Drug Safety among Older People

#### **Chapter 7**

## Pharmacovigilance in Older Adults

*Daniel Gomes, Eva Rebelo Gomes, Inês Ribeiro-Vaz, Maria Teresa Herdeiro and Fátima Roque*

#### **Abstract**

Polypharmacy and physiological changes inherent to the aging process can cause significant modifications in the pharmacokinetic and dynamic regimens of drugs, making the elderly more susceptible to adverse drug effects. Adverse drug reactions (ADR) in older adults have a significant impact on hospital admissions, increasing hospital stay and healthcare costs. Most common ADR in this population are doserelated and predictable. However, they can be difficult to diagnose as they often have nonspecific symptoms. This could be minimized by decreasing the use and prescription of potentially inappropriate medication and being aware of possible drug interactions. Besides, being older patients underrepresented in clinical trials and due to their physiological modifications, serious or atypical ADR are more common in this age range. To minimize harm in older adults, effective pharmacovigilance must be encouraged.

**Keywords:** Elderly, Medication, Adverse Drug Reactions, Drug Safety, Pharmacovigilance

#### **1. Introduction**

The World Health Organization [WHO] estimates that more than half of medicines are either inappropriately prescribed, dispensed, or sold, as the vast majority of patients fail to take their medication properly [1]. Adding the fact that no drug, taken correctly, is completely risk-free, it becomes of the outmost importance to permanently monitor its safety, to ensure that, throughout its life cycle, the benefits of each drug outweigh the risks of its use [2]. Pharmacovigilance intends to promote patient care and safety as well as an effective assessment of the risk–benefit profile of drugs [3].

With declining fertility rates and greater and better access to health care, the population aged, and the number of older adults has increased globally [4].

Aging is a risk factor for the development of chronic diseases, and to an increased incidence of pathologies such as cardiovascular diseases, strokes, cancer, or dementias. In this sense, the older population is the age group that most needs health care and medicines [5, 6]. Polypharmacy, commonly defined as the concomitant use of at least five drugs, is thus prevalent in this age group [7, 8].

Associated with aging, pharmacodynamic and pharmacokinetic changes occur at physiological level, which implies modified pharmacological responses [9]. The older are much more susceptible to adverse reactions and drug interactions than any other age group [7, 8].

Since people aged 65 and older are underrepresented in clinical trials pharmacovigilance becomes essential to allow continuous monitoring of safety and the assessment of the benefit/risk of drugs in this population [10].

#### **2. Physiological and pharmacological modifications**

The impact of aging on the human organism brings together complex changes at the molecular, cellular and tissue levels in all systems of the organism, and the effects of the most varied existing environmental factors [11, 12].

The physiological changes associated with the aging process weaken the older population. These can cause significant changes in the pharmacokinetic and dynamic regimens of medications, making them more susceptible to adverse effects [13].

#### **2.1 Age-related changes in pharmacokinetics**

With aging, pharmacokinetics processes suffer modifications [9]. Bioavailability, the extent and rate at which the active substance enters the systemic circulation to reach the action site, can be modified [9, 14].

Absorption of most drugs does not appear to decrease significantly with age, but different pathologies of the digestive system may affect drug absorption [9]. Nevertheless, drugs administered intramuscularly or subcutaneously may have their absorption modified, due to the reduction in blood perfusion of the tissues [15].

After absorption, the drug enters the bloodstream and is distributed to different tissues and organs. With the increase in fat mass and reduction in the volume of water, the volume of distribution of fat-soluble medications increases [as does the half-life of the same], as in the case for the long-acting benzodiazepines [15, 16]. In contrast, water-soluble drugs may have a lower volume of distribution, with an increase in plasma concentrations, that can be toxic, as happens with gentamicin, digoxin, theophylline, and cimetidine [9, 16]. In addition to body composition, the two main proteins involved in the transport of drugs: albumin, which binds to acidic drugs [e.g. warfarin, digoxin, lorazepam], and α1-acid glycoprotein, which binds mainly to basic drugs [ex: lidocaine, propranolol] may have their plasma concentrations altered in older population with comorbidities [15, 17].

Although other organs can metabolize drugs, the liver is the main organ involved in the process. Metabolism consists of converting an active substance in simpler and more polar substances, called metabolites, from phase I and II reactions. These metabolites are inactive or have modified activity. In the liver, maintaining its functions during aging, there are changes that can reduce its functionality [18]. The hepatic volume decreases 20–30%, and the hepatic blood flow 20–50%. There is a reduction in the first-pass hepatic effect, and thus the bioavailability of drugs that are subjected to extensive first-pass metabolism may be increased, while others, which need activation in the liver, may be reduced [15]. In addition, the hepatic clearance of drugs subjected to limited flow metabolism [e.g., propranolol and amitriptyline] can be reduced by more than 40%. Age can significantly affect the pharmacokinetics of drugs with a narrow therapeutic index [reduced margin between an effective dose and a toxic dose]. Inflammatory conditions can also affect the function of the enzymes involved in metabolism. The microbial ecosystem also stands out, with many clinically relevant drugs being co-metabolized by microflora. With changes in the composition of the intestinal microbiome, the drug's metabolism can also be altered with harmful consequences [19].

#### *Pharmacovigilance in Older Adults DOI: http://dx.doi.org/10.5772/intechopen.98665*

Excretion is also affected by the aging process. The kidney is the main organ in the removal of drugs and their metabolites and the pharmacokinetics are strongly influenced by the progressive loss of kidney function with age, thereby decreasing the excretion of drugs [20, 21]. Due to these changes, a decline in total clearance with age is expected for drugs predominantly excreted by this pathway. With the decrease in clearance, serum levels will increase, potentially causing ADR [22]. Therefore, the dosage of these drugs must be guided by kidney function and the glomerular filtration rate [GFR]. In addition, polypharmacy can increase the risk of kidney dysfunction, overloading the kidneys to excrete several drugs and their metabolites at the same time [23].

#### **2.2 Age-related changes in pharmacodynamics**

In older adults' sensitivity, meaning the effects of the same concentration of a particular drug at the site of action, vary significantly when comparing with young or adult persons. This difference can be justified by changes in drug-receptor interaction, signal transduction, adaptive homeostatic responses and, among more fragile patients, by comorbidities [24, 25]. Although age-related pharmacokinetic changes are predictable, the complex interaction between pharmacokinetic changes and homeostatic changes makes it a difficult topic to study [15].

The most relevant pharmacodynamic changes are at the central nervous system [CNS] and cardiovascular level [15]. Older adults often demonstrate an exaggerated response to psychoactive drugs due to an underlying age-related decline in CNS function, and are also more prone to adverse effects with cognitive impairment, including confusion and drowsiness. At the cardiovascular level, they may experience a greater decline in blood pressure after administration of calcium channel blockers with or without dihydropyridine, which may be the result of related changes with age in the reflex of the baroreceptors, as well as a decreased clearance of these drugs [25, 26]. In addition, β-adrenergic receptors decrease in numbers and have less sensitivity and also show changes in the G-protein involved in signal transduction. As a result, β-adrenergic activity in vascular, cardiac and respiratory tissue decreases, altering the effect of β-blocking agents and β-agonists in general [26, 27].

Pharmacodynamics not only affects the therapeutic effects of the drug but can also change the magnitude of the effect with subsequent adverse effects [20, 25]. These changes in pharmacokinetics and pharmacodynamics can thus make the older population more prone and susceptible to ADRs, either in normal therapeutic doses or by drug interactions mechanisms [27].

