Absorption

There is a delay in gastric emptying, reduction in gastric acid output and splanchnic blood flow with ageing. These changes do not significantly affect the absorption of the majority of drugs. Although the absorption of some drugs such as digoxin may be slower, the overall absorption is similar to that in the young.

First-pass metabolism

After absorption, drugs are transported via the portal circulation to the liver, where many lipid-soluble agents are metabolised extensively (more than 90–95%). This results in a marked reduction in systemic bioavailability. Obviously, even minor reductions in first-pass metabolism can result in a significant increase in the bioavailability of such drugs.

Impaired first-pass metabolism has been demonstrated in the elderly for several drugs, including clomethiazole, labetalol, nifedipine, nitrates, propranolol and verapamil. The clinical effects of some of these, such as the hypotensive effect of nifedipine, may be significantly enhanced in the elderly. In frail hospitalised elderly patients, that is, those with chronic debilitating disease, the reduction in pre-systemic elimination is even more marked.

Distribution

The age-related physiological changes which may affect drug distribution are

Increased body fat in the elderly results in an increased volume of distribution for fat-soluble compounds such as clomethiazole, diazepam, desmethyl-diazepam and thiopental. On the other hand, reduction in body water results in a decrease in the distribution volume of water-soluble drugs such as cimetidine, digoxin and ethanol.

Acidic drugs tend to bind to plasma albumin, while basic drugs bind to α₁-acid glycoprotein. Plasma albumin levels decrease with age and therefore the free fraction of acidic drugs such as cimetidine, furosemide and warfarin will increase. Plasma α₁-acid glycoprotein levels may remain unchanged or may rise slightly with ageing, and this may result in minimal reductions in free fractions of basic drugs such as lidocaine. Disease-related changes in the level of this glycoprotein are probably more important than age per se.

The age-related changes in distribution and protein binding are probably of significance only in the acute administration of drugs because, at steady state, the plasma concentration of a drug is determined primarily by free drug clearance by the liver and kidneys rather than by distribution volume or protein binding.

Renal clearance

Although there is a considerable interindividual variability in renal function in the elderly, in general the glomerular filtration rate declines, as do the effective renal plasma flow and renal tubular function. Because of the marked variability in renal function in the elderly, the dosages of predominantly renally excreted drugs should be individualised. Reduction in dosages of drugs with a low therapeutic index, such as digoxin and aminoglycosides, may be necessary. Dosage adjustments may not be necessary for drugs with a wide therapeutic index, for example, penicillins.

Hepatic clearance

Hepatic clearance (Cl_H) of a drug is dependent on hepatic blood flow (Q) and the steady state extraction ratio (E), as can be seen in the following formula:

where C_a and C_v are arterial and venous concentrations of the drug, respectively. It is obvious from the above formula that when E approaches unity, Cl_H will be proportional to and limited by Q. Drugs which are cleared by this mechanism have a rapid rate of metabolism, and the rate of extraction by the liver is very high. The rate-limiting step, as mentioned earlier, is hepatic blood flow, and therefore drugs cleared by this mechanism are called ‘flow limited’. On the other hand, when E is small, Cl_H will vary according to the hepatic uptake and enzyme activity, and will be relatively independent of hepatic blood flow. The drugs which are cleared by this mechanism are termed ‘capacity limited’.

Hepatic extraction is dependent upon liver size, liver blood flow, uptake into hepatocytes, and the affinity and activity of hepatic enzymes. Liver size falls with ageing and there is a decrease in hepatic mass of 20% and 40% between the third and tenth decade. Hepatic blood flow falls equally with declining liver size. Although it is recognised that the microsomal mono-oxygenase enzyme systems are significantly reduced in ageing male rodents, evidence suggests that this is not the case in ageing humans. Conjugation reactions have been reported to be unaffected in the elderly by some investigators, but a small decline with increasing age has been described by others.

