St.Eroid Anesthetics: Old Compounds, New Drugs

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 Relationships for Steroid Molecules

In 1941, Selye’ described the hypnotic properties of some steroids (mainly be- longing 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 esterifica- tion 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, *Clinical Reader in Anaesthetics and Hon. it produced minimal changes in cardiorespiratory function, good muscle relax- Consultant Anaesthetist ation, a low incidence of coughing, and pleasant recovery, with a very low inci- Address reprint requests to Dr. Sear at the dence of vomiting.‘a6 However, there were two unexpected side effects: induc- Nuffield Department of Anesthesia, Univer- tion took several minutes to achieve, and there was a significant incidence of sity of Oxford, John Radcliffe Hospital, irritation at the site of administration and along the vein. Headington, Oxford OX3 9DU, United In 1956, the chemists and pharmacologists at Glaxo, UK began to look for Kingdom. other steroids with the clinical advantages of hydroxydione but without the Received for publication October 12, 1995; tendency to cause pain on injection and thrombophlebitis. They found a num- revised manuscript accepted for publication ber of important structure-activity features: January 5, 1996.

Presented in part at the Annual Meeting of l For anesthetic activity presence of an oxygen func- the Society of Intravenous Anesthesia, At- tion (either hydroxy or ketone) at each end of the lanta, GA. October 20. 1995. steroid molecule (in the Cs position and C,, posi-

Journal of Clinical Anesthesia 8:91%98S, 1996 0 1996 by Elsevier Science Inc. 0952~8180/96/$15.00 655 Avenue of the Americas, New York, NY 10010 PI1 SO952-8180(96)000141 Steriod anesthetics: Sear

tion of pregnanes, or Cr, position of androstanes) applications for the use of Althesin in humans, because was necessary. the drug caused only minimal cardiovascular depression l Substitutions into the steroid structure, such as extra when given at doses up to twice the ED,, induction dose hydroxy groups, reduced anesthetic activity and oc- (100 @/kg compared with 50 $/kg Althesin).13 At the casionally introduced convulsant properties. higher dose, the steroid caused decreases in systolic (SBP) l Both ICY- and SB- compounds were highly active, and diastolic blood pressures (DBP), and a significant in- l The Cs hydroxyl group can be either in the 01 or p crease in heart rate (HR). Stroke volume decreased but conformation; but 3o-hydroxy-5or- or 3a-hydroxy- cardiac output (CO) was unchanged. In all patients, in- 5p- molecules had the greatest anesthetic activity, duction of anesthesia was followed by a period of hyper- followed by SB-hydroxy-5P- and 3@hydroxy-5ru- com- ventilation, followed by apnea and then tachypnea. Arte- pounds. 3-Keto substituents had little or no anes- rial ~0, fell, and there was a small increase in PaCO,. At thetic activity. high doses (200 @/kg), patients maintained blood pres- l Esters of hydroxy compounds were less active and sure (BP) but required ventilatory assistance.15 more slow acting than the parent alcohols.’ Althesin also had important effects on cerebral hemodynamics, cerebral metabolism, and intracranial pressure Because water solubility was considered important, At- (ICP). Turner et aLI showed that a bolus of Althesin (50 kinson et al.’ synthesized and evaluated 5S-pregnane-Sol- @/kg) administered to patients receiving general anesthe- 01, 11,20 dione 3 phosphate disodium. This was a prom- sia and controlled ventilation caused a fall in ICP propor- ising hypnotic compound in several animal species, but tional to the initial ICP, due to reductions in both cerebral when given to humans, it resulted in a delayed onset of blood flow (CBF) and cerebral blood volume. Althesin anesthesia and caused paresthesia in the arm and neck also caused decreases in cerebrospinal fluid pressure.” following IV administration.g Although paresthesia ceased Infusions of Althesin (300 pg/kg/hr) decreased both CBF before loss of consciousness and did not reoccur if a sec- and cerebral metabolic rate compared with the awake ond dose of the steroid was given during the induction state. sequence, the drug was not developed further. Following both single-dose administration or incremen- Gyermek et aLlo continued the search for a suitable tal dosing to supplement nitrous oxide (NsO) anesthesia steroid, and re-evaluated some of the pregnanes described for short surgical procedures, immediate recovery after Al- by earlier authors. The metabolites of progesterone thesin was more rapid than other thiopental, and compa- (shown by Selye to be effective hypnotic drugs) were rable with that of methohexital.18,1g In a comparison of found to be more potent than the hormone itself [as as- Althesin and propofol, the cardiovascular effects of the sessed by studies with both pregnanolone and pregnane- two drugs when used for induction of anesthesia were sim- dione]. The ll-keto analogues of pregnanolone (ll-keto ilar; but recovery to opening eyes to command and to pregnanolone and alphaxalone) were also active as hyp- giving correct date of birth was faster after propofol.20 notics. 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 Althesin Steroids acute intermittent (Swedish) and variegate (South Afri- 25 but it appeared to be an important drug for Although hydroxydione was used clinically for over ten can) types], the management of patients who were malignant hyper- years from 1955, most experience to date has been ob- pyrexia-susceptible.26 tained 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/ Adverse properties of Althesin ml)]. Because of their hydrophobicity, the two steroids were formulated in Cremophor EL. Both steroids pos- Undesirable side effects, following induction were a dose- sessed anesthetic activity in animals, but the potency of related incidence of hiccoughs, coughing, laryngospasm, alphaxalone was approximately twice that of the alphado- and involuntary muscle movements. lone acetate, the latter present solely to increase the solu- However, a major disadvantage of the drug was the bility of alphaxalone. Althesin was and still is an effective occurrence of allergic reactions. Three factors appeared induction drug for many animal species (marketed as Saf- to be significant in the predisposition to Althesin reac- fan) and can be used in most species except the dog, tions: history of asthma or other topic manifestations; where the solvent Cremophor EL often causes marked known sensitivity to other drugs; and previous administra- hypotension due to histamine release (see below). tion of Althesin. There were three main types of response: (1) histaminoid: peripheral vasodilatation, skin flushes, edema and wheals; (2) bronchospasm: usually accompa- Sam Pharmacologic and Clinical Properties of Althesin nied by vasodilatation or hypotension; and (3) cardiovas- The early animal studies showed Althesin to possess a high cular collapse: not usually accompanied by other features therapeutic index (TI = 30.4), rapid onset, and short du- of histaminoid reactions.2’ ration.“,” In the same study, the TI of hydroxydione was Estimates of the incidence of reactions to Althesin in 17.3.12 The wide therapeutic safety range had important humans has varied between 1 in 1,000 and 1 in 18,000.

