Drug absorption

Orally administered drugs are absorbed across the intestinal wall into the portal circulation, where they pass through the liver, before reaching the drug target. The proportion of the drug reaching the systemic circulation (bioavailability) depends on the amount absorbed across the intestinal mucosa and the amount metabolised in the intestinal wall and liver (first pass metabolism).

Ageing reduces gastric emptying, peristalsis and colonic transit, probably through loss of neurones . This slows movement of drugs through the gut and can delay absorption. Gastric acid secretion is reduced significantly in 5–10% of elderly people , which may impair absorption of drugs that need a low pH, such as ketoconazole, calcium and iron compounds. Achlorhydria may also lead to intestinal bacterial overgrowth, with effects on small intestinal absorption. A reduction occurs in active intestinal transport, which reduces absorption of calcium , and reduced gastrointestinal blood flow. Constipation and age-related anorexia may also make it difficult for elderly people to take oral medications .

Drug distribution

With ageing, body water decreases by 10–15%, body fat increases by 20–40% and serum albumin decreases by about 10% . These changes have diverse effects on drug pharmacokinetics. The volume of distribution for water-soluble drugs such as aminoglycosides is decreased, potentially increasing their plasma concentration and risk of toxicity. Increased body fat forms a reservoir for lipid-soluble drugs, such as diazepam, increasing their elimination half-life and prolonging drug action. The unbound fraction of drugs that are extensively protein bound, such as doxorubicin, midazolam and propofol, increases by about 10% in line with the fall in plasma albumin .

Metabolism

Metabolism converts drugs from lipid-soluble forms required for absorption and distribution, to more water-soluble forms required for excretion in urine or bile. Phase I metabolism includes oxidation by cytochrome p450 enzymes, reduction or hydrolysis. These processes predominantly occur in the liver, although cytochrome p450 metabolism also takes place in the intestinal wall, kidney and lungs. Phase I processes generally reduce activity of the drug, but can sometimes convert an inactive drug (pro-drug) to an active metabolite (e.g. enalapril, clopidogrel, diazepam) or generate a toxic metabolite (e.g. paracetamol). In phase II processes, enzymes catalyse conjugation of drugs with other molecules (e.g. sulfotransferases catalyse conjugation with sulphate, UDP-glucuronosyltransferases with glucuronide and glutathione s transferases with glutathione). The resulting conjugates are inert.

The main hepatic changes with age are about 40% reduction in hepatic blood flow and 15–30% reduction in liver mass, both of which can reduce drug clearance . In addition, changes in liver sinusoids may reduce drug transfer from blood to hepatocytes . Some reduction seems to occur in phase I, but not phase II, metabolic processes . Metabolism of drugs extensively cleared by the liver, such as diazepam, pethidine, morphine and lidocaine, may be particularly affected by age-related hepatic changes. Reduced first-pass metabolism of orally administered drugs increases plasma concentrations. Reduced hepatic clearance prolongs drug plasma half-life, and can increase steady state plasma concentrations. In practice, however, co-prescription of drugs that induce or inhibit hepatic enzyme function ( Table 2 ) , is more likely have a clinically significant effect on drug metabolism than age-related hepatic change.

Excretion

Renal function is commonly impaired in elderly people owing to comorbid disease, such as hypertension, diabetes and vascular disease, use of nephrotoxic drugs, such as non-steroidal anti-inflammatory drugs (NSAIDs), and age-related decline in glomerular filtration rate (GFR) (<1 ml/min/year) . Impaired renal excretion of drugs prolongs drug plasma half-life and can increase steady state plasma concentrations. Pharmacokinetic changes caused by renal impairment are of real clinical importance, necessitating dose adjustment of renally excreted drugs ( Table 3 ), particularly those with a narrow therapeutic range ( Fig. 1 ).

Accurate quantification of renal impairment can be difficult in elderly people. Serum creatinine may be low because of reduced skeletal muscle mass, despite renal impairment. Serum creatinine, age, and gender can be combined with weight to estimate creatinine clearance from the Cockcroft and Gault formula ( http://nephron.com/cgi-bin/CGSI.cgi ) or with race to estimate (e)GFR using the Modification of Diet in Renal Disease prediction equation ( http://nephron.org/cgi-bin/MDRD_GFR/cgi ). The British National Formulary now recommends dosage adjustment of renally excreted drugs on the basis of the eGFR , which is routinely reported by UK biochemistry laboratories. Most published information on the effects of renal impairment on drug elimination is stated in terms of creatinine clearance, and the two are not interchangeable. Furthermore, both equations may overestimate GFR in elderly people with chronic kidney disease . In clinical practice, eGFR can be used to make decisions about adjusting the dose of most drugs, but the BNF recommends the use of creatinine clearance (Cockcroft and Gault formula) for renally excreted drugs with a narrow therapeutic–toxic ratio . Drugs from the gynaecology formulary that need dose adjustment, or should be avoided in patients with renal impairment, are presented in Table 3 .

Central nervous system

Ageing causes a reduction in brain weight, loss of neurones, grey matter and synapses and altered brain phospholipid content . Dopaminergic and cholinergic receptors and neurones are reduced . Permeability of the blood–brain barrier to drugs increases with age and co-morbidity . As a consequence, sensitivity of the central nervous system (CNS) to drug side-effects, including headache, reduction in cognitive function, confusion, sedation and extrapyramidal changes, increases with age. A number of drugs on the gynaecology formulary may present an increased risk of CNS side-effects when prescribed to elderly people, including anti-muscarinic drugs, opioids, benzodiazepines and general anaesthesia.

