REVIEW ARTICLE

Clin Pharmacokinet 2006; 45 (9): 855-869

0312-5963/06/0009-0855/$39.95/0
2006 Adis Data Information BV. All rights reserved.

Pharmacokinetic and
Pharmacodynamic Characteristics
of Medications Used for
Moderate Sedation
Tong J. Gan
Department of Anesthesiology, Duke University Medical Center, Durham, North Carolina, USA

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 855
1. Optimal Sedation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 856
2. Pharmacokinetic Properties of Sedative Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 857
2.1 Midazolam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 857
2.2 Propofol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 859
2.3 Ketamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 860
2.4 Sevoflurane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 860
2.5 AQUAVAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 860
3. Relationship between Pharmacokinetic Parameters and Pharmacodynamic Effects . . . . . . . . . . . . 861
3.1 Midazolam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 861
3.2 Propofol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 861
3.3 Ketamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 862
3.4 Sevoflurane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 862
3.5 AQUAVAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 862
4. Drug Combinations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 863
5. Safety Issues and Adverse Events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 863
5.1 Midazolam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 863
5.2 Propofol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 864
5.3 Ketamine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 865
5.4 Sevoflurane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 865
5.5 AQUAVAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 865
6. Drug Interactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 865
6.1 Midazolam . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 865
6.2 Propofol . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 865
6.3 Sevoflurane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 866
6.4 AQUAVAN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 866
7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 866

Abstract

The ability to deliver safe and effective moderate sedation is crucial to the
ability to perform invasive procedures. Sedative drugs should have a quick onset
of action, provide rapid and clear-headed recovery, and be easy to administer and
monitor. A number of drugs have been demonstrated to provide effective sedation
for outpatient procedures but since each agent has its own limitations, a thorough

856

Gan

knowledge of the available drugs is required to choose the appropriate drug, dose
and/or combination regimen for individual patients. Midazolam, propofol,
ketamine and sevoflurane are the most frequently used agents, and all have a quick
onset of action and rapid recovery. The primary drawback of midazolam is the
potential for accumulation of the drug, which can result in prolonged sedation and
a hangover effect. The anaesthetics propofol and sevoflurane have recently been
used for sedation in procedures of short duration. Although effective, these agents
require monitored anaesthesia care. Ketamine is an effective agent, particularly in
children, but there is concern regarding emergence reactions. AQUAVAN
injection (fospropofol disodium), a phosphorylated prodrug of propofol, is an
investigational agent possessing a unique and distinct pharmacokinetic and pharmacodynamic profile. Compared with propofol emulsion, AQUAVAN is associated with a slightly longer time to peak effect and a more prolonged
pharmacodynamic effect. Advances in the delivery of sedation, including the
development of new sedative agents, have the potential to further improve the
provision of moderate sedation for a variety of invasive procedures.

The use of sedation for interventional procedures

has become commonplace in a number of settings,
including endoscopic procedures (e.g. colonoscopy,
bronchoscopy, gastroscopy), cardiac catheterisation,
outpatient oral/maxillofacial surgery and the emergency department.[1-3] For example, the increase in
the number of patients undergoing screening for
colorectal cancer by endoscopy has been accompanied in most settings by an increased use of sedation
for control of pain and discomfort during colonoscopy.[4] Agents that deliver moderate sedation are appropriate for these procedures because they provide
quick recovery time, few sedation-related adverse
events and greater overall patient satisfaction.[5,6]
The use of moderate sedation is also expanding to
include administration by nurse specialists and other
non-anaesthesiologists in the endoscopy setting, and
by the use of patient-controlled sedation (PCS).[7-11]
Moderate sedation is defined as that level of
sedation in which patients are lethargic but responsive to verbal or tactile stimulation and able to
maintain their own airway.[12] In the past, this has
been referred to as procedural or conscious sedation.
A number of drugs, including midazolam, propofol,
ketamine, fentanyl, remifentanil, meperidine and inhaled anaesthetics, have properties that are appropri1

ate for moderate sedation during interventional procedures.[3,6,9,13-15] These agents have distinct pharmacokinetic and pharmacodynamic properties that
affect how they may be optimally used, either alone
or in combination with other agents.
This article reviews the individual sedation
profiles and pharmacokinetic and pharmacodynamic
characteristics of the most commonly used agents
for moderate sedation during interventional procedures. These include the benzodiazepine midazolam, the sedative/hypnotic agents propofol and
ketamine, the inhalational agent sevoflurane and a
novel sedative hypnotic in clinical development,
AQUAVAN 1 (fospropofol disodium) injection.
Important interactions of these agents with other
sedation agents are also presented to increase practitioners understanding and use of sedation techniques and to improve patient satisfaction and outcomes.
1. Optimal Sedation
Physicians strive to provide an optimal level of
sedation for the individual patient and the particular
procedure. The goal is to allow patients to tolerate
unpleasant procedures by relieving anxiety, discomfort and pain and to expedite completion of the

The use of trade names is for product identification purposes only and does not imply endorsement.

2006 Adis Data Information BV. All rights reserved.

Clin Pharmacokinet 2006; 45 (9)

PK/PD of Drugs for Moderate Sedation

procedure. To this end, sedative drugs need to be

titrated to effect to reach an optimal level of sedation
and to avoid complications. The ability to achieve
the desired level of sedation is based on the characteristics of the various sedative drugs. However, the
wide variability in the temporal and dose-related
response to various sedation agents dictates careful
administration and monitoring of sedation in individual patients.
The characteristics of an ideal agent for moderate
sedation have not been established by consensus
opinion but are accepted to include rapid onset of
action, quick recovery of cognitive and physical
faculties following the procedure and a predictable
pharmacokinetic/pharmacodynamic profile.[16] Each
available sedation agent possesses characteristics
that help dictate its best use and define its limitations.[17,18] A greater understanding of sedation
agents will help physicians choose the correct drug,
dose and combination to provide the best possible
sedation for their patients.
The availability of improved drug assay techniques and pharmacokinetic modelling programmes
and the introduction of reliable infusion systems has
also led to an increased use of target-controlled
infusions (TCIs) of anaesthetic agents.[19] TCI systems are pharmacokinetically based computer-controlled infusion systems designed to automatically
adjust the rate of infusion to maintain a desired
(target) concentration. These systems can also be
combined into a patient-maintained sedation system
in which target levels of the sedative agent are
maintained via a computer-controlled infusion system in response to patient demand.[20] Because of its
short-acting pharmacokinetic profile, propofol has
become the most frequently infused drug via TCI
and a proprietary system for propofol is available.[21]
2. Pharmacokinetic Properties of
Sedative Agents
Table I lists the pharmacokinetic and pharmacodynamic properties of propofol, midazolam,
ketamine and AQUAVAN, a water-soluble
prodrug of propofol that is in clinical development
for moderate sedation during colonoscopy. The
2006 Adis Data Information BV. All rights reserved.