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The immunology of these adverse reactions was probably use by continuous infusion. 32-36 Side effects during infu- multi-etiologic; was a reaction to first exposure caused by sion anesthesia (muscle twitching, hiccoughs, salivation) either a direct nonimmunologic effect on mast cells to were minimal, and there was remarkable cardiovascular cause histamine and other autocoids to be released or by stability even at 8 times the maintenance rate when given alternative pathway complement activation; and reaction to patients receiving 67% N,O and controlled ventilation. to repeat exposure resulting from classical complement In the spontaneously breathing patient, rates up to 4 times pathway activation. It remains uncertain whether these re- the maintenance rate were associated with only small in- actions were due to the pharmacologically active compo- creases in the PaC02.“j nents, with the Cremophor EL acting as an adjuvant or to In a 1982 review article comparing the cardiovascular the Cremophor EL itself. effects of Althesin and the three commonly used inhalational drugs, Prys-Roberts3’ clearly documented greater cardiorespiratory depressant effects of halothane, enflu- Phamnacokinetics of Althesin rane, and isoflurane at equi-anesthetic doses, again em- phasizing the potential safety advantages of this steroid Following bolus dosing to surgical patients, Althesin dis- anesthetic agents. position (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 Newer Steroid Anaesthetic Drugs 44 to 55 L.28,2g The kinetics of alphadolone acetate were comparable.” Infusion studies in patients undlergoing ab Since the 198Os, there has been evaluation of SB- dominal or major vascular surgery showed a longer elimi- pregnanolone; the anesthetic properties of 5o- and SB- nation half-life (47 to 133 mins), and lower clearance (250 reduced progesterone metabolites having been recog- to 1,520 ml/min) (i.e., flow-dependent elimination)30 nized since 1957.38 (Table 1). Both steroids were hepatically biotransformed The first reported studies in animals were those of with urinary excretion of alphaxalone and Zoo-reduced Norberg et aZ.,3g~40who evaluated the actions in male rats alphaxalone glucuronides, and alphadolone glucuronide. of 3ol-hydroxy and 5a- and SB-pregnanolone formulated as No alphadolone acetate, as free steroid or glucuronide, an emulsion in Intralipid (pH 7.5). Both compounds was found in any urine samples; nor were any 1 l-reduced showed excitatory movements during infusions to EEG compounds (derived from either alphaxalone or alphado- burst suppression. The RB-isomer was the more potent, lone) or 20-reduced alphadolone. There also were no me- with a potency ratio of 6:l compared with thiopental for tabolites with additional hydroxyl groups (which increase induction of anesthesia. Loss of righting reflex occurred hydrophilicity) in samples of plasma, bile, or urine. We rapidly, but recovery was faster after 5B-pregnanolone. It also failed to confirm the presence of either steroid or also has been evaluated in other animal species and shown their metabolites in bile samples31 to have a high therapeutic index (>40). In the rat, induction of anesthesia caused minimal car- Infusions of Althesin diovascular depression, but recovery was not as rapid as following propofol or Althesin.41,42 When administered to The high systemic clearance of Althesin, and its relatively ventilated dogs receiving fentanyl (0.2 pg/kg/min), doses short duration of action, made the drug appropriate for of 0.5 to 4 mg/kg pregnanolone produced anesthesia last-

