Fluanxol Depot Mechanism of Action

Pharmacotherapeutic classification: Antipsychotics, thioxanthene derivatives. ATC-code: N 05 AF 01.
Pharmacology: Pharmacodynamics: Flupentixol belongs to the thioxanthene group of antipsychotics.
The antipsychotic effect of these drugs is related to their dopamine receptor blocking action, but blocking of the 5-HT-receptor may also contribute.
In vitro and in vivo, flupentixol has a high affinity for both dopamine D₁ and D₂ receptors, while fluphenazine in vivo is almost selective for D₂. Like flupentixol, clozapine has a similar affinity for D₁ and D₂ receptors both in vitro and in vivo. Flupentixol has a high affinity for α1-adrenoreceptors and 5-HT₂ receptors, although less so than chlorprothixene, high-dosage phenothiazines and clozapine, while having no affinity for cholinergic muscarinic receptors. It has weak antihistaminergic properties only and no α2-adrenoreceptor-blocking action.
Flupentixol is a potent antipsychotic in all behavioural models for antipsychotic (dopamine receptor-blocking) activity. There is correlation between in vivo test models, the affinity for D₂ binding sites in vitro and the mean daily oral dose of the antipsychotic.
Perioral movements in rats depend on D₁ receptor stimulation or blockade of the D₂ receptor population. Onset of these movements can be prevented by flupentixol. In addition, the results of trials in monkeys show that oral hyperkinesias are more related to D₁ receptor stimulation and less to D₂ receptor supersensitivity. This leads to the assumption that D₁ activation lies behind similar activities in humans, i.e., dyskinesia. Accordingly, D₁ blockade is considered beneficial.
Like most other antipsychotics, flupentixol increases the serum levels of prolactin in a dose-dependent manner.
Pharmacological studies have shown that flupentixol decanoate suspended in oil has prolonged antipsychotic activities, and that the amount of substance required to maintain a specific effect long-term is considerably lower with the solution for injection than with daily ingestion of oral doses. Only very high doses of flupentixol decanoate can briefly prolong the sleeping time induced by alcohol and barbiturates in mice, which indicates a very weak sedative action in clinical use.
In clinical use, Fluanxol Depot is designed for maintenance treatment of patients with chronic psychoses. The antipsychotic effect increases with increasing doses. In low to moderate doses (up to 100 mg every two weeks), flupentixol decanoate is not sedating, whereas some non-specific sedation may be expected following administration of higher doses.
Fluanxol Depot is particularly suitable in the treatment of apathetic, lethargic, depressed or poorly motivated patients.
With Fluanxol Depot, a continuous antipsychotic therapy is ensured, which reduces the rate of recurrence because of non-compliance of orally treated patients.
Pharmacokinetics: Absorption: Intramuscular injections produce peak plasma concentration (T_max) within 3 to 7 days. At an estimated half-life of ca. 3 weeks (reflecting the modified release), steady state concentrations are achieved within approximately 3 months of repeated dosing.
Distribution: The apparent volume of distribution (V_d)_β is approximately 14.1 L/kg. Plasma protein binding is approximately 99 %. Flupentixol passes the placental barrier.
Biotransformation: Flupentixol is mainly metabolised by sulfoxidation, side-chain N-dealkylation and conjugation with glucuronic acid. The metabolites show no antipsychotic activity. Concentrations of flupentixol found in the brain and other tissues are higher than those of its metabolites.
Elimination: The plasma elimination half life (t_½β) is approximately 35 hours; systemic plasma clearance (Cl_s) is approximately 0.29 L/min. Cis(Z)-flupentixol is mainly excreted with the faeces, but also to some extent with the urine.
Small amounts of flupentixol are excreted into breast milk.
The average milk/plasma concentration ratio is 1.3.
Linearity: Pharmacokinetics are linear. After a dose of 40 mg flupentixol decanoate every 2 weeks, the C_min of flupentixol is approximately 6 nmol/l at a steady state.
Elderly patients: Not investigated. For the very similar zuclopenthixol, however, the pharmacokinetic parameters are largely independent of the patient's age.
Renal impairment: Not investigated. Based on the previously mentioned elimination data, however, it is a reasonable assumption that renal impairment would not affect serum levels of flupentixol to any major degree.
Hepatic impairment: Not investigated.
Toxicology: Preclinical safety data: Acute toxicity: Flupentixol has low acute toxicity.
Chronic toxicity: Chronic toxicity studies have revealed nothing of relevance to the therapeutic use of flupentixol.
Reproductive toxicity: In fertility studies in rats, flupentixol slightly affected the pregnancy rate of female rats. Effects were seen at doses well in excess of those applied during clinical use.
Animal reproduction studies in mice, rats and rabbits have not shown evidence of teratogenic effects. Embryotoxic effects in terms of increased post implantation loss/increased absorption rates or occasional abortions were seen in rats and rabbits at doses associated with maternal toxicity.