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Antipsychotics Antipsychotics Antipsychotics - .pptx
- 1.
- 2. Contents • Introduction • Schizophrenia •Pathogenesis • Classification • Chlorpromazine
- 3.
- 4. Neuroses • Less serious •Reality not lost •Anxiety •Phobic states •OCD •Reactive depression •Post traumatic stress disorder •Hysterical
- 5. Psychoses • Severe • Distortionof thought, behaviour ,capacity to recognise reality & of perception 1. Cognitive disorders 2. Functional disorders •Schizophrenia •Paranoid states •Mood disorders Mania Depression
- 6. Psychosis ??? • Symptomof mental illnesses • Distorted or nonexistent sense of reality loss of contact with reality
- 7. Schizophrenia Substance-induced (i.e., drug-induced) Schizophreniformdisorder Schizoaffective disorder Delusional disorder Psychotic disorder due to a general medical condition
- 8. History Dementia precox – EmilKraepelin Kurt Schneider – described symptoms
- 9. Schizophrenia • Greek word“schizein” to split “phren” mind split mind Eugene Bleuler
- 10. Schizophrenia • Disorder ofthought • Commonest psychotic disorder • 1% of population • Onset in early 20s • Genetic predisposition
- 11. Positive symptoms Negativesymptoms Delusions Affective flattening Hallucinations Anhedonia Disorganized speech Avolition Disorganized behaviour Alogia Agitation Asociality 5 A’s
- 12. Pathophysiology • Not clearlyunderstood Various Hypothesis !!!!!
- 13. 1. Dopamine hypothesis 2.Glutamate - NMDA receptor hypofunction 3. Serotonin hypothesis 4. Neurodegenerative hypothesis
- 14.
- 15.
- 16. Dopamine receptors • 5GPCRs • D1,D2,D3,D4,D5 • D1 likeD1 & D5 • D2 likeD2,D3,D4
- 17. D1 like Putamen, nucleus accumbens,SN,prefrontalcortex & hypothalamus D2 like Caudate-putamen, medulla , midbrain, cortex
- 18. Pathways 5 major pathways 1.Mesolimbic -mesocortical 2. Nigrostriatal 3. Tuberoinfundibular 4. Medullary –periventricular 5. Incertohypothalamic
- 19. Ventral tegmental areaof brainstem Nucleus accumbens Prefrontal cortex M e s o l i m b i c M e s o c o r ti c a l VTA
- 20.
- 21. Dopamine hypothesis Van Rossum •Hyperfunction of mesolimbic pathway positive symptoms • Hypofunction of mesocortical pathway negative symptoms
- 22. 1. Dopamine receptorantagonist relieves symptoms 2. Drugs ↑ DA or activate DA receptors schizophrenia like state 3. Postmortem studies DA receptor density↑ 4. PET scan confirmation Mesolimbic hypothesis of positive symptoms
- 23. Dopaminergic transmission prefrontalcortex D1 receptors • D1 dysfunction ; cognitive impairment negative symptoms of schizophrenia
- 24. Limitations • Current researchone-third do not respond to non-clozapine antipsychotics high levels of D2-receptor occupancy. • No explanation cognitive and negative symptoms • Fails to explain antipsychotic action of atypical
- 25. 2. Glutamate -NMDA receptor hypofunction
- 26. Glutamate synthesis • Excitatoryneurotransmitter • Synthesis by 2 pathways Kreb’s cycle Glial cells
- 27. Type of receptors •Metabotropic receptors • Ionotropic receptors AMPA Kainate NMDA (N-methyl D-aspartate) (α amino 3OH methyl 5 isoxazole 4 propionic acid)
- 28.
- 29. NMDA hypofunction hypothesis •PCP / ketamine – produce psychotic symptoms “This lead to hypothesis that NMDA receptor has some defect” Explains positive negative and cognitive symptoms Explains dopamine hypothesis
- 30.
- 31.
- 32. NMDA hypofunctioning linkedto DA Hypothesis –Positive symptoms
- 33.
- 34. NMDA hypofunction ↑Glutamate ↑↑stimulation ofML DA pathway ↑Dopamine
- 35. NMDA hypofunctioning linkedto DA Hypothesis – Negative symptoms
- 36.
