Drug distribution and renal excretion in the elderly

0021.9681,83~010091-l2~03.~~~0 Copyright 0 19X3 Pergamon Press Ltd

.I Chron Dis Vol. 36. pp 91 102. 1983 Printed in Great Britain. All rights reserved

DRUG DISTRIBUTION AND RENAL EXCRETION IN THE ELDERLY G.R. Wilkinson,

Ph.D.

Department of Pharmacology Vanderbilt University IMedical School Nashville, Tennessee 37232

ABSTRACT Drug responsiveness in the elderly often differs from that in younger individuals. A causative factor is often thought to be age-related changes in the quantitative fashion in which the body handles the drug. It is speculated that changes in body size, composition, and tissue perfusion lead to differences in drug distribution. The limited supportive evidence for this is reviewed, along with the practical consequences in drug therapy. More definitive data is presented on the age-related impairment of renal function and its effects on the urinary elimination of drugs and metabolites. Methods are presented to permit rationale dosage regimen modifications for elderly patients with reduced renal function. KEY WORDS Aging;

elderly;

drug distribution;

impaired

renal

function;

drug therapy;

dosage

guidelines.

INTRODUCTION The elderly (> 65 yr) are well known to be predisposed to altered drug responsiveness, and this is reflected in the almost twofold greater incidence of adverse responses in this subpopulation compared to younger patients. (Hurwitz, 196Y; Seidl and co-workers, lY66; Caranasos, Stewart, and Cluff, 1974). Unfortunately, the causes of the changes in sensitivity are not well defined or understood. In certain instances the quantitative manner in which the administered drug is absorbed, distributed, metabolized and excreted is different in the elderly. However, there is increasing evidence to suggest that age-related changes also occur at the drug receptor level, and this is thought to be particularly relevant to centrally acting drugs such as sedatives, tranquilizers, and other psychotropic agents. Delineation of the relative contributions of altered pharmacokinetics and pharmacodynamics in the elderly’s change in responsiveness is difficult, and most studies have been limited to the simpler goal of quantitating differences between young and old subjects with respect to the body’s ability to handle the drug. The known changes in body composition and physiological function which occur with aging suggest a priori that certain processes involved in drug disposition would be affected in the elderly. This review will focus on the known effects of aging on drug distribution and would

renal excretion with consideration significance of any changes.

DRUG DISTRIBUTION

not only of mechanistic

factors,

but also of the clinical

AND AGING

The distribution of a drug outside the vascular system is critical to the action of most therapeutic agents, and yet it is a process of which little is known except in generalities. Important factors involved in drug uptake into tissues include the mass of tissue, its perfusion by the blood, and the partition characteristics of the drug between blood and tissue. The latter involves such variables as membrane permeability, intraand extracellular pH, and tissue and plasma drug binding. However, in vivo the only measurement of distribution is the pharmacokinetic parameter, volumeoftribution (Vd), which is estimated from the ratio of the amount of drug in the body to the blood or plasma concentration of unbound (Vd ) or total (Vd ) drug in either absolute or body weight adjusted terms. Such a determaetion is only valtijtif the drug is given intravenously since all other routes of administration raise the question of the fraction of the dose which actually reaches the systemic circulation, i.+ bioavailability may be incomplete. Some confusion also exists because, following rapid mtravenous injection of a drug, its distribution volume is continuously changing until pseudo-distribution equilibration is achieved (Gibaldi, Nagashima, and Levy, 1969; Tozer, 1981). To overcome this problem, three different values of Vd are frequently estimated; VI, representing the initial space into which drug corresponding to immediately distributes following raprd mtravenous administration; Vd the amount/concentration relationship that would exist at steady-states&d Vd indicative of the pseudo-distribution equilibrium situation. For many drugs, the differe 8 ce between Vd is small (~25%) and the two estimates of distribution are frequently co&z:d !{uivalent. However, when larger differences are present, VdSs is a better indicator of the factors determining distribution and VdB is of more value m calculating dosage regimens (Benet and Ronfeld, 1969; Tozer, i981). Cardiac output decreases at a rate of about 1% per year over the age of 25-80 years, and tissue perfusion falls accordingly, although organs such as the brain, liver, and kidney have smaller decrements (Bender, 1965). Such changes would be expected to lead to alterations in the initial volume of distribution and the rate at which pseudo-distribution equilibrium is achieved, since both of these are highly dependent on the delivery rate of drug to the various tissues (Riegelman, Loo, and Rowland, 1968). The age-related increase in the initial plasma levels of morphine following intravenous injection, &, smaller VI, is probably due to altered hemodynamics in the elderly since the age difference is not apparent 10 minutes 1975). Similarly, the prolongation of the time to after injection (Berkowitz and others, achieve pseudo-distribution equilibrium following intravenous lidocaine injections; from 20 to 40 minutes in 22-26 year old subjects to 90 to 200 min in individuals aged 61-71 years, may be partly attributable to altered tissue perfusion characteristic in the elderly (Nation, Triggs, and Selig, lY77). However, the changes in body size and composition, and hence tissue binding, which accompany aging are probably the most important factors responsible for differences in drug distribution between young and old individuals. Total body water, both in absolute terms and as a percentage of body weight, decreases by 10 to 15% between the ages of 20 and 90 years (Shock and co-workers, 1963; Vestal and colleagues, 1975). In contrast, body fat increases over this approximate age range; in men from about 18 to 36% and in women from 33 to 45% of body weight (Novak, 1972). Accordingly, the lean body mass, predominantly made up of muscles, liver, brain, and kidney, is diminished by 20 to 30% withthe decline beginning in the fifth decade (Novak, 1972). Drug distribution would be expected to be affected by such changes in body composition, however, the direction and magnitude of any change is dependent on the individual drug and the importance of the various gross physiological body spaces in the overall distribution For example, ethanol’s absolute and body surface area corrected volume of process. distribution (Vdss) declines by about 20-25% over the age range 20-80 yr (Vestal and co-