#### **3. Adverse drug reactions in older adults**

As previous mentioned, physiological aging causes pharmacodynamic and pharmacokinetic changes, imposing different pharmacological responses [9]. The drug could trigger iatrogenic problems in the geriatric patient, increasing the risk of possible ADR [28].

The vast majority of ADRs can be divided in 2 types:


reactions are therefore unpredictable and more serious, usually detected only after the drug enters the market: Type B - Bizarre, representing 20% of all ADRs in older patients [29–32].

Drugs associated with type A reactions are generally of low therapeutic index and are commonly used in older patients and therefore most ADRs in this age group are type A reactions with predictable pharmacological effect [30, 33]. Known homeostatic dysregulation, age-related changes in pharmacokinetics and pharmacodynamics and drug interactions make ADRs definitely or possibly preventable in this population. However, ADRs can be difficult to diagnose in older patients as they often have nonspecific symptoms, whether falls, fatigue, cognitive decline, or constipation, all of which have different etiologies [7]. Despite the difficulties it is estimated an average prevalence of 11% of ADR [33].

Most common ADRs causing hospitalization in older patients are related to Gastrointestinal complications [Gastrointestinal bleeding, peptic ulcer, erosive gastritis, nausea, vomiting]; Cardiovascular disorders [Hypotension, bradycardia, falls, arrhythmias] Metabolic/endocrine complications [Hypoglycemia]; Renal and urinary disorders [Renal impairment, acute renal failure]; Electrolyte disorders [Hypokalemia, hyperkalemia, hyponatremia]; Nervous system disorders [Depressed level of consciousness, mental status changes] [34]. Studies have shown that beta-blockers, antibiotics, oral anticoagulants, digoxin, ACE inhibitors, antineoplastics, calcium entry blockers, opioids, oral antidiabetics and most frequently NSAIDs as the main drug classes causing ADR hospitalization in older adults [33, 35].

#### **3.1 The healthcare impact of ADR in older patients**

ADRs cause a significant burden in healthcare services, representing 6.5% in hospital admissions, being responsible for death of 0.15% of the patients admitted. Besides, patients admitted with ADRs were significantly older than patients without ADRs, as hospitalization due to NSAIDs complications increases exponentially with aging, having an important impact in healthcare resources. The median prevalence of ADRs leading to hospitalization is 10%. Although some hospitalizations related to ADRs are inevitable, it is estimated that only 18.6–28% of ADR cases that caused hospitalization in older patients were considered inevitable. Severe ADRs are related mostly to hematological disorders and acute renal failure [33, 34].

Polypharmacy is one of the main risk factors for ADR in this population. The risk of ADR increases by 13% in patients taking two drugs to 58% when taking five and to 82% when taking seven or more drugs [4, 7]. Drug interactions, common in polypharmacy, can cause synergistic toxicity and thus be risk factors, such as the combination of corticosteroids and NSAIDs. Polypharmacy leads to problems in medication adherence and correct administration representing a risk for adverse events or ADR [31, 36, 37].

ADRs also have a strong economic impact in the health system. The costs involved in treatment are mainly associated with hospitalization, prolonged hospital stay and additional clinical investigations- Studies point to an average of 8 additional hospital stay days and costs of approximately 706 M € per year [38, 39]. Regarding avoidable ADRs, costs per hospitalization vary between € 2,851 - 9,015, with length of hospital stay between 4.2 and 13 days. In outpatient, the costs resulting from avoidable ADRs ranged between € 174 and € 8,515 [38]. Particularly in the elderly, an average cost of emergency care of 333 US \$ is pointed, with severe ADR patients costing \$ 691 per patient and \$ 7,529 per patient with severe ADR during hospitalization [40].

#### *Pharmacovigilance in Older Adults DOI: http://dx.doi.org/10.5772/intechopen.98665*

ADRs can trigger cascades of prescription when new drugs are prescribed for problems resulting from another medication, which is usually an unknown ADR, increasing therapeutic costs, in addition to increasing the risk of new ADRs. Fever, hemorrhage, diarrhea and arrhythmia are those with the greatest economic burden in a hospital environment; and NSAIDs, antibiotics, anticoagulants and antineoplastics are the main classes involved in ADRs related costs [39].

Most drugs are suitable for the older, as long as they are used in the correct dose and for the necessary period. However, since they are more susceptible to adverse events, the potential risk of certain drugs may outweigh the potential benefit. When safer alternatives are available, these drugs are considered inappropriate [PIM] [28, 41].

#### **3.2 Potentially inappropriate medication for older adults**

In recent years, in order to reduce inappropriate prescribing, and in turn, to reduce the prevalence of PIM in older population, explicit and implicit criteria strategies and tools have been developed, being very useful in clinical practice, as decision support- Explicit criteria consists in lists of drugs applied with minimal information and clinical evaluation, not considering individual differences between patients, representing important alert mechanisms on the possibility of the inappropriate use of a medication just by itself, as where implicit criteria focus on the patient's therapeutic regimen and clinical evaluation. Associating these criteria with information management tools such as Clinical decision support systems [CDSS] can allow improvements in patient therapy. These CSSDs, usually computerized, can verify interactions between medicine-disease or medicine-medicine, also detecting PIM [36].

Among the criteria most applied in research within this theme, Beers criteria stands out. In 1991, Beers and his research colleagues met with geriatric and pharmaceutical specialists to list the drugs to be avoided by older people. Explicit criteria were defined, considering 30 drugs/pharmacological groups considered inappropriate. These criteria have since been repeatedly reformulated and updated according to new information in the literature. Currently, these criteria are divided into 5 lists: Potentially inappropriate to be avoided in the elderly; Potentially inappropriate in the elderly due to drug–drug and/or drug-disease interactions; Those that should be prescribed with caution in the elderly; Combinations of drugs known to cause "drug–drug" interactions; Drugs to be avoided or whose dose adjustment is necessary when prescribed in elderly people with impaired renal function [42, 43]. However, its application in Europe is limited, where several of the drugs identified in these criteria are not commercialized in this continent and some of the drugs marketed in Europe are inappropriate and are not on the Beers list [44].

START/ STOPP criteria is also currently used. The STOPP [Screening Tool of Older Person's potentially inappropriate Prescriptions] criteria are 80 parameters organized by physiological systems. The START [Screening Tool to Alert doctors to Right Treatment], on the other hand, identify potentially beneficial omissions [which should be prescribed to the elderly], with 34 criteria divided into six physiological systems [44]. STOPP/START have advantages over Beers because they are significantly associated with adverse drug reactions. In addition, they are more in line with the European reality, also having greater sensitivity demonstrated for the identification of inappropriate prescriptions. Although the STOPP criteria is explicit, only 29 of the 81 STOPP criteria can be applied only with information on the patient's medication profile [36].

Recently, in order to develop a European list of potentially inappropriate drugs, 27 experts from 7 countries in Europe came together, creating the EU [7] -PIM list, with

282 drugs from 34 pharmacological classes in which it is found, for each drug, the justification for its inadequacy, as well as dose adjustments/special considerations of use [when applicable] and possible alternatives to that drug [45].

The EU [7]-PIM list has been used in some studies in Europe that show a range between 40.9 [Sweden] and 87% [Portugal] of older adults having PIM prescribed by the physician. Proton bomb inhibitors, Bromazepam, Diazepam, Lorazepam and Alprazolam are the most common [46].

ADRs related to PIMs were observed in some studies, with digoxin, benzodiazepines, and imipraminic antidepressants, being the most common. In hospitalized older patients, NSAIDs were the most common types of PIM-ADRs, inducing upper gastrointestinal bleeding. Benzodiazepines inducing falls with fractures and depressed mental status, as well as digoxin >0.125 mg/day inducing cardiac arrhythmias and visual disturbances due to digoxin poisoning are also common in hospital context [47, 48].

