DRUG DISPOSITION Clin Pharmacokinet 2002; 41 (10): 719-739

0312-5963/02/0010-0719/$25.00/0

© Adis International Limited. All rights reserved.

Clinical Pharmacokinetics and

Pharmacodynamics of
Cholinesterase Inhibitors
Michael W. Jann,1 Kara L. Shirley1,2 and Gary W. Small 3
1 Department of Clinical and Administrative Sciences, Southern School of Pharmacy,
Mercer University, Atlanta, Georgia, USA
2 Department of Pharmacy Practice, Albany College of Pharmacy, Albany, New York, USA
3 Department of Psychiatry and Biobehavioral Sciences, Center on Aging and Alzheimer’s Disease
Research Center, University of California, Los Angeles, California, USA

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 720
1. Pharmacokinetic Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 721
1.1 Tacrine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 721
1.1.1 Absorption, Bioavailability and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . 721
1.1.2 Metabolism and Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 723
1.1.3 Effects of Age, Hepatic and Renal Impairment . . . . . . . . . . . . . . . . . . . . . . . 723
1.2 Donepezil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 723
1.2.1 Absorption, Bioavailability and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . 723
1.2.2 Metabolism and Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 724
1.2.3 Effects of Age, Hepatic and Renal Impairment . . . . . . . . . . . . . . . . . . . . . . . 724
1.3 Rivastigmine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 724
1.3.1 Absorption, Bioavailability and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . 724
1.3.2 Metabolism and Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 725
1.3.3 Effects of Age, Hepatic and Renal Impairment . . . . . . . . . . . . . . . . . . . . . . . 725
1.4 Galantamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 725
1.4.1 Absorption, Bioavailability and Distribution . . . . . . . . . . . . . . . . . . . . . . . . . . 725
1.4.2 Metabolism and Elimination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 725
1.4.3 Effects of Age and Hepatic or Renal Impairment . . . . . . . . . . . . . . . . . . . . . . 726
2. Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 726
2.1 Tacrine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 726
2.1.1 Influence of Cytochrome P450 1A2 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 726
2.1.2 Cimetidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 726
2.1.3 Hormone Replacement Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 727
2.1.4 Fluvoxamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 727
2.1.5 Theophylline . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 727
2.2 Donepezil . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 727
2.2.1 Cimetidine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 727
2.2.2 Digoxin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 727
2.2.3 Ketoconazole . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 727
2.2.4 Psychotropic Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 728
2.2.5 Theophylline and Warfarin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 728
2.3 Rivastigmine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 728
720 Jann et al.

2.4 Galantamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 728

3. Pharmacological Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 729
3.1 Reversible versus Irreversible Inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 729
3.2 Acetylcholinesterase versus Butyrylcholinesterase Inhibition . . . . . . . . . . . . . . . . . . . 729
3.3 Dose versus Cholinesterase Inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 730
4. Pharmacodynamic Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 731
4.1 Clinical Efficacy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 731
4.1.1 Clinical Rating Scales . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 731
4.1.2 Correlation of Clinical Efficacy, Dose and Enzyme Inhibition . . . . . . . . . . . . . . . . 732
4.1.3 Effects on Behavioural Symptoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 733
4.1.4 Imaging Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 734
4.2 Adverse Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 735
4.2.1 Dose-Dependent Effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 735
4.2.2 Dose Titration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 735
4.2.3 Serum Concentration Relationships . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 736
4.2.4 Hepatotoxicity with Tacrine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 736
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 737

Abstract Cholinesterase inhibitors are the ‘first-line’ agents in the treatment of Alz-
heimer’s disease. This article presents the latest information on their pharmaco-
kinetic properties and pharmacodynamic activity.
Tacrine was the first cholinesterase inhibitor approved by regulatory agencies,
followed by donepezil, rivastigmine and recently galantamine. With the excep-
tion of low doses of tacrine, the cholinesterase inhibitors exhibit a linear relation-
ship between dose and area under the plasma concentration-time curve.
Cholinesterase inhibitors are rapidly absorbed through the gastrointestinal tract,
with time to peak concentration usually less than 2 hours; donepezil has the
longest absorption time of 3 to 5 hours. Donepezil and tacrine are highly protein
bound, whereas protein binding of rivastigmine and galantamine is less than 40%.
Tacrine is metabolised by hepatic cytochrome P450 (CYP) 1A2, and donepezil
and galantamine are metabolised by CYP3A4 and CYP2D6. Rivastigmine is
metabolised by sulfate conjugation.
Two cholinesterase enzymes are present in the body, acetylcholinesterase
(AChE) and butyrylcholinesterase (BChE). Tacrine and rivastigmine inhibit both
enzymes, whereas donepezil and galantamine specifically inhibit AChE.
Galantamine also modulates nicotine receptors, thereby enhancing acetyl-
cholinergic activity at the synapse. These different pharmacological profiles pro-
vide distinctions between these agents. Cholinesterase inhibitors show a nonlinear
relationship between dose and cholinesterase inhibition, where a plateau effect
occurs. Cholinesterase inhibitors display a different profile as each agent achieves
its plateau at different doses.
In clinical trials, cholinesterase inhibitors demonstrate a dose-dependent effect
on cognition and functional activities. Improvement in behavioural symptoms
also occurs, but without a dose-response relationship. Gastrointestinal adverse
events are dose-related. Clinical improvement occurs with between 40 and 70%
inhibition of cholinesterase. A conceptual model for cholinesterase inhibitors has
been proposed, linking enzyme inhibition, clinical efficacy and adverse effects.
Currently, measurement of enzyme inhibition is used as the biomarker for cho-

© Adis International Limited. All rights reserved. Clin Pharmacokinet 2002; 41 (10)
Cholinesterase Inhibitors 721

linesterase inhibitors. New approaches to determining the efficacy of cholines-

terase inhibitors in the brain could involve the use of various imaging techniques.
The knowledge base for the pharmacokinetics and pharmacodynamics of cho-
linesterase inhibitors continues to expand. The increased information available
to clinicians can optimise the use of these agents in the management of patients
with Alzheimer’s disease.

Alzheimer’s disease (AD) is a chronic neuro-
degenerative disorder that causes decline in cogni-
tive function, behavioural disturbances and wors-
ening of the ability to perform daily activities.
Over the past decade, a tremendous amount of
progress has been made in identifying the molecu-
lar origins of this disease and its genetic linkage.[1]
However, despite these advances, a cure for this
disease remains to be found and, as for many
chronic diseases, medications currently available
treat the symptoms of AD with an overall goal of
maintaining functional and cognitive ability and
improving behavioural disturbances.
Many different therapeutic approaches to AD
have been investigated, including antioxidants,
anti-inflammatory agents, calcium channel antag-
onists, and muscarinic and nicotinic agonists.[2-7]
The use of these agents stems from the heteroge-
neous aetiologies associated with the disease. The
cholinergic hypothesis of AD was proposed over
20 years ago, and deterioration of cholinergic neu-
rons over time for various biological reasons re-
mains a consistent finding.[8]
Only one class of medications has been exten-
sively evaluated in placebo-controlled trials with
AD patients and is approved by the US Food and
Drug Administration (FDA) and other governmen-
tal agencies for the treatment of AD. These medi-
cations are the cholinesterase inhibitors (figure 1).
Basically, cholinesterase inhibitors prevent the
breakdown of acetylcholine by inhibiting the ac-
tivity of cholinesterase enzymes that metabolise
acetylcholine. These enzymes are known as acetyl-
cholinesterase (AChE) and butyrylcholinesterase
(BChE).[9]
Tacrine was the first cholinesterase inhibitor
approved in the US and Europe, followed by
donepezil, rivastigmine and galantamine. The aim
of this paper is to compare the cholinesterase in-
hibitors in detail with respect to their pharmaco-
kinetic, pharmacological and pharmacodynamic
properties. Eptastigmine will be discussed only
briefly in supporting the concept of cholinesterase
inhibitors. Other cholinesterase inhibitors, such as
metrifonate, physostigmine and velnacrine, have
been investigated clinically; however, these agents
were not approved by regulatory agencies because
of safety issues and will not be extensively dis-
cussed in this paper.
1. Pharmacokinetic Aspects
A summary of the pharmacokinetic parameters
of the cholinesterase inhibitors is presented in table
I. With the exception of donepezil, most cholines-
terase inhibitors are rapidly absorbed and possess
elimination half-lives of ≤12 hours.[10] The phar-
macokinetics and pharmacodynamics vary be-
tween these agents which results in different dos-
ing regimens or the rationale for switching drugs
during treatment. Cholinesterase inhibitors usually
display dose-dependent linear pharmacokinetics;
however, specific details are provided on each
agent in subsequent sections.
1.1 Tacrine
Tacrine was the first medication approved by
the FDA for the treatment of Alzheimer’s disease.
Although tacrine improved psychomotor test scores
in mild to moderately impaired patients, adverse
effects were frequent and significantly elevated he-
patic transaminase levels occurred in approxi-
mately 25% of patients.[12]
1.1.1 Absorption, Bioavailability and Distribution
The pharmacokinetic properties of tacrine have
been evaluated following short- and long-term ad-
ministration.[13-16] Large interindividual variations
exist in the pharmacokinetic profile of tacrine, which

© Adis International Limited. All rights reserved. Clin Pharmacokinet 2002; 41 (10)
722 Jann et al.

