Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1     Pharmacodynamic properties

Pharmacotherapeutic group:
Neuroleptics (antipsychotics)
ATCcode: N 05 AF 01
Mechanism of action
Flupentixol 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 and in vivo Flupentixol has high affinity for both dopamine D1 and D2 receptors whereas fluphenazine is almost D2 selective in vivo. The atypical antipsychotic, clozapine, shows - as Flupentixol – equiaffinity to D1 and D2 receptors both in vitro and in vivo.

Flupentixol has high affinity for α1-adrenoceptors and 5-HT2 receptors, although lower than that of chlorprothixene, high-dose phenothiazines and clozapine, but no affinity for cholinergic muscarine receptors. It has only slight antihistaminergic properties and no α2-adrenoceptor blocking activity.

Flupentixol 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.

Perioral movements in rats are dependent on D1 receptor stimulation or blockade of the D2 receptor population. The movements can be prevented by Flupentixol. Likewise, the results form investigations in monkeys indicate that oral hyperkinesia is more related to D1 receptor stimulation and to a less degree to D2 receptor supersensitivity. This leads to the suggestion that D1 activation is responsible for similar effects in man, i.e. dyskinesia. Therefore, blockade of D1 receptors should be advantageous.

Like most other neuroleptics, flupentixol increases the serum prolactin level.

Pharmacological studies have clearly demonstrated that Flupentixol decanoate in oil has a prolonged neuroleptic effect and that the amount of drug necessary to maintain a certain effect over a long period is considerably smaller with the depot preparation than with daily oral administration of flupentixol. A very modest and short-lasting potentiation of barbiturate-induced sleeping time in mice could be demonstrated only with high doses. It is unlikely, therefore, that any significant interference with anaesthetics would occur in patients receiving the depot preparation.

Clinical efficacy
In clinical use flupentixol decanoate is intended for the maintenance treatment of chronic psychotic patients. The antipsychotic effect increases with increasing dosages. In low to moderate dosages (up to 100 mg/2 weeks) flupentixol decanoate is nonsedating while some unspecific sedation may be expected when higher doses are administered.
Flupentixol decanoate is particularly useful in the treatment of apathetic, withdrawn, depressed and poorly motivated patients.

Flupentixol decanoate permits continuous treatment especially of those patients who are unreliable in taking the oral medication prescribed for them. Flupentixol decanoate thus prevents the frequent relapses due to noncompliance in patients on oral medication.

Pharmacokinetic Properties

5.2     Pharmacokinetic properties

Absorption
By esterification of Flupentixol with decanoic acid Flupentixol has been converted to a highly lipophilic substance, Flupentixol decanoate. 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 Flupentixol.

Following intramuscular injection maximum serum concentration is generally reached over a period of 3-7 days. With an estimated half-life of 3 weeks (reflecting the release from the depot) steady state conditions will be attained after about 3 months' repeated administration.

Distribution
The apparent volume of distribution (Vd)β is about 14.1 l/kg. The plasma protein binding is about 99 %.

Biotransformation
The metabolism of Flupentixol proceeds along three main routes – sulphoxidation, side chain N- dealkylation and glucuronic acid conjugation. The metabolites are devoid of psychopharmacological activity. Flupentixol dominates over metabolites in brain and other tissues.

Elimination
The elimination half-life (T½ β) of Fupentixol is about 35 hours and the mean systemic clearance (Cls) is about 0.29 l/min.
Flupentixol is excreted mainly with feces, but also to some degree with the urine. When tritium labelled flupentixol was administered to man the excretion pattern shows the excretion via feces to be about 4 times the urinary excretion.

In nursing mothers Flupentixol is excreted in small amounts with the breast milk. The ratio milk conc./serum conc. in women is on an average 1.3.

Linearity
The kinetics is linear. The mean steady state pre-injection serum level of Flupentixol corresponding to a 40 mg dose of Flupentixol decanoate every 2 weeks is about 6 nmol/l.

Elderly patients
Pharmacokinetic investigations have not been done in elderly patients. However, for the related thioxanthene drug, zuclopenthixol, the pharmacokinetic parameters are widely independent of the age of the patients.

Reduced renal function
Based on the above 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.

Pharmacokinetic / Pharmacodynamic relationship
A pre-injection serum (plasma) concentration of 1-3 ng/ml (2-8 nmol/l) and a max./min. fluctuation < 2.5 is suggested as a guideline for maintenance treatment of schizophrenic patients with a low- moderate degree of illness.
Pharmacokinetically a dose of 40 mg/2 weeks of Flupentixol decanoate is equivalent to a daily oral dose of 10 mg flupentixol.