27 - F. Atypical antipsychotics

F. Atypical antipsychotics:

© SPMM Course F. Atypical antipsychotics: All atypicals are orally well absorbed. Drug Half life Chlorpromazine equivalents (100mg/day CPZ or 2mg Haloperidol) Risperidone 15hrs 2 mg/day Clozapine 16hrs 50 mg/day Quetiapine 6hrs 75 mg/day Olanzapine 30 hrs 5mg/day Aripiprazole 90hrs 7.5 mg/day From Woods SW. J Clin Psychiatry. 2003 Jun;64(6):663-7.  Risperidone undergoes extensive first-pass hepatic metabolism to 9-hydroxyrisperidone, an active metabolite. CYP 2D6 catalyzes hydroxylation of risperidone to 9-hydroxyrisperidone. Risperidone is 90% protein bound; its metabolite is 77% bound.  Paliperidone is the major active metabolite of risperidone (9-OH). It is a potent 5HT2 blocker apart from partially blocking D2 receptors. Its efficacy and side effects are the same as risperidone. It comes in a sustained release preparation similar to methylphenidate XL wherein gradual water absorption delivers the drug molecules slowly. Once daily administration is sufficient; there is no need to titrate the dose.  Quetiapine has a shorter half-life of 6 to 12 hours, and multiple daily dosing is required; though with longer use, as pharmacodynamic receptor action has longer duration once daily dosing may be sufficient.  Aripiprazole and its active metabolite dihydro aripiprazole have exceptionally long half-lives of 75 (nearly 3 days) and 94 hours respectively, and steady state concentrations are achieved after 14 days. Aripiprazole is metabolized by CYP 3A4 and CYP 2D6 enzymes. It is highly (99%) protein bound.  Atypical depots o Aripiprazole depot: no need to refrigerate; once monthly; gluteal administration only; only 2 weeks oral dose tapering needed. o Paliperidone depot does not need oral tapering; once monthly; no need to refrigerate; primarily renal excretion. o Risperidone microspheres are used in depot preparations; they release the active drug at therapeutic levels only 3 weeks after gluteal or deltoid injection. Long-acting risperidone should DEPOT KINETICS

Some long-acting injections (such as risperidone, pipotiazine) show delayed as well as prolonged release. These require adeqaute cover with oral antipsychotics after first dose is administered.

Steady-state plasma levels are often delayed for 2–3 months. During this time, plasma levels are likely to rise substantially even when dosages are not increased, thus producing dose-dependent side effects.

Dose–response relationships are not clearly understood for most LAIs. Test doses are often used but may not be sufficient to assess tolerability in longer-term use.