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New intravenous hypnotic and analgesic drugs
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,I vet. Anaesth. Vol 20 (December 1993)
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Current In fcrcs t
New intravenous hypnotic and analgesic drugs J.W. Sear The John Radcliffe Hospital, Headington, Oxford OX3 9DU
Despite the financial costs of developing new hypnotic and analgesic drugs, this continues - in an attempt to find agents with fewer or no adverse side-effects. Current interest includes investigation of the non-hypnotic / analgesic effects of presently available intravenous drugs as well as new formulations of existing drugs and new chemical entities.
In rats, induction causes minimal cardiovascular depression, but recovery was not as rapid as following propofol or Saffan. In man, preliminary kinetic data indicate an elimination half life of 250 minutes and a clearance of 1.40 l/kg/hour. Plasma concentrations between 800 and 1000 ng/ml cause hypnosis and recovery to eyes opening occurs at between 140 and 600 ng/ml. ED,,, induction doses in opioid and benzodiazepine premedicated patients are 0.44 mg/kg and 0.33 mg/kg respectively. These doses cause minimal haemodynamic depression (mean decrease in systolic and diastolic arterial pressure of 12%and increase in heart rate of 9%).Pain on injection was not observed, the main side-effects being involuntary movements, mild apnoea and hypertonus (Powell et al. 1992; Hering et al., 1993). The relative potency of propofol (compared to eltanolone) is about 0.3; while recovery appears slower after eltanolone (Kallela et al., 1992).Cardiovascular effects to induction of anaesthesia, laryngoscopy and intubation are similar following either of these two agents (Sear et al. 1993).
(a) EXISTING DRUGS
Among the topics of importance are the demonstration of concentration-dependent reductions in both cardiac output (and liver blood flow) and microsomal drug metabolism during propofol anaesthesia (Puttick et al., 1992; Janicki et al., 1992; Baker et al., 1993; Sear et al., 1994). These may lead to significant drug interactions during total intravenous anaesthesia. Other new side-effects of propofol are the reporting of allergictype reactions (Laxenaire et al., 1992; Leon de Casasola, 1992). The racemic components of ketamine (S+ and R-) have different kinetic and dynamic properties; the latter stereioisomer having a lower clearance and inhibiting the biodegradation of the St isomer (Schuttler et al., 1987; Geisslinger et al., 1992; Kharasch et al., 1992). Lower plasma concentrations are needed to achieve given dynamic end-points when the S+ isomer is infused alone compared with the racemate (Schuttler et al., 1992).
(d) NEWANALGESIC AGENTS Two synthetic anilino-piperidino derivatives are currently under evaluation. Remifentanil (GI87084B) is a p-agonist, with a rapid onset and short duration of action. It is metabolized by tissue and plasma esterases, has a high clearance (250 - 300 1/ hour) and short elimination half-life (10 - 20 minutes), and a blood-biphase equilibrium time of 1.3 minutes (Westmoreland et al., 1993). The effect-site context sensitive half time is 3.6 minutes. There is no histamine release. A second opioid (A3665) has comparable kinetics and dynamics (Cambareri et al., 1993; Lemmens et al., 1992). The role of these drugs as part of a balanced anaesthetic technique remains to be defined.
(b) NEWFORMULATIONS
There are ongoing evaluations of emulsion formulations of methohexitone, etomidate and propanidid in attempts to either overcome the allergenic potential of micellophor (propanidid); or to reduce the incidence of pain and venous sequelae (methohexitone, etomidate). Two recent studies with etomidate have shown unaltered dynamic properties - but lower incidence of pain on injection, myoclonus and local thrombophlebitis (Kulka et al., 1993; Vanacker et al., 1993).An additional advantage is the lower osmolality of the formulation (400 mosmol/ kg compared with 4965 msomol/kg for the propylene glycol formulation). This causes less red cell haemolysis (Nebauer et al., 1992).
REFERENCES Baker, M.T., Chadam, M.V., & Ronnenberg, W.C. (1993)Inhibitory effects of propofol on cytochrome P450 activities in rat hepatic microsomes. Anesthesia G.A n a l p i n , 76:817 - 821. Cambareri, J.J., Afifi, M.S., Glass, P.S.A., Esposito, B.F. & Campresi, E. M. (1993) A-3665, a new short-actingopioid :a comparison with alfentanil. Anc,st/min 8 Analg,sin, 76 812 - 816. Geisslinger, G., Hering, W., Kamp, H.D. & Brune, K. (1992) Pharmacokinetics and dynamics of ketaniine enantioiners using a 77:A331, sterioselective analytical method (abstract). Aiic,st/?c,t;iol[)~~!/,
( c ) NEWDRUGS :5(1PREGNANOLONE - ELTANOLONE
This 50-pregnane steroid has been evaluated in various animal species, and like other steroid agents has a high therapeutic index (TI > 40). It is water-insoluble and is formulated as an emulsion.