857

pharmacodynamic profiles of inhalational agents are

primarily determined by their physiochemical
properties; common pharmacokinetic properties
(e.g. protein binding, metabolism, renal excretion)
have little impact on the pharmacodynamic profile
of the drug.[22] The physiochemical properties of
sevoflurane are summarised in table II.
2.1 Midazolam

Midazolam is highly lipophilic, resulting in rapid

distribution into the CNS and adipose tissues.[17]
These properties allow the drug to reach the site of
action rapidly, producing an onset of action in 12
minutes. However, the drug has a longer time to
peak effect compared with propofol, making this
drug less suitable for PCS.[39] Rapid recovery from
sedation with midazolam results from the rapid redistribution of the drug from the brain to peripheral
tissues.[23] Although midazolam is well absorbed
after oral administration, the relatively high firstpass hepatic metabolism of the drug results in oral
bioavailability values ranging from 31% to 72%.[17]
Thus, oral doses of midazolam are approximately
twice those of the intravenous route.
Midazolam is eliminated by both hepatic and
renal routes.[17] Hepatic metabolism is primarily via
oxidation to three metabolites (-hydroxymidazolam, 4-hydroxymidazolam and ,4-hydroxymidazolam) that are subsequently excreted as glucuronide
conjugates.[17] Midazolam has a relatively high
clearance rate that is partially dependent on hepatic
blood flow rate.[23]
The pharmacokinetic parameters of midazolam
are variable and are dependent on the patient population and the study design.[40,41] Age, bodyweight,
and hepatic and renal function influence the elimination of midazolam. In elderly and obese patients and
those with hepatic impairment, midazolam has a
reduced clearance and prolonged half-life compared
with those patients without these characteristics.[17,23,38,42] For example, in patients with cirrhosis,
the clearance of midazolam was halved and the halflife of the drug was doubled compared with patients
with normal hepatic function.[38] Patients with renal
impairment have a higher free fraction of midazoClin Pharmacokinet 2006; 45 (9)

Hepatic (oxidation,
conjugation)

Aqueous solubility

Metabolism

2006 Adis Data Information BV. All rights reserved.

108384

0.250.54

t /2 (min) [fast]
t1/2 (min) [intermediate]
t1/2 (min) [terminal]

CL (L/h/kg)b

31 ng/mL

4557

1.02.5b
1020b
2539b

Range.

Assumes an average weight per patient of 70kg.

Median.

Mean time SD to full recovery and discharge.

Propofol emulsion (Diprivan)

Propofol prodrug (AQUAVAN)

2.5 1.2
26.3 9.3
543 223 (residual)

4.7 0.8
58.2 17.9
651 194 (residual)

13 2
82 26

2.1 1.2
48b
14.4 6.5

3.0 0.7 g/mL

>1

92
128 17

2.0d
NR
11.0d

2.1 0.5 g/mL

NR

0.542.28

12.4 4.6

4.5 2.1

1.12.11

7.5, 10.0, 12.5

35

Hepatic (hydroxylation,
conjugation)

High

9799

Two compartments (prodrug)

Three compartments
(AQUAVAN-derived propofol)

1.02.5
35

Hepatic (hydroxylation,
conjugation)

Low

9799

Three compartments

Ketamine (racemic)

NR

0.5
510b
NR

NR

2.3

0.941.2

711b
130180b

2.13.3b

0.251.0

Hepatic (demethylation)

Low

7075

Two compartments or
noncompartmental

CL = total body clearance; EC50 = blood concentration associated with loss of consciousness in 50% of patients; IV = intravenous; NR = not reported; t1/2 = initial half-life; t1/2 =
intermediate half-life; t1/2 = terminal half life; Vss = volume of distribution at steady state.

Values are expressed as mean SD unless specified otherwise.

8d (range 421)
51.6 6.6e

onset of sedation (min)

time to fully alert (min)

Sedation and recovery after IV infusion administration

onset of sedation (min)

duration of sedation (min)
time to fully alert (min)

Sedation and recovery after IV bolus administration

EC50

Pharmacodynamic parameter

Renal excretion (%)

13.1b

Vss (L/kg)c

bolus (mg/kg)
IV infusion target plasma
concentration (g/mL)

High (at pH <4)

Low (at pH >4)

Protein binding (%)b

2.55mg

9597

Compartments of distribution
modelling

Doseb

Midazolam

Two compartments

Parameter

Table I. Comparative pharmacokinetic and pharmacodynamic parameters of midazolam, propofol, AQUAVAN-produced propofol and ketamine[3,17,23-36]a

858
Gan

Clin Pharmacokinet 2006; 45 (9)

PK/PD of Drugs for Moderate Sedation

859

Table II. Physical characteristics of sevoflurane and other inhalation anaesthetic agents[22,37]
Parameter

Sevoflurane Desflurane Nitrous oxide

Boiling point (C)

58.6

23.5

NR

Vapour pressure at 20C 157

(mm Hg)

669

NR

Potency (MAC)[38]

104

18.7

1.4

1.72.05

Partition coefficient (solubility)

oil : gas

47.253.4

blood : gas
0.68
0.42
0.47
MAC = minimum alveolar concentration (i.e. concentration that
produced immobility in 50% of individuals exposed to a noxious
stimulus); NR = not reported.

lam compared with healthy controls (6.5% vs 3.9%)

because of a reduction in serum albumin concentrations.[17,23] This is significant because an increased
free fraction will result in greater pharmacodynamic
effect.
Important pharmacokinetic characteristics that
influence the duration of sedation with midazolam
include its relatively long elimination half-life
(1.86.4 hours) and its distribution to adipose tissue.[17] With repeated administration, the adipose
sites become saturated and the drug redistributes to
the blood. These properties can result in a prolongation of sedation and the potential for a hangover
effect.[17] Although the drug is generally safe, repeated administration of midazolam in early studies
resulted in fatal drug accumulation.[43]
2.2 Propofol

Propofol is a highly lipophilic sedative hypnotic

agent that is structurally unrelated to other sedative
agents. The pharmacokinetics of propofol are most
commonly described using a three-compartment
model (figure 1). This model describes the three
dominant pharmacokinetic characteristics of propofol: (i) a rapid distribution of propofol from blood
into tissues; (ii) a similarly rapid clearance of propofol from the blood; and (iii) a slow return of drug
from the deep compartments.[24] The rapid penetration of propofol into the CNS and its rapid clearance
from the blood produce the fast onset of action and
the fast recovery characteristic of the drug.
The plasma concentration-time curve of propofol
is characterised by a triphasic pattern. There is a first
2006 Adis Data Information BV. All rights reserved.

phase of elimination (t1/2) of approximately 23

minutes that represents the distribution of the drug
into body tissues. The second phase is longer and
represents the metabolism of propofol (t1/2 = 3060
minutes), while the third much longer and highly
variable phase represents the slow elimination of the
drug from poorly perfused fat tissue (t1/2 = 245
hours).[17] As expected with a lipid-soluble compound, propofol has a very large volume of distribution (Vd).[24,44] Propofol initially distributes to well
perfused tissue, then to lean tissue and finally to fat
deposits.[24]
Propofol is primarily (88%) eliminated as
sulphate and/or glucuronide conjugates in the urine
with <0.3% excreted as the parent compound.[44]
The clearance of propofol (1.12.11 L/h/kg) generally exceeds hepatic blood flow, suggesting extrahepatic metabolism.[24] The pharmacokinetic profile of propofol can be altered with longer infusion
periods, as evidenced by a larger Vd and decreased
elimination compared with shorter infusions.[45] Although most pharmacokinetic variables are similar
between elderly patients and younger adult patients,
elderly patients have a smaller Vd and a lower
clearance compared with younger patients, indicating that elderly patients will require lower doses of
the drug.[44] The clearance and Vd of propofol are
also significantly greater in obese than in non-obese
patients.[46] Hepatic and renal dysfunction do not
Dose
k12

k13

(2.46 0.40) 101

V2

(3.91 0.58) 102

V1
(5.97 0.97) 10

V3
(1.91 0.20) 10

k21

k31
ke

(0.77 0.09) 101

Fig. 1. Schematic representation of the three-compartment model

used in the pharmacokinetic evaluation of propofol. A triexponential
curve is associated with three compartments (V1, V2, V3), with
elimination taking place from the V1 compartment. k12, k21 = transfer rate constants between compartments 1 and 2; k13, k31 = transfer rate constants between compartments 1 and 3; ke = elimination
rate constant; V1 = volume of distribution of the central compartment; V2, V3 = volume of distribution of the peripheral compartments (reproduced from Kanto and Gepts,[24] with permission).

