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St.eroid Anesthetics:
Old Compounds, New Drugs
John W. Sear, MA, MBBS, PhD, FFARCS, FANZCA*
Nuffield Department of Anaesthetics, University of Oxford, John Radcliffe Hospital,
Headington, Oxford OX3 9DU, United Kingdom.
Keywords: Althesin;
eltanolone;
minaxolone
citrate; steroid anesthetics.
Introduction
There is currently renewal of interest in the pharmacology
and clinical usage of
intravenous (IV) steroid hypnotic drugs for both induction and maintenance of
anesthesia. Compared with the IV barbiturates,
these compounds have greater
therapeutic indices and faster removal from the body by hepatic (and perhaps
pulmonary)
metabolism
and elimination.
There is now evidence from basic
pharmacologic
studies that steroids act to cause hypnosis through interaction at
a specific site on the gamma-aminobutyric
acid type A (GABA*) protein and the
GABA* chloride channel complex.’
Structure-Activity
*Clinical Reader in Anaesthetics
Consultant Anaesthetist
and Hon.
Address reprint requests to Dr. Sear at the
Nuffield Department of Anesthesia, University of Oxford, John Radcliffe
Hospital,
Headington,
Oxford
OX3 9DU, United
Kingdom.
Received for publication October 12, 1995;
revised manuscript accepted for publication
January 5, 1996.
Presented in part at the Annual Meeting of
the Society of Intravenous Anesthesia, Atlanta, GA. October 20. 1995.
Relationships
for Steroid Molecules
In 1941, Selye’ described the hypnotic properties of some steroids (mainly belonging to the pregnane and androstane groups) in rats. Of the screened steroids, there was no apparent relationship
between hypnotic (anesthetic)
and
hormonal properties; the most potent anesthetic steroid, pregnane-3,20-dione
(pregnanedione),
was virtually devoid of endocrinologic
activity. The potency of
all active drugs was increased by partial hepatectomy. However, pregnanedione
and most of the synthetic steroids described by Selye were water insoluble; and
hence little progress was made until Laubach et al3 synthesized hydroxydione
(the 21-hydroxy derivative of pregnanedione
made water soluble by esterification at the C,, position as the sodium hemisuccinate).
Hydroxydione
had a high
therapeutic index, and few adverse effects in cats and dogs.4 In clinical practice,
it produced minimal changes in cardiorespiratory
function, good muscle relaxation, a low incidence of coughing, and pleasant recovery, with a very low incidence of vomiting.‘a6 However, there were two unexpected side effects: induction took several minutes to achieve, and there was a significant incidence of
irritation at the site of administration
and along the vein.
In 1956, the chemists and pharmacologists
at Glaxo, UK began to look for
other steroids with the clinical advantages of hydroxydione
but without the
tendency to cause pain on injection and thrombophlebitis.
They found a number of important structure-activity
features:
l
Journal of Clinical Anesthesia 8:91%98S, 1996
0 1996 by Elsevier Science Inc.
655 Avenue of the Americas, New York, NY 10010
For anesthetic activity presence of an oxygen function (either hydroxy or ketone) at each end of the
steroid molecule (in the Cs position and C,, posi-
0952~8180/96/$15.00
PI1 SO952-8180(96)000141
Steriod anesthetics: Sear
l
l
l
l
tion of pregnanes, or Cr, position of androstanes)
was necessary.
Substitutions into the steroid structure, such as extra
hydroxy groups, reduced anesthetic activity and occasionally introduced convulsant properties.
Both ICY- and SB- compounds were highly active,
The Cs hydroxyl group can be either in the 01 or p
conformation;
but 3o-hydroxy-5oror 3a-hydroxy5p- molecules had the greatest anesthetic activity,
followed by SB-hydroxy-5P- and 3@hydroxy-5ru- compounds. 3-Keto substituents had little or no anesthetic activity.
Esters of hydroxy compounds were less active and
more slow acting than the parent alcohols.’
Because water solubility was considered important, Atkinson et al.’ synthesized and evaluated 5S-pregnane-Sol01, 11,20 dione 3 phosphate disodium. This was a promising hypnotic compound
in several animal species, but
when given to humans, it resulted in a delayed onset of
anesthesia and caused paresthesia in the arm and neck
following IV administration.g
Although paresthesia ceased
before loss of consciousness and did not reoccur if a second dose of the steroid was given during the induction
sequence, the drug was not developed further.
the search for a suitable
Gyermek et aLlo continued
steroid, and re-evaluated some of the pregnanes described
by earlier authors. The metabolites
of progesterone
(shown by Selye to be effective hypnotic
drugs) were
found to be more potent than the hormone itself [as assessed by studies with both pregnanolone
and pregnanedione]. The ll-keto analogues of pregnanolone
(ll-keto
pregnanolone
and alphaxalone)
were also active as hypnotics.
Althesin
Steroids
Although
hydroxydione
was used clinically for over ten
years from 1955, most experience
to date has been obtained with Althesin
[alphaxalone:
3ar-hydroxy,
5~
pregnane 11,20 dione 9 mg/ml, and alphadolone
acetate
(21 acetoxy, 3o-hydroxy, 5o-pregnane 11,20 dione 3 mg/
ml)]. Because of their hydrophobicity,
the two steroids
were formulated
in Cremophor
EL. Both steroids possessed anesthetic activity in animals, but the potency of
alphaxalone was approximately
twice that of the alphadolone acetate, the latter present solely to increase the solubility of alphaxalone. Althesin was and still is an effective
induction drug for many animal species (marketed as Saffan) and can be used in most species except the dog,
where the solvent Cremophor
EL often causes marked
hypotension due to histamine release (see below).
