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ETOMIDATE, SEDATIVES, AND NEUROENDOCRINE CHANGES
276
ETOMIDATE, SEDATIVES, AND NEUROENDOCRINE CHANGES
SIR,-Professor Ledingham and Mr Watt (June 4, p 1270) and Dr
(July 2, p 54) seem to ascribe a higher patients on sedation with etomidate to mortality drug-induced adrenocortical suppression. This confirmation in man of evidence from the laboratory animal illustrates the ability of Fellows and colleagues in intensive
care
animal research to reveal subtle effects of new drugs. Further work at my laboratory shows that etomidate may provoke not only peripheral (as indicated by Fellows et al) but also central neuroendocrine changes. Etomidate and its D-isomer inhibit not only stress and drug 3-5 induced increases in plasma corticosterone but also adrenocortical activation induced by corticotropin (ACTH)
(table).
-
EFFECT OF
ACTH1_24 ON
BLOOD CORTICOSTERONE IN NORMAL MALE
ADULT RATS PRETREATED OR NOT WITH D-ETOMIDATE
’Saline 2 ml/kg or D-etomIdate 20 JAmol/kg was given tntravenously followed 1 intramuscular ACTH1_24 (cosyntropm) 700 mU/kg or saline
mm
later by
Injection into the lateral ventricles of conscious rats of D,L-etomidate or D-etomidate (011 Cmol) does not modify plasma
corticosterone. This dose reduces environmental reactivity and spontaneous activity. The inhibition of ACTH-induced adrenocortical activation by ACTH and the lack of adrenocortical suppression by intracerebroventricular injection of D-etomidate point to a peripheral rather than a central effect of the anaesthetic on the hypothalamic-hypophyseal-adrenal system, and the above data accord well with Fellows’ results. Further results from this laboratory 4,6 show that etomidate and its D-isomer (20 /-{mol/kg) suppress the rise in plasma prolactin that follows the intravenous injection procedure, surgical trauma (see figure), and chemical increase of brain serotoninergic neurotransmission by 5-hydroxytryptophan9or D-fenfluramine (unpublished). The increase in serum prolactin by a-methyl-ptyrosine methyl ester is inhibited by D-etomidate less strikingly did not modify the hyperpro(unpublished); lactinaemia that follows administration of the dopamine blocking ’agent haloperidol;and L-etomidate proved ineffective in all the above tests. Injection into the lateral ventricles of conscious rats of D,L-etomidate or D-etomidate (0’11 mol) strongly reduced serum prolactin. During the past year I have repeatedly advised Janssen Pharmaceutical to promote clinical pharmacology studies on possible effects of etomidate on prolactin release in man. Etomidate does not influence either dopamineor serotonin release from brain synaptosomes or monoamine hypothalamic depletion induced by a-methyl-p-tyrosine (unpublished). In vitro studies of the drug’s effect on lactotrophs and corticosteroidogenesis are in progress. In answer to your July 2 editorial’s question about whether adrenal suppression with etomidate was greater than that with other sedative agents I would draw attention to our evidence in the rat. Intravenous injection of steroid anaesthetics (hydroxydione 10-20
D,L-etomidate
P, Vacca M. Etomidate and corticotrophic 1982; 256: 308-10.
1. Preziosi
4. 5.
6.
Arch Int
Pharmacodyn Ther
testing drug evaluation: Problems and difficulties. In: Kuemmerle HP, Shibuya TK, Kimura M, eds. Problems of clinical pharmacology in therapeutic research Phase I (Adv Clin Pharmacol 13). Munich: Urban and Schwarzenberg, 1977: 41-69. Preziosi P, Vacca M. Etomidate diminishes adrenocortical activation by surgical trauma or chemically-increased serotonergic neurotransmission in the brain. In: Wauquier A, Borgers M, Amery WK, eds Protection of tissues against hypoxia. Amsterdam: Elsevier Biomedical, 1982: 127-29. Vacca M, Cerrito F, Preziosi P. Effect of etomidate enantiomers on CRH-ACTH and prolactin release. Arch Int Pharmacodyn Ther (in press) Preziosi P, Cerrito F, Martire M, Vacca M GABA-receptor antagonists and endocrine effects of D-etomidate. In: 3rd Capo Boi Conference on Neuroscience (May 29 to June 2, 1983; abstr 81). Oxford: Pergamon Press (in press). Preziosi P, Cerrito F, Vacca M. Etomidate inhibits prolactin release but not through a dopaminergic mechanism. Brain Res (in press).
