Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1      Pharmacodynamic properties
Pharmacotherapeutic group: Neuropleptics (antipsychotics), ATC Code: N05AF05 
Mechanism of action
Zuclopenthixol is a potent neuroleptic of the thioxanthene series with a piperazine side-chain. The antipsychotic effect of neuroleptics is related to their dopamine receptor blocking effect. The thioxanthenes have a high affinity for both the adenylate cyclase coupled dopamine D1 receptors and for the dopamine D2 receptors; in the phenothiazine group the affinity for D1 receptors is much lower than that for D2 receptors, whereas butyrophenones, diphenylbutylpiperidines and benzamides only have affinity for D2 receptors.
In the traditional tests for antipsychotic effect, e.g. antagonism of stereotypic behaviour induced by dopamine agonists, the chemical groups of neuroleptics mentioned reveal equal but dosage dependent activity. However, the antistereotypic effect of phenothiazines, butyrophenones, diphenylbutylpiperidines, and benzamindes is strongly counteracted by the anticholinergic drug, scopolamine, while the antisteriotypic effect of the thioxanthenes, e.g. zuclopenthixol, is not, or only very slightly, influenced by concomitant treatment with anticholinergics.

Pharmacokinetic Properties

5.2.   Pharmacokinetic Properties

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 this substance diffuses slowly into the surrounding body water, where enzymatic breakdown occurs releasing the active component zuclopenthixol.

Maximum serum concentrations of zuclopenthixol are usually reached 36 hours after an injection, after which the serum levels decline slowly. The average maximum serum level corresponding to the 100 mg dose is 41 ng/mL. Three days after the injection the serum level is about one third of the maximum.

Zuclopenthixol is distributed in the body in a similar way to other neuroleptics; with the higher concentrations of drug and metabolites in liver, lungs, intestines and kidneys and lower concentrations in heart, spleen, brain and blood. The apparent volume of distribution is about 20 L/kg and the protein binding about 98%.

Zuclopenthixol crosses the placental barrier in small amounts. Zuclopenthixol is excreted in small amounts with the milk - the ratio milk concentration/serum concentration in women is on average 0.3.

The metabolism of zuclopenthixol proceeds via three main routes -sulphoxidation, side chain N-dealkylation and glucuronic acid conjugation. The metabolites are devoid of psychopharmacological activity. The excretion proceeds mainly with the faeces but also to some degree with the urine. The systemic clearance is about 0.9 L/min.

The kinetics seem to be linear, since highly significant correlation exist between the dose and the area under the serum concentration curve.