Drug

Distribution

and Renal Excretion

93

workers, 1977). This is consistent with the known changes in body water to which ethanol distribution is considered to be restricted, and correction for the decrease in lean body mass negates the age-correlation. Similarly, the volume of distribution of antipyrine, which also is considered to be a measure of total body water, is modestly reduced in the elderly (Vestal and colleagues, 1975; Swift and co-workers, 1978). However, such decreases in distribution are not common with aging since most drugs bind to tissues and are not restricted to the body water space. The distribution of a number of drugs has been found to be increased in the elderly and it is often speculated that this is a result of the increased proportion of body fat and However, the supportive evidence for sequestration by partition of the lipid soluble drug. this hypothesis, in contrast to those based on altered plasma and/or tissue binding, is Perhaps the most dramatic ageextremely indirect, very sparse, and difficult to obtain. related change in distribution is that of diazepam originally described by Klotz and colleagues (1975) and subsequently confirmed by others (Greenblatt and co-workers, 1980a; Macklon and colleagues, 1980). Both the initial and steady-state volumes of this benzodiaze ine increase linearly with age over the range 20 to 80 years, such that thereis + t ree to fourfold difference between individuals at the extremes of age studied. The appears to be entirely due to the increase in the initial volume of increase in Vd distribution sin% the fractional distribution of diazepam between the initial and tissue compartments is unaffected by aging (Klotz and colleagues, 1975). In the original study, the plasma binding of diazepam did not alter with aging and, therefore, it was concluded that the increase in Vl was caused by a change in the tissue uptake and/or binding of the drug. The related drug, chlordiazepoxide, also exhibits a similar age-related increase in distribution (Vd ) of about the same magnitude as that for diazepam (Shader and co-workers, 1977; Rob&s and colleagues, 1978). Although based on oral studies which assume complete bioavailability, the same phenomenon appears to exist also for desmethyldiazepam (Klotz and Muller-Seydlitz, 1979) and nitrazepam (Kangas and co-workers, 19791, although the latter finding in elderly patients has not been confirmed in normal, healthy, old individuals (Castleden and colleagues, 1977). In contrast, the benzodiazepines, oxaze am (Shull and h.b‘ p am ( &colleagues, colleagues, 1976; Greenblatt and co-workers, 1980b), and loraze raus an 1978; Greenblatt and co-workers, 1979) do not appear to ex I it any age-related changes in Because those benzodiazepines which do not show an increase in their distribution. distribution with aging are less lipid-soluble than the drugs which do, it is possible that the mechanism of the altered distribution involves the age-related increases in body fat (Novak, 1972). However, the fact that in the case of diazepam, for example, the larger distribution is observed within 5 minutes after intravenous administration suggests that other factors are involved (Wilkinson, 1978; 19791, since body fat is generally considered to be poorly perfused and distribution into this tissue is slow (Riegelman, Loo, and Rowland, 1968). Furthermore, the distributional alterations appear to be an continuous linear function, present in individuals as young as 20-30 years when body fat changes are generally not significant. Possibly altered tissue permeability and quantitative changes in tissue binding may be the Interestingly, the age-related distributional phenomenon does not causative mechanisms. appear to be manifested in either the rabbit or the rat (Tsang and Wilkinson, 1980). Many drugs circulate in the blood as reversible complexes with plasma macromolecules such as albumin, o -acid glycoprotein and lipoproteins. Such binding restricts the distribution of drug out of t t, e vasculature and the volume of distribution is proportional to the unbound fraction (Wilkinson and Shand, 1975; Tozer, 1981). It is, therefore, frequently speculated that the age-related decrease in the plasma albumin concentration will result in enhanced drug distribution. However, the currently available evidence does not provide consistent support for this situation; the unbound fraction of some, but not all, drugs bound to albumin may be increased in the elderly, with dissimilar findings being reported by different investigators (Vestal, 1979). For example, Klotz and colleagues (1975) did not observe any age-related changes in the of diazepam; however, other studies (Greenblatt and co-workers, 1980a; Mac ues, 1980) have reported a decrease in binding in the elderly. Similar discrepant findings have been noted for warfarin (Hayes, Langman, and Short, 1975a; Shepherd and colleagues, 1977) and phenytoin (Hayes, Langman, and Short,

G.

R. WILKINSON

1975b; Bender and co-workers, 1975). Differences in the experimental techniques of estimating the extent of binding could account, in part, for some of the disparity between these studies. However, it is most probable that the findings reflect differences in the various study populations which generally have only contained a small number of subjects. For example, in some elderly study groups hypoalbuminemia was definitely present while in others the incidence of this state was not so marked. The need to rigorously define and investigate drug binding in appropriate subjects is further reinforced by studies with propranolol. Castleden and George (1979) reported that following both intravenous and oral dosing the plasma levels of propranolol were higher in elderly subjects compared to young individuals. This was not, however, confirmed by Vestal and colleagues (1979) and Schneider and co-workers (lV80). The significant difference between the various populations studied was the selection criteria for the elderly subjects. The two latter studies used noninstitutionalized active subjects with no known clinical problems. In contrast, Castleden and George (1979) investigated elderly individuals in a long-stay geriatric ward, and while the patients did not have major organ dysfunction, some suffered from osteoarthritis and were post-cerebral infarction. This difference is important since propranolol, along with many other basic drugs, binds to of-acid glycoprotein (Piafsky, IVgO), the plasma concentration of which is elevated in many unrelated inflammatory diseases common in the elderly, including arthritis and myocardial infarction (Piafsky and colleagues, 1978). A further complication in assessing changes in plasma binding of drugs in the elderly is that of multiple drug therapy. Polypharmacy is the rule rather than the exception in old patients, and this is especially so if non-prescription drugs and vitamins are considered. Such concomitant therapy may result in competitive displacement of drugs from their binding sites in the plasma. For example, elderly patients receiving two or more drugs have significantly greater unbound fractions of salicylate and sulfadiazine in their plasma compared to young subjects, but this difference is not present in elderly individuals not taking any drugs (Wallace, Whiting and Runcie, 1976). Altered drug distribution to a target organ may be directly involved in the difference in responsiveness of the elderly to certain drugs, &, larger amounts are translocated to the receptor sites. However, virtually no studies have investigated this possibility. Most of the concerns of an age-related change in distribution have been focused on the effects that this may have on the drug’s pharmacokinetics as assessed by the blood or plasma concentration/time profiles. The most significant of these is on the elimination half-life (t,,,),of the drug since this parameter is directly proportional to the volume of distribution (Equation 1)

