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new med: levosulpiride

Posted by Iansf on January 12, 2008, at 23:09:39

PHARMACODYNAMICS OF LEVOSULPIRIDE
Levosulpiride, a substituted benzamide, has very recently been
launched in India. Here are some simple take-home messages about
the pharmacodynamics of the drug (Serra et al, 1990; Mucci et al,
1995; Pani and Gessa, 2002).

ACTION ON DOPAMINE AUTORECEPTORS
Levosulpiride is a only a weak D2 dopamine receptor antagonist.
Furthermore, in the D2 receptor family (which includes D2, D3,
and D4 receptors), the affinity of levosulpiride for the D2
receptor is only 2-3 times greater than that for the D3 receptor
(this contrasts with typical antipsychotics, which are 10-20
times more potent at D2 than at D3).

In consequence of the above, at low doses levosulpiride
preferentially blocks dopamine autoreceptors, which are located
on presynaptic neurons (this is because the dopamine autoreceptor
has a greater affinity for ligands than the dopamine postsynaptic
receptor, and because D3 ligands show greater preference for
autoreceptors) .

In consequence of the above, low dose levosulpiride increases
dopaminergic neurotransmission by increasing the presynaptic
synthesis and release of dopamine (this is because it blocks the
dopamine autoreceptor, which inhibits the presynaptic synthesis
and release of dopamine).

In humans, low doses of levosulpiride generally refer to doses of
50-200 mg/day. At these doses, levosulpiride is therapeutic for
negative and cognitive symptoms of schizophrenia, and for
depressive and somatoform disorders.

ACTION ON DOPAMINE POSTSYNAPTIC RECEPTORS
In high doses, levosulpiride also blocks D2 dopamine postsynaptic
receptors. The result is decreased dopaminergic
neurotransmission. In humans, high doses of levosulpiride
generally refer to doses of 400-800 mg/day. At these doses,
levosulpiride is therapeutic for positive symptom schizophrenia.

INDIRECT ACTION ON ADRENERGIC RECEPTORS
Levosulpiride downregulates cortical beta adrenoceptors. This
action may contribute to the antidepressant action of the drug.

ABSENCE OF BINDING TO OTHER RECEPTORS
Levosulpiride does not block 5-HT2 serotonergic and H1 histaminic
receptors. Therefore, it is unlikely to occasion adverse effects
such as sedation, increased appetite, and increased weight.

Levosulpiride does not block alpha-1 adrenergic receptors, and is
therefore unlikely to cause postural hypotension.

Levosulpiride does not block muscarinic cholinergic receptors,
and is therefore unlikely to cause adverse effects such as dry
mouth, blurred vision, impaired accommodation, constipation, and
difficulty in passing urine.

CONCLUSIONS
1. In low doses (50-200 mg/day), levosulpiride blocks dopamine
autoreceptors and may therefore be effective for the negative and
cognitive symptoms of schizophrenia, and for depressive and
somatoform disorders.

2. In high doses (400-800 mg/day), levosulpiride blocks dopamine
postsynaptic receptors, and may therefore be effective for the
positive symptoms of schizophrenia.

3. Levosulpiride does not bind to 5-HT2, H1, alpha-1, muscarinic,
and other receptors, and is therefore unlikely to be associated
with sedation, increased appetite and weight, postural
hypotension, dry mouth, constipation, and other adverse effects
related to antagonism at these receptor sites.

REFERENCES
Mucci A, Nolfe G, Maj M. Levosulpiride: a review of its clinical
use in psychiatry. Pharmacol Res 1995; 31: 95-101.

Pani L, Gessa GL. The substituted benzamides and their clinical
potential on dysthymia and on the negative symptoms of
schizophrenia. Mol Psychiatry 2002; 7: 247-253.

Serra G, Forgione A, D'Aquila PS et al. Possible mechanism of
antidepressant effect of l-sulpiride. Clin Neuropharmacol 1990;
13 (suppl 1): S76-S83.


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poster:Iansf thread:806091
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