Drug Therapies in Older Adults (Part 1)
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Clinical Medicine 2015 Vol 15, No 1: 47–53 DRUG THERAPIES IN… Drug therapies in older adults (part 1) Authors: Omar MukhtarA and Stephen HD JacksonB Prescribing for older adults represents a signifi cant challenge and benefi ts of drugs, along with a relatively limited evidence as the UK population ages. Physiological decline and the base, prescribing for this population remains problematic.3–5 rising prevalence of frailty increase the likelihood of altered This fi rst review highlights a number of key issues relevant pharmacodynamics and pharmacokinetics, suboptimal to those who prescribe for older adults and describes current prescribing and adverse effects among this growing cohort drug therapies in two examples of highly age-associated disease ABSTRACT of the population. In the fi rst of two articles, we begin by states: Alzheimer’s disease (AD) and osteoporosis. considering these issues and posit four key questions which should be considered when prescribing for older adults. Prescribing considerations in older adults Does this agent refl ect the priorities of the patient? Are there alternatives – with greater effi cacy, effectiveness Ageing and frailty or tolerability – that might be considered? Are the dose, Physiological ageing is best described as the time-related loss frequency and formulation appropriate? How does this of functional units within an organ system, eg nephrons in prescription relate to concurrent medication? We also describe the kidneys, alveoli in the lungs and neurones in the brain. By current drug therapies in two disease states with a predilection contrast, frailty is defi ned by progressive physiological decline for older adults: Alzheimer’s disease (AD) and osteoporosis. in multiple organ systems resulting in loss of function, loss of Using these examples we highlight the limitations of evidence- physiological reserve and increased vulnerability to disease and based medicine and guidelines in this cohort of the population, death.6 In recent years, the recognition of this distinction has illustrating the reliance on sub-group analysis to demonstrate led to an awareness that frail adults, rather than older people the effi cacy of drug therapies for older adults in osteoporosis per se, are the primary users of healthcare resources. It can, and the underutilisation of appropriate treatments for therefore, be diffi cult to give useful prescribing advice on the patients with AD as a result of fl awed guidelines. basis of age alone – a housebound 63 year old may be frailer than a 78 year old who continues to work on a part-time basis.6 KEYWORDS: Pharmacology, elderly, geriatrics, physiology of ageing, prescribing, osteoporosis, Alzheimer’s disease, guidelines Pharmacokinetic and pharmacodynamic changes With physiological ageing, the body undergoes several changes 7 Introduction that can affect the pharmacokinetics of drugs (Table 1). The most signifi cant of these is the reduction in renal clearance, The UK’s population is ageing. The percentage of people which results in the reduced excretion of water-soluble agents – aged 65 years and over increased from 15% in 1985 to 17% in variations in drug distribution and metabolism are also 2010 – an absolute increase of 1.7 million people. By 2035 it noteworthy (Table 1). is predicted that this cohort will account for 23% of the total 1 Furthermore, pharmacodynamic changes increase the population. The fastest increase is likely to occur among the sensitivity of older adults to prescribed therapy. This is ‘oldest old’ (those aged 85 years and over) – between 1985 and particularly true for drugs which act via the central nervous 2010, this population more than doubled from approximately 1 system: neuroleptic use in older adults is associated with 0.7 million to greater than 1.4 million people. increased rates of delirium, extrapyramidal symptoms and In total, 45% of the medications prescribed in the UK are postural hypotension, while the benzodiazepines are associated for individuals aged over 65 years, and 36% of people aged with increased body sway and exaggerated sedative effects. 75 years and above take four or more prescribed drugs on a 2 Equally, agents with anticholinergic actions impair cognition daily basis. However, with increased variability in the risks and orientation, particularly in patients with a pre-existing cholinergic defi cit eg AD.7 Polypharmacy and appropriate prescribing Authors: ASpR in clinical pharmacology and therapeutics, King’s Health Partners, King’s College Hospital, London, UK; Bprofessor The use of many medicines (‘polypharmacy’) is common of clinical gerontology, Department of Clinical Gerontology, King’s among older people; a recent primary care survey in Scotland Health Partners, King’s College Hospital, London, UK found that 28.6% of adults aged 60–69 years were receiving © Royal College of Physicians 2015. All rights reserved. 