Table 1. Disposition Kinetics of Three Steroid Anesthetics (Althesin: AlphaxaIone/Alphadolone Acetate, Minaxolone Citrate, and Eltanolene)

T%B VP Vd, WQ (L) (L)

Bolus dosing Alphaxalone (Simpson) 34.2 (2) - 53.8 (7.6) 1.44 (0.27) Alphaxalone (Sear) 32 (10) 65.3 (11) 48.3 (16) 1.52 (0.50) Alphadolone (Sear) 36.4 (10) 53.7 (6) 44.0 (8) 1.09 (0.32) Minaxolone (Dunn) 47.2 (26) 98.2 (23) - 1.55 (0.46) Eltanolone (Carl) 73.0 (10) 361 (51) - 3.46 (0.53) Eltanolone (Gray) 88.8 (66) - 134 (69) 1.85 (0.37) Infusion studies Alphaxalone (Sear) 90.5 (27) - 107.3 (68) 0.84 (0.47) Minaxolone (Sear) 87.3 (23) - 149.1 (27) 1.15 (0.13) Eltanolone (Schuttler) 182 (27) - - 1.80 (0.4) Note: Data are means i SD. TW = elimination half life; VP and Vd,, = apparent volumes of distribution during the elimination phase (VP) and at steady state (Vd,,); ~1, = systemic (plasma) clearance.

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ing 10 to 15 minutes. Cardiac output, SBP, and contrac- Hering et ~1.~~recently examined the EEG power spec- tility only decreased after doses greater than 2 to 4 mg/kg. tral changes following administration of a single bolus Systemic vascular resistance (SVR) also fell, but pulmonary dose of eltanolone 0.75 mg/kg, and related these to vascular resistance appeared to increase by mechanisms at changes in the blood eltanolone concentration. Anesthe- present unknown.43 sia caused a decrease in the (x power and an increase in Further animal evaluation of the drug in instrumented delta activity, with return to baseline after about 15 min- dogs by the group from Leuven have compared utes, and the median EEG frequency declined from 9 Hz eltanolone and propofol and shown pregnanolone to have to 1.5 Hz two minutes after eltanolone dosing. Using these negative inotropic properties.44 At high doses (2.5 to 5 data, the authors have derived a sigmoidal E,, concen- mg/kg), pregnanolone caused a dose-dependent decrease tration-effect model in 7 of 15 patients. The IC,, concen- in hepatic arterial blood flow, but little effect on portal tration was 565 (SD: 74) rig/ml, and the steepness coeffi- venous flow or renal arterial flow. Although both propofol cient was (y) 7.1 (2.4). Comparative data using the same and pregnanolone are solvented in the oil phase of a fat model give IC,, values for etomidate and propofol of 0.31 emulsion, the constituents differ in that the latter contains pg/ml and 2.3 ug/ml, respectively. Unfortunately, there 7% diacetylated monoglycerides. Further investigation of are a number of methodologic problems with this study- the effect on hepatic hemodynamics has suggested these principally use of venous rather than arterial sampling. changes may be due to the lipid emulsion.45 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 Human Pharmacology of 5f3pregnanolone (Eltanolone) associated kinetic parameters were a half-life of about 3 Doses of 0.4 to 0.6 mg/kg resulted in anesthesia in volun- hours, and a clearance of 1.8 L/min. teers.4648 Loss of verbal contact occurred before loss of In a separate study, Myint et a1.56compared induction the eyelash reflex (unlike thiopental). There are only few of anesthesia with three different infusion rates of eltano- published kinetic data, both from volunteers. Carl et uZ.~~ lone to elderly unpremeditated patients. All patients re- showed a high clearance (2.16 to 4.40 L/min) and a ter- ceived fentanyl 3 pg/kg 3 to 5 minutes before induction. minal half-life of 0.91 to 1.44 hours; while Gray et cd.47 Drug was infused at 300 ml/hr, 600 ml/hr, or 1,200 ml/ reported a mean clearance between 1.23 and 1.54 L/kg/ hr, and the induction doses for loss of consciousness were hr, with a mean elimination half-life between 1.48 and 1.65 0.59 mg/kg, 0.70 mg/kg, and 0.89 mg/kg, respectively. hours, and an apparent volume of distribution of about 2 The associated induction times were 112, 73, and 50 sec- L/kg (Table I). However, both studies had poorly de- onds. Hence, for a quartering of the infusion rate, there signed venous sampling regimens. Balance studies recov- was a 120% increase in the induction time, but a 33% ered less than 1% of the drug as unconjugated preg- decrease in the dose required. If we compare data for nanolone and between 7.9% and 16.2% as conjugated eltanolone with previous data for propofol, etomidate, pregnanolone in the urine over 24 hours postanesthesia. and thiopental, there are important differences. For Other metabolites found in humans were the conjugate of eltanolone, we can see that for the increase in induction 5P-pregnane-Sa, 20a diol. time, there was a smaller reduction in the induction dose, In more recent, but as yet unpublished, kinetic studies which suggests a slower response to changes in the blood in adults, children, and the elderly, the mean values of the eltanolone concentration. elimination half-life range from 3.1 to 4.3 hours, clearance Study of cardiovascular effects during induction of an- from 1.38 to 1.90 L/kg/hour, and apparent volume of esthesia, laryngoscopy, and intubation has been made in distribution at a steady state of 1.20 to 2.30 L/kg. benzodiazepine-premeditated ASA I and II patients.57 Pa- In all studies, there was a similar dynamic profile. He- tients received either eltanolone or propofol in doses of modynamic effects were minimal and dose-related. There 1.33 times the ED,, and breathed 67% N,O in 0, supple- was only mild ventilatory depression. Significant side ef- mented by enflurane. Patients were intubated after ve- fects included excitation of short duration during the in- curonium. Both treatments caused similar decreases in BP duction of sleep and minor involuntary movements. Fol- and CO, but a greater increase in HR postlaryngoscopy lowing a single dose of 0.6 mg/kg, CBF decreased by 34%, and intubation in patients receiving eltanolone. In these with a comparable fall in 0, consumption; thereby main- patients, SVR was unaltered following induction of anes- taining a coupling between metabolism and blood flow. thesia (Fipre I). However, in studies in patients prior to A number of open studies have defined ED,, induction coronary artery bypass grafting, where eltanolone 0.5 to doses in both benzodiazepine and opioid-premeditated 1.0 mg/kg has been coadministered with fentanyl 3 pg/ patients as between 0.33 mg/kg and 0.46 mg/kg.4g-51 In- kg and pancuronium or vecuronium, Tassani et aZ.*,58 have duction resulted in minimal hemodynamic depression, shown the fall in BP to be the result of vasodilation rather the main side effects being involuntary movements, apnea, and hypertonus. The relative potency of propofol (compared with eltanolone) was 0.313 in benzodiazepine- premeditated patients. 52 In children, the ED,, to loss of *Tassani P, Groh J, Ott E, Janicke U, Haessler R, Peter K: Eltanolone, verbal command was 0.68 mg/kg in unpremeditated chil- a new induction agent: hemodynamic effects in patients with coro- dren aged 6 to 10 years, and 0.53 mg/kg between 11 and nary artery disease compared with thiopentone [Abstract]. An&he% 15 years.53 010~ 1993;79:A328.