Clin Pharmacokinet 2006; 45 (9)

860

Gan

significantly alter the pharmacokinetics of propofol.[44]

2.3 Ketamine

Ketamine is an antagonist of N-methyl-D-aspartate (NMDA) receptors and is structurally related

to phencyclidine.[47] The drug is highly lipid soluble,
resulting in extensive distribution to peripheral sites
(including the CNS) as evidenced by its relatively
large Vd.[48] The drug exhibits a biphasic plasma
concentration-time curve characterised by a rapid
elimination phase lasting approximately 45 minutes,
which corresponds to the analgesia period (t1/2 10
minutes). This is followed by a longer elimination
half-life that represents redistribution from the CNS
and hepatic metabolism (t1/2 = 23 hours).[25]
Ketamine is primarily eliminated via hepatic metabolism with conversion to an active metabolite
(norketamine). Elderly patients appear to have a
lower clearance and prolonged duration of action
compared with younger adult patients.[49] There are
modest pharmacokinetic differences between the S+
and R+ enantiomers, with the clearance of the S+
enantiomer being somewhat greater than that of the
R+ enantiomer.[25]
2.4 Sevoflurane

Sevoflurane has a low blood : gas solubility that

produces a rapid uptake and elimination of the
agent.[22,37] In healthy volunteers, the alveolar FA/FI
of sevoflurane (the rate at which fractional end-tidal
alveolar concentration [FA] approaches the fractional inspired concentration [FI]) was 0.85 (i.e. washin).[37] This increase was more rapid than that seen
with isoflurane or halothane but somewhat slower
than that seen with nitrous oxide and desflurane.[37]
Similarly, the washout of sevoflurane is faster than
that of isoflurane but slower than that of desflurane.
Elimination of the drug is primarily via the pulmonary route. A small proportion of the absorbed dose
of sevoflurane (15%) is metabolised via cytochrome P450 (CYP) 2E1, liberating inorganic fluoride ions and hexafluoroisopropanol.[37] However,
sevoflurane undergoes minimal renal defluorination.[50]
2006 Adis Data Information BV. All rights reserved.

2.5 AQUAVAN

AQUAVAN, a new sedative/hypnotic agent, is

a water-soluble prodrug of propofol that is currently
in clinical development in the US. After intravenous
administration, propofol is released from this
prodrug by the enzymatic action of alkaline phosphatases in the vascular endothelium.[51] This action
provides predictable and controlled release of propofol with a smooth rise to therapeutic plasma propofol concentrations. The pharmacokinetics of
AQUAVAN are best described by a two-compartment model,[51] while AQUAVAN-delivered propofol (once converted) is best described by a threecompartment model.[26] The parent compound has a
relatively fast distribution to the peripheral compartment, a small Vd and a short terminal half-life (t1/2 =
3846 minutes), whereas AQUAVAN-delivered
propofol, as expected, is lipophilic and has large
peripheral compartments (as described previously).[26,51]
Despite producing the same active compound,
AQUAVAN-delivered propofol has a different
pharmacokinetic and pharmacodynamic profile than
propofol emulsion. For example, in experimental
animals AQUAVAN-delivered propofol had a
longer elimination half-life, a larger Vd, and a
delayed onset of action compared with propofol
emulsion.[52] Differences between propofol emulsion and AQUAVAN-delivered propofol were also seen in healthy volunteers, although the type of
differences varied from those seen in animals. Propofol from AQUAVAN had a longer residence
time, larger Vd, higher clearance and shorter elimination half-life than propofol emulsion.[26]
The time course of plasma propofol concentrations is also different between propofol emulsion
and AQUAVAN-delivered propofol, the latter
having lower peak concentrations and more prolonged plasma concentrations (figure 2).[26] Dose
escalation of AQUAVAN results in a less than
proportional increase in exposure to AQUAVANdelivered propofol as measured by maximum plasma concentration (Cmax) and area under the plasma
concentration-time curve (AUC).[53]
Clin Pharmacokinet 2006; 45 (9)

PK/PD of Drugs for Moderate Sedation

10

861

10
1

0.1
0.01

0.001
0

480

960

1440

Propofol concentration (g/mL)

4
2
0

10

10
1

0.1

6
0.01
0

480

960

1440

4
2
0
0

20

40

60

80

100

120

Time (min)
Fig. 2. Plasma concentration-time curve for (a) propofol emulsion
and (b) AQUAVAN-delivered propofol in healthy volunteers. The
insets show the complete plasma concentration-time courses (reproduced from Fechner et al.,[26] with permission).

3. Relationship between
Pharmacokinetic Parameters and
Pharmacodynamic Effects

3.1 Midazolam

Most, but not all, evidence suggests that there is a

wide range of midazolam blood levels associated
with adequate sedation.[54-57] The level of sedation
appears to correlate better to the level of receptor
binding,[57] although some have found the correlation is relatively poor.[56] In addition, this correlation
is likely to be impaired in those with alterations in
benzodiazepine receptor density (e.g. alcoholics) as
demonstrated by a decreased sensitivity to
benzodiazepines in these patients.[58,59] Further complicating the pharmacokinetic/pharmacodynamic response of midazolam are the observations of a dis 2006 Adis Data Information BV. All rights reserved.

tinct hysteresis between plasma concentrations and

CNS effects,[55] and the greater sensitivity to the
CNS depressant effects of midazolam among elderly patients that is not explained by changes in
pharmacokinetics.[55] In addition, midazolam has also been shown to have both stimulatory and sedative
properties,[60,61] with stimulatory effects seen shortly
after infusion in small percentages of patients.[62]
This effect may explain why the drug is associated
with rebound adverse effects and tolerance.[60]
As noted earlier, protracted administration of
midazolam can produce prolonged sedation due to
accumulation of midazolam and its active metabolite in adipose tissue from which it is slowly released.[17,63] The risk of such accumulation is greatest in patients with renal impairment but can also
occur in those with normal renal function. The
benzodiazepine antagonist flumazenil is effective
for reducing the residual effects (especially sedation) of midazolam, although the duration of action
of a single dose of flumazenil may be shorter than
the hangover effect of midazolam.[64,65]
3.2 Propofol

The plasma concentration of propofol required

for sedation depends on the desired depth of sedation and whether concomitant agents are used.[44] In
general, propofol produces sedation in a dose-dependent fashion, with lower plasma concentrations
(0.51.5 g/L) needed for sedation and substantially
higher plasma concentrations (316 g/L) required
for surgical anaesthesia.[44] Loss of consciousness is
typically reported at concentrations ranging from
3.5 to 10.5 g/L.[24] There is also an inverse correlation between plasma propofol concentrations and
mean EEG frequency, and a direct correlation with
mean EEG amplitude.[24] However, there is substantial variability in the concentrations of propofol at
the site of a drug effect that induces loss of responsiveness. The effect may be due to a complex interaction between the dose, rate of administration and
time of propofol induction, which may influence the
rate of plasma effect-site equilibration.[24,66]
Clin Pharmacokinet 2006; 45 (9)

862

Gan

3.3 Ketamine

Ketamine has general anaesthetic properties most

prominently characterised by profound analgesia,
acting as an antagonist on the NMDA receptor.
Unlike opioid analgesics, ketamine does not adversely affect respiratory or cardiovascular stability.[49] However, tachycardia was reported in 27.9%
of children sedated with ketamine and midazolam
who were undergoing minor surgical procedures.[67]
The drug has a rapid onset of action (0.5 minute) and
a short duration of action. The CNS depressant
effects of ketamine are dose dependent, with concentrations of 0.62.0 g/mL associated with general anaesthesia.[68] In children receiving postoperative analgesia and sedation following cardiac surgery, the children were arousable when ketamine
concentrations fell below 1.01.5 g/mL.[69]
3.4 Sevoflurane

