapproximately 30%, but, if taken with food,bioavailability is increased to about 55%.Bioavailability is greater from the liquid

preparation, which is formulated in cyclodextrin asa solution. Cyclodextrins are cyclicoligosaccharides comprising six (a-cyclodextrin),seven (b-cyclodextrin) or eight (g-cyclodextrin)glucopyranose units. They have a ‘bucket-like’structure with a hydrophilic outer surface and ahydrophobic cavity that can accept a hydrophobicdrug molecule, forming an inclusion complex andbringing the drug into solution.The liquid preparation is much better absorbed,

with a bioavailability >70%. However, it isunpalatable and must be taken on an emptystomach. Liver function tests should be monitoredat least after 1–2 months, particularly if there is ahistory of liver dysfunction. ABPA markers willmonitor the progress of the disease, e.g. IgE andAspergillus fumigatus RAST, as well as clinicalsymptoms, e.g. wheeze, lung function and generalwellbeing. Itraconazole levels should also beconsidered when there is a lack of clinicalresponse, or if there is concern about adequatedrug absorption or patient compliance.

DNase (dornase alfa)

Patients with CF have thick tenacious sputum, theretention of which contributes to infectiveexacerbations and reduced pulmonary function.The thick secretions contain a high concentrationof extracellular DNA released by degeneratingleukocytes, which accumulate in response toinfection and add to the viscosity of the secretions.DNase (recombinant human DNase or rhDNase,Pulmozyme) is a genetically engineered version ofthe naturally occurring enzyme that cleavesextracellular DNA in the sputum; therefore itreduces its viscosity and aids sputum removal.DNase should be administered 1 hour pre-physiotherapy. DNase should be administered only

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using a jet nebuliser. Ultrasonic nebulisers are notsuitable because they may generate heat within thefluid being nebulised, resulting in the degradationof this biopharmaceutical, and indeed others.

Homecare

Homecare medicine delivery and services can bedescribed as a facility that delivers ongoingmedicines supplies and, where necessary,associated care, initiated by the hospital prescriber,direct to the patient’s home with their consent.Operating as a registered pharmacy, the homecareprovider dispenses against the prescriptionprovided by the hospital (with it effectively being aprivate prescription) for supply to the namepatient. Patients that are typically on homecare arethose with chronic diseases, such as cystic fibrosis,and stable regimens that do not require acute careinput for each supply.The benefits of using homecare for a medicine

such as DNase is that it minimises theinconvenience of patients having to attendoutpatient and day care appointments to receiveongoing supplies, thereby releasing appointmentslots for other people and increasing efficiency.There is also an opportunity to improve adherenceto treatment through regular contact with, andeducation of, patients. Homecare providers willoften be in direct contact with the pataient, andare ideally placed through checking stocks toidentify concerns with stockpiling, which can bebrought to the attention of the prescribing team tohighlight non-adherence and minimise wastage.Equally, the patient has an addtional point ofcontact in case of difficulties which can becommunicated, via the homecare provider, to theprescribing team.

— Medicines management in the homeIn addition to shared care between healthprofessionals in the different healthcare sectors,care in the home will be shared between children/young people and their parents/carers. Many CFpatients are young. Managing the medication forCF on a daily basis can be a complex task.However, as this is a life-long condition manyparents become ‘experts’ in its management, ableto judge symptoms and respond appropriately.However, parents and young people will varygreatly in their confidence in making decisions.Appropriate use of medicines and good

adherence are important for daily wellbeing and

longer-term outcomes. Managing medication canbe stressful for families. Optimal clinical outcomesdepend on optimal use of a wide range ofmedications: pancreatic enzymes, antibiotics,steroids, vitamins, inhalational therapies.Medicines management activities and ensuringgood adherence can be a significant burden foryoung people and their parents/carers and, whenproblems and concerns arise, these can bestressful. Shared-care protocols can presentadditional challenges for parents/carers becauseformal care is shared between specialists andnon-specialists (whose knowledge will be variableand between whom communication can be poor).This can lead to potential inconsistencies in adviceand uncertainties for young people and parentswith regard to optimal use of medicines.