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225-j 125 . 1 i. l 200 175 100

2 150 -z 75 E 125 E p” $ 10075 E 50

50 25 25 0 0 Pre +l +3 *5 +l +5 Pre +I +3 +5 +I *5 Post-induction Pos’t-intubation B Post-induction Post-intubation A 8 120

100 6 2 80 .-ziE 4 E 60 z z 40 2 20

0 0 Pre +l +3 +5 +I +5 Pre +I +3 +5 +I +5 C Post-induction Post-intubation D Post-induction Post-intubation

. T Figure 1. A. Systolic arterial pressure (SAP), B. Heart rate 4 (HR), C. Cardiac output (Q), D. Stroke volume (SV), and E. =*- 25 Systemic vascular resistance (SVR) values for 22 patients re- 5 ceiving eltanolone and 17 receiving propofol. Data shown are I” 20 means and SD; for clarity, only upper bar is shown. The dark E ‘5 bars represent the eltanolone patients; the lighter bars the propofol group. i-1, t5 post-induction-one and five minutes 10 after induction; +l, t5 post-intubation-one and five minutes after intubation. 5 *p < 0.05, compared with the baseline (pre-induction) value; 0 l p < 0.01, compared with prelaryngoscopy and intubation. Pre +I i-3 +5 +I +5 E Post-induction Post-intubation than myocardial depression. Further studies are clearly thiopental or propofol. The incidences of involuntary needed. muscle movements and hypertonus were higher after There are few reports where eltanolone has been given eltanolone; and immediate recovery from eltanolone was by incremental dosing to supplement either N,O or opi- prolonged, and intermediate recovery (walking, taking oid anesthesia. Rajah et aL5’ achieved satisfactory “surgical oral fluids, voiding, and home readiness) appeared slower anesthesia” in 42 of 50 patients, the remaining 8 patients than propofol but similar to thiopental. However, because requiring isoflurane to supplement N,O. Maintenance re- there is a slower dynamic response to eltanolone, it is quirements ranged between 0.015 and 0.025 mg/kg/min. possible that these studies may reflect an overdosing of the The incidence of side effects was low (involuntary move- steroid. ments 8%, apnea >15 sets 2%). Other studies by Korttila et Thus, when we come to evaluate eltanolone further, we al. 52’60 have compared increments eltanolone with either shall need to rethink our strategy for its administration as