Sam Pharmacologic and Clinical Properties of Althesin
The early animal studies showed Althesin to possess a high
therapeutic index (TI = 30.4), rapid onset, and short duration.“,”
In the same study, the TI of hydroxydione
was
17.3.12 The wide therapeutic
safety range had important
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J. Clin. Anesth., vol. 8, May 1996
applications
for the use of Althesin in humans, because
the drug caused only minimal cardiovascular
depression
when given at doses up to twice the ED,, induction dose
(100 @/kg compared with 50 $/kg Althesin).13 At the
higher dose, the steroid caused decreases in systolic (SBP)
and diastolic blood pressures (DBP), and a significant increase in heart rate (HR). Stroke volume decreased but
cardiac output (CO) was unchanged. In all patients, induction of anesthesia was followed by a period of hyperventilation,
followed by apnea and then tachypnea. Arterial ~0, fell, and there was a small increase in PaCO,. At
high doses (200 @/kg), patients maintained
blood pressure (BP) but required ventilatory assistance.15
Althesin also had important effects on cerebral hemodynamics, cerebral metabolism, and intracranial
pressure
(ICP). Turner et aLI showed that a bolus of Althesin (50
@/kg) administered to patients receiving general anesthesia and controlled ventilation caused a fall in ICP proportional to the initial ICP, due to reductions in both cerebral
blood flow (CBF) and cerebral blood volume. Althesin
also caused decreases in cerebrospinal
fluid pressure.”
Infusions of Althesin (300 pg/kg/hr)
decreased both CBF
and cerebral metabolic
rate compared with the awake
state.
Following both single-dose administration
or incremental dosing to supplement nitrous oxide (NsO) anesthesia
for short surgical procedures, immediate recovery after Althesin was more rapid than other thiopental, and comparable with that of methohexital.18,1g
In a comparison of
Althesin and propofol, the cardiovascular
effects of the
two drugs when used for induction of anesthesia were similar; but recovery to opening eyes to command and to
giving correct date of birth was faster after propofol.20
Althesin had no significant effects on either renal or
hepatic function.21-24 However, it was considered unsafe
when administered to patients with acute porphyria [both
acute intermittent
(Swedish) and variegate (South African) types],25 but it appeared to be an important drug for
the management
of patients who were malignant hyperpyrexia-susceptible.26
Adverse properties of Althesin
Undesirable side effects, following induction were a doserelated incidence of hiccoughs, coughing, laryngospasm,
and involuntary muscle movements.
However, a major disadvantage of the drug was the
occurrence of allergic reactions. Three factors appeared
to be significant in the predisposition
to Althesin reactions: history of asthma or other topic manifestations;
known sensitivity to other drugs; and previous administration of Althesin. There were three main types of response:
(1) histaminoid:
peripheral
vasodilatation,
skin flushes,
edema and wheals; (2) bronchospasm:
usually accompanied by vasodilatation
or hypotension; and (3) cardiovascular collapse: not usually accompanied by other features
of histaminoid
reactions.2’
Estimates of the incidence of reactions to Althesin in
humans has varied between 1 in 1,000 and 1 in 18,000.
Steroid anesthetics: Sear
The immunology
of these adverse reactions was probably
multi-etiologic;
was a reaction to first exposure caused by
either a direct nonimmunologic
effect on mast cells to
cause histamine and other autocoids to be released or by
alternative pathway complement
activation; and reaction
to repeat exposure resulting from classical complement
pathway activation. It remains uncertain whether these reactions were due to the pharmacologically
active components, with the Cremophor EL acting as an adjuvant or to
the Cremophor EL itself.
Phamnacokinetics of Althesin
Following bolus dosing to surgical patients, Althesin disposition (as alphaxalone)
gave a systemic clearance of 1.44
to 1.52 L/min, an elimination
half-life of about 30 minutes, and apparent volume of distribution
at steady state of
44 to 55 L.28,2g The kinetics of alphadolone
acetate were
comparable.”
Infusion studies in patients undlergoing ab
dominal or major vascular surgery showed a longer elimination half-life (47 to 133 mins), and lower clearance (250
to 1,520 ml/min)
(i.e., flow-dependent
elimination)30
(Table 1). Both steroids were hepatically biotransformed
with urinary excretion of alphaxalone
and Zoo-reduced
alphaxalone
glucuronides,
and alphadolone
glucuronide.
No alphadolone
acetate, as free steroid or glucuronide,
was found in any urine samples; nor were any 1 l-reduced
compounds (derived from either alphaxalone or alphadolone) or 20-reduced alphadolone.
There also were no metabolites with additional hydroxyl groups (which increase
hydrophilicity)
in samples of plasma, bile, or urine. We
also failed to confirm the presence of either steroid or
their metabolites in bile samples31
use by continuous infusion. 32-36 Side effects during infusion anesthesia (muscle twitching, hiccoughs, salivation)
were minimal, and there was remarkable
cardiovascular
stability even at 8 times the maintenance
rate when given
to patients receiving 67% N,O and controlled ventilation.