?I2

0.693 Vd = Clearance

Equation

1

where clearance is the measurement of the overall efficiency of drug removal from the body by all eliminating processes, e.g., urinary excretion plus hepatic metabolism and biliary excretion. Accordingly, even if clearance is unaffected in the elderly, a change in distribution will alter the rate at which the drug is removed from the body. In the case of an age-related increase in Vd, the half-life will be prolonged. Accordingly, the three-to fourfold longer half-life of diazepam at age 80 years compared to that at 20 years (Klotz and colleagues, 1975); the six- to eightfold increase across the same age range with chlordiazepoxide (Roberts and co-worker, 1978) and the approximately twofold higher value in the elderly (Nation, Triggs, and Selig, 1977) are due entirely, or When decreased drug clearance is ~~e~~~~~~, ‘t’d’;h e age-related change in distribution. also present in the elderly, then this too contributes to the lengthening of the half-life, =, chlordiazepoxide (Roberts and co-workers, 19781, and it may, in fact, completely over-ride as occurs with antipyrine (Vestal and any effects of a reduced distribution volume, colleagues, 1975; Swift and co-workers, 1978). The major effect of a prolonged half-life in the elderly is on the plasma concentration/time During the dosage interval the fluctuation profile following chronic drug administration. will be blunted between the peak and trough drug levels at the beginning and end of the

Drug

interval, respectively, following be attained more slowly in the achieved in approximately three

Distribution

and Renal Excretion

discontinuous administration. In addition, elderly compared to young patients since to four times the half-life of elimination.

95

steady-state will this condition is

An altered distribution volume may also have clinical consequences after acute drug administration. A reduction in distribution, especially in Vl, for a drug administered intravenously and/or with a narrow therapeutic margin is particularly problematic. In this case, administration of the usual drug dosage will produce higher initial plasma concentrations and therefore increase the likelihood of toxicity. The use of a smaller loading dose of digoxin in the elderly is based partly on the fact that this drug distributes into the lean body mass and, therefore, the absolute, but not the body weight corrected, distribution volume is reduced in old patients (Ewy and colleagues, 1969; Cusack and co-workers, 1979; Whiting, Lawrence, and Sumner, 1979). In the opposite situation of an increased distribution with aging, then the potential for ineffective therapy after a usual dose is obviously present. However, in practice this does not appear to be too significant a problem. Finally, it should be recognized that with the administration of additional doses, leading to accumulation to steady-state, the effects of differences in distribution immediately after dosing become of diminishing significance, since under this condition the average plasma level during the dosing interval is only dependent on the drug’s clearance. In summary, age-related changes in body size, composition and function would suggest that the distribution of drugs would be altered in the elderly. While limited examples of such changes do exist, there appears to be no consistent pattern that might aid in the prediction of either the mechanisms or the magnitude of the alterations, even in a group of closely related compounds, e.g., the benzodiazepines. Accordingly, information has to be developed on a drug by drug basis and, similarly, the clinical significance of any differences between drug distribution in young and old subjects and patients must be evaluated. With few exceptions, the currently available data does not suggest that altered distribution associated with aging is of major clinical importance. Such changes are, however, of great potential value in further understanding of the aging process and its effects on body function. RENAL FUNCTION The loss regard to longitudinal reduction acceleration maintained at about reduction and there

AND AGING

of renal function was one of the first physiological changes to be studied with drug disposition and aging. Both cross-sectional (Davies and Shock, 1950) and studies (Rowe and colleagues, 1976) have clearly demonstrated a 30 to 45% in glomerular filtration rate (GFR) over the age range 30 to 90 years, with an of the decrement after age 65 years. Similarly, total renal blood flow is well approximately through the fourth decade, but thereafter progressively declines 10% per decade (Vender, 1965; Wesson, 1969). It is generally regarded that the in renal function in the elderly results from the loss of mainly cortical nephrons is limited supportive evidence to this effect (Dunnill and Halley, 1973).

The decline in renal function has important implications in the dosage regimens of certain drugs in the elderly, analogous to the situation in renal failure at any age. Of particular concern are those drugs that are predominantly eliminated unchanged from the body by the kidney. If it is considered that the maximal decrease in GFR is about 50% in the SO-90 year range, then this means drugs for which the percentage of the absorbed dose excreted in the urine is at least 60% or greater. The margin between effective and toxic plasma levels must also be narrow, since even if all of the drug is renally excreted, the drug plasma levels in the elderly will only be about twofold greater than in young patients with normal renal function. Thus, knowledge of changes in renal clearance and elimination half-life of procaine and benzyl penicillins (Leikola and Vartia, 15157; Kampmann and co-workers, 1972), propicillin (Simon and colleagues, 1972), phenobarbital (Traeger, Kieswetter, and Kuntz, 1974), and practolol (Castleden, Kay, and Parsons, 1975) is scientifically interesting, but not of major clinical significance in the use of these drugs in the elderly. Similarly for a number of cephalosporins (Kampmann and Molholm Hansen, 1979; Simon and colleagues, 1976), although