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a maintenance anesthetic. Rapid titration of drug to effect with an elimination half-life of 47 minutes and clearance may be more difficult than with other presently available between 0.80 L/min and 2.15 L/min.” Similar kinetics hypnotic drugs. were found when the drug was given by continuous infu- sion3’ (Table 1). Renal clearance was low (~0.5% of total Other Steroid Hypnotic Drugs systemic clearance), and the main metabolites in humans were the unconjugated steroid (50%) and the N-des- Since the initial studies of Selye, investigators have looked methyl, 0-desethyl, and N-desmethyl 0-desethyl com- for water-soluble steroids with anesthetic activity. Figdor et pounds. Urinary excretion of minaxolone appeared to be al.s8 found that amino-esters of 21-hydroxypregnanedione pH-dependent, with increased elimination under acidic were water-soluble and had hypnotic properties. In 1964, conditions. There are no data as to whether minaxolone Hewett et aZ.61described the pharmacology of a number of was excreted via the biliary route in humans. derivatives of androstane or pregnane with amino-radicals This drug was withdrawn from clinical evaluation in attached at C,, C,, or C,,. The most potent in causing loss 1981 because of possible oncogenic effects in rats and no of righting reflex was a C, morpholino-steroid (3~ clear clinical advantage over other IV hypnotic drugs. hydroxy, 2@morpholino, 5o-pregnan-20-one). It had a high therapeutic index (4.69), but a number of disadvan- tages: long threshold time to onset of anesthesia and a Other Water-soluble Steroid Hypnotic Drugs long duration of effect. Addition of an II-keto group In 1993, Gemmell et uZ.~*,~~described the anesthetic prop- shortened the duration of the ED,, dose (30 to 17 min- erties of a water-soluble Z-substituted aminosteroid (ORG utes), but had little effect on potency. 20599) in the mouse, rat, and dog. This had an efficacy Further studies by Phillips et aL6’ examined a range of similar to that of Althesin, a high therapeutic index of 13, steroids carrying a basic constituent at the 11-position. and a short duration hypnotic effect. However, it is not Compounds with Ilo or llB-dialkylaminoacyloxy- or di- being studied further in humans because of difficulties alkylamino- substituents formed water soluble salts (usu- with regards to drug stability and solubility. ally the citrate), which showed anesthetic activity in mice. More recently, another water-soluble 2-substituted aminosteroid has been evaluated in animals (ORG 21465) .” Minaxolone Citrate Again, this steroid shows a high therapeutic index in mice (13.8 compared with 4 to 5 for propofol and thiopental) , This steroid had the same pregnane ring structure as al- In the monkey, ORG 21465 and propofol (in doses of 4 phaxalone and alphadolone, but with introduction of 1 la- mg/kg and 3 mg/kg, respectively) produced rapid onset dimethyl amino and a 2B-ethoxy groups. The latter was of hypnosis, but the duration of sleep and of recovery was associated with an increased potency in the mouse, cat, greater after the aminosteroid. Because preliminary eval- and dog compared with alphaxalone6s; while the dimethyl uation of this anesthetic in human volunteers revealed an amino group at the 11 position in the C ring (in place of incidence of excitatory movements of about 70%, further the dione group) conferred the water solubility. Like Al- evaluation is unlikely. thesin, minaxolone had a high therapeutic index (>5). The properties of minaxolone and Althesin were similar: less respiratory depression and more rapid recovery than Conclusion is seen after thiopental, although there was some excitatory movement during minaxolone anesthesia in dogs. Whether eltanolone offers significant contributions to IV Minaxolone had other central nervous system depres- anesthesia remains to be seen, but the challenge to find sant effects in addition to hypnosis: like Althesin and thio- novel steroid alternatives to the present IV hypnotic drugs pental, it prevented maximal electroshock seizures and continues. The future for eltanolone will depend largely foot-shock induced fighting at subanesthetic doses when on whether its dynamic profile, especially for the mainte- given to mice. However, in deeply anesthetized cats, mi- nance of anesthesia, is comparable with that of the present naxolone (like Althesin) completely abolished cortical gold standard, namely propofol. Possible advantages of electrical activity without associated respiratory depres- eltanolone may be less cardiorespiratory depression, an sion. Thiopental, on the other hand, produced apnea absence of pain following injection, and a comparable in- while the EEG still showed spike and wave activity. cidence of postoperative nausea and vomiting. However, Clinical evaluation of minaxolone citrate showed a the drug has important side effects that need further eval- slower onset of action and a more prolonged recovery uation [excitatory phenomena, airway irritability, and skin when compared with Althesin.30,64-66 When given by in- reactions (flush, rash, and urticaria)] . cremental dosing or continuous infusion to supplement Possible areas of clinical utility for eltanolone may in- N,O, the incidence of excitatory movements and hyperto- clude induction and maintenance of anesthesia in the car- nus were greater in the patients receiving minaxolone.@ diovascularly 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 Disposition of Minaxolone anesthesia technique, where responses to noxious stimuli In surgical patients, the disposition following a bolus dose are treated by incremental doses of an opioid such as al- was best described by a two compartment kinetic model fentanil or remifentanil.