Sevoflurane has been investigated for providing

sedation because of its rapid onset and offset as well
as its non-pungent property, which makes inhalation
of this agent tolerable. Sevoflurane produces dosedependent depressant effects on the central nervous,
respiratory and cardiovascular systems.[37,50] In general, sedation with sevoflurane is associated with
more rapid recovery and faster return of cognitive
function than with midazolam.[70] In a randomised,
comparative study in patients receiving sedation for
surgery, 76% of patients receiving sevoflurane had
return of cognitive function 30 minutes postoperatively compared with 35% of midazolam-treated
patients.[70]
The concentrations of sevoflurane required to
produce sedation are variable. In patients who were
slowly titrated to a moderate level of sedation with
sevoflurane prior to surgery, there was a wide interand intraindividual variability between end-tidal
sevoflurane concentrations and depth of sedation as
assessed by the bispectral index (BIS), a processed
EEG measure between 0 (no electrical activity) and
100 (awake), which makes it difficult to predict
depth of sedation.[71] For example, many patients
with 1% end-tidal sevoflurane concentrations were
unresponsive to voice at a BIS score of 98, whereas
2006 Adis Data Information BV. All rights reserved.

two patients with 1.3%1.5% end-tidal sevoflurane

concentrations were responsive to voice at BIS
scores of 41 and 52.[71]
3.5 AQUAVAN

In rats, AQUAVAN-delivered propofol was associated with a delayed onset, a sustained duration
of action and greater potency compared with propofol emulsion with respect to plasma concentration.[52] Initial studies in healthy volunteers found
that propofol from AQUAVAN had a higher potency than propofol emulsion with respect to plasma
concentration and did not show a hysteresis between
plasma concentrations and effect.[26] However, another study found that when corrected for the brain
concentration of propofol, the pharmacodynamic effect of AQUAVAN-delivered propofol was similar to that of propofol emulsion.[72]
Fechner et al.[27] demonstrated in healthy volunteers that continuous infusions of AQUAVANproduced, dose-dependent sedation, as measured by
the BIS and the Modified Observers Assessment of
Alertness/Sedation (MOAA/S) scale. Probability
curves from logistic regression analysis indicated
that an AQUAVAN-delivered propofol plasma
concentration of 1.85 g/mL or an initial intravenous bolus dose of about 10 mg/kg of AQUAVAN
had the highest probability of producing an MOAA/
S score of 3, corresponding to a moderate level of
sedation.[27,28] Gibiansky et al.[53] found that the
dose-response relationship for AQUAVAN-delivered propofol was curvilinear, with a linear relationship observed at doses up to 20 mg/kg.
A physiological model was used to compare the
pharmacokinetics and pharmacodynamics (BIS
analysis) of propofol produced after intravenous
infusion or bolus administration of AQUAVAN
with those of propofol emulsion.[73] This model took
into account the nonlinear protein binding of propofol and the metabolism of propofol in the liver and
other tissues (e.g. venous endothelium) prior to entering into the systemic circulation. Compared with
a continuous infusion of propofol emulsion (50 mg/
minute), bolus injection of an equipotent dose of
AQUAVAN produced an equivalent time to loss
Clin Pharmacokinet 2006; 45 (9)

PK/PD of Drugs for Moderate Sedation

of consciousness. However, AQUAVAN was associated with a longer time to peak BIS and a more
prolonged pharmacodynamic effect.[73] This was
probably related to a slower decrease in concentrations of AQUAVAN-delivered propofol. In addition, AQUAVAN-delivered propofol plasma concentrations were predictive of effect-site concentrations and clinical effect, although there were
concentration-related differences in the equilibration time (Ke0 = 1.2 minute1 at AQUAVAN 30
mg/kg dose) between plasma and effect-site concentrations.[73]
4. Drug Combinations
Sedation regimens for moderate sedation frequently include the use of more than one agent, such
as a hypnotic/anxiolytic (e.g. propofol, midazolam)
plus an opioid (e.g. fentanyl, remifentanil, meperidine) for the purpose of anaesthesia and analgesia.
These combinations have been used with different
degrees of patient satisfaction and procedural success, and there are limited definitive data demonstrating the superiority of combination regimens
over single agents. For example, in a randomised
study comparing propofol plus remifentanil with
propofol alone in patients undergoing colonoscopy,
the addition of remifentanil resulted in a decreased
requirement for propofol.[74] However, patients in
the combination group experienced more respiratory
and blood pressure depressant effects and had a
lower recovery and lower patient satisfaction than
with propofol alone.
A number of trials have attempted to quantify the
optimal concentrations of sedation agents that are
used in combination (e.g. propofol emulsion/various
opioids),[75] or compared sets of different drug combinations.[9] For example, low-dose midazolam
(0.03 mg/kg) plus a bolus dose of propofol (0.7 mg/
kg) followed by patient-controlled infusion of propofol (2 mg/kg/h) improved the levels of patient
acceptability and comfort during apicectomy compared with the levels achieved with propofol
alone.[76] In another study, low-dose propofol (i.e.
mean 98mg for colonoscopy and 79mg for gastroscopy) combined with midazolam and fentanyl (or
2006 Adis Data Information BV. All rights reserved.

863

meperidine) achieved a moderate level of sedation

and measures of recovery that were comparable to
those of standard-dose propofol.[6] Benzodiazepines
are frequently added to ketamine to reduce emergence reactions but may be associated with an increased risk of hypoxaemia.[77]
Initial studies also suggest that AQUAVAN can
be effectively combined with other agents. Intravenous bolus administration of AQUAVAN
(7.512.5 mg/kg) following pretreatment with intravenous fentanyl (0.51.5 g/mL) induced sedation
adequate for colonoscopy within 2 minutes of administration. Recovery to fully alert occurred within
11 minutes (median time) after end of procedure.[28]
5. Safety Issues and Adverse Events
In addition to the normal concerns with oversedation and the associated cardiopulmonary risks, adequate and safe sedation in critically ill or high-risk
patients is the primary measure of a good sedation
agent.[78] High-risk patients may include those with
end-stage renal disease, chronic liver disease, or
compromised cardiac or pulmonary function. Other
patient factors such as age and weight should also be
taken into account when calculating dosage.
Dexmedetomidine, a highly selective 2-adrenoceptor agonist with sedative and analgesic effects
used for sedating patients in the intensive care
unit,[79] has a limited role in providing sedation and
analgesia for colonoscopy because of the drugs
complicated administration regimen, prolonged recovery time, pronounced haemodynamic instability
and distressing adverse effects.[80] A dose sufficient
to produce sedation during colonoscopy results in
profound hypotension and bradycardia.[80]
5.1 Midazolam

Since midazolam is highly protein bound, hypoalbuminaemia may result in increased distribution
of the drug into the CNS, leading to increased sedation effects.[17] The reduced clearance of midazolam
in patients >65 years of age means that doses approximately half those used in younger patients are
required to produce an equivalent level of sedation.[17] There are also a number of patient groups
Clin Pharmacokinet 2006; 45 (9)

864

Gan

(e.g. elderly, critically ill, those with hepatic dysfunction) who have decreased clearance of midazolam. These patients should receive reduced doses
and should be monitored for excessive sedation.[38,42]
5.2 Propofol

Some of the limitations of propofol emulsion and

its adverse effects include the risk of extraneous
microbial contamination of the emulsion formulation, lipidaemia induced by repeated administration
of the agent over time, intravenous injection site
pain, oversedation and risk of hypotension/cardiopulmonary complications. Although short-term infusions of propofol emulsion (3 days) have no
effect on lipid levels, longer infusions produce progressive increases in serum lipid levels, particularly
triglycerides.[44] Green discoloration of the urine can
also be seen after long-term administration, although its significance is not known.[81] There are
also concerns about the safety of propofol for procedural sedation because of possible problems with
hypoxaemia, hypotension and decreased cardiac
output when administered by non-anaesthesiologists.[82] Propofol has well established respiratory
depressant effects, particularly at anaesthetic doses
and when used in combination with opioids;[74,83,84]
however, comparative studies have found that propofol does not induce greater changes in arterial
blood gases than midazolam.[44] Propofol infusions
may also decrease cardiac output, particularly in
conjunction with the coadministration of opioids
(e.g. fentanyl).[16] Propofol-induced decreases in
blood pressure are generally dose- and infusion-rate
dependent, an effect at least partially related to
decreases in peripheral vascular resistance. Notwithstanding this reduction in arterial pressure, propofol
tends to cause a modest decrease in heart rate.[44]
The vasodilatory effects of propofol are exacerbated
when patients are in a state of relative hypovolaemia.
Injection site pain is a particularly common problem with propofol emulsion, occurring in up to 80%
of patients when the drug is administered in peripheral veins.[85] The effect appears to be greater when
2006 Adis Data Information BV. All rights reserved.

