Atypical Antipsychotic pharmacology

Atypical Antipsychotic PharmacologyUsing Receptor Binding Profiles to Predict Adverse Effects

Stephanie Nichols, Pharm.D., BCPS, BCPPAssociate Professor of Pharmacy PracticeNicholsS@Husson.edu

ObjectivesRecognize atypical antipsychotics by brand and generic nameUnderstand how key pharmacological properties of antipsychotics translate into side effects Compare and contrast the pharmacology of the atypical antipsychotics Predict which antipsychotics may be more, or less, desirable in various patient scenariosChlorpromazineZiprasidoneAripiprazoleRisperidoneDroperidolAsenapineMesoridazineIloperidoneQuetiapineLurasidoneOlanzapineClozapineLoxapinePimozidePerphenazineTrifluoperazineProchlorperazineThiothixeneFluphenazineHaloperidolThioridazinePaliperidone1950201019801970196020001990Stephanie Nichols, PharmD BCPS BCPP 2014FDA Approval of AntipsychoticsWhat defines an Antipsychotic?Dopamine2 post synaptic antagonism

Reduce DA in the mesolimbic tractNucleus accumbens

Positive SymptomsEPS

Antagonism Partial Agonism

Dopamine PathwayFunctionDopamine Pathology in SchizophreniaAnti-Psychotic EfficacyAntipsychotic ToxicityNigrostriatalExtrapyramidal system & movementParkinsonism, dystonia, & dyskinesiaMesolimbicEmotions & motivationPlethoraPositive SymptomsMesocorticalCognition & executive functionPaucityNegative & Cognitive SymptomsAkathisiaTurbero-infundibularRegulates prolactin releaseHyper-prolactinemia

http://psychopharmacologyinstitute.com/antipsychotics-videos/dopamine-pathways-antipsychotics-pharmacology/Mesolimbic VTA to NA, HC, amygdalaMesocortical VTA to PFCNigrostriatal SN to BGTuberoinfundibular Hypothalamus to Pituitary Gland

What defines an Atypical Antipsychotic?Serotonin2a post-synaptic antagonism

5HT2a puts the brakes on DA in PFCDisinhibiting the inhibitor increased mesocortical DA

? Improved negative and cognitive symptomsReduced EPS at what cost?Typicals vs. AtypicalsRecognize atypical antipsychotics by brand and generic name

Atypical Antipsychotics in the USGeneric AvailabilityClozapine (Clozaril)Olanzapine (Zyprexa)Quetiapine (Seroquel)Risperidone (Risperdal)Ziprasidone (Geodon)Brand Name OnlyAripiprazole (Abilify)Paliperidone (Invega)Iloperidone (Fanapt)Asenapine (Saphris)Lurasidone (Latuda)Understand how key pharmacological properties of antipsychotics translate into side effects

Receptor Antagonism & Clinical EffectThe GoodThe BadD1 (agonism)?ameliorate cognitive deficits via DA modulation in PFC?Effects on moodD2 (antagonism)DA antagonism in the Mesolimbic Tract - positive sxEPS (parkinsonism, dystonia, dyskinesia, akathisia),hyperprolactinemia (ammenorrhea, galactorrhea, gynecomastia)The GoodThe Bad5HT1a (partial / full agonism)Antidepressant and/or anxiolytic ?Inhibit () glutamate release - positive sx

5HT2a (antagonism / inverse agonism) DA disinhibition (DA) in the:Nigrostriatal tract - EPSMesocortical tract - ? negative and cognitive sxSedation 5HT2c (antagonism / inverse agonism)Weight gain and metabolic dysfunction (hyperlipidemia, hypertriglyceridemia, hyperglycemia)5HT7 (antagonism)Circadian rhythm?pro-cognitive effects?Effects on anxiety or depression

Sedation? The GoodThe BadAlpha2a (antagonism)?Pro-cognitive effectsAlpha2c (antagonism)?Pro-cognitive effectsThe GoodThe BadAlpha7-nicotinic (antagonism)?mood and cognitionThe GoodThe BadAlpha1 (antagonism)Dizziness, orthostasis, hypotension, tachycardia, sedationH1 (antagonism)Sedation, weight gain and metabolic dysfunction?cognitionM1 (antagonism)Anticholinergic sx/sx, memory and cognitive deficitsM3 (antagonism)

?diabetes mellitusCompare and contrast the pharmacology of the atypical antipsychotics

Addressing Negative Symptoms in Schizophrenia. CPNP University 2013

NIMH Psychoactive Drug Screening Program (PDSP) KiDatabase:http://pdsp.med.unc.edu/pdsp.php

