CLIN. CHEM. 35/7, 1337-1341 (1989)

CLINICAL CHEMISTRY, Vol. 35, No. 7, 1989 1337

Special Considerations for Geriatric Therapeutic Drug MonitoringThomas M. Annesley

Numerous physiological changes during the normal agingprocess can potentially affect how drugs are handled by thebody. Gastrointestinal changes include increased gastric pH,decreased intestinal motility, and decreased blood perfusion.Age-related changes in body composition and protein con-centrations in plasma contribute to alterations in the distribu-tion of drugs. Hepatic metabolism of drugs may be affected,and renal excretion via glomerular filtration or tubular secre-tion is diminished. The importance of each of these physio-logical changes in the elderly, as well as the contribution ofmulti-drug therapy and other external factors, is discussed.

A review of the demographics of the developed countriesdemonstrates that most of us are living within a populationwhose mean age is on the increase. The last census revealedthat the group of individuals older than 65 years constituted>11% of the U.S. population. More significant is the factthat this percentage will double in the near future. Threemajor factors are contributing to this trend. First is the factthat average longevity has grown significantly over the lasthalf century. Second, the aging of the large segment of thepopulation represented by the “baby boomers” of the 1950swill have a major effect on the mean age of the overallpopulation, as well as on the demand for health-care deliv-ery. A third factor is the general downward trend in thebirth rate, which also contributes to unbalancing the agedistribution of the population.

Although the elderly make up about one-ninth of the U.S.population, they account for a significantly larger share ofthe overall national health expenditures. They occupy alarge share of beds in hospitals and other care facilities,usually as a consequence of chronic or long-term healthconcerns, and consume a disproportionate share (approxi-mately 30%) of prescribed drugs (1). This statistic is support-ed by studies showing drug consumption by as many as 66%of elderly patients (2, 3). A significant fraction of thegeriatric population are receiving multi-drug therapy (2, 4,5). In some studies nearly half of the elderly study groupreceived at least three separate medications per day. Thus itis not surprising that adverse drug reactions are frequent inelderly patients. As many as 10% of the hospital admissionsinvolving older persons result from adverse reactions to aprescribed drug (6, 7), many of which appear to be aconsequence of multiple drug therapy.

Until the “Fountain of Youth” is discovered, each of us issubject to becoming a future “senior citizen,” and must facethe fact that the aging human body becomes increasinglysusceptible to the disease processes and physiologicalchanges that accompany old age. Fortunately, a multitudeof drugs are available to correct, or at least moderate, theeffects of many disease states. To optimally prescribe anduse therapeutic agents in the geriatric population, it isimportant to understand the factors that affect the pharma-

Department of Pathology, University Hospital, University ofMichigan, 2G332, Box 0054, 1500 E. Medical Center Drive, AnnArbor, MI 48109.

ReceivedJanuary 20, 1989; acceptedFebruary 21, 1989.

cokinetics and pharmacodynamics of these drugs. In thefollowing discussion, I will address the physiological andbiochemical changes that coincide with the normal agingprocess and indicate how these changes may affect both thedosing and monitoring of drugs used in the geriatric popula-tion.

Drug Absorption

Prescribed drugs are most commonly given orally and themajority of these drugs are absorbed in the small intestineby way of passive diffusion. Thus any factors that mightaffect both the rate and degree of contact with the intestinalmucosal surface may produce significant changes in thedrug-absorption proffle.

The gastric emptying rate will directly influence drugabsorption. Although there is conflicting evidence as towhether there are changes in gastric emptying time attrib-utable to the aging process alone (8-10), numerous externalfactors affect gastric emptying, including diet, diseasestates, stress, concurrent drug therapy, pain, emotionalstate, body position, and gastric pH.

The elderly exhibit a higher incidence of reduced gastricacid secretion (11, 12), which has been associated with adelay in gastric emptying. While certain drugs are presentin the stomach, the pH of the gastric fluid may have aneffect on their stability as well as their absorption pattern.For example, drug formulations that require exposure to anacidic environment for maximal dissolution may demon-strate reduced absorption in the presence of low amounts ofgastric acid. Other drugs, which display less stability inacidic conditions, may degrade in the acidic environment ofthe stomach if gastric emptying is delayed. For some specialformulations such as enteric-coated tablets, absorption maybe altered as a result of delayed gastric emptying. Decreasesin gastric emptying rate will be important for drugs thatrequire a rapid onset of action or if drug elimination is sorapid that an effective concentration in blood cannot beachieved (see below).