propofol is injected into the dorsum of the hand

compared with the forearm or antecubital fossa.[86] It
has been suggested that the lipid solvent of propofol
induces the release of bradykinin by activating the
plasma kallikrein-kinin system, resulting in a modification of the local vein that increases the contact
between the aqueous phase of propofol and the free
nerve endings of the vessel.[87] Concomitant use of a
local anaesthetic agent (e.g. lidocaine [lignocaine])
is commonly used to reduce local pain.[88] This can
include the administration of lidocaine immediately
prior to propofol, the mixing of propofol with lidocaine or the use of topical EMLA cream (eutectic
mixture of local anaesthetics).[86] Other methods of
reducing local pain included administration of an
opioid, metoclopramide, cold saline or topical nitroglycerin prior to propofol.[86]
Several recent studies demonstrated the feasibility and safety of propofol sedation administered by
gastroenterologists, nurses and patients in shortterm endoscopic procedures.[8,9,89-92] For example,
nurse-administered propofol was associated with
faster recovery, quicker discharge and better postoperative neuropsychological test scores than with
midazolam plus fentanyl in patients undergoing outpatient colonoscopy.[90] Similarly, PCS for colonoscopy with propofol plus alfentanil produced faster
recovery, quicker discharge and similar patient satisfaction than with physician-administered midazolam and meperidine.[9]
Propofol also appears to be a safe and effective
sedation agent in critically ill or high-risk patients,
those with end-stage renal disease and the elderly.[93]
For example, in high-risk patients (American Society of Anesthesiologists [ASA] physical status III and
IV) undergoing colonoscopy, propofol produced effective sedation, although there was an increased
risk for clinically relevant short-term oxygen
desaturation (<90%) among ASA physical status III
and IV patients (3.6% vs 1.7% compared with ASA
I and II patients, p = 0.036) that necessitated dose
reductions of 1020%.[94]
Another study in patients with cirrhosis undergoing variceal screening found that propofol alone was
superior in time to sedation, adequate level of sedaClin Pharmacokinet 2006; 45 (9)

PK/PD of Drugs for Moderate Sedation

tion, time to full recovery and greater overall patient

satisfaction than combination sedation with midazolam and meperidine.[95] In elderly patients undergoing outpatient colonoscopy, patient-controlled administration of propofol produced faster recovery
time and significantly less hypotension than intravenous sedation with diazepam and meperidine.[10]
5.3 Ketamine

Ketamine has a narrow therapeutic window.

Emergence reactions such as disorientation, dreamlike experiences, vivid imagery, hallucinations and
delirium are among the most important adverse reactions. These reactions are particularly common in
adults.[77] These reactions are reduced when
ketamine is used in conjunction with a benzodiazepine or propofol. It can also increase the incidence of nausea and vomiting.[96]
5.4 Sevoflurane

As with other inhalational anaesthetics, sevoflurane can be associated with airway complications
such as breath holding, coughing, excitement and
laryngospasm.[37,50] Changes in haemodynamics are
generally small and the risk of fluoride-induced
nephrotoxicity appears to be minimal. In a comparative trial in patients undergoing moderate sedation,
sevoflurane was associated with significantly more
disinhibition excitement (70%) than with propofol
(36%) or midazolam (5%).[71]
5.5 AQUAVAN

Some of the concerns associated with the use of

propofol emulsion may be mitigated with the use of
AQUAVAN, which has not been reported to induce injection site pain[73] and does not have safety
issues relating to lipid-containing formulation (contamination, hyperlipidaemia). In healthy volunteers,
AQUAVAN-delivered propofol was generally associated with a haemodynamic profile similar to that
produced by propofol emulsion except for an initial
tachycardia in those receiving AQUAVAN.[73]
The onset of cardiovascular depression with
AQUAVAN was also delayed and smoother compared with propofol emulsion. In a phase II, open 2006 Adis Data Information BV. All rights reserved.

865

label, dose-ranging trial evaluating AQUAVAN in

patients undergoing colonoscopy, transient, mild to
moderate pelvic/perianal tingling, itching or burning
sensation was noted in 85% of patients.[28] The use
of AQUAVAN in high-risk patients (e.g. bronchoscopy and intensive care unit sedation) is currently under evaluation.
6. Drug Interactions
6.1 Midazolam

Midazolam is metabolised via CYP3A4 oxidases. Therefore, coadministration of midazolam

with CYP inhibitors (e.g. azole antifungals,
macrolide antibacterials, grapefruit juice) can result
in excess sedation because of decreased clearance.[97-99] For example, coadministration of intravenous midazolam with azole antifungals (e.g.
itraconazole, fluconazole) decreased midazolam
clearance by 5070%.[99] The interaction between
midazolam and azoles is even more pronounced
when midazolam is administered orally, which can
result in 3- to 15-fold increases in midazolam drug
exposure (as measured by the AUC).[99] This result
may be explained by the potentially greater inhibitory effect of azoles on the CYP3A4-dependent, firstpass metabolism of midazolam that occurs predominantly in the gut mucosa,[100] resulting in slower
breakdown and clearance of midazolam administered by the oral route in the presence of antifungal
azoles.
6.2 Propofol

Since propofol is metabolised via the CYP2C9

pathway, drugs that inhibit this pathway theoretically could alter the clearance of propofol. However,
coadministration of propofol with parecoxib, a
COX-2-specific inhibitor that is a substrate for
CYP2C9, demonstrated no effect on propofol
pharmacokinetic parameters.[101] Propofol inhibits
the metabolism of both alfentanil and sufentanil,
producing increases in opioid concentrations of approximately 15%.[75] Conversely, these agents increase the Vd and reduce the clearance of propofol,
resulting in increases in propofol concentrations of
Clin Pharmacokinet 2006; 45 (9)

866

Gan

approximately 20%.[102] Furthermore, combination

of propofol and these opioids has synergistic sedative and analgesic effects, with fentanyl and alfentanil concentrations of 3 ng/mL and 122 ng/mL,
respectively, reducing the propofol blood concentration associated with loss of consciousness in 50% of
patients (EC50) by 40%.[75]
6.3 Sevoflurane

The minimum alveolar concentration of sevoflurane is reduced by the concomitant administration of

nitrous oxide and opioids. Sevoflurane also potentiates the pharmacological activity of neuromuscular
blocking agents. Since sevoflurane is metabolised
by CYP2E1, agents that induce this isozyme (isoniazid, alcohol [ethanol]) may increase the metabolism
of the drug.[37,50]
6.4 AQUAVAN

Preliminary data indicate that coadministration

of AQUAVAN with fentanyl provides satisfactory
sedation with an acceptable safety profile in patients
undergoing colonoscopy.[28] In the dose-ranging
study of AQUAVAN by Pruitt et al.[28] (<619 to
>931mg), hypoxaemia (<90% O2 saturation) increased modestly at the higher doses of this agent in
combination with fentanyl pretreatment, but resolved quickly with the administration of oxygen or
repositioning. Transient apnoea was observed in 7
of 93 (7%) volunteers in this study, 5 of whom had
received the highest dose of AQUAVAN plus
fentanyl at doses >1 g/kg. One episode of apnoea
was a serious adverse event requiring a 3-minute
interval of mechanical ventilation.[28]
7. Conclusions
The increase in the total number of interventional
procedures performed annually[4] has increased interest in the types of sedation agents and protocols
that are amenable to short procedures and that also
achieve high levels of patient comfort and satisfaction. This has been paralleled by an increased interest in the administration of moderate sedation agents
by non-anaesthesiologists and trained nurses, and
via patient-controlled devices.[7-11,103]
2006 Adis Data Information BV. All rights reserved.

