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Atypical AntipsychoticsDR.MURUGAVEL.VJunior residentInstitute of Mental HealthChennai
30s 40s 50s 60s 70s 80s 90 s 00s
Aripiprazole Next-generationThe history of antipsychotic drug development
Pharmacology of Aripiprazole15/02/2010
The history of antipsychotic drug developmentOften based on chance findings that bear little relationship to the intellectual background driving observation. In 1891, Paul Ehrlich observed the antimalarial effects of methylene blue, a phenothiazine derivative. Later, the phenothiazines were developed for their antihistaminergic properties. In 1951, Laborit and Huguenard administered the aliphatic phenothiazine, chlorpromazine, to patients for its potential anesthetic effects during surgery. thereafter, Hamon et al. and Delay et al. extended the use of this treatment in psychiatric patients and serendipitously uncovered its antipsychotic activity.
The history of antipsychotic drug development Between 1954 and 1975, about 15 antipsychotic drugs were introduced in the United States and about 40 throughout the world.
Thereafter, there was a hiatus in the development of antipsychotics until the introduction of clozapine treatment in the United States in 1990 opened the era of "atypical" antipsychotic drugs.
Classic and commonly used termsProposed terms by WPANeuroleptics or Typical antipsychoticsFirst generation antipsychoticsAtypical antipsychotics (serotonin dopamine antagonists)Second generation antipsychoticsDopamine partial agonists ( aripiprazole )Third generation antipsychotics
WHY THEY ARE ATYPICAL ?
LOWER RISK OF EPS SPECTRUM OF ACTIONHigher ratio of serotonin : dopamine receptor blockadeAppear more specific for mesolimbic than striatal dopamine system
DIFFERENT SIDE EFFECT PROFILE
characteristicsLow D2 receptor blocking effectsReduced risk of extrapyramidal side effects.
Differences among Antipsychotic DrugsClozapine binds more to D4, 5-HT2, 1, and histamine H1 receptors than to either D2 or D1 receptorsRisperidoneabout equally potent in blocking D2 and 5-HT2 receptorsOlanzapinemore potent as an antagonist of 5-HT2 receptorslesser potency at D1, D2, and 1 receptorsQuetiapinelower-potency compound with relatively similar antagonism of 5-HT2, D2, 1, and 2 receptors
Differences among Antipsychotic DrugsClozapine, olanzapine and quetiapinepotent inhibitors of H1 histamine receptorsconsistent with their sedative propertiesAripiprazolepartial agonist effects at D2 and 5-HT1A receptors
Classification MARTA (multi acting receptor targeted agents)clozapine, olanzapine, quetiapine
SDA (serotonin-dopamine antagonists)risperidone, ziprasidone, sertindole
Selective D2/D3 antagonistssulpiride, amisulpiride
Available drugs (only 10 are FDA Approved)AmisulprideAripiprazoleAsenapineBlonanserinClotiapineClozapineIloperidoneLurasidoneMosapramineOlanzapinePaliperidonePerospironeQuetiapineRemoxiprideRisperidoneSertindoleSulpirideZiprasidoneZotepine
Therapeutic indicationsSchizophrenia and schizoaffective disorder acute and chronic psychoses- first line treatment all SGAs except clozapineMood disordersacute mania- all SGAs except clozapineacute bipolar depression- quetiapine,fluoxetine combinationMaintanence therapy- aripiprazole,olanzapine,quetiapineAdjunctive therapy in treatment depression-olanzapine,fluoxetine combination
Other indications:Exhibits outwardly aggressive and violent behaviourAutistic spectrum disorderTourettes syndromeHuntingtons diseaseLesch Nyhan SyndromeAlong with methylphenidate/dextroamphetamine in children with ADHD.Psychosis secondary to head trauma, dementia, treatment resistant Decreases the risk of suicide and water intoxication in patients with schizophrenia
Common Side EffectsExtra pyramidal symptomsOrthostatic hypotensionSedationWeight gainMetabolic syndromeQT prolongationAnti cholinergic side effectsHyper prolactinemiaSexual dysfunctionIncreased risk of Pneumonia
Extra pyramidal side effects (EPS):
Risperidone > Olanzapine = Ziprasidone > Quetiapine > Aripiprazole = Clozapine
Orthostatic hypotensionDefinition fall in systolic blood pressure of at least 20mm Hg or diastolic blood pressure of at least 10mm Hg when a person assumes a standing position.Treatment changing the dose of the medication or stopping it entirely.Clozapine > > Quetiapine, Risperidone > Ziprasidone, Olanzapine, Aripiprazole
Due to histaminergic receptor (H1) blockade in CNSClozapine > > Olanzapine, Quetiapine > Risperidone, Ziprasidone, Aripiprazole
WEIGHT GAINClozapine = Olanzapine > Quetiapine, Risperidone > Ziprasidone, Aripiprazole
Suggested mechanisms were 5 HT 2C antagonism, H 1 blockadeHyperprolactinemia and Increased serum leptin.