What do you think?Based upon Quetiapines binding profile, which of the following adverse effects is most likely to occur?ParkinsonismAntimuscarinic EffectsSedation

BDNFD25HT2a5HT1a5HT7a2a1H15HT2cM1Clozapine++++++++++++++++++Olanzapine+++++++0+++++++++++++++++++Quetiapine (Norquetiapine)+ (+)+++ (++++)0 (++)++ (0)+ (+)+++ (+++)++++ (++++)0 (+++)0 (+++)Risperidone (Paliperidone)+++ (++++)++++ (++++)+ (+)+++(++++)+ (+++)+++ (+++)++ (++)+++ (++)0 (0)Ziprasidone+++++++++++++++++++++0Aripiprazole++++(p.ag)+++++++++++++++++++++++0Paliperidone+++++++++++++++++++++++0Asenapine++++++++++++++++++++++++0Iloperidone+++++++++++++++++++++++++0Lurasidone++++++++++++++++++++0+00++++++++++D25HT2a5HT1a5HT7a2a1H15HT2cM1ClozapineOlanzapineQuetiapine (Norquetiapine)Risperidone (Paliperidone)ZiprasidoneAripiprazolePaliperidoneAsenapineIloperidoneLurasidone0++++++++++Metabolic ChangesDyslipidemia and hypertriglyceridemia pancreatitisHyperglycemia and insulin resistancediabetic ketoacidosis Increased body weightIncreased adiposity5HT2c and H1Quetiapine Metabolic EffectsEven low dose (0.05QTc Prolongationasenapineclozapineolanzapine

lurasidonequetiapinerisperidone

Predict which antipsychotics may be more, or less, desirable in various patient scenarios

Diabetes, Obesity or Metabolic SyndromeUsually Weight NeutralAripiprazole (except with 5HT antidepressants)LurasidoneZiprasidone

Most Weight GainClozapineOlanzapineQuetiapine

5HT2cH1Parkinsons Disease or History of Extra Pyramidal Symptoms (EPS)Less likely to cause EPSClozapineQuetiapine

More EPSParkinsonism and DystoniaRisperidonePaliperidoneAkathisiaAripiprazoleLurasidoneAsenapineZiprasidone

D2Orthostatic Hypotension, Dizziness, or Recurrent FallsHighest RiskClozapineRisperidoneIloperidoneQuetiapineLower RiskAripiprazoleLurasidoneZiprasidone1TitrateInsomniaMore SedatingQuetiapineClozapine

Less SedatingAripiprazoleZiprasidone

H15HT2a1History of Hyperprolactinemia or Concerns About its OccurrenceMore HyperprolactinemiaRisperidonePaliperidone

Less HyperprolactinemiaClozapineAripiprazoleIloperidoneAsenapineQuetiapineD2History of Ventricular ArrhythmiasMore likely to prolong QTcZiprasidoneIloperidone

Less likely to prolong QTcAripiprazole?LurasidoneK+ channel blockadeWill adjusting the dose fix the problem?Dose related effectsEPSSedationAmenorrheaAgitationActivationNon-dose related effectsWeight gainMetabolic changes

Aripiprazole somnolence at higher dosesZiprasidone activating at lower doses (5HT2c)Quetiapine less sedating at higher dosesSedationWeight gainParkisonismAkathisiaQTc prolongationHyper-prolactinemiaOrthostatic hypotensionAnticholinergic effectsAripiprazole++ (+++)+++++++++++Asenapine++++++++++++++++++++++Clozapine++++++++++++++++++++++++++Iloperidone++++++++++++++++++++++Lurasidone++++++++++++++++++++Olanzapine+++++++++++++++++++++++++Paliperidone+++++++++++++++++++++++++++Quetiapine+++++++++++++++++++++++Risperidone+++++++++++++++++++++++++++Ziprasidone++++++++++++++++++++++Take Home PointsD2 antagonism = positive symptomsEPS (ex. parkinsonism, dystonia) = high D2 antagonism Risperidone, paliperidone5HT2a antagonism = EPS may help with (or not exacerbate) negative and cognitive symptomsHistamine1, alpha1, and muscarinic antagonism = side effectsQuetiapine, clozapine, and olanzapine5HT2c + H1 antagonism = metabolic dysregulation & weight gainOlanzapine, clozapineEffects of binding 5HT1a, 5HT7, alpha2a, and alpha2c are still not fully understood but felt to contribute to efficacyThank you!!

NicholsS@Husson.edu