Pharmacology
Olanzapine has a higher affinity for 5-HT2 serotonin receptors than D2 dopamine receptors. Affinities are (Ki, nM). Olanzapine binds as an antagonist/inverse agonist at the following receptors:
- dopamine D1: 31
- dopamine D2: 11
- dopamine D4: 27
- serotonin 5-HT2A: 4
- serotonin 5-HT2C: 11
- serotonin 5-HT3: 57
- muscarinic M1: 26
- adrenergic alpha1: 19
- histamine H1: 7
Olanzapine is a potent antagonist of the muscarinic M3 receptor, which may underlie its diabetes side-effects. Additionally olanzapine also exhibits a relatively low affinity for serotonin 5-HT1, GABAA, beta-adrenergic receptors, and benzodiazepine binding sites. The mode of action of olanzapine's antipsychotic activity is unknown. It may involve antagonism of dopamine and serotonin receptors. Antagonism of dopamine receptors is associated with extrapyramidal effects such as tardive dyskinesia, and with therapeutic effects. Antagonism of muscarinic acetylcholine receptors is associated with anticholinergic side effects such as dry mouth and constipation, in addition it may suppress or reduce the emergence of extrapyramidal effects for the duration of treatment, however it offers no protection against the development of tardive dyskinesia. Antagonizing H1 histamine receptors causes sedation and may cause weight gain, although antagonistic actions at serotonin 5-HT2C and dopamine D2 receptors have also been associated with weight gain and appetite stimulation. Olanzapine may display an antiemetic effect due to its blockade of several receptors (specifically acetylcholine, dopamine, histamine, and serotonin 5-HT3) within the chemoreceptor trigger zone.
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