- 37. NMDA hypofunction ↑Glutamate GABA interneuron Inhibitionof MC DA neurons ↓Dopamine
- 38.
- 39. Serotonin synthesis &release RELEASE REUPTAKE VMAT2 VMAT 2 Release Reuptake Tryptophan 5OH Tryptophan 5OH Tryptamine
- 40. Serotonin receptors 5 HT1, 5 HT 2, 5HT 4-7 are GPCR 5 HT 3 – ligand gated ion channel
- 41. Serotonin hypothesis ofSchizophrenia • LSD, Mescaline 5HT agonist hallucinogenic • 5HT 2A/2C stimulation leads to hallucinations • These receptors regulate DA, NE , Glutamate, GABA & ACh release in cortex, limbic areas and striatum
- 42.
- 43. Inhibition of Dopaminerelease
- 44.
- 45.
- 46. • 5-HT2A Receptor↓ Dopamine • 5-HT1A Receptor ↑ Dopamine
- 47.
- 48. Genetic programming ofabnormal apoptosis & degeneration in cortical neurones Prenatal exposure of anoxia Prenatal infections Toxins Malnutrition
- 49. Hypothesis- summary 1. Dopaminehypothesis 2. Glutamate - NMDA receptor hypofunction 3. Serotonin hypothesis 4. Neurodegenerative hypothesis
- 50.
- 51. History • 1950 –CPZ used as antihistamine was found to have antipsychotic action. • 1970s – D2 blockade – Antipsychotic action !!!
- 52. Classification • Typical antipsychotics •Atypical antipsychotics
- 53. Typical Phenothiazines Thioxanthine Butyrophenones Other heterocyclic compounds Aliphatic– chlorpromazine, triflupromazine Piperidine – Thioridazine Piperazine – Trifluperazine, Fluphenazine Flupenthixol Haloperidol Trifluperidol Penfluridol Pimozide Loxapine Levosulpiride
- 54. Atypical antipsychotics • Clozapine •Olanzapine • Quetiapine • Risperidone • Asenapine • Ziprasidone • Amisulpiride • Zotepine • Aripiprazole • Cariprazine
- 55. Typical antipsychotics?? • D2blockade is responsible for antipsychotic action!!!!
- 56.
- 57.
- 58. Why do weneed atypicals ?? • Low EPS • Good for negative symptoms • Improves cognitive symptoms
- 59. What makes theseantipsychotics atypical?? 1. Weaker D2 blocking action 2. Strong D4 selectivity 3. D2 partial agonism 4. Serotonin partial agonism 5. Serotonin dopamine antagonism
- 60. Partial dopamine agonism betweena full agonist and antagonist
- 61. 5-HT Receptors • 5-HT2AReceptor ↓ Dopamine • 5-HT1A Receptor ↑ Dopamine Serotonin dopamine antagonism
- 62. D2 blockade D2& Serotonin blockade 5HT inhibits DA release Reversal of D2 blockade
- 63. 5HT2C receptor andDA • Stimulation of 5HT2C regulates DA and NE release …. • Decreases DA , mesolimbic >>> nigrostriatal Pathway
- 64. 5HT6 receptors andACh • Key regulator of release of ACh • Improves cognitive function in schizophrenia • 5HT6 blockers – Clozapine, Olanzapine, Quetiapine, Ziprasidone, Aripiprazole improves cognitive symptoms
- 65. 5HT7 receptors • Contributesto the antidepressant action of Quetiapine in combination with SSRI / SNRI.
