Although geriatric patients constitute only 11% of the population in North America, they incur 30% of the total costs of drugs. Within the next 30 years these figures are expected to reach 16-18% and 40%, respectively. Although the elderly are a major group of drug users, most drug studies are performed on patients or volunteers aged 55 years or less. There is a sevenfold increase in drug toxicities as one ages from 20 to 79 years (from 3% at 20-29 years to 21% at 70-79 years). Part of this increase may well be due to multiple medication - drug interactions. I would like to suggest also that a significant part of this increase in drug toxicities is due to incomplete understanding of changes in the ADME processes of drug disposition with aging. We will consider some of the physiological changes which occur in aging and then look at the ADME processes in turn[7,8,9,10,11].
Physiologic changes with age
Easier to look at as a table of factors, Table XXI-5. Then when considering ADME we can expand on this.
Table XXI-5 Summary of Factors affecting Drug Disposition and Responses in the Elderly
gastric acid secretion|
GI blood flow
Altered dissolution rate, possible decreased absorption rate, time of onset delayed|
total body water|
lean body weight
body fat (female > male)
Polar drugs tend to have Vd,lipid-soluble drugs Vd|
free fraction of acidic drugs, free fraction of basic drugs|
hepatic blood flow
decreased metabolism and clearance influenced by environmental factors (e.g.smoking,nutrition) oxidation system|
renal plasma flow
decreased renal clearance, half-life|
As noted in the table there are a number of physiologic changes which potentially will alter drug absorption. GI motility, pH changes, etc. There has been little evidence, however, to suggest that this is of major consequence. Reduced absorption in the elderly has been observed for some compounds which are actively absorbed (e.g. galactose, calcium, thiamine, and iron). The absorption of most drugs by passive processes is not generally affected. Only tmax was reduced for tolbutamide in the elderly versus young. For other drugs studied, including l-DOPA, metoprolol, propranolol, cimetidine, and digoxin no changes were observed which could be ascribed to absorption alone. Higher Cpmax values were observed in a number of cases, however, most of these changes could be explained by changes in distribution or clearance.
Great changes in body composition occur as the patient ages. Body fat increases from 15% to 30% and lean body weight decreases in proportion to total body weight. This should give lower V values for drugs which stay in the central compartment, while lipid soluble drugs would have somewhat larger apparent V values. The apparent volume of distribution for diazepam and chlordiazepoxide in the elderly is larger, whereas, the volumes for lorazepam and oxazepam were relatively unchanged. The lipid solubility of the first two drugs is much higher than for the second pair.
Although total plasma protein concentrations remain relatively constant, albumin concentrations are lower in the aged. The fraction of unbound phenytoin increases 25 to 40% in the aged, however, as earlier described this would also lead to increased clearance. In the case of diazepam it has been found that the percentage unbound could be correlated with age for females, but not males. Drug interactions based on protein binding, and other factors, can be more pronounced in the elderly because they tend to be taking more drugs.
Cardiac output in the elderly is reduced, thus distribution to the kidneys and liver are expected to be reduced. For high extraction drugs this could alter the overall elimination of the drug.
The liver is the major organ involved in metabolism and as shown in the table, liver blood flow and liver mass tend to decrease with age. Protein binding also is reduced, especially to albumin, as mentioned in the previous section. The third determinant of drug metabolism, intrinsic clearance is quite variable and dependent on the metabolic pathway.
Acetylation appears to be unchanged with age, isoniazid clearance is not altered. It appears that for some drugs which undergo Phase I metabolism (oxidations, reductions) metabolism reduces with increasing age. Examples are lidocaine, phenytoin, propranolol, theophylline. For other drugs which undergo Phase II metabolism (conjugations) the metabolism does not appear to change greatly with age. Some example drugs are isoniazid (acetylation), temazepam (glucuronidation).
With increasing age the glomerular filtration process is reduced by a reduction in kidney size (20%), reduction in the number of nephrons (35%), reduction in the number of functioning glomeruli (30%), and a decrease in renal blood flow (40- 50%). Serum creatinine is also decreased with age because of the reduced muscle mass. However, the formulas presented earlier in the section on renal disease can be used to calculate creatinine clearance as a function of age and thus make dosage regimen adjustments. Drug which are renally excreted and for which dosage adjustments should be made in elderly patients include; the aminoglycosides, digoxin, lithium, methotrexate, quinidine, and the tetracyclines (except doxycycline).
An illustration of the type of change in pharmacokinetics with age is shown in the following table.
Table XXI-6 Pharmacokinetic Data in the Elderly and the Young
| ||Elderly|| || ||Young|| |
|Drug||Vd (L/kg)||t1/2 (hr)||CL||Vd (L/kg)||t1/2 (hr)||CL|
|Ampicillin||0.3 +/- 0.04||6.7 +/- 5.9||0.08 L/hr/kg||0.3 +/- 0.04||1.7 +/- 0.5||0.18|
|Digoxin||4.1 +/- 0.9||70 +/- 13||0.8 +/- 0.2 ml/min/kg||5.3 +/- 0.6||37 +/- 4.5||1.7 +/- 0.2|
|Nitrazepam||4.8 +/- 1.7||40 +/- 16||4.7 +/- 1.5 L/hr||2.4 +/- 0.8||29 +/- 7.4||4.1 +/- 2|
|Phenylbutazone||0.1 +/- 0.02||87 +/- 11||2.75 ml/min/kg||0.16||110||2.9|
|Warfarin||0.2 +/- 0.01||44 +/- 10||3.3 +/- 0.5 ml/min/kg||0.2 +/- 0.3||37 +/- 2||3.8 +/- 0.6|
The effects of age on drug disposition depend on the particular compound in question and the characteristics of the population being studied. When evaluating geriatric studies it is important to distinguish between long-term-care patients who are not considered to be healthy and the active who are old (age > 65 years maybe higher) but living in the community. Some of the changes ascribed to the elderly may be due to immobility of the patient or an underlying disease or diseases. Also because of changing body composition between males and females it is often important to distinguish between these groups.
In terms of dosage regimen adjustment, for some drugs, such as the aminoglycosides dose adjustment is progressive with a steady change in creatinine clearance with age reflecting the similar change in the clearance of the drugs under question. In other cases the change in dosage may be better
Final exam from 1995
This page was last modified: 12 February 2001
Copyright 2001 David W.A. Bourne