2. Preziosi P. Predictive values of animal
3.
axis.
versus
clinical
in
Effect of etomidate and its enantiomers terone concentrations.
on
prolactin
and corticos-
Key to the columns is, left to right: (1) saline (2 mg/kg) only (open columns); (2) laparotomy only (hatched columns); (3) laparotomy+ D,L-etomidate (20 jimol/kg) (vertical shading); (4) at 15 and 60 mm only, laparotomy + D-etomidate (filled columns), (5) at 15 and 60 min only, laparotomy + L-etomidate (stippled columns). difference from saline Symbols indicate significant (p<0-01) laparotomy (double symbols). Horizontal band shows range of values in untreated
and
rats.
mg/kg7and ’Althesin’ 0
- 07ml/kg8) or of ketamine (2 mg/kgM) at doses similar to those used to induce anaesthesia in man did not prevent the adrenocortical response to handling and surgery-indeed the adrenocortical stimulation was enhanced after ketamine. During deep anaesthesia with althesin (1 - 75 ml/kg) the adrenal activation induced by handling and surgery was inhibited (though to a lesser extent than with etomidate). Hydroxydione at a full anaesthetic dose (40 mg/kg) provoked a significant adrenocortical activation and did not influence that induced by laparotomy.9 Ketamine (35 mg/kg) exercised an adrenocortical inhibition for only 4 min after injection.
Supported by
CNR grant 82.02104.04. I thank Prof M. Vacca and Dr F.
Cerrito, Dr R. del Carmine, Dr N. De Gori, Dr M. Martire, and Dr E. Regazzoni for their help; Dr P. Laduron and Dr J. F. Leysen (Janssen Pharmaceutica, Beerse, Belgium) for etomidate and its enantiomers; and MrF. Vinciarelli and Mr G. Ripanti for technical assistance. Department of Pharmacology, CNR Neuroendocrinopharmacology Unit (Gruppo Nazionale Farmacologia), Faculty of Medicine, Catholic University of the Sacred Heart, 00168 Rome, Italy
PAOLO PREZIOSI
P, Reduzzi F, Loscalzo B. Modificazioni corticosurrenali da idrossidione. In: Curri SB, Martini L, eds. Pathophysiologia diencephalica. Vienna: Springer, 1958. 299-302. 8. Nisticó G, Pisanti N, Rotiroti D, Preziosi P, Cuocolo R, De Martino G, Nisticò GM Effects of Althesin and ketamine on resting and stress stimulated adrenocortical activity in rats. Br J Anaesth 1978; 50: 891-97. 9. Preziosi P, Loscalzo B, Reduzzi F. Protegge l’idrossidione dalle modificazioni corticosurrenali da trauma chirurgico? In: Curri SB, Martini L, eds Pathophysiologia diencephalica. Vienna: Springer, 1958: 294-98. 7. Preziosi
ETOMIDATE, SEDATIVES, AND NEUROENDOCRINE CHANGES
SIR,-Professor Ledingham and Mr Watt (June 4, p 1270) and Dr
(July 2, p 54) seem to ascribe a higher patients on sedation with etomidate to mortality drug-induced adrenocortical suppression. This confirmation in man of evidence from the laboratory animal illustrates the ability of Fellows and colleagues in intensive
care
animal research to reveal subtle effects of new drugs. Further work at my laboratory shows that etomidate may provoke not only peripheral (as indicated by Fellows et al) but also central neuroendocrine changes. Etomidate and its D-isomer inhibit not only stress and drug 3-5 induced increases in plasma corticosterone but also adrenocortical activation induced by corticotropin (ACTH)
(table).
-
EFFECT OF
ACTH1_24 ON
BLOOD CORTICOSTERONE IN NORMAL MALE
ADULT RATS PRETREATED OR NOT WITH D-ETOMIDATE
’Saline 2 ml/kg or D-etomIdate 20 JAmol/kg was given tntravenously followed 1 intramuscular ACTH1_24 (cosyntropm) 700 mU/kg or saline
mm
later by
Injection into the lateral ventricles of conscious rats of D,L-etomidate or D-etomidate (011 Cmol) does not modify plasma
corticosterone. This dose reduces environmental reactivity and spontaneous activity. The inhibition of ACTH-induced adrenocortical activation by ACTH and the lack of adrenocortical suppression by intracerebroventricular injection of D-etomidate point to a peripheral rather than a central effect of the anaesthetic on the hypothalamic-hypophyseal-adrenal system, and the above data accord well with Fellows’ results. Further results from this laboratory 4,6 show that etomidate and its D-isomer (20 /-{mol/kg) suppress the rise in plasma prolactin that follows the intravenous injection procedure, surgical trauma (see figure), and chemical increase of brain serotoninergic neurotransmission by 5-hydroxytryptophan9or D-fenfluramine (unpublished). The increase in serum prolactin by a-methyl-ptyrosine methyl ester is inhibited by D-etomidate less strikingly did not modify the hyperpro(unpublished); lactinaemia that follows administration of the dopamine blocking ’agent haloperidol;and L-etomidate proved ineffective in all the above tests. Injection into the lateral ventricles of conscious rats of D,L-etomidate or D-etomidate (0’11 mol) strongly reduced serum prolactin. During the past year I have repeatedly advised Janssen Pharmaceutical to promote clinical pharmacology studies on possible effects of etomidate on prolactin release in man. Etomidate does not influence either dopamineor serotonin release from brain synaptosomes or monoamine hypothalamic depletion induced by a-methyl-p-tyrosine (unpublished). In vitro studies of the drug’s effect on lactotrophs and corticosteroidogenesis are in progress. In answer to your July 2 editorial’s question about whether adrenal suppression with etomidate was greater than that with other sedative agents I would draw attention to our evidence in the rat. Intravenous injection of steroid anaesthetics (hydroxydione 10-20
D,L-etomidate
P, Vacca M. Etomidate and corticotrophic 1982; 256: 308-10.