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Acknowledgments patients. Postgrud Med J 1972;48(Suppl 2):116-20. 19. Craig J, Cooper GM, Sear JW: Recovery from day-case anaesthe- Part of this review has been published previously in Anaesthetic Phar- sia. Comparison between methohexitone, Althesin and etomi- macology &&US (Steroidal anaesthetic agents. 1995;3:57-66) and is date. Br JAnaesth 1982;54:447-51. reproduced here by permission of the editor and publishers. Figure 1 20. Uppington J, Kay NH, SearJW: Propofol (Diprivan) as a supple- (a to e) has appeared in the ‘Journal ofClinicalAne.sth&a 1995;7:12& ment to nitrous oxide-oxygen for the maintenance of anaesthe- 131’, and is reproduced here by permission of the editor and pub sia. Postgrad Med J 1985;61:Suppl 3:80-3. lishers. 21. Clarke RS, Dundee JW, Doggart JR, Lavery T: The effects of single and intermittent administrations of althesin and other in- Addendum travenous anesthetic agents on liver function. An&h Analg 1974; Since the preparation of this review, the decision has been 53:461-8. 22. Park GR, Wilson J: Ahhesin infusion and regional blockade an- made to discontinue the clinical evaluation of eltanolone. aesthesia for major gynaecological surgery. Br JAnaesth 1978;50: 1219-26. References 23. Blunnie WP, Zacharias M, Dundee JW, Doggart JR, McIlroy PD: 1. Harrison NL, Simmonds MA: Modulation of the GABA receptor Liver enzyme studies with continuous intravenous anaesthesia. complex by a steroid anaesthetic. Brain Res 1984;323:287-92. Anaesthesia 1981;36:152-6. 2. Selye H: The anesthetic effect of steroid hormones. Proc Sot Exp 24. SearJW, Prys-Roberts C, Dye A: Hepatic function after anaesthe- Biol Med 1941;46:116-21. sia for major vascular reconstructive surgery. Br J Anaesth 1983; 3. Laubach GD, P’An SY, Rude1 Hw: Steroid anesthetic agent. Sci- 55:603-g. ence 1955;122:78. 25. Harrison GG, Meissner PN, Hift RJ: Anaesthesia for the porphy- 4. Taylor N, Shearer WM: The anaesthetic properties of 21- ric patient. Anaesthesia 1993;48:417-21. hydroxypregnanedione sodium hemisuccinate (hyd.roxydione), a 26. Harrison GG: Althesin and malignant hyperpyrexia. Br JAnaesth pharmacological and clinical study of 130 cases. Brj’Anaesth 1956; 1973;45:1019-21. 28:67-76. 27. Clarke RS, Dundee JW, Garrett FT, McArdle GK, Sutton JA: Ad- 5. Galley AH, Rooms M: An intravenous steroid anaesthetic. Expe- verse reactions to intravenous anaesthetics. BrJAnaesth 1975;47: riences with Viadril. Lancet 1956;1:990-4. 575-85. 6. Montmorency FA, Chen A, Rude1 H, Glas WW, Lee LE: Evalua- 28. Simpson ME: Pharmacokinetics of althesin-comparison with lig- tion of cardiovascular and general pharmacologic properties of nocaine. Br JAnaesth 1978;50:1231-5. hydroxydione. Anesthesiology 1958;19:450-6. 29. Sear JW, Sanders RS: Inn-a-patient comparison of the kinetics of 7. Phillips GH: Structure-activity relationships in steroidal anaes- alphaxalone and alphadolone in man. Eur JAnaesthesioZ 1984;l: thetics. J Steroid Biochem 1975;6:607-13. 113-22. 8. Atkinson RM, Davis B, Pratt MA, Sharpe HM, Tomich EG: Action 30. Sear JW, Prys-Roberts C, Gray AJ, Walsh EM, Curnow JS, Dye J: of some steroids on the central nervous system of the mouse. II. Infusions of minaxolone to supplement nitrous oxide-oxygen an- Pharmacology. J Med Chem 1965;8:426-32. aesthesia. A comparison with althesin. BrJAnaesth 1981;53:339-50. 9. P’An SY, Gardocki JF, Hutcheon DE, Rude1 H, Kodet MJ, Lau- 31. Holly JM, Trafford DJ, Sear JW, Makin HL: The in uino metabo- bath GD: General anesthetic and other pharmacological proper- lism of Althesin (alphaxalone and alphadolone acetate) in man. ties of a soluble steroid, 21-hydroxy-pregnanedione sodium suc- JPharrn Pharmacol1981;33:427-33. cinate. JPharrnacol Exp Ther 1955;115:432-41. 32. Du Cailar J: The effects in man of infusions of Althesin with 10. Gyermek L, Iriarte J, Crabbe P: Steroids. CCCX. Structure-activity particular regard to the cardiovascular system. Postgrad Med J relationship of some steroidal hypnotic agents. JMed Chem 1968; 1972;48(Suppl 2):72-9. 11:117-25. 