Hering, W., Biburger, G. & Rugheimer, E. (1993) Induction of anaesthesia with the new steroid intravenous anaesthetic eltanolone (pregnanolone). Dose finding and pharmacokinetics. Dcr Aimt,sf/rcsisf,4 2 74 - 80.
66
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T vet Anaesth. Vol 20 (December 1993) ~~~
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Janicki, P.K., James, M.F.M. & Erskine, W.A.R. (1992) Propofol inhibits enzymatic degradation of alfentanil and sufentanil by isolated liver microsomes in vitro. British /oiirnal ofAnnesthesin, 68: 311 - 312.
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Puttick, R.M., Diedericks,J., Sear, J.W., Glen, J.B., Foex, P. & Ryder W.A. (1992) Effects of graded rates of infusion of propofol on regional and global left ventricular function in the dog. British Jorrrrinl qi Annesthesin, 69: 375 - 381.
Kallela, H., Haasio, J. & Korttila, K. (1992) Comparison of eltanolone and propofol in anesthesia for termination of pregnancy (abstract). AncsthesioloXy, 77: A15.
Schuttler, J., Kloos, S. Ihmsen, H. & Pelzer, E. (1992) Pharniacokineticdynamic properties of S(+) ketamine versus racemic ketamine: a randomized double-blind study in volunteers. AnesHic~siolop/,7 7 A330.
Kharasch, E.D., Kunze, K. & Herrmann, S. (1991) Stereochemical aspects of human liver microsomal ketamine metabolism (abstract). Anesthesiology, 75: A382. Kulka, P.J., Bremer, F. & Schuttler, J. (1993) Induction of anaesthesia with etomidate in lipid emulsion. Dcr Annesthe
Schuttler, J.,Stanski, D.R., White, P.F. Trevor, A.J. Horai, Y., Verotta, D. & Sheiner, L.B. (1987)Pharmacodynamic modeling of the EEG effects of ketamine and its enantiomers in man. Joiirrinl (fP/rnrrirncuki,irtic~ and Biophnrmnceutics, 15: 241 - 253.
Laxenaire, M-C, Mata-Bermejo, E., Moneret-Vautrin, D.A. & Gueant, JL. (1992) Life threatening anaphylactoid reactions to propofol (Diprivann)Anesthesiology, 77: 275 - 280.
Sear, J.W., Diedericks, J.& Foex, P. (1994)Continuous infusions of propofol administered to dogs: effects on ICG and propofol disposition. British Journnl of Anarsthcsin, In press.
Lemmens,H.J.M., Dyck, J.B,Shafer,S.L. &Stanski,D.R. (1992)Theapplication of pharmacokinetics, dynamics and computer simulations to drug development; A-3665 versus fentanyl and alfentanil (abstract) Aiiesthi,sioloS!/, 77: A456.
Sear, J.W., Jewkes, C. & Wanigasekera, V. (1993) A comparison of hemodynamic changes during induction of anesthesia with eltanolone or propofol in ASA I or I1 patients (abstract) Aiic~st/irsiolo~!y,79: A119. Vanacker, B., Wiebalck, A., Van Aken, H., Sermeus, L., Bouillon, R. & Amery, A. (1993) Quality of induction and adrenocortical function. A clinical comparison of Etomidat-Lipuron and Hypnoniidateli Dcv Anncsthesist, 42: 81 - 89.
Leon de Casasola, O.A., Weiss, A. & Lema, M.J. (1992) Anaphylaxis due to propofol. Am,sthcsio/ogy, 77: 384 - 386. Nebauer, A.E., Doenicke, A,, Hoernecke, R., Angster, R. & Mayer, M. (1992)Does etomidate cause haemolysis? Britislz \oiivrinl ofAnnrsthesia, 69: 58 - 60.
Westmoreland, C.L.,Hoke, J.F.,Sebel, P.S.,Hug,C.C. &Muir, K.T. (1993) Pharmacokinetics of remifeiitanil (GI87084) and its major metabolite (GI90291) in patients undergoing elective inpatient surgery. A n c ~ s t h ~ s i o l o79: ~ y ,893 - 903.
Powell, H., Morgan, M. & Sear, J.W. (1992) Pregnanolone; a new steroid intravenous anaesthetic. Dose-finding study. Anncsthrsin, 4 7 287 - 290.
