Pharmacotherapeutic group: hypnotic and sedative, benzodiazepine derivative.
ATCvet code: QN05CD08
Midazolam is an imidazobenzodiazepine, differing structurally from other benzodiazepines by the presence of an imidazole ring fused at positions 1 and 2 of the benzodiazepines nucleus. Midazolam exhibits similar pharmacologic actions as other benzodiazepines. The subcortical levels (primarily limbic, thalamic, and hypothalamic) of the CNS are depressed by the benzodiazepines thus producing the mild sedative (in horses), skeletal muscle relaxant, and anticonvulsant effects seen.
Benzodiazepine agonists act by enhancing the inhibitory synaptic neurotransmission mediated by gamma-aminobutyric acid (GABA), through binding to the benzodiazepine binding site on the GABAA-receptor, a ligand-gated chloride channel consisting of five subunits. Sensitivity to benzodiazepines is conferred by the presence of a γ subunit. Four types of benzodiazepine-sensitive GABAA-receptors can be further distinguished on the basis of the presence of α1, α2, α3 or α5 subunits. The α1 GABAA receptors are mainly expressed in cortical areas and thalamus, α2 and α5 GABAA receptors are largely expressed in the limbic system, and α3 GABAA receptors are selectively expressed in noradrenergic and serotonergic neurons of the reticular activating system.
Studies with genetically modified mice have shown that the sedative and partly the anticonvulsant actions of benzodiazepines are mediated by the α1-type GABAA receptors, whereas the anxiolytic effects of benzodiazepine-receptor ligands appear to be mediated via GABAA receptors containing the α2 subunit. The myorelaxant effect of benzodiazepines also seems to be mediated by benzodiazepine-sensitive GABAA receptors other than the α1-type.
In acidic conditions (pH less than 4), the benzepine ring of midazolam is open, resulting in increased water solubility. However, at physiological pH, the ring closes and midazolam becomes lipophilic, which accounts for its rapid onset of action. When midazolam is used in combination with ketamine for co-induction of anaesthesia, time to achievement of lateral recumbency is approximately 1 minute and time to intubation is approximately 1.5 minutes.
The disposition of midazolam following intravenous administration to horses is characterized by very rapid and relatively extensive distribution (VD is 2.14 l/kg after administration of the recommended dose). Midazolam is highly protein bound (94-97%) and rapidly crosses the blood-brain barrier.
Midazolam undergoes biotransformation by hepatic microsomal oxidation followed by conjunction with glucuronic acid.
Midazolam is eliminated almost exclusively by metabolic processes. The drug has a medium blood clearance (8.8 ml/kg/min after administration of the recommended dose) and an elimination half-life of approximately 4 hours in horses.
The principal route of excretion is through the kidneys, mainly as glucuronidated metabolites.