Clinical Pharmacology and Therapeutics. Группа авторов
infarction and osteoarthritis. She takes enalapril, Simvastatin, aspirin, ibuprofen and omeprazole regularly. On examination, she appears dehydrated and confused but otherwise there is nothing unusual. Blood results showed a raised white cell count, c‐reactive protein, urea and creatinine (eGFR = 30). You are asked to complete her prescription chart taking into account the current clinical situation and to prescribe nitrofurantoin to treat the urinary tract infection.
Introduction
By 2033, it is estimated 20% of the UK population will be 65 or over. Currently 60% of prescriptions from community pharmacists in the UK are for the elderly, a trend that is likely to rise. Evidence‐based medicine has led to an increased prescription of medications intended for prognostic benefit. With an increased prevalence of chronic disease in the elderly, this has resulted in polypharmacy. This poses a new challenge for prescribers.
Drug absorption, distribution, metabolism, excretion and activity all change with age, but the presence of multiple pathologies frequently has a greater effect than ageing alone.
Adverse effects from medications are three times as likely in the elderly than in the general adult population. Unwanted side effects in this population are more often dose related than idiosyncratic and attributable to altered pharmacokinetics and pharmacodynamics. The highest incidence of side effects documented is caused by some of the most commonly prescribed drugs including sedatives, diuretics and NSAIDs.
Drug absorption
Ageing results in increased gastric pH, delayed gastric emptying, decreased intestinal motility and reduced splanchnic blood flow. However, the extent to which these factors alter bioavailability of a drug is thought to be negligible. For example, the rate of absorption of digoxin is slower in the elderly but the overall bioavailability remains the same.
Drug distribution
Age‐related changes in body composition, protein binding and organ blood flow can all have significant effects on drug disposition. Ageing increases the composition of body fat to water. Therefore, initial drug concentrations of water‐soluble drugs such as digoxin and cimetidine can be increased. Lipid‐soluble drugs such as diazepam will have an increased volume of distribution, lower plasma concentration and prolongation of the elimination half‐life resulting in a prolonged effect. Plasma protein–drug binding changes little with age.
Drug metabolism and age
Age‐related changes such as reduced blood flow and loss of hepatic volume can cause a reduction in oxidising capacity and therefore altered metabolism of some drugs. It is thought, however, that these changes are clinically, minimally significant. Drugs that undergo microsomal oxidation, such as chlordiazepoxide are likely to be metabolised slower, but the evidence is for this is not established. Conjugation pathways appear unaffected by age.
First‐pass metabolism may be reduced in the elderly, possibly a consequence of the reduction in liver mass and blood flow. As a result, drugs that undergo extensive first‐pass metabolism (e.g. labetalol and propranolol) may show considerably increased bioavailability in the elderly, an effect amplified by the presence of chronic liver disease.
Renal excretion
With ageing, there is a fall in both renal blood flow and renal function and dose reduction should be considered if prescribing a renal‐excreted drug in the elderly. Glomerular filtration falls by approximately 30% by the age of 65 years. Digoxin and the aminoglycoside antibiotics are excreted mainly by glomerular filtration and these will tend to accumulate in the elderly if the dose is not reduced.
Renal tubular function also declines and drugs that undergo active tubular secretion (in routine practice mainly penicillin) have a marked reduction in clearance, but this is of limited clinical relevance. Often acutely unwell elderly patients are dehydrated, further compromising renal function. In these circumstances (i.e. acute kidney injury), potentially nephrotoxic drugs should be withheld.
Receptor sensitivity
Although the mechanisms are poorly understood, the elderly seem to be more sensitive to certain drugs. These tend to be drugs where caution should be exercised, e.g. benzodiazepines and warfarin.
Impairment of homeostasis
Cardiovascular postural reflexes are less effective in the elderly. Falls due to presyncope and syncope are exacerbated by the use of drugs that cause postural hypotension, including diuretics, antihypertensive agents and sedatives.
Polypharmacy
The prescription of multiple drugs can lead to a multitude of problems both for the prescriber and the patient, including poor adherence, drug interactions and adverse reactions. The incidence of adverse reactions has been reported as 4% when taking less than five drugs and increases to 54% when taking over five. When prescribing in the elderly it is important to ensure that both you, as prescriber, and the patient understand the indication for the prescription (i.e. symptomatic and/or prognostic benefit) versus potential for side effects.
There is no evidence that an elderly patient whose mental function is normal is more likely to make mistakes with their medication than a younger patient. However, polypharmacy contributes to poor adherence and safety at all ages. The rate of errors when three drugs are prescribed is approximately 20% but it is close to 100% when 10 drugs are prescribed – and the high rate of prescribing for the elderly results in a greater opportunity to make errors. This is, however, potentially made worse by the prevalence of cognitive impairment, which is as high as 25% in those over the age of 85 years.
Physical disability, such as arthritis can contribute to poor adherence as opening ‘child‐proof’ containers or ‘bubble‐pack’ drugs becomes more difficult. Medication aids such as ‘blister packs’ and non‐childproof containers should be considered in this population.
1 The presentation of disease in the elderly is often non‐specific (e.g. confusion). It is important to make an accurate diagnosis to allow appropriate therapy
2 Treat only when benefit outweighs risks. Elderly patients frequently have multiple symptoms and pathologies leading to polypharmacy. This increases the risk of side effects and results in poor adherence
3 It is important to review the need for each prescription on a regular basis. If a drug is considered necessary for symptomatic or prognostic benefit, ensure the minimum dose required is used
4 Understand the change in pharmacology with age (particularly decline in renal function) for each drug used, remembering that dose alterations may be required, particularly in the acute setting
Drugs in pregnant and breastfeeding women
Drugs in pregnancy
A 28‐year‐old woman attends her GP for preconception advice. She has epilepsy and has been on carbamazepine 800 mg bd for several years. She has been seizure free for over 12 months. She has recently got married and wishes to discuss the implications of her epilepsy on planning a pregnancy. She has no other medical or family history of note. What are the risks of the medication on a developing baby and is there anything she can do to minimise this risk?