G. R. WILKINSON

96

the possibility of renal tubular necrosis in dehydrated patients with low cardiac output, and those also receiving diuretics may be relevant. In contrast, information on the impaired excretion of digoxin in the elderly (Ewy and colleagues, 1969; Cusack and co-workers, 1979; Whiting, Lawrence, and Sumner, 1979) is of critical importance in the optimal use of this cardiac glycoside; lower maintenance doses are invariably required in old patients. A similar situation arises with the amino 1 cosides such as streptomycin, gentanli6$9;: __g11_7_ kanamycin, tobramycin, amikacin, and sisomicm Kampmann and Molholm Hansen, where nephrotoxicity and auditory nerve damage are potentially serious side-effects (Vartia and Leikola, 1960; Lumholtz and colleagues, 1974). Other problematic drugs include the tetracyclines (Vartia and Leikola, 19601, procainamide (Reidenberg and colleagues, 19801, hypoglycemic a ents (Rowe, 1981) and lithium (Lehman and Merten, 1974; Hewick and Newbury, 1976 f-. The use of diuretics in the elderly is frequently associated with an adverse response (Seidl and co-workers, 1966; Caranasos, Stewart, and Cluff, 1974). However, this appears to result from electrolyte and fluid imbalances secondary to impaired homeostasis rather than altered drug disposition. Finally, it should be recognized that impaired renal function in the elderly may result in ineffective urinary concentrations of antibiotics used to (Rowe, 1981), chloramphenicol (Rowe, 1981) control urinary infections, e.g., nitrofurantoin and mecillinam (Ball and collegues, 1977). For drugs which are extensively excreted unchanged in the urine and have a narrow therapeutic index, the reduction in renal function in the elderly must be considered in any therapeutic plan. A major difficulty is, however, that considerable interpatient variability Therefore, for optimal therapy, i.e., efficacy exists in the extent of renal impairment. without toxicity, individualization of each patient’s dosage regimen is essential. In general, loading doses do not have to be modified because of the presence of decreased renal function; however, maintenance doses do require adjustment. All approaches to the latter problem are based on the estimation of glomerular filtration rate as a measure of the patient’s total renal function, and the assumption that tubular secretion and/or reabsorption The findings with para-aminochange proportionally, i.e., the intact-nephron hypothesis. hippurate and iodopyracet (Davies and Shock, 1950; Wesson, 1969) which undergo secretion by the “organic acid active transport system” support this assumption. However, recent 1980) indicate that with this, and findings with procainamide (Reidenberg and colleagues, tubular secretion declines more rapidly with aging than possibly other basic drugs, glomerular filtration. Endogenous creatinine clearance (Cl ) is not an ideal measure of glomerular filtration rate since 10% to 15% of the urinary crea’?!nine in subjects with normal renal function is secreted into the urine in the proximal tubule. In addition, the analytical procedures used to However, for determine creatinine in urine or serum may contribute further errors. virtually all practical purposes, it is the most convenient and widely available assessment of renal function. Ideally, creatinine clearance should be directly determined; however, the inherent difficulties and errors of urine collection, especially in the non-institutionalized elderly, usually lead to an indirect estimation based on the serum creatinine value (01. Unfortunately, this concentration cannot be indiscriminantly used per se since creatinine production is a reflection of muscle mass, which is dependent on sexual gender and age, and Accordingly, serum creatinine remains essentially creatinine clearance declines with aging. constant with aging, even when renal function is impaired (Bjornsson, 1979). Thus, a serum creatinine of Img/dl may indicate a creatinine clearance of 120ml/min at age 20 years, but only 60ml/min at age 80 years. Several formulae and nomograms have been suggested and evaluated to relate serum creatinine to its renal clearance (Bjornsson, 1979; Chennavasin 1981). In the healthy elderly patient, i.e., renal and Brater, 1981; Hull and colleagues, failure is not present and function is about 50% or greater than that in young healthy individuals, the relationship developed by Cockcroft and Gault (1976) provides a simple yet reliable estimation of creatinine clearance in adult men (Equation 2) Clcr

=

(140-Age) x Wt (Kg) 72 x Cr (mg/dl)

ml/min

Equation

2

Drug

Distribution

91

and Renal Excretion

This method provides The creatinine clearance for women is 85% of that for men. essentially the same results as the widely used nomogram devised by Siersbaek-Nielsen and colleagues (197 I), but has the advantage of adaptability to calculator/computer estimation. Equation 2 has been validated in several studies and proven to be extremely reliable unless renal function is grossly impaired, i.e., Cr > 5 mg/dl (Bennett and co-workers, 1978; Hull and colleagues, 198 1I. The overall objective of modifying a dosage schedule in a patient with impaired drug elimination of any etiology is to adjust the regimen so that the drug concentration is the same and is reached after a similar interval as in a patient with normal function. This may be accomplished by modifying the dose but maintaining the usual dosage interval; by administering the usual dose but at more infrequent intervals; or a combination of both approaches. However, it must be recognized that no dosage regimen can produce a plasma concentration/time profile in a patient with reduced renal function comparable to that in a normal patient. A more limited goal must be established, namely the achievement of either similar peak, trough, or average plasma levels during the dosage interval. Which of these goals is appropriate, and the means to accomplish it depends on the pharmacokinetic characteristics of the particular drug and the relationship between plasma concentrations and the therapeutic and toxic effects. Several reviews have recently described the advantages and disadvantages of the variety of procedures for dosage modification for patients with impaired renal function (Tozer, 1974; Fabre and Balant, 1976; Dettli, 1977; Chennavasin and Brater, 1981). For a drug such as digoxin where the elimination half-life relative to the dosage interval, then an appropriate goal in the in the elderly is to maintain the same average steady-state patient with normal renal function. In the case of digoxin this about 0.5 to 1.8 ng/ml. Recognition of the relationship between Absorbed/Dosage Interval), clearance (Cl), and the average (Equation 3), permits estimation of the appropriate maintenance interval. CP avg =

