Antipsychotics
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This document discusses the history and development of antipsychotic drugs. It notes that early antipsychotics like chlorpromazine were discovered serendipitously for their anesthetic or antihistamine properties in the 1930s-1950s. Between 1954 and 1975, about 15 antipsychotics were introduced in the US. Clozapine in 1990 marked the beginning of atypical or second-generation antipsychotics. The document also discusses theories around the role of dopamine and glutamate in schizophrenia, and how different drug classes target various receptors to treat symptoms.
![Dopamine hypothesis
• Schizophrenia results from excess activity of dopamine
neurotransmission in Mesolimbic and Mesocortical Pathways because:
• All antipsychotic drugs block dopamine receptors. Stimulant drugs which
act through dopamine can produce schizophreniclike behaviors
(eg.amphetamines).
• Levodopa, a dopamine precursor, can exacerbate schizophrenic
symptoms, or occasionally elicit them in non-schizophrenic patients.
• Higher levels of dopamine receptors measured in brains of
schizophrenics by PET.
• Brain [DA] increases during psychotic episodes but not during remissions.](https://image.slidesharecdn.com/antipsychotics-200829114155/85/Antipsychotics-10-320.jpg)
Antipsychotics
- 2. The history of antipsychotic drug development 30`s 40`s 50`s 60`s 70`s 80`s 90`s 00 Ziprasidone Aripiprazole Brexpiprazole Asenapine Lurasidone Iloperdone Paliperidone Clozapine Olanzapine Risperidone Quetiapione Clopenthixol Zuclopenthixol Flupenthixol Haloperidol Fluphenazine Loxapine Thioridazine Perphenazine CPZAnestheticsECT
- 3. The history of antipsychotic drug development • Often 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.
- 4. 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.
- 5. Classic and commonly used terms Proposed terms by WPA Neuroleptics or Typical antipsychotics First generation antipsychotics Atypical antipsychotics (serotonin –†dopamine antagonists) Second generation antipsychotics Dopamine partial agonists ( aripiprazole ) Third generation antipsychotics Multi-receptor modulation Next Generation
- 6. WHY THEY ARE ‘ATYPICAL’ ? SPECTRUM OF ACTION Higher ratio of serotonin : dopamine receptor blockade Appear more specific for mesolimbic than striatal dopamine System DIFFERENT SIDE EFFECT PROFILE Lower Risk of EPS
- 7. Neuroleptic: synonym for antipsychotic drug/ Antipsychotics are the drugs currently used in the prevention of psychosis. They have also been termed neuroleptics, because the suppress motor activity and emotionality.
- 8. Etiology and treatment strategies?
- 10. Dopamine hypothesis • Schizophrenia results from excess activity of dopamine neurotransmission in Mesolimbic and Mesocortical Pathways because: • All antipsychotic drugs block dopamine receptors. Stimulant drugs which act through dopamine can produce schizophreniclike behaviors (eg.amphetamines). • Levodopa, a dopamine precursor, can exacerbate schizophrenic symptoms, or occasionally elicit them in non-schizophrenic patients. • Higher levels of dopamine receptors measured in brains of schizophrenics by PET. • Brain [DA] increases during psychotic episodes but not during remissions.
- 11. The role of dopamine in Schizophrenia is quite complex : • Positive Symptoms are thought to be result of OVERACTIVITY in Mesolimbic pathway ( activating D2 receptors ). • While, negative symptoms may result from a DECREASE ACTIVITY in Mesocortical pathway (D1 receptors). • Nigrostriatal and Tuberoinfundibular pathways appear to be normal in Schizophrenia.
- 12. Glutamate Hypothesis; Glutamate : excitatory Neurotransmitter • NMDA Receptors : Ionotropic Glutamate Receptors • It is observed that NMDA hypofunction on one hand • Decrease DA in Mesocortical Pathway so Increase Negative Symptoms • And on the other hand • Increase DA in Mesolimbic Pathway , hence, Increase Positive Symptoms. • Evidence : NMDA rec Antagonists (Phencyclidine,ketamine) produce both Positive and Negative Psychotic Symptoms.
- 13. Serotonergic Pathways • Many effective antipsychotic drugs, in addition to blocking dopamine receptors, also act as 5-HT-receptor antagonists. • Many 'atypical‘ antipsychotic drugs produce fewer extrapyramidal side effects than dopamine-selective compounds, as they also combine with 5-HT2A-receptors. • Whether 5-HT2A-receptor blockade accounts directly for their antipsychotic effects, or merely reduces undesirable side effects associated with D2-receptor antagonists, remains controversial.
- 14. Classification Typical antipsychotics • Phenothiazines e.g. chlorpromazine, fluphenazine, thioridazine • Butyrophenones e.g. haloperidol, droperidol • Thioxanthines e.g. chlorprotixen, thiothixene • Atypical antipsychotics • Clozapine • Risperidone • Sulpiride • Sertindole • Lurasidone • Olanzapine • Quetiapine.
- 16. Drug Targets • Dopamine receptors: D1, D2, D3, D4, D5 • Serotonin receptors: 5- HT-1A, 2A, 3, 6, 7 • Norepinephrine: -1 & - 2 • Muscarinic acetylcholine: mACh-1 & 4 • Histamine: H-1 & 2 • Dopamine, • norepinephrine & • serotonin transporters • NMDA-glutamate receptor
- 17. RECEPTOR OCCUPANCY RECEPTOR AFFINITY
- 21. Steady State