Clopixol Depot Mechanism of Action

Pharmacotherapeutic group: Neuroleptics, Antipsychotics - Thioxanthene derivative. ATC-code: N 05 AF 05.
Pharmacology: Pharmacodynamics: Mechanism of action: Zuclopenthixol is a neuroleptic of the thioxanthene group.
The antipsychotic effect of neuroleptics is related to their dopamine receptor-blocking effect but possibly also 5-HT (5-hydroxytryptamine) receptor blockade contributes.
In vitro, zuclopenthixol has high affinity for both dopamine D₁ and D₂ receptors, for α₁-adrenoceptors and 5-HT₂ receptors but no affinity for cholinergic muscarinic receptors. It has weak histamine (H₁) receptor affinity and no α₂-adrenoceptor-blocking activity. In vivo, the affinity for D₂ binding sites dominates over the affinity for D₁ receptors.
Zuclopenthixol has proven to be a potent neuroleptic in all the behavioural studies for neuroleptic (dopamine receptor-blocking) activity. Correlation is found between the in vivo test models, the affinity for dopamine D₂ binding sites in vitro and the mean daily oral antipsychotic doses.
Like most other neuroleptics, zuclopenthixol increases the serum prolactin level in a dose-dependent manner.
Pharmacological studies have shown that zuclopenthixol decanoate in oil has extended antipsychotic activity and that the amount of drug needed to maintain a given effect over a prolonged period is substantially less with the modified-release preparation than with daily oral doses. Pharmacological studies also indicate that a prolonged antipsychotic effect can be clinically achieved with the modified-release preparation without obvious sedation. Furthermore, the risk of interaction with anaesthetic agents is expected to be low.
In clinical use, Clopixol Depot is intended for maintenance therapy of chronic psychotic patients.
Zuclopenthixol decanoate induces a transient dose-dependent sedation. However, sedation is not a problem if patients are switched from oral Clopixol or Clopixol Acuphase to maintenance therapy with Clopixol Depot. Patients rapidly develop tolerance to the non-specific sedative effect.
Clopixol Depot is particularly suitable for the treatment of psychotic patients who are agitated, restless, hostile and aggressive.
Clopixol Depot ensures continuous antipsychotic treatment and reduces the rate of recurrence due to non-compliance among patients receiving oral therapy.
Paediatric population: No data available.
Pharmacokinetics: Absorption: Intramuscular injection produces peak serum concentration (T_max) after 3-7 days. With an estimated half-life of around 3 weeks (reflecting the modified-release), steady-state concentrations are achieved after approximately 3 months of repeated administration.
Distribution: The apparent volume of distribution (V_d)_β is about 20 l/kg. The plasma protein binding is about 98-99%.
Biotransformation: The metabolism of zuclopenthixol proceeds along three main routes - sulfoxidation, side-chain N-dealkylation and glucuronic acid conjugation. The metabolites are devoid of psychopharmacological activity. Zuclopenthixol dominates over metabolites in brain and other tissues. Genetic polymorphism has been identified.
Elimination: The elimination half-life (T_{½ β}) is about 20 hours and the mean systemic clearance (Cl_s) is about 0.86 l/min.
Zuclopenthixol is excreted mainly with faeces, but also to some degree (about 10 %) with the urine. Only about 0.1 % of the dose is excreted unchanged with the urine, meaning that the drug load on the kidneys is negligible.
In nursing mothers, zuclopenthixol is excreted in small amounts with the breast milk. In steady state, the pre-dose mean ratio milk conc./serum conc. in women treated orally or with the decanoate form was about 0.29 or approximately 0.3.
Linearity: The pharmacokinetics is linear. The C_min of zuclopenthixol is approximately 25 nmol/l at steady state after a dose of 200 mg zuclopenthixol decanoate every 2 weeks.
Elderly patients: The pharmacokinetic parameters are widely independent of the patient's age.
Renal impairment: Not investigated. Based on the previously mentioned elimination data, however, it is reasonable to assume that renal impairment would not affect serum levels of zuclopenthixol to any major degree.
Hepatic impairment: Not investigated.
Toxicology: Preclinical safety data: Acute toxicity: Zuclopenthixol has low acute toxicity.
Chronic toxicity: In chronic toxicity studies, there were no findings of concern for the therapeutic use of zuclopenthixol.
Reproductive toxicity: In a three-generation study in rats a delay in mating was noted. Once mated there was no effect on fertility. In an experiment where zuclopenthixol was administered via the diet, impaired mating performance and reduced fertility were noted.
Animal reproduction studies have not shown evidence of embryotoxic or teratogenic effects. In a peri/postnatal study in rats, dosages of 5 and 15 mg/kg/day resulted in an increase of stillbirths, reduced pup survival and delayed development of pups.