Abstract
Paradoxical reactions to benzodiazepines have been thoroughly reported since the introduction of this type of drug. The mechanism of benzodiazepine action is through the gamma-aminobutyric acid receptors. Properties of benzodiazepine include sedation, anxiolysis, amnesia, anticonvulsion, and muscle relaxation. Unfortunately, adverse paradoxical reactions can be stimulated by benzodiazepines and are difficult to predict and diagnose. Two cases of paradoxical reactions associated with the use of intravenous midazolam are presented, and the management of this complication and its different etiologies are reviewed. The relationship of the paradoxical reaction to alteration of the cholinergic homeostasis, serotonin levels, the role of genetics, and gamma-aminobutyric acid receptor configuration is discussed.
Full text
PDF




Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Belelli D., Lambert J. J., Peters J. A., Wafford K., Whiting P. J. The interaction of the general anesthetic etomidate with the gamma-aminobutyric acid type A receptor is influenced by a single amino acid. Proc Natl Acad Sci U S A. 1997 Sep 30;94(20):11031–11036. doi: 10.1073/pnas.94.20.11031. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Benson J. A., Löw K., Keist R., Mohler H., Rudolph U. Pharmacology of recombinant gamma-aminobutyric acidA receptors rendered diazepam-insensitive by point-mutated alpha-subunits. FEBS Lett. 1998 Jul 24;431(3):400–404. doi: 10.1016/s0014-5793(98)00803-5. [DOI] [PubMed] [Google Scholar]
- Di Liberti J., O'Brien M. L., Turner T. The use of physostigmine as an antidote in accidental diazepam intoxication. J Pediatr. 1975 Jan;86(1):106–107. doi: 10.1016/s0022-3476(75)80717-7. [DOI] [PubMed] [Google Scholar]
- Hall R. C., Zisook S. Paradoxical reactions to benzodiazepines. Br J Clin Pharmacol. 1981;11 (Suppl 1):99S–104S. doi: 10.1111/j.1365-2125.1981.tb01844.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Jastak J. T. Physostigmine: an antidote for excessive central nervous system depression or paradoxical rage reactions resulting from intravenous diazepam. Anesth Prog. 1985 May-Jun;32(3):87–92. [PMC free article] [PubMed] [Google Scholar]
- Litchfield N. B. Complications of intravenous diazepam--adverse psychological reactions. (An assessment of 16,000 cases). Anesth Prog. 1980 Nov-Dec;28(6):175–183. [PMC free article] [PubMed] [Google Scholar]
- Löw K., Crestani F., Keist R., Benke D., Brünig I., Benson J. A., Fritschy J. M., Rülicke T., Bluethmann H., Möhler H. Molecular and neuronal substrate for the selective attenuation of anxiety. Science. 2000 Oct 6;290(5489):131–134. doi: 10.1126/science.290.5489.131. [DOI] [PubMed] [Google Scholar]
- Massanari M., Novitsky J., Reinstein L. J. Paradoxical reactions in children associated with midazolam use during endoscopy. Clin Pediatr (Phila) 1997 Dec;36(12):681–684. doi: 10.1177/000992289703601202. [DOI] [PubMed] [Google Scholar]
- McKernan R. M., Cox P., Gillard N. P., Whiting P. Differential expression of GABAA receptor alpha-subunits in rat brain during development. FEBS Lett. 1991 Jul 29;286(1-2):44–46. doi: 10.1016/0014-5793(91)80936-w. [DOI] [PubMed] [Google Scholar]
- Mihic S. J., Ye Q., Wick M. J., Koltchine V. V., Krasowski M. D., Finn S. E., Mascia M. P., Valenzuela C. F., Hanson K. K., Greenblatt E. P. Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors. Nature. 1997 Sep 25;389(6649):385–389. doi: 10.1038/38738. [DOI] [PubMed] [Google Scholar]
- Möhler H., Okada T. Benzodiazepine receptor: demonstration in the central nervous system. Science. 1977 Nov 25;198(4319):849–851. doi: 10.1126/science.918669. [DOI] [PubMed] [Google Scholar]
- Peña B. M., Krauss B. Adverse events of procedural sedation and analgesia in a pediatric emergency department. Ann Emerg Med. 1999 Oct;34(4 Pt 1):483–491. doi: 10.1016/s0196-0644(99)80050-x. [DOI] [PubMed] [Google Scholar]
- Rodrigo C. R. Flumazenil reverses paradoxical reaction with midazolam. Anesth Prog. 1991 Mar-Apr;38(2):65–68. [PMC free article] [PubMed] [Google Scholar]
- Rudolph U., Crestani F., Benke D., Brünig I., Benson J. A., Fritschy J. M., Martin J. R., Bluethmann H., Möhler H. Benzodiazepine actions mediated by specific gamma-aminobutyric acid(A) receptor subtypes. Nature. 1999 Oct 21;401(6755):796–800. doi: 10.1038/44579. [DOI] [PubMed] [Google Scholar]
- Senninger J. L., Laxenaire M. Réactions paradoxales de violence secondaires à la prise de benzodiazépines. Ann Med Psychol (Paris) 1995 Apr;153(4):278–282. [PubMed] [Google Scholar]
- Short T. G., Forrest P., Galletly D. C. Paradoxical reactions to benzodiazepines--a genetically determined phenomenon? Anaesth Intensive Care. 1987 Aug;15(3):330–331. doi: 10.1177/0310057X8701500314. [DOI] [PubMed] [Google Scholar]
- Tallman J. F., Gallager D. W. The GABA-ergic system: a locus of benzodiazepine action. Annu Rev Neurosci. 1985;8:21–44. doi: 10.1146/annurev.ne.08.030185.000321. [DOI] [PubMed] [Google Scholar]
- Thompson S. A., Whiting P. J., Wafford K. A. Barbiturate interactions at the human GABAA receptor: dependence on receptor subunit combination. Br J Pharmacol. 1996 Feb;117(3):521–527. doi: 10.1111/j.1476-5381.1996.tb15221.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Whiting P. J., Bonnert T. P., McKernan R. M., Farrar S., Le Bourdellès B., Heavens R. P., Smith D. W., Hewson L., Rigby M. R., Sirinathsinghji D. J. Molecular and functional diversity of the expanding GABA-A receptor gene family. Ann N Y Acad Sci. 1999 Apr 30;868:645–653. doi: 10.1111/j.1749-6632.1999.tb11341.x. [DOI] [PubMed] [Google Scholar]
- van der Bijl P., Roelofse J. A. Disinhibitory reactions to benzodiazepines: a review. J Oral Maxillofac Surg. 1991 May;49(5):519–523. doi: 10.1016/0278-2391(91)90180-t. [DOI] [PubMed] [Google Scholar]