- 66. Typical antipsychotics • Phenothiazines Aliphatic– chlorpromazine, triflupromazine Piperidine – Thioridazine Piperazine – Trifluperazine, Fluphenazine • Butyrophenones Haloperidol, Trifluperidol,penfluridol • Thioxanthine – Flupenthixol • Other heterocyclics- Pimozide,Loxapine,levosulpiride
- 67. History • 1950 Paul Charpentier – synthesized • 1952 Henri Laborit – marketed as Largactil • 1970 Dopamine antagonism
- 68. Mechanism of Action •Potent D2 blocker • Also D1 ,D3 & D4 blocking • Mesolimbic system & mesocortical areas
- 69. Pharmacological Actions: CNS Nonpsychotic individual • Indifference to surrounding • paucity of thought • psychomotor slowing Neuroleptic syndrome
- 70. ..CNS Psychotic individual • ↓irrational behaviour • ↓ Psychotic symptoms • Normalise thought & behaviour • Hallucinations, delusions suppressed
- 71. …CNS • Vigilance impaired •Lower seizure threshold • Poikilothermia • Antiemetic • Extrapyramidal symptoms
- 72. ANS • α blocker •Anticholinergic • Antihistaminic
- 73. Local anaesthetic • Potencysame as Procaine • Irritant • Not used
- 74. CVS • Postural hypotension •Reflex tachycardia • Higher doses: Q-T prolongation, T suppression
- 75. Endocrine • Blocks actionof DA on pituitary lactotrophs- ↑ Prolactin • ↓ ACTH • ↓ ADH; ↑ urine volume
- 76. Pharmacokinetics • Low oralbioavailability • Highly plasma protein bound • Vd : 20L/kg • Metabolized in liver CYP2D6 • t1/2 : 18-30 hours • Excreted in urine & bile
- 77. Adverse Effects CNS: • Drowsiness,lethargy, confusion • ↑ appetite, weight gain • Seizure CVS: • Postural hypotension, palpitation
- 78. …Adverse Effects Anticholinergic: • Drymouth, blurring of vision • Constipation, urinary hesitancy Endocrine: • Galactorrhea, Amenorrhea, infertility
- 79. Adverse effects -Nigrostriatal Pathway EPS
- 80. … adverse effects Reciprocalrelationship between DA & ACh ACh ACh
- 81. EPS Acute muscular dystonia(hours to days) Muscular spasm Akathisia (days- wks) • Restlessness • Feeling of discomfort • Agitation • Compelling desire to move about
- 82. …EPS Parkinsonism (wks- months) •Rigidity • Tremor • Hypokinesia • Shuffling gait • Mask like face Rabbit syndrome ( yrs)
- 83. …..EPS Tardive dyskinesia (years) •Progressive neuronal degeneration • Supersensitivity of dopamine receptors • Difficult to treat • Stop drugs with anticholinergic action
- 84. …..adverse effects • NeurolepticMalignant Syndrome (NMS) 1. Marked rigidity 2. Impaired sweating 3. Fever 4. Autonomic instability 5. Leukocytosis Supportive measures Dantrolene sodium DA agonist
- 85. …..adverse effects • Weightgain • Blood sugar & lipids rises • Blue pigmentation of skin • Corneal & lenticular opacities • Cholestatic jaundice
- 86. Interactions • Potentiate CNSdepressants • Blocks action of Levodopa • Clonidine & Methyldopa action ↓ • Inducers ↓ blood levels
- 87. Uses 1.Psychoses Schizophrenia Organicbrain syndrome 2.Vomiting 3.Intractable hiccough 4.Tetanus
- 88. Summary • Psychosis • Schizophrenia •Hypothesis • Atypical mechanisms
- 89. References • Goodman andGilman- Pharmacological basis of therapeutics(13th edition) • Katzung – Basic and Clinical Pharmacology -(12th edition) • K. D Tripathi- Essentials of Medical Pharmacology(8th edition) • David Golan- Principles of Pharmacology(4th edition) • Stahl’s psychopharmacology 4th edition
- 90.
Editor's Notes
- #6 Broadly speaking, psychosis means a loss of contact with reality; it is a symptom of a number of mental illnesses rather than a medical condition in its own right.
- #18 Medullary periventricular neurons in vagus---eating behaviour Incertohypothalamicmedial zona increta to hypo----copulatory behaviour
- #21 “mesolimbic dopamine hypothesis of positive symptoms of schizophrenia,” since it is believed that it is hyperactivity specifically in this particular dopamine pathway that mediates the positive symptoms of psychosis
- #33 (A) The cortical brainstem glutamate projection communicates with the mesolimbic dopamine pathway in the ventral tegmental area (VTA) to regulate dopamine release in the nucleus accumbens. (B) If NMDA receptors on cortical GABA interneurons are hypoactive, then the cortical brainstem pathway to the VTA will be overactivated, leading to excessive release of glutamate in the VTA. This will lead to excessive stimulation of the mesolimbic dopamine pathway and thus excessive dopamine release in the nucleus accumbens. This is the theoretical biological basis for the mesolimbic dopamine hyperactivity thought to be associated with the positive symptoms of psychosis.
