Clopixol-Acuphase Mechanism of Action

Pharmacotherapeutic group: Neuroleptics (antipsychotics). ATC Code: N05AF05.
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 muscarine 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 in the in vivo test models, the affinity for dopamine D2 binding sites in vitro and the average, daily oral antipsychotic doses.
Like most other neuroleptics zuclopenthixol increases the serum prolactin level. Pharmacological studies showed a pronounced effect 4 hours after parenteral application of zuclopenthixol acetate in oil. Somewhat more marked effect was recorded in the period one to three days after the injection. During the following days the effect declined rapidly.
Clinical efficacy and safety: In clinical use of zuclopenthixol acetate is intended for the initial treatment of acute psychoses, mania and exacerbation of chronic psychoses.
A single injection of zuclopenthixol acetate ensures a pronounced and rapid reduction of psychotic symptoms. The duration of is 2 to 3 days and normally only one or two injections are sufficient before the patients can be switched to oral or depot treatment.
Besides causing a significant reduction or complete elimination of the nuclear symptoms of schizophrenia such as hallucinations, delusions and thought disturbances zuclopenthixol also has marked effect on accompanying symptoms like hostility, suspiciousness, agitation and aggressiveness.
Zuclopenthixol induces a transient dose-dependent sedation. However, such an initial sedation is usually advantageous in the acute phase of the psychosis as it calms the patient in the period before the antipsychotic effect sets in. The unspecific sedation is present rapidly after the injection, is significant after 2 hours and reaches its maximum in about 8 hours, whereupon it declines substantially and remains weak in spite of repeated injection.
Zuclopenthixol acetate is particularly useful in the treatment of psychotic patients, who are agitated, restless, hostile, or aggressive.
Pharmacokinetics: Absorption: By esterification of zuclopenthixol with acetic acid zuclopenthixol has been converted to a more lipophilic substance, zuclopenthixol acetate. When dissolved in oil and injected intramuscularly the ester diffuses rather slowly from the oil to the body water phase where it is rapidly hydrolysed releasing the active zuclopenthixol.
Following intramuscular injection maximum serum concentration is reached over a period of 24-48 hours (average 36 hours). The mean plasma elimination half-life (reflecting the release from the depot) is about 32 hours.
Distribution: The apparent volume of distribution (Vd)β is about 20 l/kg. The plasma protein binding is about 98-99%.
Biotransformation: The metabolism of zuclopenthixol proceeds along three main routes - sulphoxidation, side chain N-dealkylation and glucuronic acid conjugation. The metabolites are devoid of psychopharmacological activity. Zuclopenthixol dominates over metabolites in brain and other tissues.
Elimination: The elimination half-life (T½ β) of zuclopenthixol is about 20 hours and the mean systemic clearance (Cls) 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 breastmilk. In steady state the pre-dose mean ratio milk conc./serum conc. in women treated orally or with the decanoate was about 0.29.
Linearity: The kinetics is linear. Average maximum serum level of zuclopenthixol corresponding to a 100 mg dose of zuclopenthixol acetate is 102 nmol/l (41 ng/ml). Three days after the injection the serum level is about one third of the maximum i.e. 35 nmol/l (14 ng/ml).
Older patients: The pharmacokinetic parameters are widely independent of the age of the patients.
Reduced renal function: Based on the previously mentioned characteristics for elimination it is reasonable to assume that reduced kidney function is likely not to have much influence on the serum levels of parent drug.
Reduced hepatic function: No data available.
Polymorphism: An in vivo investigation has shown that some part of the metabolic pathways is subject to genetic polymorphism of the sparteine/debrisoquine oxidation (CYP2D6).
Toxicology: Pre-clinical 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 conception rate was 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. The clinical significance of these findings is unclear and it is possible that the effect on pups was due maternal neglect at doses of zuclopenthixol producing maternal toxicity.
Mutagenicity and carcinogenicity: Zuclopenthixol has no mutagenic or carcinogenic potential. In a rat oncogenecity study 30 mg/kg/day for two years (top dosage) resulted in slight non-statistical increases in the incidence of mammary adenocarcinomas, pancreatic islet cell adenomas, carcinomas in females, and thyroid parafollicular carcinomas. The slight increase in the incidence of these tumors is a common finding for D2 antagonists, which increase in prolactin secretion when administered to rats. The physiological differences between rats and humans with regard to prolactin make the clinical significance of these findings unclear, but it is accepted as not predicting an oncogenic risk in patients.
Local toxicity: Local muscle damage is seen after injection of aqueous solutions of neuroleptics, including zuclopenthixol. The muscle damage shows a much higher degree after the aqueous solutions of neuroleptics than after the oily solutions of zuclopenthixol acetate and zuclopenthixol decanoate.