EXTENDED LEARNING

. Describe recent developments in genetherapy for cystic fibrosis. What are thebarriers to successful gene therapy?

. What are biopharmaceuticals? How arethey manufactured and formulated intodosage forms? What particular stabilityproblems may they present?

. Liposome delivery of gene therapy is oneexample of the use of ‘nanotechnology’ inmedicines. What other nano-sized systemshave pharmaceutical applications and whatbenefits do they confer over conventionaldrug delivery approaches?

. What strategies can formulators employ toenhance the solubility of a drug?

ADDITIONAL PRACTICE POINT

. Consider the particular needs of youngpeople with CF, as they becomeincreasingly responsible for their ownmedication.

References and further readingHanrahan JW, Sampson HM, Thomas DY (2013). Novelpharmacological strategies to treat cystic fibrosis. TrendsPharmacol Sci 34:119–25.

Prickett M, Jain M (2013). Gene therapy in cystic fibrosis.Transl Res 161:255–64.

Ryan, G, Mukhopadhyay S, Singh M (2003). Nebulisedanti-pseudomonal antibiotics for cystic fibrosis. CochraneDatabase System Rev 3:CD001021.

Smyth A, Tan KH, Hyman-Taylor P et al. (2005). Once versusthree-times daily regimens of tobramycin treatment for

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pulmonary exacerbations of cystic fibrosis – the TOPICstudy: a randomised controlled trial. Lancet 365:573–8.

Smyth A, Walters S. (2003). Prophylactic antibiotics for cysticfibrosis. Cochrane Database System Rev 3:CD001912.

Stevens DA, Moss RB, Kurup VP et al. (2003) Allergicbronchopulmonary aspergillosis in cystic fibrosis–state of theart: Cystic Fibrosis Foundation Consensus Conference. ClinInfect Dis 37(Suppl 3):S225–64.

UK Cystic Fibrosis Trust Antibiotic Working Group (2009).Antibiotic Treatment for Cystic Fibrosis, 3rd edn. Bromley:Cystic Fibrosis Trust.

Wark PAB, Gibson PG, Wilson AJ (2004) Azoles for allergicbronchopulmonary aspergillosis associated with asthma.Cochrane Database System Rev 3:CD001108.

Case 5CoughKATIE GREENWOOD

LEARNING OUTCOMES

At the end of this case you will be able to:

. Outline the pathophysiology, signs,symptoms and diagnosis of different typesof cough

. Discuss treatment options for the differenttypes of cough

. Outline the chemistry and mechanism ofaction of expectorants

. Outline the chemistry and mechanism ofaction of opiate antitussives

. Know when to refer a patient with a coughto another healthcare professional

. Effectively question a patient to helpdetermine a diagnosis

Case studyJohn, a 17-year-old student who is one of yourregular patient’s teenage sons, calls into yourpharmacy on the way to college. He has anirritating cough and would like some medicine ‘tostop him coughing’ so that he can concentrate onhis revision and exams. He looks tired and fed up.You notice that John smells of cigarette smoke.

.? What questions would you ask the patient?John explains that he has had the cough for abouta week, following a cold. He does not take anyother medicines and does not have any medicalconditions.

.? What is a cough? Explain the pathophysiology

.? What are the different types of cough and howwould you differentiate between the differenttypes?

You determine that John has a non-productivecough; he has no phlegm and feels that he has anirritation at the back of his throat.

.? What are the treatments available for thedifferent types of cough?

.? Would there be any restrictions on theproducts that you could sell due to the patient’sage?

.? What lifestyle advice, if any, would you provide?

Case discussionA cough is the most common symptom of upperrespiratory tract infection. It may linger after theinfection has gone, because the swelling andirritation in the airways can take a while to settledown. The cough can take up to 3 weeks to gocompletely.