NH2
CH3
N O
C

O
N N N

Tacrine Eptastigmine C C

CH3 O CH3
O
N O
OH CH3

N CH3
CH3 N
CH3 CH3

Galantamine Rivastigmine

OCH3

N OCH3
O

Donepezil

Fig. 1. Structure of the current cholinesterase inhibitors used in the treatment of Alzheimer’s disease.

affect both efficacy and occurrence of adverse
events. The bioavailability of tacrine ranges from
17 to 37%.[17,18]
The rate and extent [area under the concentra-
tion-time curve (AUC)] of absorption of tacrine is
decreased by about 25% when it is given with food
or within 2 hours after food intake.[12,18] When
taken 1 hour before meals, absorption is not af-
fected. In patients with AD, time to reach peak
plasma concentration (tmax) was 0.5 to 3.0 hours
following oral administration. Tacrine appears to
have a wide tissue distribution, which is reflected
by its large volume of distribution of 3.7 to 5.0
L/kg.[19] Tacrine has also been found to be about
75% bound to plasma proteins (42% for albumin
and 23% for α1-acid glycoprotein).[20]
Tacrine concentrations were compared between
plasma and cerebrospinal fluid (CSF) in seven pa-
tients with AD.[21] Tacrine dosages ranged be-
tween 40 and 140 mg/day. Mean plasma and CSF
concentrations were 8.01 ± 7.07 and 5.21 ± 6.00
μg/L, respectively. The mean ratio of CSF to plas-
ma concentrations was 0.50 ± 0.45, with no rela-
tionship to dose.
Nonlinear disposition at low doses may also
contribute towards the wide interpatient variability
of tacrine. In comparing single doses of 25 and
50mg, their respective mean AUCs were 29.0 ± 6.0
and 83.2 ± 26.7 μg • h/L.[14] With repeated 50mg
doses given three times a day for 1 month, the mean
AUC after the last morning dose was 143.6 ± 68.4
μg • h/L. In another study comparing tacrine dos-
age and AUC under steady-state conditions, it was
found that the mean (SD not provided) AUC in-
creased from 19.7 to 82.9 μg • h/L for dosages of
40 and 80 mg/day, respectively. A smaller increase

