Contents Contents

Foreword by Catherine Duggan " vii 3 Nebulised therapy for chronic obstructive " Acknowledgements " viii pulmonary disease 97 4 Paediatric cystic fibrosis " 101 About the editors " ix 5 Cough " 108 List of contributors " x Abbreviations " xiii 4 Central nervous system cases " 113 Introduction " xvii INTRODUCTION " 113 1 Types of anxiety, their treatment and 1 Gastrointestinal, liver and renal associated issues " 116 cases " 1 2 Treatment options in schizophrenia – ff " INTRODUCTION " 1 antipsychotics and side e ects 118 " 1 Uninvestigated dyspepsia " 3 3 Bipolar disorder and its treatment 122 2Inflammatory bowel disease " 7 4 Treatment-resistant depression in a patient " 3 Treatment of threadworm " 10 on haemodialysis 124 ’ 4 Liver disease in an elderly patient " 13 5 Self-medication of depression with St John s " 5 Alcoholic liver cirrhosis " 15 wort, a herbal remedy 128 6 Liver disease with ascites " 19 6 Extemporaneous preparation of 7 Management of paracetamol overdose with methadone " 131 " acetylcysteine " 22 7 Neuropathic pain 134 ff 8 Chronic kidney disease " 26 8Dierential indicators for migraine and " 9 Haemofiltration " 31 medication-overuse headache 138 " 10 Renal replacement therapy " 35 9 Epilepsy 142 10 Phenytoin and acute therapeutics " 146 11 Drug therapy of Parkinson’s disease " 149 2 Cardiovascular cases " 39 12 Smoking cessation in community " INTRODUCTION " 39 pharmacy 153 1 Atrial fibrillation " 43 13 Dementia/Alzheimer’s disease " 159 2 Angina management " 49 14 Dementia and its pharmacotherapy " 163 3 Heart failure " 52 4 Acute coronary syndromes " 56 5 Infections cases " 169 5 Management of hypertension in black " patients " 61 INTRODUCTION 169 6 Cardiovascular (blood pressure) support in 1 Cellulitis and MRSA " 173 " an elderly hypotensive patient " 66 2 Typhoid 178 " 7 Deep vein thrombosis and warfarin " 70 3 Community-acquired pneumonia 183 " 8 Treatment of acute ischaemic stroke " 75 4 Urinary tract infection 187 9 Secondary stroke prevention " 78 5 Uncomplicated genital Chlamydia " 10 Drug interactions " 82 trachomatis infection 189 6 Surgical antibiotic prophylaxis " 193 7 Diarrhoea and antibiotic treatment " 196 3 Respiratory cases " 87 8 ‘Fever with no focus’ in a young infant " 198 INTRODUCTION " 87 9 Management of tuberculosis and its 1 Asthma " 89 complications " 202 2 Treating an acute severe asthma — [continued over] exacerbation " 93 v

Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 10 Management of latent TB infection and 2 Approaches to the effective treatment of pharmacy interventions " 205 non-specific, low back pain " 314 11 Influenza " 207 3 DMARDs and treatment for rheumatoid Contents 12 Chronic hepatitis C " 210 arthritis " 317 13 Primary HIV Infection " 215 4 Glucosamine supplements for osteoarthritis 14 Immunisations against infectious diseases and joint stiffness " 324 and malaria chemoprophylaxis " 221 5 Treating juvenile idiopathic arthritis in young people " 327 6 Systemic lupus erythematosus " 331 6 Endocrinology cases " 225 INTRODUCTION " 225 " 1 Insulin pump use in a child " 228 9 Eye, nose and throat cases 335 2 Hypoglycaemia during insulin therapy " 232 INTRODUCTION " 335 3 Type 2 diabetes mellitus " 235 1 Conjunctivitis in pregnancy " 337 4 Serious lactic acidosis induced by 2 Chronic open-angle glaucoma " 341 metformin " 239 3 Wet age-related macular degeneration " 345 5 An unusual case of Cushing’s 4 Sore throat " 348 syndrome " 242 5 Hay fever " 352 6 Addisonian crisis " 248 7 Hypothyroidism " 254 " 8 Osteoporosis in a younger woman " 258 10 Skin cases 357 9 Osteoporosis in an elderly woman " 262 INTRODUCTION " 357 10 Treatment for Hypercalcaemia " 266 1 Atopic eczema " 359 2 Contact dermatitis " 363 3 Management of an acute flare of 7 Malignant disease, psoriasis " 366 immunosuppression and haematology 4 Acne " 369 cases " 271 5 Antibacterial treatment of acne in young INTRODUCTION " 271 people " 372 1 Lung cancer " 274 6 Fungal infection of the foot " 376 2 The use of antimetabolites in the treatment 7 Treatment of head lice " 380 of breast cancer " 278 3 Clinical verification of prescriptions for oral " anticancer medicines " 282 11 Special cases 383 4 Thromboprophylaxis in a patient undergoing INTRODUCTION " 383 surgery for cancer " 287 1 Paediatric pharmacokinetics in a newborn 5 Febrile neutropenia in paediatric preterm infant " 385 oncology " 291 2 Falls and care of elderly people " 389 6 Managing chemotherapy-induced nausea and 3 Treating a patient with benign prostatic vomiting in a patient with lung cancer " 295 hyperplasia " 396 7 Drug therapy of multiple sclerosis " 299 4 Pain management using strong opiates in 8 Management of vaso-occlusive crisis in sickle palliative care " 399 cell disease " 304 5 Human papillomavirus and cervical cancer " 404 6 Black cohosh for menopausal 8 Musculoskeletal and joint disease symptoms " 406 cases " 309 Index " 411 INTRODUCTION " 309 1 Gout " 311 vi

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

BOTHAINA B JERAGH ALHADDAD, BSc, MSc, PhD | Assistant MEE-ONN CHAI, MSc, DipClinPharm, BPharm | Clinical – ’ List of contributors Professor and Lecturer in Clinical Pharmacy, Department of Pharmacist, Team Leader Renal Services, King s College Pharmaceutical Sciences, Public Authority for Applied Hospital NHS Foundation, London, UK Education and Training, Shwaikh, Kuwait BARBARA CLARK, MPharm(Hons), GPhC, ClinDip | Lead Clinical FATEMAH MOHAMMAD ALSALEH, BPharm, MSc, PhD | Assistant Pharmacist, London Bridge Hospital; Chair UKCPA Professor, Department of Pharmacy Practice, Faculty of Haemostasis, Anticoagulation and Thrombosis (HAT) Pharmacy, Kuwait University, Kuwait Group, London, UK SOTIRIS ANTONIOU, MRPharmS, MSc, DipMgt | Independent JESSICA CLEMENTS, MPharm, CertPharm Pract, DipPharmPract, prescriber; Consultant Pharmacist, Cardiovascular Medicine, Cert Independent prescribing practice | Highly Specialised Bart’s Health NHS Trust, London, UK Pharmacist HIV at Medway Maritime Hospital, Gillingham, ANA ARMSTRONG, BPharm, PgDipClinPharm | Lead Pharmacist, Kent, UK Medical Division, Surrey and Sussex Healthcare NHS Trust, LOUISE COGAN, BSc, MRPharmS, PgDipFHEA | Teacher UK Practitioner, University of Central Lancashire, Preston, NELA RONČEVIĆ ASHTON, BSc, PgDip | Clinical Tutor, School of Lancashire, UK Pharmacy and Biomedical Sciences, University of Central ANDREW CONSTANTI, BSc, PhD, FBPharmacolS | Reader in Lancashire; Advanced Primary Care Pharmacist, Cumbria Pharmacology, UCL School of Pharmacy, London, UK and Lancashire Clinical Support Unit, UK SHANI CORB, MRPharmS, MSc | Independent prescriber; Lead ZOE ASLANPOUR, BPharm, PhD | Member of UKPHR, FRSPH, Pharmacist, Paediatric Oncology, Royal Alexandra Children’s Head of Pharmacy and Public Health Practice, University of Hospital, BSUH NHS Trust, Brighton, Sussex, UK Hertfordshire; Consultant in Public Health, NHS JOYETA DAS, MPharm, DipClinPharm | Independent prescriber; Bedfordshire, UK Lead Pharmacist, Hepatology, Imperial College London NHS PAUL BAINS, DipClinPharm, MRPharmS | Independent Trust, London, UK prescriber; Senior Lead Pharmacist for Medicine, Imperial HALA M FADDA, MPharm, PhD | Assistant Professor, College of College Healthcare NHS Trust, Pharmacy Department, Pharmacy and Health Sciences, Butler University, Hammersmith Hospital, London, UK Indianapolis, IN, USA JOANNE BARTLETT, BPharm, ClinDipPharm | Specialist Clinical JOSEPHINE FOLASADE FALADE, BPharm, MSc, FHEA | Highly Pharmacist, End of Life Care, John Taylor Hospice, Specialist Pharmacist, Bart’s Health NHS Trust; Clinical Birmingham, UK Lecturer, UCL School of Pharmacy, London, UK GORDON BECKET, BPharm, PhD, MRPharmS, MRSC, FNZCP SALLY-ANNE FRANCIS, BPharm, PhD, MRPharmS, FHEA | Professor of Pharmacy Practice, School of Pharmacy and | Honorary Senior Lecturer, UCL School of Pharmacy, Biomedical Sciences, University of Central Lancashire, London, UK Preston, Lancashire, UK CLAIRE GOLIGHTLY, MPharm ClinDipHosp, PGCertEd SIÂN BENTLEY, BPharm, MRPharmS, DipClinPharm | Specialist | Lecturer in Professional Practice, Bradford School of Pharmacist, Paediatrics, Royal Brompton and Harefield NHS Pharmacy, University of Bradford, Bradford, UK Foundation Trust, London, UK LARRY GOODYER, PhD, MRPharmS, FFTMRCPS(Glas), FRGS RANIA BETMOUNI, BPharm, DipClinPharm | Independent | Professor, Head of the Leicester School of Pharmacy, prescriber; MSc Quality and Safety in Healthcare, Clinical Faculty of Health and Life Sciences, De Montfort University, Pharmacist – BUPA Cromwell Hospital, London, UK Leicester, UK ANNETT BLOCHBERGER, DipClinPharm | Independent prescriber; NICOLA J GRAY, BSc, PhD, MRPharmS, FHEA, FSAHM(US) Lead Pharmacist, Neurosciences, St George’s NHS | Independent pharmacist researcher; Director, Green Line Healthcare Trust, London, UK Consulting Limited, Manchester, UK LISA BOATENG, BSc, MSc, MRPharmS, Certificate in Clinical KATIE GREENWOOD, MRPharmS, PGCertTLHE, FHEA Pharmacy | Independent prescriber; Highly Specialised | Lecturer in Pharmacy Practice, Placement Co-ordinator and Pharmacist, Antimicrobials and Infection Control, London, Pre-Registration Facilitator, School of Pharmacy and UK Biomedical Sciences, University of Central Lancashire, MARK BORTHWICK, MPharmS, MSc | Consultant Pharmacist, Preston, Lancashire, UK Critical Care, John Radcliffe Hospital, Oxford University ELIZABETH HACKETT, BSc, MSc | Independent prescriber; Hospitals NHS Trust, Oxford, UK Principal Pharmacist for Diabetes, University Hospitals SIMONE BRACKENBOROUGH, BSc, DipClinPharm | Independent Leicester, Leicester, UK prescriber; Senior Lead Pharmacist for Medicine at Imperial DELYTH HIGMAN JAMES, PhD, MSc, BPharm, MRPharmS, College Hospitals NHS Trust (St Mary’s Hospital Site), AMBPsS, FHEA | Senior Lecturer, Programme Director, MSc London, UK in Pharmacy Clinical Practice (Community and Primary NADIA BUKHARI, BPharm, MRPharmS, PgDipFHEA | Clinical Care), Cardiff, South Wales, UK Lecturer, MPharm Student Support Manager & Pre Registration Coordinator, UCL School of Pharmacy, London, x UK

Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 TIM HILLS, MRPharmS, DipClin | Independent prescriber; Lead CARL MARTIN, PhD, GPhC registrant, MRPharmS, PGCHE Pharmacist Antimicrobials and Infection Control, | Senior Clinical Teacher, Department of Practice and Policy, Nottingham University Hospitals NHS Trust, Nottingham, UCL School of Pharmacy, London, UK UK JAYMI MISTRY, MPharm, DipGPP | Highly Specialist Pharmacist STEPHEN HUGHES, MPharm | Specialist Renal Pharmacist, – Acute Medicine (general medicine) and Medicines Safety, Central Manchester Foundation Trust, Manchester, UK London, UK LYNN HUMPHREY, BPharm, DipPharmPrac, IPP | Senior Lead SANDEEP SINGH NIJJER, MPharm, MBA, GPhC | Pharmacist, UK Pharmacist – Cardiovascular, Imperial College Healthcare LELLY OBOH, BPharm, DipClinPharm | Independent prescriber; List of contributors NHS Trust, London, UK Consultant Pharmacist, Care of Older People, Guy’s and St ANDY HUSBAND, DProf, MSc, BPharm, MRPharmS | Dean of Thomas’ Community Health Services, London, UK Pharmacy, Durham University, Durham, UK JIGNESH PATEL, PhD, MRPharmS | Clinical Senior Lecturer/ MATTHEW D JONES, MPharm, PhD, MRPharmS | Senior Honorary Consultant Pharmacist, Anticoagulation, King’s Pharmacist – Medicines Information, Royal United Hospital College London/King’s College Hospital, London, UK Bath NHS Trust, Bath, UK NEIL POWELL, MPharm, ClinDip, MRPharmS | Antibiotic and SARAH C JONES, MPharm, MSc, MRPharmS | Locality Lead HIV Pharmacist, Royal Cornwall Hospital Trust, Truro, UK Pharmacist, Avon and Wiltshire Mental Health Partnership ANNA PRYOR, MPharm, MRPharmS | Lead Pharmacist, A&E NHS Trust, Bath, UK and Admissions, Imperial College Healthcare NHS Trust (St NAVEED IQBAL, MPharm, PGClinDip, MSc | Teaching Fellow, Mary’s site), London, UK Aston University; Prescribing Support Pharmacist for NHS, GEMMA QUINN, PGDip, MRPharmS | Course Director MSc Birmingham Cross City CCG; community pharmacist Clinical Pharmacy (Hospital) and MPharm Stage Tutor KUMUD KANTILAL, BSc(Pharm), DipPharmPract, Postgraduate (Stage 4), University of Bradford, Bradford, UK award in clinical oncology | Macmillan Principal Pharmacist, TIMOTHY RENNIE, MPharm, PhD | Head of School of Pharmacy Lead for Cancer Education and Training, Guy’s and St (Associate Dean), University of Namibia, Namibia, Africa Thomas’ NHS Foundation Trust, London, UK IAN ROWLANDS, MRPharmS, DipClinPharm | Independent NAZANIN KHORSHIDI, MPharm, PGDip | Highly Specialist prescriber; Lead Pharmacist Stroke Services, Imperial College Pharmacist; Orthopaedics and Plastics at Guy’s and St Healthcare NHS Trust, London, UK Thomas’ NHS Foundation Trust, London, UK IMOGEN SAVAGE, BPharm, PhD, MRPharmS | Senior Lecturer STEPHANIE KIRSCHKE, PhD | Senior Lead Pharmacist (retired), UCL School of Pharmacy, London, UK Haematology, Imperial College Healthcare NHS Trust, JENNY SCOTT, BSc, PhD, MRPharmS | Independent prescriber; London, UK Senior Lecturer in Pharmacy Practice, University of Bath, ROGER DAVID KNAGGS, BSc, BMedSci, PhD, MRPharmS Bath, UK | Associate Professor in Clinical Pharmacy Practice, LOUISE SEAGER, BPharm, ClinDipPharm, MRPharmS | Senior University of Nottingham; Advanced Pharmacy Practitioner Specialist Clinical Pharmacist End of Life Care, John Taylor – Pain Management, Nottingham University Hospitals NHS Hospice, Birmingham, UK Trust, Nottingham, UK RITA SHAH, BPharm, MRPharmS, MSc | Senior Clinical SARAH KNIGHTON, MPharm, MPharmS | Independent Pharmacist, Critical Care, King’s College Hospital NHS prescriber; Clinical Pharmacy Team Leader, Liver and Private Foundation Trust, London, UK Patient Services, King’s College Hospital NHS Foundation KATE SHARDLOW, MBBS, BPharm, MRCGP | GP and speciality Trust, London, UK doctor in genitourinary medicine, Chelmsford, Essex, UK ROMAN LANDOWSKI, BSc(Pharm), DipClinPharm | Ward NEELAM SHARMA, BA, PGCert Psychiatric Therapeutics Pharmacist, Maternity Care Unit, University College | Registered Pharmacy Technician, Chief Pharmacy Hospital, London, UK Technician, Medicines Management and E&T, South London JEREMY LEVY, MBBChir, PhD, FHEA, FRCP | Consultant and Maudsley NHS Foundation Trust, London, UK Nephrologist, Imperial College Healthcare NHS Trust, ROB SHULMAN, BScPharm, MRPharmS, DipClinPharm, DHC London, UK (Pharm) | Lead Pharmacist – Critical Care, Pharmacy NATALIE LEWIS, MPharm, ClinDipPharm, PGCertEd | Senior Department, University College Hospital; Honorary Associate Pharmacist – Teacher Practitioner, Aston University and Professor in Clinical Pharmacy Practice, UCL School of University Hospitals Birmingham NHS Foundation Trust, Pharmacy; Honorary Lecturer, Department of Medicine, Birmingham, UK University College London, London, UK TRACY LYONS, BSc(Pharm), MSc | Lead Pharmacist, Infection, MERVYN SINGER, MBBS MD MRCP | Professor of Intensive Imperial College Healthcare NHS Trust, London, UK Care Medicine; Head, Research Department of Clinical FIONA MACLEAN, MSc, MRPharmS | Independent prescriber; Physiology, Division of Medicine, University College London, Lead Clinical Pharmacist, Cancer and Neurosciences, NHS UK Greater Glasgow and Clyde, Glasgow, UK TIMOTHY J SNAPE, PhD MSci MRSC, CChemCSci | Lecturer in JANET E MCDONAGH, MB BS, MD, FRCP | Clinical Senior Medicinal Chemistry, University of Central Lancashire, Lecturer in Paediatric and Adolescent Rheumatology, Preston, Lancashire, UK University of Birmingham and Birmingham Children’s NUTTAN KANTILAL TANNA, MRPharmS, DComP, PhD Hospital NHS Foundation Trust, Birmingham, UK | Pharmacist Consultant, Women’s Health and Older People, DUNCAN MCROBBIE, MSc, FRPharmS | Associate Chief Women’s Services and affiliated with the Arthritis Centre, Pharmacist, Guy’s and St Thomas’ NHS Hospital Trust; NW London Hospitals NHS Trust, London, UK Clinical Reader, Kings College London, London, UK; Visiting Professor, UCL, UK xi

Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 NEIL TICKNER, MPharm, MRPharmS, PGDipClinPharm | Lead PETER S WHITTON, BSc, MSc, PhD | Senior Lecturer in Pharmacist Paediatrics, St Mary’s Hospital, Imperial College Pharmacology, UCL School of Pharmacy, London, UK Healthcare NHS Trust, London, UK HELEN WILLIAMS, BPharm, PGDip(Cardiol), MRPharmS ADAM TODD, MPharm, PhD, MPharmS, MRSC | Lecturer in | Independent prescriber; Consultant Pharmacist for Pharmacy Practice, Division of Pharmacy, Durham Cardiovascular Disease, South London, hosted by Southwark University, Durham, UK CCG, London, UK MARK TOMLIN, PhD, FRPharmS | Independent prescriber; ELIZABETH M WILLIAMSON, BSc, PhD, MRPharmS, PhD, FLS Consultant Pharmacist Critical Care, Southampton General | Professor of Pharmacy and Director of Practice, University List of contributors Hospital, Southampton, UK of Reading School of Pharmacy, Reading, UK STEPHEN TOMLIN, BPharm, FRPharmS | Consultant Pharmacist KEITH A WILSON, BSc, PhD | Professor, Aston University, – Children’s Services, London, UK Birmingham, UK CHARLES TUGWELL, BPharm, MSc, MRPharmS, MCLIP STEWART WILSON, BPharm, ClinDipPharm | Lead Pharmacist | Specialist Clinical Pharmacist, Neurology/Neurosurgery, Cardiology, Imperial College NHS Healthcare Trust, London, Royal London Hospital, Bart’s Health NHS Trust, London, UK UK KAY WOOD, BSc, DipClinPharm, PhD, MRPharmS, PGPCTL SINEAD TYNAN, MPharm, IP, ClinDip, MSc, MRPharmS | Senior | Senior Lecturer in Clinical Pharmacy, Birmingham, UK Clinical Pharmacist – Liver Services, King’s College Hospital, KIRSTY WORRALL, BSc, MRPharmS | Teacher Practitioner London, UK working with Boots and UCL School of Pharmacy, London, SAMIR VOHRA, BPharm | Lecturer in Clinical Pharmacy Practice, UK School of Pharmacy and Biomedical Science, University of PAUL WRIGHT, MRPharmS, MSc | Specialist Cardiac Pharmacist, Central Lancashire, Preston, Lancashire, UK Bart’s Health NHS Trust, London, UK

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

An integrated approach to learning they are fit for purpose. It has published a Within the healthcare team, pharmacists are the document containing a comprehensive set of recognised medicines experts. They have a breadth standards and outcomes against which and depth of understanding about all aspects of programmes are accredited and reaccredited medicines that set them apart from other health (GPhC, 2011). This document highlights: professionals. As a result of their extensive, ‘Curricula must be integrated ... the component specialist education and training, pharmacists can parts of education and training must be linked in a conceptualise a drug molecule, together with its coherent way’ and ‘Learning opportunities must be formulation and delivery, as a medicine, and can structured to provide an integrated experience of ensure its safe and effective use by patients. relevant science and pharmacy practice’. Pharmacists also have a deep understanding of pharmacology and therapeutics, the The conception and design of this physicochemical properties of drugs and book excipients, biopharmacy and pharmacokinetics, Integration of science with practice, together with side effects, contraindications and drug its practical application, is at the core of modern interactions. This is combined with knowledge of pharmacy programmes. The need for pharmacy the legal and ethical framework in which students to integrate their learning has been a medicines are supplied, as well as biological causes guiding principle in the design and production of of disease, and the social and behavioural factors this book. True integration of all the elements that that determine whether a patient will obtain contribute to pharmacists’ knowledge is difficult. optimal benefit from their medication. This hugely This text aims to present the fundamental aspects varied, complex, integrated, expert knowledge of pharmaceutical chemistry, pharmacology, allows pharmacists to make professional pharmaceutics and therapeutics within a patient- judgements relating to medicines, giving them an care context. Traditional attempts at integration unchallengeable sphere of expertise, which, when commonly begin with sections of ‘underpinning’ utilised for patient benefit, legitimises pharmacists’ science, and then build clinical and professional professional status. elements onto it. This approach can be superficial To be effective, pharmacists’ education must and undermines the credibility of any resultant prepare them to be scholars, scientists, learning exercise. By contrast, in this text, with the practitioners and professionals – no mean feat. A help of many experienced practitioner colleagues, modern undergraduate Masters pharmacy each case study is grounded in a real-life clinical curriculum recognises the importance of both setting, which has then been used as a starting pharmaceutical science and pharmacy practice, point to illustrate how pharmacists’ practice and which, when seamlessly integrated, prepares decision-making are informed by pharmaceutical graduates for the many professional roles and science. activities that they will be called upon to Thus, the case studies in this book were initially undertake now and in the future. Nowadays, written by pharmacist practitioners, based on their pharmacy programmes aim to achieve this own practice and experience, with additional integration during a student’s studies, increasingly science content being incorporated later through incorporating opportunities for workplace learning collaboration with the editorial team. In this way, to provide a context in which they learn and apply the science concepts included have a direct their scientific knowledge. relevance to contemporary practice. In particular In the UK, the General Pharmaceutical Council the science is included in the case because it helps (GPhC) regulates the education and training of inform understanding and decision-making in pharmacists. The GPhC is responsible for real-life practice settings: it has earned the right to accrediting pharmacy degrees and ensuring that be there! xvii

Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 The cases have been organised into sections, undergraduate studies. It is not a textbook. There broadly based on the British National Formulary, are plenty of excellent textbooks that will provide the most widely used reference source in a detailed understanding of the subjects that are pharmacy, where the chapters relate to particular introduced here. The case studies provided are of Introduction systems of the body (e.g. the cardiovascular varying complexity, independent of each other and system) or to aspects of medical care (e.g. not intended to be read sequentially. infections). Although this has allowed us to Each case begins with a set of Learning impose some structure, our cases are very diverse outcomes which provides an overview of what is and reflect the fact that real patients experience contained in the case study and highlights what multiple pathologies. They include material the reader should be able to do having studied the relevant to the wider clinical picture. case. We have striven to include cases covering the Each, detailed Case study begins with broadest range of clinical conditions, from both contextual information about a patient, including community and hospital practice. All the case the medical and drug histories. This equates to the studies have a similar structure. Within each case level of information likely to be available to a we have integrated a significant science pharmacist on consulting medical notes, or talking component from one or more of pharmaceutical with other members of the healthcare team or to chemistry, pharmacology or pharmaceutics, and in the patient and/or their carer. The cases are many cases all three. We have included what we interspersed with, and followed by, a series of believe are the key science concepts. However, it questions. These are the sort of questions that would be impossible to cover in a single set of case pharmacists will ask themselves when studies all the pharmaceutical, clinical and encountering such a case in practice, or questions behavioural science that appears in an that might be asked of pharmacists by patients or undergraduate pharmacy programme. The goal other health professionals. We recommend that here is to demonstrate the potential diversity of readers consider each question based initially on clinical scenarios and the relevance of science their current knowledge, before accessing across all. additional sources such as the current British Most cases describe the use of many drugs in a National Formulary, lecture notes, NICE guidance, particular clinical setting. Again it has not been websites and textbooks. At times, supplementary possible to detail the chemistry, pharmacology, information may be revealed as the case indications, posology, contraindications, side progresses, which may take readers in a different effects and formulations for every drug. However, direction or cause them to reflect and re-evaluate these case studies can be used as a starting point their previous responses and recommendations. to expand learning and application of knowledge The cases and questions are followed by a across the science and practice disciplines. Each section entitled Case discussion. We have chosen case ends with references/further reading and not to supply discrete answers for each question. extended learning points, designed to take the Such an approach gives the impression that a reader’s learning beyond the specific case; definite answer is possible; that all questions have highlighting other relevant, tangential areas of right and wrong answers. Professional practice science and practice. demonstrates that real-life issues cannot be considered in such a black-and-white manner, and How to use this book what demarcates the professional is their This book has been designed primarily for use by appreciation and acceptance of uncertainty and undergraduate pharmacy students and pre- their ability to make judgements based on the registration trainees. However, it may also be available evidence. ‘Answers’ to the questions can useful for qualified pharmacists, pharmacy be found in this section, but there is much more technicians and other health professionals. It will besides, because the case is considered in its also provide a resource for tutors and lecturers to clinical, practice and science context. Having read plan and use in learning activities. this section, refer back to the questions posed in We intend this book to be free standing: a the case, consider how you might answer them in learning and teaching aid to promote integration light of this information, and think of what xviii and contextualisation of material learned during additional questions you might now ask and what

Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 further information you would like. This is the has also been included, where this is appropriate spur to References and further reading. We have to the context of the case. also provided some Extended learning questions, representing our own thoughts for how this case The editorial team and the case study might encourage useful further study. Hopefully, authors Introduction you will also have formulated your own questions. The authors of the cases were chosen because of Finally, although all the cases are ‘practice’ their experience as practising pharmacists, their focused, in some instances we have included unique knowledge of a particular area of practice Additional practice points, highlighting or therapeutics, and their ability to communicate supplementary practice issues that may be to early years pharmacists. The large majority of tangentially linked to the substance of the case the authors currently practise as pharmacists in study, or alluding to pertinent debates and the community and hospitals, and the cases reflect concerns within pharmacy. that contemporary practice. Their enormous, The cases have been written by practitioners learned contributions to this text are testament to with academic input, representing current clinical the vast expertise that UK clinical pharmacists and scientific knowledge, and are informed by the now possess and use daily for patient benefit. experience, expertise and opinions of the authors. The editorial team, all with pharmacy degrees, They should not be taken as a template for has extensive experience in teaching professional practice. Readers are reminded that undergraduate and postgraduate pharmacists, as knowledge, pharmacotherapy and treatment well as pharmacy technicians. Between them, they guidelines are continually changing and that conduct research and teach in the core disciplines pharmacists are called on to make judgements of pharmacy, namely pharmacy practice, based on their own knowledge and experience. Be pharmaceutics, chemistry and pharmacology. They prepared, at times, to disagree with what you read! have worked together building up the case studies supplied by the authors to ensure that each case Conventions used in the text integrates current science and practice, is With the widely different backgrounds of the coherent, and provides a tool for effective learning. contributing authors, there were inevitably The authors and editors have worked together differences in terminologies, units of with the shared belief that this is a valuable and measurement, etc., between cases. Also clinical worthwhile project. The collaboration has led to and science conventions often diverge. Thus, in an innovative learning resource, which has drawn this text we express drug doses as mg, micrograms on the collective knowledge and experience of a (written in full), etc., as is accepted in clinical very diverse group. practice (to minimise the risk of prescribing This collection of case studies has been a great errors), but follow scientific conventions for pleasure to produce. In the process, we have clinical data and other measurements, e.g. we have realised the enormous range of subjects of which used mg throughout (rather than microgram or pharmacists require a deep knowledge and mcg) to express 10-6 grams. understanding, in order to make their unique Most cases include medicines that are currently contribution to healthcare. We hope that readers being used or are to be used by a patient. Note will derive the same enjoyment, and that this book that all doses are for the oral route (p.o.), unless clearly illustrates how the various disciplines that otherwise stated; dosing instructions are indicated comprise pharmacy can complement, support and as standard Latin abbreviations, e.g. t.d.s. We have inform each other, such that pharmacists truly are ensured that the names of the medicines referred medicines experts. to in the case studies are as found in the most current version of the British National Formulary Reference (BNF 68, September 2014) at the time of writing. General Pharmaceutical Council. Future Pharmacists: Occasionally, the proprietary name of a product Standards for the initial education and training of pharmacists. London: GPhC, 2011.

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Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 3 3 Respiratory cases

INTRODUCTION exacerbation, such as medicines, allergens, This section contains five cases centred on exercise, non-compliance and infection, are fi patients with respiratory diseases, namely: identi ed. The chemistry and delivery of asthma, chronic obstructive pulmonary disease beclometasone dipropionate are considered, before fi the various treatment options in asthma Introduction

(COPD), cystic brosis and cough. | exacerbations, such as high-flow oxygen, nebulised b2-adrenergic receptor agonists, oral steroids and Case 1 nebulised ipratropium bromide, are outlined. The Asthma " 89 pharmaceutical monitoring, follow-up and treatment are described. The case also allows for a This case is based on a patient with asthma who is comparison of the key features of various types of receiving regular treatment with a salbutamol

inhalation device (pMDIs, dry powder inhalers, Respiratory cases pressurised metered-dose inhaler (pMDI). The nebulisers) and emphasises the need for patient pathophysiology, signs and symptoms of asthma counselling in the use of these devices. are outlined, then the treatment options in asthma are described, particularly in relation to stepping up and stepping down therapy. The mainstays of Case 3 Nebulised therapy for chronic obstructive asthma therapy are inhaled b2-adrenoreceptor agonists and glucocorticoids, and the chemistry of pulmonary disease " 97 these agents is briefly outlined. The most This case describes an elderly ex-smoker, frequently prescribed inhalation devices, pMDIs, previously diagnosed with, and treated for, COPD, are described and their formulation considered. To requiring hospitalisation for an exacerbation. The enhance the efficiency of drug delivery in the pathophysiology, symptoms, signs and diagnosis of airways, and ease of use by patients who COPD are outlined, followed by the treatment experience difficulties with pMDIs, they may be options, particularly in relation to exacerbations. used with spacer devices. Alternatively dry powder The chemistry and pharmacology of long- and inhalers may be prescribed as a means of short-acting b2-adrenergic receptor agonists, delivering drugs to the lungs. The formulation and particularly salbutamol and salmeterol, are use of these devices are outlined. Ultimately, as the described, and related to their clinical use and case illustrates, the benefit that patients receive adverse effects. The place of nebuliser therapy in from prescribed medicines will depend on their COPD is described, together with the operating adherence to the prescribed regimen and the principles and designs of commercially available ability to use their inhalation device correctly. nebulisers (air-jet, ultrasonic and mesh). Practical considerations relating to patients’ use and Case 2 maintenance of nebulisers are considered. Treating an acute severe asthma exacerbation " 93 Case 4 This case continues the theme of asthma, with an Paediatric cystic fibrosis " 101 acute exacerbation as the focus. It considers the This case describes the treatment of allergic pathophysiology and classifications of acute bronchopulmonary aspergillosis (ABPA) in a child asthma, and the signs and symptoms of acute with cystic fibrosis (CF). The aetiology of CF and ff asthma exacerbations. Common triggers of an the role of di erent medications routinely 87

Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 3 prescribed for a patient with CF are outlined. The chemistry and mode of action of the proton pump inhibitor (PPI), omeprazole, used to treat gastro- oesophageal reflux, frequently presenting in CF patients, are described. Itraconazole is used to treat patients with ABPA. The formulation strategies to enhance this water-insoluble drug’s bioavailability are outlined. The clinical use and delivery of nebulised antibiotics and dornase alfa (DNase), an enzyme that cleaves extracellular DNA in the sputum, aiding its removal, are described. The case ends with a discussion of the use of shared-care protocols to ensure consistency – Introduction of care across the primary care secondary care

| interface, and consideration of medicines management in the home, which can be a complex task for this patient group.

Case 5 Cough " 108

Respiratory cases This case describes the treatment of cough in a young person, which is, possibly, smoking related. The case starts by considering the pathophysiology, signs, symptoms and diagnosis of different types of cough and the appropriate treatment. The use of mnemonics such as WWHAM is outlined, to ensure effective questioning of a patient when determining a diagnosis. The chemistry and mechanism of action of expectorants and opiate antitussives, widely used to treat coughs, are considered. Symptoms indicating that a patient with a cough should be referred to another healthcare professional are described. The opportunity for a pharmacist to offer lifestyle advice, particularly in relation to smoking cessation, is highlighted.

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Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 3 Case 1 Asthma GEMMA QUINN

LEARNING OUTCOMES prescription for beclometasone (Clenil) At the end of this case, you will be able to: 200 micrograms twice daily, via a spacer. . Outline the pathophysiology, and signs and .? When is it appropriate to start treatment with symptoms of asthma inhaled corticosteroids? .? What is a pMDI and what are the benefits of . Describe the treatment options in asthma, using a spacer?

particularly in relation to stepping up and Asthma

stepping down therapy Miss GN continued to collect her prescriptions for | . Outline the chemistry of glucocorticoids salbutamol and beclometasone, but after a few months she complained that she was still using her and b2-adrenoreceptor agonists used in the

treatment of asthma salbutamol up to four times a week and was Case 1 waking at night. She also found it difficult to carry . Outline the formulation of pressurised the spacer and two inhalers around with her, metered-dose inhalers meaning that she sometimes missed doses. The . Describe the use of spacers with pharmacist suggested seeing her GP again for a pressurised metered-dose inhalers review. Miss GN subsequently presented with a . Outline the formulation of dry powder prescription for budesonide/formoterol (Symbicort inhalers 100/6 Turbohaler), two puffs twice daily and one ff . Consider the issues that may affect pu when required (SMART regimen: single adherence in asthma, and make appropriate inhaler maintenance and reliever therapy). treatment recommendations to improve .? What sort of inhalation device is a Turbohaler, this and how does it differ from a pMDI? .? Draw the structures of budesonide and formoterol. How are they related to other Case study steroids and b2-adrenergic receptor agonists Miss GN is a 19-year-old young woman who is used in asthma? currently studying for a degree in English at the .? What issues may affect adherence with asthma local university. She was diagnosed with asthma treatments, particularly in Miss GN’s case? when she was 7 years old and her regular .? What is the SMART regimen and when is it prescription is for salbutamol pMDI recommended? 200 micrograms when required. Miss GN asks you whether she might be able to .? What is asthma? reduce her inhalers in the future. .? What are the most common signs and .? When should inhaler therapy be stepped down? symptoms of asthma? .? How is a diagnosis made? .? What non-pharmacological treatment options Case discussion are available? — Asthma and its pathophysiology fi .? What is the rst-line pharmacological Asthma is one of the most common respiratory treatment in asthma? diseases in the UK, with about a fifth of children ff Miss GN came to the pharmacy to collect her third (21%) and 15% of adults a ected. It is ‘ ’ prescription for a salbutamol pMDI in 4 weeks. characterised by reversible obstruction of the The pharmacist asked to speak to her and airways, caused by a combination of bronchial fl discovered that she was currently using her inhaler hyper-responsiveness, in ammatory changes in the five to six times a day. Miss GN was referred to her airways, and increased numbers of eosinophils and GP and returned a few days later with a activated T cells. It is usually an allergic condition, with common triggers including pollen, dust, 89

Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 3 animal dander, respiratory infections, medicines need to use their b2 agonist three times a week or (e.g. b-blockers and non-steroidal more, if their symptoms wake them at least once a anti-inflammatory drugs [NSAIDs]), cold air, week or if they have had an exacerbation in the strong emotions and exercise. last 2 years. The use of two or more canisters of b2 agonist a month, or 10–12 puffs per day, indicates — Signs and symptoms of asthma that patients are poorly controlled and at risk of Symptoms characteristic of asthma include fatal or near-fatal asthma. wheeze, breathlessness, chest tightness and cough. Adults are usually started on the equivalent of Symptoms usually occur in response to a trigger 200 micrograms beclometasone twice daily, and are often worse at night and early in the whereas 100 micrograms twice daily is usually morning. There is also frequently a family history prescribed for children. It is important to note that of asthma or atopic (hyperallergic) disorders. different formulations of beclometasone are not

Asthma There is no agreed definition of asthma, so a bioequivalent; some pMDI products are solution | diagnosis is made based on the pattern of signs formulations in hydrofluoroalkane (HFA) and symptoms, where there is no probable propellants and others are suspension alternative diagnosis. Spirometry is the preferred formulations producing different drug deposition Case 1 method of demonstrating fluctuating airflow profiles within the lung. Consequently, obstruction in asthma, although a normal preparations should always be prescribed by brand spirogram does not exclude a diagnosis of asthma. proprietary name. — Pharmacological and non-pharmacological — Chemical properties of glucocorticoids and treatment options for asthma b -adrenoreceptor agonists Many patients can identify triggers for their 2 Budesonide is a glucocorticoid that is closely asthma and, where possible, these should be related to beclometasone dipropionate, and both avoided, particularly where they include dust mites drugs have essentially the same steroid skeleton. and passive smoking. Where dust mites are felt to The principal difference is that beclometasone is be a trigger, patients can try methods such as prepared as the dipropionate ester, whereas mattress barrier systems and high temperature budesonide contains an acetal group. washing of bed linen. However, this can be Beclometasone dipropionate is a prodrug: the less- expensive and is not of proven benefit. hindered ester (at carbon-21) is hydrolysed to give Management of asthma is mainly the more active monopropionate metabolite. pharmacological, with the aim of achieving Budesonide already has a free primary hydroxyl at ‘complete control’. This can be defined as: carbon-21 so is not a prodrug. . No daytime symptoms Formoterol is structurally similar to other long- . No night-time awakening due to asthma acting b -adrenoreceptor agonists such as . 2 No need for rescue medication (b2-agonist) salmeterol. Formoterol has an extended lipophilic . No exacerbations substituent on the secondary amine nitrogen. This . No limitations on activity, including exercise results in a greater affinity for, and longer . Normal lung function (FEV and/or PEF >80% 1 residence time, on the b2-receptor, thereby of predicted or best) prolonging its duration of action. Only the (R,R) . ff Minimal side e ects of medication. stereoisomer of formoterol is biologically active. Mild asthma may be managed with a b - 2 — Pressurised metered-dose inhalers adrenoreceptor agonist taken only when required. The pMDIs comprise an aluminium container/ The British Thoracic Society/Scottish canister containing a liquefied aerosol propellant Intercollegiate Guidelines Network (BTS/SIGN) (HFA 134a or 227). The drug is either dissolved or guidelines do not recommend one drug over any dispersed as micronised particles (usually 2–5 mm) other, but in practice salbutamol is the usual in the propellant liquid within the canister. choice. Evaporation of propellant within the headspace of — Stepping up treatment: initiating inhaled the canister provides a pressure (the saturation corticosteroids vapour pressure of the propellant gas), which Patients should be considered for inhaled expels liquid from the canister, via a metering 90 corticosteroids if they are symptomatic and/or valve; this sits in a plastic actuator. Excipients in

Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 3 Asthma | Case 1

the formulation may include a surfactant, such as tried, but there is little evidence to confirm the sorbitan ester, lecithin or oleic acid, which acts as effectiveness of any of these interventions. a suspending agent in suspension formulations, and ethanol as a co-solvent to aid in the — Dry powder inhalers dissolution of drug or surfactant. The Symbicort Turbohaler is a dry powder inhaler (DPI) from which drug is inhaled as a cloud of fine — Use of spacers particles. DPIs have several advantages over Many patients find using a pMDI very difficult and pMDIs. They are propellant free and usually do use it incorrectly. One study found that only 23– not contain any excipients, other than a carrier 43% of patients can use a pMDI correctly; this (see below). They are breath actuated, so the figure was 55–57% for patients using a pMDI with problems for patients of coordinating actuation a spacer. and inhalation are removed. Spacers are plastic devices used by some The drug (with a particle size usually <5 mm) patients together with a pMDI. They reduce the and excipients (if present) is either preloaded in an velocity of the aerosol emitted from the pMDI, inhalation device (e.g. Turbohaler, Accuhaler), or remove large droplets by impaction with the put into hard gelatin capsules (e.g. Handihaler), spacer walls, provide time and space for propellant which are loaded into a device before use. to evaporate from droplets, allowing a fine The small drug particles produced by aerosol to be produced, and remove the need for micronisation (milling) have poor flow properties, patients to inhale at the same time as actuating due to their high surface energy. To improve their the pMDI. flow, and aid device manufacture and delivery of The use of a b2-adrenoreceptor agonist with a drug from the device, particles are generally mixed spacer in mild and moderate exacerbations has with larger ‘carrier’ particles (30–150 mm) of an been shown to be as effective as treatment with a excipient, usually lactose. Some formulations also nebuliser, making a spacer a vital part of an contain fine lactose particles or magnesium asthma personal management plan. It is important stearate to optimise the formulation properties. to note that spacers should be cleaned monthly During inhalation, the turbulent airflow generated and changed at least every 6–12 months. within the inhalation device should be sufficient The use of a spacer with inhaled corticosteroids for the deaggregation of the drug/carrier may also reduce the risk of oral candidiasis. aggregates, with drug particles carried in the Rinsing the mouth with water or brushing the inhaled air deep into the airways. Most DPI teeth after inhaling the dose are also sometimes formulations contain a carrier; some Turbohaler 91

Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 3 formulations do not. Instead, drug particles are the regimen will require review if they need to use loosely aggregated, and these aggregates are the reliever once a day or more on a regular basis. broken up by turbulent airflow created in the This may aid adherence because the patient device during inhalation by patients. requires only one dry powder inhaler (and — Factors affecting adherence with asthma therefore no spacer). treatments — Stepping down treatment Patients may find it difficult to adhere to Once a patient’s asthma has been controlled, treatments for asthma. This may be intentional or ‘stepping down’ should be considered. The most unintentional. As already discussed, achieving appropriate drug to be reduced should be correct inhaler technique is very difficult. DPIs considered in view of current dose, side effects and may be preferable (53–59% of patients use correct beneficial effects of the current dose, as well as the inhaler technique), although alternative devices to

Asthma severity of asthma and patient preference.

| a pMDI should be prescribed according to patient If stepping down inhaled steroids, reductions preference and local cost. The type of device may should be considered every 3 months, with a dose be limited by the drug, so it may be appropriate to reduction of 25–50% at a time. change the drug, e.g. beclometasone is not Case 1 available as a Turbohaler, whereas budesonide is. EXTENDED LEARNING There are also devices available to measure . How are inhalation products formulated patients’ inspiratory flow and match this to the and manufactured? most appropriate device. . The side effects of inhaled corticosteroids may What are the mechanisms whereby inhaled discourage patients from adhering to their particles are deposited in and cleared from prescribed regimen, as may lifestyle issues. As a the airways? student Miss GN may have a busy social life and . Why is particle size such an important live away from home; this may impact on her property of inhalation aerosols? ability to have inhalers with her when needed and . What methods are used to reduce the size fi she may bene t from having more than one of of particles and to measure the size each inhaler available, e.g. one to keep at both her distribution of particles? student and her home addresses. Pharmacists can make a huge impact by ADDITIONAL PRACTICE POINT teaching patients how to use their inhalers . How will you counsel a patient to use a correctly, recommending changes to alternative pMDI, pMDI with spacer or DPI? devices when appropriate and making other practical suggestions that may help with adherence. Further reading British Thoracic Society/Scottish Intercollegiate Guidelines — The SMART regimen Network (2012). British Guidelines on the Management of Studies have shown that the SMART (single Asthma. London: BTS/SIGN, May 2008, updated January inhaler maintenance and reliever therapy) 2012. combination of budesonide/formoterol can safely Murphy A (2010). Asthma: The condition and its diagnosis. ff Clin Pharmacist 2:203–07. and e ectively be used as an asthma reliever as Murphy A (2010). Asthma: Treatment and monitoring. Clin well as a preventer in primary care asthma Pharmacist 2:209–14. management, with formoterol acting as quickly as Taylor KMG (2013). Pulmonary drug delivery. In: Aulton ME, salbutamol. This can be prescribed if control is not Taylor KMG (eds), Aulton’s Pharmaceutics: The design and – achieved with standard dose inhaled manufacture of medicines, 4th edn, Elsevier: London, 638 56. corticosteroids. When this regimen is prescribed, Thomas M, Pavord I (2012). Single inhaler maintenance and the total daily dose of inhaled steroid should not reliever therapy (SMART) in general practice asthma be decreased, and patients should be advised that management: where are we? Primary Care Respir J 21:8–10.

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Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 3 Case 2 Treating an acute severe asthma exacerbation ANNA PRYOR

LEARNING OUTCOMES On examination

At the end of this case, you will be able to: . Blood pressure (BP) 95/75 mmHg . Outline the pathophysiology of asthma . Heart rate (HR) 120 beats/min . . Explain the signs, symptoms and common Respiratory rate (RR) 30 breaths/min . triggers of acute asthma exacerbations Widespread expiratory polyphonic wheeze . Oxygen saturations PaO = 59 mmHg . Outline the different classifications of acute 2 (7.8 kPa) (normal 80–100 mmHg [10– asthma 13 kPa]); SpO = 92% on air (normal >92%) . 2 Discuss the treatment options in asthma . arterial blood pH 7.3 exacerbations . Peak expiratory flow (PEF) = 200 L/min . Outline the key features of the various (best = 450 L/min) inhalation devices (pressurised metered dose inhalers, dry powder inhalers, .? What is the underlying pathophysiology of nebulisers) asthma? . Outline the pharmaceutical monitoring .? What factors could have contributed to Miss required when looking after asthma SA’s asthma exacerbation? patients and be able to make .? Beclometasone is administered as the recommendations on therapy dipropionate ester. How is beclometasone metabolised in lung tissue to give its active

metabolite? Treating an acute severe asthma exacerbation

Case study .? What is the fate of the beclometasone | Miss SA is a 19-year-old white young woman who dipropionate that is NOT deposited in the has had asthma since the age of 5. She has been respiratory tract? brought to the A&E by ambulance suffering with .? What other investigations should be performed Case 2 an asthma attack after collapsing during a local on Miss SA and why? charity summer fun run. .? How would you classify the severity of her Her mother tells you that her regular medications asthma attack? What features of her history and are as follows: presentation give cause for concern? .? Beclometasone pMDI 100 micrograms two puffs b.d. What treatment should she be given Salbutamol pMDI 100 micrograms two puffs p.r.n. immediately? She does not respond to initial treatment. Past medical history: hay fever .? What further therapy could you recommend? Miss SA has recently been taking ibuprofen 400 mg .? What are the key differences between the which she purchased over the counter (OTC) for a various types of inhaler devices available? knee sprain she sustained while training for the fun Once she has been stabilised, she is taken to the run. admissions ward. She has been admitted to hospital with her asthma .? What recommendations would you make for before, as a child, but hasn’t had any problems for her further treatment and which specific a long time and ‘hasn’t been using her brown parameters should you monitor as a inhaler much lately’. pharmacist? On admission, she is severely short of breath and unable to speak in full sentences; she is holding on Case discussion to the sides of the trolley, leaning forward and — Pathophysiology of asthma gasping for breath. Her observations are as shown Asthma is a chronic inflammatory disorder of the in the box. airways, characterised by bronchoconstriction, 93

Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 3 increased vascular permeability, excess mucus cleaved by lung esterases to give the highly active production and impaired mucociliary clearance beclometasone 17-monopropionate (17-BMP) (the process whereby the cilia of the cells lining metabolite. After absorption from the lungs, the the airways propel mucus, and deposited materials, 17-BMP is rapidly cleared to inactive metabolites upwards towards the throat). Due to airway in the liver. hyper-responsiveness, both specific and non-specific stimuli can trigger the complex inflammatory response in people with asthma, which is mediated by eosinophils, mast cells lymphocytes and neutrophils. — Possible trigger factors for an exacerbation in this case . Medicines: NSAIDs, such as ibuprofen, can induce bronchospasm in people with asthma. This is due to the drug’seffect on arachidonic acid metabolism: production of prostaglandins – is blocked, causing increased production of Only around 10 30% of an inhaled dose is leukotrienes which cause bronchoconstriction. deposited in the respiratory tract, the remainder . Allergens: grass pollen is prevalent in June and being deposited in the oral mucosa and July and mould spores (Cladosporium and subsequently swallowed. Very little beclometasone Alternaria spp.) are common in late summer. dipropionate is absorbed from the gastrointestinal Given that Miss SA is known to have hay fever (GI) tract due to its very low polarity and very and was outside participating in the ‘fun run’, poor water solubility; most is simply eliminated unchanged in the faeces. Any small fraction that is this could have been a contributory factor. No fi fi antihistamine medication is mentioned. Of absorbed undergoes signi cant rst-pass Treating an acute severe asthma exacerbation note, in the UK there is a peak of asthma metabolism in the liver, minimising systemic | deaths in people aged up to 44 years in July and availability. August. . Running: vigorous exercise causes narrowing of Case 2 the airways in most people with asthma. — Recommended further investigations . Non-compliance with medication: Miss SA . Chest radiograph: although not recommended mentioned that she has not been using her as routine, radiography is useful to rule out steroid inhaler as prescribed. other causes for breathlessness, such as . Infection: respiratory tract infections can pneumothorax or pneumonia. provoke a transient increase in airway . Arterial blood gas (ABG): this will help responsiveness in normal individuals, as well as determine the severity of Miss SA’s asthma. A people with asthma. Upper respiratory tract low PaO2 (partial pressure of oxygen dissolved infections, principally of viral aetiology, are the in arterial blood) could be indicative of life- most common trigger factor for acute asthma. threatening asthma and an SpO2 (blood oxygen — Less likely triggers in this case saturation: percentage of Hb molecules bound to oxygen) <92% is associated with a risk of . Changes in weather, particularly high humidity hypercapnia (elevated arterial CO ; normal . Possible premenstrual component 2 PaCO = 40 mmHg [5.3 kPa]). . Psychological stimuli, such as stress or anxiety. 2 . Blood tests: including CRP (C-reactive protein, — Beclometasone dipropionate produced by the liver as a measure of general Beclometasone is a potent glucocorticoid steroid. level of inflammation in the body) and full In the management of asthma, beclometasone is blood count (FBC) to look for evidence of administered as a diester – the hydroxyl groups at infection. carbon-17 and carbon-21 are both esterified as the . Temperature: to diagnose or exclude infection. propionate (propanoate) esters. After inhalation, . Echocardiogram (ECoG): to exclude a cardiac 94 the more accessible ester at carbon-21 is rapidly cause or complication for her symptoms.

Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 — Signs of acute severe asthma: considerations be delivered via an oxygen-driven nebuliser with a 3 in this case minimum flow rate of at least 6 L/min because of In this case, Miss SA’s PEF is <50% of her best, the risk of desaturation with air-driven devices. and both her heart rate (HR) and respiratory rate Back-to-back nebulisation is recommended, e.g. (RR) are elevated. She is unable to complete salbutamol 5–10 mg/h. sentences and is having to use her accessory Steroids: early administration of steroids is muscles to breathe (note: ‘holding on to the sides imperative. Their use has been shown to reduce of the trolley, leaning forward and gasping for mortality and lower requirements of b2-agonist breath’). therapy. Oral steroids are as effective as parenteral therapy, provided that the patient is able to FEATURES OF ACUTE ASTHMA swallow and retain the tablets. Recommended doses are prednisolone 40–50 mg daily, . Peak expiratory flow (PEF) 33–50% of best hydrocortisone 100 mg 6-hourly or (use percentage predicted if recent best methylprednisolone 160 mg intramuscularly. unknown) Nebulised ipratropium bromide (anticholinergic) . Cannot complete sentences in one breath 500 micrograms 4- to 6-hourly via an oxygen- . Respirations 25 breaths/min driven nebuliser: combining an anticholinergic . Pulse 110 beats/min with the nebulised b2-agonist will produce significantly greater bronchodilatation than the b2- Miss SA is also exhibiting worrying signs that agonist alone. could indicate that she is close to progression to life-threatening asthma, including hypotension and — Possible add-on therapy dangerously low oxygen saturation. A blood gas Magnesium sulfate: there is some evidence that, in reading would be essential at this stage to adults, magnesium sulfate has bronchodilator determine her risk and plan her treatment. effects. A single dose has been shown to be safe ff and e ective in acute severe asthma unresponsive Treating an acute severe asthma exacerbation

LIFE-THREATENING FEATURES OF to initial therapy. The recommended dosage is | ASTHMA 1.2–2 g intravenous infusion administered over 20 . < minutes. PEF 33% of best or predicted fl Intravenous uid rehydration: patients with acute Case 2 . < a PaO2 8 kPa and/or low pH on ABG asthma tend to be dehydrated because they are too . < SpO2 92% breathless to drink adequate amounts of fluid, in . Silent chest, cyanosis or feeble respiratory addition to experiencing increased fluid loss from effort the respiratory tract. Dehydration causes the . production of more viscous mucus, making Hypotension ffi . clearance more di cult and risking mucus Exhaustion plugging. Consider potassium supplementation to . Altered conscious level, confusion or coma compensate for the hypokalaemic effect of . Arrhythmias salbutamol and corticosteroids. Antibiotics: routine prescribing of antibiotics is not aNormal arterial pH = 7.35–7.45 indicated in asthma exacerbations. Most infective — Immediate treatment of an asthma precipitants are viral in origin. Only if there is exacerbation objective evidence of bacterial infection, e.g. High-flow oxygen is the most important elevated white cell and neutrophil counts, high immediate treatment and should be the first temperature and radiological changes, should intervention, because hypoxia can put the patient broad-spectrum antibiotics, such as amoxicillin, be at risk of cell injury and death. Give 15 L O2 via a initiated. re-breathe mask, aiming for an arterial SpO2 94– Intravenous aminophylline: some patients may 98%. derive benefit from the addition of an infusion of High-dose nebulised b2-agonist, either salbutamol intravenous (i.v.) aminophylline; however, it is no 5 mg or terbutaline 10 mg: there is no evidence to longer considered routine therapy. The loading suggest superior efficacy of either agent. This must dose is 5 mg/kg over 20 min followed by 95

Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 3 ! TABLE 3.1 Comparison of inhaler devices

Device A pMDI DPI Nebuliser Principle of operation Pressurised gas, e.g. HFA Powder particles dispersed by Compressed air/oxygen, or: patient’s inhalation Ultrasonic Mesh Drug presentation Drug dissolved or suspended Micrometre-sized drug Drug dissolved or suspended in liquid propellant particles as powder in water Possible excipients Propellant, surfactant, Carrier particles, e.g. lactose Tonicity and pH modifiers co-solvent Storage of medication In inhaler In inhaler or capsules As unit-dose ‘nebules’, independent of device (rarely multidose in vials) Treatment time <1 s One breath Up to 20 min Advantages Small, portable, no Small, portable, minimal Ease of use, potential for preparation preparation delivering large doses Disadvantages Poor patient compliance Inspiratory effort required Relatively large, cost, duration of treatment, non-availability of devices on NHS

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

continuous infusion of 500 micrograms/kg per . Steroids: hyperglycaemia, hypertension. hour (maximum concentration 25 mg/mL). Be . Switch steroids to oral prednisolone 40 mg sure to check the drug history and for interactions. daily and continue for at least 5 days. At this Treating an acute severe asthma exacerbation Therapeutic drug monitoring will be required if dose, they can be stopped abruptly on discharge | the infusion is continued for more than 24 hours. with no need for weaning. Tapering is necessary Parenteral b2-agonist: intravenous salbutamol may only if the patient has had repeated courses, be beneficial in addition to the nebulised route in doses >40 mg prednisolone or received over 3 Case 2 severe cases, or for patients who are ventilated, weeks of treatment. although there is limited evidence to support this. . Step-up inhaler therapy: suggest switching to a Recommend prescribing: 5 mg salbutamol combination inhaler containing a long-acting b- 1 mg/mL diluted in 500 mL 5% glucose or 0.9% agonist + corticosteroid, e.g. Symbicort 200/6 sodium chloride and infusing at 0.3–2 mL/min (3– or Seretide 125/25 (step 3 of BTS guidelines); 20 micrograms/min) and titrating to response. this can be stepped down at a later date as — Recommended pharmaceutical monitoring, control is maintained. follow-up and treatment ff . PEF: PEF readings should improve, but be — The key di erence between types of inhaler careful to watch out for any diurnal variation – device asthmatics typically dip first thing in the See Table 3.1. morning and failure to consider this could lead to inappropriately hasty step-down of treatment — Counselling and discharge. It is important to reinforce the need for . Electrolytes: watch for hypokalaemia in view of compliance with treatment, and to ensure that the high dose steroid and salbutamol therapy. inhalers are used correctly with the optimal . Side effects: monitor for side effects from all devices prescribed. Using these devices to achieve drugs, e.g.: optimum effect is not easy. In particular, pMDIs . Salbutamol: tremor, tachycardia, headaches, require coordination of inhaling and actuation, as palpitations part of a routine with a number of steps to . Ipratropium: dry mouth, urinary retention, promote effective drug delivery to the lungs. 96 nausea, headache Patients should be assisted to ensure that they

Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 sustain a good technique in the operation of EXTENDED LEARNING 3 devices. . Outline the British Thoracic Society A personalised self-management plan should be guidelines for treatment of asthma. devised and a written plan issued to the patient on . Describe the pharmacology of long- and discharge. These, together with self-management short-acting b -agonists. education, have been shown to reduce 2 . – hospitalisation and A&E attendance, particularly in Describe the anatomy of the lung how people with asthma who have had recent does this impact on the way in which exacerbations. therapeutic aerosols are deposited and The plan should include: cleared from the airways? . . Structured education, with specific advice about Describe how particles delivered from recognising loss of asthma control assessed by inhaler devices deposit in the airways, and symptoms and/or PEF monitoring outline the importance of particle size and . What to do if asthma deteriorates, such as density in these mechanisms. seeking medical attention, increasing inhaled steroids or starting oral steroids, depending on severity. Further reading Taylor KMG (2013). Pulmonary drug delivery. In: Aulton ME, Consider the need for supplementary Taylor, KMG (eds), Aulton’s Pharmaceutics: The design and treatments such as non-sedating antihistamines, manufacture of medicines, 4th edn. London: Elsevier, 638– e.g. cetirizine 10 mg daily. 56.

Case 3 Nebulised therapy for chronic obstructive pulmonary disease BOTHAINA ALHADDAD

LEARNING OUTCOMES Case study At the end of this case, you will be able to: Mrs MM is a 75-year-old white woman, who has

. Outline the pathophysiology, symptoms, smoked for the previous 40 years. She was Nebulised therapy for chronic obstructive pulmonary disease signs and diagnosis of COPD diagnosed with COPD 5 years ago, and has since | been prescribed bronchodilators, including . Describe the treatment options in COPD, salmeterol, delivered from a pMDI to relieve her particularly in relation to exacerbations

breathlessness. Salmeterol is a long-acting b - Case 3 . 2 Outline the place of nebuliser therapy in adrenergic receptor agonist. COPD, and describe the variations in .? What is COPD? operating principles and designs of .? What are the classic symptoms of COPD? available nebulisers .? How is a diagnosis of COPD confirmed? . Describe the practical aspects relating to .? How is stable COPD managed? patients’ use and maintenance of nebulisers Mrs MM began to feel unwell on Christmas Eve. . Outline the pharmacological mechanism of She was increasingly breathless despite using her action of b -adrenergic receptor agonists 2 inhalers and had just managed to call for an on bronchial smooth muscle ambulance. The paramedics noted that Mrs MM . Outline the common side effects of b - 2 was out of breath and her PaO2 was markedly low. adrenergic receptor agonists She was given oxygen as well as nebulised . Appreciate the structural characteristics of bronchodilators. During her stay in hospital, Mrs long- and short-acting b2-adrenergic MM was started on an antibiotic and a course of receptor agonists that are important in their oral steroids. On discharge, she was lent a pharmacological activity and clinical use nebuliser by the hospital for use with prescribed 97

Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 3 salbutamol nebules. Salbutamol is a short-acting caused by smoking. COPD is an umbrella term b2-adrenergic receptor agonist. used to describe a range of different overlapping .? What is an exacerbation of COPD? conditions affecting the airways, such as chronic .? How is it managed? bronchitis, emphysema, long-standing asthma and .? What is the mechanism of action of salbutamol small airway disease. In COPD, the airways and salmeterol in the treatment of respiratory become inflamed as a result of an exogenous disease? factor, often smoking, and produce elastases .? What structural characteristics of the which, over time, result in disruption of the salmeterol molecule result in a longer duration elastin/elastase balance in the lung. This, coupled of action compared with shorter-acting b2- with inactivation of the protective anti-elastases in agonists, such as salbutamol? the lung (as a result of the oxidants in cigarette .? What other structural features are important in smoke), leads to loss of lung elastin, destruction of the clinical use of these agents? lung tissue and emphysema. Loss of elastin also .? What is the rationale for using a nebuliser in causes the lungs to become hyperinflated due to the management of COPD? air being trapped in the small airways. In addition, .? What are the advantages of using a nebuliser smoking causes inflammation and mucus rather than a dry powder or pressurised production, which accelerate the decline in lung metered-dose inhaler in this case? function and predispose patients to infections. The Mrs MM’s condition improved and she was consequences of this are breathlessness on stabilised after 14 days. She visited her GP who exertion, hypoxia, pulmonary hypertension and recommended that she continue to use a nebuliser peripheral oedema. because her COPD had not been adequately — Symptoms, signs and diagnosis of COPD controlled with her previous medication; she had Patients with COPD often experience symptoms of increased breathlessness, which limited her daily breathlessness on exertion, coughing, sputum activities, a productive cough with purulent production and wheezing. However, clinical signs sputum, and a history of recurrent respiratory such as barrel chest, prominent accessory muscle infections in the last few years. of respiration, recession of lower costal margins, Mrs MM is very keen on controlling her symptoms abdominal breathing, weight loss, central cyanosis, and wanted the GP to help her choose the ‘best’ peripheral oedema and raised jugular venous nebuliser available. pressure (JVP) are seen only when the disease is in

Nebulised therapy for chronic obstructive pulmonary disease .? What are the different types of nebuliser the severe stage. Diagnosis of COPD often | systems available? includes full clinical assessments for symptoms .? Given the variation between different available and the presence of any clinical signs, as well as nebuliser systems, what factors should influence complete history taking. Measurement of lung Case 3 the choice of the doctor/patient? function by spirometry is essential in making a .? What factors will determine the proportion of diagnosis of COPD. However, in uncertain cases, drug in the prescribed salbutamol nebules that bronchodilator or steroid reversibility testing may will reach the deep lung of a patient using a be useful. nebuliser? Spirometry is a standardised measure of a Mrs MM comes to the pharmacy and asks you for forced expiration (and sometimes inspiration) into guidance on the use of her nebuliser. a spirometer (a calibrated measuring device). Spirometers usually measure flow and then .? Can you explain when and how the nebuliser calculate volume with respect to time. The most should be used, giving clear instructions on common measurements are: cleaning and maintenance? . FEV1: the forced expiratory volume in 1 s, Case discussion which is the amount of air blown out in 1 s. . — COPD and its pathophysiology FVC: the forced vital capacity, which is the total Chronic obstructive pulmonary disease, amount of air blown out in one breath. . characterised by airflow obstruction that is not A FEV1 : FVC ratio is then calculated. fully reversible and does not change over several There are several manufacturers of equipment, 98 months, is usually progressive and frequently and all spirometers need, as a minimum, to meet

Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 the standards of measuring and recording as gastrointestinal (GI) side effects were considered 3 specified in international guidelines. To perform too significant and potentially life threatening, and quality-assured spirometry testing and provide so were withdrawn. The main pharmacologic valid results for patients, a systematic approach effects of b2-adrenergic receptor agonists on would need to be employed by trained staff bronchial smooth muscle are mediated through a according to local standards. coupling of the b2-adrenergic receptor with a so- called stimulatory G-protein (G ), which then — Treatment options for stable COPD, and s activates intracellular adenylyl cyclase, the enzyme during an exacerbation responsible for catalysing the conversion of COPD is mainly managed in primary care with intracellular adenosine triphosphate (ATP) to pharmacological and non-pharmacological cyclic adenosine monophosphate (cAMP). The options. Drug options include inhaled increased intracellular cAMP levels, via activation bronchodilators, theophylline, oral or inhaled of protein kinase A, lead to a decrease in corticosteroids, and combination therapy of more intracellular Ca2+ concentration and myosin light than one of these. Non-pharmacological options chain kinase activity, which ultimately causes include smoking cessation, pulmonary smooth muscle relaxation (bronchodilatation). In rehabilitation programmes and oxygen therapy. addition, b -agonists directly open large (size) Exacerbations are common health problems in the 2 conductance Ca2+-activated potassium [BK(Ca)] natural development of COPD. The National channels in the cell membrane, leading to Institute for Health and Care Excellence (NICE) hyperpolarisation and relaxation of airway smooth defines an exacerbation as ‘a sustained worsening muscle cells. The combination of all these effects of the patient’s symptoms from his or her usual is responsible for the beneficial bronchodilator stable state that is beyond normal day-to-day action. variations, and is acute in onset. Commonly reported symptoms are worsening breathlessness, — Chemistry of salbutamol and salmeterol cough, increased sputum production and change Salmeterol is considerably more lipophilic than in sputum colour. The change in these symptoms salbutamol due to the extended lipophilic often necessitates a change in medication.’ substituent on the nitrogen atom. This extended Treatment of an exacerbation includes large doses lipophilic group makes a specific non-covalent of inhaled bronchodilators, systemic hydrophobic interaction with part of the b - corticosteroids, antibiotics, intravenous 2 adrenergic receptor resulting in a higher (10-fold) theophylline and oxygen. Nebulised therapy for chronic obstructive pulmonary disease

potency, and localises the drug in the active site | — Pharmacology of b2-adrenergic receptor for longer. agonists The secondary amino group nitrogen atom The clinical usefulness of drugs such as salbutamol present in both b -agonists is basic, with a pK 2 a Case 3 and salmeterol as bronchodilators relies on their value of around 9.0 for the conjugate acid. At ability to ‘select’ for the b2-subtype of adrenergic physiological pH 7.4, the amino group is receptor that is present on bronchial smooth protonated and therefore positively charged. This muscle cells. Salbutamol was originally introduced positive charge is essential in making an into practice for bronchodilatation in 1968 and electrostatic force of attraction with a negatively immediately became successful in asthma and charged part of the receptor. The basic amino COPD treatment, because it produced fewer group also means that both agonists can be serious (particularly cardiac) side effects. (The formulated as salts, which have improved water most common side effects reported for inhaled b2- solubility and dissolution. Hence, salbutamol adrenergic receptor agonists in the BNF are: fine nebules contain an aqueous solution of salbutamol tremor in the hands, nervous anxiety, dizziness, as the salbutamol sulphate salt. headache, muscle cramps, dry mouth and The carbon atom bonded to the hydroxyl group palpitations/cardiac arrhythmias.) (-OH) is a chiral centre. Although both salmeterol Up to that time, the less-selective b-adrenergic and salbutamol are manufactured as racemic agonist drugs isoprenaline and orciprenaline were mixtures (50 : 50 mixtures of R- and S-enantiomers), commonly used for such conditions, but their only the R-enantiomer has the correct shape to cardiovascular, central nervous system (CNS) and bind to the b2-receptor, because the R-enantiomer 99

Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 3

has the same relative configuration as the — Rationale for using a nebuliser to inhale neurotransmitter noradrenaline and the bronchodilators during an exacerbation circulating hormone adrenaline. The mode of bronchodilator delivery is changed A bulky substituent on the nitrogen atom and a from regular hand-held inhalers to a nebuliser hydroxymethyl (-CH2OH) substituent on the during an exacerbation. A nebuliser is preferred in aromatic ring are important for b2 selectivity. The this situation as higher doses can be administered hydroxymethyl group also hydrogen bonds with to the patient more easily. It is also convenient for the receptor-binding site and prevents the drug’s healthcare staff to administer, as less patient metabolism by COMT (catechol-O-methyl education and cooperation are required, since the transferase – the enzyme responsible for drug is administered during normal tidal metabolising noradrenaline). breathing, via a mouthpiece or facemask. This is particularly helpful if the patient is distressed. — Nebulisers and their modes of operation Additionally, the nebulised medication may reduce A nebuliser is a device that converts a drug the viscosity of the mucus and assist in its solution or, less frequently, a suspension into a expectoration from the airways. fine aerosol for inhalation. The nebuliser system consists of a nebuliser chamber and a driving/ — Prescribing nebuliser therapy energy source. Broadly speaking, there are three Nebulisers are indicated when a patient has severe, types of nebuliser: distressing breathlessness, despite optimal therapy 1 Air-jet nebulisers, which are most commonly with pMDIs or DPIs, or is too ill or incapable of used in practice and comprise a nebuliser using a hand-held inhaler. Domiciliary nebuliser chamber and a compressor that generates air therapy is prescribed after assessment of COPD at high pressure to atomise the nebuliser patients in hospital or general practice. Nebulised therapy for chronic obstructive pulmonary disease liquid Components of the assessment should include a | fl 2 Ultrasonic nebulisers, which use high-frequency review of the diagnosis, peak ow rate monitoring ff sound waves to agitate the fluid and cause the at home, and sequential testing of di erent fl drug-containing droplets to be generated from treatment regimens using peak ow and subjective Case 3 the surface responses. Only patients who have a clear fl 3 Mesh nebulisers, in which fluid is forced subjective and peak ow response to domiciliary through a mesh with micrometre-sized holes to nebuliser treatment should be advised to continue. < form droplets. If there is a subjective response with 15% improvement over baseline peak flow, a physician Each of these devices has advantages and should make a clinical judgement, whereas all other disadvantages. The proportion of available drug outcomes should not result in continued treatment. that reaches the deep airways depends on the design and mode of operation of the nebuliser, — Use and maintenance of nebulisers duration of nebulisation, fluid volume (which can When a nebuliser is prescribed, patients (and/or be increased by diluting the contents of the carers) should be provided with the equipment, nebule) and fluid physicochemical properties, such servicing, advice and support, and should have as viscosity and surface tension. In addition to the regular reviews. They are given clear instructions device/fluid characteristics, patient technique and on how and when to use the nebuliser, how to breathing pattern are important factors that clean it, when to replace parts and when to service determine the proportion of drug that reaches the the equipment. The nebuliser chamber and the site of action and hence the effectiveness of mouthpiece or facemask should be washed in 100 therapy and clinical outcomes. warm soapy water and dried after each use.

Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 Tubing should not be washed because it is difficult patients with asthma or COPD, due to 3 to dry. It is advised that air be blown through bronchial b2-receptor blockade and tubing by running the compressor for a few consequent bronchospastic complications seconds to dry it out, after the nebulisation session and risk of respiratory failure/death. is complete and the chamber is detached from Practitioners reviewing asthma or COPD tubing. The chambers should be replaced after 3 therapy should therefore routinely months of regular use and the compressor should investigate whether there is any ongoing be serviced regularly according to the ocular (or systemic) use of b-blockers manufacturer’s recommendations. before formulating a treatment plan

EXTENDED LEARNING . How are COPD and asthma distinguished? References and further reading Bellamy D, Booker R (2004). Chronic Obstructive Pulmonary . What are the latest developments in Disease in Primary Care. London: Class Publishing Ltd. nebuliser design and therapy? Boe, J, Dennis JH, O’Driscoll BR, Bauer TT et al. (2001). . European Respiratory Society Guidelines on the use of What conditions other than COPD and nebulizers. Eur Respir J 18:228–42. asthma may be treated by nebulised Boe, J, O’Driscoll BR, Dennis JH (2004). Practical Handbook of Nebulizer Therapy. London: Martin Dunitz, Taylor & therapy? Paediatric cystic fibrosis Francis Group plc. . | What is the place and operation of British Thoracic Society (1997). Current best practice for smoking cessation programmes in the nebuliser treatment. Thorax 52(Suppl 2):S1–106. prevention of chronic disease? Levy ML, Quanjer PH, Booker R, Cooper BG, Holmes S, Small

IR (2009). Diagnostic spirometry in primary care: proposed Case 4 ADDITIONAL PRACTICE POINTS standards for general practice compliant with American . Familiarise yourself with a nebuliser and its Thoracic Society and European Respiratory Society. Primary – component parts Care Respir J 18:130 47. National Institute for Health and Clinical Excellence (2004). . Topical use of b-adrenergic receptor Chronic Obstructive Pulmonary Disease: National guideline blockers such as timolol, betaxolol, for management of COPD in adults in primary and levobunolol or carteolol in the treatment of secondary care. Thorax 59:(Suppl I). glaucoma may lead to sufficient drug being Primary Care Commissioning (2013). A guide to performing quality assured diagnostic spirometry. Available at: www.pcc- absorbed systemically to pose a threat to cic.org.uk (accessed 25 May 2013).

Case 4 Paediatric cystic fibrosis SIÂN BENTLEY

LEARNING OUTCOMES . Describe the properties of itraconazole and At the end of this case, you will be able to: outline formulation strategies to enhance . Outline current knowledge of the aetiology its bioavailability of cystic fibrosis (CF) . Understand the application of shared-care . Explain the role of different medications protocols in prescribing of specialist routinely prescribed for a patient with CF medication outside the hospital setting . Describe the presentation and management of allergic bronchopulmonary aspergillosis Case study in a CF patient Charlotte, a 7-year-old girl weighing 21 kg, is . Outline the chemistry and mode of action admitted to the ward after presenting at her of omeprazole outpatient clinic with increased shortness of breath, increased sputum production (sputum darker than 101

Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 3 normal), tiredness and generally feeling unwell for ! TABLE 3.2 the last 3 days. Blood tests and sputum culture results

+ – CASE NOTES~ Na 136 mmol/L (normal: 134 145 mmol/L) K+ 4.5 mmol/L (normal: 3.5–5.2 mmol/L) Past medical history Urea 3.3 mmol/L (normal: 2.5–6.5 mmol/L) . Cystic fibrosis (CF) – . Pancreatic insufficiency Creatinine 35 mmol/L (normal: 32 94 mmol/L) WBC 17.4 6 109/L (normal: 4–13.5 6 109/L) Allergies . No known drug allergy (NKDA) Most recent sputum culture results:

Drug history Pseudomonas aeruginosa sensitivity: . Creon 10 000 with snacks and meals Azithromycin R . Dalivit multivitamin drops 1.2 mL o.d. Ceftazidime S . Tocopheryl acetate 100 mg o.d. Chloramphenicol S . Omeprazole MUPS 20 mg o.d. . Flucloxacillin 250 mg b.d. Colistin S . Colistin (Polymyxin E) 1000 000 units b.d. Gentamicin S Paediatric cystic fibrosis nebuliser solution | Tobramicin S . Salbutamol 100 pMDI two puffs inhaled via a spacer p.r.n. and pre-physiotherapy Amikacin S Temocillin S Case 4 Aztreonam R On examination Timentin S . Temperature 38.58C Meropenem S Ciprofloxacin R A diagnosis of an infective exacerbation of CF is Staphylococcus aureus sensitivity: made. A new sputum sample is taken and sent to microbiology for culture and sensitivity testing. Flucloxacillin S Charlotte is empirically prescribed ceftazidime and Penicillin S fl gentamicin. The ucloxacillin is increased to a Erythromycin R treatment dose: Gentamicin S Ceftazidime: 1000 mg t.d.s. i.v. Tobramycin: 210 mg o.d. i.v. R=resistant; S=sensitive. Flucloxacillin: 500 mg q.d.s. . ? What is CF? Outline the current understanding wheezy. Her FEV1 (% predicted) falls from 65% to of its aetiology and symptoms 50%. Her blood results show an IgE of .? Explain what each of Charlotte’s medicines on 1054 units/mL and Aspergillus fumigatus RAST admission are being used for and how they (radioallergosorbent test) of 19.8 units/mL, and would be administered. Charlotte is unable to Aspergillus sp. is noted in her recent sputum take capsules/tablets (Hint: also think about sample. A diagnosis of ABPA is made and timing with physiotherapy) Charlotte is started on prednisolone 30 mg each .? What organisms, common in CF, are the morning and itraconazole liquid 100 mg twice . intravenous (i.v.) antibiotics covering? daily. ? Are the doses of the i.v. antibiotics appropriate, .? What does ABPA stand for? What is this? Is and how do they relate to altered the therapy appropriate? . pharmacokinetics in CF patients? .? Comment on the formulation and oral ? How should the i.v. antibiotics be monitored? bioavailability of itraconazole in both capsule Charlotte receives these antibiotics for a week, but and liquid form does not improve and becomes progressively more 102

Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 .? How would you counsel Charlotte and her the CFTR channel protein in the cell endoplasmic 3 carer to take itraconazole? reticulum (ER), thus preventing it from being .? How would you monitor itraconazole therapy? trafficked to the plasma membrane. The poorly functioning CFTR channel in CF means that there Charlotte responds well to the itraconazole and is an imbalance of chloride and subsequently water prednisolone. However, her sputum remains across the epithelial cell, leading to accumulation difficult to expectorate and she is started on DNase of thick mucus secretions at mucosal surfaces in 2.5 mg once daily pre-physiotherapy. the lungs that are difficult to clear, and therefore She continues to improve and is ready for discharge particularly prone to bacterial infection and after 3 weeks. Her discharge medications are as chronic inflammation. The CFTR mutations also follows: affect the exocrine functions of the pancreas, Creon 10 000: with snacks and meals intestine, liver, bile duct, salivary and sweat glands. Dalivit: 1.2 mL o.d. There has been extensive research in recent Tocopheryl: 100 mg o.d. years, with limited success, into the use of gene Omeprazole: 20 mg o.d. therapy for the treatment of CF, with delivery of Flucloxacillin: 250 mg b.d. the CFTR gene directly to the airways. Transfer of Colistin: 1000 000 units b.d. nebuliser solution genes into the airway cells requires the use of a ff Salbutamol 100 pMDI: two pu s via spacer p.r.n. vector, which may be viral (e.g. adenoviruses, Paediatric cystic fibrosis

and pre-physiotherapy adeno-associated viruses) or non-viral (e.g. | Itraconazole: 100 mg b.d. liposomes). Prednisolone: 30 mg mane to be reviewed in clinic Pharmacological treatment in CF: consideration in 2 weeks Case 4 DNase: 2.5 mg o.d. nebuliser solution in this case .? What is DNase (dornase alfa) and how does it — Pancreatic insufficiency work? Approximately 90% of CF patients in northern Europe are pancreatic insufficient because of the The clinical nurse specialist for CF contacts reduction of pancreatic secretions, which leads to ’ Charlotte s GP to explain the changes to her poor digestion of fats and malabsorption of regimen, to be told that they are not able to proteins and carbohydrates. Patients have prescribe the DNase under the new commissioning steatorrhoea (fatty stools), decreased absorption of arrangements, and the hospital must provide fat-soluble vitamins (A, D, E and K), malnutrition ongoing supplies. They ask if it can be provided as and failure to thrive, and therefore require part of a homecare scheme. pancreatic enzyme supplementation. Creon 10 000 .? In the NHS, what is meant by ‘homecare’? is usually administered as delayed-release capsules, What are the potential benefits of using such a which contain enteric-coated microspheres of service? porcine-derived lipases, proteases and amylases. The microspheres are enteric coated to prevent the Case discussion breakdown of the enzymes in the acidic — Causes and symptoms of cystic fibrosis environment of the stomach. It is taken with all Cystic fibrosis is an autosomal recessive, life- meals and fat-containing snacks. The capsules limiting disease caused by mutations in the cystic should be swallowed whole at the start of a meal fibrosis transmembrane conductance regulator and the microspheres not chewed to ensure that (CFTR) gene (discovered in 1989), which codes for adequate enzyme levels reach the duodenum. For aClÀ ion channel normally present in lung young children/babies, capsules can be opened and epithelial cells. More than 1900 mutations have so the microspheres mixed with acidic fluid or soft far been found in the gene, but only a relatively food. This could be apple sauce or yoghurt or any small number of these mutations (so-called class I– fruit juice with a pH <5.5, e.g. apple, orange or V, with different biological outcomes) can account pineapple juice. If the granules are mixed with fluid for most of the CF patients so far characterised or food it is important that they are taken with the condition. The most frequent mutation is immediately and the mixture not stored, otherwise a deletion of a phenylalanine amino acid residue at dissolution of the enteric coating may result. They position 508 (DF508) which results in misfolding of must not be mixed with the food that requires 103

Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 3 chewing, because this can cause a sore mouth and should be taken immediately or within 30 min. The put children off eating, as well as reducing efficacy dispersion is stirred just before drinking and rinsed as described previously. The number of capsules down with half a glass of water. It is important that taken varies from patient to patient, and the dose the tablets should not be crushed or chewed. and strength are adjusted according to the patient’s fat intake, stool consistency/frequency and weight. Dieticians usually advise on the enzyme replacement therapy for each patient. High- strength preparations such as Pancrease HL and Nutrizym 22 are not recommended because of their association with colonic strictures in children. However, no association was found with Creon The omeprazole MUPS tablets consist of 25 000. It was also recommended that the total multiple enteric-coated pellets. The polymeric daily dose of lipase should not usually exceed coating is specifically designed to dissolve only in 10 000 units/kg. the higher pH environment of the small intestine, It follows that all pancreatic-insufficient patients hence the need to disperse the tablets in a slightly require supplementation with the fat-soluble acidic medium before administration. On reaching