Dose Absorbed/Dosage Clearance

is long, both absolutely and presence of renal impairment plasma level (Cp ) as in a would be within #&range of the drug delivery rate (Dose steady-state plasma level dose for any chosen dosage

Interval Equation

3

For example, in a patient with a digoxin clearance of 70 ml/min, a daily absorbed dose of 0.101 mg would achieve the target Cp of 1.0 ng/ml. If the digoxin was to be administered orally then, because only asvAt 83% of the administered dose is absorbed (Benet and Sheiner, 19801, then the appropriate dose would be 0.121 mg which, in practice, would be given as 0.125 mg daily. Estimation of digoxin’s clearance (ml/min/kg) in an elderly patient may be obtained from its relationship to the creatinine clearance also in ml/min/kg; Digoxin clearance = 0.88 Cl + 0.33. If heart failure is not present, then the coefficient of Cl should be 1.0 (Benet ans’sheiner, 1980). Similar relationships for other drugs, including th&‘aminoglycosides, have been determined (Benet and Sheiner, 1980), and further ones will hopefully become available in the future. A requirement for applying Equation 3 is that a target plasma level can be defined which implies knowledge of the relationship of the steady-state plasma concentration and the effects of the drug. However, this is not always established. In which case, the appropriate maintenance dose to be administered at the usual dosage frequency in the elderly patient with impaired renal elimination may be estimated as a fraction of the dose usually administered to a patient with normal renal function. This fraction may be calculated from the ratio of the drug’s clearance in the patient with impaired function to that in the normal individual, using the known relationship of drug to creatinine clearance (Benet and Sheiner, 1980). Alternatively, a simple and easy to use nomogram with good physician acceptance is available for this purpose (Dettli, 1977). In the last resort, if the latter is not known then a conservative approximation may be made simply by expressing the creatinine clearance in the old patient as a fraction of the normal value (120 ml/min). For digoxin and a creatinine

9x

G.

clearance of 50 ml/min, these approaches 42%, respectively, of the usual dose (0.25 administration of 0.125 mg/day.

R.

WILKINSON

would suggest a maintenance mg/day) which, in practice,

dose of 51, 55, and would again indicate

The use of a decreased maintenance dose administered at the usual dosing frequency in elderly patients with impaired renal elimination has the advantage of producing the same average steady-state plasma concentration as in younger patients with normal function, but the peak plasma level (Cp ) is lower and the trough concentration (Cp ) is higher. Accordingly, it prevents druta$ccumulation and associated toxicity, avoids lar&“fluctuations between peak and trough values and, at least in the elderly where renal impairment is not major, avoids a prolonged duration of sub-effective plasma concentrations. However, for drugs which have a short elimination half-life relative to the dosing interval and/or the peak plasma level is considered to be of more importance than Cp e.g., antibiotics such as the aminoglycosides, then this approach may be inappropriate. ???&ich cases the primary goal should be to obtain similar Cp plasma levels, and several nomograms are available for this purpose (Chennavasin and q?&er, 1981). In severe renal failure this approach, while producing comparable peak plasma levels, leads to above normal average and minirnum concentrations. Thus, the patient is exposed to a greater concentration of drug over time with the attendant risks that this may have. To overcome this problem, a combination strategy may be more desirable in which both the maintenance dose and the dosing frequency are altered (Hull and Sarubbi, 1976; Dettli, IY77; Sarubbi and Hull, 197X). However, in the elderly without frank renal failure this added degree of complexity is usually not required. The use of dosing guidelines such as those described must recognize their limitations, not the least of which are the assumptions that other dispositional processes such as distribution and metabolism are not altered, nor is the pharmacodynamic responsiveness affected by aging. It is critical to realize that the estimated dosage regimen is only a first approximation that may require further refinement. When available, the plasma concentration should be monitored as an additional guideline to the appropriateness of the dosing regimen. However, in all instances optimal individualization of therapy must be based on the clinical assessment of each patient. Finally, it is becoming increasingly recognized that the enhanced side-effects of certain drugs which are extensively metabolized in the elderly are caused not by the drug per se, but This occurs because the metabolite accumby a pharmacologically active metaboliteis). ulates to a greater level than in young patients as a result of the reduced renal function. The ratio of hydroxylated metabolites to unchanged tricyclic antidepressants such as nortriptyline (Bertilsson, Mellstrom, and Sjdqvist, 1979) and desipramine (Kitanaka and colleagues, 1YXl) have been shown to be increased in the elderly. The role of this metabolite accrual versus altered metabolism of the drug itself in the increased incidence of A similar side-effects in the elderly is, however, not well-defined at the present time. phenomenon appears to occur with the N-acetyl metabolite of procainamide (Reidenberg and co-workers, 19X0). In summary, the reduction in renal function and the associated impairment of urinary excretion of drugs and their metabolites in the elderly is established beyond doubt. The magnitude of the functional decrease in the absence of non-age-related renal failure, is frequently no greater than about 50%. Accordingly, modification of therapeutic drug regimens are only of importance for drugs which are extensively excreted unchanged in the urine (> 60% of the dose) and have a relatively small difference between the concentration of the drug producing the desired response and that causing unacceptable adverse effects. For example, digoxin, procainamide, lithium, aminoglycosides, certain hypoglycemic agents Simple nomograms and formulae are available which permit and possibly methotrexate. rationale adjustment of the dosage regimen, and these have in general been validated. Due to interpatient variability, such modification is only a first approximation which may need further refinement based on the plasma drug levels achieved and clinical assessment. However, it is a far superior approach to empirical individualization based on a rough guess

Drug

because potential

it does not expose to elicit toxicity.