— Pathophysiology of a coughCoughing is a reflex action initiated by stimulationof sensory nerves in the lining of the respiratorypassages. The cough reflex is a vital part of thebody’s defence mechanisms. Normally, the lungsand the lower respiratory passages are sterile.Coughing usually means that there is something inthe respiratory passages that should not be there.This can be caused either by breathing in air-borne dust particles or if a piece of food has gonedown the ‘wrong way’. If dust or dirt gets into thelungs, it could become a breeding ground forbacteria and cause pneumonia or infection in theairways. It could also be a sign that an infection inthe lungs is causing the respiratory passages toproduce phlegm.

— Mechanism of cough productionMechano- and chemosensitive cough receptors(afferent sensory nerve fibres) in the epithelial

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layer of the pharynx and trachea are fired by thestimuli of excessive mucus or perceived foreignbody or irritant (tussigenic) chemical stimulus, andimpulses are transmitted to the cough centre inthe medulla oblongata of the brain stem via vagalafferent nerve fibres. Impulses are sent back, viaefferent neurons, to respiratory muscles of thediaphragm, chest wall and abdomen; thesecontract, producing a deep inspiration followed bya forced expiration of air, forcing open the glottisand producing a cough.

— Classification of coughs: signs, symptoms andcauses

There are two classifications of cough:

. Productive: producing sputum

. Non-productive: dry, with no sputum.

Coughs can further be classified as acute orchronic. This is dependent on their duration andfrequency. Acute coughs last <3 weeks, whereaschronic coughs last >8 weeks. Coughs between 3and 8 weeks’ duration are classified as subacute.

Productive cough: a productive, chesty cough, isone in which sputum/phlegm is coughed up. Theoversecretion of sputum causes the cough. Theappearance of the sputum can often help indicatethe underlying cause of the cough: clear or whitesputum is usually of little significance; pink/frothysputum may indicate congestive heart failure,because the blood has congested in the lungs andthere has been a leakage of plasma into the airpockets. Coloured sputum can indicate a bacterialinfection and lower respiratory tract infection,such as bronchitis or pneumonia, where thesputum is yellow, green, rust coloured (particularlyin pneumonia) and/or foul smelling, and thicker.However, it may just represent cell debris beingcleared from the air passages. Blood might bepresent: this is not always a serious sign becausecapillaries can burst due to violent coughing, but itcan be an indication for referral because it mightalso indicate a pulmonary embolism, tuberculosis(TB), bronchitis or lung cancer. The yellow tingein allergic cough sputum, as can be seen inasthma, is caused by the presence of largequantities of eosinophils from the blood as part ofthe allergic response.

Non-productive cough: a non-productive coughmay be described as dry, tickly or irritating. Itproduces no sputum and generally is unlikely tobe bacterial, although this should be consideredalong with other symptoms. Non-productive

coughs are irritating to the patient and also tothose around them, so the treatment is to try tosuppress the cough. A non-productive cough isusually the result of a viral infection, smoking or adry environment. However, it can also indicateasthma (especially if at night) or lung cancer, ormay be due to ongoing medication, e.g. ACEinhibitors.A cough can be caused by:

. Viral cough associated with a cold (tends to bedry and lasts 7–10 days)

. Postnasal drip

. Allergies

. Croup: viral in origin, affects children aged 9–18 months; barking cough. Occurs commonlyin the middle of the night, treated with steaminhalation or referral

. Chronic bronchitis (coughing up mucus onmost days for more than 3 months for 2 years)associated with smoking and cough worse onwaking

. Asthma can present as just a non-productivecough, especially in young children.

A cough can also be provoked by:

. Smoking

. Sucking material into the airways from themouth

. Gastro-oesophageal reflux

. Medicines, in particular ACE inhibitors used totreat hypertension and heart failure. Cough maydevelop within days of starting the course ofmedicine, or after a few weeks or months. ACEinhibitors, in addition to their main therapeuticeffects on the angiotensin production system,inhibit the breakdown of bradykinin and otherkinins in the lungs and this triggers thecharacteristic coughing side effect that is dry,non-productive in type and, in some patients,sufficiently irritating and persistent to warrant aswitch in therapy to angiotensin receptorantagonists

. Damage to the nerves that supply the vocalfolds (known as vocal fold palsy) and chroniccough can occur.