Impaired clearance of many hepatically eliminated drugs has been demonstrated in the elderly. Morphological changes rather than impaired enzymatic activity appear to be the main cause of impaired elimination of these drugs. In frail debilitated elderly patients, however, the activities of drug-metabolising enzymes such as plasma esterases and hepatic glucuronyltransferases may well be impaired.

Reduced homeostatic reserve

Age-related changes in specific receptors and target sites

Many drugs exert their effect via specific receptors. Response to such drugs may be altered by the number (density) of receptors, the affinity of the receptor, postreceptor events within cells resulting in impaired enzyme activation and signal amplification, or altered response of the target tissue itself. Ageing is associated with some of these changes.

Dementia

Dementia is characterised by a gradual deterioration of intellectual capacity. Alzheimer’s disease (AD), vascular dementia (VaD), dementia with Lewy bodies and frontotemporal dementia are the most important diseases of cognitive dysfunction in the elderly. AD has a gradual onset, and it progresses slowly. Forgetfulness is the major initial symptom. The patient has difficulty in dressing and other activities of daily living. He or she tends to get lost in his or her own environment. Eventually, the social graces are lost. VaD is the second most important cause of dementia. It usually occurs in patients in their 60s and 70s, and is more common in those with a previous history of hypertension or stroke. It is commonly associated with mood changes and emotional lability. Physical examination may reveal focal neurological deficits. A number of drugs and other conditions cause confusion in the elderly, and their effects may be mistaken for dementia. These are listed in Box 11.1.

In patients with AD, damage to the cholinergic neurones connecting subcortical nuclei to the cerebral cortex has been consistently observed. Postsynaptic muscarinic cholinergic receptors are usually not affected, but ascending noradrenergic and serotonergic pathways are damaged, especially in younger patients. Based on those abnormalities, several drugs have been investigated for the treatment of AD. Lecithin, which increases acetylcholine concentrations in the brain, 4-aminopyridine, piracetam, oxitacetam and pramiracetam, all of which stimulate acetylcholine release, have been tried, but have produced no, or unimpressive, improvements in cognitive function. Anticholinesterases block the breakdown of acetylcholine and enhance cholinergic transmission. Donepezil, galantamine and rivastigmine are recommended for treatment of patients with AD of moderate severity only (those with a Mini Mental State Examination (MMSE) score of between 10 and 20 points; NICE, 2009). Donepezil is a piperidine-based acetylcholinesterase inhibitor. It has been shown to improve cognitive function in patients with mild to moderately severe AD. However, it does not improve day-to-day functioning, quality-of-life measures or rating scores of overall dementia. Rivastigmine is a non-competitive cholinesterase inhibitor. It has been shown to slow the rate of decline in cognitive and global functioning in AD. Galantamine, a reversible and competitive inhibitor of acetylcholinesterase, has also been shown to improve cognitive function significantly and is well tolerated. Adverse effects of cholinesterase inhibitors include nausea, vomiting, diarrhoea, weight loss, agitation, confusion, insomnia, abnormal dreams, muscle cramps, bradycardia, syncope and fatigue. Treatment with these drugs should only be continued in people with dementia who show an improvement or no deterioration in their minimental score, together with evidence of global (functional and behavioural) improvement after first few months of treatment. The treatment effect should then be reviewed critically every 6 months, before a decision to continue drug therapy is made.

Memantine, an N-methyl-d-aspartate (NMDA) antagonist, has also been used for the treatment of moderate to severe AD. It acts mainly on subtypes of glutamate receptors related to memory (i.e. NMDA), resulting in improvements in cognition. It has also been shown to have some beneficial effects on behaviour and its use is recommended in patients with moderate to severe AD as part of well-designed clinical studies (NICE, 2009).

