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