Paediatric cystic fibrosis vitamins A, D and E. Dalivit is a liquid the small intestine, the omeprazole (which itself is

| multivitamin preparation (containing mainly inactive) is absorbed into the systemic circulation, vitamins A, B , C and D) available in the form of 2 from where it reaches the highly acidic environment drops, and tocopheryl acetate (vitamin E acetate: of the parietal cells, undergoing a pH-dependent

Case 4 the ester form of tocopherol) is a 100 mg/mL chemical rearrangement to its active form. This liquid formulation. Levels of vitamins A, D and E activated intermediate reacts with the thiol (-SH) are usually checked every year at the annual review group of a cysteine residue present on the H+/K+ and supplement doses amended accordingly. ATPase (the proton pump), covalently modifying — Gastro-oesophageal reflux and permanently inactivating it. If the omeprazole Many CF patients also have gastro-oesophageal were not formulated with an enteric coating, this reflux which is believed to be due to the rearrangement would occur in the contents of the hyperacidic gastric secretions and relaxed lower stomach, which would prevent the drug from ever oesophageal sphincter tone. Symptom relief is being absorbed and reaching the parietal cells. usually obtained with proton pump inhibitors — Staphylococcus aureus infections (PPIs) ± prokinetics such as domperidone and Long-term prophylaxis against Staphylococcus low-dose erythromycin. Long-term treatment is aureus is prescribed in order to reduce the usually required. frequency of infective exacerbations caused by this PPIs (e.g. omeprazole) and histamine H - 2 organism. The use of anti-staphylococcal receptor blockers (e.g. ranitidine) may also be prophylaxis from diagnosis until 3 years of age was prescribed as adjuvant therapy to enhance the shown by a Cochrane review to be effective in effect of pancreatic enzyme replacement therapy, reducing the incidence of infection with S. aureus, because pancreatic enzymes are inactivated by although an improvement in clinical outcomes was gastric acid; therefore, by decreasing acidity, the not shown. Current guidance is to start it in all CF enzyme efficacy is increased. children identified by newborn screening or — Omeprazole: mode of administration and diagnosed clinically, unless there is a compelling molecular properties reason not to, i.e. not tolerated, or allergy. Once Omeprazole may be administered to Charlotte as a aged 3 years, flucloxacillin prophylaxis is reviewed. MUPS (multiple unit pellet system) tablet Although policies vary from institution to formulation. The tablets may be dispersed in institution, an example of such a policy is to 10 mL non-carbonated water and then suspended continue only if S. aureus is repeatedly cultured, in a small amount of any fruit juice with a pH <5, i.e. more than two isolates of S. aureus in a year. e.g. apple, orange or pineapple juice, or in apple Cephalosporins are generally not used for long- sauce or yoghurt after gentle mixing. Milk or term prophylaxis for S. aureus because of worries 104 carbonated water must not be used. The dispersion about increased pseudomonas isolation in a US

Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 cephalexin trial and also evidence from the bacteria, particularly P. aeruginosa, compared with 3 European database. second-generation cephalosporins. However, it is In the case of Charlotte, flucloxacillin is less active against Gram-positive bacteria such as administered as the 250 mg/5 mL preparation, S. aureus compared with the second-generation taken on an empty stomach to maximise cephalosporins. absorption. As prophylaxis it is administered twice Tobramycin is an aminoglycoside that is daily to facilitate compliance and to fit better with bactericidal and active against some Gram-positive Charlotte’s school day. organisms, including S. aureus and many Gram- — Nebulised colistin negative organisms, including P. aeruginosa. Nebulised antibiotics are prescribed for patients Tobramycin is the aminoglycoside of choice who are chronically colonised with P. aeruginosa because there is evidence that it is less (grown on three or more isolates in a year) or for nephrotoxic than other aminoglycosides in eradication of first growth. Long-term nebulised patients with CF. therapy has been shown to reduce the frequency Larger doses of many antibiotics are used in CF of infective exacerbations and the need for due to altered pharmacokinetics, notably an intravenous anti-pseudomonal antibiotics, and to increased volume of distribution and increased improve lung function. The most frequently used clearance (renal and non-renal). It is not fully nebulised antibiotics are colistin (colistimethate understood why this occurs. In addition, due to Paediatric cystic fibrosis sodium) and tobramycin. It is currently the severity of the disease, high concentrations of | recommended that colistin be used initially in antibiotics are needed at the site of action. patients chronically colonised with P. aeruginosa. Both ceftazidime and tobramycin have an

Nebulised colistin achieves low systemic and high increased clearance in CF, so the high doses Case 4 local concentrations in the lung, which makes it prescribed are appropriate (ceftazidime 50 mg/kg very useful for long-term therapy, because patients three times daily and tobramycin 10 mg/kg once do not have the adverse effects associated with the daily). There is evidence, from a randomised use of these antibiotics administered intravenously. controlled trial of once versus three times daily Patients must have a bronchoconstriction trial tobramycin (the TOPIC study), that once-daily ffi before starting therapy to ensure that the treatment is equally e cacious and associated with nebulised antibiotic does not cause less nephrotoxicity in children, although the study ff bronchoconstriction. Colistin nebulisers should be showed no di erence in ototoxicity between the administered post-physiotherapy. This enhances two regimens. In addition, less money is spent on their effects because physiotherapy has removed equipment such as needles and syringes and, much of the sputum, enabling better penetration importantly for the child with CF, fewer blood to the site of action. tests are needed because only trough serum levels need to be monitored. It also saves on nursing — Salbutamol time for drug administration. Some patients with CF also have asthma (small The antibiotic therapy must be monitored to fi airway disease) and therefore bene t from the use ensure that it is effective and not causing adverse of bronchodilators, such as salbutamol (b2- effects. Temperature and clinical response (general adrenoreceptor agonist). Before starting treatment, wellbeing, sputum production and lung function) patients should undergo a bronchodilator trial in should be monitored to check efficacy. which their lung function is measured before and In this case, Charlotte’s trough serum after treatment. In patients who demonstrate an tobramycin level should be measured 23 hours improvement, bronchodilator treatment is after administration of the second dose (i.e. shortly initiated. Nebulised or pMDI bronchodilators are before the third dose), 48 hours after any also used by some patients before nebulising adjustment and weekly thereafter, aiming for a antibiotics, in order to prevent trough level <1 mg/L. This will prevent bronchoconstriction. nephrotoxicity or ototoxicity associated with — Intravenous antibiotics in CF: spectrum of elevated levels of aminoglycosides. Serum urea and activity, dose and monitoring creatinine should be measured at the time of first Ceftazidime is a third-generation cephalosporin cannula insertion, and with each trough level. and so has greater activity against Gram-negative 105

Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 3 Charlotte’s liver function and blood count systemic circulation. Dissolution and absorption should also be monitored as ceftazidime can cause are enhanced in the case of the capsules by disturbances in LFTs (liver function tests) and forming a solid dispersion of the drug in the blood disorders such as leukopenia. rapidly dissolving polymer, hydroxypropyl methylcellulose (HPMC, hypromellose) coated on Allergic bronchopulmonary aspergillosis to sugar spheres. As dissolution requires an acidic ABPA is an immune-mediated disease causing environment for dissolution, acid-reducing bronchiectasis (destruction and widening of the therapies should be stopped wherever possible large airways) induced by Aspergillus fumigatus, and, if not possible, administered at opposite ends ff and is not uncommon in CF (occurring in of the day to minimise the e ects on absorption. approximately 1–11% of patients). The typical Bioavailability from solid dosage forms is presentation is wheezing, new pulmonary approximately 30%, but, if taken with food, infiltrates on chest radiograph, a rise in serum bioavailability is increased to about 55%. total IgE and specific IgE to A. fumigatus, with a Bioavailability is greater from the liquid fall in lung function. preparation, which is formulated in cyclodextrin as The mainstay of treatment is oral corticosteroid a solution. Cyclodextrins are cyclic therapy to attenuate the inflammatory process, but oligosaccharides comprising six (a-cyclodextrin),

Paediatric cystic fibrosis this may need to be continued for several months seven (b-cyclodextrin) or eight (g-cyclodextrin)

| ‘ ’ and is associated with significant adverse effects. glucopyranose units. They have a bucket-like Treatment is with oral prednisolone: an example structure with a hydrophilic outer surface and a regimen of 2 mg/kg in the morning (non-enteric hydrophobic cavity that can accept a hydrophobic

Case 4 coated due to difficulty in absorption of enteric- drug molecule, forming an inclusion complex and coated preparations in CF patients as a result of bringing the drug into solution. pancreatic insufficiency) for 2 weeks, then 1 mg/kg The liquid preparation is much better absorbed, > per day for 2 weeks, and then 1 mg/kg on with a bioavailability 70%. However, it is alternate days for 2 weeks. If an improvement in unpalatable and must be taken on an empty clinical symptoms, lung function and radiological stomach. Liver function tests should be monitored – changes has occurred, and when the IgE levels fall at least after 1 2 months, particularly if there is a appropriately, prednisolone dose should be tapered history of liver dysfunction. ABPA markers will to zero over the next 8–12 weeks. monitor the progress of the disease, e.g. IgE and Aspergillus fumigatus RAST, as well as clinical Itraconazole symptoms, e.g. wheeze, lung function and general wellbeing. Itraconazole levels should also be Itraconazole is used to reduce the antigenic considered when there is a lack of clinical burden of A. fumigatus in the respiratory tract. response, or if there is concern about adequate Studies of itraconazole, initially in an uncontrolled drug absorption or patient compliance. setting in CF, and recently in randomised trials in adults with asthma and ABPA, have shown DNase (dornase alfa) evidence of benefit, including the ability to reduce Patients with CF have thick tenacious sputum, the steroid dosage. It should be given for 3–6 months. retention of which contributes to infective — Formulation, pharmacokinetics and exacerbations and reduced pulmonary function. monitoring of oral itraconazole preparations The thick secretions contain a high concentration Itraconazole is a water-insoluble, hydrophobic of extracellular DNA released by degenerating drug with a log P value of 5.66. The poor solubility leukocytes, which accumulate in response to results in poor bioavailability, particularly from a infection and add to the viscosity of the secretions. solid dosage form, because the drug tends to pass DNase (recombinant human DNase or rhDNase, through the GI tract without dissolving, ultimately Pulmozyme) is a genetically engineered version of being eliminated in the faeces. As a weakly basic the naturally occurring enzyme that cleaves drug, however, dissolution is improved somewhat extracellular DNA in the sputum; therefore it in acidic conditions. Once in solution, the reduces its viscosity and aids sputum removal. proportion of drug in the deprotonated DNase should be administered 1 hour pre- 106 (unionised) form can be readily absorbed into physiotherapy. DNase should be administered only

Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 using a jet nebuliser. Ultrasonic nebulisers are not longer-term outcomes. Managing medication can 3 suitable because they may generate heat within the be stressful for families. Optimal clinical outcomes fluid being nebulised, resulting in the degradation depend on optimal use of a wide range of of this biopharmaceutical, and indeed others. medications: pancreatic enzymes, antibiotics, steroids, vitamins, inhalational therapies. Homecare Medicines management activities and ensuring fi Homecare medicine delivery and services can be good adherence can be a signi cant burden for described as a facility that delivers ongoing young people and their parents/carers and, when medicines supplies and, where necessary, problems and concerns arise, these can be associated care, initiated by the hospital prescriber, stressful. Shared-care protocols can present direct to the patient’s home with their consent. additional challenges for parents/carers because Operating as a registered pharmacy, the homecare formal care is shared between specialists and provider dispenses against the prescription non-specialists (whose knowledge will be variable provided by the hospital (with it effectively being a and between whom communication can be poor). private prescription) for supply to the name This can lead to potential inconsistencies in advice patient. Patients that are typically on homecare are and uncertainties for young people and parents those with chronic diseases, such as cystic fibrosis, with regard to optimal use of medicines. and stable regimens that do not require acute care Paediatric cystic fibrosis input for each supply. EXTENDED LEARNING | The benefits of using homecare for a medicine . Describe recent developments in gene such as DNase is that it minimises the therapy for cystic fibrosis. What are the inconvenience of patients having to attend barriers to successful gene therapy? Case 4 outpatient and day care appointments to receive . What are biopharmaceuticals? How are ongoing supplies, thereby releasing appointment they manufactured and formulated into ffi slots for other people and increasing e ciency. dosage forms? What particular stability There is also an opportunity to improve adherence problems may they present? to treatment through regular contact with, and . education of, patients. Homecare providers will Liposome delivery of gene therapy is one ‘ ’ often be in direct contact with the pataient, and example of the use of nanotechnology in are ideally placed through checking stocks to medicines. What other nano-sized systems identify concerns with stockpiling, which can be have pharmaceutical applications and what fi brought to the attention of the prescribing team to bene ts do they confer over conventional highlight non-adherence and minimise wastage. drug delivery approaches? Equally, the patient has an addtional point of . What strategies can formulators employ to contact in case of difficulties which can be enhance the solubility of a drug? communicated, via the homecare provider, to the ADDITIONAL PRACTICE POINT prescribing team. . Consider the particular needs of young — Medicines management in the home people with CF, as they become In addition to shared care between health increasingly responsible for their own professionals in the different healthcare sectors, medication. care in the home will be shared between children/ young people and their parents/carers. Many CF patients are young. Managing the medication for References and further reading Hanrahan JW, Sampson HM, Thomas DY (2013). Novel CF on a daily basis can be a complex task. pharmacological strategies to treat cystic fibrosis. Trends However, as this is a life-long condition many Pharmacol Sci 34:119–25. parents become ‘experts’ in its management, able Prickett M, Jain M (2013). Gene therapy in cystic fibrosis. to judge symptoms and respond appropriately. Transl Res 161:255–64. However, parents and young people will vary Ryan, G, Mukhopadhyay S, Singh M (2003). Nebulised fi anti-pseudomonal antibiotics for cystic fibrosis. Cochrane greatly in their con dence in making decisions. Database System Rev 3:CD001021. Appropriate use of medicines and good Smyth A, Tan KH, Hyman-Taylor P et al. (2005). Once versus adherence are important for daily wellbeing and three-times daily regimens of tobramycin treatment for 107

Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 3 pulmonary exacerbations of cystic fibrosis – the TOPIC UK Cystic Fibrosis Trust Antibiotic Working Group (2009). study: a randomised controlled trial. Lancet 365:573–8. Antibiotic Treatment for Cystic Fibrosis, 3rd edn. Bromley: Smyth A, Walters S. (2003). Prophylactic antibiotics for cystic Cystic Fibrosis Trust. fibrosis. Cochrane Database System Rev 3:CD001912. Wark PAB, Gibson PG, Wilson AJ (2004) Azoles for allergic Stevens DA, Moss RB, Kurup VP et al. (2003) Allergic bronchopulmonary aspergillosis associated with asthma. bronchopulmonary aspergillosis in cystic fibrosis–state of the Cochrane Database System Rev 3:CD001108. art: Cystic Fibrosis Foundation Consensus Conference. Clin Infect Dis 37(Suppl 3):S225–64.