#### **4. Promoting drug safety in older adults**

Older adults have a higher chronic diseases burden and consume more prescription drugs than any other age group. Besides drug–drug interactions, the prevalence of concurrent use of prescription drugs and herbal medicinal products [HMPs] by older adults is significant, and can also lead to serious ADR, as risk of bleeding due to the use concomitant use of *Ginkgo biloba*, garlic or ginseng with antithrombotics [49].

#### **4.1 Older participants in clinical trials**

Including older patients in the clinical trial process is important, as on average older adults carry 60% of the national disease burden but represent only 32% of participants in Phase II and III clinical trials [50, 51]. This population is underrepresented, especially the >75-year-old. and current guidelines recommend to have a significant number of older participants in the trials [that can be estimated with the help of epidemiological studies targeting the disease that the drug intends to treat] in order to assess the risk–benefit ratio of the drug in this age group. Phase I trials might not need older participants, but phase II and III clinical trials should include them, to assess dosage, safety, adverse effects, and effectiveness [52, 53]. Decentralized clinical trials could facilitate the appropriate inclusion of these patients [50].

Nevertheless, including this age group implies some methodological considerations. As it exists a progressive impairment of the renal or hepatic function or drug–drug interactions, an appropriate assessment of pharmacokinetic profiles and pharmacodynamic endpoints are needed [54, 55]. Besides, since they have a high risk of cognitive function impairment, determining adverse CNS events is of the outmost relevant clinical importance during the trial design. Aware of these needs, the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use [ICH] developed guidelines for studies in special populations, namely older adults, aiming for a sufficient representation in phase III. It is advisable 100 minimum participants and, when the disease is associated with aging, older people should form most of the participants [55, 56].

These studies should compare older and younger patients or evaluate drug disease interaction studies in older adults. Population pharmacokinetic analyses intends to determine the sources and correlation of variability of the drug concentration in the target patient population, comparing the older with the young group.

#### *Pharmacovigilance in Older Adults DOI: http://dx.doi.org/10.5772/intechopen.98665*

Safety and efficacy should also be of the outmost importance, as outcomes must be explored to provide evidence base support to the dose selection during drug approval, impacting regulatory procedures. Finding significant differences in safety and efficacy outcomes between young and older patients, pharmacokinetic studies plays an important role to understand these differences and assess benefit–risk of a drug administration [55–57].

#### **4.2 Medication labelling**

After drug development, providing quality information to health care professionals about the safe and effective use of drugs in geriatric patients is fundamental. And so, it is required by the Food and Drug Administration [FDA] and the European Medicines Agency [EMA] that the labeling of these drugs must have safety and efficacy information for the older. Particularly for EMA, it is mandatory to present on the Summary of Product Characteristics [SmPC] and the Patient Information Leaflet information regarding dosage, frequency and seriousness of ADR, or the need of monitoring in this population [57, 58].

#### **4.3 Pharmacovigilance in older patients**

Pharmacovigilance plays a key role in ADR detection in post authorization period, improving the safe and rational drug use and thereby improving patient care [59, 52]. In 2012, new legislation came into force within EU, creating the Pharmacovigilance Risk Assessment Committee and giving a central role to pharmacovigilance. A significant increase in the participation of health professionals and patients in the system was seen, and the electronic transmission of information from Pharmacovigilance became mandatory in November 2005, with EudraVigilance being the system for analyzing and managing information on suspected ADR, allowing the electronic exchange of reports of ADR cases, used by the various partners of the European regulatory network to monitor the safety of medicines [60].

A strong pharmacovigilance system can perform safety surveillance with processes, tools, and experts to monitor ADRs from medication taken by older patients. During this post-authorization surveillance, safety risks may be detected, particularly in patients with comorbidity and polypharmacy, suffering physiologic changes inherent to the aging process [61, 62]. Adequate pharmacovigilance systems considering HMPs is also necessary to increase the likelihood of ADR detection, and appropriately identify and manage older patients at risk [49, 63].

Risk management plans [RMP] must also be submitted to EMA when applying for a marketing authorization, including relevant information on medicine's safety profile, how the risks will be prevented or minimized and how to promote knowledge regarding safety and efficacy of a determined drug.. The elaboration of this document allows the understanding of safety concerns in older adults, planning how to reduce the possibility of suffering ADR. The RMP must be modified whenever it is determined important safety risks, as well as the labeling [54, 64].

Nevertheless, signal detection using spontaneous reporting systems is one of the most important sources for safety monitoring in post authorization "real-life" setting, especially in populations underrepresented in preapproval clinical trials such as older adults [61, 62]. Even tough underreporting, low sensitivity and selectivity are disadvantages to be considered regarding this reporting system, the fact that broadens all medicines on the market throughout all the life cycle, in all patients, not interfering with prescription habits, not only allows the identification of common ADR, as well as rare, unexpected ADRs in groups and scenarios not studied, as the older patients. This makes spontaneous reporting a fundamental report system for the safety monitoring of approved medicines [60, 65]. Due to the widespread of under-reporting of ADRs to spontaneous reporting systems, including serious or severe ADRs, the use of new technology is a great opportunity to empower patients to report, such as the programmes WEB-RADR [66] in Europe and Medwatch [67] in the United States. Although these tools were developed to facilitate reporting by both healthcare professionals and patients, a better understanding of the relation that the older patients have with health technologies is need [68].

In the European Economic Area [EEA], the electronic transmission of information from Pharmacovigilance became mandatory in November 2005, with EudraVigilance being the system for analyzing and managing information on suspected ADR, facilitating electronic exchange of individual case safety reports between EMA, national competent authorities, marketing authorization holders and sponsors of clinical trials in the EEA, as it allows early detection and evaluation of possible safety signals [60, 69].

EudraVigilance allows researchers and/or interested readers to perform same analysis in the ADR database EudraVigilance of the EMA, even though with different levels of access for different stakeholders. As some studies explore national databases, some studies have explored EudraVigilance database, accessing suspected medication and common ADR reported in older adults. Antineoplastic and immunomodulating agents, Nervous system, Cardiovascular system, Blood, and blood forming organs represent a significant part of suspected medication spontaneously reported in elderly. Rash, Confusional state, Dizziness, Pruritus, Pyrexia, Thrombocytopenia, Diarrhea, Vomiting, Dyspnea and Nausea are the most reported Preferred Terms in elderly spontaneous cases [62, 70, 71].

#### **5. Conclusions**

Older adults, having comorbidities, in polypharmacy regimens, associated with physiological age-related changes, are more susceptible to ADRs. With the demographic aging being a reality worldwide, the healthcare demand increases, as well as drug safety vigilance efforts.

Only recently older people start to have a significant presence in clinical trials. Pharmaceutical companies and the regulatory agencies joined efforts to provide evidence on the benefits and harms of medicines in older patients, giving more importance to efficacy and safety during drug development targeting diseases mostly related with aging or chronic diseases.

Pharmacovigilance regulatory agencies at a local and national level should promote monitoring and reporting programs of adverse effects observed, particularly in older populations, adding reliable safety data and identifying age related.

Drug safety studies in this age group need to be constantly improved to present evidence-based data to enhance quality of prescriptions in a highly healthcare demanding age group.

#### **Acknowledgements**

This work was financially supported by the project APIMedOlder [PTDC/ MED-FAR/31598/2017], funded by FEDER, through COMPETE2020 – Programa Operacional Competitividade e Internacionalização [POCI-01-0145- FEDER-031598], and by national funds [OE], through FCT/MCTES. Replace the entirety of this text with acknowledgments.

