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Effects of Pharmacokinetic and Pharmacodynamic Changes in the Elderly

Effects of Pharmacokinetic and Pharmacodynamic Changes in the Elderly

Basic pharmacokinetic process: an orally ingested drug passes from the stomachFigure 1
Representation of the action of the P-glycoprotein pumpFigure 2
Selected P-glycoprotein (ABCB1) substrates, inhibitors, and inducersTable 1
Clinically relevant CYP450 drug interactionsTable 2

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At the end of this article, readers should be able to:

1. Appreciate and analyze the pharmacodynamic and pharmacokinetic changes that occur as patients age.

2. Develop/modify appropriate treatment strategies for older adults based on pharmacodynamic and pharmacokinetic changes.

3. Assess signs of problems associated with medication pharmacodynamics and pharmacokinetics in older patients.

Heterogeneity is a hallmark of the geriatric population, and nowhere is this as evident as it is in geriatric pharmacotherapy. Variable changes in organ and receptor function with aging make it difficult, in fact, to formulate rules that apply to all patients in the geriatric population. Comorbid disease and coadministered medications, which generally increase with age, add to the complexity.

Certain determinants of drug response in younger patients continue into old age. This is true, for example, of genetic endowment related to cytochrome P-450 (CYP450) metabolizing capacity. Other processes, such as drug absorption and glucuronidation, are little affected by aging. As a general rule, however, all other pharmacological processes change with aging.

Basic pharmacokinetic processes

Absorption. As shown in Figure 1, an orally ingested drug passes from the stomach to the proximal small intestine, where most absorption takes place. Absorption was once thought to be a simple, passive process, but research over the past few decades has shown that enterocytes lining the intestinal villi express a variety of specific drug transporters to take in drugs and efflux mechanisms to extrude them back into the gut lumen. The enterocytes are thus able to regulate how much drug is passed on to the liver.

P-glycoproteins (Pgp) that are first encountered in the gut wall act as “pumps” to move absorbed drug back into the gut lumen, where it can be metabolized by resident CYP3A4 enzymes, reabsorbed, or passed along the gut for excretion. The action of the Pgp pump is shown schematically in Figure 2. This pump has a general efflux function in the liver, the brain, the kidneys, and other organs. The Pgp pump has specific drug substrates, inhibitors, and inducers, similar to CYP450 enzymes. Of particular interest to psychiatrists are drugs listed in Table 1.

As with CYP450 enzymes, genetic variations that result in expression and activity of the Pgp pump have been identified in the MDR1 gene that codes for Pgp.1 With aging, reduced Pgp pump function at the blood-brain barrier has been demonstrated in vivo.1,2 This results in a “leakier” blood-brain barrier that is more porous to drugs and toxins.

How quickly a drug is absorbed determines in part how quickly it takes effect. Among the elderly, the rate of absorption may be affected by reduced gastric motility or delayed emptying due to diseases (eg, diabetes) or drugs (eg, antacids). In the absence of significant disease, however, the extent of absorption is little affected in the elderly.3

Distribution. Drugs that pass from the GI tract to the liver travel by way of the portal circulation. In the liver, the drugs can travel unchanged into the general circulation by way of hepatic veins. Alternatively, drugs can be metabolized in the liver before entering the circulation, via first-pass metabolism. The extent of first-pass metabolism is determined by the activity of enzymes such as CYP450 and uridine 5'-diphosphate-glucu­ronosyltransferase (UGT). Any drug that is conjugated before leaving the liver for the general circulation can be excreted directly by the kidneys. A drug can also be removed by Pgp pump action in the liver, which results in the secretion of substrate drugs and toxins into bile, where they are removed as waste through the GI tract.

Pharmacokinetic processes up to this point are circumvented by intramuscular or intravenous administration of the drug. Avoiding first-pass metabolism renders drugs nearly 100% bioavailable, so that the dose required for the same effect is usually much smaller. Intravenous administration of drugs in geriatric patients should be approached with caution, because dangerous adverse effects can emerge quickly. In addition, intramuscular administration of drugs is not recommended for geriatric patients with small muscle mass, because this leads to erratic absorption and painful injection.

As shown in Figure 1, drugs that pass into the general circulation are distributed to target organs, peripheral storage sites in fat or muscle, the kidneys for elimination, or the liver for metabolism. Distribution to peripheral storage sites is significantly affected by aging, because as lean body mass decreases, there is a relative increase in fat stores. This is true even for thin elderly patients. These changes create a larger volume of distribution for fat-soluble drugs (including most psychotropics) and a smaller volume of distribution for water-soluble drugs, such as lithium.4 Because the elimination half-life of a drug is directly proportional to its volume of distribution, the practical significance of these changes is that most psychotropics remain in the body longer in geriatric patients.


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