33. Savege TM, Ramsay MA, Curran JP, Cotter J, Walling PT, Simp- 11. Child KJ, Davis B, Dodds MG, Twissell DJ: Anaesthetic, cardio- son BR: Intravenous anaesthesia by infusion. A technique using vascular and respiratory effects of a new steroidal agent CT 1341: alphaxalone/alphadolone (althesin). Anaesthesia 1975;30:757-64. a comparison with other intravenous anaesthetic drugs in the 34. Dechene JP: Alfathesin by continuous infusion supplemented unrestrained cat. Br JPharmacoZ 1972;46:189-200. with intermittent pentazocine. Can Anaesth Sot J 1977;24:702-6. 12. Child KJ, Currie JP, Davis B, Dodds MG, Pearce DR, Twissell DJ: 35. Sear JW, Prys-Roberts C: Plasma concentrations of alphaxalone The pharmacological properties in animals of CT 1341-a new during continuous infusion of Althesin. Br J Anaesth 1979;51: steroid anaesthetic agent. Br JAnaesth 1971;43:2-13. 861-5. 13. Campbell D, Forrester AC, Miller DC, et al: A preliminary clinical 36. Sear JW, Prys-Roberts C: Dose-related haemodynamic effects of study of CT1341-a steroid anaesthetic agent. Br J.Anaesth 1971; continuous infusions of Althesin in man. BrJ Anaesth 1979;51: 43314-24. 867-73. 14. Savege TM, Foley EI, Ross L, Maxwell MP: A comparison of the 37. Prys-Roberts C: Cardiovascular effects of continuous intravenous cardiorespiratory effects during induction of anaeisthesia of Al- anaesthesia compared with those of inhalational anaesthesia. Acta thesin with thiopentone and methohexitone. Postgrad Med J1972; Anaesthesiol Stand 1982;Suppl 75:10-7. 48:Suppl 2:66-72. 38. Figdor SK, Kodet MJ, Bloom BM, Agnello EJ, P’An SY, Laubach 15. Clarke RS, Montgomery SJ, DundeeJW, Bovill JG: Clinical studies GD: Central activity and structure in a series of water-soluble of induction agents. XXXIX: CT1341, a new steroid anaesthetic. steroids. JPhannacol Exp Ther 1957;119:299-309. Br JAnaesth 1971;43:947-52. 39. Norberg L, Wahlstrom G, Backstrom T: The anaesthetic potency 16. Turner JM, Coroneos NJ, Gibson RM, Powell D, Ness MA, Mc- of 3n+hydroxy-5a-pregnan-20-one and 3a-hydroxy-5B-pregnan-PO- Dowall DG: The effect of althesin on intracranial pressure in one determined with an intravenous EEGthreshold method in man. Br JAnaesth 1973;45:168-72. male rats. Pharmacol Toxic01 1987;61:42-7. 17. Takahashi T, Takasaki M, Namiki A, Doi S: Effects of althesin on 40. Larsson-Backstrom C, Lustig LL, Eklund A, Thorstensson M: An- cerebrospinal fluid pressure. Br JAnaesth 1973;45:179-84. aesthetic properties of pregnanolone in mice in an emulsion 18. Hannington-Kiff JG: Comparative recovery rates following induc- preparation for intravenous administration: a comparison with tion of anaesthesia with Althesin and methohexitone in out- 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 56. Myint Y, Peacock JE, Reilly CS: Induction of anaesthesia with emulsion. A new steroid preparation for intravenous anaesthesia: eltanolone at different rates of infusion in elderly patients. BrJ an experimental study in mice. Anaesthesia 1987;42:58690. Anaesth 1994;73:771-4. 42. Hogskilde S, Wagner J, Carl P, Sorensen MB: Anaesthetic prop- 57. SearJW, Jewkes C, WanigasekeraV: Hemodynamic effects during erties of pregnanolone emulsion. A comparison with alphaxa- induction, laryngoscopy, and intubation with eltanolone (SF- lone/alphadolone, propofol, thiopentone and midazolam in a pregnanolone) or propofol. A study in ASA I and II patients. J rat model. Anaesthesia 1987;42:1045-50, CZin Anesth 1995;7:12631. 43. Hogskilde S, Wagner J, Strom J, Sjontoft E, Olesen HP, 58. Tassani P, Janicke U, Ott E, Groh J, Conzen P: Hemodynamic Bredgaard Sorensen M: Cardiovascular effects of pregnanolone effects of anesthetic induction with eltanolone-fentanyl versus emulsion: an experimental study in artificially ventilated dogs. thiopental-fentanyl in coronary artery bypass patients. Anesth Acta Anaesthesiol &and 1991;35:669-75. Analg 1995;81:469-73. 