The Journal of pharmacology and experimental therapeutics
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J. Pharmacol. Exp. Ther. · Jan 1987
Activation of cholinergic mechanisms in the medulla oblongata reverse intravenous opioid-induced respiratory depression.
The role of cholinergic mechanisms in opioid-induced respiratory depression was investigated in isoflurane-anesthetized rats. In these animals, the i.v. administration of fentanyl, a clinically useful potent opioid analgesic/anesthetic, induced a prolonged period of apnea and subsequent rise in the end-tidal CO2, hypotension and bradycardia. The centrally acting anticholinesterase, physostigmine, significantly decreased fentanyl-induced respiratory and circulatory depression. ⋯ In conclusion, opioid-induced respiratory depression after systemic administration is obtunded greatly by facilitation of muscarinic mechanisms in the ventrolateral medulla. Inhibition of a cholinergic link in the central chemosensor may underlie opioid-induced respiratory depression. Manipulation of this cholinergic link could lead to the use and development of analgesics devoid of respiratory depression.
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J. Pharmacol. Exp. Ther. · Jan 1987
Differential effects of the imidazole derivatives etomidate, ketoconazole and miconazole and of metyrapone on the secretion of cortisol and its precursors by human adrenocortical cells.
The direct effects of etomidate, ketoconazole, miconazole and metyrapone were investigated on the secretion of cortisol and its precursors by dispersed cells from the adrenal cortex of a normal individual and four patients with Cushing's syndrome. The drugs interfered with adrenocorticotropic hormone-stimulated cortisol secretion in a dose-dependent way. Desoxycortisol concentrations in the medium were increased after the addition of metyrapone and low doses of etomidate but were suppressed with higher doses of etomidate. ⋯ It is concluded that etomidate at a low concentration (IC50, 10(-8) M) inhibits 11 beta-hydroxylase, whereas, at higher concentrations (10(-7)-10(-6) M), the side-chain cleavage enzyme system is also inhibited; metyrapone is a weaker (IC50, 10(-7) M) but pure 11 beta-hydroxylase inhibitor; miconazole inhibits adrenal 21-hydroxylase at 10(-6) M; and ketoconazole inhibits 17-hydroxylase. Etomidate, ketoconazole, miconazole and metyrapone inhibit cortisol biosynthesis in the human adrenal gland in different manners, which appear to involve the four cytochrome P-450-dependent monooxygenase reactions. Interestingly, these drugs affect corticosteroidogenesis by normal, hyperplastic and adenomatous adrenal cells in a similar manner.