In the spontaneously breathing patient, rates up to 4 times
the maintenance
rate were associated with only small increases in the PaC02.“j
In a 1982 review article comparing the cardiovascular
effects of Althesin and the three commonly used inhalational drugs, Prys-Roberts3’ clearly documented
greater
cardiorespiratory
depressant effects of halothane, enflurane, and isoflurane at equi-anesthetic
doses, again emphasizing the potential safety advantages of this steroid
anesthetic agents.
Newer Steroid Anaesthetic
Drugs
The high systemic clearance of Althesin, and its relatively
short duration of action, made the drug appropriate
for
Since the 198Os, there has been evaluation
of SBpregnanolone;
the anesthetic properties of 5o- and SBreduced progesterone
metabolites
having been recognized since 1957.38
The first reported studies in animals were those of
Norberg et aZ.,3g~40who evaluated the actions in male rats
of 3ol-hydroxy and 5a- and SB-pregnanolone
formulated as
an emulsion in Intralipid
(pH 7.5). Both compounds
showed excitatory movements during infusions to EEG
burst suppression. The RB-isomer was the more potent,
with a potency ratio of 6:l compared with thiopental for
induction of anesthesia. Loss of righting reflex occurred
rapidly, but recovery was faster after 5B-pregnanolone.
It
also has been evaluated in other animal species and shown
to have a high therapeutic index (>40).
In the rat, induction of anesthesia caused minimal cardiovascular depression, but recovery was not as rapid as
following propofol or Althesin.41,42 When administered
to
ventilated dogs receiving fentanyl (0.2 pg/kg/min),
doses
of 0.5 to 4 mg/kg pregnanolone
produced anesthesia last-
Table 1. Disposition Kinetics of Three Steroid Anesthetics
AlphaxaIone/Alphadolone
Infusions of Althesin
(Althesin:
Acetate,
Minaxolone
Citrate,
and Eltanolene)
T%B
WQ
Bolus dosing
Alphaxalone
(Simpson)
Alphaxalone
(Sear)
Alphadolone
(Sear)
Minaxolone
(Dunn)
Eltanolone
(Carl)
Eltanolone
(Gray)
Infusion studies
Alphaxalone
(Sear)
Minaxolone
(Sear)
Eltanolone
(Schuttler)
34.2
32
36.4
47.2
73.0
88.8
VP
(L)
-
(2)
(10)
(10)
(26)
(10)
(66)
65.3
53.7
98.2
361
-
90.5 (27)
87.3 (23)
182 (27)
-
Note: Data are means i SD.
TW = elimination half life; VP and Vd,, = apparent volumes of distribution
systemic (plasma) clearance.
(11)
(6)
(23)
(51)
during the elimination
Vd,
(L)
53.8 (7.6)
48.3 (16)
44.0 (8)
134
(69)
107.3 (68)
149.1 (27)
-
1.44
1.52
1.09
1.55
3.46
1.85
(0.27)
(0.50)
(0.32)
(0.46)
(0.53)
(0.37)
0.84 (0.47)
1.15 (0.13)
1.80 (0.4)
phase (VP) and at steady state (Vd,,); ~1, =
J. Clin. Anesth., vol. 8, May 1996
93s
Steriod anesthetics: Sear
ing 10 to 15 minutes. Cardiac output, SBP, and contractility only decreased after doses greater than 2 to 4 mg/kg.
Systemic vascular resistance (SVR) also fell, but pulmonary
vascular resistance appeared to increase by mechanisms at
present unknown.43
Further animal evaluation of the drug in instrumented
dogs by the group
from Leuven
have compared
eltanolone and propofol and shown pregnanolone
to have
negative inotropic
properties.44 At high doses (2.5 to 5
mg/kg), pregnanolone
caused a dose-dependent
decrease
in hepatic arterial blood flow, but little effect on portal
venous flow or renal arterial flow. Although both propofol
and pregnanolone
are solvented in the oil phase of a fat
emulsion, the constituents differ in that the latter contains
7% diacetylated monoglycerides.
Further investigation
of
the effect on hepatic hemodynamics
has suggested these
changes may be due to the lipid emulsion.45
Human Pharmacology of 5f3pregnanolone (Eltanolone)
Doses of 0.4 to 0.6 mg/kg resulted in anesthesia in volunteers.4648 Loss of verbal contact occurred before loss of
the eyelash reflex (unlike thiopental).
There are only few
published kinetic data, both from volunteers. Carl et uZ.~~
showed a high clearance (2.16 to 4.40 L/min)
and a terminal half-life of 0.91 to 1.44 hours; while Gray et cd.47
reported a mean clearance between 1.23 and 1.54 L/kg/
hr, with a mean elimination half-life between 1.48 and 1.65
hours, and an apparent volume of distribution
of about 2
L/kg (Table I). However, both studies had poorly designed venous sampling regimens. Balance studies recovered less than 1% of the drug as unconjugated
pregnanolone and between 7.9% and 16.2% as conjugated
pregnanolone
in the urine over 24 hours postanesthesia.
Other metabolites found in humans were the conjugate of
5P-pregnane-Sa,
20a diol.
In more recent, but as yet unpublished,
kinetic studies
in adults, children, and the elderly, the mean values of the
elimination half-life range from 3.1 to 4.3 hours, clearance
from 1.38 to 1.90 L/kg/hour,
and apparent volume of
distribution
at a steady state of 1.20 to 2.30 L/kg.
In all studies, there was a similar dynamic profile. Hemodynamic effects were minimal and dose-related. There
was only mild ventilatory
depression. Significant side effects included excitation of short duration during the induction of sleep and minor involuntary
movements. Following a single dose of 0.6 mg/kg, CBF decreased by 34%,
with a comparable fall in 0, consumption;
thereby maintaining a coupling between metabolism and blood flow.