Co-administration of certain drugs, antacids, and otherproducts will reduce absorption, either by altering thegastric emptying rate or by binding a specific drug ofinterest. Drugs with anticholinergic properties-.-such asantihistamines, sleeping aids, and antidepressants-willreduce drug absorption. Metocloprainide will modify theabsorption of paracetamol (acetaminophen), levodopa, anddigoxin. Drug absorption will also be reduced during theinteraction of antacids with digoxin, salicylates, and indo-methacin, and by the physical binding of digoxin andanticoagulants by cholestyramine. Because of their high useof analgesics, antacids, sleeping aids, digoxin, and antide-pressants (13, 14), changes from normal absorption patternsare likely to occur in the elderly.

Current evidence suggests that the morphological struc-ture of the intestinal mucosal surface changes with age. Thenumber of cells comprising the mucosal surface decreases(15), making more probable a reduction in the efficiency ofdrug absorption. A statistically significant decrease insplanchnic/gastrointestinal blood flow has been demonstrat-ed with increasing age (16); however, for most drugs, this

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1338 CLINICAL CHEMISTRY, Vol. 35, No. 7, 1989

may not be as clinically important as one might expect. Intheory, the diminished blood flow should correspond with areduced ability to effectively absorb drug presented to thegastrointestinal tract. However, this effect may be offset bythe generalized decrease in intestinal motility believed tooccur with advanced age, which increases the time availablefor absorption within the intestinal tract. Furthennore, it isgenerally thought that the gut is normally well perfusedand that the changes in blood flow are not great enough tobe a limiting factor in the efficiency of drug absorption.

Despite all of the above age-related physiological changesin gastric emptying, reduced mucosal cell number, reducedintestinal blood flow, and reduced intestinal motility, it isrelieving to know that most oral drug absorption is general-ly not significantly affected by changes associated withaging alone. One exception is the group of drugs thatundergo extensive first-pass metabolism in the liver, such aspropranolol (17). These drugs may be affected by gastricemptying rate in two ways. First, in the presence of near-normal gastric emptying, the reduced first-pass metabolismresulting from a diminished portal blood flow may provide agreater bioavailability and increased concentrations of thesedrugs in plasma. However, should disease or other externalfactors delay gastric emptying, the rate of presentation tothe intestine for absorption will be slowed. In this case,elimination of the drug may be rapid enough so thateffective blood concentrations cannot be achieved. This willbe discussed further in the sections concentrating on drugmetabolism and distribution.

Drug Distribution

Once a drug is absorbed from the gastrointestinal tract, itis carried to the site of action via the bloodstream. Themajority of drugs exist in an equilibrium between a free(active) and bound form in the blood. The most importantbinding component in blood is albumin. Because of itsimportance as a binder of drugs, any significant changes inthe concentration of serum albumin will result in changes inthe unbound fraction of the drug. Increases in the free(active) concentration of drug should be transient, becausethe free drug is also available for metabolism as well asdistribution into the tissues. Drugs with a high volume ofdistribution will be rapidly taken up by tissues, resulting inlittle change in the concentration of free drug. Thus reduc-tions in albumin concentrations will produce an increase inthe free fraction of the total drug, but not necessarily in theconcentration of free drug.

There is a decline in serum albumin (Figure 1) associatedwith the normal aging process (18, 19). Concentrations ofalbumin in serum decline by approximately 15% betweenages 30 and 80, with 10% of the elderly having albuminconcentrations <30 gIL. Because a lower albumin concen-tration is often associated with an increase in the freefraction of drug, determinations of total drug concentrationswill not always be accurate reflections of free drug concen-trations: desired therapeutic concentrations of free drug willbe present at lower concentrations of total drug. Cliniciansmust be aware of this so that they will not make inappropri-ate adjustments in dosage.

Another protein of potential clinical importance is alpha1-acid glycoprotein, an acute-phase reactant that may beincreased in illnesses such as inflammatory diseases andinfections or after surgery. Several clinically importantdrugs are appreciably bound by this protein, includingquinidine, propranolol (20), lidocaine (21), and tricyclic

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antidepressants. Unlike albumin, which decreases in con-centration in the elderly patient, alpha i-acid glycoproteinconcentrations will be increased in many cases. Theseincreases in alpha1-acid glycoprotein will increase totaldrug concentrations while decreasing the free fraction ofdrug.

