Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1 Pharmacodynamic properties
Zuclopenthixol is a neuroleptic of the thioxanthene group.
The antipsychotic effect of neuroleptics is related to their dopamine receptor-blocking activities, but blocking of the 5-HT-receptor may also contribute.

In vitro, zuclopenthixol has a high affinity for both dopamine D1 and D2 receptors, to α1-adrenergic and 5- HT2 receptors, but no affinity for cholinergic muscarinic receptors. It has a weak affinity for histamine (H1) and no α2-adrenoceptorblocking activity. In vivo, the affinity for D2 binding sites dominates over the affinity for D1 receptors.

Zuclopenthixol is a potent neuroleptic in all behavioural models for neuroleptic (dopamine receptor- blocking) activity. A correlation exists between in vivo test models, the affinity for D2 binding sites in vitro and the mean daily oral dose of the antipsychotic.

Inhibition of motor activity and prolonged sleeping time induced by alcohol and barbiturates in mice indicate sedative effects in clinical use.

Like most other neuroleptics, zuclopenthixol increases the serum level of prolactin in a dose-dependent manner.
In clinical use, Clopixol is intended for the treatment of acute psychosis.

In addition to causing a significant reduction in or a complete elimination of hallucinations, delusions and thought disturbances, zuclopenthixol also has a marked effect on the accompanying symptoms such as hostility, suspiciousness, agitation and aggressiveness.

Zuclopenthixol induces a transient dose-dependent sedation. However, initial sedation is usually an advantage in the acute phase of the psychosis, since it calms the patient during the period before the antipsychotic action sets in.
Tolerance to the non-specific sedative effect develops rapidly.

Pharmacokinetic Properties

5.2 Pharmacokinetic properties
Absorption
Oral administration produces maximum serum concentration (Tmax) within about 4 hours. Food has no effect on absorption. Oral bioavailability: about 44 %.

Distribution
Apparent volume of distribution(Vd)β: about 20 l/kg. Plasma protein binding: 98-99 %.

Biotransformation
Zuclopenthixol is mainly metabolised by sulfoxidation, side-chain N-dealkylation and conjugation with glucuronic acid. The metabolites show no neuroleptic activity. Zuclopenthixol dominates over metabolites in the brain and other tissues. Genetic polymorphism has been demonstrated.

Elimination
The plasma elimination half life (t½ β) is about 20 hours; systemic plasma clearance (Cls) is about 0.86 l/min. Zuclopenthixol is excreted mainly with the faeces, but also to some extent with the urine (approx.
10%). Only about 0.1% is excreted unchanged with the urine.

Small amounts of zuclopenthixol are excreted in breast milk.
The milk/serum concentration ratio in women treated with oral zuclopenthixol or the decanoate was about 0.3.

Linearity
The kinetics is linear. After a dose of 20 mg of zuclopenthixol once daily, the Cmin of zuclopenthixol is about 25 nmol/l at steady state.

Older patients
The pharmacokinetic parameters are largely independent of the patient's age.

Renal impairment
Not studied. Based on the above elimination data, however, it is a reasonable assumption that renal impairment would not affect the serum levels of zuclopenthixol to any major degree.

Hepatic impairment
Not studied.