A number of open studies have defined ED,, induction
doses in both benzodiazepine
and opioid-premeditated
patients as between 0.33 mg/kg and 0.46 mg/kg.4g-51 Induction resulted in minimal hemodynamic
depression,
the main side effects being involuntary movements, apnea,
and hypertonus. The relative potency of propofol (compared with eltanolone)
was 0.313 in benzodiazepinepremeditated
patients. 52 In children, the ED,, to loss of
verbal command was 0.68 mg/kg in unpremeditated
children aged 6 to 10 years, and 0.53 mg/kg between 11 and
15 years.53
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J. Clin. Anesth., vol. 8, May 1996
Hering et ~1.~~recently examined the EEG power spectral changes following administration
of a single bolus
dose of eltanolone
0.75 mg/kg,
and related these to
changes in the blood eltanolone concentration.
Anesthesia caused a decrease in the (x power and an increase in
delta activity, with return to baseline after about 15 minutes, and the median EEG frequency declined from 9 Hz
to 1.5 Hz two minutes after eltanolone dosing. Using these
data, the authors have derived a sigmoidal E,,
concentration-effect model in 7 of 15 patients. The IC,, concentration was 565 (SD: 74) rig/ml, and the steepness coefficient was (y) 7.1 (2.4). Comparative data using the same
model give IC,, values for etomidate and propofol of 0.31
pg/ml and 2.3 ug/ml, respectively. Unfortunately,
there
are a number of methodologic
problems with this studyprincipally
use of venous rather than arterial sampling.
However, a parallel study by Schuttler et aZ.55has used
arterial sampling, and determined an tl,, K,, of 6.9 minutes, an IC,, of 470 rig/ml, and a y function of 6.0. The
associated kinetic parameters were a half-life of about 3
hours, and a clearance of 1.8 L/min.
In a separate study, Myint et a1.56compared induction
of anesthesia with three different infusion rates of eltanolone to elderly unpremeditated
patients. All patients received fentanyl 3 pg/kg 3 to 5 minutes before induction.
Drug was infused at 300 ml/hr, 600 ml/hr, or 1,200 ml/
hr, and the induction doses for loss of consciousness were
0.59 mg/kg, 0.70 mg/kg, and 0.89 mg/kg, respectively.
The associated induction times were 112, 73, and 50 seconds. Hence, for a quartering of the infusion rate, there
was a 120% increase in the induction
time, but a 33%
decrease in the dose required. If we compare data for
eltanolone
with previous data for propofol,
etomidate,
and thiopental,
there are important
differences.
For
eltanolone, we can see that for the increase in induction
time, there was a smaller reduction in the induction dose,
which suggests a slower response to changes in the blood
eltanolone concentration.
Study of cardiovascular effects during induction of anesthesia, laryngoscopy, and intubation
has been made in
benzodiazepine-premeditated
ASA I and II patients.57 Patients received either eltanolone or propofol in doses of
1.33 times the ED,, and breathed 67% N,O in 0, supplemented by enflurane. Patients were intubated
after vecuronium. Both treatments caused similar decreases in BP
and CO, but a greater increase in HR postlaryngoscopy
and intubation
in patients receiving eltanolone. In these
patients, SVR was unaltered following induction of anesthesia (Fipre I). However, in studies in patients prior to
coronary artery bypass grafting, where eltanolone 0.5 to
1.0 mg/kg has been coadministered
with fentanyl 3 pg/
kg and pancuronium
or vecuronium, Tassani et aZ.*,58have
shown the fall in BP to be the result of vasodilation rather
*Tassani P, Groh J, Ott E, Janicke U, Haessler R, Peter K: Eltanolone,
a new induction agent: hemodynamic effects in patients with coronary artery disease compared with thiopentone [Abstract]. An&he%
010~ 1993;79:A328.
Steroid anesthetics: Sear
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125
.
200
175
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E
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i.
l
100
150
125
100
75
-z
75
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50
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0
0
Pre
A
+l
+3
*5
Post-induction
+l
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Pos’t-intubation
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B
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+3
+5
Post-induction
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Post-intubation
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T
Figure 1. A. Systolic arterial pressure (SAP), B. Heart rate
(HR), C. Cardiac output (Q), D. Stroke volume (SV), and E.
4
*- 25
=
5
I” 20
E ‘5
Systemic vascular resistance (SVR) values for 22 patients receiving eltanolone and 17 receiving propofol. Data shown are
means and SD; for clarity, only upper bar is shown. The dark
bars represent the eltanolone patients; the lighter bars the
propofol group. i-1, t5 post-induction-one
and five minutes
after induction; +l, t5 post-intubation-one
and five minutes
after intubation.
*p < 0.05, compared with the baseline (pre-induction) value;
l p < 0.01, compared with prelaryngoscopy and intubation.
10
5
0
Pre
E
+I
i-3
+5
Post-induction
+I
+5
Post-intubation
than myocardial
depression. Further studies are clearly
needed.
There are few reports where eltanolone has been given
by incremental
dosing to supplement
either N,O or opioid anesthesia. Rajah et aL5’ achieved satisfactory “surgical
anesthesia” in 42 of 50 patients, the remaining 8 patients
requiring isoflurane to supplement N,O. Maintenance
requirements ranged between 0.015 and 0.025 mg/kg/min.