Changes in protein binding of drugs will be clinicallyrelevant only for the highly bound drugs (>85% bound), andnot all of them will be potential sources of problems. Thosedrugs requiring careful monitoring are those that (a) arenormally highly protein bound, (b) have a narrow therapeu-tic index and margin for safety, (c) have a lower volume ofdistribution, and (d) are low-extraction drugs that do notundergo significant first-pass metabolism by the liver.

Multi-drug therapy and renal insufficiency are additionalfactors that will alter drug distribution. As stated earlier,multi-drug therapy is common in the elderly, and is accom-panied by an increased incidence of adverse drug reactions.One potential source of toxicity is an increased concentra-tion of free drug resulting from competitive displacement bya second or third drug that has been added to the therapeu-tic regimen. Renal insufficiency may lead to hypoalbumine-mia in the geriatric patient. The consequences of this aresimilar to those discussed earlier in relation to proteinbinding. Uremia may result in accumulation of materialsthat are normally eliminated and that may displace drugsfrom proteins. There may also be changes in pH, which mayaffect the degree of protein binding. Renal insufficiency mayalso reduce the clearance of drug metabolites, which maycompete for binding sites on albumin. The importance ofrenal clearance will be discussed later in greater detail.

Age-related changes in body composition may also alterthe normal distribution of a drug within tissue. Total bodywater and lean body mass decline with age, while thepercentage of body fat increases (22, 23). Age-relatedchanges in body composition will be reflected in changes inthe apparent volume of distribution (Vd) for a number ofimportant drugs. Drugs such as lithium, which is distribut-ed largely in the central compartment, and digoxin, which isconcentrated within the lean tissues such as muscle, willhave a reduced Vd in the elderly. On the other hand,lipophilic drugs such as diazepam demonstrate an increasedVd in the elderly (24,25). The results of studies evaluatingVd vs age are often conflicting (26-29). Other variables suchas renal function, tissue perfusion, general health, andstudy design may contribute to differences in the observedVd values.

there was no difference between smokers and nonsmokers inthe elderly group of subjects. Thus, experimental evidencesuggests that it is changes in the degree of enzyme inductionrelated to cigarette usage, rather than increased age, thatare the source of the observed decrease in hepatic enzymeactivity observed in the elderly. These studies point out theimportance of considering habits such as tobacco and caf-feine use when instituting long-term therapeutic drug treat-ment, because age-related decreases in enzyme inductionwould create a need to decrease dosages as the patient ages.

Liver blood flow has been shown to decrease with age (38)by about 0.5 to 1.5% per year after age 25, in a manner notrelated to changes in cardiac output (39). This decrease isobserved in both smokers and nonsmokers, as well as inboth sexes. The consequences of this reduction are mostimportant for high-extraction drugs that undergo signifi-cant first-pass metabolism, e.g., lidocaine (40), propranolol,and verapamil (41). These drugs will have both increasedbioavailability and increased concentrations in circulatingblood, so appropriate reductions in dosage may be necessary.

In summary, the effects of the aging process on drugmetabolism have not been clearly delineated, but somegeneral conclusions can be drawn from the available evi-dence. Drugs with high extraction ratios will exhibit in-creased concentrations in plasma and longer halflives inthe geriatric patient as a result of diminished hepatic bloodflow. Regarding hepatic function and capacity, aging alonemay be associated with a decrease in the intrinsic ability ofthe liver to metabolize drugs via oxidative (Phase I) mecha-nisms. However, there is strong evidence that extramuralfactors, especially those with a potential to cause enzymeinduction, are of greater significance and account for muchof the change observed in drug metabolism during the agingprocess. These include smoking, dietary habits, drug-druginteractions, and concurrent disease processes.

The major route of metabolism of drugs is via enzymaticbiotransformation and (or) conjugation by the liver. Twomajor enzymatic pathways are involved in drug metabo-lism. Phase I reactions, catalyzed by the monooxygenaseenzymes of the smooth endoplasmic reticulum, are impor-tant in producing more polar and often inactive metabolites,which can be excreted in the urine. Phase H reactions,which can occur in the cytosol, mitochondria, or smoothendoplasmic reticulum, are not catabolic by nature, butinvolve the production of water-soluble drug conjugates,which can be excreted by the kidney.

