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Vol. 281, Issue 3, 1317-1329, 1997
Clinical Pharmaceutical Scientist Program, Departments of Pharmacy and Therapeutics (R.J.B., F.S.S.) and Pharmaceutical Sciences (P.D.K.), School of Pharmacy, University of Pittsburgh, Pittsburgh, Pennsylvania; Departments of Medicine (F.J.K.) and Pharmacology (I.J.R.), School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Clinical Pharmacokinetics, The Upjohn Company, Kalamazoo, Michigan (C.E.W.); and Novum Inc., Pharmaceutical Research Services, Pittsburgh, Pennsylvania (R.B.S.)
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Abstract |
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 Top
Abstract
Introduction
Methods
Results
Discussion
References
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This study was designed to determine whether age influences sensitivity to alprazolam and/or rate of acute tolerance development to the effects of alprazolam. Three treatments were each separated by 4 weeks. Twenty-five young (ages 22- 35) and 13 elderly (ages 65-75) men received 2 mg of alprazolam/2 min i.v. Blood samples were obtained over 48 hr, and sedative, psychomotor and memory effects were assessed serially for 12 hr. Clearance was lower (P = .05) and elimination t[1/2] was longer (P = .005) in the elderly, but area under the concentration curve to 12 hr and maximum concentration did not differ by age group. Maximum impairment was greater in the elderly for all assessments. Mean EC50 values differed between the elderly (25.3 and 25.0 ng/ml) and the young (39.8 and 36.5 ng/ml) on card sorting and digit symbol substitution, respectively (P < .001). Bolus treatment data were used to individualize doses for the crossover of placebo and alprazolam; infusions were designed to maintain a plateau alprazolam concentration between 1 and 9 hr. Alprazolam concentrations through 12 hr did not differ between the young and elderly. Median t[1/2] for offset of effect for digit symbol substitution was 2.8 hr in the young and 4.9 hr in the elderly (P = .05). Therefore, aging decreases alprazolam clearance and increases sensitivity to effects of alprazolam through a mechanism other than pharmacokinetics; aging also decreases the rate of offset of effect of alprazolam. In addition, the data provide insight into the intensity of initial effect as a determinant of rate of tolerance development.
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Introduction |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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A1,2
report from the Food and Drug Administration by Baum et al.
(1986)
noted that patients 
60 years of age received 66% more prescriptions for sedative-hypnotic benzodiazepines than did patients 40 to 59 years of age. Unfortunately, there is also evidence that the
elderly experience more adverse effects from these drugs (Thompson et al., 1983; Ray et al., 1989). Several groups
of investigators have reported that the increased magnitude of
pharmacological effects such as sedation and memory and psychomotor
impairment observed in the elderly is associated with higher
benzodiazepine plasma concentrations (Greenblatt et al.,
1991; Nikaido et al., 1987; Pomara et al., 1984).
This is supported by studies that demonstrate lower benzodiazepine
clearance in the elderly, as reviewed by Greenblatt et al.
(1989) and reported by Dehlin et al. (1991).
Numerous studies have evaluated the effect of aging on benzodiazepine
response; most have defined elderly as 60 years. Castleden et
al. (1977) reported that psychomotor effects of 10 mg of
nitrazepam were greater than placebo in an elderly population but not
in the young despite similar concentrations measured 12 and 36 hr after
a single oral dose, suggesting an increase in sensitivity with age.
Reidenberg et al. (1978) and Cook et al. (1984)
reported that plasma concentrations of intravenous diazepam required
for sedation in patients undergoing elective cardioversion and
endoscopic procedures, respectively, were as much as 2- to 3-fold lower
in the elderly than in young patients, with a significant inverse relationship between age and dose of diazepam. Other groups
demonstrated that single-dose diazepam 2.5 mg (Pomara et
al., 1985) or 10 mg (Swift et al., 1985) produced
greater memory and psychomotor performance impairment and significantly
higher concentrations of diazepam and desmethyldiazepam in the elderly
than the young. Using logistic regression of the presence or absence of
response to a verbal command, it was recently demonstrated that the
elderly were more sensitive to the hypnotic effects of an intravenous
dose of midazolam (Jacobs et al., 1995). Nikaido et
al. (1990) assessed the effect of single oral doses of alprazolam
and triazolam and found a more prolonged duration of psychomotor
effects in the elderly than in the young. Triazolam was recently
evaluated in young and elderly subjects using psychomotor performance
and sedation measures after a single doses of 0.125 and 0.25 mg;
results indicated that the greater impairment in the elderly than young
subjects could be attributed to higher plasma concentrations rather
than to sensitivity differences (Greenblatt et al., 1991).