The incidence of side effects was low (involuntary
movements 8%, apnea >15 sets 2%). Other studies by Korttila et
al. 52’60 have compared increments eltanolone with either
thiopental
or propofol.
The incidences
of involuntary
muscle movements
and hypertonus
were higher after
eltanolone; and immediate recovery from eltanolone was
prolonged,
and intermediate
recovery (walking, taking
oral fluids, voiding, and home readiness) appeared slower
than propofol but similar to thiopental. However, because
there is a slower dynamic response to eltanolone,
it is
possible that these studies may reflect an overdosing of the
steroid.
Thus, when we come to evaluate eltanolone further, we
shall need to rethink our strategy for its administration
as
J. Clin. Anesth., vol. 8, May 1996
95s
Steriod anesthetics: Sear
a maintenance anesthetic. Rapid titration of drug to effect
may be more difficult than with other presently available
hypnotic drugs.
Other Steroid Hypnotic
Drugs
Since the initial studies of Selye, investigators have looked
for water-soluble steroids with anesthetic activity. Figdor et
al.s8 found that amino-esters of 21-hydroxypregnanedione
were water-soluble and had hypnotic properties. In 1964,
Hewett et aZ.61described the pharmacology of a number of
derivatives of androstane or pregnane with amino-radicals
attached at C,, C,, or C,,. The most potent in causing loss
of righting
reflex was a C, morpholino-steroid
(3~
hydroxy, 2@morpholino,
5o-pregnan-20-one).
It had a
high therapeutic index (4.69), but a number of disadvantages: long threshold time to onset of anesthesia and a
long duration
of effect. Addition
of an II-keto group
shortened the duration of the ED,, dose (30 to 17 minutes), but had little effect on potency.
Further studies by Phillips et aL6’ examined a range of
steroids carrying a basic constituent
at the 11-position.
Compounds with Ilo or llB-dialkylaminoacyloxyor dialkylamino- substituents formed water soluble salts (usually the citrate), which showed anesthetic activity in mice.
Minaxolone
Citrate
This steroid had the same pregnane ring structure as alphaxalone and alphadolone, but with introduction
of 1 ladimethyl amino and a 2B-ethoxy groups. The latter was
associated with an increased potency in the mouse, cat,
and dog compared with alphaxalone6s; while the dimethyl
amino group at the 11 position in the C ring (in place of
the dione group) conferred the water solubility. Like Althesin, minaxolone
had a high therapeutic
index (>5).
The properties of minaxolone
and Althesin were similar:
less respiratory depression and more rapid recovery than
is seen after thiopental, although there was some excitatory movement during minaxolone
anesthesia in dogs.
Minaxolone
had other central nervous system depressant effects in addition to hypnosis: like Althesin and thiopental, it prevented maximal electroshock
seizures and
foot-shock induced fighting at subanesthetic doses when
given to mice. However, in deeply anesthetized cats, minaxolone
(like Althesin)
completely
abolished cortical
electrical activity without associated respiratory
depression. Thiopental,
on the other hand, produced apnea
while the EEG still showed spike and wave activity.
Clinical evaluation
of minaxolone
citrate showed a
slower onset of action and a more prolonged
recovery
when compared with Althesin.30,64-66 When given by incremental dosing or continuous infusion to supplement
N,O, the incidence of excitatory movements and hypertonus were greater in the patients receiving minaxolone.@
Disposition of Minaxolone
In surgical patients, the disposition following a bolus dose
was best described by a two compartment
kinetic model
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J. Clin. Anesth., vol. 8, May 1996
with an elimination
half-life of 47 minutes and clearance
between 0.80 L/min and 2.15 L/min.”
Similar kinetics
were found when the drug was given by continuous infusion3’ (Table 1). Renal clearance was low (~0.5% of total
systemic clearance), and the main metabolites in humans
were the unconjugated
steroid (50%) and the N-desmethyl, 0-desethyl,
and N-desmethyl
0-desethyl
compounds. Urinary excretion of minaxolone
appeared to be
pH-dependent,
with increased elimination
under acidic
conditions. There are no data as to whether minaxolone
was excreted via the biliary route in humans.
This drug was withdrawn from clinical evaluation in
1981 because of possible oncogenic effects in rats and no
clear clinical advantage over other IV hypnotic drugs.
Other
Water-soluble Steroid Hypnotic Drugs
In 1993, Gemmell et uZ.~*,~~described the anesthetic properties of a water-soluble Z-substituted aminosteroid
(ORG
20599) in the mouse, rat, and dog. This had an efficacy
similar to that of Althesin, a high therapeutic index of 13,
and a short duration hypnotic effect. However, it is not
being studied further in humans because of difficulties
with regards to drug stability and solubility.
More recently, another water-soluble 2-substituted aminosteroid has been evaluated in animals (ORG 21465) .”
Again, this steroid shows a high therapeutic index in mice
(13.8 compared with 4 to 5 for propofol and thiopental) ,
In the monkey, ORG 21465 and propofol (in doses of 4
mg/kg and 3 mg/kg, respectively) produced rapid onset
of hypnosis, but the duration of sleep and of recovery was
greater after the aminosteroid.
Because preliminary
evaluation of this anesthetic in human volunteers revealed an
incidence of excitatory movements of about 70%, further
evaluation is unlikely.