© Adis International Limited. All rights reserved. Clin Pharmacokinet 2002; 41 (10)
Cholinesterase Inhibitors
in AUC, up to 139.0 μg • h/L, was noted for the
120 mg/day dosage.[15] Although the mechanism
of the nonlinear metabolism is uncertain, it was
suggested that the lower bioavailability at lower
doses may reflect saturable hepatic first-pass in-
take of tacrine.[15,17]
1.1.2 Metabolism and Elimination
Tacrine is rapidly and extensively metabolised
by cytochrome P450 (CYP) isoenzymes 1A2 and
2D6. Five major metabolites have been found in
serum and urine.[19] Tacrine reactive metabolites
then undergo glutathione conjugation.[22] The pre-
sence of genetic deficiencies in the glutathione S-
transferase system was found to increase suscepti-
bility to tacrine hepatotoxicity in patients with
mild to moderate AD.[22] The elimination half-life
(t1⁄2β) of tacrine has been observed to range from
1.3 to 7 hours in patients with AD,[14,15,17,18] and
most investigators agree on a value of about 4
hours.[13,23]
The major tacrine metabolites include phenol
tacrines and 1-, 2-, 4- and 7-hydroxy-tacrine.[17]
The major metabolite, 1-hydroxy-tacrine, is pres-
ent in plasma and is found in the CSF at a concen-
tration 10 times higher than that of tacrine.[18] The
t1⁄2β of the 1-hydroxy-tacrine metabolite appears to
be similar to that of the parent compound.[17] Its
formation and elimination are stereospecific,
favouring the dextrorotary isomer. The metabo-
lism of 1-hydroxy-tacrine to dihydroxy-tacrines
appears to be nonstereospecific.[17] The 1-hydroxy-
tacrine metabolite (which was under development
as velnacrine at the time) can produce clinical ef-
fects through additional inhibition of cholinester-
ase.[24]
Table I. Summary of the pharmacokinetic parameters of the cholinesterase inhibitors[11]
Drug Bioavailabilty (%) tmax (h)
Tacrine 17-37 0.5-3.0
Donepezil 100 3-5
Rivastigmine 40 0.8-1.7
Galantamine 85-100 0.5-1.5
CYP = cytochrome P450; tmax = time to maximum serum concentration.
© Adis International Limited. All rights reserved.
723
1.1.3 Effects of Age, Hepatic and
Renal Impairment
Tacrine pharmacokinetics were reported to be
unaffected in elderly patients with renal insuffi-
ciency.[12] Because of the hepatotoxicity of tacr-
ine, most clinicians agree that patients with hepatic
impairment would not be suitable candidates for
treatment.
1.2 Donepezil
Donepezil was the next cholinesterase inhibitor
to be available. Donepezil is a selective reversible
inhibitor for AChE rather than BChE, as shown by
comparison with tacrine and physostigmine in in
vitro and ex vivo rat studies.[25]
1.2.1 Absorption, Bioavailability and Distribution
After oral administration, peak plasma done-
pezil concentrations are achieved after 3 to 5 hours
(table I), which is longer than for other cholines-
terase inhibitors. Food does not affect its absorp-
tion rate, Cmax, tmax or AUC. The relationship be-
tween donepezil dose and AUC is linear over the
dosage range 1 to 10 mg/day.[26,27] Under steady-
state conditions, the mean AUCs for the 1, 3 and
5mg doses were 118.5 ± 52.3, 357.7 ± 64.0 and
546.0 ± 52.6 μg • h/L, respectively.[28] Under clini-
cal trial conditions, mean trough (Cmin) plasma
drug concentrations were 25.9 ± 0.7 and 50.6 ± 1.9
μg/L with therapeutic doses of 5 and 10mg, respec-
tively.[29]
Donepezil clearance is independent of dose, as
observed in short- or long-term administration in
volunteers.[27,28] Information concerning the dis-
tribution of donepezil, particularly in the CNS as
measured by CSF concentrations, is not available.
Donepezil is highly protein bound (96%; 75% to
Protein binding Elimination Hepatic metabolism Linear/nonlinear
(%) half-life (h)
75 1.3-7.0 CYP1A2, CYP 2D6 Nonlinear
96 60-90 CYP2D6, CYP3A4 Linear
40 2 Nonhepatic Linear
18 5-7 CYP2D6, CYP3A4 Linear
Clin Pharmacokinet 2002; 41 (10)
724
albumin and 21% to α1-acid glycoprotein).[26]
Steady-state pharmacokinetics of donepezil are
reached within 14 to 22 days after repeated admin-
istration of 5 or 10mg for 21 or 28 days.[27,28]
1.2.2 Metabolism and Elimination
Donepezil is primarily metabolised by CYP2D6
and 3A4 and undergoes extensive first-pass meta-
bolism.[25,26,30] The major metabolites of donepezil
consist of a hydrolysis product (6-O-desmethyl-
donepezil) and an oxidation product (donepezil-
cis-N-oxide).[31] However, donepezil has only
one active metabolite (6-O-desmethyl-donepezil),
which has equal pharmacological activity to the
parent drug. 6-O-Desmethyl-donepezil is present
at about 20% of the plasma concentration of
donepezil.[30] The t1⁄2β of donepezil was reported to
be between 70 and 80 hours.[25]
1.2.3 Effects of Age, Hepatic and
Renal Impairment
Comparison of the pharmacokinetics of done-
pezil 2mg in elderly patients (68 to 82 years) versus
young adults (20 to 27 years) found that mean tmax
(5.2 vs 3.2 hours), t1⁄2β (103.8 vs 59.7 hours) and
mean residence time (MRT; 144 vs 85 hours) were
significantly (p < 0.05) greater in the elderly pa-
tients.[32] However, AUC and clearance did not dif-
fer significantly between populations. The slower
absorption rate in the elderly accounts for the
slightly longer tmax. The greater t1⁄2β and MRT were
due to the significantly greater mean volume of
distribution found in the elderly (1217.2 vs
852.5L). These changes were not considered clin-
ically significant, and dosage adjustments were not
suggested.
Donepezil disposition was reported to be unaf-
fected by hepatic or renal impairment. With the
exception of Cmax in patients with impaired liver
function (37.5% higher, p < 0.02), pharmaco-
kinetic parameters did not differ significantly be-
tween healthy volunteers and patients with chronic
compensated liver cirrhosis and patients with mod-
erate to severe renal impairment (creatinine clear-
ance <30 ml/min).[33,34] Although these were single-
dose studies, the situation for steady-state conditions
should not differ.
© Adis International Limited. All rights reserved.
Jann et al.
1.3 Rivastigmine
Rivastigmine is considered a ‘pseudoirreversi-
ble’ cholinesterase inhibitor that forms a carba-
moylated complex with the enzymes, and has been
reported to inhibit both AChE and BChE with
equal potency.[18,35] After single-dose administra-
tion, enzyme inhibition was reported to persist for
10 to 12 hours.[36] This longer duration of action is
unique among cholinesterase inhibitors.
1.3.1 Absorption, Bioavailability and Distribution
Rivastigmine exhibits rapid and nearly com-
plete oral absorption, with tmax of 0.8 (0.5 in some
reports[18]) to 1.7 hours (table I). Food slows ab-
sorption and results in a decrease of Cmax of about
30% with an increase in the extent of absorption,
also by 30%.[37] Rivastigmine should be taken with
meals (breakfast and dinner), which decreases gas-
trointestinal problems. ZNS 114-666 (NAP-226-
90), its decarbamylated metabolite, is also rapidly
detected within 2 hours of administration.[35]
About 96% of a radiolabelled dose is absorbed, but
the presystemic biotransformation is high, indicat-
ing a significant first-pass effect with an AUC ratio
of oral to intravenous drug of 0.355 (35% bioavail-
ability).[35,37] Protein binding of rivastigmine is
quite low at 40%, with about 40 to 50% of rivas-
tigmine bound with red blood cells. The volume of
distribution of rivastigmine and its metabolite are
1.8 to 2.7 and 4.3 to 5.9 L/kg, respectively.[38]
Rivastigmine displays a linear relationship of
dose to AUC.[39]. When doses of 2, 8 and 12mg
were administered, the corresponding mean AUCs
were 6.2 ± 3.2, 41.7 ± 13.0 and 55.9 ± 16.5 μg •
h/L, respectively. Under multiple dose conditions
maintained for at least 3 days, the tmax of rivastig-
mine in the CSF was 1.4 to 3.8 hours, which was
slightly longer than the plasma tmax due to com-
partmentalisation from drug in the plasma entering
into the CSF.[39] Peak CSF concentrations were
about 40% of those detected in plasma, with rapid
clearance characterised by a t1⁄2β that ranged from
0.3 to 3.0 hours. A significant correlation was
found between dose and AUC for rivastigmine and
its NAP-226-90 metabolite (r = 0.84, p < 0.0001; r
Clin Pharmacokinet 2002; 41 (10)
Cholinesterase Inhibitors
= 0.92, p < 0.0001, respectively). Similar results
were found comparing rivastigmine plasma and
CSF AUCs (r = 0.93, p < 0.0001). In another phar-
macokinetic study with a 3mg single dose, CSF
rivastigmine concentrations were below the lower
limit of quantification (<0.65 μg/L); however,
NAP-226-90 was detectable for over 15 hours.[38]
Mean tmax for NAP-226-90 was 2.93 hours and
mean Cmax was 3.14 ± 0.57 μg/L.
1.3.2 Metabolism and Elimination
Rivastigmine is not significantly metabolised
by hepatic oxidative CYP isoenzymes.[35,37] Rivas-
tigmine is rapidly and extensively metabolised,
primarily by cholinesterases, to the NAP-226-90
metabolite.[37] NAP-226-90 may then undergo N-
demethylation and/or sulphate conjugation. After
metabolism, it undergoes rapid renal elimination.
Accumulation of rivastigmine and NAP-226-90
does not occur after repeated administration of 1
to 6 mg/day.[37] The t1⁄2β of rivastigmine from the
CSF was reported to range from 0.31 to 2.95 hours
with multiple dose administration.[39]
1.3.3 Effects of Age, Hepatic and
Renal Impairment
The t1⁄2β of rivastigmine was slightly prolonged
in the elderly compared with adult volunteers
(ranges 0.88 to 1.25 vs 0.80 to 0.99 hours), which
does not appear to be clinically significant.[39] In
patients with renal and moderate hepatic impair-
ment, the AUC of rivastigmine was 1.4-fold and
2.3-fold higher, respectively, than in adult healthy
controls.[40] The AUC of NAP-226-90 was also
0.8-fold lower in renally impaired patients, but
1.5-fold greater in hepatically impaired patients.
Significant differences in the t1⁄2β of parent drug
were not found in patients with moderate or severe
renal impairment. The t1⁄2β of NAP-226-90 was
longer only in patients with severe renal impair-
ment (6.0 vs 3.4 hours). Although the AUC of
rivastigmine was higher in patients with hepatic
impairment, specific dosage recommendations
may not be needed in these special populations.
Rivastigmine has not been studied in patients with
severe hepatic impairment.
© Adis International Limited. All rights reserved.
725
1.4 Galantamine
Galantamine is a phenanthrene alkaloid similar
to codeine, and was isolated from the snowdrop
plant Galanthus nivalis.[18] In addition to its ac-
tions upon AChE, in vitro evidence suggests that
it also modulates nicotinic receptors, thereby en-
hancing acetylcholine activity at the synapse.[41]
These two actions form a different type of ‘dual’
pharmacological mechanism to enhance acetyl-
choline function.
1.4.1 Absorption, Bioavailability and Distribution
Galantamine has been administered by a variety
of routes, including intravenous, oral, rectal and
subcutaneous.[41-44] Only the oral formulation will
be described in detail regarding its pharmaco-
kinetic parameters and compared with other for-
mulations.
Galantamine is readily absorbed after oral ad-
ministration (tablet and solution) with an 85 to
100% bioavailability.[43,44] After oral administra-
tion, tmax ranged from 0.5 to 2.0 hours.[18,41,44]
Food did not affect AUC, but Cmax was decreased
by 25% and tmax was delayed by 1.5 hours. The
mean volume of distribution in the central com-
partment was 0.93 L/kg, indicating an initial rapid
distribution, and the mean volume of distribution
at steady state was 2.64 L/kg, reflecting tissue ac-
cumulation.[44] Plasma protein binding was rela-
tively low at 18%,[41] but in patients with AD who
received 30 or 40mg, plasma protein binding at 2
to 3 hours post-dose was reported to be 28 to 34%,
without correlation with amounts of total protein
or albumin.[41] Although galantamine concentra-
tions were not measured, mean CSF AChE inhibi-
tion (reported as units/ml) in patients was found to
increase from 76.5 ± 10.4 to 221.5 ± 17.7 units/ml
(p = 0.028), indicating significant pharmaco-
dynamic activity from the drug.[45]
1.4.2 Metabolism and Elimination
The major (75%) route of metabolism of
galantamine occurs via hepatic CYP isoenzymes.
In vitro studies indicate that CYP2D6 and 3A4 are
involved with galantamine metabolism.[41] San-
guinine (O-demethyl-galantamine) is the major
Clin Pharmacokinet 2002; 41 (10)
726
metabolite of galantamine. It is formed by CYP-
2D6, can account for up to 20% of orally adminis-
tered galantamine, and is reported to be three times
more potent than galantamine as an AChE inhibi-
tor.[46] Other less significant metabolites include
galantaminone and N-demethyl-galantamine.
About 97% of a single radiolabelled 4mg dose of
galantamine to healthy volunteers was recovered
in the urine and the remaining portion in the fae-
ces.[41] Significant differences in the urinary and
faecal excretion amounts between poor and exten-
sive metabolisers of CYP2D6 were not found.[41]
The t1⁄2β of galantamine ranges between 5 and 7
hours (table I). Mean total clearance was reported
to be 0.34 L/h/kg with a 25% lower mean renal
clearance of 0.084 L/h/kg, which represents about
25% of the total drug clearance.[44] Population
pharmacokinetic analysis indicated a 20% lower
clearance in females, which was not considered to
be of clinical relevance. Clearance was reduced by
25% in poor metabolisers of CYP2D6, and again
this finding may not be clinically significant be-
cause of the wide interpatient variability and in-
volvement of CYP3A4.[41,46]
1.4.3 Effects of Age and Hepatic or
Renal Impairment
Patients with AD have Cmax values for galan-
tamine 30 to 40% higher than those found in
healthy adult volunteers.[41] However, differences
were not observed in AUC and t1⁄2β.[41] Galantamine
disposition did not significantly differ between
healthy volunteers and patients with mild hepatic
impairment (Child Pugh score 5 to 6), but in pa-
tients with moderate hepatic impairment (Child
Pugh score 7 to 9), AUC and t1⁄2β were increased by
about 30%.[41] In patients with creatinine clearan-
ces ≥9 ml/min, peak and trough galantamine con-
centrations were similar to those found in patients
with AD.[41]
A maximum dosage of 16 mg/day is recom-
mended for patients with moderate hepatic impair-
ment. No dosage adjustments are suggested for pa-
tients with mild hepatic or renal impairment
(creatinine clearance ≥9 ml/min). Galantamine is
contraindicated in patients with severe hepatic
© Adis International Limited. All rights reserved.
Jann et al.
