Precision Medicine and Adverse Drug Reactions Related to Cardiovascular Drugs †
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diseases Review Precision Medicine and Adverse Drug Reactions Related to Cardiovascular Drugs † James D. Noyes 1 , Ify R. Mordi 1 , Alexander S. Doney 2, Rahman Jamal 3 and Chim C. Lang 1,* 1 Division of Molecular and Clinical Medicine, School of Medicine, University of Dundee, Dundee DD1 9SY, UK; [email protected] (J.D.N.); [email protected] (I.R.M.) 2 Division of Population Health and Genomics, School of Medicine, University of Dundee, Dundee DD1 9SY, UK; [email protected] 3 UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur 56000, Malaysia; [email protected] * Correspondence: [email protected]; Tel.: +44-1382-383283 † Precision medicine in cardiology. Abstract: Cardiovascular disease remains the leading global cause of death. Early intervention, with lifestyle advice alongside appropriate medical therapies, is fundamental to reduce patient mortality among high-risk individuals. For those who live with the daily challenges of cardiovascular disease, pharmacological management aims to relieve symptoms and prevent disease progression. Despite best efforts, prescription drugs are not without their adverse effects, which can cause significant patient morbidity and consequential economic burden for healthcare systems. Patients with cardiovascular diseases are often among the most vulnerable to adverse drug reactions due to multiple co-morbidities and advanced age. Examining a patient’s genome to assess for variants that may alter drug efficacy and susceptibility to adverse reactions underpins pharmacogenomics. This strategy is increasingly being implemented in clinical cardiology to tailor patient therapies. The Citation: Noyes, J.D.; Mordi, I.R.; Doney, A.S.; Jamal, R.; Lang, C.C. identification of specific variants associated with adverse drug effects aims to predict those at greatest Precision Medicine and Adverse risk of harm, allowing alternative therapies to be given. This review will explore current guidance Drug Reactions Related to available for pharmacogenomic-based prescribing as well as exploring the potential implementation Cardiovascular Drugs. Diseases 2021, of genetic risk scores to tailor treatment. The benefits of large databases and electronic health records 9, 55. https://doi.org/10.3390/ will be discussed to help facilitate the integration of pharmacogenomics into primary care, the diseases9030055 heartland of prescribing. Academic Editor: Gaetano Santulli Keywords: precision medicine; adverse drug reaction; cardiology Received: 13 July 2021 Accepted: 9 August 2021 Published: 12 August 2021 1. Introduction The term ‘patient-centred care’ resonates throughout healthcare settings, providing a Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in constant reminder to tailor treatments to individual patients. Despite clinical similarities, published maps and institutional affil- retaining the knowledge that patients may react differently to the same intervention iations. underpins the importance of precision medicine. This is true for both pharmacological and non-pharmacological treatments. Over the last twenty years, our knowledge of why certain therapies work well on some, but not others, has improved. Recognised initially through anecdotal phenotypic variation, advances in genomics have provided the mechanistic insight to uncover drug-gene interactions. Pharmacogenomics is an exciting Copyright: © 2021 by the authors. and fast-moving field that has already broken through into drug regulatory approval Licensee MDPI, Basel, Switzerland. This article is an open access article bodies. However, much work remains in order to fully integrate these scientific advances distributed under the terms and at the bedside. This review aims to address the importance of the clinical implementation conditions of the Creative Commons of pharmacogenomics to reduce patient harm. Additionally, the strategies available to help Attribution (CC BY) license (https:// incorporate pharmacogenomic-based prescribing into clinical practice will be discussed. creativecommons.org/licenses/by/ Cardiovascular disease is the leading cause of death in the United Kingdom, and 4.0/). multiple pharmacological therapies are prescribed to vast quantities of patients for both Diseases 2021, 9, 55. https://doi.org/10.3390/diseases9030055 https://www.mdpi.com/journal/diseases Diseases 2021, 9, x FOR PEER REVIEW 2 of 11 Diseases 2021, 9, 55 Cardiovascular disease is the leading cause of death in the United Kingdom, and2 of 11 multiple pharmacological therapies are prescribed to vast quantities of patients for both primary and secondary prevention of disease. For this reason, cardiovascular therapies willprimary be the andfocus secondary