*Pharmacovigilance in Older Adults DOI: http://dx.doi.org/10.5772/intechopen.98665*

### **Conflict of interest**

The authors declare no conflict of interest.

### **Appendices and Nomenclature**


### **Author details**

Daniel Gomes1,2, Eva Rebelo Gomes3 , Inês Ribeiro-Vaz4,5, Maria Teresa Herdeiro6 and Fátima Roque1,7\*

1 Research Unit for Inland Development, Polytechnic of Guarda (UDI-IPG), Guarda, Portugal

2 Faculty of Economics, University of Coimbra (FFUC), Coimbra, Portugal

3 Allergy and Clinical Immunology Service, University Hospital Center of Porto, Porto, Portugal

4 Porto Pharmacovigilance Centre, Faculty of Medicine, University of Porto, Portugal

5 Center for Health Technology and Services Research (CINTESIS), Faculty of Medicine, University of Porto, Portugal

6 Department of Medical Sciences, Institute of Biomedicine, University of Aveiro (iBIMED-UA), Aveiro, Portugal

7 Health Sciences Research Centre, University of Beira Interior (CICS-UBI), Covilhã, Portugal

\*Address all correspondence to: froque@ipg.pt

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Pharmacovigilance in Older Adults DOI: http://dx.doi.org/10.5772/intechopen.98665*

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[41] Pirmohamed M, James S, Meakin S, Green C, Scott AK, Walley TJ, et al. Adverse drug reactions as cause of admission to hospital: Prospective analysis of 18 820 patients. Br Med J [Internet]. 2004 Jul 3 [cited 2020 Nov 30];329[7456]:15-9. Available from: http://www.bmj.com/

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[46] Rodrigues DA, Herdeiro MT, Thurmann PA, Figueiras A, Coutinho P, Roque F. Operacionalização para Portugal da Lista EU[7]-PIM para Identificação de Medicamentos Potencialmente Inapropriados nos Idosos Operationalisation for Portugal of the EU[7]-PIM List for Identification of Potentially Inappropriate Medicines in Older Adults. Acta Med Port [Internet]. 2020 Nov 23 [cited 2020 Nov 30];33[13]. Available from: www. actamedicaportuguesa.com

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[49] Agbabiaka TB, Wider B, Watson LK, Goodman C. Concurrent Use of Prescription Drugs and Herbal Medicinal Products in Older Adults: A Systematic Review [Internet]. Vol. 34, Drugs and Aging. Springer International Publishing; 2017 [cited 2020 Nov 30]. p. 891-905. Available from: /pmc/articles/ PMC5730633/?report=abstract

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[52] COMMITTEE FOR HUMAN MEDICINAL PRODUCTS. ADEQUACY OF GUIDANCE ON THE ELDERLY REGARDING MEDICINAL PRODUCTS FOR HUMAN USE [Internet]. 2012 [cited 2020 Nov 30]. Available from: http://www.emea.europa.eu

[53] Herrera AP, Snipes SA, King DW, Torres-Vigil I, Goldberg DS, Wenberg AD. Disparate inclusion of

older adults in clinical trials: priorities and opportunities for policy and practice change. Am J Public Health [Internet]. 2010 Apr 1 [cited 2020 Nov 30];100[SUPPL. 1]:S105. Available from: /pmc/articles/PMC2837461/? report=abstract

[54] Medicines Agency E. Guideline on good pharmacovigilance practices [GVP] - Module VI – Collection, management and submission of reports of suspected adverse reactions to medicinal products [Rev 2] [Internet]. 2017 [cited 2020 Sep 20]. Available from: www.ema.europa.eu

[55] ICH. ICH Topic E7 Studies in Support of Special Populations: Geriatrics [Internet]. 1994 [cited 2020 Nov 30]. Available from: http://www. emea.eu.int

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[64] Risk management plans | European Medicines Agency [Internet]. [cited 2020 Nov 30]. Available from: https:// www.ema.europa.eu/en/humanregulatory/marketing-authorisation/ pharmacovigilance/risk-management/ risk-management-plans

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**Chapter 8**

## Drug-Induced Delirium among Older People

*Fabiana Rossi Varallo, Alan Maicon de Oliveira, Ariane Cristina Barboza Zanetti, Helaine Carneiro Capucho, Leonardo Régis Leira Pereira, Lucas Borges Pereira, Maria Olívia Barboza Zanetti, Thalita Zago Oliveira and Vinícius Detoni Lopes*

#### **Abstract**

Although underdiagnosed, delirium is a common and potentially preventable problem in older patients, being associated with morbimortality. Drugs have been associated with the development of delirium in the geriatric population and may be considered the most easily reversible trigger. Polypharmacy, prescription of deliriogenic, anticholinergic and potentially inappropriate drugs are contributing factors for the occurrence of the disturb. Furthermore, changes in pharmacokinetic and pharmacodynamic parameters, which are intrinsic of the aged process, may contribute for cognitive impairment. Identification and reversal of clinical conditions associated with delirium are the first step to treat the disturbance, as well as mitigation of environmental factors and the exposition to deliriogenic drugs. Current evidence does not support the prescription of antipsychotics and benzodiazepines for the treatment of delirium. However, the judicious use of first- or second-generation antipsychotics can be considered in severe cases. Multi-component non-pharmacological, software-based intervention to identify medications that could contribute to delirium, predictive models, tools, training of health professionals and active actions of pharmacovigilance may contribute to the screening, prevention, and management of delirium in older people. Besides, it is also important to improve the report of drug-induced delirium in medical records, to develop properly risk management plans and avoid cascade iatrogenesis.

**Keywords:** aged, emergency service, hospital, drug-related side effects and adverse reactions, delirium, pharmacovigilance

#### **1. Introduction**

#### **1.1 Definition, diagnosis and treatment**

According to the Diagnostic and Statistical Manual of Mental Disorders [1], delirium is defined as a complex syndrome characterized by disturbance in attention (reduced ability to direct, focus, sustain, and shift attention), awareness (reduced orientation to the environment), and an additional disturbance in cognition

(memory deficit, disorientation, language, visuospatial ability, or perception), which are not better explained by another preexisting, established, or evolving neurocognitive disorder. There is evidence that it is a direct physiological consequence of another medical condition, substance intoxication or withdrawal (i.e., due to a drug of abuse or to a medication), or exposure to a toxin, or is due to multiple etiologies [1]. The disturbance develops over a short period of time, usually from hours to a few days, and tends to fluctuate during the course of the day, often with worsening in the evening and night when external orienting stimuli decrease [1].

Delirium is considered a serious global public health problem because it can increase the rate of morbidity and mortality [2], prolong hospitalization, promote institutionalization, worsen physical, cognitive and social outcomes [3], besides to increase health costs [4] and loss of independence among people affected by this health condition [5].

Regarding clinical presentation of delirium based on the psychomotor behavior changes, delirium can be classified into: a) hyperactive (the individual has a hyperactive level of psychomotor activity that may be accompanied by mood lability, agitation, and/or refusal to cooperate with medical care); b) hypoactive (the individual has a hypoactive level of psychomotor activity that may be accompanied by sluggishness and lethargy that approaches stupor); c) mixed level of activity (the individual has a normal level of psychomotor activity even though attention and awareness are disturbed. It also includes individuals whose activity level rapidly fluctuates) [1]. Delirium can also be classified in 5 subtypes: i) substance intoxication delirium; ii) substance withdrawal delirium; iii) medication-induced delirium; iv) delirium due to another medical condition; and v) delirium due to multiple etiologies [1].