(Child Pugh score >9) and/or renal (creatinine
clearance <9 ml/min) impairment.
2. Drug Interactions
2.1 Tacrine
2.1.1 Influence of Cytochrome P450 1A2
CYP1A2 activity was investigated in patients
with AD (n = 19) who received a 40mg single dose
of tacrine together with a caffeine probe (2 mg/kg)
followed by breath and urine tests.[47] Tacrine oral
clearance showed a 15-fold interpatient variability.
Oral clearance of tacrine significantly correlated
with the 2-hour production of 13CO2 (r = 0.56, p =
0.01), with the p-xanthine/caffeine metabolic uri-
nary ratio (r = 0.76, p = 0.0002) and the caffeine
metabolic urinary ratio (r = 0.76, p = 0.0001).
These observations support a central role for
CYP1A2 in the in vivo disposition of tacrine and
demonstrate a potential for drug-drug interactions,
but did not support the routine use of caffeine to
individualise tacrine therapy.
Significantly higher plasma concentrations of
tacrine have been reported in women compared
with men.[48] Although mean values were not pro-
vided, the tacrine plasma concentrations ranged
from 11 to 30 μg/L in women compared with 8 to
15 μg/L in men. It was proposed that this difference
may be due to lower CYP1A2 isoenzyme activity
in women.[18,48] Smoking is a well-known inducer
of CYP1A2, and smokers have a significantly
lower tacrine t1⁄2β than nonsmokers (2.1 vs 3.2
hours), with consistently lower concentrations of
tacrine and metabolites.[49]
2.1.2 Cimetidine
Coadministration of cimetidine with tacrine in
an elderly population (n = 12) resulted in a 39%
increase in tacrine AUC (mean 56 vs 75 μg • h/L)
with a corresponding decrease in clearance by 30%
(mean 23.4 vs 16.3 L/min).[50] As a result of in-
creased parent drug, the AUCs of the 1-, 2- and
4-hydroxy metabolites of tacrine also showed in-
creases that ranged from 17 to 60%.[51]
Clin Pharmacokinet 2002; 41 (10)
Cholinesterase Inhibitors
2.1.3 Hormone Replacement Therapy
Ten healthy female volunteers received hor-
mone replacement therapy (HRT) [estradiol valer-
ate 2mg plus levonorgestrel 0.25mg] or placebo for
10 days in a randomised crossover study. At 1 hour
after the last dose of HRT or placebo, a single
40mg dose of tacrine was given and its pharmaco-
kinetic profile evaluated.[52] Coadministration of
HRT with tacrine resulted in an increase of tacrine
AUC by 60% (p = 0.009) with a reduction of mean
clearance by 31% (p = 0.14). Significant changes
in t1⁄2β were not found. The metabolic ratio of 1-
hydroxy-tacrine to tacrine was significantly re-
duced in all subjects (mean 26%, p < 0.001). This
interaction between HRT and tacrine, resulting in
reduced metabolism of the parent drug, indicates
inhibition of CYP1A2 during the first-pass phase.
2.1.4 Fluvoxamine
In vitro and in vivo studies have been conducted
to investigate the interaction between tacrine and
fluvoxamine.[53,54] Fluvoxamine is a potent
CYP1A2 inhibitor. Healthy volunteers were ran-
domised to receive fluvoxamine 100 mg/day or
placebo for 6 days and then crossed over to the
other treatment arm. On the last day, tacrine was
coadministered with fluvoxamine or placebo.[54]
Mean oral tacrine clearance significantly de-
creased from 1683 ± 802 to 200 ± 106 L/h (p <
0.05). The AUCs of all three tacrine hydroxy me-
tabolites significantly increased with fluvoxamine
coadministration, and five of the thirteen volun-
teers experienced gastrointestinal adverse events.
In vitro modelling using human liver micro-
somes and yeast-expressed human CYP1A2 re-
ported changes in kinetic parameters during
coincubation of tacrine and fluvoxamine that cor-
related with the in vivo study.[53]
2.1.5 Theophylline
Concomitant administration of tacrine and
theophylline resulted in a reduction in theophyl-
line clearance by about 50% (from a mean of 41.8
to 21.6 L/min).[12]
© Adis International Limited. All rights reserved.
727
2.2 Donepezil
2.2.1 Cimetidine
The coadministration of cimetidine 800 mg/day
with donepezil 5 mg/day for 7 days in 19 healthy
male volunteers aged 18 to 55 years resulted in
significantly higher donepezil mean Cmax (26.6 ±
1.5 vs 29.9 ± 1.3 μg/L, p = 0.0002) and AUC (472.3
± 26.9 vs 526.9 ± 24.3 μg • h/L, p = 0.0001).[55]
However, coadministration did not significantly ef-
fect tmax, t1⁄2β and drug accumulation profiles. Al-
though these changes are considered clinically not
significant, clinicians should carefully monitor pa-
tients when cimetidine is used.
2.2.2 Digoxin
The pharmacokinetic parameters of digoxin
0.25 mg/day for 6 days were not affected by co-
adminstration of donepezil (5 mg/day for 6 to 10
days or 10 mg/day for 12 days) in 12 healthy male
volunteers.[50] Changes in ECG or cardiac conduc-
tion did not occur. The pharmacokinetic parame-
ters of donepezil (tmax, Cmax, AUC and t1⁄2β) were
not altered by digoxin.
2.2.3 Ketoconazole
Ketoconazole is a potent CYP3A4 inhibitor,
and the possibly of a significant interaction with
donepezil was evaluated. Coadministration of
donepezil 5 mg/day and ketoconazole 200 mg/day
for 7 days significantly altered the pharmacokinet-
ics of donepezil.[56] Significant increases in Cmax
(27.6 ± 1.7 vs 37.7 ± 2.2 μg/L, p < 0.0001), AUC
(501.1 ± 38.3 vs 680.9 ± 48.4 μg • h/L, p < 0.0001)
and drug accumulation ratio (4.2 ± 0.2 vs 5.0 ± 0.2,
p < 0.0001) were observed, but tmax and t1⁄2β were
unaltered. The clinical significance of this interac-
tion remains to be determined, but clinicians
should always carefully monitor patients. Keto-
conazole pharmacokinetics were unaffected by
donepezil. Extrapolation of donepezil data was
conducted to estimate the effects of ketoconazole
on steady-state concentrations of donepezil, and a
23 to 30% increase was predicted by using the
maximum effect (Emax) model.[56]
Clin Pharmacokinet 2002; 41 (10)
728
2.2.4 Psychotropic Drugs
Two case reports have documented a possible
interaction between paroxetine (a potent CYP2D6
inhibitor) 20 mg/day and donepezil 5 mg/day.[57]
Both patients experienced gastrointestinal adverse
effects (severe diarrhoea and flatulence), insom-
nia, agitation, confusion and aggression. Done-
pezil plasma concentrations were not measured
(and are not routinely conducted in the clinical set-
ting). Drug-drug interactions with serotonin reup-
take inhibitors could be very complex, and could
involve other CYP isoenzymes and drug transport
systems.[58]
Another case report described fulminant hepa-
titis when sertraline and donepezil were com-
bined.[59] Donepezil plasma concentrations were
not obtained, but a possible mechanism suggested
was inhibition of CYP3A4 and 2D6. Although
these cases do not prove an actual pharmacokinetic
drug interaction with donepezil, the possibility of
this type of interaction cannot be fully dismissed
and careful patient monitoring is recommended.
Drug interaction studies with risperidone and
thioridazine have been reported. Both agents in-
hibit CYP2D6. In healthy young subjects (n = 12),
a 50mg single dose of thioridazine was given prior
to and after 14 days of administration of donepezil
5mg.[60] Donepezil produced no significant changes
in thioridazine pharmacokinetics (AUC and tmax).
All ECGs remained normal during coadministra-
tion, indicating a lack of significant pharmaco-
dynamic interaction between thioridazine and
donepezil. In the second study, risperidone 1 to 4
mg/day was maintained in schizophrenic patients
(n = 16) and donepezil 5mg was coadministered for
7 days.[61] Risperidone pharmacokinetic parame-
ters were evaluated prior to and during donepezil
coadministration, and no significant changes in
risperidone disposition were reported.
2.2.5 Theophylline and Warfarin
When donepezil (5 mg/day for 6 to 10 days or
10 mg/day for 12 days) was coadministered with
theophylline (100mg twice daily titrated up to op-
timal plasma concentrations) in healthy volun-
teers, the pharmacokinetic profile of theophylline
© Adis International Limited. All rights reserved.
Jann et al.
was not significantly affected.[62] Similarly, the phar-
macokinetic parameters of (R)- and (S)-warfarin
(given as a single 25mg dose of racemic warfarin)
were not significantly affected when given with
donepezil (5 mg/day for 6 to 10 days or 10 mg/-
day for 12 days) in healthy volunteers.[63] Subse-
quently, no significant changes in prothrombin
times occurred. Therefore, it was concluded that
donepezil can be safely given with theophylline or
warfarin without dosage adjustments to either
agent.
2.3 Rivastigmine
Drug-drug interactions of clinical importance
are not expected with rivastigmine because of its
short pharmacokinetic t1⁄2β, low protein binding and
minimal metabolism by CYP.[35,37] In vitro and phar-
macokinetic studies conducted in humans who
received digoxin, warfarin, diazepam or fluoxetine
reported no significant interactions.[37] However
pharmacodynamic interactions may occur with
medications that affect the cholinergic system.[37]
A retrospective analysis of the four major clinical
trials (2459 patients) found that no increase in ad-
verse events occurred among those patients who
received 22 different classes of medication com-
monly used in elderly populations, including anti-
anginal, antihypertensive, antiemetic, antihista-
mine, anxiolytic, anti-inflammatory or estrogenic
agents.[64]
2.4 Galantamine
Since this agent is metabolised by CYP3A4 and
2D6, potent inhibitors of these isoenzymes could
result in significant drug-drug interactions. The
bioavailability of galantamine was reported to be
increased by 40% when coadministered with
paroxetine, and by 30 and 12% when given with
ketoconazole and erythromycin, respectively.[41]
Galantamine had no significant effect upon the
pharmacokinetics of warfarin or digoxin.[41]
Clin Pharmacokinet 2002; 41 (10)
Cholinesterase Inhibitors
3. Pharmacological Aspects
The main pharmacological action of cholines-
terase inhibitors is to inhibit the enzymes AChE
and BChE responsible for the breakdown of ace-
tylcholine at the synapse. This action produces
acetylcholine accumulation or prolongs its effects
at the synapse, which can be equivalent to exces-
sive stimulation of cholinergic receptors (both
muscarinic and nicotinic) throughout the central
and peripheral nervous system.[9] This section de-
scribes how cholinesterase inhibitors accomplish
this function.
3.1 Reversible versus Irreversible Inhibition
The structure of AChE and BChE is well
known. The active centre consists of two sites, an
anionic site and an esteratic site. Acetylcholine and
related compounds bind to the anionic site by cou-
lombic and hydrophobic forces, whereas binding
occurs at the esteratic site via nucleophilic binding
on the acyl carbon (figure 2).[65] The terms ‘revers-
ible’ and ‘irreversible’ have a long history.[9] Cur-
rently, cholinesterase inhibitors are classified
pharmacologically into three groups on the ba-
sis of their duration of inhibition – short-acting,
intermediate-acting and long-acting.
Reversible or short-acting agents such as tacr-
ine and donepezil bind reversibly to cholinesterase
and their durations of action are very short (min-
utes). Rivastigmine is classified as an intermediate-
acting or ‘pseudo-irreversible’ agent, as its alcohol
moiety is cleaved to form a carbamoyl enzyme and
the inhibition lasts for 10 to 12 hours after a single
dose.[23,35,65] However, since the body does not
need to synthesise new enzyme protein, rivastig-
mine can be considered a ‘reversible’ carbamate
inhibitor[9] and indeed is so described in the pack-
age insert.[66]
Long-acting agents or irreversible inhibitors
bind to cholinesterase and prevent any further en-
zyme activity. The body must synthesise new en-
zymes for replacement and continued pharmaco-
logical function. An example of an irreversible
© Adis International Limited. All rights reserved.
729
agent is metrifonate, which is no longer in clinical
development.[35,65]
3.2 Acetylcholinesterase versus
Butyrylcholinesterase Inhibition
Both AChE and BChE are present in the human
brain.[18,67] The three-dimensional structures of
these enzymes have been published, and only a
simple schematic diagram is presented in figure 2.
AChE plays an important role in the development
of neurons and neurite outgrowths.[10] It is found
in erythrocytes, platelets and lymphocytes. The ac-
tivity of AChE has been reported to be decreased
in the brains of patients with AD.
The structure of BChE is similar to that of
AChE, but it has a slight difference in its amino
acid sequence. BChE is synthesised in the liver and
secreted into the plasma. It is found in the gastro-
intestinal tract and heart with AChE, and in the
neurons and glial cells of the brain. BChE activity
was reported to be increased in the brains of pa-
tients with AD, in association with increased β-
amyloid density.[68]
Cholinesterase inhibitors may exert additional
pharmacological actions beyond inhibition of cho-
Cholinesterase enzyme
E A
+
O N
O Gorge area
Ach
A/B
Hypothetical ChEI
A
B
E Peripheral area
Fig. 2. Model of cholinesterase activity on acetylcholine (ACh).
Two types of binding sites have been identified, known as es-
teratic (E) and anionic (A) sites, located in the gorge and pe-
ripheral areas of the enzyme. The hypothetical cholinesterase
inhibitor (ChEI) A/B must bind to at least one site in the gorge.
The drug can also bind to either of the peripheral sites (section
B of the hypothetical drug).
Clin Pharmacokinet 2002; 41 (10)
730
linesterases. In vitro models have shown that cho-
linesterase inhibitors can increase the secretion of
the soluble amyloid precursor protein (APP).[69]
The long-term efficacy of cholinesterase inhibitors
may be related to their dual inhibitory action on
acetylcholine and on AChE and/or BChE.[35,69]
The different molecular structures of the cholin-
esterase inhibitors (figure 1) account for their se-
lective binding to AChE and/or BChE. The three-
dimensional structure of AChE and BChE forms a
‘gorge’ around the esteratic and anionic sites (fig-
ure 2).[67] Acetylcholine binds at both sites in the
gorge. Each drug binds to the enzyme in a different
three-dimensional manner, either alone or in com-
bination at the esteratic and anionic sites. Esteratic
and anionic sites are located in the gorge and pe-
ripheral areas. The inhibitor (hypothetical drug
A/B) must bind to one site in the gorge area to
produce inhibition. However, cholinesterase inhibi-
tors can additionally bind to either site in the peri-
pheral areas, as shown by section B of a hypothet-
ical drug.