Deposition of amyloid (in particular the peptide β/A4) derived from the Alzheimer amyloid precursor protein (APP) is an important pathological feature of the familial form of AD that accounts for about 20% of patients. Point mutation of the gene coding for APP (located in the long arm of chromosome 21) is thought to be associated with familial AD. Future treatment strategies, therefore, might involve development of drugs which inhibit amyloidogenesis.

In some studies, donepezil and galantamine have been shown to improve cognition, behaviour and activities of daily living in patients with VaD, and in those with AD and coexistent cerebrovascular disease. Memantine has been reported to stabilise progression of VaD compared with placebo. However, acetylcholinesterase inhibitors and memantine should not be prescribed for the treatment of cognitive decline in patients with VaD, except as part of properly constructed clinical studies (National Collaborating Centre for Mental Health, 2007). Aspirin therapy has also been reported to slow the progression of VaD. The incidence of VaD is likely to decrease with other stroke prevention strategies such as smoking cessation, anticoagulation for atrial fibrillation, control of hypertension and hyperlipidemia.

Parkinsonism

Parkinsonism is a relatively common disease of the elderly with a prevalence between 50 and 150 per 100,000. It is characterised by resting tremors, muscular rigidity and bradykinesia (slowness of initiating and carrying out voluntary movements). The patient has a mask-like face, monotonous voice and walks with a stoop and a slow shuffling gait.

The elderly are more susceptible than younger patients to some of the adverse effects of antiparkinsonian drugs. Age-related decline in orthostatic circulatory responses, means that postural hypotension is more likely to occur in elderly patients with levodopa therapy. The elderly are more likely to have severe cardiac disease, and levodopa preparations should be used with caution in such patients because of the risk of serious ventricular dysrhythmias. Psychiatric adverse effects such as confusion, depression, hallucinations and paranoia occur with dopamine agonists and levodopa preparations. These adverse effects may persist for several months after discontinuation of the offending drug and may result in misdiagnosis (e.g. of AD) in the elderly. Bromocriptine and other ergot derivatives should be avoided in elderly patients with severe peripheral arterial disease as they may cause peripheral ischaemia. ‘Drug holidays’, which involve discontinuation of drugs, for example, for 2 days per week, may reduce the incidence of adverse effects of antiparkinsonian drugs, but their role is questionable.

Stroke

Stroke is the third most common cause of death and the most common cause of adult disability in the UK. About 110,000 people in England and Wales have their first stroke each year and about 30,000 people go on to have further strokes (National Collaborating Centre for Chronic Conditions, 2008). The incidence of stroke increases by 100-fold from the fourth to the ninth decade. About 85% of strokes are ischaemic and 15% are due to haemorrhages.

Osteoporosis

Osteoporosis is a progressive disease characterised by low bone mass and micro-architectural deterioration of bone tissue resulting in increased bone fragility and susceptibility to fracture. It is an important cause of morbidity in postmenopausal women. The most important complication of osteoporosis is fracture of the hip. Fractures of wrist, vertebrae and humerus also occur. Increasing age is associated with higher risk of fractures, which occur mostly in those aged over 75 years. In the UK, over 200,000 fractures occur each year, costing the NHS £1.8 billion per year, of which 87% is spent on hip fractures (Poole and Compston, 2006).

Arthritis

Osteoarthrosis, gout, pseudogout, rheumatoid arthritis and septic arthritis are the important joint diseases in the elderly. Treatment of these conditions is similar to that in the young. If possible, NSAIDs should be avoided in patients with osteoarthrosis. Total hip and knee replacements should be considered in patients with severe arthritis affecting these joints.

Hypertension

Hypertension is an important risk factor for cardiovascular and cerebrovascular disease in the elderly. The incidence of myocardial infarction is 2.5 times higher, and that of cerebrovascular accidents twice as high in elderly hypertensive patients compared with non-hypertensive subjects. Elevated systolic blood pressure is the single most important risk factor for cardiovascular disease and more predictive of stroke than diastolic blood pressure.

