In treating patients with highly protein-bound drugs, like phenytoin, one should expect toxic reactions at a normal serum level because more of the drug is unbound, and, hence, active. Elderly patients with low albumin levels secondary to malnutrition or liver disease will have an even more pronounced effect.
Effects of Metabolism
Many drugs undergo hepatic metabolism to produce more soluble forms for subsequent elimination through renal excretion. Though hepatic metabolism is affected by multiple variables including genotype, lifestyle, hepatic blood flow, hepatic diseases, and interactions with other medications, aging also plays a significant role.7
Of the two biotransformation systems through which hepatic metabolism occurs, it is the cytochrome P450 system (Phase I) most affected by increasing years. For most drugs, this leads to increased serum levels of the unmetabolized entity, leading to a greater potential for toxicity. Disease states that reduce blood flow to the liver, like congestive heart failure and cirrhosis, further inhibit this process. For drugs whose pharmacological activity requires biotransformation from a pro-drug form, inhibition can lead to decreased efficacy.
In contrast, Phase II metabolism, including acetylation, sulfonation, conjugation, and glucuronidation, is little influenced by advanced age.
Drug Elimination
The renal elimination of drugs is altered by aging, although there is significant variation between individuals for any given decade.8 Drug excretion does correlate with creatinine clearance, which declines by 50% by age 75. However, because lean body mass decreases with aging, the serum creatinine level tends to overestimate the creatinine clearance of older adults.
Utilization of the Cockroft-Gault formula (Figure 1, above) allows for an accurate estimation of the creatinine clearance in these patients.9 For example, a 25-year-old man and an 85-year-old man, each weighing 158 pounds and having a serum creatinine value of 1 mg per dL, would have different estimated creatinine clearance even though their serum creatinine value is the same. The younger man would have an estimated creatinine clearance of 115 mL per minute, while the older man’s would be 55 mL per minute.
Approximating creatinine clearance is particularly important when prescribing medications that have a narrow therapeutic index (aminoglycosides, lithium, digoxin, procainamide, vancomycin). Even minimally excessive doses of these drugs will result in a prolonged the half-life, and an increased potential for toxic effects.
Expect and account for these alterations in drug metabolism in elderly patients. Typical changes result in increased active serum concentrations of the drug and extended half-life. Elevated drug concentrations result in more adverse drug events, and these include not only known complications, but also uncommon problems such as blood dyscrasias. If a rare adverse drug reaction does occur, it is most likely to happen in an elderly person.
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The Acute Care Setting
In light of the physiologic changes associated with aging, as well as the problems posed by taking multiple medications, it is clear that active intervention is required to prevent adverse drug reactions in geriatric patients.
A large cohort study of Medicare enrollees with more than 30,000 patient-years of observation found that 28% of adverse drug reactions were potentially avoidable. Most errors occurred during prescribing and monitoring. A number of strategies have been proposed for reducing these unwanted medication consequences in the hospital setting, including:
- Avoid inappropriate drug prescribing;
- Avoid overprescribing;
- Implement age-appropriate dosing; and
- Encourage a multidisciplinary ap-proach.
Drugs to Avoid
Though precise clinical data regarding which medications are harmful to elderly patients in the acute care setting is lacking, multiple expert panels have attempted to delineate which drugs should be generally avoided in this population (Table 1, above).
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