Author:
Peter Crome, Frank Lally

Correspondence:
Keele University Medical School
Courtyard Annexe
City General Hospital
Newcastle Road
Stoke-on-Trent
Staffordshire ST4 6QG
UK
Tel: 01782 553968
Fax: 01782 553978
E-mail: p.crome@keele.ac.uk

Introduction

Prescribing for older people poses clinicians with challenges that are not apparent in younger people. Older people are, of course, a heterogeneous group, but they have an increased likelihood of developing illnesses as they age. Illnesses lead to the prescription of drugs, both to treat the symptoms and to prevent further complications. Thus it is not uncommon to find people in their eighties taking ten or more different drugs. Age itself results in physiological changes which affect the way in which the body handles, or reacts to the drugs. These features together with a dearth of robust evidence for the effectiveness of drugs in later life combine to make prescribing more problematic and adverse drug reactions more likely. Strategies to improve prescribing have been developed based on the concept of "appropriate prescribing" in which both under-prescribing and over-prescribing are avoided and the risks of adverse drug reactions are minimised. These issues are discussed in this review.

Demographic predictions (Figure 1) indicate that the proportion of the population over 65 will continue to increase both in the UK and elsewhere with the most rapid changes occurring in the developing world⁽¹⁾.

Figure 1: World population ageing

The Middle East and North Africa has recorded the highest population growth worldwide over the past century⁽²⁾. The proportion of the population over the age of 65 in that region was 4.4% in 2000 and is expected to rise to 8.4% in 2030⁽³⁾. One study⁽⁴⁾ , looking at changes in use by the elderly (>65) of the ER of a major hospital in Al-Ain in the years 1989 and 1999 found that patient numbers rose from 321 in 1989 to 1347 in 1999. Attendance rose 5.4 fold while non-urgent attendance rose 14.7 fold, demonstrating rising use, but falling illness severity over time.

However, not all people living longer are necessarily living in good health. The difference between life expectancy and healthy life expectancy can be regarded as an estimate of the number of years a person can expect to live in poor health. In 1981 the expected time lived in poor health for a man was 6.5 years. By 2001 this had risen to 8.7 years^(5:6). The good news was that total life expectancy had risen by about five years for men and three years for women over the same time period. Recent figures show that 45% of drugs in the UK are prescribed for people over 65 who themselves make up about 18% of the population⁽⁷⁾. Demographic changes, the development of new classes of medications and Government policies (National Service Frameworks, NICE Guidelines etc) all indicate that prescribing for older people will increase.

Age-Related Physiological Changes: Pharmacokinetics and Pharmacodynamics

Body composition changes with advancing age with the percentage of muscle and body water declining by as much as 25% by the age of 70. Body fat increases. This and other physiological changes influence the pharmacokinetics of drugs in older people (Table 1).

Table 1: Age-related physiological changes

As a generality the absorption of drugs through the gut is little changed. Distribution is altered with lipid soluble drugs being distributed more widely and being cleared more slowly (e.g. diazepam). On the other hand hydrophilic drugs have reduced distribution volumes and have higher concentrations in body water compartments. Ageing is associated with reduced first-pass metabolism and systemic clearance of many hepatically metabolised drugs can be affected. This is due to a reduction in liver mass and blood flow and results in an increased bioavailability of drugs that undergo first-pass metabolism^(8-11). Conversely, pro-drugs such as ACE-inhibitors, which require activation in the liver, may have lowered systemic concentrations, as more of the inactive parent compound will reach the circulation. The specific content of cytochrome P450 (CYP) enzymes also diminishes during ageing⁽¹²⁾. This combined with reduced blood flows and decreased liver mass may combine to decreased hepatic clearance of drugs in older people.

In addition, many drugs have different racemic forms with the stereo-isomers having different pharmacological properties. Age may have a selective effect on the pharmacokinetics of these different isomers. Age-related changes in the kidney result in altered renal function with age^(13;14). This results in reduced clearance and increased half-life of drugs eliminated predominately by the kidney. Such drugs include digoxin, aminoglycosides and lithium. The pharmacokinetics of new drugs are usually investigated as part of that drug's development but this may not be the case for older medications which sometimes remain the most effective.

The pharmacodynamic effects (what the drug does to the body) of ageing have been less well evaluated than the pharmacokinetic changes. Among the drugs producing a greater effect, are benzodiazepines, anaesthetics and warfarin. On the other hand older people may appear more resistant to the effect of others e.g. beta-receptor agonists and antagonists. These changes may be due to factors at the target organ, or at the receptor level. The overall effects of a drug may also be influenced by changes in body homeostatic mechanisms.