Properties of an ideal agent for moderate sedation

include rapid onset, rapid recovery, clear-headed
recovery, ease of use, safety and no requirement for
monitored anaesthesia care. The currently available
agents most commonly used in short-term moderate
sedation (e.g. midazolam, propofol, ketamine) are
generally effective sedative agents and have some,
but not all, of these characteristics. For example, the
benzodiazepine midazolam is an effective agent
when administered alone or in combination with
other agents (e.g. opioids) for providing moderate
sedation during short procedures. The primary
drawback of this agent is the prolongation of sedation and hangover effects induced by the relatively
long half-life of midazolam and its metabolites and
their slow release from adipose tissue after repeated
administration.
Recent studies have also shown that the shortacting agent propofol, an anaesthetic/hypnotic agent
used previously for deep sedation, can be used successfully and safely for moderate sedation during a
variety of interventional procedures. Combinations
of propofol and other sedation agents can achieve
excellent results in sedation and patient satisfaction
while providing many of the characteristics of an
ideal procedural sedation agent for colonoscopy.
In addition, the availability of open TCI devices
precluding the use of prefilled syringes that allow
for nearly no propofol wastage has rendered this
technique economically attractive as well as clinically efficient. However, the use of propofol emulsion is limited by injection site pain, oversedation
and the risk of hypotension/cardiopulmonary complications. Possibly of most importance is the labelling requirement for monitored anaesthesia care,
meaning that it is recommended to be administered
only by physicians trained in anaesthesia care. The
water-soluble prodrug of propofol, AQUAVAN,
may have the potential to address some of these
limitations and safety concerns.
In conclusion, there have been substantial advances in the delivery of moderate procedural sedation in recent years. The development of new sedative agents and improvements in techniques may
Clin Pharmacokinet 2006; 45 (9)

PK/PD of Drugs for Moderate Sedation

fulfil many unmet needs in the provision of moderate sedation for invasive procedures.
Acknowledgements
Editorial assistance was provided on this manuscript
through an unrestricted grant from MGI Pharma. The author
is grateful for editorial assistance provided by Nexus Communications, Inc., North Wales, PA, USA.
The author serves on the advisory board of MGI Pharma
and has received grant support related to research activities.

References
1. Bahn EL, Holt KR. Procedural sedation and analgesia: a review
and new concepts. Emerg Med Clin North Am 2005; 23:
503-17
2. Javorski JJ, Hansen DD, Laussen PC, et al. Paediatric cardiac
catheterization: innovations. Can J Anaesth 1995; 42: 310-29
3. Cillo Jr JE. Propofol anesthesia for outpatient oral and maxillofacial surgery. Oral Surg Oral Med Oral Pathol Oral Radiol
Endod 1999; 87: 530-8
4. Heuss LT, Froehlich F, Beglinger C. Changing patterns of
sedation and monitoring practice during endoscopy: results of
a nationwide survey in Switzerland. Endoscopy 2005; 37:
161-6
5. Froehlich F, Schwizer W, Thorens J, et al. Conscious sedation
for gastroscopy: patient tolerance and cardiorespiratory parameters. Gastroenterology 1995; 108: 697-704
6. Cohen LB, Hightower CD, Wood DA, et al. Moderate level
sedation during endoscopy: a prospective study using lowdose propofol, meperidine/fentanyl, and midazolam. Gastrointest Endosc 2004; 59: 795-803
7. Kulling D, Bauerfeind P, Fried M, et al. Patient-controlled
analgesia and sedation in gastrointestinal endoscopy. Gastrointest Endosc Clin N Am 2004; 14: 353-68
8. Heuss LT, Drewe J, Schnieper P, et al. Patient-controlled versus
nurse-administered sedation with propofol during colonoscopy: a prospective randomized trial. Am J Gastroenterol 2004;
99: 511-8
9. Bright E, Roseveare C, Dalgleish D, et al. Patient-controlled
sedation for colonoscopy: a randomized trial comparing patient-controlled administration of propofol and alfentanil with
physician-administered midazolam and pethidine. Endoscopy
2003; 35: 683-7
10. Lee DW, Chan AC, Sze TS, et al. Patient-controlled sedation
versus intravenous sedation for colonoscopy in elderly patients: a prospective randomized controlled trial. Gastrointest
Endosc 2002; 56: 629-32
11. Irwin MG, Thompson N, Kenny GN. Patient-maintained propofol sedation. Assessment of a target-controlled infusion
system. Anaesthesia 1997; 52: 525-30
12. American Society of Anesthesiologists. Practice guidelines for
sedation and analgesia by non anesthesiologists. Anesthesiology 2005; 96: 1004-17
13. Gilger MA, Spearman RS, Dietrich CL, et al. Safety and effectiveness of ketamine as a sedative agent for pediatric GI
endoscopy. Gastrointest Endosc 2004; 59: 659-63
14. Ristikankare M, Julkunen R, Mattila M, et al. Conscious sedation and cardiorespiratory safety during colonoscopy. Gastrointest Endosc 2000; 52: 48-54

2006 Adis Data Information BV. All rights reserved.

867

15. Stewart RD. Nitrous oxide sedation/analgesia in emergency

medicine. Ann Emerg Med 1985; 14: 139-48
16. Skues MA, Prys-Roberts C. The pharmacology of propofol. J
Clin Anesth 1989; 1: 387-400
17. Horn E, Nesbit SA. Pharmacology and pharmacokinetics of
sedatives and analgesics. Gastrointest Endosc Clin N Am
2004; 14: 247-68
18. Karan SB, Bailey PL. Update and review of moderate and deep
sedation. Gastrointest Endosc Clin N Am 2004; 14: 289-312
19. Gepts E. Pharmacokinetic concepts for TCI anaesthesia. Anaesthesia 1998; 53 Suppl. 1: 4-12
20. Rodrigo MR, Irwin MG, Tong CK, et al. A randomised crossover comparison of patient-controlled sedation and patientmaintained sedation using propofol. Anaesthesia 2003; 58:
333-8
21. Egan TD. Target-controlled drug delivery: progress toward an
intravenous "vaporizer" and automated anesthetic administration. Anesthesiology 2003; 99: 1214-9
22. Behne M, Wilke HJ, Harder S. Clinical pharmacokinetics of
sevoflurane. Clin Pharmacokinet 1999; 36: 13-26
23. Fragen RJ. Pharmacokinetics and pharmacodynamics of
midazolam given via continuous intravenous infusion in intensive care units. Clin Ther 1997; 19: 405-19
24. Kanto J, Gepts E. Pharmacokinetic implications for the clinical
use of propofol. Clin Pharmacokinet 1989; 17: 308-26
25. Persson J, Hasselstrom J, Maurset A, et al. Pharmacokinetics
and non-analgesic effects of S- and R-ketamines in healthy
volunteers with normal and reduced metabolic capacity. Eur J
Clin Pharmacol 2002; 57: 869-75
26. Fechner J, Ihmsen H, Hatterscheid D, et al. Comparative
pharmacokinetics and pharmacodynamics of the new propofol
prodrug GPI 15715 and propofol emulsion. Anesthesiology
2004; 101: 626-39
27. Fechner J, Ihmsen H, Schiessl C, et al. Sedation with GPI
15715, a water-soluble prodrug of propofol, using targetcontrolled infusion in volunteers. Anesth Analg 2005; 100:
701-6
28. Pruitt RE, Cohen LB, Gibiansky E, et al. A randomized, openlabel, multicenter, dose-ranging study of sedation with
AQUAVAN injection (GPI 15715) during colonoscopy. In:
Digestive Disease Week; 2005 May 14-19, Chicago (IL), 2005
29. Greenblatt DJ, Ehrenberg BL, Culm KE, et al. Kinetics and
EEG effects of midazolam during and after 1-minute, 1-hour,
and 3-hour intravenous infusions. J Clin Pharmacol 2004; 44:
605-11
30. Wehrmann T, Kokabpick S, Lembcke B, et al. Efficacy and
safety of intravenous propofol sedation during routine ERCP: a
prospective, controlled study. Gastrointest Endosc 1999; 49:
677-83
31. Zakko SF, Seifert HA, Gross JB. A comparison of midazolam
and diazepam for conscious sedation during colonoscopy in a
prospective double-blind study. Gastrointest Endosc 1999; 49:
684-9
32. Full prescribing information. Richmond (ON): Novex Pharma,
2000 [online]. Available from URL: http://www.apotexcorp.com/pdf/Midazolam%20Inj%20bio%20&%20PI.pdf
[Accessed 2005 Jun 20]
33. Wilson KE, Girdler NM, Welbury RR. Randomized, controlled,
cross-over clinical trial comparing intravenous midazolam sedation with nitrous oxide sedation in children undergoing
dental extractions. Br J Anaesth 2003; 91: 850-6
34. Geisslinger G, Hering W, Kamp HD, et al. Pharmacokinetics of
ketamine enantiomers. Br J Anaesth 1995; 75: 506-7