From published data it is not possible to determine whether a
receptor-based or other pharmacodynamic change occurs with age separate
from the observed change in pharmacokinetics. Some studies did not
include a young population for comparison (Pomara et al., 1984). Others did not control for potential confounding factors such as
chronic diseases or drug interactions (Castleden et al., 1977; Cook et al., 1984; Reidenberg et al.,
1978). In some cases, no concentration data (Bell et al.,
1987; Nikaido et al., 1990) or very minimal concentration
and assessment data were obtained (Castleden et al., 1977;
Reidenberg et al., 1978; Cook et al., 1984).
Controlling for variability due to gender (Ellinwood et al.,
1984; Kroboth et al., 1985; McAuley et al., 1995)
and race (Kalow et al., 1986) may also be important when
determining the effects of age on drug sensitivity to limit variability
due to factors other than age. None of the previous comparative studies assessed response relative to concentrations of drug to quantify sensitivity in the young and elderly.
Acute tolerance to the psychomotor effects of benzodiazepines such as
diazepam (Ellinwood et al., 1985), triazolam (Kroboth et al., 1993), midazolam (Fleishaker et al.,
1996) and alprazolam (Ellinwood et al., 1985; Kroboth
et al., 1988) is known to occur in humans. Acute or rapid
tolerance is defined as a shortened duration and decreased intensity of
drug effects that occurs within hours after administration (Crabbe
et al., 1979; Frey et al., 1986). The rate of
development of acute tolerance to the psychomotor effects of triazolam
(Kroboth et al., 1993) and alprazolam (Kroboth et
al., 1988) has been quantified in young adult men. Tolerance is
important to the assessment of sensitivity because acute tolerance shifts the effect-concentration curve to the right, causing an apparent
decrease in sensitivity. Thus, a difference in rate of development of
tolerance between young and elderly could account for a difference in
apparent sensitivity.
This study was designed with two major objectives. The first was to
determine whether age influences sensitivity to alprazolam (i.e., to determine whether response is greater in the
elderly after taking into account concentration differences). The
second objective was to determine whether age influences the effect
offset rate (rate of acute tolerance development) of a benzodiazepine. Alprazolam was chosen because it is a widely prescribed
intermediate-acting triazolobenzodiazepine, ranking ninth among all
drugs in total prescriptions dispensed for 1993 (Simonsen, 1994). In
addition, its availability in an intravenous formulation for
experimental use and metabolic profile made it appropriate for use in
this design. Alprazolam is oxidized to less active metabolites that are
rapidly conjugated and appear to have an insignificant role in the
pharmacological activity (Greenblatt and Wright, 1993; Smith et
al., 1984).
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Methods |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Twenty-five young and 13 elderly nonsmoking, healthy white men
gave written informed consent to participate in this study, which was
approved by the University of Pittsburgh Biomedical Institutional
Review Board. Women were excluded because the effects of progesterone
on response to benzodiazepines (McAuley et al., 1995) may
have confounded the effects of aging with changes in hormone
concentrations. All men were screened by history, physical examination,
laboratory, urine drug screen and blood alcohol concentration before
participation. Subjects were excluded if they were taking any chronic
medications (other than a multiple vitamin), had laboratory values that
were abnormal (>10% out of normal range), had physical examination
findings indicating the presence of a chronic disease, had a positive
urine drug screen or blood alcohol level or had a history of
psychiatric illness, drug or alcohol abuse or dependency. Subjects were
also excluded if they had participated in a clinical drug study using
central nervous system drugs within the previous 6 months.
Study design. This three-way crossover study was conducted in two parts. In part 1, all subjects received alprazolam as a rapid (2-min) intravenous infusion in an open-label, single-dose design. Four weeks later, subjects began part 2, which was a randomized two-way double-blind crossover of placebo or an individualized infusion of alprazolam. All treatment days were separated by 28 days. For part 2, the infusion regimen was individualized for each subject to target either a concentration that would produce a 30% psychomotor performance decrement (EC30) predicted from the sigmoid Emax model in the bolus treatment or the maximum maintainable concentration with a dosage limit of 2 mg of alprazolam, whichever was lower.
