Clorazepate
Clorazepate is a **benzodiazepine** primarily used in veterinary medicine as an adjunctive anticonvulsant and for managing anxiety or phobia-related behavioral disorders. * **Clinical Pearl**: Clorazepate is a prodrug. It requires the acidic environment of the stomach to be rapidly decarboxylated into its active metabolite, **nordiazepam** (desmethyldiazepam), before absorption. * In dogs, it is frequently paired with phenobarbital for refractory seizures. While tolerance to its anticonvulsant effects can develop, it is reported to occur less rapidly than with clonazepam. * In cats, it is utilized as an anxiolytic and occasionally as an alternative to phenobarbital for seizure management, though caution is required due to the risk of idiosyncratic hepatotoxicity associated with oral benzodiazepines in felines.
กลไกการออกฤทธิ์: Benzodiazepines exert their effects by enhancing the inhibitory activity of **gamma-aminobutyric acid (GABA)** in the central nervous system. * **Mechanism**: They bind to specific allosteric sites on the **GABA-A receptor** complex → increases the frequency of chloride channel opening → cellular hyperpolarization → decreased neuronal excitability. * This depression of subcortical CNS levels (primarily limbic, thalamic, and hypothalamic) produces the characteristic anxiolytic, sedative, skeletal muscle relaxant, and anticonvulsant effects. * Other postulated mechanisms include antagonism of serotonin and diminished release or turnover of acetylcholine in the CNS.
ขนาดยาตามชนิดสัตว์
- Anxiolytic or for compulsive behaviors · 0.2-0.5 mg/kg PO q12-24h · PO · q12-24h
- Alternative drug to phenobarbital for seizures · 3.75-7.5 mg (total dose per cat) PO once to twice daily · PO · q12-24h · Similar precautions are necessary as described for diazepam use in cats (risk of hepatic necrosis).
- Adjunctive medication in the treatment of seizures (in combination with phenobarbital) · 1-2 mg/kg PO q12h, but may need to divide q12h dose and give q8h to minimize adverse effects and maintain therapeutic levels · PO · q8-12h
- Adjunctive medication in the treatment of seizures (in combination with phenobarbital) · 0.5-1 mg/kg PO q8h · PO · q8h · No advantage gained with using sustained release products. May affect phenobarb levels; monitor 2 and 4 weeks later.
- Adjunctive medication in the treatment of seizures · 1-2 mg/kg PO q12h · PO · q12h
- Adjunctive medication in the treatment of seizures · 2-4 mg/kg PO twice daily, some dogs may require three times daily · PO · q8-12h
- Third-line agent for seizures · 1-2 mg/kg PO q8-12h · PO · q8-12h
- Management of cluster seizures · 0.5-2 mg/kg two to three times daily · PO · q8-12h · 48-96 hours · Give immediately after first seizure and stop after 48-96 hours. Used only during seizure activity, not as maintenance.
- Adjunctive therapy for fears and phobias · 11.25-22.5 mg per dog PO once to twice daily · PO · q12-24h · Recommends the sustained-delivery product (Tranxene-SD).
วิธีการให้ยา
ข้อห้ามใช้
- Hypersensitivity to benzodiazepines
- Significant liver disease/dysfunction
- Acute narrow angle glaucoma
- Fear-induced aggression (relative contraindication; may disinhibit bite inhibition)
อาการไม่พึงประสงค์
- Sedation (most common)
- Ataxia
- Physical dependence (with chronic use)
- Acute hepatic necrosis (idiosyncratic in cats)
- Paradoxical excitation or disinhibition of aggression
อันตรกิริยาระหว่างยา
- Azole Antifungals (itraconazole, ketoconazole) · May increase serum levels of benzodiazepines by inhibiting their metabolism.
- Cimetidine · May decrease the metabolism of benzodiazepines, leading to prolonged effects.
- CNS Depressants (barbiturates, narcotics, anesthetics) · Additive CNS depression; may cause profound sedation or respiratory depression.
- Erythromycin · May decrease the metabolism of benzodiazepines.
- Phenobarbital · Complex interaction: Clorazepate may initially increase phenobarbital serum levels. Over time, clorazepate levels may decrease, leading to decreased phenobarbital levels. Requires close monitoring.
- Phenytoin · May decrease clorazepate concentrations.
- Rifampin · May induce hepatic microsomal enzymes and decrease the pharmacologic effects of benzodiazepines.
การติดตาม
- Clinical efficacy (seizure frequency or behavioral improvement)
- Adverse effects (sedation, ataxia)
- Liver enzymes (especially critical in cats due to risk of acute hepatic necrosis)
- Phenobarbital serum levels (if used concurrently, monitor at 2 and 4 weeks after adding clorazepate)
การได้รับยาเกินขนาด
When used alone, clorazepate overdoses are generally limited to significant **CNS depression** (confusion, coma, decreased reflexes, profound sedation). * **Treatment**: Consists of standard protocols for removing and/or binding the drug in the gut (e.g., emesis if asymptomatic and recent, activated charcoal) and supportive systemic measures. * The use of analeptic agents (CNS stimulants such as caffeine, amphetamines) is generally **not recommended**. * **Flumazenil** (a specific benzodiazepine reversal agent) may be considered for very serious, life-threatening overdoses.
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