of this review. prevention Despite of numerous disease. For trials this showing reason, cardiovascularthe population benefits therapies ofwill lowering be the cardiovascular focus of this review. disease Despite risk with numerous pharmacological trials showing treatments, the population it is important benefits of tolowering remember cardiovascular that many patients disease experience risk with pharmacologicalsignificant iatrogenic treatments, harm. A it systematic is important re- to viewremember identified that that many between patients 4.6 experienceand 12.1% significantof hospitalisations iatrogenic were harm. attributed A systematic to medicine review relatedidentified problems. that between Interestingly, 4.6% and they 12.1% also fo ofund hospitalisations that cardiovascular were attributed and diabetes to medicine medi- cinesrelated were problems. most often Interestingly, responsible they [1]. also Furt foundher studies that cardiovascular have shown andthat diabetes the median medicines bed staywere in mosta hospital often from responsible an adverse [1]. Furtherdrug reaction studies is have 8 days, shown resulting that the in mediana predicted bed annual stay in a costhospital to the from NHS an of adverse a staggering drug reaction £466 million is 8 days, [2]. resultingAs our main in a predictedpopulation annual demographic cost to the continuesNHS of ato staggering age, this figure £466 millionis likely [ 2to]. increase As our main significantly population over demographic the coming years. continues to age, this figure is likely to increase significantly over the coming years. 2. Pharmacological Principles 2. Pharmacological Principles Given the scale of the problem, it is important to fully appreciate the underlying mechanismsGiven behind the scale an ofadverse the problem, drug reaction. it is important There are to many fully complex appreciate factors the underlyingand inter- actionsmechanisms which ultimately behind an contribute adverse drug to this reaction. (Figure There 1). However, are many a complex basic understanding factors and inter- of pharmacologicalactions which ultimately principles contribute helps to clarify to this the (Figure role that1). However, genetic variation a basic understanding plays. Pharma- of cokineticspharmacological describes principles the actions helps that to the clarify body the carries role thatout after genetic exposure variation to a plays. drug. Pharma- There cokinetics describes the actions that the body carries out after exposure to a drug. There are four main actions: absorption, distribution, metabolism and excretion. These processes are four main actions: absorption, distribution, metabolism and excretion. These processes are dependable on enzymes and co-transporters, which are susceptible to interindividual are dependable on enzymes and co-transporters, which are susceptible to interindividual variation based on differences in the protein-coding sections of genes. The clinical effects variation based on differences in the protein-coding sections of genes. The clinical effects of such changes can be significant, resulting in harm from either under or over exposure of such changes can be significant, resulting in harm from either under or over exposure to to the drug’s therapeutic action. the drug’s therapeutic action. FigureFigure 1. 1.ContributingContributing factors factors to toan an adverse adverse drug drug reaction. reaction. Differences in genetic code can also influence how a drug acts in the body, which Differences in genetic code can also influence how a drug acts in the body, which underpins the drug’s pharmacodynamic properties. The receptor on which a drug acts on is underpins the drug’s pharmacodynamic properties. The receptor on which a drug acts on comprised of proteins that are subject to structural changes based on genetic variation. This is comprised of proteins that are subject to structural changes based on genetic variation. can markedly alter the clinical response from the drug as described before. These examples This can markedly alter the clinical response from the drug as described before. These depict the mechanisms underlying an ‘on-target’ adverse drug reaction. Nevertheless, examples depict the mechanisms underlying an ‘on-target’ adverse drug reaction. Never- despite advances in design and manufacturing, drugs are not entirely specific to their theless,intended despite target advances receptor. in They design often and act manufa on numerouscturing, other drugs receptors are not throughoutentirely specific the body to theirwith intended varying target clinical receptor. significance. They often Alterations act on numerous in ‘off-target’ other receptors, receptors caused throughout by genetic the bodyvariants, with varying can result clinical