Tacrine forms ionic bonds with the amino acids
on the anionic site and displays slight specificity
for BChE inhibition versus AChE inhibition.[10]
Rivastigmine interacts with the esteratic and an-
ionic sites at the foot of the gorge.[10] Based upon
measurements with CSF in healthy volunteers
given rivastigmine 1 to 6mg twice a day, rivastig-
mine shows an equal potency to inhibit both AChE
and BChE.[39] Donepezil binds to the anionic site
at the bottom of the gorge and at the peripheral
anionic site.[10] Donepezil and galantamine display
higher potency for AChE than for BChE.[25,41]
Based upon in vitro data, donepezil has much
greater potency and specificity for AChE inhibi-
tion than for BChE inhibition, with an AChE/-
BChE ratio of 1265 : 1.[70] The selectivity of done-
pezil for AChE is based upon its binding with
amino acids Trp-279 and Phe-330, which are ab-
sent from BChE.[10] Galantamine displays inhibi-
tion for both AChE and BChE, but its AChE/BChE
ratio is much lower at about 53 : 1.[70] The O-
demethyl metabolite of galantamine also displays
AChE and BChE inhibition, with 50% inhibitory
© Adis International Limited. All rights reserved.
Jann et al.
concentrations (IC50) of 0.12 and 24.0 μmol/L, re-
spectively.[46] Galantamine binds at the esteratic
site of the gorge, and its tertiary amine group ap-
pears to be associated with Asp-72, binding it to
the peripheral esteratic site.[10]
Cholinesterase inhibitors can also bind to an al-
losteric site on the nicotinic acetylcholine receptor
and may further enhance cholinergic transmission.
This independent function is separate from cho-
linesterase inhibition. Galantamine and physos-
tigmine were shown to possess this additional
nicotinic binding action in vivo.[41] However,
galantamine demonstrated the most potent ability
to modulate the nicotinic receptor.[71] The modula-
tion results in increased ion channel opening in-
duced by acetylcholine and nicotinic agonists and
slows down receptor desensitisation. Cell culture
models have shown potentiation by galantamine of
the action of acetylcholine in HEK-293 cells trans-
fected with human α4β2 nicotinic acetylcholine
receptors.[71] The 50% effective concentration
(EC50) for acetylcholine was improved from 2.3
μmol/L without galantamine to 0.9 μmol/L with
galantamine. The Hill coefficient (nH) also im-
proved from 1.2 without galantamine to 1.7 with
galantamine.
3.3 Dose versus Cholinesterase Inhibition
A comparison of the relationship between the
doses of the different cholinesterase inhibitors and
their effects on cholinesterase inhibition is pre-
sented in table II. With the exception of eptastig-
mine and galantamine, these doses reflect those
used in clinical practice.[72] Galantamine has been
evaluated up to 32 mg/day, but recommended dos-
ages are from 16 to 24 mg/day.[41]
Data regarding tacrine dose and enzyme inhibi-
tion have not been published. Data with more than
two doses studied are only available for rivastig-
mine and eptastigmine, but demonstrate the fol-
lowing biochemical features common to cholines-
terase inhibitors. Rivastigmine displays equal
inhibition of AChE and BChE, although there was
some disparity reported at the 6mg dose which is
most probably due to assay variability or interpati-
Clin Pharmacokinet 2002; 41 (10)
Cholinesterase Inhibitors
Table II. Relationship between dose and cholinesterase inhibition for cholinesterase inhibitors
Reference Drug
Tacrine
73 Donepezil
39 Rivastigmine
44 Galantamine
72 Eptastigmine
a Intravenous administration.
AChE = acetylcholinesterase; BChE = butyrylcholinesterase.
ent variation. Enzyme inhibition data was evalu-
ated for only the 5 and 10mg doses of donepezil.
A general picture for these agents emerges of inhi-
bition reaching a plateau, with different drugs
reaching nonlinearity at different doses. The cho-
linesterase inhibitors exhibit linear disposition,
and increasing the dosage can lead to a correspond-
ing increase in AUC, but the increase in enzyme
inhibition may or may not be reflective of the dos-
age change.
4. Pharmacodynamic Aspects
Cholinesterase inhibitors can be evaluated by a
variety of methods in the areas of clinical efficacy
and adverse effects. These two areas can be further
divided into dose-related and dose-unrelated ac-
tions.
4.1 Clinical Efficacy
4.1.1 Clinical Rating Scales
The nature of AD presents several unique
challenges in the design and analysis of clinical
trials. The majority of the assessment tools used
have limited value in the clinical setting and are
unfamiliar to many clinicians. However, a basic
understanding of the many scores and their impli-
© Adis International Limited. All rights reserved.
731
Dose (mg) Enzyme inhibition
40-160 40% (BChE)
5 63.7% (AChE)
10 77.3% (AChE)
2 20% (AChE); 24% (BChE)
4 36% (AChE); 28% (BChE)
6 46% (AChE); 76% (BChE)
10 55% (AChE); 51% (BChE)
12 62% (AChE); 62% (BChE)
5a 34% (AChE)
10a 53% (AChE)
10 42% (AChE)
8 20% (AChE)
20 29% (AChE)
32 45% (AChE)
40 54% (AChE)
cations is needed. Tacrine was the first cholines-
terase inhibitor to be approved for AD, and many
issues were discovered and eventually resolved
during and after its clinical trials.[74]
Assessment of AD consists of three domains:
cognitive impairment, behavioural symptoms, and
functional changes in daily activities. The inter-
relationship between these three domains forms
the basis of evaluating antidementia compounds,
and cholinesterase inhibitors have led the way in
this field. This section will briefly describe the
most widely accepted standardised clinical assess-
ment tools to evaluate cholinesterase inhibitors in
AD. The usual duration for a clinical trial in AD is
6 months, and changes are compared (the delta
score) from baseline to the study endpoint.
The assessment tool that has become recog-
nised by many clinicians to reflect changes in cog-
nition is the Alzheimer’s Disease Assessment
Scale – cognitive section (ADAS-cog).[75] ADAS-
cog scores range from 0 to 70 points, with high
scores indicating impairment; however, its short-
comings are that changes in the delta score from
baseline to study endpoint may not reflect mean-
ingful changes in the patient’s status. Yet, the
ADAS-cog has become the standardised tool to as-
sess cognition in AD trials. Regulatory agencies
Clin Pharmacokinet 2002; 41 (10)
732
have also specified that cognition cannot be the
only indicator of response, and that a global assess-
ment by the clinician is equally if not more import-
ant in determining drug response. The clinical as-
sessment tool utilised to evaluate global changes
is the Clinical Global Impression of Change
(CGIC).[76] The patient and their caregiver is inter-
viewed by the clinician. Based upon the clinician’s
total experience with this population, the rater
makes an assessment of the patient’s cognition,
behaviour and functional ability scored as one
evaluation score. Both ADAS-cog and CGIC
scores have been used to develop pharmaco-
dynamic models of clinical response to cholines-
terase inhibitors.[77] Perhaps the best known instru-
ment used to assess cognition is the Folstein
Mini-Mental Status Exam (MMSE).[78] Although
well known, its use has been restricted in clinical
trials for inclusion/exclusion of patients and sec-
ondary outcome measures.
Although cognition declines progressively with
time, behavioural symptoms can increase or de-
crease in frequency and/or severity. The Neuropsy-
chiatric Inventory (NPI) scale is commonly used to
evaluate behavioural symptoms in AD patients by
the clinician, accounting for both frequency and
severity.[79] Scores are tabulated and range from 10
to 120 points, but again the delta score is used to
evaluate the efficacy of cholinesterase inhibitors.
A variety of assessment scales are available to
evaluate functional daily activities of the patient.
A widely used validated scale is the Progressive
Deterioration Scale (PDS), in which the patient is
evaluated by their caregiver.[80] PDS scores range
from 0 to 100 points, and average scores for mild,
moderately and severely ill patients are 48, 34 and
15 points, respectively. Like the other rating
scales, the delta PDS score is used to determine
changes in a patient’s function over time.
4.1.2 Correlation of Clinical Efficacy, Dose and
Enzyme Inhibition
A common method to evaluate the pharmaco-
dynamic actions of cholinesterase inhibitors in-
volves the measurement of plasma and/or erythro-
cyte cholinesterase inhibition in venous blood
© Adis International Limited. All rights reserved.
Jann et al.
samples.[77,81] Cholinesterase inhibitors typically
display a dose-dependent activity where the thera-
peutic index measured by changes in cognitive
scores closely approaches the maximum tolerated
dose. Many factors complicate these findings, in-
cluding wide interpatient variability in metabo-
lism, tolerance, disease stage and efficacy. Fur-
thermore, in dose-ranging studies, cholinesterase
inhibitors appear to be better tolerated in AD pa-
tients compared with healthy volunteers.[81]
A conceptual model for cholinesterase inhibi-
tors, relating enzyme inhibition to clinical efficacy
and adverse effects, is presented in figure 3. As
some cholinesterase inhibitors bind to both en-
zymes, plasma and erythrocyte cholinesterase
have been used as ‘surrogate’ biomarkers for clini-
cal efficacy. Direct comparisons between cholin-
esterase inhibitors cannot be conducted, as their
dose and plasma concentrations differ when com-
paring these parameters to cholinesterase inhibi-
tion. The approximate range for cholinesterase in-
hibition to achieve clinical efficacy varies between
40 and 70% (60% for donepezil, tacrine and
rivastigmine, 74% for galantamine and 35% for
eptastigmine).[77,81] Tables II and III also illustrate
this concept of enzyme inhibition in relationship to
dose and clinical efficacy. The maximal level of
inhibition without adverse effects differs among
Clinical efficacy
Adverse effects
Adverse effects
Efficacy
0 10 40 70 100
Cholinesterase inhibition (%)
Fig. 3. Conceptual model relating cholinesterase inhibition to
clinical efficacy and adverse events.
Clin Pharmacokinet 2002; 41 (10)
Cholinesterase Inhibitors
the cholinesterase inhibitors. The higher the level
of inhibition that can be achieved without or with
only minimal adverse effects, the greater proba-
bility of meaningful therapeutic benefit for the pa-
tient.[82]
These factors are expressed in the conceptual
model for cholinesterase inhibitors in figure 3. The
range of 40 to 70% probably represents the optimal
therapeutic range for enzyme inhibition. Adverse
effects are also dose-dependent, as their incidence
and severity increase with increasing dosage. At
lower dosages, the likelihood of adverse effects is
minimal but can rapidly increase as enzyme inhi-
bition gradually increases. The point where the
lines of clinical efficacy and adverse effects cross
becomes the maximal tolerated dose (MTD). As
enzyme inhibition increases (a function of dose),
clinical efficacy is maximised but adverse effects
predominate. This relationship cannot be de-
scribed as an inverted U-shaped curve, since clini-
cal efficacy can be maximised with increasing en-
zyme inhibition. Theoretically, one can have 100%
enzyme inhibition with maximal benefit from the
drug; however, its adverse effects would become
intolerable and the risk of continued drug exposure
would outweigh the benefits of continued therapy.
The relationship between dose of cholinester-
ase inhibitors and clinical response (delta ADAS-
cog scores) is presented in table III.[73,83-85] All
cholinesterase inhibitors appear to display a mini-
mum dose ‘threshold’ where a statistically signifi-
cant difference from placebo can be found. For
example, although a slight decrease (or improve-
ment) in the mean ADAS-cog score was observed
for tacrine 80mg, the difference was not signifi-
cant. Similar findings occurred with rivastigmine
1 to 4mg and galantamine 8mg. Correspondingly,
changes in functional daily activities paralleled the
improvement in cognitive scores shown in table
III. The daily dosages of cholinesterase inhibitors
needed to achieve a consistent cholinesterase inhi-
bition of 40 to 70% correspond to those causing
improvements in ADAS-cog and functional activ-
ity scores. These findings fit into the conceptual
© Adis International Limited. All rights reserved.
733
model proposed for cholinesterase inhibitors in
figure 3.
A linear relationship between ADAS-cog, PDS,
CGIC and MMSE was suggested for rivastigmine
for the pooled data from four large multicentre
clinical trials.[86] The maximum daily rivastigmine
dosage reported in the linear-regression model was
12mg, which corresponded to the maximum dos-
age used in the study. It remains unknown whether
or not higher dosages could further improve cog-
nition or functional activities in patients with AD.
Galantamine dosages of 16 and 24 mg/day were
reported to be the optimal dosages for therapeutic
response. When higher dosages of 32 mg/day were
used, the mean ADAS-cog score (versus placebo)
was 3.8 points, whereas the 24 mg/day dosage had
a mean ADAS-cog score of 3.9 points. The inci-
dence of adverse effects was much higher in the 32
mg/day group versus the 24 mg/day dose group,
which provides a ‘ceiling’ dosage for maximum
benefit.[87] The improvement did not significantly
decrease, which further supports the proposed con-
ceptual model.
4.1.3 Effects on Behavioural Symptoms
A small nonblinded study with tacrine assessed
behavioural symptoms in 28 patients with AD.[88]
Tacrine dosages started at 40 mg/day and were in-
creased to 160 mg/day at 6-week intervals; how-
ever, only 10 patients were able to tolerate the
maximum daily dosage. NPI evaluations were
completed at 6-week intervals, and mean scores
were consistently lower (better) as the tacrine dos-
ages were increased. The mean changes in NPI
scores were –4.53, –6.92 and –8.0 points with tac-
rine dosages of 80, 120 and 160 mg/day, respec-
tively. Statistical significance was achieved with
the 120 (p = 0.04) and 160 (p = 0.01) mg/day dos-
ages.
Another nonblinded study with donepezil in 25
patients with AD showed similar findings, where
both 5 and 10 mg/day produced improvement in
emotional and behavioural symptoms.[89] A dose-
dependent effect could not be found with done-
pezil, as all patients started with 5mg and the dose
increased to 10mg after 4 months.
Clin Pharmacokinet 2002; 41 (10)
734 Jann et al.

