Olanza 10 Mechanism of Action

Pharmacology: Mechanism of Action: The exact mechanism by which Olanzapine exerts its antipsychotic effect is unknown. However, this effect may be mediated through a combination of dopamine and serotonin 5-HT₂ antagonism. Olanzapine is a selective monoaminergic antagonist with a strong affinity for serotonin 5-HT_2A and 5-HT_2C receptors and dopamine D₁, D₂, D₃, D₄ receptors.
Olanzapine binds weakly to gamma-aminobutyric acid type A (GABA_A), benzodiazepine (BZD, and beta-adrenergic receptors.
Olanzapine's high affinity binding to, and antagonism of, muscarinic M₁, M₂, M₃, M₄, and M₅ receptors may explain its anticholinergic effects. Olanzapine also binds with high affinity to histamine H₁ and alpha₁-adrenergic receptors. Antagonism of histamine H₁ and alpha₁-adrenergic receptors may be responsible for the occurrence of somnolence and orthostatic hypotension, respectively, seen with Olanzapine use.
Pharmacokinetics: Absorption: Well absorbed; however, 40% of the absorbed drug is metabolized before reaching systemic circulation. The rate and extent of Olanzapine absorption are unaffected by food. Oral bioavailability of Olanzapine was not affected by single doses of Cimetidine (800 mg) or Aluminum and Magnesium containing antacids.
Distribution: Extensively distributed throughout the body, with a volume distribution of approximately 1000 L.
Protein binding: High (93%); primarily to albumin and alpha₁-acid glycoprotein.
Olanzapine is metabolized primarily through oxidation mediated by cytochrome P450 (CYP) enzymes and by direct glucuronidation. In vitro studies suggest that oxidation is mediated by cytochrome P450 isozymes 1A₂ (CYP1 A2) and IID₆ (CYP2D6), and by the flavin-containing monooxygenase system. However, studies in subjects who are deficient in CYP2D6 indicate that CYP2D6-mediated metabolism is a minor pathway of Olanzapine metabolism.
Half-life: Elimination: Mean, 30 hours; range, 21 to 54 hours. Mean apparent plasma clearance is 25 L per hour (L/hr); range, 12 to 47 L/hr.
Time to peak concentration: Peak plasma concentration of Olanzapine occurs approximately 6 hours following oral administration. Kinetics are linear over the therapeutic dosage range.
Time to steady-state plasma concentration: Steady-state plasma concentration of Olanzapine, which is approximately twice the concentration seen after a single dose, is achieved in about 1 week with once-a-day dosing.
Elimination: Renal: Approximately 57% of an administered dose is renally excreted, 7% as unchanged drug. Pharmacokinetics of Olanzapine were similar in patients with severe renal function impairment and in patients with normal renal function. Pharmacokinetics of the metabolites of Olanzapine were not studied in patients with renal function impairment.
Fecal: Approximately an administered dose.
In dialysis: Olanzapine is not removed by dialysis.