Subjects were instructed to avoid all medications for 1 week and alcohol and caffeine 48 hr before and throughout the placebo and alprazolam treatment days. Subjects were admitted to the General Clinical Research Center at Montefiore University Hospital (Pittsburgh, PA) on the evening before the study day to allow acclimation to the study environment and for practice of the psychomotor tests. Each was permitted an evening snack and fasted from 10:00 p.m. until a light breakfast was provided at 7:00 a.m. Indwelling catheters were inserted into veins in both forearms before base-line psychomotor testing. At ~8:30 a.m. (0 hr), the administration of alprazolam or placebo was initiated. In part 1 (alprazolam bolus), 2 mg of alprazolam (1 mg/ml concentration of 50% propylene glycol/water) was administered through a catheter over 2 min followed by a normal saline flush. For the alprazolam treatment in part 2 (continuous-infusion treatments), alprazolam 1 mg/ml in 50% propylene glycol (lot #25,704; The Upjohn Co., Kalamazoo, MI) was diluted to a concentration of 10 µg/ml with normal saline solution. A 30-min loading infusion was administered with an IMED pump (ALARIS Medical Systems, Inc. San Diego, CA); this was followed by an infusion designed to maintain the targeted plateau alprazolam concentration throughout the 9-hr study day. For the placebo treatment, an identical-appearing solution containing propylene glycol (lot #26,583; The Upjohn Co.) was diluted and infused in the same manner. Neither the order nor the identification of treatments in part 2 was known by the investigator or subject. For all treatments, subjects were restricted to bed after drug administration for the first 9 hr of the study day with minimal environmental stimulation, including no conversation or radio, television or telephone use. Dietary intake was controlled on the study day and was the same for each subject. Subjects received juice at 11:00 a.m. (2.5 hr) and a light lunch at 12:30 p.m. (4 hr). A standardized dinner was served at ~6:00 p.m. (9.5 hr). In the bolus treatment, subjects were allowed to ambulate after dinner until 1 hr before the 12-hr session in which they again were restricted to bed with environmental limitations until the completion of psychomotor tests. Subjects were discharged the next morning. Subjects were allowed to participate in part 2 if in part 1 (bolus treatment), their MaxOE was >40% from base line (Eo) and if their impairment at 1 hr was25% on at least one of the psychomotor performance tests. These criteria were designed to ensure that in the
continuous-infusion treatment, the rate of offset of effect was slow
enough to be assessed. All 13 elderly but only 13 of 25 young subjects
participated in the continuous-infusion treatments. Ten of the young
did not meet the performance decrement criteria, and 2 withdrew from
the study for personal reasons.
Pharmacokinetic evaluation.
Blood samples of 7 ml each were
obtained in heparinized collection tubes from the opposite forearm
catheter. In the bolus treatment, samples were obtained at time 0 (just
before drug administration) and 5, 10, 20 and 40 min and 1, 1.5, 2, 3.5, 5, 7, 9, 12, 16 and 24 hr after the dose. Subjects returned to
provide two additional samples at ~36 hr (range, 29.5-38.2 hr) and
48 hr (range, 45.6-55.6 hr); actual times were used in the
pharmacokinetic analysis. An additional 5-ml sample was collected
before alprazolam administration for serum protein binding
determination. In part 2, blood samples were obtained at time 0 (just
before initiation of the infusion), at 0.5 hr (end of the loading
infusion) and at 1, 2.5, 4, 5.5, 7 and 9 hr. Samples were centrifuged,
and plasma was harvested and frozen at 
20°C until analysis.
Psychomotor performance, sedation and memory. Subjects practiced the battery of psychomotor tests on four occasions, including the evening before each of the three treatment days, to a plateau of performance defined as no improvement in score on two consecutive trials. Base-line performance was assessed after one practice session on the morning of each treatment. After the alprazolam bolus dose, testing sessions were administered nine times from 20 min to 12 hr. The RMT was administered six times: at 0 and 40 min and 2, 3.5, 5 and 9 hr. Sedation scores were obtained before each blood sample through 12 hr. In the continuous-infusion treatments, the battery of tests was administered at base line plus six times from 1 to 9 hr after initiation of the infusion.
The battery of psychomotor tests used to assess responses consisted of CS, DSST and CPT, which is a computerized Neurobehavioral Evaluation System II test (Baker et al., 1985). The entire battery of
tests takes ~10 min to complete. CS requires subjects to sort a deck
of playing cards by suits as quickly as possible with a maximum of 90 sec allotted to complete the task. DSST is a 90-sec pen-and-paper test
in which subjects are required to draw symbols corresponding to numbers
in a key at the top of the page. Different forms of the DSST were used
for the repeated testing. For CPT, subjects are instructed to press a
control button as quickly as possible to identify the letter "S"
among distractor letters flashed on a computer screen; letters appear
at a rate of 1/1500 msec for 5 min.
Memory was assessed using an adaptation of the RMT (Randt and Brown,
1983) in which subjects are shown seven black-and-white drawings at the
rate of 1/sec; immediately thereafter, subjects are tested on their
ability to recognize those seven drawings in a series of 15 pictures
that includes eight distractors. Different forms of the RMT were used.
Delayed memory recall was tested by presenting five colored pictures of
objects at 2 hr after alprazolam administration; 7 hr later, subjects
are given a questionnaire that asks whether they have seen any colored
pictures of objects. If they have, they are to name the objects.
Sedation was rated by an observer using the NRSS, which ranges from 0 (wide awake and alert) to 4 (soundly sleeping, unable to perform tasks)
(Kroboth et al., 1990).
Assays.
Alprazolam plasma concentrations were determined by
a validated capillary gas chromatographic method using electron capture detection with triazolam as the internal standard. This is a
modification of a previously reported assay (Derry et al.,
1995; Greenblatt et al., 1981). Intra-assay and interassay
variability was 
10% for concentrations of 0.25 to 16 ng/ml. Samples
from 5 min to 12 hr were diluted with blank plasma to attain
concentrations within the detectable range.
