Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Antipsychotics, psychopharmaca, neuroleptics ATC code N05A L05

Amisulpride binds selectively with a high affinity to human dopaminergic D2/D3 receptor subtypes whereas it is devoid of affinity for D1, D4 and D5 receptor subtypes.

Unlike classical and atypical neuroleptics, amisulpride has no affinity for serotonin, α-adrenergic, histamine H1 and cholinergic receptors. In addition, amisulpride does not bind to sigma sites.

In animals, at high doses it blocks post-synaptic D2 receptors located in the limbic structures in preference to those in the striatum. Unlike classical neuroleptics it does not induce catalepsy and hypersensitivity of D2 dopamine receptors does not develop after repeated treatment. At low doses it preferentially blocks pre-synaptic D2/D3 receptors, producing dopamine release responsible for its disinhibitory effects.

This atypical pharmacological profile may explain amisulpride’s antipsychotic effect at higher doses through post-synaptic dopamine receptor blockade and its efficacy against negative symptoms, at lower doses, through pre-synaptic dopamine receptor blockade. In addition, the reduced tendency of amisulpride to produce extrapyramidal side effects may be related to its preferential limbic activity.

In clinical studies including schizophrenic patients with acute exacerbations amisulpride significantly alleviated secondary negative symptoms as well as affective symptoms such as depressed mood.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties
In man, amisulpride shows two absorption peaks: one which is attained rapidly, one-hour post-dose and a second between 3 and 4 hours after administration. Corresponding plasma concentrations are 39 ± 3 and 54 ± 4 ng/ml after a 50mg dose.
The volume of distribution is 5.8 l/kg. As plasma protein binding is low (16%) drug interactions are unlikely.

Absolute bioavailability is 48%. Amisulpride is weakly metabolized: two inactive metabolites, accounting for approximately 4% of the dose, have been identified. There is no accumulation of amisulpride and its pharmacokinetics remain unchanged after the administration of repeated doses. The elimination half-life of amisulpride is approximately 12 hours after an oral dose.

Amisulpride is eliminated unchanged in the urine. Fifty percent of an intravenous dose is excreted via the urine, of which 90% is eliminated in the first 24 hours. Renal clearance is in the order of 20 l/h or 330ml/min. Kinetic profile of amisulpride is not influenced by diet.

A carbohydrate rich meal (containing 68% fluids) significantly decreases the AUCs, Tmax and Cmax of amisulpride but no changes were seen after a high fat meal. However, the significance of these findings in routine clinical use is not known.
Hepatic insufficiency: since the drug is weakly metabolized a dosage reduction should not be necessary in patients with hepatic insufficiency.

Renal insufficiency: The elimination half-life is unchanged in patients with renal insufficiency while systemic clearance is reduced by a factor of 2.5 to 3. The AUC of amisulpride in mild renal failure increased two-fold and almost tenfold in moderate renal failure (see section 4.2). Experience is however limited and there is no data with doses greater than 50 mg.
Amisulpride is very weakly dialyzed.

Limited pharmacokinetic data in elderly subjects (>65 years) show that a 10- 30 % rise occurs in Cmax, T1/2 and AUC after a single oral dose of 50 mg.
No data are available after repeat dosing.