Distribution

the elderly

patient

99

and Renal Excretion

to inappropriately

high drug levels

with

their

CONCLUSION Large increases in the number and proportion of the population constituted by the elderly in the so-called developed countries are projected in the next several decades. Such patients consume a disproportionate share of both prescribed and over-the-counter drugs, and suffer an increased incidence of untoward effects of these. A variety of factors are involved in the enhanced responsiveness of the elderly, including impaired homeostatic mechanisms, altered drug receptor sensitivity, and changes in drug disposition. The latter is particularly amenable to characterization and compensation by modification of the dosage regimen. This is particularly true with respect to the totally predictable impairment in renal failure with aging. However, it must be recognized that aging is not a uniform process and that interpatient variability increases considerably in the elderly. Accordingly, individualization of therapy is essential and is assisted by frequency assessment of the overall clinical status of the patient. The clinical problems are frequently difficult and challenging, but the rewards are often particularly satisfying.

ACKNOWLEDGEMENT Supported

by Grant

AC-01395

from

the U.S. Public

Health

Service.

REFERENCES Ball,

A.P., A.K. Viswan, M. Mitchard, and R. Wise (1978). Plasma concentrations and excretion of mecillinam after oral administration of pivmecillinam in elderly patients. J. Antimicrob. Chem. Therap., 4, 241-246. The effect of increasing age on the distribution of peripheral blood Bender, A.D. (19651 flow in man. J.‘Amer. Geriat. Sot., 13, 192-198. Bender, A.D., A. Post, J.P. Meier, J.E. Kgson, and G. Reichard, Jr. (1975). Plasma protein binding of drugs as a function of age in adult human subjects. J. Pharm. Sci., 2, 17111713. Benet, L.Z. and R.A. Ronfeld (1969). Volume terms in pharmacokinetics. J. Pharm. Sci., 2, 639-641. Benet, L.Z. and L.B. Sheiner (1980). Design and optimization of dosage regimens: pharmacokinetic data. In A. G. Gilman, L.S. Goodman, and A. Gilman (Eds.), The Pharmacological Basis of Therapeutics, 6th ed., MacMillan Publ. Co., New York, . 5-l/3/ Bent%, W.M., G:A. Porter, S.P. Babgy, and W.J. McDonald (1978). Drugs and Renal Diseases. Churchill Livingstone, New York. pp. 9-10. Berkowitz,.A., S.H. Ngai, J.C. Yang, J. Hempstead, and S. Spector (1975). The disposition of morphine in surgical patients. Clin. Pharmacol. Ther., ‘7, 629-635. Bertlisson, L., B. Mellstrom, and F. Sjbqvist (lY/91. Pronounced inhibition of noradrenaline uptake by lo-hydroxy-metabolites of nortriptyline. Life Sci., 25: 1283-1292. Bjornsson, T.D. (1979). Use of serum creatinine concentrations toaetermine renal function. Clin. Pharmacokin, 4, 200-222. Caranasos, G.J., R.B. Stewart, and L.E. Cluff (1974). Drug-induced illness leading to hospitalization J. Amer. Med. Assoc., 228, 713-717. Castleden, C.M. anhC.F. George (lY/VT. Te effect of aging on the hepatic clearance of propranolol. Br. J. Clin. Pharmac., 7, 49-54. Castleden, CM., C.M. Kaye, and R.L. &-sons (1975). The effect of age on plasma levels of propranolol and practolol in man. Br. J. Clin. Pharmac., 2, 303-306. Castleden, C.M., C.F. George, D. Marcer, and C Hallett (r977). Increased sensitivity to nitrazepam in old age. Brit. Med. J., ‘, 10-12.’

100

G.

R.