Conclusion
Whether eltanolone offers significant contributions
to IV
anesthesia remains to be seen, but the challenge to find
novel steroid alternatives to the present IV hypnotic drugs
continues. The future for eltanolone will depend largely
on whether its dynamic profile, especially for the maintenance of anesthesia, is comparable with that of the present
gold standard, namely propofol. Possible advantages of
eltanolone
may be less cardiorespiratory
depression, an
absence of pain following injection, and a comparable incidence of postoperative
nausea and vomiting. However,
the drug has important side effects that need further evaluation [excitatory phenomena, airway irritability,
and skin
reactions (flush, rash, and urticaria)] .
Possible areas of clinical utility for eltanolone may include induction and maintenance of anesthesia in the cardiovascularly at-risk patient (ASA physical status III and
IV); use in monitored
anesthesia care sedation; and
as the basal hypnotic component
of a total intravenous
anesthesia technique, where responses to noxious stimuli
are treated by incremental
doses of an opioid such as alfentanil or remifentanil.
Steroid anesthetics: Sear
Acknowledgments
Part of this review has been published previously in Anaesthetic Pharmacology &&US (Steroidal anaesthetic agents. 1995;3:57-66) and is
reproduced here by permission of the editor and publishers. Figure 1
(a to e) has appeared in the ‘Journal ofClinicalAne.sth&a
1995;7:12&
131’, and is reproduced here by permission of the editor and pub
lishers.
Addendum
the preparation
made to discontinue
Since
of this review, the decision has been
the clinical evaluation of eltanolone.
References
1. Harrison NL, Simmonds MA: Modulation of the GABA receptor
complex by a steroid anaesthetic. Brain Res 1984;323:287-92.
2. Selye H: The anesthetic effect of steroid hormones. Proc Sot Exp
Biol Med 1941;46:116-21.
3. Laubach GD, P’An SY, Rude1 Hw: Steroid anesthetic agent. Science 1955;122:78.
4. Taylor N, Shearer WM: The anaesthetic properties
of 21hydroxypregnanedione
sodium hemisuccinate (hyd.roxydione), a
pharmacological and clinical study of 130 cases. Brj’Anaesth 1956;
28:67-76.
5. Galley AH, Rooms M: An intravenous steroid anaesthetic. Experiences with Viadril. Lancet 1956;1:990-4.
6. Montmorency FA, Chen A, Rude1 H, Glas WW, Lee LE: Evaluation of cardiovascular and general pharmacologic properties of
hydroxydione. Anesthesiology 1958;19:450-6.
7. Phillips GH: Structure-activity
relationships in steroidal anaesthetics. J Steroid Biochem 1975;6:607-13.
8. Atkinson RM, Davis B, Pratt MA, Sharpe HM, Tomich EG: Action
of some steroids on the central nervous system of the mouse. II.
Pharmacology. J Med Chem 1965;8:426-32.
9. P’An SY, Gardocki JF, Hutcheon DE, Rude1 H, Kodet MJ, Laubath GD: General anesthetic and other pharmacological properties of a soluble steroid, 21-hydroxy-pregnanedione
sodium succinate. JPharrnacol Exp Ther 1955;115:432-41.
10. Gyermek L, Iriarte J, Crabbe P: Steroids. CCCX. Structure-activity
relationship of some steroidal hypnotic agents. JMed Chem 1968;
11:117-25.
11. Child KJ, Davis B, Dodds MG, Twissell DJ: Anaesthetic, cardiovascular and respiratory effects of a new steroidal agent CT 1341:
a comparison with other intravenous anaesthetic drugs in the
unrestrained cat. Br JPharmacoZ 1972;46:189-200.
12. Child KJ, Currie JP, Davis B, Dodds MG, Pearce DR, Twissell DJ:
The pharmacological
properties in animals of CT 1341-a new
steroid anaesthetic agent. Br JAnaesth 1971;43:2-13.
13. Campbell D, Forrester AC, Miller DC, et al: A preliminary clinical
study of CT1341-a steroid anaesthetic agent. Br J.Anaesth 1971;
43314-24.
14. Savege TM, Foley EI, Ross L, Maxwell MP: A comparison of the
cardiorespiratory
effects during induction of anaeisthesia of Althesin with thiopentone and methohexitone. Postgrad Med J1972;
48:Suppl 2:66-72.
15. Clarke RS, Montgomery SJ, DundeeJW, Bovill JG: Clinical studies
of induction agents. XXXIX: CT1341, a new steroid anaesthetic.
Br JAnaesth 1971;43:947-52.
16. Turner JM, Coroneos NJ, Gibson RM, Powell D, Ness MA, McDowall DG: The effect of althesin on intracranial pressure in
man. Br JAnaesth 1973;45:168-72.
17. Takahashi T, Takasaki M, Namiki A, Doi S: Effects of althesin on
cerebrospinal fluid pressure. Br JAnaesth 1973;45:179-84.
18. Hannington-Kiff
JG: Comparative recovery rates following induction of anaesthesia with Althesin and methohexitone
in out-
patients. Postgrud Med J 1972;48(Suppl 2):116-20.
19. Craig J, Cooper GM, Sear JW: Recovery from day-case anaesthesia. Comparison between methohexitone,
Althesin and etomidate. Br JAnaesth 1982;54:447-51.
20. Uppington J, Kay NH, SearJW: Propofol (Diprivan) as a supplement to nitrous oxide-oxygen for the maintenance of anaesthesia. Postgrad Med J 1985;61:Suppl 3:80-3.