Frailty and Drugs

The earliest studies of pharmacokinetics in old age usually compared young volunteers with hospitalised patients or those in care homes. The marked differences in pharmacokinetics found in these studies result from multiple co-morbidity and frailty and need to be differentiated from those due to age alone, which have a less marked effect. Recently more attention has been paid to the interaction between age and disease and the consequent changes in drug handling as well as the effects of frailty. The latter group are recognised as those older people who have the least functional reserve and are at greatest risk of becoming dependent and moving to institutional care⁽¹⁵⁾. A decline in metabolic activity of plasma aspirin esterase, the conjugation of paracetamol (acetaminophen) and metoclopramide has been reported in the frail^(16-19).

Age Discrimination?

There is ample evidence that older people are not prescribed potentially beneficial drugs such as statins and antihypertensives^(20-22). Additionally the evidence for their efficacy in the very old is lacking⁽²³⁾ so that it is difficult to be dogmatic that these older people are missing out. It is drug regulatory authority guidance that the efficacy of drugs should be evaluated in age groups for which a drug is likely to be prescribed. However, very few drugs have been adequately tested in the over-eighties. This creates a major dilemma for prescribers, particularly if the drug is intended to prevent further complications rather than give immediate symptomatic relief. On the one hand the drug may prove useless or produce side effects if prescribed whilst if it is not given then worthwhile benefit will be missed. Such prescribing dilemmas are not easy to resolve. Discussion with the patient on the established risks and benefits, the relative importance of the treatment under review in relation to other conditions the patient may have and the time course before benefit may be observed are all relevant factors to consider with the patient.

Adverse Drug Reactions

Numerous studies have shown the link between increasing age and increasing frequency of adverse drug reactions (ADR)^(24;25). In addition the consequences may be more serious. For example a fall as a result of excess sedation from a tranquillising drug is more likely to result in a fracture and a gastro-intestinal bleed from a non-steroidal anti-inflammatory drug is more likely to result in a fatal outcome. ADR are common. One study found that of 2,643 hospitalised patients. ADR was detected in 191; of these a fifth were classified as preventable⁽²⁶⁾. In the United States Lazarou et al found ADR to be ranked between 4-6 of the leading causes of death in hospitalised older patients⁽²⁷⁾. The association between patients' age and the risk of an adverse drug reaction was confirmed by Pirmohammed et al⁽²¹⁾ who found that the average age for an admission with an ADR was 76 years compared to 66 years for a patient admitted for other reasons. In this study 16.6% of ADRs were due to a drug interaction, an important point in a patient group treated with multiple drugs.

Improving Prescribing

One of the approaches that have been advocated to reduce ADRs is the categorisation of certain drugs as "inappropriate" for use in older people. Thus Beers et al in the USA⁽²⁸⁾ have produced lists of drugs that 1) generally should be avoided in older people, 2) drugs that should be prescribed up to defined daily doses and 3) drugs to avoided when specific co-morbidities exist. The decision as to which drugs should be listed has been achieved through a modified Delphi process and the list has been updated⁽²⁹⁾. An obvious disadvantage is that regular updating is required and the translation of the recommendations to other countries may be problematic. For example the latest classification from the USA classifies dypridamole as inappropriate whilst in UK the drug is mandated for use following stroke⁽²⁹⁾. A slightly different approach to the development of lists of inappropriate drugs has been described by the ACOVE (Assessing Care of Vulnerable Elders) project⁽³⁰⁾. This seeks to identify ill older people and use evidence-based indicators of quality of care to assess the care at the health service level.

In the UK a number of prescribing indicators have been developed which are suitable as a basis for audit in hospital or nursing home settings. Batty et al's indicators include the appropriate use of anti-thrombotics, aspirin and benzodiazepines^(31;32). The National Service Framework for Older People (NSFOP)⁽³³⁾ has set out a series of strategies to improve prescribing. These include active management of medication, regular reviews of repeat prescriptions and greater involvement of pharmacists as well as more education and training. However a recently published independent report on the NSFOP⁽³⁴⁾ criticised the fact that many older people taking more than four medicines are still not receiving a review every six months.

Audit mechanisms, such as conformity with the British National Formulary, are also recommended.