Clin Pharmacokinet 2006; 45 (9)

868

35. Hijazi Y, Boulieu R. Protein binding of ketamine and its active

metabolites to human serum. Eur J Clin Pharmacol 2002; 58:
37-40
36. Sipe BW, Rex DK, Latinovich D, et al. Propofol versus midazolam/meperidine for outpatient colonoscopy: administration by
nurses supervised by endoscopists. Gastrointest Endosc 2002;
55: 815-25
37. Patel SS, Goa KL. Sevoflurane: a review of its pharmacodynamic and pharmacokinetic properties and its clinical use in general anaesthesia. Drugs 1996; 51: 658-700
38. MacGilchrist AJ, Birnie GG, Cook A, et al. Pharmacokinetics
and pharmacodynamics of intravenous midazolam in patients
with severe alcoholic cirrhosis. Gut 1986; 27: 190-5
39. Cook LB, Lockwood GG, Moore CM, et al. True patientcontrolled sedation. Anaesthesia 1993; 48: 1039-44
40. Maitre PO, Funk B, Crevoisier C, et al. Pharmacokinetics of
midazolam in patients recovering from cardiac surgery. Eur J
Clin Pharmacol 1989; 37: 161-6
41. Zomorodi K, Donner A, Somma J, et al. Population
pharmacokinetics of midazolam administered by target controlled infusion for sedation following coronary artery bypass
grafting. Anesthesiology 1998; 89: 1418-29
42. Pentikainen PJ, Valisalmi L, Himberg JJ, et al. Pharmacokinetics of midazolam following intravenous and oral administration in patients with chronic liver disease and in healthy
subjects. J Clin Pharmacol 1989; 29: 272-7
43. Bell GD, Spickett GP, Reeve PA, et al. Intravenous midazolam
for upper gastrointestinal endoscopy: a study of 800 consecutive cases relating dose to age and sex of patient. Br J Clin
Pharmacol 1987; 23: 241-3
44. Fulton B, Sorkin EM. Propofol. An overview of its pharmacology and a review of its clinical efficacy in intensive care
sedation. Drugs 1995; 50: 636-57
45. Frenkel C, Schuttler J, Ihmsen H, et al. Pharmacokinetics and
pharmacodynamics of propofol/alfentanil infusions for sedation in ICU patients. Intensive Care Med 1995; 21: 981-8
46. Servin F, Farinotti R, Haberer JP, et al. Propofol infusion for
maintenance of anesthesia in morbidly obese patients receiving nitrous oxide: a clinical and pharmacokinetic study. Anesthesiology 1993; 78: 657-65
47. Peyton SH, Couch AT, Bost RO. Tissue distribution of
ketamine: two case reports. J Anal Toxicol 1988; 12: 268-9
48. Xie H, Wang X, Liu G, et al. Analgesic effects and
pharmacokinetics of a low dose of ketamine preoperatively
administered epidurally or intravenously. Clin J Pain 2003; 19:
317-22
49. Tsui BC, Wagner A, Finucane B. Regional anaesthesia in the
elderly: a clinical guide. Drugs Aging 2004; 21: 895-910
50. Goa KL, Noble S, Spencer CM. Sevoflurane in paediatric anaesthesia: a review. Paediatr Drugs 1999; 1: 127-53
51. Fechner J, Ihmsen H, Hatterscheid D, et al. Pharmacokinetics
and clinical pharmacodynamics of the new propofol prodrug
GPI 15715 in volunteers. Anesthesiology 2003; 99: 303-13
52. Schywalsky M, Ihmsen H, Tzabazis A, et al. Pharmacokinetics
and pharmacodynamics of the new propofol prodrug GPI
15715 in rats. Eur J Anaesthesiol 2003; 20: 182-90
53. Gibiansky E, Struys MM, Gibiansky L, et al. AQUAVAN
injection, a water-soluble prodrug of propofol, as a bolus
injection: a phase I dose-escalation comparison with
DIPRIVAN (part 1): pharmacokinetics. Anesthesiology 2005;
103: 718-29
54. Oldenhof H, de Jong M, Steenhoek A, et al. Clinical
pharmacokinetics of midazolam in intensive care patients, a

2006 Adis Data Information BV. All rights reserved.

Gan

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

wide interpatient variability? Clin Pharmacol Ther 1988; 43:

263-9
Albrecht S, Ihmsen H, Hering W, et al. The effect of age on the
pharmacokinetics and pharmacodynamics of midazolam. Clin
Pharmacol Ther 1999; 65: 630-9
Short TG, Young KK, Tan P, et al. Midazolam and flumazenil
pharmacokinetics and pharmacodynamics following simultaneous administration to human volunteers. Acta Anaesthesiol
Scand 1994; 38: 350-6
Tolia V, Brennan S, Aravind MK, et al. Pharmacokinetic and
pharmacodynamic study of midazolam in children during esophagogastroduodenoscopy. J Pediatr 1991; 119: 467-71
Volkow ND, Wang GJ, Hitzemann R, et al. Decreased cerebral
response to inhibitory neurotransmission in alcoholics. Am J
Psychiatry 1993; 150: 417-22
Abi-Dargham A, Krystal JH, Anjilvel S, et al. Alterations of
benzodiazepine receptors in type II alcoholic subjects measured with SPECT and [123I]iomazenil. Am J Psychiatry
1998; 155: 1550-5
Lau CE, Wang Y, Ma F. Pharmacokinetic-pharmacodynamic
modeling of the coexistence of stimulatory and sedative components for midazolam. Eur J Pharmacol 1998; 346: 131-44
Golparvar M, Saghaei M, Sajedi P, et al. Paradoxical reaction
following intravenous midazolam premedication in pediatric
patients: a randomized placebo controlled trial of ketamine for
rapid tranquilization. Paediatr Anaesth 2004; 14: 924-30
Massanari M, Novitsky J, Reinstein LJ. Paradoxical reactions in
children associated with midazolam use during endoscopy.
Clin Pediatr (Phila) 1997; 36: 681-4
Bauer TM, Ritz R, Haberthur C, et al. Prolonged sedation due to
accumulation of conjugated metabolites of midazolam. Lancet
1995; 346: 145-7
The Flumazenil in Intravenous Conscious Sedation with
Diazepam Multicenter Study Group I. Reversal of central
benzodiazepine effects by flumazenil after conscious sedation
produced by intravenous diazepam. Clin Ther 1992; 14: 895909
Short TG, Galletly DC. Residual psychomotor effects following
reversal of midazolam sedation with flumazenil. Anaesth Intensive Care 1989; 17: 290-7
Doufas AG, Bakhshandeh M, Bjorksten AR, et al. Induction
speed is not a determinant of propofol pharmacodynamics.
Anesthesiology 2004; 101: 1112-21
Cheuk DK, Wong WH, Ma E, et al. Use of midazolam and
ketamine as sedation for children undergoing minor operative
procedures. Support Care Cancer 2005; 13: 1001-9
Ketamine 2005 [online]. Available from URL: http://www.metrohealthanesthesia.com/edu/ivanes/ketamine5.htm [Accessed
2005 Aug 29]
Hartvig P, Larsson E, Joachimsson PO. Postoperative analgesia
and sedation following pediatric cardiac surgery using a constant infusion of ketamine. J Cardiothorac Vasc Anesth 1993;
7: 148-53
Ibrahim AE, Ghoneim MM, Kharasch ED, et al. Speed of
recovery and side-effect profile of sevoflurane sedation compared with midazolam. Anesthesiology 2001; 94: 87-94
Ibrahim AE, Taraday JK, Kharasch ED. Bispectral index monitoring during sedation with sevoflurane, midazolam, and propofol. Anesthesiology 2001; 95: 1151-9
Levitt DG, Schnider TW. Human physiologically based
pharmacokinetic model for propofol. BMC Anesthesiol 2005;
5: 1-29