During the aging process three potential changes mayaffect normal drug metabolism by the liver a decrease inthe concentration or activity of the Phase I microsomalenzymes, a decrease in the concentration or activity of thePhase H conjugating enzymes, and a decrease in blood flowto the liver. Data obtained so far indicate that the conjugat-ing capacity (Phase H enzyme systems) of the liver does notchange with age. Studies involving the drug isoniazid,which is metabolized through conjugation, have shown thatthe half-life and clearance rate for this drug are the same inboth young and elderly subjects (30,31). The same bimodaldistribution of acetylation rate is observed in all age groups,so it appears that the genetically controlled polymorphic N-acetyl transferase system is preserved in old age (31). Otherdrugs metabolized primarily by conjugation-e.g., temaze-pam, acetaminophen, salicylate, and oxazepam-have alsobeen shown to have similar clearance rates in both youngand older subjects.

Results of investigations into changes in Phase I micro-somal enzyme activity have not been as uniform. Age-related reductions in the metabolism of various drugs,including antipyrine, diazepam, imipramine, amitriptyline,and phenytoin, have been reported (32,34). Studies involv-ing antipyrine as the drug model have yielded interestingobservations and conclusions. This drug has been used tostudy intrinsic hepatic enzyme activity because antipyrineis not protein bound, is a low-extraction drug, and ismetabolized via the microsomal oxidase enzymes of theliver. There is a clear decrease in the metabolic clearance ofthis drug with increasing age (35,36). However, studies byVestal et al. (36, 37) have demonstrated that whereasyounger cigarette smokers exhibited a greater clearance ofantipyrine than did nonsmokers of the same age (Figure 2),

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As outlined earlier, the liver is responsible for the biocon-version of active drugs to water-soluble metabolites andconjugates. In addition to the liver, the kidney is also anorgan of major importance for the clearance and eliminationof drugs, metabolites, and drug conjugates. In fact, renalexcretion is very often the primary means of clearance foractive drugs. Age-related changes in renal function areamong the most important factors that must be consideredwhen one is prescribing drugs for the geriatric patient.

There are several well-documented changes in the kidneythat accompany the normal aging process. There is areduction in renal size and in the number of functionalnephrons, possibily as a result of the reduction in renalblood flow (42). Renal blood flow, like hepatic blood flow, isdisproportionately reduced relative to any changes in cardi-ac output. Studies of inulin and iodopyracet clearance (42)have demonstrated that renal function, as reflected in theglomerular filtration rate and tubular secretory capacity,declines steadily after age 20 to 30 years.

Unlike with the liver, changes in the functional capacityof the kidney are much more predictable and can be readilymonitored. Creatinine clearance, which can be determinedfrom routine chemical determinations of serum and urinecreatinine, is a direct and reliable reflection of the glomeru-lar filtration rate. Creatinine clearance decreases with age(Figure 3) in a manner paralleling the changes in theglomerular ifitration rate. Although Rowe et al. (43) con-structed a useful nomogram for determining age-adjusted

CLINICALCHEMISTRY, Vol. 35, No. 7, 1989 1339

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conjugates of these drugs. Some evidence indicates thatthese unexcreted metabolites may ultimately be hydrolyzedback to the active drug form, contributing to undesiredeffects or drug toxicity (49-51).

Many physiological changes take place during the agingprocess. Many of these changes have the potential to modilrthe pharmacokinetics and pharmacodynanucs of drugs andmust certainly be considered as reasons for altered drugresponse in the geriatric patient.

In addition to factors discussed here, more needs to belearned about the changes in tissue and receptor responsedescribed in the elderly. Also, the elderly are physically lessactive than the rest of the population, and their dietaryhabits are often different. The effects of diet, nutritional

10 20 0 40 50 70 80 90 state, exercise, and body position on drug absorption, distri-AGE. years bution, and action all need to be explored further if we are to

Fig. 3. Relationship between creatinine clearance and age effectively treat the geriatric population with pharmaceuti-Fromref. 43, used with permissionof The GerontologicaiSocietyof Anice cal agents.

percentile evaluations of creatinine clearance, the accurate Referencesdetermination of creatimne clearance relies on proper collec- 1. Vestal RE. Pharmacology and aging [Review]. J Am Geriatr Soction of 24-h urine specimens, which may be difficult to 1982;30:191-200.control in the elderly population. 2. Klein LE, German PS, Levine DM, Feroli ER, Ardery J. Medica-

