title: Pharmacologic and pharmacokinetic considerations in choosing an antipsychotic.
abstract: Recent advances in our understanding of schizophrenia along with neuroscience insights into antipsychotic medication mechanisms of action have led to a renaissance in new drug development, including an expanded therapeutic spectrum encompassing more of the symptoms encountered in schizophrenia. Atypical antipsychotics, or new generation therapies, also demonstrate greater selectivity for therapeutic actions than for extrapyramidal symptoms (EPS). Our modern armamentarium of drugs spans a wide range of pharmacologies, and it is more accurate to envision shades of gray rather than a black-and-white description for typical versus atypical properties of medications. As our paradigms for antipsychotic efficacy have shifted, a reexploration of the "older" neuroleptics is warranted to determine if they possess pharmacologic attributes that might have been overlooked during the era of high-dose neuroleptic therapy. Loxapine appears to be in the center of this spectrum, somewhere between haloperidol and risperidone. Dosing implications for drugs with a more even serotonin-2A (5-HT2A) receptor and dopamine-2 (D2) receptor blocking effect are discussed. Loxapine might have a window of partial atypicality at doses < or = 50 mg/day. These lower doses might have potential as both monotherapy in responsive patients with persistent psychotic disorders and as an adjunctive treatment in partially responding patients on concurrent atypical antipsychotic treatments. The pharmacologic properties of loxapine within its usable dosage range are quite complex and are the net sum of the parent's plus metabolites' contributions (demethylation and hydroxylation by cytochrome P450 enzymes). These pharmacologic effects include alpha-adrenergic blockade, inhibition of the noradrenergic transporter protein (reuptake inhibition), and antimuscarinic effects. Drug interactions and cigarette smoking might alter the parent-to-metabolite concentration ratios, affecting the relative atypicality of this antipsychotic therapy. Moreover, with the intramuscular formulation, which does not undergo first-pass metabolism, the parent compound of loxapine, i.e., not its metabolites, is predominantly detected in the plasma of patients, reducing the likelihood for EPS during emergency interventions in patients with positive symptoms. Further study is warranted to determine loxapine's place in our treatment of schizophrenia.
authors.affiliation: College of Pharmacy, The University of Texas at Austin, USA. ereshefsky@uthscsa.edu
authors.forename: L
authors.initials: L
authors.lastname: Ereshefsky
mesh_terms: D014150:Antipsychotic Agents / Q000493:pharmacokinetics* / Q000494:pharmacology* / Q000627:therapeutic use; D002352:Carrier Proteins / Q000187:drug effects; D003024:Clozapine / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D006801:Humans; D008152:Loxapine / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D008562:Membrane Glycoproteins / Q000187:drug effects; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D012559:Schizophrenia / Q000188:drug therapy*; D050486:Serotonin Plasma Membrane Transport Proteins
chemical_list: D014150:Antipsychotic Agents; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D003577:Cytochrome P-450 Enzyme System; D003024:Clozapine; D008152:Loxapine