21. Clarke RS, Dundee JW, Doggart JR, Lavery T: The effects of
single and intermittent administrations of althesin and other intravenous anesthetic agents on liver function. An&h Analg 1974;
53:461-8.
22. Park GR, Wilson J: Ahhesin infusion and regional blockade anaesthesia for major gynaecological surgery. Br JAnaesth 1978;50:
1219-26.
23. Blunnie WP, Zacharias M, Dundee JW, Doggart JR, McIlroy PD:
Liver enzyme studies with continuous intravenous anaesthesia.
Anaesthesia 1981;36:152-6.
24. SearJW, Prys-Roberts C, Dye A: Hepatic function after anaesthesia for major vascular reconstructive surgery. Br J Anaesth 1983;
55:603-g.
25. Harrison GG, Meissner PN, Hift RJ: Anaesthesia for the porphyric patient. Anaesthesia 1993;48:417-21.
26. Harrison GG: Althesin and malignant hyperpyrexia. Br JAnaesth
1973;45:1019-21.
27. Clarke RS, Dundee JW, Garrett FT, McArdle GK, Sutton JA: Adverse reactions to intravenous anaesthetics. BrJAnaesth 1975;47:
575-85.
28. Simpson ME: Pharmacokinetics of althesin-comparison
with lignocaine. Br JAnaesth 1978;50:1231-5.
29. Sear JW, Sanders RS: Inn-a-patient comparison of the kinetics of
alphaxalone and alphadolone in man. Eur JAnaesthesioZ 1984;l:
113-22.
30. Sear JW, Prys-Roberts C, Gray AJ, Walsh EM, Curnow JS, Dye J:
Infusions of minaxolone to supplement nitrous oxide-oxygen anaesthesia. A comparison with althesin. BrJAnaesth 1981;53:339-50.
31. Holly JM, Trafford DJ, Sear JW, Makin HL: The in uino metabolism of Althesin (alphaxalone and alphadolone acetate) in man.
JPharrn Pharmacol1981;33:427-33.
32. Du Cailar J: The effects in man of infusions of Althesin with
particular regard to the cardiovascular system. Postgrad Med J
1972;48(Suppl 2):72-9.
33. Savege TM, Ramsay MA, Curran JP, Cotter J, Walling PT, Simpson BR: Intravenous anaesthesia by infusion. A technique using
alphaxalone/alphadolone
(althesin). Anaesthesia 1975;30:757-64.
34. Dechene JP: Alfathesin by continuous infusion supplemented
with intermittent pentazocine. Can Anaesth Sot J 1977;24:702-6.
35. Sear JW, Prys-Roberts C: Plasma concentrations of alphaxalone
during continuous infusion of Althesin. Br J Anaesth 1979;51:
861-5.
36. Sear JW, Prys-Roberts C: Dose-related haemodynamic effects of
continuous infusions of Althesin in man. BrJ Anaesth 1979;51:
867-73.
37. Prys-Roberts C: Cardiovascular effects of continuous intravenous
anaesthesia compared with those of inhalational anaesthesia. Acta
Anaesthesiol Stand 1982;Suppl 75:10-7.
38. Figdor SK, Kodet MJ, Bloom BM, Agnello EJ, P’An SY, Laubach
GD: Central activity and structure in a series of water-soluble
steroids. JPhannacol Exp Ther 1957;119:299-309.
39. Norberg L, Wahlstrom G, Backstrom T: The anaesthetic potency
of 3n+hydroxy-5a-pregnan-20-one
and 3a-hydroxy-5B-pregnan-POone determined with an intravenous EEGthreshold
method in
male rats. Pharmacol Toxic01 1987;61:42-7.
40. Larsson-Backstrom C, Lustig LL, Eklund A, Thorstensson M: Anaesthetic properties of pregnanolone
in mice in an emulsion
preparation for intravenous administration:
a comparison with
thiopentone. Pharrnacol Toxic01 1988;63:143-9.
J. Clin. Anesth., vol. 8, May 1996
97s
Steriod anesthetics: Sear
41. Hogskilde S, Nielsen JW, Carl P, Sorensen MB: Pregnanolone
emulsion. A new steroid preparation for intravenous anaesthesia:
an experimental study in mice. Anaesthesia 1987;42:58690.
42. Hogskilde S, Wagner J, Carl P, Sorensen MB: Anaesthetic properties of pregnanolone
emulsion. A comparison with alphaxalone/alphadolone,
propofol, thiopentone and midazolam in a
rat model. Anaesthesia 1987;42:1045-50,
43. Hogskilde
S, Wagner J, Strom J, Sjontoft E, Olesen HP,
Bredgaard Sorensen M: Cardiovascular effects of pregnanolone
emulsion: an experimental study in artificially ventilated dogs.
Acta Anaesthesiol &and 1991;35:669-75.
44. Wouters PF, Van de Velde MA, Marcus MA, Deruyter HA, Van
Aken H: Hemodynamic changes during induction of anesthesia
with eltanolone and propofol in dogs. Anesth Analg 1995;81:12531.
45. Wouters PF, Van de Velde MA, Marcus MA, Van Aken H: Negative inotropic properties of pregnanolone in dogs due to the lipid
emulsion [Abstract]. Anesth Analg 1995;8O:S559.
46. Carl P, Hogskilde S, NielsenJW, et al: Pregnanolone emulsion. A
preliminary pharmacokinetic
and pharmacodynamic
study of a
new intravenous anaesthetic agent. Anaesthesia 1990;45:189-97.
