1. Antipsychotic DrugsFaraza JavedMphil Pharmacology

2. PSYCHOSISPsychosis (from the Greek , psyche, "mind/soul", and -osis,"abnormal condition or derangement") refers to anabnormal condition of the mind.A syndrome of chronic disordered thinking anddisturbed behavior (schizophrenia, mania,depression)The most important types of psychosis are:SchizophreniaAffective disorders (e.g. depression, mania)Organic psychoses (mental disturbances caused by headinjury, alcoholism, or other kinds of organic disease). 3. SchizophreniaA chronic mental disorder involvinga breakdown in the relationbetween thought, emotion, andbehaviour, leading to faultyperception, inappropriate actionsand feelings, withdrawal fromreality and personal relationshipsinto fantasy and delusion, and asense of mental fragmentation.The disorder is characterized by adivorcement from reality in themind of the person (psychosis). 4. Schizophrenia 5. EtiologyDOPAMENERGIC SYSTEM:There are four major pathways for thedopamenergic system in brain :I. The Nigro-Striatal Pathway.II. The Mesolimbic Pathway.III. The Mesocortical Pathway.IV. The Tuberoinfundibular Pathway. 6. The Dopamine HypothesisSchizophrenia results from excess activity of dopamineneurotransmission in Mesolimbic and MesocorticalPathways because: All antipsychotic drugs block dopamine receptors.Higher levels of dopamine receptors measured inbrains of schizophrenics by PET. Stimulant drugs which act through dopamine canproduce schizophrenic-like behaviors(eg.amphetamines). 7. SYMPTOMSPOSITIVESYMPTOMS: Delusions Hallucinations Combativeness Insomnia 8. SYMPTOMSNEGATIVE SYMPTOMS: Affective Flattening(blunt) Alogia Avolition Amotivation Apathy Asocial Behavior 9. SYMPTOMSDISORGANIZEDSYMPTOMS: Disorganizedthought, speech,behavior. Poor Attention. 10. Antipsychotic AgentsAntipsychotic drugs are able to reduce psychoticsymptoms in a wide variety of conditions,including schizophrenia, bipolar disorder,psychotic depression and drug inducedpsychosis.They have also been termed neuroleptics, becausethey suppress motor activity and emotionality.** These drugs are not a cure **Psychotic diseases are life long and it is preferableto prevent the psychotic episodes than to treatthem. 11. Classification of AntipsychoticDrugsTypical antipsychoticsPhenothiazines (Chlorpromazine, Perphenazine,Fluphenazine, Thioridazine)Thioxanthenes (Flupenthixol, Clopenthixol)Butyrophenones (Haloperidol, Droperidol)Atypical antipsychotics(Clozapine, Risperidone, Sulpiride, Olanzapine,Aripiprazole) 12. Distinction between typical and atypicalgroups is not clearly defined, but rests on:Incidence of extrapyramidal side-effects(less in atypical group)Efficacy in treatment-resistant group ofpatientsEfficacy against negative symptoms. 13. Drug TargetsDopamine receptors: D1, D2, D3, D4, D5Serotonin receptors: 5-HT-1A, 2A, 3, 6, 7Norepinephrine: Alpha-1 & Alpha-2Muscarinic Acetylcholine: M1 & M4Dopamine, Norepinephrine & SerotonintransportersNMDA-glutamate receptor 14. TypicalAntipsychotics 15. MECHANISM OF ACTION There are many type of DA-receptors. The antipsychotic drugs probably owe theirtherapeutic effects mainly to blockade of D2receptors. The main groups, phenothiazines, thioxanthines andbutyrophenones, show preference for D2 over D1receptors; whereas clozapine is relatively non-selectivebetween D1 and D2, but has high affinity forD4. 16. Therapeutic Uses Treatment of psychotic disorders:schizophrenia, mania, paranoid states. Treatment of nausea and vomiting of certaincauses. Anesthesia in hypothermia and artificialhibernation (used with pethidine andpromethazine). 17. Adverse EffectsExtrapyramidal motor disturbances: Parkinson-like symptoms Neuroleptic Malignant Syndrome Tardive dyskinesia (involuntary movementsof face, tongue and limbs , appearing aftermonths or years of antipsychotic treatment). Acute dystonias.SeizuresCardiac toxicity Produce hypotension(primarily postural) by -adrenergic blocked. 18. Endocrine effects: Increase prolactin : whichmay result in gynecomastia. They reducegonadotropin secretion but infertility occuronly occasionally.ACTH release in response to stress is diminish.Decreased release of ADH may result in anincrease in urine volume.Urticarial skin reactions are common butusually mild. Excessive sensitivity to ultravioletlight may also occur. 