This month's column concerns alterations in the last of the four phases of pharmacokinetics (absorption, distribution, metabolism, and elimination) that can affect drug therapy. To watch an animated video demonstrating the process of drug elimination in the body, go to http://links.lww.com/A471.

Elimination is the process by which a drug or its metabolites are removed from the body. (Actually, elimination refers to a combination of the processes of drug metabolism and excretion of the drug from the body. While technically different, the terms "excretion" and "elimination" are commonly used interchangeably, and most practitioners use the latter term, as I have in this four-part series. For the purposes of this discussion, elimination refers to drug excretion.) Drugs are most commonly eliminated through urine, bile in the gastrointestinal tract, expired air, breast milk, sweat, and saliva (although sweat and saliva aren't clinically significant routes). Metabolism changes the structure of lipophilic drugs so they become hydrophilic and can be excreted in urine. Drug molecules that are still lipophilic when they reach the kidneys are reabsorbed into the bloodstream. The time it takes to eliminate half the blood concentration of a drug is considered its "half-life," and this period of time varies according to pharmacologic properties and metabolism and elimination rates; some drugs' half-lives last minutes whereas others' last days. (It's important to understand that in one half-life a specific percentage of drug molecules is eliminated from the blood, not an absolute number of molecules.)

Renal disease, conditions that cause a decrease in the flow of blood to the kidneys, and changes that normally accompany the aging process all decrease the effectiveness of the kidneys in drug excretion. Drugs with long half-lives can produce adverse effects in older adults that are similar to those produced in patients with renal disease. The Beers criteria for potentially inappropriate medication use in older adults describe certain difficulties presented in that population. (First published in 1991, the Beers criteria is a consensus-based list of drugs that are thought to pose more risk than benefit in people older than age 65.) For example, the half-lives of long-acting benzodiazepines (used to treat anxiety) are increased in elderly patients-the half-life of diazepam (Valium) increases from about one to two days to as long as seven days, the half-life of the principal active metabolite of chlorazepate (Tranxene) increases from 46 hours to as long as 120 hours in older men (interestingly, it does not increase significantly in older women), and the half-life of the second active metabolite of quazepam (Doral) increases from 84 hours to more than twice that duration in older adults. Fick and colleagues note that in the Beers criteria, the very long half-lives of long-acting benzodiazepines produce in elderly adults "prolonged sedation [horizontal ellipsis] increasing the risk of falls and fractures. Short- and intermediate-acting benzodiazepines are preferred if a benzodiazepine is required."

Diminished liver function also increases the half-life of a drug because metabolism is prolonged, and therefore the drug or its metabolites cannot be excreted in the interval expected. The normally four-to-16-day half-life of the active metabolite of fluoxetine (Prozac), for example, is lengthened by diminished liver function, and as a result little excretion of the unmetabolized drug occurs. In the normal course of aging, liver function is diminished, and the Beers criteria note that daily use of fluoxetine increases the risks of excessive central nervous system stimulation, sleep disturbance, and agitation in older adults.

Another possible alteration in drug excretion is the reabsorption of active drug into the bloodstream from the renal tubules. An example is seen in the use of lithium (Eskalith, Lithobid) in treating mania in manic-depressive illness (bipolar disorder). Lithium, as an ion, is processed in the body in the same manner in which sodium ions are. When the sodium level is low, the body compensates by reabsorbing sodium ions into the bloodstream from the kidney. When a patient takes lithium in the presence of a low sodium level, the kidney reabsorbs lithium ions from the urine, sensing them to be sodium ions. Therefore, conditions that deplete the sodium level (such as excessive sweating, prolonged diarrhea, diuretic therapy, and sodium-restrictive diets) or that decrease perfusion to the kidney, thereby promoting greater retention of sodium and water (such as dehydration, inadequate fluid intake, or heart failure) cause the kidneys to mistakenly reabsorb lithium at a rate greater than normal, possibly causing lithium toxicity.

Nurses should assess patients for possibly altered drug elimination-according to the patients' condition, certain drugs might be inappropriate. Close monitoring is warranted in patients who need to take a particular drug despite being at risk for its adverse effects because of such possible alterations in elimination. Further, changes in a patient's health can increase the risk of adverse effects attributable to changes in drug elimination.