The diagnosis for medication-induced delirium is applied when disturbance in attention and an additional disturbance in cognition arise as an adverse drug reaction [1]. The codes for diagnoses, according to the 10th revision of the International Classification of Diseases and Related Health Problems (ICD-10), depend on the type of substance related to delirium (**Table 1**).

In June 2018, the World Health Organization (WHO) released a pre-final version of the ICD-11 [6]. Under mental, behavioral or neurodevelopmental disorders, the neurocognitive disorders group (6), includes delirium (6D70), which can also be classified as being due to: a medical condition classified elsewhere (6D70.0), psychoactive substances, including medications (6D70.1); multiple etiological factors (6D70.2), unknown or unspecified etiological factors (6D70.3), delirium, other specified cause (6D70.Y) and; delirium, unspecified or unknown cause (6D70.Z) [6].

Although the pathophysiological mechanisms of delirium remain unclear, several evidences suggest the participation of different neurotransmitters and biomarkers. Among the most investigated mechanisms is cholinergic dysfunction,


#### **Table 1.**

*ICD-10-clinical modification codes for the [specific substance] related to delirium.*

#### *Drug-Induced Delirium among Older People DOI: http://dx.doi.org/10.5772/intechopen.95470*

which may contribute to some of the manifestations known to be present in delirium, such as cognitive deficits associated with memory loss [7, 8].

Identification and reversal of clinical conditions associated with delirium are the first step to treat the disturbance, as well as mitigation of environmental factors and the exposure to deliriogenic drugs [9]. Non-pharmacological approaches should be provided in order to prevent and manage the neuropsychiatric symptoms related to delirium, such as: avoid the use of physical restraints, catheters, and bed alarms, ambulate patient, address sensory impairment, encourage exposure to bright light during the day, among others [8].

Current literature does not support the prescription of antipsychotics [10] and benzodiazepines [11] for the treatment of delirium in hospitalized patients. A meta-analysis study found that the prescription of antipsychotics did not control the symptoms of delirium nor reduced the severity and mortality associated with the disorder, when compared to other treatments. In addition, no differences were observed between typical and atypical antipsychotics in patients hospitalized in non-critical wards, regarding symptom resolution of delirium [12]. However, the judicious use of first- and second-generation antipsychotics can be considered for the treatment of severe delirium symptoms, especially in the management of agitation associated with the hyperactive subtype [13], as well as when non-pharmacological interventions have failed and the symptoms put the affected individual at risk and they are distressing for family and caregivers. In these cases, the treatment should start with low doses and be further titrated until the required effect is achieved [8].

Regarding prevention, multi-component non-pharmacological interventions have shown to reduce the incidence of delirium, compared to usual care adopted among non-critical inpatients [14]. However, there is no clear evidence that cholinesterase inhibitors, antipsychotic medication or melatonin is able to reduce its incidence [14]. Nevertheless, the use of technology to help pharmacist to identify medications associated with the occurrence of delirium may contribute to decrease the incidence of the disturbance in older people [15]. This approach allows for drug adjustments aiming to prevent or solve drug-related problems associated with neurological disorders.

#### **2. Epidemiology of delirium**

Delirium is the most common psychiatric syndrome in hospitalized patients [16]. The general occurrence of delirium cases in hospitals can be between 29 and 82%. In a systematic literature review, which assessed the occurrence of delirium in inpatients at the admission, the authors related an occurrence rate in Europe between 4% in France to 31% in Sweden [17]. In the community, this occurrence is reduced to 1–2%. This great difference in percentages results from the emergency units being the places where people presenting the signs and symptoms of delirium normally go to. In fact, 17% of the older people in the community and 40% of those who live in nursing homes frequently attend emergency units with this diagnosis. Moreover, during hospitalization there are many contributor factors for the increased risk of delirium occurrence [18, 19]. Therefore, differences in the incidence of delirium are observed among the different inpatient units within a hospital (**Table 2**). The intensive care units (ICU), palliative care, oncology and postoperative are usually the places where delirium events occur the most, around 50–82% [18, 19].

This wide variation in the occurrence of delirium, when comparing different units, can be extrapolated to its prognosis. The main prognoses in patients with delirium are falls, catheter-associated infection, weakness, longer hospital stay and death, with this risk being 2 to 4 times greater in patients admitted to the ICU, and

1.5 times greater in patients admitted to general wards [19]. For this reason, the prevention of delirium is very important in health care. Thus, improved knowledge of the main delirium-related risk factors is essential for all health professionals who assist these patients directly.

Although a single factor may cause delirium, especially in the older people, its occurrence is usually considered multifactorial. In addition, as noted in the incidence of cases, the occurrence of delirium is associated with patient's vulnerability to harmful factors, for example, critically ill patients may begin to experience delirium from the administration of a sedative, in contrast to healthy patients where this syndrome is unlikely to occur due to the involvement of a single stimulus. Consequently, there are individual-associated vulnerability factors, as well as precipitating factors that may potentially increase or not the risk of triggering delirium (**Table 3**) [18, 19].


#### **Table 2.**

*Incidence of associated delirium in different inpatient units. Adapted from Inouye, 2014 [18].*


#### **Table 3.**

*Vulnerability factors of the individual and precipitating factors associated with the occurrence of delirium. Adapted from setters, 2017 [19].*

#### *Drug-Induced Delirium among Older People DOI: http://dx.doi.org/10.5772/intechopen.95470*

In relation to the individual's vulnerability factors in the general population, the occurrence of delirium is normally more associated with involvement by other comorbidities, such as stroke and depression. In people admitted to hospitals, other factors are also associated with the occurrence of delirium, such as dementia, cognitive impairment, functional impairment, visual impairment, a history of high alcohol consumption, and advanced age (> 70 years) [18].

Regarding the precipitating factors, the occurrence of delirium in the general population is mostly associated with abnormal laboratory parameters, such as high serum urea. In inpatients, in addition to metabolic disorders resulting from laboratory tests, it is worth mentioning other important factors, such as polypharmacy (≥ 5 drugs), the use of psychoactive drugs, and especially physical restrictions [18].

#### **3. Delirium in older people**

Delirium is a common and potentially preventable syndrome in older people hospitalized patients, being associated with high mortality rates ranging from 25–33%, thus resulting in longer hospital stays, high health costs, functional decline, increased falls, hospital readmissions, development of dementia or long-term cognitive impairment, and higher rates of morbidity. Delirium can also cause adverse events after hospitalization, including lasting functional limitations, persistent cognitive decline, and loss of quality of life for the patient and caregivers. The occurrence of new cases of delirium during hospitalization of older people varies from 6–56%; while the prevalence of delirium at the time of admission of older people varies from 14–24%. Furthermore, with the population's advancing age, delirium stands as a public health concern as it tends to increase in the future [20–23].

Although in some cases delirium can be caused by a single drug or underlying disease, in most cases delirium is the result of the combined action of predisposing and precipitating factors. It is, therefore, a multifactorial condition, which involves the interrelation between the patient's vulnerability to delirium at the time of hospital admission (predisposing factors) and precipitating factors that may arise during hospitalization. In this perspective, patients considered vulnerable (for example, those with dementia or a serious underlying disease) may experience delirium due to the use of a single dose of a sedative aimed to sleep. In contrast, patients resistant to the development of delirium may present this condition after a series of combinations, such as general anesthesia, major surgery, sleep deprivation, immobilization and the use of multiple psychoactive drugs [20]. In general, an intervention in one or more of these factors is considered sufficient for the delirium to be resolved [23].

