Elderly patients, particularly those aged 85 years or older (the "oldest old"), take an average of 5 to 8 drugs each day. This is attributable principally to the number of chronic conditions that affect this age group. Polypharmacy heightens the risk of significant drug-drug interactions and other adverse events, particularly in frail elderly persons. Moreover, many drugs that are used safely by younger persons are inappropriate for older ones because of age-related changes and comorbid conditions that affect absorption, distribution, metabolism, and elimination.
A number of reports have shown that the risk of adverse drug events in elderly patients rises with comorbidity; increasing numbers of medications; inappropriate medications; the use of antipsychotics, anticoagulants, diuretics, and antiepileptics; and the use of multiple prescribers and pharmacies by patients and caregivers.1-4
Here I review the principal considerations that affect prescribing practices for elderly patients and offer strategies that will help prevent or minimize adverse drug reactions.
AGE-RELATED PHARMACOKINETIC CHANGES
The normal aging processes that affect the major organ systems should prompt a reduction in the dosages of specific classes of drugs, particularly those eliminated mainly by the kidney or metabolized by the liver or whose effect is primarily on the CNS. Basic guidelines for prescribing that take into account normal changes of aging are reviewed in Table 1. The principal drugs that are considered potentially inappropriate in elderly patients are listed in Table 2.
Distribution. Changes related to aging, such as increased total body fat, decreased muscle mass, and decreased total body water, necessitate dosage reductions in elderly persons.5,6 These changes dramatically reduce the volume of distribution for water-soluble compounds and for compounds distributed only in lean tissue, such as digoxin and lithium. Moreover, the age-related rise in body fat increases the volume of distribution of lipid-soluble compounds, such as diazepam. The clearance of such compounds is significantly prolonged, which increases the risk of adverse events.
Elimination. Because aging of the kidney is associated with decreased creatinine clearance, the dosage of agents that are excreted primarily by the kidney must be reduced in order to prevent toxicity. This is especially true in the oldest patients, in whom creatinine clearance slows dramatically.
A frequently used formula for determining creatinine clearance in men is ([140 2 age]) 3 lean body weight [kg]/72 3 serum creatinine level [mg/dL]).7 For women, the total is multiplied by 0.85. Blood urea nitrogen and serum creatinine levels may be in the normal range despite significant reductions in creatinine clearance. One study of nursing home residents indicated that 1 of 3 renally excreted drugs was inappropriately dosed based on the calculated creatinine clearance.8
Agents that require dosage reduction in patients with reduced creatinine clearance include the aminoglycosides, fluoroquinolones, penicillins, procainamide, lithium, angiotensin-converting enzyme (ACE) inhibitors, digoxin, metformin, fluconazole, bisphosphonates, thiazides, nizatidine, atenolol, and clofibrate.9 Once-daily dosing of aminoglycosides is associated with a decreased risk of morbidity (ototoxicity and renal failure) in patients with reduced creatinine clearance (usually below 50 mL/min). It also alleviates the need for expensive peak and trough testing.10 A good rule of thumb to follow until creatinine clearance can be calculated is to reduce the total dose of the agent by half in frail elderly persons or in the presence of established renal disease (when blood urea nitrogen and serum creatinine levels are typically elevated).
Metabolism. Changes in the liver related to age include reduced blood flow and decreased phase I metabolism (oxidation, reduction, and hydroxylation). Agents that use pathways involved in phase I reactions include long-acting benzodiazepines (eg, diazepam, chlordiazepoxide, and flurazepam). These agents must be avoided in elderly persons because of the risk of sedation, hypotension, falls, and confusion. Short-acting benzodiazepines are preferred because they do not have to be metabolized by phase I and otherwise are deactivated though conjugation, sulfation, methylation, or acetylation (phase II).6
Other agents that require hepatic metabolism includeNSAIDs, aspirin, calcium channel blockers, acetaminophen, b-blockers, erythromycin, statins, ketoconazole, phenytoin, tetracyclines, valproic acid, lidocaine, carbamazepine, metoprolol, tricyclic antidepressants, selective serotonin reuptake inhibitors, neuroleptics, cimetidine, ranitidine, famotidine, terfenadine, and proton pump inhibitors.9 Some of these agents use components of the cytochrome system (CYP1A2, CYP2C, CYP2D, and CYP3A) that may involve interactions between model compounds, drug substrates, inducers, and inhibitors. This may result in toxic levels of one agent or inadequate levels of another and what may appear as noncompliance with drug therapy or lack of efficacy. In cases where 2 specific agents are necessary but the potential for adverse interaction exists, attention to specific time of administration, dosage, and requirement to ingest the agent with or without food or beverage is critical.9,11 Pharmacology texts provide information about agents to be avoided for specific cytochrome pathways. Consultation with a pharmacist may also be helpful.
Liver disease (cirrhosis, hepatitis, or malignancy) or malnutrition typically results in decreased serum albumin and total protein levels that directly affect protein binding for highly bound agents. This may be associated with an increase in the free active fraction of the specific agent and a heightened risk of toxicity. Examples of such agents include barbiturates, phenytoin, carbamazepine, and warfarin.12
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