indication

For the treatment of schizophrenia and related psychotic disorders.

pharmacology

Quetiapine is a psychotropic agent belonging to the chemical class of benzisoxazole derivatives and is indicated for the treatment of schizophrenia. Quetiapine is a selective monoaminergic antagonist with high affinity for the serotonin Type 2 (5HT₂), and dopamine type 2 (D2) receptors. Quetiapine is an antagonist at serotonin 5-HT_1A and 5HT₂, dopamine D1 and D2, histamine H1, and adrenergic alpha 1 and alpha 2 receptors. Quetiapine has no significant affinity for cholinergic muscarinic or benzodiazepine receptors. Drowsiness and orthostatic hypotension associated with use of quetiapine may be explained by its antagonism of histamine H1 and adrenergic alpha 1 receptors, respectively. Quetiapine's antagonism of adrenergic a1 receptors may explain the orthostatic hypotension observed with this drug.

mechanism of action

Quetiapine's antipsychotic activity is likely due to a combination of antagonism at D2 receptors in the mesolimbic pathway and 5HT2A receptors in the frontal cortex. Antagonism at D2 receptors relieves positive symptoms while antagonism at 5HT2A receptors relieves negative symptoms of schizophrenia.

toxicity

Symptoms of overdose include drowsiness and sedation, tachycardia, and hypotension.

biotransformation

Hepatic. The major metabolic pathways are sulfoxidation, mediated by cytochrome P450 3A4 (CYP3A4), and oxidation of the terminal alcohol to a carboxylic acid. The major sulfoxide metabolite of quetiapine is inactive. Quetiapine also undergoes hydroxylation of the dibenzothiazepine ring, O-deakylation, N-dealkylation, and phase II conjugation. The 7-hydroxy and 7-hydroxy- N-delakylated metabolites appear to be active, but are present in very low concentrations.

absorption

Rapidly and well absorbed.

half life

6 hours

route of elimination

Elimination of quetiapine is mainly via hepatic metabolism. Following a single oral dose of 14C-quetiapine, less than 1% of the administered dose was excreted as unchanged drug, indicating that quetiapine is highly metabolized. Approximately 73% and 20% of the dose was recovered in the urine and feces, respectively.

drug interactions

Artemether: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Clarithromycin: The macrolide, clarithromycin, may increase the effect and toxicity of quetiapine.

Donepezil: Possible antagonism of action

Erythromycin: The macrolide, erythromycin, may increase the effect and toxicity of quetiapine.

Ethotoin: Phenytoin decreases the effect of quetiapine

Fosphenytoin: Phenytoin decreases the effect of quetiapine

Galantamine: Possible antagonism of action

Ketoconazole: Ketoconazole may increase the therapeutic and adverse effects of quetiapine.

Lumefantrine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Mephenytoin: Phenytoin decreases the effect of quetiapine

Phenytoin: Phenytoin decreases the effect of quetiapine

Quinupristin: This combination presents an increased risk of toxicity

Rivastigmine: Possible antagonism of action

Tacrine: The therapeutic effects of the central acetylcholinesterase inhibitor (AChEI), Tacrine, and/or the anticholinergic/antipsychotic, Quetiapine, may be reduced due to antagonism. This interaction may be beneficial when the anticholinergic action is a side effect. AChEIs may also augment the central neurotoxic effect of antipsychotics. Monitor for extrapyramidal symptoms and decreased efficacy of both agents.

Tacrolimus: Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Telithromycin: Telithromycin may reduce clearance of Quetiapine. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Quetiapine if Telithromycin is initiated, discontinued or dose changed.

Tetrabenazine: May cause dopamine deficiency. Monitor for Tetrabenazine adverse effects.

Thiothixene: May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.

Toremifene: Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.

Trimethobenzamide: Trimethobenzamide and Quetiapine, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Monitor for enhanced anticholinergic effects.

Trimipramine: Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Triprolidine: Triprolidine and Quetiapine, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Additive CNS depressant effects may also occur. Monitor for enhanced anticholinergic and CNS depressant effects.

Trospium: Trospium and Quetiapine, two anticholinergics, may cause additive anticholinergic effects and enhanced adverse/toxic effects. Monitor for enhanced anticholinergic effects.

Voriconazole: Voriconazole, a strong CYP3A4 inhibitor, may increase the serum concentration of quetiapine by decreasing its metabolism. Additive QTc prolongation may also occur. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of quetiapine if voriconazole is initiated, discontinued or dose changed.

Vorinostat: Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).

Ziprasidone: Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.

Zuclopenthixol: Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).