67
.~
~
~
_
_
_
,I vet. Anaesth. Vol 20 (December 1993)
_ _____
.
__
Current In fcrcs t
New intravenous hypnotic and analgesic drugs J.W. Sear The John Radcliffe Hospital, Headington, Oxford OX3 9DU
Despite the financial costs of developing new hypnotic and analgesic drugs, this continues - in an attempt to find agents with fewer or no adverse side-effects. Current interest includes investigation of the non-hypnotic / analgesic effects of presently available intravenous drugs as well as new formulations of existing drugs and new chemical entities.
In rats, induction causes minimal cardiovascular depression, but recovery was not as rapid as following propofol or Saffan. In man, preliminary kinetic data indicate an elimination half life of 250 minutes and a clearance of 1.40 l/kg/hour. Plasma concentrations between 800 and 1000 ng/ml cause hypnosis and recovery to eyes opening occurs at between 140 and 600 ng/ml. ED,,, induction doses in opioid and benzodiazepine premedicated patients are 0.44 mg/kg and 0.33 mg/kg respectively. These doses cause minimal haemodynamic depression (mean decrease in systolic and diastolic arterial pressure of 12%and increase in heart rate of 9%).Pain on injection was not observed, the main side-effects being involuntary movements, mild apnoea and hypertonus (Powell et al. 1992; Hering et al., 1993). The relative potency of propofol (compared to eltanolone) is about 0.3; while recovery appears slower after eltanolone (Kallela et al., 1992).Cardiovascular effects to induction of anaesthesia, laryngoscopy and intubation are similar following either of these two agents (Sear et al. 1993).
(a) EXISTING DRUGS
Among the topics of importance are the demonstration of concentration-dependent reductions in both cardiac output (and liver blood flow) and microsomal drug metabolism during propofol anaesthesia (Puttick et al., 1992; Janicki et al., 1992; Baker et al., 1993; Sear et al., 1994). These may lead to significant drug interactions during total intravenous anaesthesia. Other new side-effects of propofol are the reporting of allergictype reactions (Laxenaire et al., 1992; Leon de Casasola, 1992). The racemic components of ketamine (S+ and R-) have different kinetic and dynamic properties; the latter stereioisomer having a lower clearance and inhibiting the biodegradation of the St isomer (Schuttler et al., 1987; Geisslinger et al., 1992; Kharasch et al., 1992). Lower plasma concentrations are needed to achieve given dynamic end-points when the S+ isomer is infused alone compared with the racemate (Schuttler et al., 1992).
(d) NEWANALGESIC AGENTS Two synthetic anilino-piperidino derivatives are currently under evaluation. Remifentanil (GI87084B) is a p-agonist, with a rapid onset and short duration of action. It is metabolized by tissue and plasma esterases, has a high clearance (250 - 300 1/ hour) and short elimination half-life (10 - 20 minutes), and a blood-biphase equilibrium time of 1.3 minutes (Westmoreland et al., 1993). The effect-site context sensitive half time is 3.6 minutes. There is no histamine release. A second opioid (A3665) has comparable kinetics and dynamics (Cambareri et al., 1993; Lemmens et al., 1992). The role of these drugs as part of a balanced anaesthetic technique remains to be defined.
(b) NEWFORMULATIONS
There are ongoing evaluations of emulsion formulations of methohexitone, etomidate and propanidid in attempts to either overcome the allergenic potential of micellophor (propanidid); or to reduce the incidence of pain and venous sequelae (methohexitone, etomidate). Two recent studies with etomidate have shown unaltered dynamic properties - but lower incidence of pain on injection, myoclonus and local thrombophlebitis (Kulka et al., 1993; Vanacker et al., 1993).An additional advantage is the lower osmolality of the formulation (400 mosmol/ kg compared with 4965 msomol/kg for the propylene glycol formulation). This causes less red cell haemolysis (Nebauer et al., 1992).
REFERENCES Baker, M.T., Chadam, M.V., & Ronnenberg, W.C. (1993)Inhibitory effects of propofol on cytochrome P450 activities in rat hepatic microsomes. Anesthesia G.A n a l p i n , 76:817 - 821. Cambareri, J.J., Afifi, M.S., Glass, P.S.A., Esposito, B.F. & Campresi, E. M. (1993) A-3665, a new short-actingopioid :a comparison with alfentanil. Anc,st/min 8 Analg,sin, 76 812 - 816. Geisslinger, G., Hering, W., Kamp, H.D. & Brune, K. (1992) Pharmacokinetics and dynamics of ketaniine enantioiners using a 77:A331, sterioselective analytical method (abstract). Aiic,st/?c,t;iol[)~~!/,
( c ) NEWDRUGS :5(1PREGNANOLONE - ELTANOLONE
This 50-pregnane steroid has been evaluated in various animal species, and like other steroid agents has a high therapeutic index (TI > 40). It is water-insoluble and is formulated as an emulsion.
