Zoletil Injection

Indications

• Anxiety disorders
• Sedation
• Muscle relaxation
• Pre-anesthetic medication

Dosage

Children: Refer to the BNF for Children for appropriate dosing recommendations.

Adults: Refer to specific guidelines and the BNF for appropriate dosing recommendations.

Mechanism of action

Zolazepam functions by modulating the activity of gamma-aminobutyric acid (GABA) at the GABA-A receptor, enhancing the inhibitory effects of GABA, which results in increased neuronal hyperpolarization and decreased excitability. This mechanism underlies its anxiolytic, hypnotic, and muscle relaxant effects.

Pharmacodynamics

The pharmacodynamic profile of zolazepam includes sedation, anxiolysis, muscle relaxation, and anticonvulsant effects. It produces its effects relatively quickly, leading to rapid onset of sedation. The duration of action can vary based on the dose and the presence of other medications.

Pharmacokinetics

Zolazepam is well-absorbed following administration, with peak plasma concentrations typically occurring within a few hours. It is metabolized in the liver, with metabolites that may have pharmacological activity. The elimination half-life can vary, influencing the duration of sedation and therapeutic effects. Excretion occurs primarily through the kidneys.

Contra-indications

• Hypersensitivity to zolazepam or any of its components
• Severe respiratory insufficiency
• Myasthenia gravis
• Severe hepatic impairment

Adverse effects

• Sedation
• Dizziness
• Hypotension
• Ataxia
• Confusion
• Paradoxical reactions
• Dependence and withdrawal symptoms

Interactions

• Caution with other CNS depressants such as alcohol, opioids, and sedative-hypnotics
• May enhance the effects of drugs that cause sedation
• Potential for increased side effects when combined with other medications that affect liver enzymes

Precautions

• Use with caution in patients with a history of substance abuse
• Monitor for signs of respiratory depression
• Assess for potential interactions with concomitant medications
• Consider lower doses in elderly patients or those with compromised hepatic function

Pregnancy

Zolazepam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. It is classified as a Category C drug.

Breast-feeding

Zolazepam is excreted in breast milk. Caution is advised when administering to nursing mothers.

Storage

Store in a well-closed container at room temperature, away from light and moisture.

Formulations

• Tablets
• Injectable solution

Mechanism of action

Neurochemical interactions of tiletamine, a potent phencyclidine (PCP) receptor ligand, with the N-methyl-D-aspartate (NMDA)-coupled and -uncoupled PCP recognition sites were examined. Tiletamine potently displaced the binding of [3H]1-(2-thienyl)cyclohexylpiperidine with an IC50 of 79 nM without affecting sigma-, glycine, glutamate, kainate, quisqualate, or dopamine (DA) receptors. Like other PCP ligands acting via the NMDA-coupled PCP recognition sites, tiletamine decreased basal, harmaline-, and D-serine-mediated increases in cyclic GMP levels and induced stereotypy and ataxia. Tiletamine was nearly five times more potent than PCP at inhibiting the binding of 3-hydroxy[3H]PCP to its high-affinity NMDA-uncoupled PCP recognition sites. However, following parenteral administration, dizocilpine maleate (MK-801), ketamine, PCP, dexoxadrol, and 1-(2-thienyl)cyclohexylpiperidine HCl, but not tiletamine, increased rat pyriform cortical DA metabolism and/or release, a response modulated by the NMDA-uncoupled PCP recognition sites. Pretreatment with tiletamine did not attenuate the MK-801-induced increases in rat pyriform cortical DA metabolism, a result suggesting that tiletamine is not a partial agonist of the NMDA-uncoupled PCP recognition sites in this region. However, following intracerebroventricular administration (100-500 ug/rat), tiletamine increased pyriform cortical DA metabolism with a bell-shaped dose-response curve. These data indicate a differential interaction of tiletamine with the NMDA-coupled and -uncoupled PCP recognition sites. The paradoxical effects of tiletamine suggest that tiletamine might activate receptor(s) or neuronal pathways of unknown pharmacology. ...This study shows tiletamine to be similar to ketamine and to phencyclidine, agents known to interact with the N-methyl-D,L-aspartate (NMA) receptor. Effects of tiletamine on synaptic transmission and on direct excitatory responses to exogenous amino acids were examined in rat hippocampal and striatal slices. In striatal slices, tiletamine inhibited the NMA-mediated, but not the spontaneous, release of [3H]acetylcholine, with an IC50 of 70 nM. In hippocampal CA1 cells, 3 uM tiletamine in the perfusate reversibly blocked the intracellularly recorded responses to ionophoretically applied NMA, but not to glutamate, quisqualate and kainate. Tiletamine, 3 to 100 uM, had no effect on the orthodromically elicited excitatory postsynaptic potential, action potential amplitude or duration, resting membrane potential, or input resistance. In Mg++-free perfusate, the excitatory postsynaptic potential was greatly augmented to give a paroxysmal depolarization shift and was reversibly blocked by 10 uM tiletamine. /These/ results show that tiletamine is a potent and reversible antagonist of NMA-mediated responses without itself having major effects in low concentrations on normal membrane and synaptic pyramidal cell properties.