WILKINSON

Chennavasin, P. and D.C. Brater (1981). Nomograms for drug use in renal disease. Clin. Pharmacokin., 6, 193-214. Cockroft, D.W. and M.K Gault (1976). Prediction of creatinine clearance from serum creatinine. Ne hron 16, 31-41. Cusack, B., J. Ke7f+ y, Omalley, J. Noel, J. Lavan, and J. Horgan (1979). Digoxin in the elderly: pharmacokinetic consequences of old age. Clin. Pharmacol. Ther., 2, 772-776. Davies, D.F. and N.W. Shock (1950). Age changes in glomerular filtration rate, effective renal plasma flow, and tubular excretory capacity in adult males. J. Clin. Invest., 29: 496-507. Dettli, L. (1977). Elimination kinetics and dosage adjustment of drugs in patients with kidney disease. Progress in Pharmacology, I, l-34. Dunnill, MS. and W. Halley (lY/jl Some observations on the quantitative anatomy of the kidney. J. Pathol., 110, 113-121. apadi-. Yao, M. Lullin, and F.I. Marcus (1969). Digoxin metabolism in Ewy, G.A., Gr the elderly. Circulation, 39, 449-453. Fabre, J. and L. Balant (19m. Renal failure, drug pharmacokinetics, and drug action. Clin. Pharmacokin., L, 99-120. GibaIdi, M R. Nagashima, and C. Levy (1969). Relationship between drug concentration in plasmzor serum and amount of drug in the body. J. Pharm. Sci., 58, 193-197. M.D. Allen, A. Locniskar, J.S. tiarmatz, anhR.1. Shader (1979). Greenblatt, D.J., Lorazepam kinetics in the elderly. Clin. Pharmacol. Ther., 26, 103-l 13. Greenblatt, D.J., M.D. Allen, J.S. Harmatz, and R I Shader (1980a). Diazepam disposition determinants. Clin. Pharmacol. Ther., 2, 301-3i2. Greenblatt, D.J., M. D~voll, J.S., Harmatz, and R-1. Shader (1980b). Oxazepam kinetics effects of age and sex. J. Pharmacol. Exp. Ther., 215, 86-91. Hayes, M.J., M.J.S. Langman, and A.H. Short (IY//farChanges in drug metabolism with increasing age: 1. Warfarin binding and plasma proteins. Br. J. Clin. Pharmac., 2, 69-72. Hayes, M.J., M.J.S. Langman, and A.H. Short (1975b). Changes m drug metabolism with increasing age. 2. Phenytoin clearance and protein binding. Br. J. Clin. Pharmac., 2,73-79. Hewick, D.S. and P.A. Newbury (1976). Age: its influence on lithium dosage ana plasma levels. Br. J. Clin. Pharmac., 3, 354P. Hull, J.H. and F A 5 bb (lY/q. Gentamicin serum concentrations: pharmacokinetic predictions. ‘A&r. ?iFeri. Med 85 183-189. argin, S.L. Chi, and A.M. Mattocks (1981). Influence Hull, J.H., L.J. Hak, G.G. Koch, %?A of range of renal function and liver disease on predictability of creatinine clearance. Clin. Pharmacol. Ther., 29, 516-521. Hurwitz, N. (1969). PredispoTng factors in adverse reactions to drugs. Br. Med. J., h 536539. __. Kampmann, J.P. and J.E. Mldlholm Hansen (1979). Renal excretion of drugs. In 3. Crooks and I.H. Stevenson (Eds.), Drugs and the Elderly: Perspectives in Geriatric Clinical Pharmacolo y. The MacMillan Press, Ltd., London. Ch 8 //-8/ olholm Hansen, K. Siersbaek-Nielsen, anadP*H[ !%rsen (1972). Kam& Effect of some drugs on penicillin half-life in blood. Clin. Pharmacol. Ther., 13, 516-519. Kangas, L., E. Iisalo, 3. Kanto, V. Lehtinen, S. Pynnonen, S., I. Kuikz, J. Salminen, M. Sillanpaa, and E. Syvalahti (1979). Human pharmacokinetics of nitrazepam: Effect of age and disease. Europ. 3. Clin. Pharmacol., 15, 163-170. Kitanaka, I., A.P. Zivadil, N.R. Cutler, and W.Z. ntter (1981). Altered hydroxydesipramine concentrations in the elderly. Clin. Pharmacol. Ther., 29, 258. Klotz, U., G.R. Avant, A. Hoyumpa, S. Schenker, and G.R.vilkinson (1975). The effects of age and liver disease on the disposition and elimination of diazepam in adult man. J. Clin. Invest., 55, 347-359. Klotz, U. and P Muir-Seydlitz (1979). Altered elimination of desmethyldiazepam in the elderly. Br.‘J. Clin. Pharmac., 7, 119-120. Kraus, J.W., k.V. Desmond, J.P. I&shall, R.F. Johnson, S. Schenker, and G.R. Wilkinson (1978). Effects of aging and liver disease on disposition of lorazepam. Clin. Pharmacol. Ther., 24, 411-419. Die elimination von lithium in abhangigkeit vom Lehmann, K. aniTK. Merten (1974). Int. J. Clin. Pharmacol., ‘0, 292-298. lebensalter bei gesunden und niereninsuffizienten.

