Salveo ODT Mechanism of Action

Antipsychotic.
Pharmacology: Pharmacodynamics: Olanzapine is an atypical antipsychotic agent that shows a broad pharmacologic profile across a number of receptor systems.
Olanzapine binds with high affinity to the following receptors: serotonin 5HT_2A/2C, 5HT₆, dopamine D_1-4, histamine H₁, and adrenergic α₁, receptors. Olanzapine is an antagonist with moderate affinity binding for serotonin 5HT₃, and muscarinic M_1-5. It binds weakly to GABA_A, benzodiazepine and β-adrenergic receptors.
Antagonism at receptors other than dopamine and 5HT₂, may explain some of olanzapine's other therapeutic and side effects. Olanzapine's antagonism of muscarinic M_1-5 receptors may explain its anticholinergic-like effects; antagonism of histamine H₁ receptors may explain somnolence, and antagonism of adrenergic α₁ receptors may explain orthostatic hypotension observed with this drug.
Pharmacokinetics: Olanzapine is well absorbed after oral administration, Peak plasma concentrations of film-coated and orodispersible olanzapine tablets are reached in approximately six and five hours, respectively. It is eliminated extensively by first pass metabolism, with approximately 40% of the dose metabolized before reaching the systemic circulation. Olanzapine displays linear kinetics over the clinical dose range of 1 to 20 mg. Food does not affect the rate or extent of olanzapine absorption.
The half-life of olanzapine ranges from 21 to 54 hours. Administration of olanzapine once daily leads to steady-state concentrations in about one week that are approximately twice the concentrations after single doses. Plasma concentration, half-life and clearance of olanzapine may vary between individuals on the basis of smoking status, gender and age.
Olanzapine is extensively distributed throughout the body. Its volume of distribution is approximately 1,000 L. The drug is highly protein-bound (93%) over the concentration range of 7 to 1,110 ng/mL, binding primarily to albumin and α₁-acid glycoprotein. Olanzapine and its glucuronide metabolite have been shown to cross the placenta in humans. It is also distributed into milk.
Olanzapine is metabolized in the liver primarily by direct glucuronidation and cytochrome P450 (CYP)-mediated oxidation. It is highly metabolized, with 7% of the dose recovered in the urine as unchanged drug. Approximately 57% and 30% of the dose was recovered in the urine and feces, respectively. The major circulating metabolite is the 10-N-glucuronide, which is pharmacologically inactive and does not pass the blood brain barrier. Cytochrome P450 CYP 1A2 and P450 CYP2D6 contribute to the formation of the N-desmethyl and 2-hydroxymethyl metabolites; both exhibited significantly less in vivo pharmacological activity than olanzapine in animal studies. The predominant pharmacologic activity is from the parent, olanzapine.
Olanzapine's mean terminal elimination half-life is 33 hours (21 to 54 hours) and the mean olanzapine plasma clearance is 26 L/hr (12 to 47 L/hr).
Special Populations: Renal Impairment: Olanzapine is highly metabolized before excretion and only 7% of the drug is excreted unchanged. The pharmacokinetic characteristics of olanzapine were similar in patients with severe renal impairment and normal subjects, indicating that dosage adjustment based on the degree of renal impairment is not required. The effect of renal impairment on metabolite elimination has not been studied.
Hepatic Impairment: While the presence of hepatic impairment may be expected to reduce the clearance of olanzapine, a study of the effect of impaired liver function in subjects with clinical significant (Child-Pugh Classification A and B) cirrhosis showed little effect on the pharmacokinetics of olanzapine.
Elderly: In a study involving 24 healthy subjects, the mean elimination half-life of olanzapine was about 1.5 times greater in elderly (≥65 years old) than in nonelderly subjects (<65 years old). Caution should be exercised in dosing the elderly, particularly if there are other factors that might additively influence drug metabolism and/or pharmacodynamic sensitivity.
Adolescents (13 to 17 years old): Since most adolescents have a lower average body weight, administration of olanzapine in this population resulted to higher average drug exposure compared to adults.
Gender: Olanzapine's clearance is approximately 30% lower in women compared to men. However, there are no apparent differences between men and women in terms of efficacy and safety. Dosage modifications based on gender is not needed.
Smoking: Clearance of olanzapine is about 40% higher in smokers than in nonsmokers. However, dosage modifications are not recommended.
Combined Effects: The combined effects of age, smoking and gender could lead to substantial pharmacokinetic differences in populations. Example, the clearance in young smoking males may be three times higher than that in elderly nonsmoking females. Dosing adjustment may be necessary in patients who exhibit a combination of factors that may result in slower metabolism of olanzapine.