Clin Pharmacokinet 2006; 45 (9)

PK/PD of Drugs for Moderate Sedation

73. Struys MM, Vanluchene AL, Gibiansky E, et al. AQUAVAN

injection, a water-soluble prodrug of propofol, as a bolus
injection: a phase I dose-escalation comparison with
DIPRIVAN (part 2): pharmacodynamics and safety. Anesthesiology 2005; 103: 730-43
74. Moerman AT, Struys MM, Vereecke HE, et al. Remifentanil
used to supplement propofol does not improve quality of
sedation during spontaneous respiration. J Clin Anesth 2004;
16: 237-43
75. Vuyk J. Clinical interpretation of pharmacokinetic and pharmacodynamic propofol-opioid interactions. Acta Anaesthesiol
Belg 2001; 52: 445-51

869

tion by nurses supervised by endoscopists. Clin Gastroenterol

Hepatol 2003; 1: 425-32
91. Seifert H, Schmitt TH, Gultekin T, et al. Sedation with propofol
plus midazolam versus propofol alone for interventional endoscopic procedures: a prospective, randomized study. Aliment
Pharmacol Ther 2000; 14: 1207-14
92. Koshy G, Nair S, Norkus EP, et al. Propofol versus midazolam
and meperidine for conscious sedation in GI endoscopy. Am J
Gastroenterol 2000; 95: 1476-9

76. Kucukyavuz Z, Cambazoglu M. Effects of low-dose midazolam

with propofol in patient-controlled sedation (PCS) for
apicectomy. Br J Oral Maxillofac Surg 2004; 42: 215-20

93. Knibbe CA, Zuideveld KP, DeJongh J, et al. Population

pharmacokinetic and pharmacodynamic modeling of propofol
for long-term sedation in critically ill patients: a comparison
between propofol 6% and propofol 1%. Clin Pharmacol Ther
2002; 72: 670-84

77. Mason KP, Michna E, DiNardo JA, et al. Evolution of a protocol

for ketamine-induced sedation as an alternative to general
anesthesia for interventional radiologic procedures in pediatric
patients. Radiology 2002; 225: 457-65

94. Heuss LT, Schnieper P, Drewe J, et al. Safety of propofol for

conscious sedation during endoscopic procedures in high-risk
patients: a prospective, controlled study. Am J Gastroenterol
2003; 98: 1751-7

78. Walder B, Tramer MR. Analgesia and sedation in critically ill

patients. Swiss Med Wkly 2004; 134: 333-46

95. Weston BR, Chadalawada V, Chalasani N, et al. Nurse-administered propofol versus midazolam and meperidine for upper
endoscopy in cirrhotic patients. Am J Gastroenterol 2003; 98:
2440-7

79. Bhana N, Goa KL, McClellan KJ. Dexmedetomidine. Drugs

2000; 59: 263-8
80. Jalowiecki P, Rudner R, Gonciarz M, et al. Sole use of
dexmedetomidine has limited utility for conscious sedation
during outpatient colonoscopy. Anesthesiology 2005; 103:
269-73
81. Motsch J, Schmidt H, Bach A, et al. Long-term sedation with
propofol and green discolouration of the liver. Eur J Anaesthesiol 1994; 11: 499-502
82. Koch ME, Gevirtz C. Propofol may be safely administered by
trained nonanesthesiologists. Con: Propofol: far from harmless. Am J Gastroenterol 2004; 99: 1208-11

96. Badrinath S, Avramov MN, Shadrick M, et al. The use of a

ketamine-propofol combination during monitored anesthesia
care. Anesth Analg 2000; 90: 858-62
97. Eilers H, Niemann C. Clinically important drug interactions
with intravenous anaesthetics in older patients. Drugs Aging
2003; 20: 969-80
98. Dresser GK, Spence JD, Bailey DG. Pharmacokinetic-pharmacodynamic consequences and clinical relevance of cytochrome
P450 3A4 inhibition. Clin Pharmacokinet 2000; 38: 41-57

83. Godambe SA, Elliot V, Matheny D, et al. Comparison of

propofol/fentanyl versus ketamine/midazolam for brief orthopedic procedural sedation in a pediatric emergency department. Pediatrics 2003; 112: 116-23

99. Yuan R, Flockhart DA, Balian JD. Pharmacokinetic and pharmacodynamic consequences of metabolism-based drug interactions with alprazolam, midazolam, and triazolam. J Clin
Pharmacol 1999; 39: 1109-25

84. Sternlo JE, Sandin RH. Recurrent respiratory depression after

total intravenous anaesthesia with propofol and alfentanil.
Anaesthesia 1998; 53: 378-81

100. Paine MF, Shen DD, Kunze KL, et al. First-pass metabolism of
midazolam by the human intestine. Clin Pharmacol Ther 1996;
60: 14-24

85. Grauers A, Liljeroth E, Akeson J. Propofol infusion rate does

not affect local pain on injection. Acta Anaesthesiol Scand
2002; 46: 361-3

101. Ibrahim A, Park S, Feldman J, et al. Effects of parecoxib, a

parenteral COX-2-specific inhibitor, on the pharmacokinetics
and pharmacodynamics of propofol. Anesthesiology 2002; 96:
88-95

86. Bryson HM, Fulton BR, Faulds D. Propofol: an update of its use
in anaesthesia and conscious sedation. Drugs 1995; 50: 513-59
87. Nakane M, Iwama H. A potential mechanism of propofolinduced pain on injection based on studies using nafamostat
mesilate. Br J Anaesth 1999; 83: 397-404
88. Scott RP, Saunders DA, Norman J. Propofol: clinical strategies
for preventing the pain of injection. Anaesthesia 1988; 43:
492-4
89. Chen SC, Rex DK. Review article: registered nurse-administered propofol sedation for endoscopy. Aliment Pharmacol
Ther 2004; 19: 147-55
90. Ulmer BJ, Hansen JJ, Overley CA, et al. Propofol versus
midazolam/fentanyl for outpatient colonoscopy: administra-

2006 Adis Data Information BV. All rights reserved.

102. Vuyk J. Pharmacokinetic and pharmacodynamic interactions

between opioids and propofol. J Clin Anesth 1997; 9: 23S-6S
103. Vargo JJ. Propofol may be safely administered by trained
nonanesthesiologists. Pro: Propofol demystified: it is time to
change the sedation paradigm. Am J Gastroenterol 2004; 99:
1207-8

Correspondence and offprints: Dr Tong J. Gan, Department

of Anesthesiology, Duke University Medical Center, 3094
Erwin Road, Durham, NC 27710, USA.
E-mail: GAN00001@mc.duke.edu

Clin Pharmacokinet 2006; 45 (9)