Rarely, coughing can be provoked by:

. Psychological illness

. Heart failure

. TB

. Pneumonia

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. Carcinoma of the lung.

— Differential diagnosisA cough with no serious underlying cause will beself-limiting; however, to confirm this, the patienthas to be questioned to ensure that all the relevantinformation is elicited. Various acronyms can beused as an aide memoire for this questioningprocess, e.g. WWHAM questions:

Who is the patient?What are the symptoms?How long have the symptoms been present?Action that has been taken to date?Medication already being taken?

Other useful pharmacy mnemonics includeASMETHOD, ENCORE and SIT DOWN SIR: Forfurther details see: www.resourcepharm.com/pre-reg-pharmacist/pharmacy-mnemonics.htmlIn practice, often a combination or selected

questions from these are used depending on thepatient’s presentation. It is important that youdetermine the age of the patient, the duration ofthe cough, whether it is dry or productive and, ifproductive, the appearance of the sputum. Anyassociated symptoms such as a cold, or shortnessof breath, should be established. The previoushistory relating to the cough and whether thepatient has other medical conditions andmedicines should also be established.

— Treatments available for the different types ofcough

If in doubt about phlegm production, it is best toregard a cough as productive.Productive coughs: treatment of a productivecough involves encouraging the removal of thesputum and therefore should be treated with anexpectorant cough mixture to help loosen thephlegm and make it easier to cough up from theairways. Expectorants contain ingredients such asguaifenesin (a glycerol derivative), ipecacuanha(derived from the dried root of the Brazilianipecacuanha plant) and ammonium citrate/chloride or sodium citrate. Two mechanisms ofaction have been suggested: stimulating bronchialmucus secretion making sputum less viscous, orirritation of the GI tract which subsequentlyaffects the respiratory tract, the former being moreprobable.Non-productive coughs: these are irritating to thepatient and those around them, so the treatment isa cough suppressant to reduce the cough reflex.

Cough suppressants include opiates such ascodeine, pholcodine, and dextromethorphan.

— Chemical properties and actions of opiateantitussives

Codeine, pholcodine and dextromethorphan are allexamples of opioid receptor agonists and are allstructurally related to the principal opium alkaloidmorphine. Each contains a polycyclic four- or five-ring system, which includes a six-membered,nitrogen-containing, aliphatic heterocycle. Thenitrogen atom in each is therefore part of a basic,tertiary amino group. Codeine is a naturallyoccurring analogue of morphine, being methylatedat the phenolic hydroxyl group to produce amethyl ether. In pholcodine, a synthetic analogue,the methyl group of the ether is replaced by anextended chain with a morpholine ring at the end,which gives the drug an additional basic centre.The configuration of the ring system indextromethorphan is opposite to that found incodeine and pholcodine; this can clearly be seenwhen comparing the structures in the diagrambecause the ring systems are almost mirror imagesof each other (opposite relative configurations ateach chiral centre).

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Opiate antitussives exert their effects centrallyby acting primarily on m- and k-type (G-protein-coupled) opioid receptors present on relayneurons in the brain-stem medullary cough centre(in or around the nucleus tractus solitarius [NTS])to inhibit neuronal firing and excitability; they dothis through inhibition of excitatory (glutamate)neurotransmitter release and by openingpostsynaptic neuronal G-protein, inwardlyrectifying K+ (GIRK) channels. The involvement ofd-opioid receptors in the antitussive action is,however, debatable.Other treatments: demulcents, e.g. simple linctusand glycerin, lemon and honey linctus, coat andsoothe the back of the throat. Antihistamines, e.g.diphenhydramine and promethazine, reduce thecough reflex and also dry up nasal secretions,which can be useful for coughs that are caused bya postnasal drip (mucus running down the back ofthe throat) or associated with a cold. Some coughremedies also contain sympathomimetics, such aspseudoephedrine, for their airway-relaxing anddecongestant effects, and can be useful if thepatient has a blocked nose as well as a cough. Apractical consideration for patients with diabetes isthat the cough medicine be sugar free.It should be noted that there is limited