19. Other side-effects (dry mouth, constipation,blurred vision, hypotension, etc.) are due toblock of other receptors, particularly adrenoceptors and muscarinic ACh receptors. Contact dermatitis, blood dyscrasias,obstructive jaundice sometimes occurs withphenothiazines. 20. Limitations OfConventional/TypicalAntipsychoticsApproximately one-third of patients withschizophrenia fail to respondLimited efficacy against Negative symptomsHigh proportion of patients relapseSide effects and compliance issuesAtypical/New generation Antipsychotics arepreffered for the treatment of variouspsychotic disorders. 21. AtypicalAntipsychotics 22. ClozapineEffective in treating some patients withpsychosis unresponsive to standard neurolepticdrug.Blocks D4 receptor and have low affinity for D1and D2 dopamine receptors.Relative high selectivity for D4 and 5-HT2receptorsLacks extrapyramidal side effects.Must monitor the granulocyte counts due tohigher incidence of agranulocytosis and otherblood dyscrasias. 23. RisperidoneCombination of D2 + 5-HT2 receptor blockade.In addition it has high affinity for 1, 2 and H1receptors; blockade of these may contribute toefficacy as well as side effects like posturalhypotension.Risperidone is more potent D2 blocker thanclozapine; extrapyramidal side effects are less.Prolactin levels rise during risperidone therapy,but it is less epileptogenic than typical agents.Caution: increased risk of stroke in the elderly. 24. OlanzapineBroader spectrum of efficacy covering schizo-affectivedisorders.Resembles clozapine in blocking multiplemonoaminergic (D2, 5- HT2, 1, 2) as well asmuscarinic and H1 receptors.Both positive and negative symptoms ofschizophrenia appear to be benefited.Monotherapy with olanzapine may be as effectiveas a combination of lithium/valproate +benzodiazepines.Incidence of stroke may be increased in the elderly.Agranulocytosis has not been reported witholanzapine. 25. Therapeutic usesTreatment of schizophreniaPrevention of severe nausea and vomitingOther uses: Treatment of mania, organic brainsyndromes, anxiety.Chlorpromazine is used to treat intractablehiccups. Risperidone and haloperidol are alsocommonly prescribed for this tic disorder. 26. Adverse eventsParkinson-like symptoms of bradykinesia,rigidity, and tremor usually occur within weeksto months of initiating treatment.Tardive dyskinesiaHypersensitivity reaction: Cholestatic jaundice,myocarditis, agranulocytosis.Miscellaneous: Weight gain (not withhaloperidol), blood sugar and lipids may tendto rise. Risk of worsening of diabetes and bluepigmentation on skin and retinal degenerationmay increases. 27. Clinical Efficacy ofAntipsychotic DrugsAntipsychotic drugs are effective in controllingsymptoms of acute schizophrenia, when largedoses may be needed.Long-term antipsychotic treatment is ofteneffective in preventing recurrence ofschizophrenic attacks, and is a major factor inallowing schizophrenic patients to leadnormal lives. 28. Depot preparations are often used formaintenance therapy.Antipsychotic drugs are not generallyeffective in improving negative schizophrenicsymptoms.Approximately 40% of chronic schizophrenicpatients are poorly controlled byantipsychotic drugs; clozapine may beeffective in some of these antipsychotic-resistantcases. 29. Second generation antipsychotics haveweak D2 blocking but potent 5-HT2antagonistic activity. Extrapyramidal sideeffects are minimal, and they may improvethe impaired cognitive function inpsychotics. 30. Modern AdvancementIn February, 2011, Jonathan Sebat, at the University ofCalifornia, and his colleagues, published researchidentifying a gene which holds particular promise inthe treatment of schizophrenia. According to Dr.Sebats research, Vasoactive Intestinal PeptideReceptor 2 or VIPR2 is much more likely to be foundin those with schizophrenia. Because VIPR2 respondsto synthetic peptides, already available, targeting thisgene is a promising treatment strategy. 31. References Katzung Pharmacology, 12th Edition.Rang & Dale Pharmacology, 6th Edition. Lippincotts Pharmacology, 5th Edition. Alstrom, D. Schizophrenia Research Breakthrough.The Irish Times. (April 2011). LaFee, S. Schizophrenia Gene Mutation Found;Target for New Drugs. UC San Diego. (February,2011).