The main predisposing factors for the occurrence of delirium at the time of hospital admission are the severity of the underlying disease, visual deficit, basal cognitive level, and dehydration. On the other hand, there are precipitating factors contributing for the development of delirium during hospitalization, for example: use of physical restrictions, malnutrition, addition of more than three drugs in the previous day, especially psychoactive drugs, use of urinary catheter. It is known that dementia is the most prevalent predisposing factor at the time of hospital admission, since it is able to increase the possibility of developing delirium by two to five times; however, any chronic disease can predispose delirium. Among the precipitating factors, the use of drugs is emphasized, being considered an extremely usual factor during hospitalization, originating up to 40% of cases. Consequently, the occurrence of delirium increases in direct proportion to the number of drugs used, due to the greater chance of adverse events and drug interactions take place [23].

Thus, in order to prevent the development of delirium resulting from the use of drugs, it became necessary to develop risk management plans, which is currently a prerequisite for a good pharmacovigilance service [9].

It is a fact that the prevention of delirium in the older people should stand as the main goal throughout the health care supply provided by health professionals, since the delirium prevention is always preferable to its treatment. However, when delirium occurs, early intervention and adequate management have been shown to improve the results for these patients [21, 22]. Despite the adverse consequences associated with delirium, the performance of health professionals in recognizing, registering, and treating it is still inappropriate. The lack of knowledge of the risk factors related to delirium in hospitalized older people is responsible for failures in the records in medical charts, in the notification and in the communication of the occurrence of delirium. In addition, the existence of knowledge gaps in screening and diagnosis using evidence-based tools are the main barriers to care [22].

Confirming the diagnosis of delirium in older people can be a challenge in complex clinical situations, with multiple demands and even more when the diagnosis is made by non-specialized health centers or unskilled professionals. The clinical manifestations of delirium and the factors associated with this condition can be confused with elements characteristic of aging, as well as being recognized as only cases of dementia or depression [24, 25]. The assessment of delirium superimposed on pre-existing dementia must be part of the differential diagnosis, as it happens in 90% of the cases with hospitalized older people [26]. In addition, hyperactive presentations of delirium can be misdiagnosed as hypomanic episodes [24, 25]. Estimates indicate that the recognition of delirium in the usual care only happens in 12–35% of the occurrences [26].

Considering that the prevention of delirium is essential in health institutions, clinical guidelines and models promoting the prevention, diagnosis and treatment of delirium have been developed and published internationally. However, it appears that they have not been properly implemented in clinical practice, which reinforces the need to initiate patient-centered care approach in the detection, prevention, and treatment of delirium, as well as in discharge planning [27].

The prediction of delirium in health services is extremely relevant to direct resources to prevention programs for patients most likely to have the syndrome. Although different tools have been developed in recent years, there are still no predictive models with adequate performance and recommendations for routine use in health services. Considering the current period of evidence, the insertion of predictive modeling and artificial intelligence in the health sector is a promising field for future research [28]. Moreover, when associated with a patient safety program, it has the potential to significantly improve the quality of care.

To improve this scenario, there are support strategies and tools for the delirium evaluation. Initially, it is extremely important to be aware of the signs and symptoms, as well as in the early observation of their onset (appearance of disorders and mental fluctuations), to avoid undesirable worsening [18, 26]. Therefore, the history of the episode is fundamental, with the record consistency of the steps that resulted in the event and thus it will be possible to carry out a comprehensive assessment of the potential triggering causes [18, 26]. Thus, the notoriety of providing instruction for people is justified because, in addition to the health team, family members and/or caregivers will also be crucial for the collection of this information [18].

Regarding the diagnostic decision support tools, studies in the literature have shown to provide validated instruments for this purpose [29]. Among them, it is worth highlighting the Confusion Assessment Method (CAM) [30], due to the reliability of its psychometric properties (specificity of 89% and sensitivity of 94%)

#### *Drug-Induced Delirium among Older People DOI: http://dx.doi.org/10.5772/intechopen.95470*

and because of the amount of evidence supporting the improvements in the evaluation resulting from its use [18, 31].

Acute beginning, confused thinking, lack of concentration, impaired consciousness, disorientation, noticeable disorders, hypoactivity and hyperactivity, detriment of memory and alteration of the sleep–wake cycle are the factors analyzed by CAM, with an application time of 5 minutes [30]. Still on the applicability, this tool has versions adapted to the areas that differ in the levels of health care for the older people (nursing home, emergency and intensive care units) [32, 33]. In order to guarantee the sensitivity and specificity of the CAM, there is an indication for the rater to be trained for the timely administration of the method and, to ensure the hypothesis of delirium, the older people's cognition should be evaluated by some specific test (for example, Short Portable Mental Status Questionnaire [34], Mini-Mental State Examination [35], Montreal Cognitive Assessment [36] or the Mini-Cog [37]).

#### **The Confusion Assessment Method (CAM) Diagnostic Algorithm** [30].

• **Feature 1: Acute onset and fluctuating course**

This feature is usually obtained from a reliable reporter, such as a family member, caregiver, or nurse, and is shown by positive responses to the questions: Is there evidence of an acute change in mental status from the patient's baseline? Did the (abnormal) behavior fluctuate during the day, that is, tend to come and go, or did it increase or decrease in severity?

• **Feature 2: Inattention**

This feature is demonstrated by a positive response to the question: Did the patient have difficulty focusing attention, for example, being easily distractible, or have difficulty keeping track of what was being said?

#### • **Feature 3: Disorganized thinking**

This feature is shown by a positive response to the question: Was the patient's thinking disorganized or incoherent, such as rambling or irrelevant conversation, unclear or illogical flow of ideas, or unpredictable switching from subject to subject?

#### • **Feature 4: Altered level of consciousness**

This feature is demonstrated by any answer other than "alert" to the question: Overall, how would you rate this patient's level of consciousness? (alert [normal], vigilant [hyperalert], lethargic [drowsy, easily aroused], stupor [difficult to arouse], or coma [unarousable]).

**The diagnosis of delirium by CAM requires the presence of features 1 and 2 and either 3 or 4.** Copyright © 1990 Annals of Internal Medicine. All rights reserved.

However, the implementation of delirium screening, detection, documentation, and notification guidelines present several challenges, being associated with a series of contextual and organizational issues. One of the major issues to be considered by health professionals is the use of a variety of descriptors to document and communicate their delirium assessments, since important and necessary information for the prevention and treatment of delirium may not be efficiently communicated in the medical records [22].

Medical records generally include descriptors, such as disorientation, agitation, altered level of consciousness, fluctuating mental state, confusion, negative behavior and hallucinations, but the term delirium is rarely mentioned [22]. This factor restricts the identification of this type of incident in an active pharmacovigilance system, as well as impairs the proper assessment of the case in the process of passive surveillance of drug-related adverse events. Therefore, it is essential to take into consideration on these evidence-based techniques, given that episodes of delirium are related to geriatric syndromes (incontinence, pressure injuries and falls), and with a long-term prognosis of attenuated survival rate, health conditions that result

in the need for rehabilitation and other adversities that affect cognition, such as dementia [18, 38]. Older people who were affected by delirium can be stratified in a public vulnerable to poor outcomes and this context predicts an alarming epidemic, given the increase in population longevity [38].

The Agency for Healthcare Research and Quality (AHRQ ) points out delirium as an indicator of healthcare quality, because it is estimated that up to 40% of cases can be avoided in the general population and preventive interventions must involve the care environment (for example, lighting, availability of calendar, clock and other signages), the culture of team practices (for example, implementation of protocols for screening and continuous assessment of delirium, deprescribing and review of pharmacotherapy), in addition to measures for preliminary identification of risk factors [39]. Preventing, recognizing, and treating delirium has become a public health priority.