- #36 (A) The cortical brainstem glutamate projection communicates with the mesocortical dopamine pathway in the ventral tegmental area (VTA) via pyramidal interneurons, thus regulating dopamine release in the prefrontal cortex. (B) If NMDA receptors on cortical GABA interneurons are hypoactive, then the cortical brainstem pathway to the VTA will be overactivated, leading to excessive release of glutamate in the VTA. This will lead to excessive stimulation of the brainstem pyramidal neurons, which in turn leads to inhibition of mesocortical dopamine neurons. This reduces dopamine release in the prefrontal cortex and is the theoretical biological basis for the negative symptoms of psychosis. Chapter 4: Psychosis and schizophrenia 113
- #39 COMT –not found in sympathetic neurons---only for catecholamines---found in cytoplasm –liver ,kidney MAO –fond in outer memb of mitochondria—in periphery--MAO a- liver..MAO B-platelets, lymphocytes, liver In brain MAO A- all regions cont catecholamines-locus ceruleus---MAO B-raphe nucleus-(5HT ),hypothalamus
- #43 (1) Serotonin is released in the cortex and binds to 5HT2A receptors on glutamatergic pyramidal neurons, causing activation of those neurons. (2) Activation of glutamatergic pyramidal neurons leads to glutamate release in the brainstem, which in turn stimulates GABA release. GABA binds to dopaminergic neurons projecting from the substantia nigra to the striatum, inhibiting dopamine release (indicated by the dotted outline of the dopaminergic neuron).
- #56 The pharmacologicalmechanism of EPS therefore seems to be a relative dopamine deficiency and a relative acetylcholine excess.
- #59 D4 sparse in basal ganglia
- #61 (A) Postsynaptic dopamine 2 (D2) receptors are being blocked by a serotonin–dopamine antagonist (SDA) in the nigrostriatal dopamine pathway. This shows what would happen if D2 blockade were the only active action of an atypical antipsychotic – the drug would only bind to postsynaptic D2 receptors and block them. In contrast, (B) shows the dual action of the SDAs, in which both D2 and 5HT2A receptors are blocked. The interesting thing is that the second action of 5HT2A antagonism actually reverses the first action of D2 antagonism. This happens because dopamine is released when serotonin can no longer inhibit its release. Another term for this is disinhibition. Thus, blocking a 5HT2A receptor disinhibits the dopamine neuron, causing dopamine to pour out of it. The consequence of this is that dopamine can then compete with the SDA for the D2 receptor and reverse the inhibition there. As D2 blockade is thereby reversed, SDAs cause little or no extrapyramidal symptoms (EPS) or tardive dyskinesia
- #62 Normally, 5HT inhibits DA release. (A) DA is being released because no 5HT is stopping it. Specifically, no 5HT is present at its 5HT2A receptor on the nigrostriatal DA neuron. (B) Now DA release is being inhibited by 5HT in the nigrostriatal dopamine pathway. When 5HT occupies its 5HT2A receptor on the DA neuron (lower red circle), this inhibits DA release, so there is no DA in the synapse blocking a 5HT2A receptor disinhibits the dopamine neuron The consequence of this is that dopamine can then compete with the SDA for the D2 receptor and reverse the inhibition there. As D2 blockade is thereby reversed, SDAs cause little or no extrapyramidal symptoms (EPS) or tardive dyskinesia
- #63 Target of novel antipsychotics – Vabacaserin
- #81 involving jaw, facial, & neck muscles
- #82 Quetiapine and risperidone
- #83 Stop drugs with anticholinergic action. VMAT2 INHIBITORS are used Deutetrabenazine valbenazine
- #84 bromocriptine
- #87 Schizophrenia: + symptoms > − symptoms Restore cognitive, affective & motor disturbances Agitated, combative & violent