). Briefly,
[14C]alprazolam (specific activity, 29.74 mCi/mM; purity,
>95%) was diluted in phosphate buffer (pH 7.4) to a concentration of
~25 ng/ml and dialyzed for 8 hr at 37°C against an equal volume of subject serum obtained before alprazolam administration. The free fraction was calculated by dividing disintegrations/min in the buffer
by those in serum at the end of dialysis. The intraday and interday
variability in free fraction using control serum was 6%. Plasma
obtained during the placebo treatment was not analyzed.
Pharmacokinetic analysis.
Alprazolam plasma
concentration-time data from the bolus treatment was analyzed by
compartmental and noncompartmental methods using PCNONLIN Version 4.2. (1992). For the noncompartmental analysis, 
(linear regression of
terminal points), t[1/2]
(0.693/), AUC0-
(trapezoidal rule + last
concentration/) and clearance
(dose/AUC0-) were determined for each subject. Vd was calculated as
dose/*AUC0-.
AUMC0- was determined by calculating the
area of the concentration*time vs. time plot (linear
trapezoidal rule + last concentration/2), and mean
residence time was determined by
[AUMC0-/AUC0- (infusion time/2)]. Vdss was calculated by
clearance*mean residence time. AUC0-5hr,
AUC0-9hr and AUC0-12hr were also determined
using the linear trapezoidal rule (Yeh and Kwan, 1978). The 5-min
concentration point for each subject was excluded from all analyses
because it often was lower than the 10-min sample or was so high that
it was physiologically unexplainable. A two-compartment model with
micro-rate constants was also used to describe this data; results were
used to individualize the continuous-infusion treatment.
Pharmacodynamic analysis. The CS score is the number of cards sorted per second; DSST score is the number of symbols correctly drawn in 90 sec. CS and DSST percent decrements were calculated by dividing the difference between the base-line and actual score by the base-line score and multiplying by 100, where the maximum possible decrement is 100%. CPT score is the average latency to press a control button (n = 40 Ss; maximum latency, 1500 msec). Percentage decrement was calculated with the following formula:
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Bolus treatment.
Plots of effect-time and
effect-concentration data were made for each subject. The MaxOE and
tMaxOE were determined for each test for each
subject. AUEC values were calculated for each subject using percent
decrement vs. time data from 0 to 9 hr for psychomotor tests
and scores from 0 to 12 hr for NRSS. For RMT data, AUEC (from 0 to 5 hr) was calculated by using the difference between a perfect score area
and the actual score area, which provides a measure of recognition
decrement (Kroboth et al., 1995). The intervals for AUEC
evaluation were chosen to include all subjects in the analysis. Effect
ratios (AUEC/AUC) for each subject were also calculated to correct for
interindividual variation in concentration during the time of
pharmacodynamic evaluation.
) was fit to data from DSST, CS, and CPT. The
inhibitory sigmoid Emax model (Holford and Sheiner, 1981)
was also fit to scores from individual subjects for DSST and CS. The
equation for the latter model is:
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Continuous-infusion treatment.
The target psychomotor
decrement for each subject was 30% decrease from baseline based on
data from the bolus treatment. To determine the accuracy of prediction
and quantify the rate of tolerance development to each psychomotor
performance test, percent decrement was calculated for each time. The
data for each subject for DSST, CS and CPT in the alprazolam treatment
were plotted on a semilogarithmic scale. A tolerance rate constant or
effect offset rate constant (kt) was
determined for individual subjects using natural log-linear regression
of the data from 1 through 9 hr or through the time that the score
returned to base line, whichever occurred first (Kroboth et
al., 1993). The kt is the slope
of the resulting regression analysis; the corresponding half-life for
offset of effect (t[1/2]t) is
0.693/kt. Scores were considered to
be at base line when they were within 10% of base line; these
decrements are a conservative estimate of the observed variability in
these tests. For any score 0% decrement from base line, a natural
log value of 0 (equivalent to a 1% change from base line) was assigned
to allow inclusion of that point in the regression. Regression analysis
was performed on subject data that included a performance decrement of
25%, provided visual evidence of a decline in performance decrement over time and included at least three data points for the regression. A
quadratic term was added to the regression to assess whether there was
an improvement in model fit.
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4 of a possible 7 were categorized as
significant impairment; for sedation, NRSS ratings of 3 were
considered significant sedation. The proportion of patients with
significant impairment was calculated at each assessment time, and a
logistic transformation was performed. A slope and intercept were
calculated using linear regression of the logistic transformation of
the proportion of patients with significant impairment vs.
time. A predicted probability curve of significant impairment at a
given time was then generated for the young and elderly.
Statistical analysis.