Owing to achieve quality and safety attributes at all levels of care for the older people, in addition of taking into account the severity of the complications caused (as poor quality of life, increased hospital stay and risk of death) and the high consecutive costs (from \$ 143 to \$ 152 billion per year), it is necessary to encourage the training of health professionals enabling them to recognize cases of delirium, as well as risk factors, treatment and prevention [18, 26]. The adequate documentation concerning the occurrence of delirium in health services and the initiative to educate the population about this disorder, can greatly contribute to the improvements in the management of this clinical condition [18, 26].

#### **4. Drug related problems (DRPs) in the context of drug-induced delirium**

Older people are a population at high risk for presenting DRPs and unnecessarily suffer from diseases and injuries resulting from excessive or inadequate consumption of drugs. Drug-induced delirium appears as a frequent consequence of these DRPs, which are associated with aspects of necessity, adherence, effectiveness, or safety of pharmacological treatment. In the care of older patients, the regular review of the pharmacotherapy is an essential service, but it is often neglected. Hospital and community pharmacists are in an ideal position to perform this task [40].

The behavior of the health professional team in just renewing previous prescriptions of polymedicated patients, without practicing review of pharmacotherapy, may result in the maintenance of treatments that are no longer necessary. Thereby, it becomes essential to assess the maintenance of each drug in terms of its benefit, when compared to the deliriogenic potential and the anticholinergic burden, with additional caution in drug discontinuation in those patients displaying an increased probability of delirium due to substance withdrawal syndrome [41]. The review should also include over-the-counter or easily accessible medications, herbal medicines and supplements, which are also associated with delirium (e.g. anticholinergics, antihistamines, non steroidal inflammatory drugs, muscle relaxants) [41, 42].

Any drug used to treat delirium, such as antipsychotics and benzodiazepines, will cause psychoactive effects and may further impair the state of consciousness. Therefore, the prescription of such drugs should be discouraged as they consist in a DRP of necessity (unnecessary drug), except in cases with severe symptoms that put the older people at risk, especially in the management of agitation associated with the hyperactive subtype of delirium. If the use of antipsychotics is indeed mandatory, the lowest dose and the shortest treatment period possible should be the chosen option. Benzodiazepines are restricted to the management of delirium due to alcohol and other drugs withdrawal [13, 43].

#### *Drug-Induced Delirium among Older People DOI: http://dx.doi.org/10.5772/intechopen.95470*

On the other hand, pharmacological treatment is regularly necessary in the management of factors that can contribute to the alteration of the state of consciousness, such as pain, infections, kidney disease, dehydration, metabolic and hydroelectrolytic disorders, among others [18, 19]. The absence of pharmacological interventions in this regard also constitutes a DRP (necessary drug not prescribed).

Delirium can also be a result of adherence problems (DRP of adherence). Aging brings a series of physical, mental, and social barriers to the adequate follow-up of pharmacotherapy, such as impaired vision, hearing and dexterity, difficulty in understanding and lack of home support. In the pharmacotherapeutic scheme, confusion predisposes to the occurrence of overdoses or even to the abrupt withdrawal of drugs, situations that trigger delirium. The pharmacist can develop strategies to make self-administration easier, aware the patient and reduce the complexity of pharmacotherapy (drug or formulation change, making boxes and guidelines, activation of alarms, etc.), in addition to educational actions for encouraging adherence [40, 44].

Some non-pharmacological factors can also contribute to the development of delirium and, when treated ineffectively (DRP of effectiveness), they may increase the chance of its occurrence. The sharp change in attention, awareness and cognitive functions can be triggered, for example, by uncontrolled infection, dehydration condition not reversed, and inadequate pain management (insufficient doses of opioids) [45].

All subtypes of delirium can be induced by Adverse Drug Reactions (ADR) [46]. When attention and cognition disturbance appear as a side effect of a drug taken as prescribed, this is characterized as a DRP of safety [1].

In older people, especially those diagnosed with dementia [46], most of these deliriogenic drugs have anticholinergic properties and are considered potentially inappropriate for this age group [47–49], with pyrilamine and methscopolamine being recently added to the list of drugs to be avoided [48].

Other drugs previously reported as capable of inducing delirium are opioids, antihypertensives (beta blockers associated with higher delirium rates when compared to calcium channel blockers), diuretics with the potential to cause hyponatremia, and dopaminergics [46, 50–52]. Abrupt withdrawal of benzodiazepines is related to hyperactive delirium, so de-escalation is advised [46].

Although the drugs described above are more often related to the development of delirium, it is essential to consider most drugs as risk factors in older people, due to the delirogenic potential of the aging process, illness or hospitalization [50]. Therefore, deprescribing should be considered when feasible.

In the case of drugs with anticholinergic activity, mainly muscarinic, changes in pharmacokinetic and pharmacodynamic parameters with advancing age increase the susceptibility to induce delirium [53]. After identifying those who potentiate delirium, they should be stopped or replaced by safer medicines [54].

Strategies for identifying, preventing, and solving actual and potential DRP essentially include the review of the pharmacotherapy and pharmacotherapeutic follow-up. These pharmaceutical services contribute to the prevention and resolution of deliriogenic drugs-induced ADR, decrease the incidence of delirium, minimize the occurrence of adverse events in people who are being treated with antipsychotics and allow polypharmacy to be assessed [55, 56].

#### **5. Auxiliary instruments in the active search for DRPs in the context of drug-induced delirium**

Most adverse events in the older people, especially those related to delirium, could be prevented by avoiding the prescription of Potentially Inappropriate

Medication (PIM), especially when safer alternatives are available for use. Most deliriogenic drugs have anticholinergic properties and are considered to be PIMs [47–49].

The development of evidence-based PIM lists is a complex task, as the geriatric population is usually excluded from clinical trials. Based on the opinion and consensus of experts, including pharmacists, geriatricians, nurses and other health professionals, several tools have been developed to assess whether drug use in the older people is appropriate [57]. One of the most used is the American Geriatrics Society (AGS) Beers Criteria, which was developed in the United States in 1991 and has further undergone several updates, the most recent one being published in 2019 [48]. The latest version of the AGS Beers Criteria organizes PIMs in five lists: drugs that are potentially inappropriate for the majority of the older people (high risk of adverse events and the existence of safer alternatives); drugs that should be avoided in older adults with specific clinical conditions; drugs to be used with caution; combinations of drugs that can cause harmful interactions; drugs that should be avoided or that require dose adjustment in the older people with impaired kidney function [48].

Another widely used prescription screening tool in the older people is the STOPP/START criteria, created in 2008 in Europe and updated in 2014 [58]. This tool is composed by the topics STOPP (Screening Tool of Older Persons' Prescriptions), which presents a list of PIMs organized by physiological systems, and START (Screening Tool to Alert to Right Treatment), which warns about missing treatments that should be initiated in older adults. This instrument also includes drug–drug interactions and drug-physiological status interactions [58].

Despite the existence of a large number of lists, tools and criteria for PIMs within the scientific literature, other factors should also be considered when reviewing pharmacotherapy, such as the older people's particularities, biological age, other therapeutic options and the specific needs of each patient.

The risk of drug-induced delirium in older adults can be assessed by the Delirium Drug Scale (DDS) [59]. The rank for the deliriogenic burden ranges from 0 to 3, according to the potential of the drug to induce delirium. Considering each drug with a potential delirium risk, the weighted DDS score should be calculated, so the exposure to the drugs that induce delirium is considered low when the scores vary between 0 and 1 excluding the value of 0; and high the score obtaind from DDS is greater than 1 [60]. Low exposure to drugs leading to delirium does not significantly increase the chances of delirium. For this reason, if the benefits of the therapy outweigh the risks, the prescribed doses can be safely tolerated [60].

