ANTIPSYCHOTICS: Atypical Drugs (p.1) 1. Introduction the “atypical” antipsychotic drugs are defined as atypical because: both dopamine & serotonin antagonists low incidence of extrapyramidal symptoms (EPSEs) good efficacy for treating the negative Sxs of psychosis there were initially (in the 1960s) antipsychotics developed that were somewhat different from haloperidol (Haldol): molindone (Moban) loxapine (Loxitane) pimozide (Orap) (introduced 1996) introduced in the 1970s, but less widely used now are chemically closer to the traditional antipsychotics than they are to the now named “atypicals” but were noteworthy because interacted with 5HT systems as well as DA systems…had a “dual action” aspect 2. True “Atypicals” (dual action antipsychotics) all were developed since 1989, starting with clozapine a. clozapine (Clozaril) introduced 1989 most closely resembles loxapine (Loxitane) is more effective than the traditional antipsychotics can be used to treat treatment-resistant Ss effective in treating both + and – Sxs, very few EPSEs has less of a negative effect on cognitive abilities/executive functions than do traditional antipsychotics esp. good for tx. of “disorganized schizophrenics” so…why is it not used now more widely? can --- agranulocytosis (reversible when D/C drug)ANTIPSYCHOTICS: Atypical Drugs (p.2) 2. True “Atypicals” (cont.) a. clozapine (Clozaril) (cont.) pharmacokinetics: taken PO, well absorbed metabolized by the liver, 2 fairly inactive metabolites ½ life = 9-30 hours SEs – sedation, wt. gain, constipation, urinary incontinence, hypotension, esophagitis, seizures, drooling, and NMS (rare) therapeutic window: 200-350 nanograms/milliLiter dependence/withdrawal: unpleasant w/d Sxs, so must gradually taper off Clozaril or immediately substitute olanzapine (Zyprexa) delusion, hallucinations, hostility, paranoid reaction nausea, vomiting, diarrhea headache restlessness, agitation, confusion sweating mechanisms of action: low rate of DA2 binding (blockage) higher rate of 5HT2 blockage also decreases glutamate RS mRNA (via affecting a 2nd messenger system)ANTIPSYCHOTICS: Atypical Drugs (p.3) 2. True Atypicals (cont.) b. risperidone (Risperdal) introduced in 1993 is highly plasma protein bound has an active metabolite ½ life of parent molecule = 3 hours; of active metabolite = 22 hours is a potent blocker of both DA2 and 5HT2 RSs end result of its actions is to normalize GABA & NMDA systems in frontal lobes is as effective as clozapine/Clozaril at decreasing – Sxs is not as effective as “ / “ at decreasing + Sxs can be used to tx autistics, pervasive developmental disorder can be used to tx conduct disorder (decreases aggression, rage) can be used to tx Tourette’s Syndrome SEs: sedation, somnolence agitation, anxiety, insomnia headache nausea some wt. gain (not as bad as clozapine or olanzapine) EPSEs (esp. a doses > 8mg/day; still < traditional antipsychotics) NMS (rare)ANTIPSYCHOTICS: Atypical Drugs (p.4) 2. True Atypicals (cont.) c. olanzapine (Zyprexa) introduced in 1996 structurally similar to clozapine blocks several RSs, including DA2 and5HT2 blocks DA2 RS as much as risperidone, but few EPSEs good for treating both + and – Sxs pharmacokinetics: PO, well absorbed metabolized by liver ½ life = 27-38 hours effective in treating bipolar pts, aggressive psychotic pts, & pervasive developmental disorder SEs: sedation, somnolence dizziness orthostatic hypotension dry mouth wt. gain (< clozapine, > riperidone) no agranulocytosis, rare NMS d. sertindole/Serlect introduced in 1997 binds to (blocks): 5HT2 > NEalpha#1 > DA2 RSs decreases both + and – Sxs low incidence of EPSEs no blocking of H1 RS --- so what SE is not seen? ½ life = 60-95 hours serious SE: can prolong Q-T interval --- severe EKG arrhythmiasANTIPSYCHOTICS: Atypical Drugs (p.5) 2. True Atypicals (cont.) e. quetiapine (Seroquel) introduced 1999 ½ life = 7 hours blocks 5HT2 > DA2 (similar to clozapine) also blocks NMDA/glutamate RSs (also similar to clozapine) comparable to traditional antipsychotics in decreasing + Sxs less consistent in decreasing – Sxs few EPSEs f. ziprasidone (Zeldox) introduced 2000 as effective as traditional antipsychotics, esp. for tx of + Sxs low risk of EPSEs ½ life = 6 hours unique effects: blocks 5HT2 & DA2 agonist at 5HT1A RS (similar to buspirone/BuSpar) little wt. gain metabolized to inactive forms can be used to tx Tourette’s Syndrome g. amisulpride (Solian) introduced 2001 is a “dual action” drug that blocks two separate DA RSs blocks DA2 postsynaptic RS in limbic system but not in basal ganglia! implications… does so only at higher doses effective for tx of psychosis (decreases both + and – Sxs) also blocks the DA3 presynaptic autoreceptors ---? does so at lower doses effective for tx of dysthymia & depression does not bind to the 5HT2 RSs…unusualANTIPSYCHOTICS: Atypical Drugs (p.6) 2. True Atypicals (cont.) g. amisulpride (Solian) (cont.) ½ life = 12 – 16 hours (child – adult) weakly metabolized by liver, two inactive metabolites SEs: insomnia, anxiety, agitation (5-10%)