Blood pressure lowering has been shown to be beneficial in those patients below and above the age of 65 years with no substantial variation in reduction in major vascular events with different drug classes (Blood Pressure Lowering Treatment Trialists’ Collaboration, 2008). There is evidence that treatment of both systolic and diastolic blood pressure in the elderly is beneficial. One large study has shown reductions in cardiovascular events, and mortality associated with cerebrovascular accidents in treated elderly patients with hypertension (Amery et al., 1986). The treatment did not reduce the total mortality significantly. Another study (SHEP, 1991), which used low-dose chlortalidone to treat isolated systolic hypertension (systolic blood pressure 160 mmHg or more with diastolic blood pressure less than 95 mmHg), showed a 36% reduction in the incidence of stroke, with a 5-year benefit of 30 events per 1000 patients. It also showed a reduction in the incidence of major cardiovascular events with a 5-year absolute benefit of 55 events per 1000 patients. In addition, this study reported that antihypertensive therapy was beneficial even in patients over the age of 80 years. There is increasing evidence that antihypertensive therapy in patients over 80 years of age is beneficial. Subgroup meta-analysis of seven randomised controlled trials, which included 1670 patients over 80 years, showed that antihypertensive therapy for about 3.5 years reduces the risk of heart failure by 39%, strokes by 34% and major cardiovascular events by 22% (Gueyffier, 1999). In one placebo-controlled study which included 3845 patients who were 80 years of age or older and had a sustained systolic blood pressure of 160 mmHg or more, treatment with the diuretic indapamide (sustained release, 1.5 mg) plus perindopril (2 or 4 mg) to achieve the target blood pressure of 150/80 mmHg resulted in a 30% reduction in the rate of fatal or non-fatal stroke, a 39% reduction in the rate of death from stroke, a 21% reduction in the rate of death from any cause, a 23% reduction in the rate of death from cardiovascular causes and a 64% reduction in the rate of heart failure (Beckett et al., 2008).

Myocardial infarction

The diagnosis of myocardial infarction in the elderly may be difficult in some patients because of an atypical presentation (Bayer et al., 1986). In the majority of patients, chest pain and dyspnoea are the common presenting symptoms. Confusion may be a presenting factor in up to 20% of patients over 85 years of age. The diagnosis is made on the basis of history, serial electrocardiograms and cardiac enzyme estimations.

The principles of management of myocardial infarction in the elderly are similar to those in the young. Thrombolytic therapy has been shown to be safe and effective in elderly patients.

Cardiac failure

In addition to the typical features of cardiac failure, that is, exertional dyspnoea, oedema, orthopnoea and paroxysmal nocturnal dyspnoea (PND), elderly patients may present with atypical symptoms. These include confusion due to poor cerebral circulation, vomiting and abdominal pain due to gastro-intestinal and hepatic congestion, or insomnia due to PND. Dyspnoea may not be a predominant symptom in an elderly patient with arthritis and immobility. Treatment of cardiac failure depends on the underlying cause and is similar to that in the young. Diuretics, ACE inhibitors, β-blockers and digoxin are the important drugs used in the treatment of cardiac failure in the elderly.

Leg ulcers

Leg ulcers are common in the elderly. They are mainly of two types: venous or ischaemic. Other causes of leg ulcers are blood diseases, trauma, malignancy and infections (Cornwall et al., 1986), but these are less common in the elderly. Venous ulcers occur in patients with varicose veins who have valvular incompetence in deep veins due to venous hypertension. They are usually located near the medial malleolus and are associated with varicose eczema and oedema. These ulcers are painless unless there is gross oedema or infection. Ischaemic ulcers, on the other hand, are due to poor peripheral circulation, and occur on the toes, heels, foot and lateral aspect of the leg. They are painful and are associated with signs of lower limb ischaemia, such as absent pulse or cold lower limb. There may be a history of smoking, diabetes or hypertension.