Compliance and Concordance

One study showed that 50% of drugs prescribed for older people with chronic conditions are not taken⁽³⁵⁾. Such "non-compliance" may be deliberate or accidental due to confusion, loss of manual dexterity in removing tablets from packaging and bottles or more likely due to misunderstanding about the nature of the medication and the way it should be taken. The term "compliance" is now regarded as pejorative and "concordance" is now preferred. Underlying the concept of concordance is greater patient involvement in partnership with prescribers^(36-38). A model of concordance has been developed with the aim of achieving agreement regarding the choice and outcomes of treatment⁽³⁹⁾.

Substance use misuse and dependence

In addition to the many complex interactions discussed above, there is growing recognition of the role of the use of alcohol, nicotine and illicit drugs in older people. It is well documented that each of these substances have physical, psychological, psychiatric and social complications and indeed, may be used as a result of psychosocial distress and medical illness⁽⁴⁰⁾. To further compound the issue older people may be using over the counter and prescribed medication non-compliantly. All these drugs and medications may interact e.g. alcohol and benzodiazepines may predispose to falls.

Thus it is important that practitioners are competent to take a substance misuse history so as to delineate the effects of individual substances and plan treatment appropriately. Failure to be aware of these complicated interrelationships will undoubtedly lead to erroneous diagnostic formulations and deprive older people of the benefit of a wide range of pharmacological and psychological treatments for substance misuse and dependence.

Age-related physiological changes, the presence of co-morbidity and concomitant medication together with an inadequate evidence-base conspire to make prescribing in this age group problematic. Minimising risk and maximising benefit requires knowledge of the effects of each drug a patient might be taking and a degree of pragmatism in decision making. The additional benefits of the ninth or tenth drug should be carefully considered. Probably the best approach is for the patient and the prescriber to review regularly the medication that is being taken and jointly agree which are important drugs to take.

1. United Nations -Three Centuries of World Population Ageing. 2000.
   Ref Type: Generic
   
2. Population trends and challenges in the middle east and north Africa. Accessed 05 February 2007 . 2001.
   Ref Type: Internet Communication
   
3. Kinsella K, Phillips D. Global aging: The challenge of success. 60[1]. 2005. Population Reference Bureau.
   Ref Type: Report
   
4. Margolis SA, Reed RL. Changing use of the emergency department by the elderly in the United Arab Emirates, 1989 and 1999. Eastern Mediterranean Health Journal 8, 2-3. 1999.
   Ref Type: Journal (Full)
   
5. Office for National Statistics. 2006.
   Ref Type: Report
   
6. Government Actuary's Department for expectation of life data. 2004.
   Ref Type: Report
   
7. Department of Health Statistics of prescriptions dispensed in the Family Health Service Authorities: England 1989-1999. Statistical Bulletin . 2002.
   Ref Type: Report
   
8. Anantharaju A, Feller A, Chedid A. Aging Liver. Gerontology 2002; 48(6):343-353.
   
9. Zeeh J, Platt D. The Aging Liver. Gerontology 2002; 48(3):121-127.
   
10. Greenblatt DJ, Harmatz JS, Shapiro L, Engelhardt N, Gouthro TA, Shader RI. Sensitivity to triazolam in the elderly. N Engl J Med 1991; 324(24):1691-1698.
    
11. Castleden CM, George CF. The effect of ageing on the hepatic clearance of propranolol. Br J Clin Pharmacol 1979; 7(1):49-54.
    
12. Sotaniemi EA, Arranto AJ, Pelkonen O, Pasanen M. Age and cytochrome P450-linked drug metabolism in humans: An analysis of 226 subjects with equal histopathologic conditions. Clinical Pharmacology & Therapeutics 1997; 61(3):331-339.
    
13. Kaplan C, Pasternack B, Shah H, Gallo G. Age-related incidence of sclerotic glomeruli in human kidneys. Am J Pathol 1975; 80(2):227-234.
    
14. Muhlberg W, Platt D. Age-dependent changes of the kidneys: pharmacological implications. Gerontology 1999; 45(5):243-253.
    
15. Fried LP, Ferrucci L, Darer J, Williamson JD, Anderson G. Untangling the Concepts of Disability, Frailty, and Comorbidity: Implications for Improved Targeting and Care. J Gerontol A Biol Sci Med Sci 2004; 59(3):M255-M263.
    
16. Groen K, Horan MA, Roberts NA, Gulati RS, Miljkovic B, Jansen EJ et al. The relationship between phenazone (antipyrine) metabolite formation and theophylline metabolism in healthy and frail elderly women. Clin Pharmacokinet 1993; 25(2):136-144.
    
17. Williams FM, Wynne H, Woodhouse KW, Rawlins MD. Plasma aspirin esterase: the influence of old age and frailty. Age Ageing 1989; 18(1):39-42.
    