Table III. Summary of the pharmacodynamic properties of cholinesterase inhibitors

Agent Enzyme inhibition Clinical effects
selectivity dose (mg) inhibition (%) dosage (mg/day) Δ ADAS-cog Δ daily activity score
Tacrine BChE > AChE 160 40 (BChE) P NR NR
80 –1.4 3.1
120 –2.0* 4.5*
160 –2.1* 4.6*
Donepezil AChE >>> BChE 10 77 (AChE) P 1.82 NR
5 –0.67* NR
10 –1.06* NR
Rivastigmine AChE = BChE 12 62 (BChE) P 4.15 –4.90a
62 (AChE) 1-4 2.27 –5.19
6-12 –0.79* –1.52*
Galantamine AChE >> BChE NR NR P 1.8 –4.0a
8 0.1 –3.1
16 –1.5* –0.5*
24 –1.8* –1.6*
a Decline from baseline.
AChE = acetylcholinesterase; ADAS-cog = Alzheimer’s Disease Assessment Scale – cognitive section; BChE = butyrylcholinesterase; NR
= not reported; P = placebo; Δ = change in score from baseline to study endpoint; * indicates significantly different from placebo, p < 0.05.

In the multicentre galantamine trial, the mean
NPI scores improved in patients in the 16 mg/day
(–0.1 points) and 24 mg/day (–0.1 points) groups
compared with placebo recipients (+2.3 points)
and the 8 mg/day group (+2.3 points).[84]
Psychotropic benefits of cholinesterase inhibi-
tors have been proposed.[11] Various clinical stud-
ies with different cholinesterase inhibitors, both
nonblinded and controlled multicentre trials, have
noted improvement in behavioural symptoms. Re-
duced psychosis was reported with rivastigmine.
Delusions, agitation, pacing, aberrant motor activ-
ity, hallucinations, apathy and depression were
found to improve with tacrine, physostigmine and
metrifonate. Improvements in total NPI scores
were noted with donepezil, rivastigmine and
metrifonate. These findings support the sugges-
tions of a psychotropic benefit with cholinesterase
inhibitors; however, a relationship between beha-
vioural symptoms and drug dose or enzyme inhi-
bition remains to be established.
4.1.4 Imaging Studies
The concept and application of using noninvas-
ive imaging techniques for diagnostic and drug
therapeutic monitoring in AD appeals to many cli-
nicians and scientists. However, to date, imaging
studies have only been completed in very small
patient numbers and in nonblinded studies. Two
small separate studies with a total of 13 patients
with AD have used single photon emission com-
puted tomography (SPECT).[90,91] In each study,
patients were treated with physostigmine and tacr-
ine plus lecithin. Scans were conducted prior to and
after several weeks of treatment. One study re-
ported increased cortical perfusion in the left fron-
tal and high frontal regions,[90] whereas the other
reported no significant changes.[91]
Recently, functional magnetic resonance imag-
ing (fMRI) coupled with apolipoprotein E (apoE)
genotyping was evaluated in 30 neurologically
normal subjects.[92] apoE has been established as a
potential risk factor for AD, but does not appear to
be a predictor of response to cholinesterase inhib-
itors.[86] Patterns of brain activation in the hippo-
campal, parietal and prefrontal areas detected by
fMRI, and carriage of the apoE-4 genotype, were
found to be associated with memory impairment.
These combined tests may eventually be used to
examine effects of cholinesterase inhibitors.[92]
Positron emission tomography (PET) can be a
valuable tool for the early detection of AD, identi-
fication of patients with mild cognitive impair-

