Predicting and detecting adverse drug reactions in old age: challenges and opportunities

Increased, often inappropriate, drug exposure, pharmacokinetic and pharmacodynamic changes, reduced homeostatic reserve and frailty increase the risk of adverse drug reactions (ADRs) in the older population, thereby imposing a significant public health burden. Predicting and diagnosing ADRs in old age presents significant challenges for the clinician, even when specific risk scoring systems are available. The picture is further compounded by the potential adverse impact of several drugs on more 'global' health indicators, for example, physical function and independence, and the fragmentation of care (e.g., increased number of treating doctors and care transitions) experienced by older patients during their clinical journey. The current knowledge of drug safety in old age is also curtailed by the lack of efficacy and safety data from pre-marketing studies. Moreover, little consideration is given to individual patients' experiences and reporting of specific ADRs, particularly in the presence of cognitive impairment. Pending additional data on these issues, the close review and monitoring of individual patients' drug prescribing, clinical status and biochemical parameters remain essential to predict and detect ADRs in old age. Recently developed strategies, for example, medication reconciliation and trigger tool methodology, have the potential for ADRs risk mitigation in this population. However, more information is required on their efficacy and applicability in different healthcare settings.     

某院45例新型冠状病毒肺炎患者药品不良反应分析

目的分析我院新型冠状病毒肺炎(COVID-19)患者治疗期间发生的药品不良反应(ADR)。方法临床药师通过问卷星调查、康网系统、查阅病程等方式收集ADR,对其性别、年龄、既往病史、过敏史、报告类型、怀疑药品、用法用量、不良反应临床表现等进行回顾性分析。结果收集ADR共45例,ADR发生率为12.4%,其中一般的44例(已知的39例、新的5例)、严重的1例。ADR发生较多的为抗病毒药物洛匹那韦/利托那韦片(LPV/r)、糖皮质激素甲泼尼龙(MP)、抗菌药物莫西沙星。结论临床使用多种药物治疗COVID-19时应严格掌握用药指征以及患者基本情况、药物相互作用、注意事项等。关注疗效同时对ADR也应积极宣教、及时发现与上报,进一步保障患者安全用药。     

The role of the clinical pharmacologist in the management of adverse drug reactions.

The classical definition of clinical pharmacology is the study or the knowledge of the effects of drugs in humans. The activities of a clinical pharmacologist can vary from country to country, usually ranging from involvement in clinical trials, especially fundamental pharmacodynamic studies, to studies of pharmacokinetics and drug metabolism, to pharmacogenetics. Most clinical pharmacologists outside industry are in hospitals or university hospitals and research centres. In addition to research, this implies teaching of clinical pharmacology, and interacting with other medical staff: in the field of research, giving advice on clinical trials methodology and often managing a therapeutic drug monitoring centre. Some clinical pharmacologists have clinical departments with beds or consulting offices. Can there be another role for the clinical pharmacologist that would increase his or her usefulness for the medical community? Adverse drug reactions (ADRs) are remarkably complex events, related to drug effects, patient characteristics (background diseases, genetics), and drug/disease interactions. Evaluation of ADRs requires understanding of drug mechanisms and interactions, and of disease diagnostics, especially in the discussion of alternative diagnoses. This implies expertise as a pharmacologist and a clinician. In addition, because not all adverse reactions or interactions are in the Summary of Product Characteristics, and because problems arise long before they report in the literature, it is necessary for the clinical pharmacologist to have knowledge of ongoing regulatory processes, in addition to having access to the published literature. Helping clinicians cope with individual patient problems will also improve the clinical pharmacologist's integration into the healthcare process.     

Rational pharmacotherapy and pharmacovigilance

Pharmacovigilance is defined as "the detection, evaluation, understanding and prevention of adverse drug reactions (ADRs)". The ultimate aim of pharmacovigilance is the optimization of the risk-benefit ratio of marketed drugs at the individual level (i.e. the choice of the most suitable treatment for a given patient) and at the population level (i.e. maintenance or removal of a drug from the market, informing prescribers of its potential risks, etc.). Prevalence of drug-related morbidity and mortality increase in correlation with the increase in drug use. Both physicians and patients prefer polypharmacy because of different reasons such as insufficient knowledge, lack of enough time for the patients, being misled by non-scientific newspaper/TV news, etc. Polypharmacy is among the major causes of drug-related morbidity and requires additional medication as treatment. On the other hand, adverse reactions might be minimized by adequate knowledge and rational prescribing, simply by reducing inappropriate polypharmacy. Therefore, physicians' prescribing habits based on rational pharmacotherapy processes which include choosing suitable drug(s), at an optimum dose and duration of use, among the effective and safe treatment alternatives, and informing patients about the diagnosis and treatment, can be a major contribution to optimize the risk-benefit ratio of drugs. As an essential step in the rational pharmacotherapy process, giving adequate information to the patients about their treatment (i.e. dosage, use instructions, warnings, effects, side effects, etc.) may prevent some of the drug-related problems. In addition, informed patients are more likely to seek advice from their physicians to seek advice for ADRs. In this review article, therefore, the influence of rational pharmacotherapy training on the pharmacovigilance of drugs will be discussed.     