18. Wynne HA, Cope LH, Herd B, Rawlins MD, James OF, Woodhouse KW. The association of age and frailty with paracetamol conjugation in man. Age Ageing 1990; 19(6):419-424.
    
19. Wynne HA, Yelland C, Cope LH, Boddy A, Woodhouse KW, Bateman DN. The association of age and frailty with the pharmacokinetics and pharmacodynamics of metoclopramide. Age Ageing 1993; 22(5):354-359.
    
20. Allen Maycock CA, Muhlestein JB, Horne BD, Carlquist JF, Bair TL, Pearson RR et al. Statin therapy is associated with reduced mortality across all age groups of individuals with significant coronary disease, including very elderly patients. J Am Coll Cardiol 2002; 40(10):1777-1785.
    
21. Berlowitz DR, Ash AS, Hickey EC, Friedman RH, Glickman M, Kader B et al. Inadequate Management of Blood Pressure in a Hypertensive Population. N Engl J Med 1998; 339(27):1957-1963.
    
22. Ho SF, O'Mahony MS, Steward JA, Burr ML, Buchalter M. Left ventricular systolic dysfunction and atrial fibrillation in older people in the community - a need for screening? Age Ageing 2004; 33(5):488-492.
    
23. Crome P, Pollock K. Age-discrimination in prescribing: accounting for concordance. Reviews in Clinical Gerontology 14, 1-4. 2005.
    Ref Type: Generic
    
24. Routledge PA, O'Mahony MS, Woodhouse KW. Adverse drug reactions in elderly patients. British Journal of Clinical Pharmacology 2004; 57(2):121-126.
    
25. 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. BMJ 2004; 329(7456):15-19.
    
26. Onder G, Landi F, Cesari M, Gambassi G, Carbonin P, Bernabei R. Inappropriate medication use among hospitalized older adults in Italy: results from the Italian Group of Pharmacoepidemiology in the Elderly. Eur J Clin Pharmacol 2003; 59(2):157-162.
    
27. Lazarou J, Pomeranz BH, Corey PN. Incidence of Adverse Drug Reactions in Hospitalized Patients: A Meta-analysis of Prospective Studies. JAMA 1998; 279(15):1200-1205.
    
28. Beers MH. Explicit criteria for determining potentially inappropriate medication use by the elderly. An update. Arch Intern Med 1997; 157(14):1531-1536.
    
29. Fick DM, Cooper JW, Wade WE, Waller JL, Maclean JR, Beers MH. Updating the Beers Criteria for Potentially Inappropriate Medication Use in Older Adults: Results of a US Consensus Panel of Experts. Arch Intern Med 2003; 163(22):2716-2724.
    
30. Knight EL, Avorn J. Quality indicators for appropriate medication use in vulnerable elders. Ann Intern Med 2001; 135(8 Pt 2):703-710.
    
31. Batty GM, Grant RL, Aggarwal R, Lowe D, Potter JM, Pearson MG et al. National Clinical Sentinel Audit of Evidence-based Prescribing for Older People. Journal of Evaluation in Clinical Practice 2004; 10(2):273-279.
    
32. Batty GM, Grant RL, Aggarwal R, Lowe D, Potter JM, Pearson MG et al. Using prescribing indicators to measure the quality of prescribing to elderly medical in-patients. Age Ageing 2003; 32(3):292-298.
    
33. Department of Health. Medicines and older people - Implementing medicines-related aspects of the NSF for older people. 2001.
    Ref Type: Report
    
34. Living well in later life - A review of progress against the National Service Framework for Older People. 2006. Audit commission; Healthcare commission; Commission for Social Care Inspection.
    Ref Type: Report
    
35. Brian Haynes R, Ann McKibbon K, Kanani R. Systematic review of randomised trials of interventions to assist patients to follow prescriptions for medications. The Lancet 1996; 348(9024):383-386.
    
36. Department of Health. The expert patient: a new approach to chronic disease management for the 21st century. 2001. DOH, London.
    Ref Type: Report
    
37. Department of Health. Involving patients and the public in healthcare. A discussion document. 2001. DOH, London.
    Ref Type: Report
    
38. Department of Health. Patient partnership: Building a collaborative strategy. London DOH . 1996.
    Ref Type: Report
    
39. Royal Pharmaceutical Society of Great Britain. From compliance to concordance: achieving shared goals in medicine taking. 1997. London, Royal Pharmaceutical Society of Great Britain.
    Ref Type: Report
    
40. McGrath A, Crome P. Substance misuse in the older population. Postgraduate Medical Journal 2005;(81):228-231.