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Antipsychotic drug
- 1. Writing prescription is easy, understanding people is hard Franz Kafka, (1883-1924)
- 2. History Introduction Different hypothesis for schizophrenia Classification Mechanism of action Uses Adverse effects Recent advances
- 3. 1931 Sen and Bose – publish therapeutic effect of reserpine in Hypertension and Insanity Hans Laborit – note the antipsychotic effect of chlorpromazine, which was being tried as preanesthetic medication 1950 - Jean Delay and Piere Deniker conducted trial 1960-1970: identification of D2 blockade as the key mechanism, development of these first- generation of antipsychotic agents Janssen introduced Haloperidol & Pimozide
- 4. Neuroleptics/ Major tranquillisers/ Dopamine antagonist Psychoses and Neuroses Psychotic disorders – Schizophrenia, severe forms of depression and mania
- 6. Positive symptoms: the presence of inappropriate behaviors Delusions Hallucinations Disorganized talking Movements Negative symptoms: the absence of appropriate behaviors Flat affect Anhedonia Catatonia
- 7. Excessive dopaminergic activity: • Drugs which increase dopamine activity • Postmortem – receptor density high in nucleus accumbens, caudate, putamen • Imaging studies – amphetamine – high dopamine in striated areas Diminished dopaminergic activity • Cortical/hippocampal – cognitive and negative • Postmortem – cortical, limbic, nigral, striatal
- 8. 5HT2A and 5HT2C – hallucination 5HT2A- depolarization of glutamate receptors stabilization of NMDA 5HT 2C- inhibition of cortical dopamine release 5HT1C- anxiolytic effect, exert procognitive effects in schizophrenia
- 9. Hypofunctioning of NMDA receptors located on GABAergic interneurons, leading to diminished inhibitory influence on neuron function GABA ergic activity induce disinhibiton of downstream glutamate activity hyperstimulation of cortical neuron through non NMDA receptor NMDA requires glycine In schizophrenia, glycine site is not fully occupied
- 11. Phenothiazines With aliphatic tertiary amine side chain Chlorpromazine With piperadine moiety in side chain Thioridazine With piperazine moiety in side chain Trifluperazine, fluphenazine
- 13. Typical or first generation antipsychotics (FGA) Atypical antipsychotics or second generation antipsychotics (SGA) D2 receptor blockade 5HT and Dopamine receptor block Less effective against negative symptoms More effective against negative symptoms Not effective in refractory cases Effective in refractory cases More side effects (EPS) Less side effects profile Clozapine Olanzapine Quetiapine Zotepine Risperidone Ziprasidone Paliperidone Aripiprazole Sertindole
- 14. Increased dopamine Rise in Number of brain D2 receptors Receptor supersensitivity Excess availability of dopamine due to over production Reduced destruction through enzyme deficiency SCHIZOPHRENIA
- 15. Typical/ FGA – D2 antagonist Initially – increased synthesis of DA – later decreases HVA and DOPAC level in blood & urine Molindone, loxapine, sulpiride and amisulpiride In between typical and atypical antipsychotics
- 17. Most of the antipsychotics are given orally but incompletely absorbed. Significant first-pass metabolism. Bioavailability is 25-65%. Most are highly lipid soluble. Most are highly protein bound (92-98%). High volumes of distribution (>20 L/Kg).
- 18. Plasma half life • Quetiapine – 7h • Clozapine – 12h • Fluphenazine- 20h (depot – 14.3days) • Haloperidol – 24-48h (depot – 21days) • Olanzapine – 33h Depot preparation – 2-4 weeks Measurable plasma concentration with I.M route is seen within 15-30min
- 19. Most antipsychotics are almost completely metabolized- phase 1 and subsequent phase 2 Exceptions are asenapine(phase 2), ziprasidone(aldehyde oxidase system) and paliperidone(oxidized metabolite) Most metabolites- inactive. Chlorpromazine – 160 metabolites, 70 have been identified.