Pharmacokinetic parameter estimates
were assessed for differences between groups using one-way analysis of
variance. Repeated measures analysis of variance was used to assess
differences in repeated assessments. Duncan's post hoc test
was used to assess specific differences when indicated. Parameter
estimates from the inhibitory sigmoid Emax model were
compared using the nonparametric Mann-Whitney U test with
the two-group t test approximation because of unequal
variances. All analyses were performed using SAS Version 6.03 (1985).
Differences were considered significant if P .05.
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Results |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Twenty-five young and 13 elderly healthy men completed the alprazolam bolus treatment. Unless otherwise specified, results are based on these 38 subjects. The mean age was 27.5 years (range, 22-35 years) in the young and 68.2 years (range, 65-75 years) in the elderly; mean weight was 77.9 kg (range, 61.2-98.6 kg) for young and 80.2 kg (range, 62.2-106.3 kg) for elderly subjects. In the continuous-infusion treatments, there were 13 young and 13 elderly men. All had participated in the bolus treatment 28 days earlier.
Adverse effects were minor and required no intervention; effects included burning on injection (two), dizziness (one), nausea (one) and hiccups (seven). Drowsiness and sleep also occurred and is reported in the NRSS data. Pulse, respirations and blood pressure were monitored throughout the study day and remained stable in all subjects, with little deviation from prealprazolam values.
Pharmacokinetics.
Figure 1 demonstrates mean
concentration-time plots for the alprazolam bolus (fig. 1A) and
infusion (fig. 1B) treatments for each age group. Table
1 summarizes mean pharmacokinetic parameter estimates
for the young and elderly in the bolus treatment.
AUC0-12hr and Cmax values illustrate that mean
concentrations did not differ between groups over the 12 hr of effect
assessments. However, data from the entire 48 hr of sampling (fig. 1A,
insert) indicate that the elderly have a slower clearance and longer
t[1/2], which would result in
increased steady-state concentrations and longer time to steady state
during chronic treatment.
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Pharmacodynamics in the bolus treatment.
Figure
2A is a plot of DSST score vs. time in the
bolus treatment. CS, CPT, NRSS and RMT data from the bolus treatment
are summarized in table 2. Predose base-line
(Eo) and MaxOE values for all psychomotor performance tests
are presented in table 3 for young and elderly.
Impairment is indicated by a lower score on CS (cards/sec), DSST
(symbols) and RMT (pictures recognized); a higher score on CPT (latency
in msec) indicates impairment. Nearly all (12 of 13) elderly but only 5 of 25 young had a performance decrement of 75% on at least one
psychomotor test.
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0.3%
(range, 25.0% to 16.7%) in the young and 13.2% (range, 9.3% to
32.0%, P = .004) in the elderly (see fig. 2A). Despite similar
concentrations, only 3 of 10 elderly had decrements of <10% at 12 hr
vs. 20 of 22 young. CPT latency returned to base line in the
22 young (1.05%) and 10 elderly (0.35%) in whom performance was
assessed at 12 hr (P = .27). For CS, mean decrements at 12 hr were
9.6% in the young and 13.2% in the elderly (P = .51).
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Pharmacodynamics in the continuous-infusion treatments.
Figure
2, B and C, shows DSST score vs. time data for the
continuous-infusion treatments of alprazolam and placebo, respectively. Tables 6 and 7 summarize response data
from the young and elderly men after the continuous-infusion and
placebo treatments, respectively. Figure 2C demonstrates the stability
of DSST scores during the placebo treatment day in young and elderly
subjects; placebo CPT and CS data show similar stability (table
7). Repeated-measures analysis of variance revealed that
there was no effect due to time or to a group-by-time interaction for
any psychomotor test (P .26); thus, time did not influence
performance scores in either group during the placebo treatment. On the
RMT, no subject had a score 4 of 7 in either age group at any time on
the placebo day.
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) represents no
evidence of effect offset. In two elderly subjects, there was no
evidence of offset of effect during the continuous infusion; one
subject did not develop tolerance to DSST impairment, and another did
not develop tolerance to CS impairment. Repeated-measures analysis of
variance showed significant group-by-time interaction for DSST (P = .02) but not CS (P = .17). Trend analysis of the DSST
interaction term showed that the linear component was significant
(P = .05), whereas the higher-order quadratic component was not
(P = .95). Thus, adding a quadratic term to the offset rate
regression model did not significantly improve the model fit. Because
the MaxOE value for CPT during continuous infusion was low and subjects
returned rapidly to base line (<5% decrement in 20 of 26 subjects by
4 hr), mathematical determination of effect offset rate constant was
precluded for CPT data.
Figure 4, A and B, shows mean percent recovery during
the alprazolam continuous infusion. The figures demonstrate apparent biphasic recovery, with a similar rate of recovery in the young and the
elderly through 4 hr and slowing at 5.5 and 7 hr in the elderly. There
were no differences in percent recovery at any time point between the
young and elderly for CS (P > .05). Recovery differences were
evident at the 5.5- and 7-hr time points for DSST with average
recoveries of 42.0% and 37.3%, respectively, in the elderly and
64.5% and 61.7% in the young (P .04 for both times). The
group-by-time interaction term approached significance for DSST (P = .115) but not for CS (P = .209). Trend analysis showed the
linear (P = .067) but not the quadratic (P = .485) component
of the DSST interaction was significant.