Hering, W., Biburger, G. & Rugheimer, E. (1993) Induction of anaesthesia with the new steroid intravenous anaesthetic eltanolone (pregnanolone). Dose finding and pharmacokinetics. Dcr Aimt,sf/rcsisf,4 2 74 - 80.
66
__
~~
T vet Anaesth. Vol 20 (December 1993) ~~~
~~
~
~~
~
Janicki, P.K., James, M.F.M. & Erskine, W.A.R. (1992) Propofol inhibits enzymatic degradation of alfentanil and sufentanil by isolated liver microsomes in vitro. British /oiirnal ofAnnesthesin, 68: 311 - 312.
~~
~~
Puttick, R.M., Diedericks,J., Sear, J.W., Glen, J.B., Foex, P. & Ryder W.A. (1992) Effects of graded rates of infusion of propofol on regional and global left ventricular function in the dog. British Jorrrrinl qi Annesthesin, 69: 375 - 381.
Kallela, H., Haasio, J. & Korttila, K. (1992) Comparison of eltanolone and propofol in anesthesia for termination of pregnancy (abstract). AncsthesioloXy, 77: A15.
Schuttler, J., Kloos, S. Ihmsen, H. & Pelzer, E. (1992) Pharniacokineticdynamic properties of S(+) ketamine versus racemic ketamine: a randomized double-blind study in volunteers. AnesHic~siolop/,7 7 A330.
Kharasch, E.D., Kunze, K. & Herrmann, S. (1991) Stereochemical aspects of human liver microsomal ketamine metabolism (abstract). Anesthesiology, 75: A382. Kulka, P.J., Bremer, F. & Schuttler, J. (1993) Induction of anaesthesia with etomidate in lipid emulsion. Dcr Annesthe
Schuttler, J.,Stanski, D.R., White, P.F. Trevor, A.J. Horai, Y., Verotta, D. & Sheiner, L.B. (1987)Pharmacodynamic modeling of the EEG effects of ketamine and its enantiomers in man. Joiirrinl (fP/rnrrirncuki,irtic~ and Biophnrmnceutics, 15: 241 - 253.
Laxenaire, M-C, Mata-Bermejo, E., Moneret-Vautrin, D.A. & Gueant, JL. (1992) Life threatening anaphylactoid reactions to propofol (Diprivann)Anesthesiology, 77: 275 - 280.
Sear, J.W., Diedericks, J.& Foex, P. (1994)Continuous infusions of propofol administered to dogs: effects on ICG and propofol disposition. British Journnl of Anarsthcsin, In press.
Lemmens,H.J.M., Dyck, J.B,Shafer,S.L. &Stanski,D.R. (1992)Theapplication of pharmacokinetics, dynamics and computer simulations to drug development; A-3665 versus fentanyl and alfentanil (abstract) Aiiesthi,sioloS!/, 77: A456.
Sear, J.W., Jewkes, C. & Wanigasekera, V. (1993) A comparison of hemodynamic changes during induction of anesthesia with eltanolone or propofol in ASA I or I1 patients (abstract) Aiic~st/irsiolo~!y,79: A119. Vanacker, B., Wiebalck, A., Van Aken, H., Sermeus, L., Bouillon, R. & Amery, A. (1993) Quality of induction and adrenocortical function. A clinical comparison of Etomidat-Lipuron and Hypnoniidateli Dcv Anncsthesist, 42: 81 - 89.
Leon de Casasola, O.A., Weiss, A. & Lema, M.J. (1992) Anaphylaxis due to propofol. Am,sthcsio/ogy, 77: 384 - 386. Nebauer, A.E., Doenicke, A,, Hoernecke, R., Angster, R. & Mayer, M. (1992)Does etomidate cause haemolysis? Britislz \oiivrinl ofAnnrsthesia, 69: 58 - 60.
Westmoreland, C.L.,Hoke, J.F.,Sebel, P.S.,Hug,C.C. &Muir, K.T. (1993) Pharmacokinetics of remifeiitanil (GI87084) and its major metabolite (GI90291) in patients undergoing elective inpatient surgery. A n c ~ s t h ~ s i o l o79: ~ y ,893 - 903.
Powell, H., Morgan, M. & Sear, J.W. (1992) Pregnanolone; a new steroid intravenous anaesthetic. Dose-finding study. Anncsthrsin, 4 7 287 - 290.
67