Are drugs really toxic for older people?

Many diseases are now treatable with modern drugs. Elderly people, because they suffer from age-related illnesses, stand to gain the most, but they are also at risk from adverse drug reactions (ADRs). There are complex reasons for the increased frequency of ADRs, including poor prescribing, polypharmacy, altered drug handling and response, and poor compliance. Difficulties with interpretation of apparent ADR data include uncertainties about exposure and various confounding factors, for example, confounding by indication. Some simple prescribing guidelines can significantly help to minimise the extent of the clinical problem. These include:     

Are drugs really toxic for older people?

Many diseases are now treatable with modern drugs. Elderly people, because they suffer from age-related illnesses, stand to gain the most, but they are also at risk from adverse drug reactions (ADRs). There are complex reasons for the increased frequency of ADRs, including poor prescribing, polypharmacy, altered drug handling and response, and poor compliance. Difficulties with interpretation of apparent ADR data include uncertainties about exposure and various confounding factors, for example, confounding by indication. Some simple prescribing guidelines can significantly help to minimise the extent of the clinical problem. These include:     

Early clinical evaluation in man: the buck stops here

The development of new drugs as potential therapeutic agents involves multi-discipline 'team' research. The clinician has to deal with scientific and ethical issues and keep in mind the axiom 'Primum no nocere--Above all, do no harm.' The clinical pharmacologist has to address the pharmacologic actions of a potential new drug and if any antidotes are available. Species in pharmacologic actions, assessment of animal laboratory data to determine the sensitive organs, and the role of drug metabolism in evaluating and correlating animal data all need to be addressed. The clinical pharmacologist has an important role in new drug development which is unique and includes the responsibility to ensure the welfare of the volunteer subjects or patients.     

Database size and power to detect safety signals in pharmacovigilance

Most regulatory agencies and pharmaceutical companies focus the majority of their pharmacovigilance on safety signal identification in large databases. GlaxoSmithKline (GSK) has > 100 drugs marketed worldwide. In order to determine which database has the highest statistical power to detect safety signals in three large global databases, ten GSK marketed drugs were randomly selected for review in the three databases. At the time of data lock, the FDA database (Adverse Event Reporting System [AERS]) contained approximately 6.2 million total records of adverse drug reactions (ADRs). The WHO database (VIGIBASE) contained 7.2 million total records of ADRs. GSK's global safety database (OCEANS) contained approximately 2 million total ADRs for all of its marketed drugs. For the ten drugs selected, there was an average of 7566 reports found in AERS, 8661 reports found in VIGIBASE and 15,496 reports in OCEANS. The information from all three databases was used in pairs (AERS/OCEANS; AERS/VIGIBASE; and OCEANS/VIGIBASE) to calculate power using the maximum likelihood estimation. The OCEANS database contained more ADRs for all 10 drugs than AERS. OCEANS also contained more ADRs for 8/10 drugs than VIGIBASE. The highest statistical power to detect safety signals was determined by the pair of databases which had the greatest number of reports for the given drug. Based on this data, it was concluded that the highest power may be achieved by combining those databases with the most drug-specific data. It is also believe that early safety signal detection should involve the use of multiple large global databases because this permits the use of the largest number of reports for a given drug, and that reliance on a single database may reduce statistical power and diversity of ADRs.     

Patients' role in reporting adverse drug reactions

This review discusses the involvement of patients in the reporting of adverse drug reactions (ADRs). Patients benefit from drugs but also experience their adverse effects. Since concerns about the safety of drugs are also patients' concerns, the patient could also play a part in decreasing the risks of drug therapy. Patient interest in the safety aspects of drugs is evident. At an international level, the merits of patient reports are being considered. To date, the literature does not yet provide any actual results in relation to the detection of ADRs by patients. Different considerations regarding ADR reporting by patients are discussed. The authors conclude that we should positively value patients' involvement in drug therapy and their concern regarding possible adverse effects. As a consequence, patients' reports on ADRs should be accepted.     