© Adis International Limited. All rights reserved. Clin Pharmacokinet 2002; 41 (10)
Cholinesterase Inhibitors
ment, and development of surrogate markers for
diagnosis and pharmacological interventions.[93] A
PET method for detecting β-amyloid plaques and
neurofibrillary tangles in the brains of AD patients
has been described with the development of a
hydrophobic radiofluorinated derivative of 1,1-
dicyano-[2- (6-dimethylamino)naphthalen- 2-yl]-
propene (FDDNP).[93] When injected intrave-
nously into seven AD patients, FDDNP showed
greater accumulation and slower clearance in
brain regions with high concentrations of amyloid
plaques and neurofibrillary tangles, particularly
the hippocampus, amygdala and entorhinal cortex.
The FDDNP residence time in these areas had sig-
nificant correlations with immediate and delayed
memory performance.
Other PET applications include combining ge-
netic risk factors (apoE-4), longitudinal studies
with glucose metabolism in persons at risk for de-
mentia and clinical trials with surrogate markers.
Two placebo-controlled trials are underway with
celecoxib (a cyclo-oxygenase-2 inhibitor) and done-
pezil that combine PET imaging with apoE-4 ge-
netic analysis in patients with mild cognitive im-
pairment to determine if these medications can
affect progression to AD.
4.2 Adverse Effects
Adverse effects from cholinesterase inhibitors
are linked to their pharmacological cholinergic ac-
tions upon various organ systems. The majority of
adverse effects presented in this article were ob-
served in the multicentre clinical trials with vari-
ous cholinesterase inhibitors.
4.2.1 Dose-Dependent Effects
The most often reported adverse effects with
cholinesterase inhibitors occur in the gastrointes-
tinal tract. A summary of these effects is presented
in table IV. Increasing dosages resulted in in-
creased adverse effects. Of the gastrointestinal ad-
verse effects, the most frequently reported were
nausea, vomiting and diarrhoea. The incidence of
nausea and vomiting was reported to increase with
tacrine doses from 20 to 80mg.[94] In the tacrine
high dose study, where maximum daily dosages of
© Adis International Limited. All rights reserved.
735
80 to 160 mg/day were evaluated, safety data was
presented for the entire patient population but a
dose-dependent pattern could not be determined.
The overall incidence of nausea and vomiting was
35%, and of diarrhoea 18%.[83] Since these rates of
adverse effects were higher than in the lower dose
tacrine study, it is a reasonable assumption that a
dose-dependent effect can be found with tacrine.
The incidences of gastrointestinal adverse ef-
fects with the other cholinesterase inhibitors are
shown in table IV. Like tacrine, the other cholin-
esterase inhibitors display dose-dependent adverse
effects. At maximum doses, the incidence appears
to increase by at least 2-fold. However, methods to
improve gastrointestinal adverse effects have been
recommended (see section 4.2.2).
Dose-dependent CNS adverse effects may be
present with cholinesterase inhibitors. The main
CNS adverse effect reported is dizziness, but not
all clinical trials with cholinesterase inhibitors se-
lectively reported this particular event. The fre-
quency of dizziness with donepezil 5 and 10mg
was reported to be 5 and 9%, respectively.[95] This
pattern was not found with the earlier donepezil
trial, where dizziness was reported to be 10 and
8% with the 5 and 10mg doses, respectively.[73]
Rivastigmine had a reported incidence of dizziness
of 8 and 14% with the 1 to 4mg and 6 to 12mg dose
groups, respectively.[86] Trials with galantamine
reported rates of dizziness of 14 and 19% for the
24 and 32mg dose groups, respectively.[87]
4.2.2 Dose Titration
The incidence of gastrointestinal adverse ef-
fects decreases substantially when cholinesterase
inhibitors are titrated every 4 to 6 weeks rather than
over shorter time periods.[73,83-85] The design of the
clinical trials with rivastigmine with a forced
weekly dose titration scheme is typical. [84,96] In
these studies, patients had to reach their assigned
dosage range by week 7 or be discontinued from
the study. A slower dose titration can greatly re-
duce the incidence of adverse effects with
rivastigmine. When the maintenance dosages were
achieved, the frequency of adverse effects in the
high dosage group decreased to nausea 20%, vomi-
Clin Pharmacokinet 2002; 41 (10)
736 Jann et al.

