Most polar drugs or polar drug metabolites are eliminated by the kidney after filtration at the glomerulus. In addition, drugs such as the fl-lactam antibiotics are actively secreted in the proximal tubules. As part of normal ageing, both renal functional capacity and renal reserve diminish. The structural changes include a decrease in renal weight, thickening of the intrarenal vascular intima, a reduction in the number of glomeruli with increased sclerogenous changes within those remaining and infiltration by chronic inflammatory cells and fibrosis in the stroma (Muhlberg and Platt, 1999). Altered renal tubular function may also lead to impaired handling of water, sodium and glucose in old age. There is a steady decline in the glomerular filtration rate by approximately 8 ml/minute per decade (Rowe et al., 1976). By the age of 70, therefore, a person may have a 40% -50% reduction in renal function (even in the absence of overt renal disease).
Drug elimination may be reduced even in patients with normal serum creatinine concentrations because creatinine production decreases with age. Many drugs which are dependent on the kidney for elimination will accumulate to toxic levels if given in the usual doses to elderly people. Examples include digoxin (Smith, 1973), atenolol (McAinsh, 1977) and amiloride (George, 1980). Furthermore, many drugs themselves adversely affect renal function in the elderly, e.g. aminogly-cosides, diuretics, NSAIDs and angiotensin-con-verting enzyme (ACE) inhibitors. In this way age-dependent changes in renal function are responsible for altered pharmacokinetics in the elderly but in many cases the kidneys are the target for the adverse drug reactions produced by these changes (Muhlberg and Platt, 1999).
As drug elimination is correlated to creatinine clearance, estimating the creatinine clearance may be helpful in deciding whether a dose reduction is necessary. A useful method that may be used at the bedside is the Cockcroft formula (Cockcroft and Gault, 1976):
Creatinine clearance (male)
1.23 x (140 — age) x body weight (kg) Plasma creatinine (mmol l—!) Creatinine clearance (female)
1.04 x (140 — age) x body weight (kg) Plasma creatinine (mmol l—!)
The diagnostic value of age and creatinine clearance (calculated by the Cockcroft formula) for the prediction of potentially toxic drug plasma levels has recently been reviewed by Muhlberg and Platt (1999). They found that 256 geriatric patients with many different illnesses have been studied in 17 pharmacokinetic studies with 17 different drugs, including angiotensin-converting enzyme inhibitors, NSAIDs, antibiotics, beta-blockers, bronchodilators and benzodiazepines. Mathematical simulation and pharmacokinetic methods were used to determine whether a dose reduction was necessary in elderly patients with a reduced creatinine clearance determined by the Cockcroft formula. For most drugs studied elevated plasma levels at steady state could be correctly predicted when the creatinine clearance was < 40 ml/min, particularly when age was taken into account, suggesting that a dose reduction was necessary. This confirms the usefulness of the Cockcroft formula for clinical use in elderly patients taking drugs which are eliminated in the kidney and which are toxic at higher plasma concentrations.
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