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  2. 2. Brain Mind
  3. 3.  Psychosis ……… Thinking  Depression …… Mood
  4. 4.  Brain • CNS Stimulant (Analeptics) • CNS Depressant  Mind • Antidepressants • Psychosis …. Antipsychotics… (Neuroleptics)
  5. 5. Psychosis a variety of mental disorders e.g., Schizophrenia: characterized by a “ clear sensorium ” but a “ marked-disturbed thinking ” - Hallucination - Delusions ( False beliefs)
  6. 6. Not curatives  Decrease intensity of symptoms i.e. • Hallucination,  Auditory, Visual, Tactile, Olfactory • Delusions (False Beliefs) Patient can function/move in supportive enviornament
  7. 7. Pathophysiology
  8. 8. Genetic & Environmental Factors  Single gene predisposes  Environmental factors required for Schizophrenia to develop.(appear with age)  Identical twins one has schizophrenia…. Probability 50% … points towards Environmental factors  Neurodegeneration ? [Prgressive Development
  9. 9. Neuroanatomical & Neurochemical Basis of Shizopherania  Malfunction in different Neuronal Circuits • Changes in Mesolimbic pathways +ive • Changes in Mesocortical pathways - ive  Dopamine Hypothesis  Serotonin Hypothesis  Glutamate Hypothesis • (NMDA Hypofunction Hypothesis [Coyle 2006]) On the basis of indirect pharmacological evidence
  10. 10. Symptoms of Schizophrenia Positive Symptoms  Delusions  Hallucinations  Thought Disorders  Abnormal disorganized behaviour  Catatonia (purposeless motor activity) Negative Symptoms  Withdrawal from social contact  Flattening of emotional responses  Anhedonia (inability to express pleasure)  Reluctance to perform every day tasks
  11. 11. Amphetamine release dopamine in brain behavioural syndrome …. Mimic Schizophrenia “CARLSON 2000” I. Dopamine-Hypothesis: Evidence of Dopaminergic activity underlying this disorder. a). D - agonists leads to Schizophrenic symptoms. b). Increased Dopamine-Density in brains of Schizophrenic patients ( post mortalm reports ). c). Typical Antipsychotic are D2 blockers…… d). Positron Emission Tomography (haloperidol binding) “excessive”
  12. 12. Against Dopamine Hypothesis Dopminergic activity is suggesteted as cause of Cognitive Impairment & Negative symptoms of Scizopherania  Dopaminergic Innervation in Medial Temporal Cortex, Dorsolateral prefrontal cortex, Hippocampus In decreased levels of DOPAC (dihydroxyphenylacetic acid)  Several atypical drugs has much less effect on D2 receptors & yet are effective
  13. 13. Serotonin Hypothesis  5HT2A receptor blockade is key factor In M.O.A. of ATYPICAL drugs (Inverse agonists)  5HT2A receptors modulate the releases of Dopamine (Cortex, Limbic Region)  5HT2A stimulation leads to depolarization of Glutamate Neurons  5HT2A Also stabilize NMDA receptors  5HT2C currently being studied as antipsychotic
  14. 14. Glutamate/NMDA Hypofuntion Hypothesis  NMDA receptor antagonists (ketamine, Phencyclidine,dizocilpine) can produce +ive & -ive symptoms • Amphetamine produce only +ive symptoms  It has been postulated  “ schizophrenia may result from disruption of Glutamatergic neurotransmission [Moghaddam, 2003]… Evident as reduction in function of NMDA receptors [ Coyle, 2006]”
  15. 15. Dopamine Receptors Two Families: D1-like receptors group (Gs coupled …. Stimulate adenylcyclase ( no correlated antipsychotic activity ).
  16. 16. D2-like receptor group (correlated with antipsychotic activity ) (Gi/G0 coupled … inhibitadeny cyclase …activate K+ channels, inhibit Ca++, may also activate Phosphlipase C) i. D-2 receptor ( found pre- & postsynaptically in the caudate-putamen, nucleus accumbens and olfactory tubercle ):decreases cAMP and inhibits Ca++ channels but opens K+ channels. ii. D-3 receptors ( located in the frontal cortex, medulla and midbrain ): decreases cAMP. iii. D-4 receptors also decreases cAMP.
  17. 17. Dopaminergic Pathways Five important pathways / systems in the brain. 1. Mesolimbic-mesocortical Pathways: more closely related to behavior; ( it projects from cell bodies near to substantia nigra to the limbic system and neocortex ) …+ive & -ive Symptoms 2. Nigrostriatal Pathways: involved in coordination of voluntary movement; ( it projects from substantia nigra to the caudate and putamen.) [ Extrapyramydal Effects …. Dystonias, Tardive dyskinasias]
  18. 18. 3. Tuberoinfundibular System: inhibits prolactin secretion; ( connects arcuate nuclei and periventricular neurons to the thalamus and posterior pituitary.) 4. Medullary-periventricular Pathways: involved in eating behavior; ( consists of neurons in the nucleus of the vagus whose projections are not well defined.) 5. Incertohypothalamic Pathways: It regulates the anticipatory motivational phase of copulatory behavior in rats; ( connections from the medial zone incerta to the hypotalamus and amygdala.)
  19. 19. II. Role of Other Neurotransmitters: excessive Serotonin / GABA etc. Activity. a). Decreased 5-HT2 activity by Risperidone, Olanzapine. b). Decreased GABA, Glutamatergic & Cholinergic activity, or some α1-blockers.
  20. 20. 5-HT Receptors i. 5-HT1A receptors ii. 5-HT2A receptors: LSD – Lysergic acid Diethylamide - is an agonist here produces transient hallucinations and other mental aberrations including insomnia. Similarly Psilocin ( found in mushrooms ), DMT- Dimethyltryptamine - are also hallucinogens. Ectasy produces euphoria followed by depression etc.