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Discussion |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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The data from this study demonstrate that age influences both the pharmacokinetics and pharmacodynamics of alprazolam. In addition to decreasing alprazolam clearance, age increases sensitivity to the psychomotor, sedative and memory effects of alprazolam through a mechanism other than increased concentrations. Age also decreases the rate of offset of effect of the psychomotor, memory and sedative effects of alprazolam. Additionally, the data provide insight about the intensity of initial effect as a determinant of rate of tolerance development.
An important but unsurprising observation is the lower performance
scores in the elderly in the absence of drug (base line and placebo).
Hinrichs and Ghoneim (1987) reported that lower performance scores are
evidence for homeostatic changes with aging present in the absence of
drug. In the presence of alprazolam, our data show that the elderly
experience greater impairment than young men: the elderly have lower
absolute performance scores, greater absolute decrements in scores and
greater percentage decrements than do young subjects at equivalent
concentrations.
Pharmacokinetics and sensitivity.
Although there is a lower
clearance and a longer t[1/2]
in the elderly men, these differences do not explain the increased
psychomotor effects observed after bolus alprazolam administration.
Mean plasma alprazolam concentrations are similar in the young and
elderly during the first 12 hr; in contrast, memory and psychomotor
performance impairment as well as sedation are greater in the elderly.
Furthermore, when response is corrected for individual variability in
alprazolam concentration and for differences in base-line scores
between young and elderly using AUEC/AUC, the elderly have higher
ratios than the young; effect-concentration modeling with either the
linear or the sigmoid Emax model shows a greater response
through the range of alprazolam concentrations.
. The elderly are more sensitive to
the effects of scopalamine (although concentrations were not obtained)
(Molchan et al., 1992) and diazepam (Reidenberg et
al., 1978) but less sensitive to the effects of propranolol (Feely
and Stevenson, 1979). The elderly also showed less suppression of
endogenous cortisol despite higher concentrations of prednisolone (Stuck et al., 1988). Thus, generalizations about the
influence of aging on sensitivity to drugs cannot be made.
Pharmacokinetics and evidence for tolerance. Despite the maintenance of plateau concentrations of alprazolam during the continuous infusion, subjects demonstrated a gradual improvement in psychomotor performance and memory and an offset of sedation after 1 hr. This pattern of response can be explained by the development of acute functional tolerance.
Before accepting tolerance as the explanation for declining effect in the presence of plateau alprazolam concentrations, a pharmacokinetic explanation for improvement in scores over time was considered. To achieve relatively stable plasma concentrations within 1 hr, a 30-min loading infusion followed by a continuous infusion (for 8.5 hr) was administered. This regimen resulted in plasma concentrations at 30 min that were higher than the target. To project the potential impact of these concentrations on brain concentrations, simulations were done using mean two compartment pharmacokinetic parameter estimates from the bolus treatment for young and elderly subjects. The results indicate that equilibrium between the central (plasma) and peripheral (brain) compartments is achieved before 2.5 hr and that the concentration peak evident in the plasma compartment is not observed in the peripheral (brain) compartment; concentrations would theoretically increase slowly in the peripheral compartment to reach the plateau by 2.5 hr. In contrast, the observed decline in psychomotor response continues through 9 hr. Therefore, improvement in performance over time and differences between the young and elderly do not appear to be explained by pharmacokinetics and are consistent with development of tolerance. Development of acute tolerance causes the effect-concentration curve to shift to the right and results in a higher apparent EC50 value (Kroboth et al., 1993; Porchet et al.,
1988). Thus, slower development of tolerance in the elderly could
explain some of the increased sensitivity to benzodiazepines with age.
In this study, there was no way to assess the hypothesis that acute
tolerance can be explained by redistribution of benzodiazepines from
the central nervous system to peripheral tissues (Greenblatt et
al., 1990).
Tolerance and aging. The data from this study suggest that the elderly develop acute tolerance to alprazolam effects more slowly than the young. Again, alprazolam concentrations do not explain the observations because there were no significant differences in concentrations between the young and elderly at any time point during the continuous infusion. This study was designed so that the young and elderly would achieve the same level of initial psychomotor decrement (MaxOE) during the alprazolam continuous-infusion treatment. This was achieved with DSST and CPT. Despite the fact that MaxOE for DSST was similar in young and in elderly men, the MnE1-9hr was greater in the elderly (table 8). In addition, the elderly have a shallower slope of the regression line for offset of effect (kt) and a longer t[1/2]t (table 8), and they recovered function more slowly than the young (fig. 4A). Furthermore, the only two subjects who did not show any evidence of offset of effect during the alprazolam continuous infusion were elderly. As stated earlier, the offset of CPT effect occurred too rapidly to allow mathematical evaluation (MnE1-9hr <8% for both young and elderly men). CS results are discussed in the section on intensity of effect. The elderly also had a slower offset of effect of sedation and memory impairment (fig. 5).
