Another result of the relative increase in body fat with aging is that highly lipophilic drugs, such as diazepam, are rapidly taken up by fat storage sites, so that drug concentration in the blood falls quickly below a minimum effective threshold. With one-time dosing, the duration of effect is short for diazepam. The drug is removed slowly from fat stores, and significant accumulation of the drug can occur with repeated dosing. Moreover, the drug may be released erratically, which can result in changing serum levels over time. For these and other reasons, diazepam is not recommended for the elderly.
On the other hand, the smaller volume of distribution for water-soluble drugs, such as lithium, is associated with a greater amount of drug in the circulation and a correspondingly greater amount available to the brain as the target organ. This is one reason why smaller doses of lithium are used in elderly patients. Drugs that reach the blood-brain barrier gain access to the brain by passive diffusion or by transporters. Those drugs that are substrates for the Pgp pump residing in capillary endothelial cells may be extruded back into the circulation, a process that can be blocked by Pgp pump inhibitors or facilitated by inducers.
Metabolism. Drug metabolism occurs by phase 1 (oxidation) and/or phase 2 (primarily glucuronidation) processes. The most important drug-metabolizing enzymes are the phase 1 CYP450 enzymes and the phase 2 UGT enzymes. In general, phase 1 oxidation processes are more affected by aging than are UGT processes. Given the choice in treating an elderly patient, a drug metabolized by glucuronidation (also known as “conjugation”) would be preferred to a drug metabolized by those CYP450 enzymes whose activity is reduced with aging. Among benzodiazepines, for example, lorazepam, oxazepam, and temazepam are preferred to other drugs because these drugs are simply conjugated and excreted. Diazepam and chlordiazepoxide—not recommended for the elderly—have several active metabolites, some with long half-lives (eg, desmethyldiazepam).
Three families of CYP enzymes are relevant to psychopharmacology: CYP1, CYP2, and CYP3. Current evidence suggests that within these families, 5 enzymes are primarily responsible for the metabolism of commonly used psychotropics. The activity of each CYP450 enzyme can be reduced by inhibitors or facilitated by inducers. Inhibitory effects are additive when more than one inhibitor is present. For most drugs metabolized by CYP450 enzymes, it is the parent drug that is active, and metabolism results in an inactive or less active metabolite. For certain drugs (eg, codeine, tramadol), the parent drug is a pro-drug with little activity, and metabolism to an active metabolite is necessary for drug effect. In these cases, inducers result in greater drug effect. Clinically relevant substrates, inhibitors, and inducers of CYP450 enzymes are listed in Table 2.
Genetic polymorphisms expressed as the absence or changed activity of certain CYP enzymes may result in marked differences in serum levels of psychotropic drugs among individuals administered the same dose. The following are CYP450 metabolizer phenotypes5:
• Poor (slow): little or no enzyme activity, leading to high levels of parent drug
• Intermediate: depending on the specific genotype, activity ranges from slightly more than the poor phenotype to slightly less than the extensive phenotype
• Extensive (average, rapid): normal enzyme activity but can be converted to a poor metabolizer by sufficient CYP enzyme inhibition
• Ultrasensitive (ultrarapid): parent drug is metabolized so rapidly that higher drug doses may be needed; in the case of a pro-drug, toxicity may be seen at usual therapeutic doses
Only 2 of the CYP enzymes important in psychotropic prescribing decline meaningfully with aging: CYP1A2 and CYP3A. Aging also brings a gradual reduction in liver mass, reduced blood flow, and reduced hepatic metabolic rate.4 Among other processes, these changes affect demethylation reactions involved in the conversion of tertiary amines (eg, amitriptyline) to secondary amines (eg, nortriptyline), which may cause the accumulation of more active and more toxic tertiary compounds.
Excretion. Most drugs and metabolites are excreted from the body by the kidneys at a rate determined by the glomerular filtration rate (GFR).3 For many individuals, this rate falls linearly with aging at a rate of about 1 mL/min/1.73 m2 of body surface area (the average for an adult), starting at around age 20 to 30. Thus, the GFR for such an individual at age 80 years is about half what it was at 30 years.
Drugs cleared solely by renal excretion—lithium and hydroxylated metabolites (eg, hydroxy-bupropion, hydroxy-venlafaxine, hydroxy-nortriptyline, and hydroxy-risperidone)—are most affected by this change in GFR. Reduced clearance of lithium has led to the recommendation that elderly patients be treated with a single nightly dose of short-acting lithium. This schedule allows the serum level to drift downward so that the kidneys have time to recover before the next dose.
Reduced GFR with aging is not a universal phenomenon; some elderly persons show no decline in renal function with aging. Nevertheless, in the elderly with reduced renal function, psychotropics should be used with great caution. The following recommendations apply:
• Optimize hydration
• Beware of coadministration of nephrotoxic drugs (eg, NSAIDs)
• Evaluate renal function to determine dosage
• Do not rely on serum creatinine value to gauge renal function
• Use laboratory-generated report of the GFR or calculate GFR using the Cockroft-Gault equation