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Pharmacology: Pharmacodynamics: Mode or Mechanisms of Action: Diazepam is a benzodiazepine with anticonvulsant, anxiolytic, sedative, muscle relaxant and amnesic properties.
In general, benzodiazepines act as depressants of the central nervous system (CNS), producing all levels of CNS depression from mild sedation to hypnosis to coma depending on dose.
The precise sites and mechanisms of action have not been completely established. Although various mechanisms of action have been proposed, it is believed that benzodiazepines enhance or facilitate the inhibitory neurotransmitter action of gamma-aminobutyric add (GABA), which is one of the major inhibitory neurotransmitters in the brain and mediates both pre- and post-synaptic inhibition in all regions of the CNS, following interaction between the benzodiazepine and a specific neuronal membrane receptor.
Benzodiazepines reportedly act as agonists at the benzodiazepine receptors, which have been shown to form a component of a functional supra-molecular unit known as the benzodiazepine-GABA receptor-chloride ionophore complex. The receptor complex, believed to reside on neuronal membranes that regulate cell firing, functions mainly in the gating of the chloride channel. Activation of the GABA receptor results in the opening of the chloride channel, allowing the flow of' chloride ions through the neuronal membrane. Usually this results in hyperpolarization of the post-synaptic neuron, which inhibits firing of that neuron. That inhibition translates into decreased neuronal excitability, thus attenuating subsequent depolarising excitatory transmitters.
Benzodiazepines reportedly increase the frequency of the chloride channel opening, probably by enhancing the binding of GABA to its receptor or by facilitating the link of the GABA receptors to the chloride ion channels. Benzodiazepines also appear to act at GABA-independent receptors.
Antianxiety agent; sedative-hypnotic: Believed to stimulate GABA receptors in the ascending reticular activating system. Since GABA is inhibitory, receptor stimulation increases inhibition and blocks both cortical and limbic arousal following stimulation of the brain stem reticular formation.
Amnestic: Mechanism of action has not been determined. However, as may occur with all sedative-hypnotic medications, preanesthetic doses of diazepam impair recent memory and interfere with the establishment of the memory trace, thus producing anterograde amnesia for events occurring while therapeutic concentrations of the benzodiazepine are present.
Anticonvulsant: Appear to act, at least partially, by enhancing presynaptic inhibition. Suppress the spread of seizure activity produced by epileptogenic foci in the cortex, thalamus, and limbic structures but do not abolish the abnormal discharge of the focus.
Skeletal muscle relaxant adjunct: The exact mechanism of action of benzodiazepines has not been completely established but these medications appear to produce skeletal muscle relaxation primarily by inhibiting spinal polysynaptic afferent pathways; however, monosynaptic afferent pathways may also be inhibited. Benzodiazepines may also directly depress motor nerve and muscle function.
Pharmacokinetics: Absorption: Following IM administration: Diazepam absorption may be slow and erratic depending upon the site of administration. When diazepam is injected into the deltoid muscle, absorption is usually rapid and complete.
Distribution: Diazepam is highly lipid soluble and crosses the blood-brain barrier; these properties qualify it for intravenous use in short-term anaesthetic procedures, since it acts promptly on the brain, and its initial effects decrease rapidly as it is redistributed into fat depots and tissues.
Biotransformation: Hepatic. Diazepam is metabolised by oxidation to active, as well as inactive, metabolites before final inactivation as glucuronide conjugates. In addition to desmethyldiazepam, its active metabolites include oxazepam, and temazepam.
Binding: Diazepam is extensively bound (98 - 99%) to albumin in plasma.
Accumulation: During repeated dosing with long half-life benzodiazepines, there is accumulation of the parent compound and/or any pharmacologically active metabolites. Accumulation continues until a steady-state plasma concentration is reached, which usually takes 5 days to 2 weeks after initiation of therapy. Following termination of treatment, drug elimination is slow since active metabolites may remain in the blood for several days or even weeks, possibly resulting in persistent effects.
Half-life: The plasma half-life of diazepam and/or its metabolites is prolonged in neonates, in the elderly, and in patients with liver disease.
Excretion: Diazepam is excreted in the urine, mainly in the form of its metabolites, either free or in conjugated form.
Duration of action: The duration of clinical effects of the benzodiazepines is not always predictable from the elimination half-life.