Venous ulcers respond well to treatment, and over 75% heal within 3 months. Elevation of the lower limbs, exercise, compression bandage, local antiseptic creams when there is evidence of infection, with or without steroid cream, are usually effective. There is no evidence of benefit from the use of oral zinc sulphate in patients with chronic leg ulcers. Dressings impregnated with silver have not been shown to be better than simple low-adherent dressings for the healing of venous leg ulcers. Use of 5% Eutectic Mixture of Local Anaesthetics (EMLA): lidocaine–prilocaine cream results in statistically significant reduction in debridement pain scores but it appears to have no impact on wound healing. Ibuprofen dressings have not been shown to offer pain relief (Briggs et al., 2010). Antiseptics should not be used when there is granulation tissue. Topical streptokinase may be useful to remove the slough on ulcers. Gell colloid occlusive dressings may also be useful in treating chronic ulcers. Skin grafting may be necessary for large ulcers. Ischaemic ulcers do not respond well to medical treatment, and the patients should be assessed by vascular surgeons.

Urinary incontinence

Urinary incontinence in the elderly may be of three main types:

Constipation

The age-related decline in gastro-intestinal motility and treatment with drugs which decrease gastro-intestinal motility predispose the elderly to constipation. Decreased mobility, wasting of pelvic muscles and a low intake of solids and liquids are other contributory factors. Faecal impaction may occur with severe constipation, which in turn may cause subacute intestinal obstruction, abdominal pain, spurious diarrhoea and faecal incontinence. Adequate intake of dietary fibre, regular bowel habit and use of bulking agents such as bran or ispaghula husk may help to prevent constipation. When constipation is associated with a loaded rectum, a stimulant laxative such as senna or bisacodyl may be given. Frail, ill elderly patients with a full rectum may have atonic bowels that will not respond to bulking agents or softening agents, and in such cases a stimulant is more effective. A stool-softening agent such as docusate sodium is effective when stools are hard and dry. For severe faecal impaction a phosphate enema may be needed. Long-term use of stimulant laxatives may lead to abuse and atonic bowel musculature.

Gastro-intestinal ulceration and bleeding

Gastro-intestinal bleeding associated with peptic ulcer is less well tolerated by the elderly. The clinical presentation may sometimes be atypical with, for example, patients presenting with confusion. Helicobacter pylori infection is common and its treatment is similar to that in younger patients. NSAIDs are more likely to cause gastroduodenal ulceration and bleeding in the elderly (Griffin et al., 1988).

Avoid unnecessary drug therapy

Before commencing drug therapy it is important to ask the following questions:

In patients with mild hypertension, non-drug therapies which are of proven efficacy should be considered in the first instance. Similarly, unnecessary use of hypnotics should be avoided. Simple measures such as emptying the bladder before going to bed to avoid having to get up, avoidance of stimulant drugs in the evenings or night, or moving the patient to a dark, quiet room may be all that is needed.

Effect of treatment on quality of life

The aim of treatment in elderly patients is not just to prolong life but also to improve the quality of life. To achieve this, the correct choice of treatment is essential. In a 70-year-old lady with severe osteoarthrosis of the hip, for example, total hip replacement is the treatment of choice rather than prescribing NSAIDs with all their attendant adverse effects.

Treat the cause rather than the symptom

Symptomatic treatment without specific diagnosis is not only bad practice but can also be potentially dangerous. A patient presenting with ‘indigestion’ may in fact be suffering from angina, and therefore treatment with proton pump inhibitors or antacids is clearly inappropriate. When a patient presents with a symptom every attempt should be made to establish the cause of the symptom and specific treatment, if available, should then be given.

Drug history

A drug history should be obtained in all elderly patients. This will ensure the patient is not prescribed a drug or drugs to which they may be allergic, or the same drug or group of drugs to which they have previously not responded. It will help to avoid potentially serious drug interactions.

