Geriatric medicine consultant Dr Sinéad O'Mahony introduces our nine-part series by outlining the principles behind pharmacology and ageing
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Forty-five per cent of prescriptions in the UK are for people aged 65 and over. Eighty per cent of people aged 75 and over take at least one medicine, and more than a third take four or more. Much prescribing is justified as most chronic disease is strongly age related and there is substantial potential for health gain in older people.
Unfortunately, clinical trials often exclude older people and those with co-morbidities. This makes it difficult to estimate drug safety, as adverse drug reactions are much more common in real-world populations than in selected clinical-trial populations. This under-representation of older people in trials also means applying disease-specific guidelines to them is a challenge, particularly in relation to optimal drug doses.
Adverse drug reactions in older people
Adverse drug reactions (ADRs) cause 6.5% of all hospital admissions in the UK and contribute to up to 30% of admissions in older people.1 Older people are at higher risk of ADRs because of polypharmacy, age-related changes in pharmacokinetics and pharmacodynamics and drug-disease interactions in those with co-morbidities. The single biggest determinant of drug interactions is the number of medicines a person is taking.
More than 80% of ADRs experienced by older people are type A reactions – that is, predictable from the pharmacology of the drug and potentially avoidable either by better drug choice or more appropriate dosing for that individual.
How pharmacokinetics underpin ADRs in older people
Age brings key changes in pharmacokinetics (what the body does to the drug), including substantial effects on drug clearance.
Liver mass and blood flow fall by 30-40% with healthy ageing, leading to a loss in oxidative drug metabolism of the order of 20-30%. This causes reduced drug clearance for many drugs – so the dose needs to be reduced or the dosing interval extended.
Bioavailability is increased for drugs such as nifedipine and propranolol, which normally undergo significant first-pass metabolism. Doses commonly need to be reduced in older people.
The number of nephrons almost halves throughout life and renal blood flow falls by 10% per decade of adult life. These changes affect drugs predominantly eliminated by the kidneys, including digoxin, lithium, diuretics, water soluble ß-blockers and some NSAIDs.
Other pharmacokinetic changes in older people include:
• The volume of distribution for fat-soluble drugs increases because of increased body fat. This contributes to prolongation of half-life for drugs like diazepam, chlormethiazole and the hangover-type effect we observe with hypnotics in older people.
• The volume of distribution of water-soluble drugs is reduced with age because of reduced protein mass and body water – so water-soluble drugs like morphine have higher serum levels and their doses need to be reduced.
• Serum albumin, which binds acidic drugs like phenytoin and warfarin, falls abruptly during acute illness. Alpha-1-acid glycoprotein, which binds basic drugs like lignocaine and propranolol, rises in acute illness. Changes in plasma proteins during acute illness contribute to drug displacement and drug interactions in older people.
Pharmacodynamics and ageing
Pharmacodynamic changes (what the drug does to the body) are probably equally important in increasing the susceptibility of older people to ADRs. Even when appropriate dose adjustments are made – so that an older person has a similar plasma drug level to that of a younger subject – the older person often remains more sensitive to drug effects because of age-related changes in the physiological systems on which the drug is acting. Homeostatic mechanisms that commonly fail with ageing and underpin the susceptibility of older people to ADRs include:
• Postural blood-pressure control – many older people develop dizziness, postural hypotension and an increased risk of falls with cardiovascular medications.
• Posture control and the maintenance of balance is impaired with ageing, so most CNS-acting drugs can contribute to falls in older people.
• The extrapyramidal system declines with ageing. Metoclopramide, prochlorperazine and antipsychotics commonly induce parkinsonism.
• Cognitive function and reserve decline with ageing. Drugs with anticholingeric effects, sedatives and other CNS-acting drugs commonly induce confusion or hallucinations in older people.
• Thermoregulation may be blunted. Drugs such as ethanol, barbiturates and neuroleptics may cause additional problems in older people.
Drug metabolism in frail older people
Frail older people often have further reductions in drug metabolism over and above those due to age alone. Differences in drug clearance between frail and fit old people are commonly much greater than differences between fit old and young adults. So there is a need to individualise prescribing and drug dosing around the biological fitness of the older patient. For drug metabolism purposes, the frail old are defined as patients in nursing homes, or those in the community with poor mobility and nutritional status and dependent on others for activities of daily living.
Medicines in care home residents
ADRs are common in care homes because of the high volume of prescribing, high use of neuroleptics and the frail status of care home residents. Confusional episodes and falls are the two most common ADRs in care homes, although they often are not recognised as ADRs. Psychoactive medications – antipsychotics, antidepressants and sedatives/hypnotics – are commonly associated with preventable ADRs in care homes.
Antipsychotics are widely used off licence for behavioural symptoms in dementia, despite only limited evidence of benefit and definite evidence of harm to older people. A report published by the Department of Health2 estimates 180,000 people with dementia in the UK are being treated with antipsychotics at a cost of 1,620 additional strokes and 1,800 additional deaths a year. The reduction in use of antipsychotics in dementia is to be made a clinical governance priority.
Medication errors are also a problem in care homes. One recent study3 found there were drug errors among 69% of residents in care homes in England. The reasons include the frail status of residents, high levels of cognitive impairment and vulnerability to adverse effects of drugs, poor systems for medicines management, poor communication between doctors, care home staff and residents, high workloads and staff turnover.
Improving prescribing for older people
Key prescribing principles include:
• Avoid unnecessary drug therapy. For example, it is possible to safely withdraw up to half of diuretics prescribed for older people.
• Consider alternative treatments, such as sleep hygiene instead of sedatives and behavioural management rather than neuroleptic agents.
• Ensure appropriate drug choice given co-morbidities.
• Use a lower starting dose and increase doses slowly.
• Consider an extended dosing interval to compensate for reductions in drug clearance.
• Titrate dose to maximum therapeutic effect.
• Keep a heightened awareness for ADRs.
Regular medication review with particular vigilance for ADRs is essential if we are to get the most out of medicines for older people. A recently developed STOPP/START screening tool4 of older persons' prescriptions may help when undertaking structured medication reviews. This tool identifies potentially inappropriate prescribing including drug-drug and drug-disease interactions (STOPP), and prescribing omissions (START), equally important if we are to improve the overall quality of prescribing in older patients.
Dr Sinéad O'Mahony is chair of the British Geriatrics Society's drugs and prescribing section and consultant physician and senior lecturer in geriatric medicine at the University Hospital Llandough, Cardiff
Competing interests: None declared
Prescribing in older people Prescribing in older peopleThis series was produced in conjunction with the drugs and prescribing section of the British Geriatrics Society.
The BGS is holding a multidisciplinary day on 5 November 2010 in Brighton providing medical, nursing and therapy perspectives on the following topics: aggression, alcohol, epilepsy, care homes and quality care. For further details click here.