47. Gray HS, Holt BL, Whitaker DK, Eadsforth P: Preliminary study
of a pregnanolone emulsion (KABI 2213) for i.v. induction of
general anaesthesia. BrJAnaesth 1992;68:272-6.
48. Wolff J, Carl P, Hansen PB, Hogskilde S, Christensen MS, Sorensen MB: Effects of eltanolone on cerebral blood flow and
metabolism in healthy volunteers. Anesthesiology 1994;81:623-7.
49. Powell H, Morgan M, Sear JW: Pregnanolone: a new steroid intravenous anaesthetic. Dose-finding study. Anaesthesia 1992;47:
287-90.
50. Hering W, Biburger G, Rugheimer E: Induction of anesthesia
using the new intravenous steroid anesthetic eltanolone (pregnanolone). Dose determination and pharmacodynamics. Der Anaesthkst 1993;42:74-80.
51. van Hemelrijck J, Muller P, Van Aken H, White PF: Relative
potency of eltanolone, propofol, and thiopental for induction of
anesthesia. Anesthesiology 1994;80:3641.
52. Kallela H, Haasio J, Korttila K: Comparison of eltanolone and
propofol in anesthesia for termination of pregnancy. Anesth Analg
1994;79:512-6.
53. Beskow A, Westrin P, Werner 0: Induction of general anesthesia
with eltanolone in children 6-15 years of age [Abstract]. Anesthesiology 1994;81:A1336.
54. Hering W, Schlecht R, Geisslinger G, Biburger G, Dinkel M,
Brune K, Rugheimer E: EEG analysis and pharmacodynamic
modelling after intravenous bolus injection of eltanolone (pregnanolone). Eur JAnaesthesioZ 1995;12:407-15.
55. Schuttler J, Hering W, Ihmsen H, Geisslinger G, Rugheimer E:
Pharmacokinetic/-dynamic
modeling of the new intravenous anesthetic eltanolone [Abstract]. Anesthesiology 1994;81:A409.
98s
J. Clin. Anesth., vol. 8, May 1996
56. Myint Y, Peacock JE, Reilly CS: Induction of anaesthesia with
eltanolone at different rates of infusion in elderly patients. BrJ
Anaesth 1994;73:771-4.
57. SearJW, Jewkes C, WanigasekeraV: Hemodynamic effects during
induction, laryngoscopy, and intubation with eltanolone
(SFpregnanolone)
or propofol. A study in ASA I and II patients. J
CZin Anesth 1995;7:12631.
58. Tassani P, Janicke U, Ott E, Groh J, Conzen P: Hemodynamic
effects of anesthetic induction with eltanolone-fentanyl
versus
thiopental-fentanyl
in coronary artery bypass patients. Anesth
Analg 1995;81:469-73.
59. Rajah A, Powell H, Morgan M: Eltanolone for induction of anaesthesia and to supplement nitrous oxide for minor gynaecological surgery. Anaesthesia 1993;48:951-4.
60. Eriksson H, Haasio J, Korttila K Comparison of eltanolone and
thiopental in anaesthesia for termination of pregnancy. Actu Anaesthesiol Scan 1995;39:479-84.
61. Hewett CL, Savage DS, Lewisg, Sugrue MF: Anticonvulsant and
interneuronal
blocking activity in some synthetic amino-steroids.
JPhann Pharmacol1964;16:765-7.
62. Phillipps GH, Ayres BE, Bailey EJ, Ewan GB, Looker BE, May PJ:
Water-soluble steroidal anaesthetics. JSteroid Biochem 1979;11:7986.
63. Davis B, Dodds MG, Dolamore PG, et al: Minaxolone:
a new
water-soluble steroid anaesthetic. Br JAnaesth 1979;51:564P.
64. Aveling W, Sear JW, Fitch W, et al: Early clinical evaluation of
minaxolone: a new intravenous steroid anaesthetic agent. Lancet
1979;2(8133):71-3.
65. Punchihewa VG, Morgan M, Lumley J, Whitwam JC: Initial experience with Minaxolone. A water-soluble steroid intravenous
anaesthetic agent. Anaesthesia 1980;35:214-7.
66. SearJW, Cooper GM, Williams NB, Simpson PJ, Prys-Roberts C:
Minaxolone or Althesin supplemented by nitrous oxide. A study
in anaesthesia for short operative procedures. Anaesthesia 1980;
35:169-73.
67. Dunn GL, Morison DH, McChesney J, Pine W, Kumana CR,
Gupta RN: The pharmacokinetics
and pharmacodynamics
of
minaxolone. J CZin PharmacoZ1982;22:316-20.
68. Venning-Hill
C, Callachan H, Peters JA, Lambert JJ, Gemmell
DK, Campbell AC: Modulation of the GABA* receptor by ORG
20599: a water-soluble steroid [Abstract]. Br JPhamacoZ 1994;lll
(suppl):183P.
69. Gemmell DK, Campbell AC, Anderson A, Byford A, Hill-Venning
C, Marshall RJ: ORG 20599: a new water soluble aminosteroid
intravenous
anaesthetic [Abstract].
Br J Pharmacol 1994;lll
(suppl):189P.
70. Gemmell DK Byford A, Anderson A, et al: The anaesthetic and
GABA modulatory actions of ORG 21465, a novel water soluble
steroidal intravenous anaesthetic agent [Abstract]. BrJPharmacoZ
1995;116(suppl.):443P.