Patients’ role in reporting adverse drug reactions

This review discusses the involvement of patients in the reporting of adverse drug reactions (ADRs). Patients benefit from drugs but also experience their adverse effects. Since concerns about the safety of drugs are also patients’ concerns, the patient could also play a part in decreasing the risks of drug therapy. Patient interest in the safety aspects of drugs is evident. At an international level, the merits of patient reports are being considered. To date, the literature does not yet provide any actual results in relation to the detection of ADRs by patients. Different considerations regarding ADR reporting by patients are discussed. The authors conclude that we should positively value patients’ involvement in drug therapy and their concern regarding possible adverse effects. As a consequence, patients’ reports on ADRs should be accepted.     

Can pharmacogenetics help rescue drugs withdrawn from the market?

Observations over the later half of the last century have suggested that genetic factors may be the prime determinant of drug response, at least for some drugs. Retrospectively gathered data have provided further support to the notion that genotype-based prescribing will improve the overall efficacy rates and minimize adverse drug reactions (ADRs), making personalized medicine a reality. During the last 16 years, 38 drugs have been withdrawn from major markets due to safety concerns. Inevitably, a question arises as to whether it might be possible to 'rescue' some of these drugs by promoting genotype-based prescribing. However, ironically pharmacogenetics has not perceptibly improved the risk/benefit of a large number of genetically susceptible drugs that are already in wide clinical use and are associated with serious ADRs. Drug-induced hepatotoxicity and QT interval prolongation (with or without torsade de pointes) account for 24 (63%) of these 38 drug withdrawals. In terms of the number of drugs implicated, both these toxicities are on the increase. Many others have had to be withdrawn due to their inappropriate use. This paper discusses the criteria that a drug would need to fulfill, and summarizes the likely regulatory requirements, before its pharmacogenetic rescue can be considered to be realistic. One drug that fulfils these criteria is perhexiline (withdrawn worldwide in 1988) and is discussed in some detail. For the majority of these 38 drugs there are, at present, no candidates for genetic traits to which the toxicity that led to their withdrawal may be linked. For a few other drugs where a potential candidate for a genetic trait might explain the toxicity of concern, the majority of patients who experienced the index toxicity had easily managed nongenetic risk factors. It may be possible to rescue these drugs simply by careful attention to their dose, interaction potential and prescribing patterns, but without the need for any pharmacogenetic test. In addition, the pharmacogenetic rescue of drugs might not be as effective as anticipated as hardly any pharmacogenetic test is known to have the required test efficiency to promote individualized therapy. Multiple pathways of drug elimination, contribution to toxicity by metabolites as well as the parent drug, gene-gene interactions, multiple mechanisms of toxicity and inadequate characterization of phenotype account for this lack of highly predictive tests. The clinical use of tests that lack the required efficiency carries the risks of over- or under-dosing some patients, denying the drug to others and decreasing physician vigilance of patients. Above all, at present, prescribing physicians lack an adequate understanding of pharmacogenetics and its limitations. It is also questionable whether their prescribing will comply with the requirements for pretreatment pharmacogenetic tests to make pharmacogenetic rescue a realistic goal.     

Post marketing surveillance of 13 products: safety and effectiveness

We surveyed the safety and effectiveness of 13 drug products under the reexamination system in Japan. Until the time of reexamination, a total of 106,328 case reporting forms were collected in the drug use investigations, while 1340 adverse drug reactions (ADRs) were reported in the spontaneous case reporting on ADRs. In the drug use investigations, the data were primarily obtained on the incidence of unexpected ADRs and the incidence of ADRs in special patient populations. The spontaneously reported ADR provided the data on serious and unexpected ADRs. We established proper use of the 13 products by examining the data for significant risk factors for serious ADRs, including agranulocytosis, jaundice, hypotension, and QT prolongation. We revised the package inserts of the 13 products with the new safety information a total of 50 times and passed on the revisions to health care professionals. We also assessed the safety and effectiveness of the 13 products compared with that before marketing. We summarized the data and submitted them to the Japanese Ministry of Health and Welfare (JMHW). For all 13 products, the same indications and dosage and administration as those approved previously were approved at the reexamination.     

Collecting data about drug use by elderly people

A random sample of 805 people aged 65 or more were interviewed in their homes in England about the drugs they were taking, and about their experiences with and views about the way drugs were prescribed. Assessments by a pharmacologist and pharmacists identified inappropriate prescribing and labelling and revealed the extent of elderly people's knowledge of their drugs. Information obtained from general practitioners, with the consent of the elderly people, showed that over a third of the elderly people were taking prescribed drugs of which their physician was unaware, but over four-fifths of the drugs reported by both patients and physicians were thought by both groups to be taken appropriately or as prescribed. The processes and problems of drug utilization and drug prescribing are demonstrated by approaching both patients and physicians and further illuminated by the expertise of pharmacologist and pharmacist.     