scientific evidence that cough remedies areeffective, although some contain ingredients suchas paracetamol which reduce pain or fever. Thus,with the exception of antitussives, cough remedieshave for many years not been prescribable on theNHS. However, some patients believe that they getsome relief and the products are not consideredharmful (Schroeder and Fahey, 2002).There have been questions asked as to whether

pharmacists should promote or recommendproducts with such a doubtful evidence base.

Legal restrictions on the sale of cough medicines

— CodeineA UK review of scientific evidence has concludedthat the risks associated with OTC oral liquidcough medicines containing codeine outweigh thebenefits in children and young people aged <18years. Consequently, OTC oral liquid medicinescontaining codeine should not be used to treatcough in children and young people aged <18years (Medicines and Healthcare productsRegulatory Agency [MHRA], 2010).

— OTC cough and cold medicines for childrenThe Commission on Human Medicines (CHM)has advised on a package of measures to improvesafe use of cough and cold medicines for childrenaged <12 years. The advice is that parents andcarers should no longer use OTC cough and coldmedicines in children aged <6 years: there is noevidence that they work, and they can cause sideeffects, such as allergic reactions, effects on sleepor hallucinations (MHRA, 2009).

WHEN TO REFER

. Coughing up phlegm that is green, rustybrown, yellow, blood-stained or foulsmelling

. Chest pain

. Shortness of breath or wheezing

. Pain and swelling in the calf (deep veinthrombosis)

. Recurrent night-time cough (asthma)

. Whooping cough or croup

. Worsening smoker’s cough

. Sudden weight loss

. Fever and sweating

. Hoarseness of the voice with a chroniccough that doesn’t clear up spontaneously.

— Lifestyle advice in this casePharmacists have a major role to play in thegovernment’s public health agenda. The smell ofcigarette smoke should lead to a conversation withJohn about the benefits of smoking cessation andthe products available. Smoking will exacerbatethe cough and therefore, even if the patient doesnot want to stop smoking, he or she should beencouraged to limit the number of cigarettessmoked because this will help to resolve thecough.

EXTENDED LEARNING

. What are the respective roles of theMHRA/EMA (European MedicinesAgency) and CHM/CHMP (Committee forMedicinal Products for Human Use) inmedicines regulation and guidance forhealth professionals?

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References and further readingBlenkinsopp A, Paxton P, Blenkinsoppp J (2009). Symptoms in

the Pharmacy, 6th edn. London: Wiley- Blackwell.Edwards C, Stillman P (2006 ). Minor Illness or Major Disease?,4th edn. London: Royal Pharmaceutical Press.

Medicines and Healthcare products Regulatory Agency (2009).Cough and Colds in Children. London: MHRA. Available at:www.mhra.gov.uk/Safetyinformation/Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/CON038908(accessed 3 August 2012).

Medicines and Healthcare products Regulatory Agency (2010).Codeine. London: MHRA. Available at: www.mhra.gov.uk/SearchHelp/GoogleSearch/index.htm?q=codeine%20over-the-counter%20products (accessed 3 August 2012).

Nathan A (2012). Managing Symptoms in the Pharmacy, 2ndedn. London: Pharmaceutical Press.

Rutter P (2009). Community Pharmacy: Symptoms, Diagnosisand Treatment, 2nd edn. London: Churchill Livingstone.

Schroeder K, Fahey T (2002). Systematic review of randomisedcontrolled trials of over the counter cough medicines foracute cough in adults. BMJ 324:329–31.

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