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.
Mechanism: 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 โ increases the frequency of chloride channel opening โ cellular hyperpolarization โ 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.
Dosing by species
- Anxiolytic or for compulsive behaviors ยท 0.2-0.5 mg/kg PO q12-24h ยท PO ยท q12-24h
- Alternative drug to phenobarbital for seizures ยท 3.75-7.5 mg (total dose per cat) PO once to twice daily ยท PO ยท q12-24h ยท 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) ยท 1-2 mg/kg PO q12h, but may need to divide q12h dose and give q8h to minimize adverse effects and maintain therapeutic levels ยท PO ยท q8-12h
- Adjunctive medication in the treatment of seizures (in combination with phenobarbital) ยท 0.5-1 mg/kg PO q8h ยท PO ยท q8h ยท 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 ยท 1-2 mg/kg PO q12h ยท PO ยท q12h
- Adjunctive medication in the treatment of seizures ยท 2-4 mg/kg PO twice daily, some dogs may require three times daily ยท PO ยท q8-12h
- Third-line agent for seizures ยท 1-2 mg/kg PO q8-12h ยท PO ยท q8-12h
- Management of cluster seizures ยท 0.5-2 mg/kg two to three times daily ยท PO ยท q8-12h ยท 48-96 hours ยท 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 ยท 11.25-22.5 mg per dog PO once to twice daily ยท PO ยท q12-24h ยท Recommends the sustained-delivery product (Tranxene-SD).
Routes of administration
Contraindications
- Hypersensitivity to benzodiazepines
- Significant liver disease/dysfunction
- Acute narrow angle glaucoma
- Fear-induced aggression (relative contraindication; may disinhibit bite inhibition)
Adverse effects
- Sedation (most common)
- Ataxia
- Physical dependence (with chronic use)
- Acute hepatic necrosis (idiosyncratic in cats)
- Paradoxical excitation or disinhibition of aggression
Drug interactions
- Azole Antifungals (itraconazole, ketoconazole) ยท May increase serum levels of benzodiazepines by inhibiting their metabolism.
- Cimetidine ยท May decrease the metabolism of benzodiazepines, leading to prolonged effects.
- CNS Depressants (barbiturates, narcotics, anesthetics) ยท Additive CNS depression; may cause profound sedation or respiratory depression.
- Erythromycin ยท May decrease the metabolism of benzodiazepines.
- Phenobarbital ยท Complex interaction: Clorazepate may initially increase phenobarbital serum levels. Over time, clorazepate levels may decrease, leading to decreased phenobarbital levels. Requires close monitoring.
- Phenytoin ยท May decrease clorazepate concentrations.
- Rifampin ยท May induce hepatic microsomal enzymes and decrease the pharmacologic effects of benzodiazepines.
Monitoring
- 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)
Overdose
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.
VetSheet drug reference is intended for licensed veterinary professionals as a clinical decision-support aid, not a substitute for professional judgement or the manufacturerโs current label.