Cardiovascular system

One of the best described pharmacodynamic changes with ageing is loss of sensitivity of adrenergic receptors, with reduced sensitivity to both agonists and antagonists. Older people have less increase in cardiac contractility with isoprenaline , less reduction in blood pressure with beta adrenoceptor blockers , and less bronchodilatation with beta 2 adrenoceptor agonists than younger people. By contrast, blunting of compensatory vascular reflexes makes elderly people more susceptible to the hypotensive effects of many drugs, with resulting orthostatic (postural) hypotension and increased risk of falls. Drugs on the gynaecology formulary do not generally have adverse cardiovascular effects. Hypotension is predominantly an adverse effect of drugs designed to lower blood pressure (e.g. diuretics, angiotensin converting enzyme [ACE] inhibitors, and calcium channel blockers) and centrally acting drugs (drugs for Parkinson’s disease, antidepressants, and anti-psychotics) .

Organs and tissues with fast cell turnover

With ageing, a decrease in cell proliferation occurs that may be mediated by defects in growth factor receptor and signal transduction . This particularly affects the organs and tissues with relatively fast cell turnover, including the bone marrow, gastrointestinal mucosa, skin and hair. Elderly people are therefore increasingly susceptible to haematological, gastrointestinal, and other side-effects of anticancer chemotherapy, which may limit its application . Ageing also increases the risk of peptic ulceration with NSAIDs, with hospitalisation or death from acute gastrointestinal adverse events from NSAIDs being 14 times more likely in people aged 75 years or older than in those younger than 63 years .

Geriatric syndromes

Geriatric syndromes are multifactorial clinical conditions in elderly people that cannot be fitted easily into disease categories. These include frailty (increased vulnerability to environmental factors), dizziness, falls, musculoskeletal decline, cognitive impairment, incontinence, and dependency. Geriatric syndromes are common. In people aged 65 years or older living in the community, prevalence of frailty was 14–24%; cognitive impairment 5–17%; impaired activities of daily living 5–18%; and skeletal muscle wasting and weakness 50–52% . In women aged 65 years or older undergoing gynaecologic oncology procedures, 27% were intermediately frail and 16% were frail . Prevalence of geriatric syndromes increases with age, with falls, dizziness, and mobility problems doubling in frequency between the ages of 70 and 85 years . Geriatric syndromes are associated with poor survival , increased risk of postoperative complications after gynaecological surgery and higher risk of functional decline, loss of independence and death after hospitalisation .

A strong interdependent relationship exists between medication use and geriatric syndromes. In community-dwelling men aged 70 years or older, every additional medicine added to treatment was associated with a 13% increased risk of frailty, 8% increased risk of disability and 7% increased risk of falls . Medication use may contribute to the cause of geriatric syndromes. In people aged 65 years or older admitted to acute medical wards, delirium was associated with use of antidepressants, antipsychotics and antiepileptics, and pre-hospital falls were associated with identification of an adverse drug event at admission . Additionally, geriatric syndromes may increase sensitivity to adverse drug events. People aged over 65 years admitted to acute medical wards with a prior history of falls and dependency in at least one activity of daily living were twice as likely to develop an adverse drug reaction during hospital stay as those without .

Polypharmacy

Polypharmacy can be defined as the concurrent use of five or more prescribed medicines. Using this definition, the prevalence of polypharmacy was 45% in people aged 75 years or older attending an emergency department , 80% in people aged over 65 years with cancer attending oncology clinics , and 68% in nursing home residents with cognitive impairment . Polypharmacy is associated with a high risk of adverse drug events. One in three patients taking more than five medicines experienced at least one adverse drug event over 1 year, with 65% of these requiring clinician contact, including emergency room attendance (10%) or hospitalisation (11%) . An alternative definition of polypharmacy is ‘use of more medicines than are clinically indicated’ . Elderly people are particularly risk of this because of inaccurate diagnosis, prescription of new medications to treat adverse effects of existing medicines, and failure to stop medicines when the indication is no longer present. Thus, many adverse drug reactions in elderly people are preventable.

Under-treatment

Clinical trial evidence to support use of medicines in elderly people is less robust than in younger people . For example, older women with ovarian cancer have been under-represented in clinical trials . Elderly people may be excluded from trials by design, because of age, comorbidity or polypharmacy, or by default, where functional limitation prevents participation. As a result, new treatments are often tested in people who are healthier than those who will be prescribed medicines in the general population. Once prescribed to elderly people with complex medical problems, medicines may have less benefit than predicted, and unexpected side-effects may emerge.

Even where clinical trials have been conducted, elderly people are less likely than younger people to receive evidence-based treatments. For example, older women with ovarian cancer were less likely to undergo complete debulking surgery or adjuvant chemotherapy, and received lower dose chemotherapy than younger women . Under-treatment in older people is partly explained by the prevalence of co-morbidities, lowered life expectancy and increased risk–benefit ratio. Nihilistic attitudes of clinicians, patients and families to cancer treatment in elderly people, however, as well as social factors, including difficulty getting to the hospital for regular appointments, also contribute .