47 CMJ_15_1-Mukhtar.indd 47 10/01/15 12:55 AM Omar Mukhtar and Stephen HD Jackson Table 1. Major physiological changes observed with ageing and their pharmacokinetic effects. Pharmacokinetic Physiological change Pharmacokinetic effect Drugs most affected process Distribution Decreased total body mass, increased Increased Vd of highly lipid soluble Benzodiazepines, morphine and proportion of body fat and decreased drugs amiodarone proportion of body water Decreased Vd of hydrophilic drugs Gentamicin, digoxin, lithium and theophylline Metabolism Reduced hepatic mass, hepatic blood Drugs with a high E are associated Clomethiazole, dextropropoxyphene, flow and metabolic capacity with the largest reductions in hepatic glyceryl trinitrate, lidocaine, clearance pethidine and propranolol Excretion Reduced glomerular filtration rate, renal Accumulation of renally cleared Digoxin, lithium, gentamicin and tubular function and renal blood flow drugs ACEi = = = ACEi angiotensin-converting-enzyme inhibitor; E hepatic extraction ratio; Vd apparent volume of distribution. between four and nine medications, while 7.4% were receiving some of these practices are evidence based, most are ten or more; among those aged 80 years and over, the fi gures consensus statements, due to limited study data. Electronic were 51.8 and 18.6%, respectively.8 While the published prescribing, educational initiatives and a limitation in the literature suggests that such polypharmacy is associated with number of prescribers demonstrably improve the quality adverse clinical outcomes and increased healthcare costs, such of prescribing;14–16 however, medication reviews and new analyses fail to account for the appropriateness (or otherwise) prescription checklists may offer the greatest potential to of the prescribed drugs.9,10 improve prescribing for older adults. The term appropriate prescribing has far greater clinical The ‘National Service Framework for Older People’, published relevance; it addresses both the problem of inappropriate over a decade ago, recommended regular medication reviews: medication use and the failure to prescribe or use appropriate for patients receiving four or more drugs a review was treatments. This latter aspect of appropriate prescribing suggested at six-monthly intervals, while an annual review was is frequently neglected (particularly among older adults). suggested for those taking three or fewer medicines.17 For each With regard to the former, patients taking more than fi ve prescription, we propose that prescribers consider four key medications are approximately three times more likely to questions. receive an inappropriately prescribed drug.11 1. Does this agent refl ect the priorities of the patient? The evidence base 2. Are there alternatives – with greater effi cacy, effectiveness or tolerability – that might be considered? In order to determine whether a treatment is appropriate, it 3. Are the dose, frequency and formulation appropriate? is necessary to have an idea of its relative risks and benefi ts. 4. How does this prescription relate to the concurrent Clinicians routinely base this assessment on their interpretation medication? of clinical trials. While these provide evidence of the relative benefi ts of a treatment, they are rarely powered to determine While more formal approaches have sought to list differences in uncommon or rare adverse effects – sequelae medications that may be inappropriate for older adults, eg the 17 18 which often have signifi cant clinical consequences for individual NSF prescribing indicators or STOPP/START checklists, patients.12 Moreover, the application of trial data to older the application of these is challenging in routine clinical adults is problematic as subjects over the age of 65 or 75 years practice. As an alternative, the four questions listed above are frequently excluded, despite the fact that many patients should lead to the cessation of inappropriate therapies and with the disease process being studied are in their eighties or the judicious use of new drugs. nineties.6 The process of extrapolation should, therefore, be applied with caution. Although there is some evidence that the Alzheimer’s Disease effi cacy of drug treatments does not differ signifi cantly between older adults and adults in general, important discrepancies AD is the commonest cause of dementia worldwide, may occur. For example, in metastatic breast cancer, tumour with its global prevalence estimated to be as high as 24 million people. This fi gure is set to double every 20 years response rates to chemotherapy (intervention) versus hormone 19 therapy (control) are age dependent: in older adults (≥60