44. Wouters PF, Van de Velde MA, Marcus MA, Deruyter HA, Van 59. Rajah A, Powell H, Morgan M: Eltanolone for induction of an- Aken H: Hemodynamic changes during induction of anesthesia aesthesia and to supplement nitrous oxide for minor gynaeco- with eltanolone and propofol in dogs. Anesth Analg 1995;81:125- logical surgery. Anaesthesia 1993;48:951-4. 31. 60. Eriksson H, Haasio J, Korttila K Comparison of eltanolone and 45. Wouters PF, Van de Velde MA, Marcus MA, Van Aken H: Nega- thiopental in anaesthesia for termination of pregnancy. Actu An- tive inotropic properties of pregnanolone in dogs due to the lipid aesthesiol Scan 1995;39:479-84. emulsion [Abstract]. Anesth Analg 1995;8O:S559. 61. Hewett CL, Savage DS, Lewisg, Sugrue MF: Anticonvulsant and 46. Carl P, Hogskilde S, NielsenJW, et al: Pregnanolone emulsion. A interneuronal blocking activity in some synthetic amino-steroids. preliminary pharmacokinetic and pharmacodynamic study of a JPhann Pharmacol1964;16:765-7. new intravenous anaesthetic agent. Anaesthesia 1990;45:189-97. 62. Phillipps GH, Ayres BE, Bailey EJ, Ewan GB, Looker BE, May PJ: 47. Gray HS, Holt BL, Whitaker DK, Eadsforth P: Preliminary study Water-soluble steroidal anaesthetics. JSteroid Biochem 1979;11:79- of a pregnanolone emulsion (KABI 2213) for i.v. induction of 86. general anaesthesia. BrJAnaesth 1992;68:272-6. 63. Davis B, Dodds MG, Dolamore PG, et al: Minaxolone: a new 48. Wolff J, Carl P, Hansen PB, Hogskilde S, Christensen MS, So- water-soluble steroid anaesthetic. Br JAnaesth 1979;51:564P. rensen MB: Effects of eltanolone on cerebral blood flow and 64. Aveling W, Sear JW, Fitch W, et al: Early clinical evaluation of metabolism in healthy volunteers. Anesthesiology 1994;81:623-7. minaxolone: a new intravenous steroid anaesthetic agent. Lancet 49. Powell H, Morgan M, Sear JW: Pregnanolone: a new steroid in- 1979;2(8133):71-3. travenous anaesthetic. Dose-finding study. Anaesthesia 1992;47: 65. Punchihewa VG, Morgan M, Lumley J, Whitwam JC: Initial ex- 287-90. perience with Minaxolone. A water-soluble steroid intravenous 50. Hering W, Biburger G, Rugheimer E: Induction of anesthesia anaesthetic agent. Anaesthesia 1980;35:214-7. using the new intravenous steroid anesthetic eltanolone (preg- 66. SearJW, Cooper GM, Williams NB, Simpson PJ, Prys-Roberts C: nanolone). Dose determination and pharmacodynamics. Der An- Minaxolone or Althesin supplemented by nitrous oxide. A study aesthkst 1993;42:74-80. in anaesthesia for short operative procedures. Anaesthesia 1980; 51. van Hemelrijck J, Muller P, Van Aken H, White PF: Relative 35:169-73. potency of eltanolone, propofol, and thiopental for induction of 67. Dunn GL, Morison DH, McChesney J, Pine W, Kumana CR, anesthesia. Anesthesiology 1994;80:3641. Gupta RN: The pharmacokinetics and pharmacodynamics of 52. Kallela H, Haasio J, Korttila K: Comparison of eltanolone and minaxolone. J CZin PharmacoZ1982;22:316-20. propofol in anesthesia for termination of pregnancy. Anesth Analg 68. Venning-Hill C, Callachan H, Peters JA, Lambert JJ, Gemmell 1994;79:512-6. DK, Campbell AC: Modulation of the GABA* receptor by ORG 53. Beskow A, Westrin P, Werner 0: Induction of general anesthesia 20599: a water-soluble steroid [Abstract]. Br JPhamacoZ 1994;lll with eltanolone in children 6-15 years of age [Abstract]. Anesthe- (suppl):183P. siology 1994;81:A1336. 69. Gemmell DK, Campbell AC, Anderson A, Byford A, Hill-Venning 54. Hering W, Schlecht R, Geisslinger G, Biburger G, Dinkel M, C, Marshall RJ: ORG 20599: a new water soluble aminosteroid Brune K, Rugheimer E: EEG analysis and pharmacodynamic intravenous anaesthetic [Abstract]. Br J Pharmacol 1994;lll modelling after intravenous bolus injection of eltanolone (preg- (suppl):189P. nanolone). Eur JAnaesthesioZ 1995;12:407-15. 70. Gemmell DK Byford A, Anderson A, et al: The anaesthetic and 55. Schuttler J, Hering W, Ihmsen H, Geisslinger G, Rugheimer E: GABA modulatory actions of ORG 21465, a novel water soluble Pharmacokinetic/-dynamic modeling of the new intravenous an- steroidal intravenous anaesthetic agent [Abstract]. BrJPharmacoZ esthetic eltanolone [Abstract]. Anesthesiology 1994;81:A409. 1995;116(suppl.):443P.

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