Table IV. Summary of the main gastrointestinal adverse effects of cholinesterase inhibitors
References Drug Dosage (mg/day) Patients with adverse effect (%)a
nausea vomiting diarrhoea
94 Tacrine P 3.2 3.2 3.2
20 4.7 4.7 3.4
40 5.9 5.9 3.2
80 11.7 11.7 10.0
73,95 Donepezil P 7, 7 2, 4 7, 4
5 4, 7 3, 4 9, 10
10 17, 24 10, 16 17, 16
84,94 Rivastigmineb P 11, 10 3, 6 NR, 9
1-4 14, 17 7, 8 NR, 10
6-12 48, 50 27, 34 NR, 17
85,87 Galantamine P 4.5, 3.1 1.4, 7.5 5.9, 9.9
8 5.7, NA 3.6, NA 5.0, NA
16 13.3, NA 6.1, NA 12.2, NA
24 16.5, 37.3 9.9, 20.8 5.5, 12.3
32 NA, 43.6 NA, 25.6 NA, 19.4
a Where two values are shown, these represent data from separate trials.
b Forced dose titration data.
NA = not applicable; NR = not reported; P = placebo.

ting 16% and diarrhoea 17%. These findings were
similar to rates of adverse effects reported with
donepezil.[35] Similar results occurred with done-
pezil and galantamine titrated every 4 to 6 weeks.
Gradual dose titration methods are practical and
often used in the clinical setting. This time period
of 4 to 6 weeks is consistent among these agents,
and may represent a feature of cholinesterase in-
hibitors whereby the body needs time to adjust to
the pharmacodynamic effects of enzyme inhibi-
tion. Another factor is drug absorption rate, since
cholinesterase inhibitors that are rapidly absorbed
may cause a rapid stimulation of the cholinergic
system with adverse effects closely following.[10]
Administering the drug with food can lower the
amount of gastrointestinal effects by delaying tmax.
Donepezil has a longer tmax of 3 to 5 hours, and may
not have this problem.
4.2.3 Serum Concentration Relationships
A therapeutic window for tacrine serum con-
centration was suggested to be between 7.5 and 20
μg/L, and concentrations were reported to predict
adverse effects.[48] Symptomatic adverse effects
were defined as the presence of gastrointestinal ef-
fects, tremors, restlessness, sweating, delusions,
faintness and skin rash. Patients with adverse ef-
fects had significantly higher mean serum concen-
trations than patients without adverse effects (16
vs 7 μg/L, p < 0.001). Women with a concentration
of 17 μg/L had a higher frequency of adverse ef-
fects than women who had a concentration of 7
μg/L (borderline significant, p value not provided).
Men with a concentration of 13 μg/L had a signifi-
cantly higher incidence of adverse effects than men
with a concentration of 8 μg/L (p < 0.01).
4.2.4 Hepatotoxicity with Tacrine
The hepatotoxicity associated with tacrine was
well documented in clinical trials.[83,94] Women
were reported to be more susceptible than men to
developing elevated (three times greater than the
normal range) serum alanine aminotransferase
(ALT).[97] A dose-dependent relationship between
hepatotoxicity and tacrine has not been estab-
lished, since its peak occurrence is between 4 and
10 weeks of initial treatment with patients on lower
dosages of 40 to 80 mg/day.[97] Correlations be-
tween serum tacrine concentrations and hepatotoxi-
city were not found.[48]

© Adis International Limited. All rights reserved. Clin Pharmacokinet 2002; 41 (10)
Cholinesterase Inhibitors
A link between tacrine-induced ALT elevations
and the genotype of glutathione S-transferase has
been proposed, where patients with hepatoxicity
had combined deficient alleles of M1 (mu) and T1
(tau) isoenzymes.[22] Analysis of only one geno-
type could not provide a significant link with sus-
ceptibility to hepatotoxicity.[98] Therefore, geno-
typing for these two isoenzymes may be needed for
patients who are likely candidates for tacrine ther-
apy. However, with the use of tacrine use dimini-
shing, the likelihood of genotyping may not be
economically justified.
5. Conclusions
Cholinesterase inhibitors have become the
‘first-line’ agents in the treatment of AD.[99] A
thorough understanding of their pharmacokinetic
and pharmacodynamic profiles is necessary in
order to maximise therapeutic benefits while
minimising adverse events. With the exception of
low doses of tacrine, cholinesterase inhibitors have
linear pharmacokinetics, but have nonlinear phar-
macodynamic actions in the inhibition of cholin-
esterase enzymes. Measurement of enzyme inhibi-
tion is the only method currently widely used as a
biomarker for cholinesterase inhibitors. A sigmoi-
dal curve for the relationship between cholinester-
ase inhibition and efficacy has been proposed. A
similar, but slightly different, sigmoidal curve has
been proposed for the adverse event profile. Un-
derstanding these relationships can identify the
maximum tolerated dose for cholinesterase inhibi-
tors.
Future pharmacodynamic methods to evaluate
cholinesterase inhibitors may include the use of
various imaging techniques. Coupled with clinical
observations and/or standardised assessments of
neurochemical biomarkers such as β-amyloid or
tau protein measurements in CSF or plasma, these
may represent future tools for monitoring the ef-
fects of cholinesterase inhibitors. Long-term trials
have demonstrated the continued benefits of cho-
linesterase inhibitors in patients with AD.[76] Cli-
nicians, caregivers and healthcare organisations
© Adis International Limited. All rights reserved.
737
need to design appropriate outcome measures for
the long-term treatment of these patients.[100]
Acknowledgements
Kara L. Shirley, Pharm.D., at the time of this paper was
the Novartis Fellow in Clinical Neuropsychopharmacology,
and received only salary support from Novartis for her
training. Michael W. Jann, Pharm.D., has received research
grant support from Novartis and Janssen, Otsuka, Bristol
Myers Squibb, Solvay, Glaxo Smith Kline, Lipocine, Lilly
and Pfizer Pharmaceuticals.
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Correspondence and offprints: Dr Michael W. Jann, South-
ern School of Pharmacy, Mercer University, 3001 Mercer
University Drive, Atlanta, GA 30341, USA.
E-mail: jann_mw@mercer.edu
Clin Pharmacokinet 2002; 41 (10)