The stability of DSST, CS and CPT scores during the placebo treatment in young or elderly men (fig. 2C and table 7) indicates that the age groups were equivalent in achieving a true base line during training. Practice effects were minimized. However, two factors can contribute to the observed apparent tolerance: age-related receptor-mediated changes and age-related differences in learning to adapt to drug-induced impairment during repeated testing. Published reports support the observation that tolerance develops more slowly with aging. In a study in rats, Stijnen et al. (1992)
assessed the effect of age on the time course of anticonvulsant response after a single intravenous bolus of oxazepam and found a
biphasic response of anticonvulsant effect followed by a proconvulsant effect in young, but not in aged (35-month-old), BN/BiRij rats. The
investigators attributed the results to the absence of a
tolerance/withdrawal phenomena with aging. Other investigators have
suggested that the elderly may have an altered homeostatic reserve
(Feely and Coakley, 1990; Swift, 1990), to which differences in
sensitivity and tolerance development may both be attributed. The
elderly may not be able to compensate as readily for the effects of
benzodiazepines on cognitive function, coordination and motor skills,
an adaptation that may involve the many steps after receptor binding
and activation. Nikaido et al. (1990) reported longer drug
effect half-lives in the elderly than in the young after the
administration of triazolam and alprazolam and indicated consistency of
their data with an age-related decline in adaptive capacity to inhibit
adverse drug effects. We have observed that psychomotor performance of
healthy elderly men did not return to base line during four days of
multiple-dose alprazolam (Kroboth et al., 1990); this
contrasts with results in the young in a similar 4-day study (Smith and
Kroboth, 1987). Together, the results of the latter two studies in
humans suggest that chronic tolerance to alprazolam also develops more
slowly in the elderly than in the young. The present study is the first to attempt to quantify and compare rates of offset (tolerance) of acute
benzodiazepine effects in the young and elderly while drug
concentrations were maintained constant.
The mechanism of tolerance development to benzodiazepines is poorly
understood. Although acute functional tolerance occurs within hours and
maximally within 1 day (Crabbe et al., 1979; Frey et
al., 1986; Haefley, 1986; Jaffe, 1990), chronic tolerance develops
over days or weeks of continuous drug use (Jaffe, 1990); the latter has
been studied more extensively. Investigators have reported
benzodiazepine receptor down-regulation and a decrease in chloride ion
flux (Miller et al., 1989), a change in the setpoint of the
benzodiazepine receptor with chronic agonist exposure (Nutt et
al., 1992) and an uncoupling of benzodiazepine binding to
GABAA receptor (Nutt et al., 1992). Studies
supporting the setpoint theory have shown an attenuation of chronic
tolerance development when the antagonist flumazenil is administered
(Gonsalves and Gallager, 1988) or a partial, rather than a full
agonist, is administered (Hernandez et al., 1989). All of
these effects take several days or weeks to develop. Changes that occur
in acute tolerance have not been apparent in receptor binding and
functional studies in animals. Despite probable mechanistic
differences, acute tolerance has been used to predict chronic tolerance
and cross-tolerance between ethanol and pentobarbital in rats,
suggesting that these forms of tolerance may be related (Khanna
et al., 1991).
Tolerance and intensity of effect. Two separate observations from the bolus and continuous-infusion treatments lead to the generation of a hypothesis that the greater the intensity of initial effect, the more rapidly is tolerance developed. First, in the bolus treatment, the elderly had a greater psychomotor decrement and a significantly steeper slope of the effect vs. concentration curve (slope and s, depending on model).
The second observation is from the continuous-infusion treatment. When MaxOE was the same in the two groups (DSST), the elderly had a slower offset of effect than the young. When MaxOE was higher in the elderly (CS), the offset of effect occurred at a similar rate in the two groups. Thus, the higher CS MaxOE in the elderly may have masked a difference between the young and elderly in offset of effect. To rigorously evaluate this hypothesis, a study that is designed to assess the offset of effect with different initial intensities of effect is needed. The literature also suggests that initial effect intensity influences the rate of tolerance development. When triazolam was given by continuous rectal infusion to healthy subjects, concentrations rose slowly until steady state was achieved at ~8 to 10 hr; tolerance was not noted until the second day of administration (Breimer et al., 1985). Kroboth et al. (1993) have shown in a
crossover study of young men that relative to a bolus dose, infusion of intravenous triazolam over 9 hr increases apparent sensitivity to
psychomotor effects; the higher intensity of initial effect after the
bolus dose appears to result in more rapid development of tolerance to
benzodiazepine effects than does slow administration. These
benzodiazepine data are also consistent with morphine data in rabbits.