Drug

Distribution

and Renal Excretion

101

Leikola, E. and K.O. Vartia (1957). On penicillin levels in young and geriatric subjects. J. Gerentol., 12, 48-52. Lumholtz, B J. Empmann, K. Siersbaek-Nielsen, and 3.E. M&iolm Hansen (1974). Doseregimen’bf kanamycin and gentamicin. Acta Med. Stand., 196, 521-524. Macklon, A.F., M. Barton, 0. James, and ti.D. Rawlins (198rThe effect of age on the pharmacokinetics of diazepam. Clin. Sci., 59, 479-483. Nation, R.L., E.J. Triggs, and M. SerTifi.7ignocaine kinetics in cardiac patients and aged subjects. Br. J. Clin. Pharmac., 4, 439-448. Novak, L.P. (1972). Aging, total body potassium, fat free mass, and cell mass in males and females between ages 18 and 85 years. J. Gerontol., 2, 438-443. Piafsky, K.M. (1980). Disease-induced changes in the plasma binding of basic drugs. Clin. Pharmacokin., 5, 246-262. Piafsky, K.M., 0. Borga,T. Odar-Cederlijff, C. Johansson, and F. Sjiiqvist (1978). Increased plasma protein binding of propranolol and chlorpromazine mediated by disease-induced elevations of ccl-acid glycoprotein. New Engl. J. Med., 299, 1435-1439. Aging and renal Reidenberg, M.M., M. Camacho, J. Kluger, and D.~z. Drzr (1980). clearance of procainamide and acetylprocainamide. Clin. Pharmacol. Ther., 2, 732-735. Riegelman, S., J.C.K. Loo, and M. Rowland (1968). Shortcomings in pharmacokinetic analysis by conceiving the body to exhibit properties of a single compartment. J. Pharm. Sci. ., 57, 11-7-123. Roberts, R.K., G.R. Wilkinson, R.A. Branch, and S. Schenker (1978). Effect of age and parenchymal liver disease on the disposition and elimination of chlordiazeioxide (Librium). Gastroenterol., 75, 479-485. Rowe, J.W. (1981). Aging and renal function, and response to drugs. In L.F. Jarvik, D.J. Greenblatt, and D. Harmann. Clinical Pharmacology and the Aged Patient (Aging, Vol. 16). Raven Press, New York. pp. 115-130. Rowe, R. Andres, J.D. Tobin, A.H. Norris, and N.W. Shock, (1976). The effect of age on creatinine clearance in men: a cross-sectional and longitudinal study. J. Gerontol., 31, 155-163. Sarum, F.A. and J.H. Hull (1978). Amikacin serum concentrations: prediction of levels and dosage guidelines. Ann. Intern. Med., 89, 612-618. Schneider, R.E., H. Bishop, R.A. Yates, CT. Quartermain, and M.J. Kendall (1980). Effect of age on plasma propranolol levels. Br. J. Clin. Pharmac., 10, 169-171. Seidl, L.C., G.R. Thornton, J.W. Smith, and L.t. Cluff (lY6fl . Studies of the epidemiology of adverse drun reactions. III. Reactions in patients on a neneral medical service. Bull. Johns Hopiins Hospital., 119, 299-315. . Shader, K.I., D.J. Greenblatt, J.S. Harmatz, K. Franke, and J. Koch-Weser (1977). Adsorption and disposition. of chlordiazepdxide in -vounn_ and elderly male volunteers. J. Clin. Pharmacol.; 17, 709-718. Shepherd, A.M.M., D.S.Tewick, T.A. Moreland, and I.H. Stevenson (1977). Age as a detekminant oi sensitivity to.warfarin. Br. J. Clin. Pharmac., i, 315-320. Shock N.W., D.M. Watkin, M.J. Yiengst, A.H. Norris, G.W. Gaffney, R.I. Gregerman, and J.A. Falzone (1963). Age differences in the water content of the body as related to basal oxygen consumption in males. 3. Gerontol. Is, l-8. Shull, H.J., G.R. Wilkinson, R. Johnson, and S. Schenker (1976). Normal disposition of oxazepam in acute viral hepatitis and cirrhosis. Ann. Intern. Med., 84, 420-425. Siersbaek-Nielsen, K., J. Mdholm Hansen, J. Kampmann, and M. Kristensen (1971). Rapid evaluation of creatinine clearance. Lancet, 1, 1133- 1134. Simon, C., V. Malerczyk, U. Muller, and lhuller (1972). Zur pharmakokinetik von propidillin bei geriatrischen pat&ten im vergleich zu jungeren eiwachsenen. Dtsche Med. Wschr., 97, 1999-2003. Simon, C., V. tiaxrczyk, B. Tenschert, and F. Mohlenbeck (1976). Die geriatrische pharmakologie von cefazolin, cefradin and sulfisomidine. Arzneim. Forsch., 26;1377-1382. Swift, C.G., M. Homeida, M. Halliwell, and C.J.C. Roberts (lY/S). Antipyriiik disposition and liver size in the elderly. Europ. J. Clin. Pharmacol., 14, 149-152. Tozer, T.N. (1974). Nomogram for modification of dosage rermens in patients with chronic renal function impairment. J. Pharmacokin. Biopharm., 2, 13-28.

102

G. R. WILKINSON

Tozer, T.N. (1981). Concepts basic to pharmacokinetics. Pharmac. Ther., 12, 109-131. Traeger, A., R. Kieswetter, and Kuntz (1974). Zur pharmakokmetik von3enobarbital bei erwachsenen und griesen. Dtsch. Gesundheitswes., 29, 1040-1042. Tsang, C.F. and G.R. Wilkinson (1980). Diazepam zposition in aged rabbit and rat. V,,,ha;m;.coi;$;, 22! 230. Eikola (1960). Serum levels of antibiotics in young and old subjects f&lowing administration of dihydrostreptomycin and tetracycline. J. Gerontol., 11, 392-394. Vestal, R.E. (1979). Aging and pharmacokinetics: impact of altered physiology in the elderly. In A. Cherkin, C.E. Finch, N. Kharasch, T. Makinodan, F.L. Scott, and B. Strehler (Eds.), Physiology and Cell Biology of Aging (Aging, Vol. 8j. Raven Press, New York. pp. 185-201. Vestal, R.E.; A.H. Norris, J.D. Tobin, B.H. Cohen, N.W. Shock, and R. Andres (1975). Antipyrine metabolism in man: influence of age, alcohol, caffeine, and smoking. Clin. Pharmacol. Ther., 18, 425-432. Vestal, K.b., E.A. McG’iirre, J.D. Tobin, R. Andres, A.H. Norris, and E. Mezey (1977). Aging and ethanol metabolism. Clin. Pharmacol. Ther., 2, 343-354. Vestal, R.E., A.J.J. Wood, R.A. Branch, D.G. Shand, and G.R. Wilkinson (1979). Effects of age and cigarette smoking on propranolol disposition. Clin. Pharmacol. Ther., 26, 8-15. Wallace, S., B. Whiting, and J. Runcie (1976). Factors affecting drug binding in $sma of elderly patients. Br. J. Clin. Pharmac., 2, 327-330. Wesson, L.C., Jr. (1969). Renal hemodynamics in physiological states. In L.G. Wesson, Physiology of the Human Kidney, Grune and Stratton, New York. pp. 96-108. Whiting, B J.K. Lawrence, and D.J. Sumner (1979). Digoxin pharmacokinetics in the elderI;: In J. Crooks and I.H. Stevenson (Eds.), Drugs and the Elderly: Perspectives in Geriatric Clinical Pharmacology, MacMillan Press Ltd., London. pp. 89-101. Wilkinson, G.R. (lY/s). The etfects of liver disease and aging on the disposition of diazepam, chlordiazepoxide, oxazepam and lorazepam in man; Acta Psychiat. Stand., Wi*ki~&_56-74.

(1979). The effects of aging on the disposition of benzodiazepines in man. In J. ‘Crooks and I.H. Stevenson (Eds.), Drugs and the Elderly: Perspectives in Geriatric Clinical Pharmacology. MacMillan Press Ltd., London. pp. 103-l 16. WilkInson, G.R. and D G Shand (1975). A physiological approach to hepatic drug clearance. Clin. Pharmacol. fher., g, 377-390.