- 20. Psychiatric indication: • Schizophrenia – advantage V/s disadvantage • First psychotic episode – start with atypical • Olanzapine (10mg), risperidone (4mg), quetiapine (25mg) • 2 weeks later increase the dose • Previously treated with typical – continue • Long acting depot preparations – haloperidol, fluphenazine • Rapid tranquillizers – lorazepam – 1-2mg i.v • Haloperidol – 2-10mg i.m Drug Dose Maximum Chlorpromazine 25-100mg TDS 1g/day Thioridazine 50-100mg TDS 800mg/day Fluphenazine 1-3mg TDS 20mg/day Trifluoperazine 2-5mg BD 40mg/day Flupenthixol 3-9mg TDS 18mg/day Zuclopenthixol 20-50 mg daily 200mg I.M depot Haloperidol 0.5-5mg TDS 60mg /day Penfluridol 20-60mg once a week 250mg once a week Pimozide 2-4mg /day 12mg/day Loxapine 10-25mg BD 75mg/day Drug Dose Maximum dose Sulpiride 400-800mg Amisulpride 200-400mg/day 1g/day Levosulpride 200-300mg/day Aripiprazole 10-15mg/day 30mg/day Clozapine 12.5mg OD/BD 300mg/day Olanzapine 5-10mg/day 20mg/day Risperidone 1mg BD 3mg BD Paliperidone 6mg/day 12mg/day Ziprasidone 20mg BD 80mg BD Quetiapine 25mg BD 300mg BD
- 21. • Drug induced psychoses –LSD , amphetamine • Schizo-affective disorder – schizo part – antipsychotic, affective part – anti depressant or lithium Neuro psychiatric indication • Tourette’s syndrome – haloperidol or pimozide • Huntington’s disease – haloperidol or chlorpromazine Non psychiatric indication: • Antiemetic – D2 block at CTZ,GIT – prochlorperazine, domperidone • Preanaesthetic medication - promethazine • Intractable hiccups – parenteral haloperidol, CPZ
- 22. CNS side effects: • Behavioral effects – sedation more with phenothiazines, thioxanthenes, olanzapine Less with butyrophenones, pimozide • Tolerance and dependence – tolerance develops to sedation and autonomic side effects
- 23. Treatment: Promethazine, Diphenhydramine Treatment: non selective b-blocker like Propranolol Treatment: Trihexyphenidyl, Procyclidine Treatment: withdraw neuroleptic drug and add diazepam
- 24. *Parkinsonism • Due to disturbance in DA-Ach imbalance • Treatment with anticholinergic- antiparkinsonian drugs •Trihexyphenyidyl, procyclidine •DO NOT START WITH LEVODOPA *Neurolept malignant syndrome •Hyperpyrexia, muscle rigidity, fluctuating BP, increase CK, myoglobin •Central mechanism •Peripheral mechanism •Stop neuroleptic •Supportive care •Dantrolene •Diazepam, bromocriptine
- 25. Autonomic (ANS) side effects: • Alpha adrenergic blockade- Postural hypotension • Antimuscarinic effects- dryness of mouth, constipation etc. (except clozapine) Endocrinal side effects: chlorpromazine, thioxanthene Agranulocytosis - clozapine Photosensitivity – UV rays oxidizes phenothiazines – accumulates in melanin containing tissues Retinal pigmentation, , corneal opacities- thioridazine Epileptogenic effects- clozapine, chlorpromazine Poikilothermic effects- impair the ability of hypothalamic thermoregulation
- 26. Mechanism Therapeutic effects Adverse effects α1 block -- Dizziness, orthostatic hypotension, reflex tachycardia. D2 block +ve symptom ↓ EPS & ↑ Prolactin D1 & D4 block -ve symptom & EPS ↓ -- H1 block Sedation Drowsiness & ↑ appetite & weight M block -- Dry mouth, etc. 5-HT2 block -ve symptom & EPS ↓ Anxiety & insomnia
- 27. Thioridazine: ventricular arrythmias, cardiac conduction block, sudden death Pimozide, ziprasidone: prolong QT, hypokalemia Quetiapine: cataract formation, priapism, peripheral edema, hyperventilation
- 28. Drug Effects Antacids Decrease absorption of antipsychotics Anticholinergics Increased anticholinergic effect Alcohol More sedation Antithyroid drugs Agranulocytosis Barbiturates Decreased effect but more sedation Carbamazepines and phenytoin Decreased effect but lower threshold Chloroquine May precipitate EPS Lithium Enhancement of neurotoxicities Levodopa Decrease efficacy Oral contraceptives Hyperprolactinemia Cigarette smoking Increased metabolism
- 29. Aspirin Minocycline Raloxifene Estrogen N-acetyl cysteine
- 31. Raloxifene Exhibit agonistic and protective action on the brain by modulating the monoaminergic neurotransmission of dopamine, serotonin and GABA Addition of Raloxifene (60 mg/day) to regular antipsychotic treatment ↓ negative, positive & general psychopathological symptoms in comparison with women receiving antipsychotic medication alone (Usall et al., 2011)
- 32. *Short term Rapid membrane effects by altering functional activity in the dopaminergic synapse (Di Paolo, 1994) *Long term Modifies synthesis in dopamine receptors (Di Paolo, 1994) *Estrogen alters serotonergic system (Moses et al., 2000) *Estrogen promotes neuronal regeneration & blocks mechanisms of neuronal death (DonCarlos et al., 2009)
- 33. Glutathione is a major antioxidant that protects cells against oxidative stress (Meister and Anderson, 1983) Glutathione potentiates NMDA receptors (Choi and Lipton, 2000)
- 34. * Targeted gene therapy Dysbindin, Neurogelin 1, COMT, DISC1 * Enhancement of BDNF * Targets GSK 3, PKC , GABAA receptor * PDE inhibitors (particularly at PDE1B) *Cannabinoid receptor antagonist *Currently glycine transport inhibitors are in trials *Preliminary study with LY2140023 (agonist at glutamate receptor) is also been tried
- 35. Thank you