Major issues facing the pharmaceutical industry and their relationship to clinical pharmacy

There are two major issues that have potential for positive interactions between the industry and clinical pharmacy. These are drug selection and reimbursement, and clinical research. The first issue embodies the drug prescribing process, which has been, until recently, almost the sole purview of physicians. For this reason, pharmaceutical manufacturers have marketed their products primarily to this group. Changes are occurring; other licensed practitioners, including clinical pharmacists, are gaining prescribing authority. Schools of pharmacy have trained several thousand clinical pharmacists over the past decade, while the pharmacology component of medical education and the time devoted to clinical therapeutics either has stagnated or declined during the same period. Meanwhile, drug information has increased and the need to monitor drug selection to curtail costs has widened the opportunities for clinical pharmacists to exert an influence. The pharmaceutical industry needs to recognize the role clinical pharmacists play in drug selection. Drug selection decisions obviously influence drug reimbursement decisions, which influence drug sales, which influence profits. Clinical research is the backbone of a company's financial success and is becoming technologically sophisticated. Companies are becoming aware that many clinical pharmacists are able to collect and analyze clinical drug data as well as, or possibly better than, physicians. Clinical pharmacists can play a significant role in monitoring the safety and efficacy of marketed drugs. Good postmarketing surveillance data collection systems need to be developed.     

Retrospective clinical analysis for drug rescue: for new indications or stratified patient groups

The increasing realization that many existing drugs do indeed provide opportunities for additional therapeutic indications suggests we should not only be alert for this potential among marketed drugs but also within the pool of developmental drugs, of which (owing to attrition) there are many more examples in existence. We present examples of drug repurposing by retrospective clinical trial analysis and suggest that this strategy presents a promising way of rescuing failed developmental candidates. We contend that the commercial barriers to successful drug rescue are less problematic than for drug repurposing. We indicate practical means for mining data from past clinical trials, either for new indications or for specific patient groups.     

浅析双氯芬酸钠的药物联用

双氯芬酸钠在临床上被广泛应用于镇痛、消炎,但出现胃肠道不良反应几率较大。将双氯芬酸钠与其他药物联用,能达到较好疗效并减少药物不良反应(ADRs)发生几率。本文通过查阅近十年国内外与双氯芬酸钠相关的文献报道,综合整理分析了双氯芬酸钠与抗炎药物、镇痛药物、胃肠道保护药物、传统中药等的联用状况、疗效及ADRs,为双氯芬酸钠与其他药物临床联用时的有效性与安全性提供了相关信息与参考依据。     

New drugs of 2001

OBJECTIVE: To provide information regarding the most important properties of the new therapeutic agents marketed in 2001. DATA SOURCES: Published studies, drug information reference sources, and product labeling. DATA SYNTHESIS: In 2001, 26 new therapeutic agents were marketed. The indications and information on dosage and administration for the new agents are reviewed, as are the most important pharmacokinetic properties, adverse events, drug interactions, and other precautions. Practical considerations for the use of the new agents are also discussed. Where possible, the properties of the new drugs are compared with those of older drugs marketed for the same indications. CONCLUSION: A number of the new therapeutic agents marketed in 2001 have important advantages over older medications. An understanding of the properties of these agents is important if the pharmacist is to effectively counsel patients about their use and to serve as a valuable source of information for other health professionals regarding these drugs.     

New drugs of 2002

OBJECTIVE: To provide information regarding the most important properties of the new therapeutic agents marketed in 2002. DATA SOURCES: Published studies, drug information reference sources, and product labeling. DATA SYNTHESIS: In 2002, 26 new therapeutic agents were marketed. The indications and information on dosage and administration for the new agents are reviewed, as are the most important pharmacokinetic properties, adverse events, drug interactions, and other precautions. Practical considerations for the use of the new agents are also discussed. Where possible, the properties of the new drugs are compared with those of other drugs marketed for the same indications. CONCLUSION: A number of the new therapeutic agents marketed in 2002 have important advantages over older medications. An understanding of the properties of these agents is important for the pharmacist to effectively counsel patients about their use and to serve as a valuable source of information for other health professionals regarding these drugs.     

New drugs of 2000

OBJECTIVE: To provide information regarding the most important properties of the new therapeutic agents marketed in 2000. DATA SOURCES: Published studies, drug information reference sources, and product labeling. DATA SYNTHESIS: In 2000, 33 new therapeutic agents were marketed. The indications and information on dosage and administration for the new agents are reviewed, as are the most important pharmacokinetic properties, adverse events, drug interactions, and other precautions. Practical considerations for the use of the new agents are also discussed. Where possible, the properties of the new drugs are compared with those of older drugs marketed for the same indications. CONCLUSION: A number of the new therapeutic agents marketed in 2000 have important advantages over older medications. An understanding of the properties of these agents is important if the pharmacist is to effectively counsel patients about their use and to serve as a valuable source of information for other health care professionals regarding these drugs.