ELSEVIER

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 92s

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 94s

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

225-j

125

.

200 175 2 E

E $

1

i.

l

100

150 125 100 75

-z

75

p” E

50

50 25

25

0

0 Pre

A

+l +3 *5 Post-induction

+l +5 Pos’t-intubation

Pre B

8

+I +3 +5 Post-induction

+I *5 Post-intubation

120 100

2 .-E zi z

6 80

E z

4

60 40

2 20 0

0 Pre

C

+l +3 +5 Post-induction

+I +5 Post-intubation

Pre D

+I +3 +5 Post-induction

+I +5 Post-intubation

. 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 96s

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.