Concomitant medical illness

Concurrent medical disorders must always be taken into account. Cardiac failure, renal impairment and hepatic dysfunction are particularly common in the elderly, and may increase the risk of adverse effects of drugs.

Choosing the drug

Once it is decided that a patient requires drug therapy, it is important to choose the drug likely to be the most efficacious and least likely to produce adverse effects. It is also necessary to take into consideration coexisting medical conditions. For example, it is inappropriate to commence diuretic therapy to treat mild hypertension in an elderly male with prostatic hypertrophy.

Dose titration

In general, elderly patients require relatively smaller doses of all drugs compared with young adults. It is recognised that the majority of adverse drug reactions in the elderly are dose related and potentially preventable. It is, therefore, rational to start with the smallest possible dose of a given drug in the least number of doses and then gradually increase both, if necessary. Dose titration should obviously take into consideration age-related pharmacokinetic and pharmacodynamic alterations that may affect the response to the chosen drug.

Choosing the right dosage form

Most elderly patients find it easy to swallow syrups or suspensions or effervescent tablets rather than large tablets or capsules.

Packaging and labelling

Many elderly patients with arthritis find it difficult to open child-resistant containers and blister packs. Medicines should be dispensed in easy-to-open containers that are clearly labelled using large print.

Good record keeping

Information about a patient’s current and previous drug therapy, alcohol consumption, smoking and driving habits may help in choosing appropriate drug therapy and when the treatment needs to be altered. It will help to reduce costly duplications and will also identify and help to avoid dangerous drug interactions.

Regular supervision and review of treatment

A UK survey showed that 59% of prescriptions to the elderly had been given for more than 2 years, 32% for more than 5 years and 16% for more than 10 years. Of all prescriptions given to the elderly, 88% were repeat prescriptions; 40% had not been discussed with the doctor for at least 6 months, especially prescriptions for hypnotics and anxiolytics. It also showed that 31% of prescriptions were considered pharmacologically questionable, and 4% showed duplication of drugs. It is obvious that there is a need for regular and critical review of all prescriptions, especially when long-term therapy is required.

Adverse drug reactions (ADRs)

It is recognised that ADRs occur more frequently in the elderly. A multicentre study in the UK in 1980 showed that ADRs were the only cause of admission in 2.8% of 1998 admissions to 42 units of geriatric medicine. It also showed that ADRs were contributory to a further 7.7% of admissions. On the basis of this study it can be estimated that up to 15,000 geriatric admissions per annum in the UK are at least partly due to an ADR. Obviously, this has enormous economic implications.

The elderly are more susceptible to ADRs for a number of reasons. They are usually on multiple drugs, which in itself can account for the increased incidence of ADRs. It is, however, recognised that ADRs tend to be more severe in the elderly, and gastro-intestinal and haematological ADRs are more common than would be expected from prescribing figures alone. Age-related pharmacokinetic and pharmacodynamic alterations and impaired homeostatic mechanisms are the other factors which predispose the elderly to ADRs, by making them more sensitive to the pharmacological effects of the drugs. Not surprisingly, up to 80% of ADRs in the elderly are dose-dependent and therefore predictable.

Adherence

Although it is commonly believed that the elderly are poor compliers with their drug therapy, there is no clear evidence to support this. Studies in Northern Ireland and continental Europe have shown that the elderly are as adherent with their drug therapy as the young, provided that they do not have confounding disease. Cognitive impairment, which is common in old age, multiple drug therapy and complicated drug regimens may impair adherence in the elderly. Poor adherence may result in treatment failure. The degree of adherence required varies depending on the disease being treated. For treatment of a simple urinary tract infection, a single dose of an antibiotic may be all that is required, and therefore compliance is not important. On the other hand, adherence of 90% or more is required for successful treatment of epilepsy or difficult hypertension. Various methods have been used to improve adherence. These include prescription diaries, special packaging, training by pharmacists and counselling.