Regarding the anticholinergic burden, the sum of the scores of anticholinergic activity magnitude for each prescribed drug, ranging from 1 to 3, is performed. The higher magnitude of anticholinergic activity leads to a higher score attributed to the drug [61]. Although there is no consensus in the literature, the average daily anticholinergic load ≥2 is considered high [62]. High anticholinergic burden is associated with increased risk of morbidity and mortality, hospital stay length, institutionalization, functional and cognitive decline [61].

#### **6. Strategies for mitigating and preventing drug-induced delirium**

#### **6.1 Risk management: active and passive monitoring strategies for drug-related adverse events**

Ensuring the safe use of drugs is one of the priorities of health systems worldwide, given that the estimated global cost due to failures in the process of using

#### *Drug-Induced Delirium among Older People DOI: http://dx.doi.org/10.5772/intechopen.95470*

these technologies is approximately US \$ 42 billion annually. The safety use of drugs is a complex concept comprising multifactorial origins in different stages of the prescription, dispensing and administration processes, and in all these processes there is a risk of drug-related adverse events, meaning, the harms that may arise from the inadequate/inappropriate use of these medicines [63].

The occurrence of drug-related adverse events is distinguished as a relevant cause of morbidity and mortality, by causing suffering and dissatisfaction of patients and rising health care costs [64]. Thus, it is important to use strategies to prevent the incidence of adverse events and to mitigate the resulting social and economic impacts.

Drug-related adverse events are the main cause of preventable harms to the patient, with monitoring strategies occurring through two types of surveillance systems: active and passive. In this context, in order to reduce incidents, including drug-related adverse events, many health systems have implemented passive surveillance systems, which are allusive to spontaneous incident reports, aiming to identify and describe the risks and causes associated with adverse events, harmless incidents and near misses [64]. As they are cost-effective, these voluntary notification systems are responsible for a large part of the reports containing drug-related adverse events, conferring the potential to improve health care through the monitoring, reduction, and prevention of adverse events. However, there are still challenges associated with the data obtained from these systems, as this information is often difficult to interpret and manipulate due to underreporting, as well as their content and variability in the attribution of event categories by notifiers [64, 65].

Therefore, active surveillance systems complement passive systems. Although the active system is more costly, the information is obtained through direct contact, at regular intervals, between the team responsible for the active search and intensive monitoring of adverse events and the sources of information, mainly through the analysis of documents linked to the medical records of the patients, either retrospectively or prospectively [64, 66].

#### **6.2 Patient safety, pharmacovigilance, and delirium**

Delirium is an indicator of health quality in older people and, therefore, its prevention is an essential parameter for patient safety. Given the association between delirium and other common geriatric syndromes, its prevention benefits the improvement of the quality and efficiency of health services. The prevalence of delirium, its severity and duration can be significantly reduced when considering the existing risk factors [67].

The current management of delirium emphasizes the importance of its prevention, preferably through a non-pharmacological approach implemented in multiple sectors of health services. In this context, the following actions for patient safety are highlighted as [56, 59, 67]:


such as charts with personal information, date, and year, as well as clocks visible to patients. In addition, suitable accessories can be made available to prevent falls;


It is noteworthy that drug toxicity and polypharmacy are two of the main risk factors associated to delirium, especially in older patients with underlying comorbidities [62]. Anticholinergic, antipsychotic, benzodiazepine, and opioid agents are known to be highly deliriogenic [50]. However, several case reports show that drugs with a low suspicion of being deliriogenic can, in fact, present this particularity [68]. Therefore, the institutionalization of pharmacovigilance protocols for the management of delirium risks associated with the use of medications are of utmost importance.

The pharmacovigilance system is responsible for monitoring the safety of drugs and for adopting measures to reduce the risks and increase the benefits related to the use of drugs, as well as enabling improvements in patient safety and quality of life. Pharmacovigilance activities include: collecting and managing data on drug safety; the analysis of individual case reports to detect new drug-related adverse events; the proactive risk management to minimize any potential risks related to medication use; the communication and information to stakeholders and patients [69].

The suspected cases of delirium associated with the use of drugs identified by health service professionals, users and caregivers are notified to the drug manufacturers and health authorities in order to record these potential adverse events in the pharmacovigilance system. Such conduct makes it possible to screen and investigate the real association between these notified drugs and delirium. Notifications are generally sent voluntarily and reviewed by governmental organizations responsible for the safety of drugs on the market, which, in turn, forward the notifications to the Uppsala Monitoring Center, the World Health Organization collaborating centre for international drug monitoring.

For these reasons, it is highly important to establish a database to assess the safety issues of drugs in the post-marketing stage. This database system will allow to increase public knowledge regarding the drugs capable of inducing delirium, namely by identifying and monitoring the already known deliriogenic drugs, those

#### *Drug-Induced Delirium among Older People DOI: http://dx.doi.org/10.5772/intechopen.95470*

potentially deliriogenic, as well as new drugs displaying the potential to cause delirium [68].

Finally, the knowledge regarding the frequency with which these potentially deliriogenic drugs are attributed as the primary cause of delirium has shown to help in the clinical practice and in the possible prevention of the [20]. Therefore, the elaboration of a list of drugs that are notably potentially deliriogenic and have the potential to cause delirium demands a plausibility research to determine a definitive association. This list of drugs associated with delirium can provide valuable information to health professionals, allowing for the prevention of delirium or its timely diagnosis, apart from avoiding other adverse events [68].

The knowledge about this important drug-related adverse event involving the occurrence of delirium can promote concrete actions to improve the quality of care for the older people, with the active participation of the multidisciplinary team, especially with a systematic implementation of institutional protocols for the prevention of delirium. Thus, it is essential to increase the population's knowledge, especially of health professionals, about delirium, its associated risks, and the need to document suspected cases of delirium associated with the use of drugs. Pharmacovigilance is the right tool for this.

#### **7. Conclusions**

In sum, delirium may increase morbidity and mortality, prolong the length of hospital stay, promote institutional long-term care, worsen functional, cognitive, and social outcomes, increase health costs, and exacerbate the loss of independence of older people. The most common factors significantly associated with delirium among this population are severity of medical illness, visual impairment, urinary catheterisation, electrolyte disturbance, immobility, frailty, and length of hospital stay. The use of deliriogenic, anticholinergic and potentially inappropriate drugs, as well polypharmacy, are also contributing factors to the occurrence of delirium.

To prevent the harm associated with acute cognitive impairment, pharmacovigilance activities, pharmaceutical care in the geriatric population and predictive models are advised, since they may contribute to the screening, prevention, and management of delirium. Furthermore, it is important to improve competences of healthcare professionals to properly report the occurrence of delirium in medical records and apply patient-centred clinical methods to prevent iatrogenic cascades.

#### **Appendices and Nomenclature**


#### **Author details**

Fabiana Rossi Varallo1 \*, Alan Maicon de Oliveira1 , Ariane Cristina Barboza Zanetti1 , Helaine Carneiro Capucho2 , Leonardo Régis Leira Pereira1 , Lucas Borges Pereira1 , Maria Olívia Barboza Zanetti1 , Thalita Zago Oliveira1 and Vinícius Detoni Lopes1

1 School of Pharmaceutical Sciences of Ribeirao Preto, University of Sao Paulo, Ribeirão Preto (SP), Brazil

2 Pharmacy Department, University of Brasilia, Brasilia (DF), Brazil

\*Address all correspondence to: frvarallo@fcfrp.usp.br

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Drug-Induced Delirium among Older People DOI: http://dx.doi.org/10.5772/intechopen.95470*

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Section 4