1. Preziosi
4. 5.
6.
Arch Int
Pharmacodyn Ther
testing drug evaluation: Problems and difficulties. In: Kuemmerle HP, Shibuya TK, Kimura M, eds. Problems of clinical pharmacology in therapeutic research Phase I (Adv Clin Pharmacol 13). Munich: Urban and Schwarzenberg, 1977: 41-69. Preziosi P, Vacca M. Etomidate diminishes adrenocortical activation by surgical trauma or chemically-increased serotonergic neurotransmission in the brain. In: Wauquier A, Borgers M, Amery WK, eds Protection of tissues against hypoxia. Amsterdam: Elsevier Biomedical, 1982: 127-29. Vacca M, Cerrito F, Preziosi P. Effect of etomidate enantiomers on CRH-ACTH and prolactin release. Arch Int Pharmacodyn Ther (in press) Preziosi P, Cerrito F, Martire M, Vacca M GABA-receptor antagonists and endocrine effects of D-etomidate. In: 3rd Capo Boi Conference on Neuroscience (May 29 to June 2, 1983; abstr 81). Oxford: Pergamon Press (in press). Preziosi P, Cerrito F, Vacca M. Etomidate inhibits prolactin release but not through a dopaminergic mechanism. Brain Res (in press).
2. Preziosi P. Predictive values of animal
3.
axis.
versus
clinical
in
Effect of etomidate and its enantiomers terone concentrations.
on
prolactin
and corticos-
Key to the columns is, left to right: (1) saline (2 mg/kg) only (open columns); (2) laparotomy only (hatched columns); (3) laparotomy+ D,L-etomidate (20 jimol/kg) (vertical shading); (4) at 15 and 60 mm only, laparotomy + D-etomidate (filled columns), (5) at 15 and 60 min only, laparotomy + L-etomidate (stippled columns). difference from saline Symbols indicate significant (p<0-01) laparotomy (double symbols). Horizontal band shows range of values in untreated
and
rats.
mg/kg7and ’Althesin’ 0
- 07ml/kg8) or of ketamine (2 mg/kgM) at doses similar to those used to induce anaesthesia in man did not prevent the adrenocortical response to handling and surgery-indeed the adrenocortical stimulation was enhanced after ketamine. During deep anaesthesia with althesin (1 - 75 ml/kg) the adrenal activation induced by handling and surgery was inhibited (though to a lesser extent than with etomidate). Hydroxydione at a full anaesthetic dose (40 mg/kg) provoked a significant adrenocortical activation and did not influence that induced by laparotomy.9 Ketamine (35 mg/kg) exercised an adrenocortical inhibition for only 4 min after injection.
Supported by
CNR grant 82.02104.04. I thank Prof M. Vacca and Dr F.
Cerrito, Dr R. del Carmine, Dr N. De Gori, Dr M. Martire, and Dr E. Regazzoni for their help; Dr P. Laduron and Dr J. F. Leysen (Janssen Pharmaceutica, Beerse, Belgium) for etomidate and its enantiomers; and MrF. Vinciarelli and Mr G. Ripanti for technical assistance. Department of Pharmacology, CNR Neuroendocrinopharmacology Unit (Gruppo Nazionale Farmacologia), Faculty of Medicine, Catholic University of the Sacred Heart, 00168 Rome, Italy
PAOLO PREZIOSI
P, Reduzzi F, Loscalzo B. Modificazioni corticosurrenali da idrossidione. In: Curri SB, Martini L, eds. Pathophysiologia diencephalica. Vienna: Springer, 1958. 299-302. 8. Nisticó G, Pisanti N, Rotiroti D, Preziosi P, Cuocolo R, De Martino G, Nisticò GM Effects of Althesin and ketamine on resting and stress stimulated adrenocortical activity in rats. Br J Anaesth 1978; 50: 891-97. 9. Preziosi P, Loscalzo B, Reduzzi F. Protegge l’idrossidione dalle modificazioni corticosurrenali da trauma chirurgico? In: Curri SB, Martini L, eds Pathophysiologia diencephalica. Vienna: Springer, 1958: 294-98. 7. Preziosi