Case 5 Cough Cough

| KATIE GREENWOOD

LEARNING OUTCOMES You determine that John has a non-productive Case 5 At the end of this case you will be able to: cough; he has no phlegm and feels that he has an irritation at the back of his throat. . Outline the pathophysiology, signs, symptoms and diagnosis of different types .? What are the treatments available for the ff of cough di erent types of cough? .? Would there be any restrictions on the . Discuss treatment options for the different products that you could sell due to the patient’s types of cough age? . Outline the chemistry and mechanism of .? What lifestyle advice, if any, would you provide? action of expectorants . Outline the chemistry and mechanism of Case discussion action of opiate antitussives A cough is the most common symptom of upper . Know when to refer a patient with a cough respiratory tract infection. It may linger after the to another healthcare professional infection has gone, because the swelling and . Effectively question a patient to help irritation in the airways can take a while to settle determine a diagnosis down. The cough can take up to 3 weeks to go completely. — Case study Pathophysiology of a cough Coughing is a reflex action initiated by stimulation John, a 17-year-old student who is one of your of sensory nerves in the lining of the respiratory ’ regular patient s teenage sons, calls into your passages. The cough reflex is a vital part of the pharmacy on the way to college. He has an body’s defence mechanisms. Normally, the lungs ‘ irritating cough and would like some medicine to and the lower respiratory passages are sterile. ’ stop him coughing so that he can concentrate on Coughing usually means that there is something in his revision and exams. He looks tired and fed up. the respiratory passages that should not be there. You notice that John smells of cigarette smoke. This can be caused either by breathing in air- .? What questions would you ask the patient? borne dust particles or if a piece of food has gone down the ‘wrong way’. If dust or dirt gets into the John explains that he has had the cough for about lungs, it could become a breeding ground for a week, following a cold. He does not take any bacteria and cause pneumonia or infection in the other medicines and does not have any medical airways. It could also be a sign that an infection in conditions. . the lungs is causing the respiratory passages to ? What is a cough? Explain the pathophysiology produce phlegm. .? What are the different types of cough and how would you differentiate between the different — Mechanism of cough production types? Mechano- and chemosensitive cough receptors 108 (afferent sensory nerve fibres) in the epithelial

Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 layer of the pharynx and trachea are fired by the coughs are irritating to the patient and also to 3 stimuli of excessive mucus or perceived foreign those around them, so the treatment is to try to body or irritant (tussigenic) chemical stimulus, and suppress the cough. A non-productive cough is impulses are transmitted to the cough centre in usually the result of a viral infection, smoking or a the medulla oblongata of the brain stem via vagal dry environment. However, it can also indicate afferent nerve fibres. Impulses are sent back, via asthma (especially if at night) or lung cancer, or efferent neurons, to respiratory muscles of the may be due to ongoing medication, e.g. ACE diaphragm, chest wall and abdomen; these inhibitors. contract, producing a deep inspiration followed by A cough can be caused by: a forced expiration of air, forcing open the glottis . Viral cough associated with a cold (tends to be and producing a cough. dry and lasts 7–10 days) — Classification of coughs: signs, symptoms and . Postnasal drip Cough causes . Allergies | There are two classifications of cough: . Croup: viral in origin, affects children aged 9– . Productive: producing sputum 18 months; barking cough. Occurs commonly Case 5 . Non-productive: dry, with no sputum. in the middle of the night, treated with steam inhalation or referral Coughs can further be classified as acute or . Chronic bronchitis (coughing up mucus on chronic. This is dependent on their duration and most days for more than 3 months for 2 years) frequency. Acute coughs last <3 weeks, whereas associated with smoking and cough worse on chronic coughs last >8 weeks. Coughs between 3 waking and 8 weeks’ duration are classified as subacute. . Asthma can present as just a non-productive Productive cough: a productive, chesty cough, is cough, especially in young children. one in which sputum/phlegm is coughed up. The oversecretion of sputum causes the cough. The A cough can also be provoked by: appearance of the sputum can often help indicate . the underlying cause of the cough: clear or white Smoking . sputum is usually of little significance; pink/frothy Sucking material into the airways from the sputum may indicate congestive heart failure, mouth . fl because the blood has congested in the lungs and Gastro-oesophageal re ux . there has been a leakage of plasma into the air Medicines, in particular ACE inhibitors used to pockets. Coloured sputum can indicate a bacterial treat hypertension and heart failure. Cough may infection and lower respiratory tract infection, develop within days of starting the course of such as bronchitis or pneumonia, where the medicine, or after a few weeks or months. ACE sputum is yellow, green, rust coloured (particularly inhibitors, in addition to their main therapeutic ff in pneumonia) and/or foul smelling, and thicker. e ects on the angiotensin production system, However, it may just represent cell debris being inhibit the breakdown of bradykinin and other cleared from the air passages. Blood might be kinins in the lungs and this triggers the ff present: this is not always a serious sign because characteristic coughing side e ect that is dry, capillaries can burst due to violent coughing, but it non-productive in type and, in some patients, ffi can be an indication for referral because it might su ciently irritating and persistent to warrant a also indicate a pulmonary embolism, tuberculosis switch in therapy to angiotensin receptor (TB), bronchitis or lung cancer. The yellow tinge antagonists . in allergic cough sputum, as can be seen in Damage to the nerves that supply the vocal asthma, is caused by the presence of large folds (known as vocal fold palsy) and chronic quantities of eosinophils from the blood as part of cough can occur. the allergic response. Rarely, coughing can be provoked by: Non-productive cough: a non-productive cough may be described as dry, tickly or irritating. It . Psychological illness produces no sputum and generally is unlikely to . Heart failure be bacterial, although this should be considered . TB along with other symptoms. Non-productive . Pneumonia 109

Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 3 . Carcinoma of the lung. Cough suppressants include opiates such as codeine, pholcodine, and dextromethorphan. — Differential diagnosis A cough with no serious underlying cause will be self-limiting; however, to confirm this, the patient has to be questioned to ensure that all the relevant information is elicited. Various acronyms can be used as an aide memoire for this questioning process, e.g. WWHAM questions: Who is the patient? What are the symptoms? — Chemical properties and actions of opiate

Cough How long have the symptoms been present? antitussives

| Action that has been taken to date? Codeine, pholcodine and dextromethorphan are all Medication already being taken? examples of opioid receptor agonists and are all Other useful pharmacy mnemonics include structurally related to the principal opium alkaloid

Case 5 ASMETHOD, ENCORE and SIT DOWN SIR: For morphine. Each contains a polycyclic four- or five- further details see: www.resourcepharm.com/pre- ring system, which includes a six-membered, reg-pharmacist/pharmacy-mnemonics.html nitrogen-containing, aliphatic heterocycle. The In practice, often a combination or selected nitrogen atom in each is therefore part of a basic, questions from these are used depending on the tertiary amino group. Codeine is a naturally patient’s presentation. It is important that you occurring analogue of morphine, being methylated determine the age of the patient, the duration of at the phenolic hydroxyl group to produce a the cough, whether it is dry or productive and, if methyl ether. In pholcodine, a synthetic analogue, productive, the appearance of the sputum. Any the methyl group of the ether is replaced by an associated symptoms such as a cold, or shortness extended chain with a morpholine ring at the end, of breath, should be established. The previous which gives the drug an additional basic centre. history relating to the cough and whether the The configuration of the ring system in patient has other medical conditions and dextromethorphan is opposite to that found in medicines should also be established. codeine and pholcodine; this can clearly be seen when comparing the structures in the diagram ff — Treatments available for the di erent types of because the ring systems are almost mirror images cough of each other (opposite relative configurations at If in doubt about phlegm production, it is best to each chiral centre). regard a cough as productive. Productive coughs: treatment of a productive cough involves encouraging the removal of the sputum and therefore should be treated with an expectorant cough mixture to help loosen the phlegm and make it easier to cough up from the airways. Expectorants contain ingredients such as guaifenesin (a glycerol derivative), ipecacuanha (derived from the dried root of the Brazilian ipecacuanha plant) and ammonium citrate/ chloride or sodium citrate. Two mechanisms of action have been suggested: stimulating bronchial mucus secretion making sputum less viscous, or irritation of the GI tract which subsequently affects the respiratory tract, the former being more probable. Non-productive coughs: these are irritating to the patient and those around them, so the treatment is 110 a cough suppressant to reduce the cough reflex.

Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 Opiate antitussives exert their effects centrally — OTC cough and cold medicines for children 3 by acting primarily on m- and k-type (G-protein- The Commission on Human Medicines (CHM) coupled) opioid receptors present on relay has advised on a package of measures to improve neurons in the brain-stem medullary cough centre safe use of cough and cold medicines for children (in or around the nucleus tractus solitarius [NTS]) aged <12 years. The advice is that parents and to inhibit neuronal firing and excitability; they do carers should no longer use OTC cough and cold this through inhibition of excitatory (glutamate) medicines in children aged <6 years: there is no neurotransmitter release and by opening evidence that they work, and they can cause side postsynaptic neuronal G-protein, inwardly effects, such as allergic reactions, effects on sleep rectifying K+ (GIRK) channels. The involvement of or hallucinations (MHRA, 2009). d-opioid receptors in the antitussive action is,

however, debatable. Cough WHEN TO REFER

Other treatments: demulcents, e.g. simple linctus | and glycerin, lemon and honey linctus, coat and . Coughing up phlegm that is green, rusty soothe the back of the throat. Antihistamines, e.g. brown, yellow, blood-stained or foul smelling diphenhydramine and promethazine, reduce the Case 5 cough reflex and also dry up nasal secretions, . Chest pain which can be useful for coughs that are caused by . Shortness of breath or wheezing a postnasal drip (mucus running down the back of . the throat) or associated with a cold. Some cough Pain and swelling in the calf (deep vein remedies also contain sympathomimetics, such as thrombosis) pseudoephedrine, for their airway-relaxing and . Recurrent night-time cough (asthma) decongestant effects, and can be useful if the . Whooping cough or croup patient has a blocked nose as well as a cough. A . Worsening smoker’s cough practical consideration for patients with diabetes is . that the cough medicine be sugar free. Sudden weight loss It should be noted that there is limited . Fever and sweating scientific evidence that cough remedies are . Hoarseness of the voice with a chronic effective, although some contain ingredients such cough that doesn’t clear up spontaneously. as paracetamol which reduce pain or fever. Thus, with the exception of antitussives, cough remedies have for many years not been prescribable on the — Lifestyle advice in this case NHS. However, some patients believe that they get Pharmacists have a major role to play in the some relief and the products are not considered government’s public health agenda. The smell of harmful (Schroeder and Fahey, 2002). cigarette smoke should lead to a conversation with There have been questions asked as to whether John about the benefits of smoking cessation and pharmacists should promote or recommend the products available. Smoking will exacerbate products with such a doubtful evidence base. the cough and therefore, even if the patient does not want to stop smoking, he or she should be encouraged to limit the number of cigarettes smoked because this will help to resolve the Legal restrictions on the sale of cough medicines cough. — Codeine A UK review of scientific evidence has concluded that the risks associated with OTC oral liquid EXTENDED LEARNING cough medicines containing codeine outweigh the . What are the respective roles of the fi < bene ts in children and young people aged 18 MHRA/EMA (European Medicines years. Consequently, OTC oral liquid medicines Agency) and CHM/CHMP (Committee for containing codeine should not be used to treat Medicinal Products for Human Use) in < cough in children and young people aged 18 medicines regulation and guidance for years (Medicines and Healthcare products health professionals? Regulatory Agency [MHRA], 2010). 111

Sample pages from Integrated Pharmacy Case Studies, published by Pharmaceutical Press, 2015 3 References and further reading Medicines and Healthcare products Regulatory Agency (2010). Blenkinsopp A, Paxton P, Blenkinsoppp J (2009). Symptoms in Codeine. London: MHRA. Available at: www.mhra.gov.uk/ the Pharmacy, 6th edn. London: Wiley- Blackwell. SearchHelp/GoogleSearch/index.htm?q=codeine%20over- Edwards C, Stillman P (2006 ). Minor Illness or Major Disease?, the-counter%20products (accessed 3 August 2012). 4th edn. London: Royal Pharmaceutical Press. Nathan A (2012). Managing Symptoms in the Pharmacy, 2nd Medicines and Healthcare products Regulatory Agency (2009). edn. London: Pharmaceutical Press. Cough and Colds in Children. London: MHRA. Available at: Rutter P (2009). Community Pharmacy: Symptoms, Diagnosis www.mhra.gov.uk/Safetyinformation/ and Treatment, 2nd edn. London: Churchill Livingstone. Safetywarningsalertsandrecalls/ Schroeder K, Fahey T (2002). Systematic review of randomised Safetywarningsandmessagesformedicines/CON038908 controlled trials of over the counter cough medicines for (accessed 3 August 2012). acute cough in adults. BMJ 324:329–31. Cough | Case 5

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