Hovac and Weinstock (1987) demonstrated that increasing the dosage of
morphine, and thus the degree of initial intensity of effect, results
in an accelerated rate of acute tolerance development to cardiovascular
and respiratory effects of morphine.
Although a difference in effect intensity is a plausible and likely
explanation for the disparate results of DSST and CS in the young and
elderly, an alternative exists. Nine hours may not have been long
enough to realize potential differences in CS between the young and
elderly. For reasons that are not clear, the estimated t[1/2]t for CS in the young (5.5 hr) was nearly twice that of DSST (2.8 hr). For CS, <60% recovery in
psychomotor function was evident for both the young and the elderly at
9 hr; differences between the young and elderly on DSST were not
apparent until recovery reached ~50%.
Conclusions and implications. Based on the data from this study, the elderly would be more impaired than the young during treatment with alprazolam for two reasons: (1) higher alprazolam concentrations during chronic treatment and (2) greater sensitivity coupled with slower offset of effect. To estimate the clinical impact of these differences during a treatment regimen of 0.5 mg of alprazolam orally every 6 hr, steady-state concentrations and corresponding psychomotor impairment were calculated for young and elderly. Predicted average steady-state concentrations (using mean clearance data and assuming 90% bioavailability) are 16.7 and 20.3 ng/ml in the young and elderly, respectively. The corresponding decrements at these concentrations (from the sigmoid Emax model and mean CS data) are 11.8% in the young and 28.7% in the elderly. In other words, although mean steady-state concentrations for the elderly would be ~1.2-fold higher than in the young, psychomotor performance decrement would be 2.4-fold higher. The estimate of psychomotor decrement does not take into account the tolerance development and therefore is more accurate for potential age-related differences at the initiation of therapy. The effect of aging on the therapeutic effect is uncertain, as is the presence of anxiety on psychomotor impairment. However, low doses and caution should be used while titrating response in the elderly.
This study also shows that aging is associated with a slower rate of acute tolerance development, which in turn could explain some of the differences in sensitivity between the young and elderly. Furthermore, the data also indicate that in addition to aging, initial effect intensity may also influence the rate of tolerance development. To define more clearly the impact of MaxOE on tolerance development rate, future studies should be done that target specific different intensities of performance decrement during a pseudo-steady state infusion. To accomplish those objectives, doses larger than those used in this study would be needed, however, because 2 mg/9 hr achieved a mean impairment of only ~30% during the 9 hr. Other, theoretically more specific measures of central nervous system function such as electroencephalography and saccadic eye movement should be included. In addition, first-order rather than zero-order infusion pumps should be used to avoid peak concentrations higher than the targeted concentration.| |
Acknowledgments |
|---|
The authors would like to thank Sharon E. Corey, Ph.D., for her help with the alprazolam concentration analysis and the staff from the General Clinical Research Center of the University of Pittsburgh Medical Center (Pittsburgh, PA) for their assistance during the study. We also acknowledge the statistical advice from Saul Schiffman, Ph.D., and the assistance of Susan Price and Janie Bradish in the preparation of this manuscript.
| |
Footnotes |
|---|
Accepted for publication February 5, 1997.
Received for publication July 11, 1996.
1 This research was sponsored by The Upjohn Company and by NIH/NCRR/GCRC Grant 5-M01-RR00056 and was presented in two parts at the American Society for Clinical Pharmacology and Therapeutics (ASCPT) annual meetings in March 1994 and March 1995.
2 Fellow of the American Foundation for Pharmaceutical Education. Present address: Abbott Laboratories, Research Pharmacokineticist, Department of Pharmacokinetics and Biopharmaceutics.
Send reprint requests to: Patricia D. Kroboth, Ph.D., University of Pittsburgh/Pharmacodynamic Research Center, 904 Salk Hall, Pittsburgh, PA 15261
| |
Abbreviations |
|---|
AUC, area under the plasma concentration curve;
AUEC, area under the effect curve;
CS, card sorting task;
CPT, continuous performance test;
DSST, digit symbol substitution test;
EC50, concentration that elicits half-maximal response;
Eo, baseline;
kt, tolerance rate constant or effect offset rate constant;
MaxOE, maximum
observed effect;
Mn1-9hr, mean alprazolam concentration
from 1 to 9 hr;
MnE1-9hr, mean effect from 1 to 9 hr;
NRSS, nurse-rated sedation score;
RMT, Randt Memory Test;
tMaxOE, time to maximum effect;
t[1/2], half-life for
elimination of drug;
t[1/2]t, half-life for offset of effect.
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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) and elderly (
) men after a 2 mg/2 min i.v. dose through
the time of last pharmacodynamic assessment at 12 hr and through 48 hr (insert). Error bars represent S.D. B, Concentrations at the end of the
loading infusion (0.5 hr) and during the time of performance testing
from 1 to 9 hr in the alprazolam continuous-infusion treatment in young
(
) and elderly (
)
and elderly (