ESKAZEPAM TABLET

Indications

• Anxiety disorders
• Muscle spasms
• Seizure disorders (including status epilepticus)
• Premedication for medical procedures
• Sedation in dental procedures
• Acute alcohol withdrawal symptoms

Dosage

Adults: For anxiety: 2 mg to 15-30 mg daily in divided doses. For muscle spasms: 5-10 mg 1-2 hours before the procedure. For seizures: 3-10

Mechanism of action

Diazepam binds to specific sites on GABA-A receptors in the brain and spinal cord, enhancing the inhibitory effects of GABA. This increased GABAergic activity results in reduced neuronal excitability and has various effects including anxiolytic, sedative, muscle relaxant, and anticonvulsant actions. It may also affect other neurotransmitter systems, contributing to its broader impact on mood and cognition.

Pharmacodynamics

The pharmacodynamic effects of diazepam are primarily mediated through its action on GABA-A receptors, leading to increased chloride ion influx, hyperpolarization of neurons, and decreased neuronal excitability. This results in a reduction of anxiety, muscle relaxation, sedation, and anticonvulsant activity. The drug's properties make it useful in acute management scenarios, including seizures and muscle spasms.

Pharmacokinetics

Diazepam is well absorbed after oral administration, with peak plasma concentrations typically occurring within 1 to 2 hours. It has a long half-life, ranging from 20 to 50 hours, allowing for once or twice daily dosing. Diazepam is extensively metabolized in the liver, primarily by CYP2C19 and CYP3A4 enzymes, producing active metabolites. It is excreted mainly through the urine. Its pharmacokinetics can be affected by age, liver function, and concurrent medications.

Contra-indications

• Severe respiratory insufficiency
• Myasthenia gravis
• Sleep apnoea syndrome
• Hypersensitivity to diazepam or any of its components
• Acute narrow-angle glaucoma

Adverse effects

• Drowsiness
• Fatigue
• Ataxia
• Confusion
• Paradoxical reactions (agitation, aggression)
• Dependence and withdrawal symptoms

Interactions

• Severe interaction with NNRTIs (e.g., efavirenz) leading to increased exposure
• Severe interaction with ritonavir leading to increased exposure
• Severe interaction with rifampicin leading to decreased exposure
• Moderate interaction with antiepileptics affecting concentration
• Moderate interaction with monoclonal antibodies decreasing exposure

Precautions

• Use with caution in patients with a history of substance abuse
• Caution in elderly patients due to increased sensitivity and risk of falls
• Monitor for signs of respiratory depression
• Adjust dosage in patients with hepatic impairment

Pregnancy

Use during pregnancy only if the potential benefit justifies the potential risk to the fetus. Risk of teratogenic effects.

Breast-feeding

Diazepam is excreted in breast milk. Caution is recommended; consider alternative treatments.

Storage

Store in a cool, dry place away from direct sunlight. Keep out of reach of children.

Formulations

• Oral tablets (2 mg, 5 mg, 10 mg)
• Oral solution
• Injectable solution (IV, IM)
• Rectal solution

Mechanism of action

Diazepam is a benzodiazepine tranquilliser with anticonvulsant, sedative, muscle relaxant and amnesic properties. Benzodiazepines, such as diazepam, bind to receptors in various regions of the brain and spinal cord. This binding increases the inhibitory effects of gamma-aminobutyric acid (GABA). GABAs functions include CNS involvement in sleep induction. Also involved in the control of hypnosis, memory, anxiety, epilepsy and neuronal excitability. Diazepam is a benzodiazepine that exerts anxiolytic, sedative, muscle-relaxant, anticonvulsant and amnestic effects. Most of these effects are thought to result from a facilitation of the action of gamma aminobutyric acid (GABA), an inhibitory neurotransmitter in the central nervous system. Benzodiazepines are widely used in clinical anesthesia as premedication, but also to induce general anesthesia. Recent in vitro studies suggest that gamma-aminobutyric acid type A receptors, harboring a classical high-affinity benzodiazepine binding site, possess another "nonclassical" binding site for benzodiazepines. At present, it is unclear if, and to what extent, this novel nonclassical binding site is of relevance for the actions of benzodiazepines in the central nervous system. Because neocortex is involved in mediating the sedative and hypnotic properties of general anesthetics, ... the actions of diazepam /were quantified/ over a wide range of concentrations (from 10 nM up to 100 uM) in organotypic slice cultures using extracellular multiunit recordings of spontaneous action potential activity. Up to a concentration of 6.25 uM, diazepam reduced the activity of neocortical neurons, approaching a maximum of approximately 20%. This action was nullified by the benzodiazepine antagonist flumazenil. At concentrations >12.5 uM, diazepam evoked a second concentration-dependent dampening of network activity. Unlike the low concentration effect, this high concentration component was resistant to flumazenil. Diazepam induced a biphasic attenuation of spontaneous action potential firing of neocortical neurons. Low to moderate concentrations caused a monotonic, mild depression that is mediated via the classical binding site as it is antagonized by flumazenil. However, the effects of diazepam observed at high concentrations were not affected by flumazenil. Hence, these findings support the concept of at least 2 different binding sites for benzodiazepines on gamma-aminobutyric acid type A receptors. Furthermore, /these/ results are consistent with the hypothesis that the classical high-affinity binding site mediates low-dose diazepam actions, such as amnesia, anxiolysis, and sedation, while a second, nonclassical and independent site contributes to the anesthetic effects of diazepam, such as hypnosis and immobility. Benzodiazepine site agonists or inverse agonists enhance or reduce gamma-aminobutyric acid(A) (GABA(A)) receptor-mediated inhibition of neurons, respectively. Recently, it was demonstrated that the point mutation gamma 2F77I causes a drastic change in the affinity of a variety of benzodiazepine agonists or inverse agonists in receptor binding studies. Here we investigated the potency and efficacy of 10 benzodiazepine site ligands from 6 structural classes in wild-type and gamma 2F77I point mutated recombinant GABA(A) receptors composed of alpha 1 beta 3 gamma 2, alpha 2 beta 3 gamma 2, alpha 3 beta 3 gamma 2, alpha 4 beta 3 gamma 2, alpha 5 beta 3 gamma 2, and alpha 6 beta 3 gamma 2 subunits. Results indicate that the effects of the benzodiazepine site ligands zolpidem, zopiclone, Cl218872, L-655,708 and DMCM were nearly completely eliminated in all mutated receptors up to a 1 microM concentration. The effects of bretazenil, Ro15-1788 or abecarnil were eliminated in some, but not all mutated receptors, suggesting that the gamma 2F77I mutation differentially influences the actions of these ligands in different receptor subtypes. In addition, this point mutation also influences the efficacy o

Pharmacodynamics

Diazepam is a benzodiazepine that exerts anxiolytic, sedative, muscle- relaxant, anticonvulsant and amnestic effects. Most of these effects are thought to result from facilitation of the action of gamma aminobutyric acid (GABA), an inhibitory neurotransmitter in the central nervous system.