Metabolic effectsWeight gain over 1 year (kg)aripiprazole1amisulpride1.5quetiapine2 3risperidone2 3olanzapine> 6clozapine> 6
DIABETES MELLITUSHow they cause??5 HT 2A/2C antagonismIncreased plasma lipidsWeight gainLeptin resistance
Most sensitive test to detect isOral Glucose tolerance test.
High Risk withCLOZAPINE>OLANZAPINE>>RISPERIDONE>QUETIAPINELow risk withARIPIPRAZOLE,AMISULPIRIDE
METABOLIC SYNDROME (contd)
DYSLIPIDEMIARaise in triglycerides levels are more common than serum cholesterol.Treated withFibratesStatinDietary & life style modificationHYPERTENSIONPosibly due to alpha 2 antagonismSlow,steady rise over a period of timeclozapine
Insulin resistancePrediabetes (impaired fasting glycaemia) has ~ 10% chance / year of converting to Type 2 diabetesPrediabetes plus olanzapine has a 6-fold increased risk of conversionIf olanzapine is stopped 70% will revert back to prediabetes
Stroke in the elderlyRisperidone and olanzapine associated with increased risk of stroke when used for behavioural control in dementiaRisperidone 3.3% vs 1.2% for placeboOlanzapine 1.3% vs 0.4% for placeboHowever, large observational database studies Show no increased risk of stroke compared with typical antipsychotics or untreated dementia patients
Blockade of potassium channelsCausing torsades des pointes and sudden cardiac deathHigh effectAny intravenous antipsychoticHaloperidolSertindoleAmisulprideChlorpromazineQuetiapineZiprasidoneNo effect on QT intervalAripiprazoleSSRIsCarbamazepine ValproateBZDs
Clozapine > Olanzapine > others
Risperidone,amisulpirideNormal values:Male 0-20 ng/dlFemale 0-25 ng/dl
Level around 30-50 ng/dlReduced libidoinfertilityLevel around >100 ng/dlGalactorrheaAmenorrhea Rule out a prolactinoma if levels >118 ng/dl
Non prolactin elevating antipsychoticsAripiprazoleZiprasidoneOlanzapineClozapineQuetiapine
result from decreased dopaminergic activity centrally and alpha adrenergic blockade peripherally.Risperidone>olanzapine>quetiapine>aripiprazole
Increased susceptiblity to pneumonia
60% more risk in elderly populationHighest in the first week of treatmentSeen only with SGAs
Possible mechanisms:SedationDrymouthEffects on immune response
TypeManifestationsMechanismAutonomic nervous systemLoss of accommodation, dry mouth, difficulty urinating, constipationMuscarinic cholinoceptor blockadeOrthostatic hypotension, impotence, failure to ejaculateAlpha adrenoceptor blockadeCentral nervous systemParkinson's syndrome, akathisia, dystoniasDopamine receptor blockadeTardive dyskinesiaSupersensitivity of dopamine receptorsToxic-confusional stateMuscarinic blockadeEndocrine systemAmenorrhea-galactorrhea, infertility, impotenceDopamine receptor blockade resulting in hyperprolactinemiaOtherWeight gainPossibly combined H1 and 5-HT2 blockade
RISPERIDONEBenzisoxazoleUndergoes first pass metabolismPeak plasma level levels 1 hr (parent compound) , 3 hrs for metaboliteCombined half life 20 hrs (once daily dosing)Antagonist of serotonin 5HT2A, dopamine D2, 1, 2 adrenergic histamine H1 receptors.
Weight gainAnxietyNauseaDizziness, hyperkinesias, somnolence, Vomiting RhinitisErectile dysfunction
Dosages Initially 1-2 mg/day , raised to 4 mg/ dayOnly SDA available in depot formation IM injection every 2 weeks (25mg,50mg or 75 mg)Drug interactions Paroxetine and Fluoxetine (blocks the formation of RISPERIDONES active metabolite)RISPERIDONE + SSRI significant elevation of prolactin - galactorrohea and breast enlargement
OLANZAPINE85% absorbed from the GI tract40% is inactivated by first pass metabolismPeak concentration - 5hrsHalf life - 31 hrs5HT2A ,D1, D4, 1 ,5HT1A , muscarinic M1 through M5 and H1 receptors
Weight gainSomnolenceDry mouthDizzinessConstipationDyspepsiaIncreased appetiteAkathisiatremor
Periodic assessment of blood sugar and transaminase.Increased stroke among patients with dementiaDOSAGES initial dose for treatment of psychosis 5-10 mg , acute mania- 10-15 mg.Start 5-10 mg , raise to 10 mg per day30-40 mg in treatment resistant cases.
Drug interactionsFLUVOXAMINE and CIMETIDINE increasesCARBAMAZEPINE and PHENYTOIN - decreases
QUETIAPINEDIBENZOTHIAZEPINERapidly absorbed from GI tractsPeak plasma concentration 1-2 hrsSteady half life 7 hrs (2- 3 dosing per day)lower-potency compound with relatively similar antagonism of 5-HT2, D2, 1,