Serum creatinine, which is often used to detect changes in tion problems among outpatients. Arch Intern Med 1984;144:1185-normal renal function and integrity, cannot be used alone as 8.a reliable test of renal function in the elderly. As determined 3. Aoki FY, Hildahl VK, Large VW, Mitenko PA, Sitar DS. Aging

and heavy drug use: a prescription survey in Manitoba. J Chronicin the general population, a large decrease in renal function Dis 1983;36:75-84.is often required before a corresponding increase in serum 4. Reynolds MD. Institutional prescribing for the elderly. J Amcreatinine is observable. This problem is compounded in the Geriatr Soc 1984;32:640-4.elderly population, which already has decreased creatinine 5. Alexander N, Goodwin JS, Currie C. Comparison of admissionproduction, given the age-related decrease in lean body and discharge medications in two geriatric populations. J Am(muscle) mass, as discussed earlier. Consequently, a reduc- Geriatr Soc 1985;33:827-32.tion in their glomerular ifitration is artifactually compen- 6. Petersen DM, Thomas CW. Acute drug reactions among thesated for by the diminished production of creatinine. Despite elderly. In: Petersen DM, Thomas CW, eds. Drugs and elderly:this potential limitation, various investigators have derived social and pharmaceutical issues. Springfield, IL: Charles C Thom-formulas for estimating creatinine clearance from a single 1979:41-50.determination of serum creatinine, with a correction forage 7.Williamson J, Chopin JM. Adverse drug reactions to prescribedand weight (44): drugs in the elderly: a multicentre investigation. Age Ageing

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9. Moore JG, Tweedy C, Christian PE, Data FL. Effect of age onThere are no routine tests of tubular secretion. However, gastric emptying of liquid-solid meals in man. Dig Dis Sci

evidence suggests that changes in glomerular ifitration and 1983;28:340-4.tubular secretion proceed simultaneously (45). Davies and 10. Van Liere EJ, Northrup DW. The emptying time of theShock (42) have reported that the ratio between the glomer- stomachof old people. Am J Physiol 1941;134:719-22.ular filtration rate and the tubular secretion capacity re- 11. Polland W. Histamine test meals. An analysis of 988 consecu-mains constant during the aging process, which supports tive tests. Arch Intern Med 1933;51:903-19.the hypothesis that a nephron loses its function as a unit. 12.Baron JH. Studies of basal and peak acid output with augment-

Age-related reductions in glomerular filtration and tubu- ed histamine test. Gut 1963;4:136-44.lar secretion affect the elimination of many clinically impor- 13. Guttman D. Patterns of legal drug use by older Americans.tant drugs (46). Glomerular ifitration serves as the major Addict Dis 1978;3:337-56.route of elimination for digoxin, and there is a direct 14. Chien CP, Townsend EJ, Townsend A. Substance use andcorrelation between digoxin clearance and creatinine clear- abuseamong the community elderly: the medical aspect.Addict Dis1978;3:357-72.ance (47, 48). The age-related reduction in glomerular 15. Warren PM, Papperman MA, Montgomery RD. Age changesin

filtration is also responsible for the increased half-lives of small intestinal mucosa. Lancet 1978;ii:849-50.drugs such as lithium and aminoglycosides in the elderly. 16. Bender AD. The effect of increasing age on the distributionofWithout appropriate reductions in dosage, toxicity is a peripheral blood flow in man. J Am Geriatr Soc 1965;13:192-8.likely consequence in the older patient. Other drugs and 17. Castle CM, George CF. The effect of aging on the hepatictheir metabolites are excreted via tubular secretion; these clearance of propranolol. Br J Clin Pharmacol 1979;7:49-54.include procainanude, cimetidine, penicillin and cephalospo- 18. Greenblatt DJ. Reducedalbumin concentration in the elderly: arin antibiotics, salicylates, and diuretics. report from the Boston collaborative surveillance program. J Am

Renal insufficiency may result in the accumulation not Geriatr Soc 1979;27:20-2.only of active drugs or their metabolites, but also of inactive 19. Adir J, Miller AK, Vestal RE. Effectsof total plasma concentra-

1340 CLINICALCHEMISTRY, Vol.35, No. 7, 1989

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48. Ewy GA, Kapadia GG, Yao L, Lulhin M, Marcus E. Digoxinmetabolism in the elderly. Circulation 1969;39:449-53.49. Verbeeck R. Glucuromdation and disposition of drug glucuro-nides in patients with renal failure. Drug Metab Dispos 1982;10:87-9.50. Upton RA, Williams RL, Kelly J,Jones RM. Naproxenpharma-cokinetics in the elderly. Br J Chin Pharmacol 1984;18:207-14.51. Upton RA, Buskin JN, Williams RL, Holford N}IG, RiegelmanS. Negligible excretion of unchanged ketoprofen, naproxen, andprobenecidin urine. J Pharm Sci 1980;69:1254-7.