  21. 21. Classification
  22. 22.  Typical…. (First generation, Classical, Conventional) • Chlorpromazine • Haloperidol • Fluphenazine • Flupentixol • Clopentixol  Atypical…. (2nd generation) • Clozapine • Risperidone Recpetor Profile • Sertindole Incidence of ex.P.effects • Quetipine Efficacy in Resistant cases • Amisulpride Efficacy against -ive sympt. • Aripiprazole • Zotepine • Ziprasodine
  23. 23. According to Receptor Selectivity ( In descending order ) a) On Dopamine Receptors Thiothixene, Chlorpromazine, Fluphenazine, Haloperidol, Aripiprazole, Clozapine, Risperidone, Olanzapine, Quetiapine, Ziprasidone. b) On 5-HT2A Receptors Clozapine, Risperidone, Olanzapine, Quetiapine, Ziprasidone, Aripiprazole, Haloperidol, Chlorpromazine, Fluphenazine, Thiothixene.
  24. 24. Highly selective for D2 Receptors (Newer Drugs)  Sulpride  Amisulpride  Remoxipride
  25. 25.  On Basis of Clinical uses • Behavioural Changes  Chlorpromazine  Haloperidol  Olanzepine  Risperidone • Schizophrenia  Flupentixol  Amisulpride  Clozapine
  26. 26. Classification ( Chemically – Based ) I. Phenothiazines a). Open-Chain: 1. Chlorpromazine 2. Promazine 3. Promethazine b). Piperazine-Chain: 1. Trifluoperazine 2. Perphenazine 3. Fluphenazine c). Piperidine-Chain: 1. Thioridazine
  27. 27. II. Thioxanthines 1. Thiothixen 2. Chlorprothixene III. Butyrophenones 1. Haloperidol 2. Droperidol
  28. 28. IV. New / Atypical Drugs (Hetrocyclics) a). Di-benzodiazepine: Clozapine b). Dihydro-indolone: Ziprasidone Molindone c). Di-benzo-oxazepine: Loxapine d). Dibenzo-thiazepine: Quatiapine e). Dihydro-carbostyril: Aripiprazole f). Benzisoxazole: Risperidone g). Thienobenzodiazepine: Olanzapine h). Fluorophenylindole: Sertindole V. Anti-manic Lithium
  30. 30. Neuroleptics Li+ Neuroleptics Some Antipsychotics Sites of Action of Neuroleptics & Lithium DA Li+ DA ATP cAMP DA Presynaptic Postsynaptic Dopamine Neurons Receptive Membrane
  31. 31. Relative Affinities of Clozapine, Chlorpromazine, Haloperidol. at D2 & D1- receptors More antipsychotic activity
  32. 32.  Rapid but incomplete absorption;  Significant first pass metabolism ( oral bioavailability of chlorpromazine & thioridazine is 25% to 35% while of haloperidol is about 65%.)  Highly lipid soluble & protein-bounded ( 92-99%);  Vd > 7 L/kg.  Prolonged D2 & other receptors occupancy, so longer duration of action than their half lives. Pharmacokinetics
  33. 33. Pharmacokinetics ( cont.) metabolites are not so active but mesoridazine, a metabolite of thioridazine is more potent than parent drug. Excretion Almost all are completely metabolized into more water soluble substances. Metabolites of chlorpromazine may be excreted in the urine after weeks of the last dose of chronically given drugs.
  34. 34. Concerning hypothesis for pathophysiological basis of schizophrenia, which statement is accurate?  a: All clinically effective antipschotic drugs have high affinity for D2 receptors  b: Dopamine receptor blocking drugs are used to alleviate psychotic symptoms in parkinsonism  c: Drug induced psychosis can occur without activation of brain dopamine receptors  d: Serotonin receptors are present at lower than normal levels in the brains of untreated schizophrenics  E: The clinical potency of clozapine correlate well with its dopamine receptor blocking activity C
  35. 35. Regarding Classification of antipsychotic drugs which is highly selective for D2 receptors a: Sulpride b: Clozapine c: Olanzapine d: Quetiapine e: Risperidone a
  36. 36. Pharmacological Effects
  37. 37. Risperidone Clozapine,etc. Serotonin Receptors All Typical Anti- psychotics esp. Haloperidol Dopamine Receptors
  38. 38. a ). CNS 1. i). Behavioral Effects dopaminergic site at limbic system & reticulating activating system: - Depressing- anesthesia like state; - Open Chain are more sedating & less Antipsychotic; but chlorpromazine after longer use is antipsychotic ( pt. is less disturbed & having fewer hallucinations & delusions ); - In acute cases– a quietening effect in agitated & disturbed patients.
  39. 39. Tolerance develops only to sedative effects ii). Extra pyramidal Effects(acute dystonias & Tardive dyskinesias) Dystonia …involunry movements, retlessness, Muscle spasm, Protuding tounge, fixed upward gaze, Torticolis (Involuntry spasm of neck muscles) Dopaminergic Sites: at Nigrostriatal Sites: rarely in acute cases; Parkinsonism like: due to increased cholinergic activity in CNS ( to counter act the decreased dopaminergic activity ) so Antipsychotic with high anticholinergic activity like Thioridazin will have lowest incidence of parkinsonism like symptoms but has high esdative & hypotensive effects.
  40. 40. Tardive Dyskinesia: ( after months ….. Tardive) Disabeling. Irreversible, involuntry movements of face & tongue, also trunk & limbs perhaps due to imbalance of Ach. & Dopamine activity ( esp. decreased cholinergic activity leads to up regulation of dopaminergic receptors – super sensitivity which may occur after prolong therapye.g., by thioridazine like drugs which intensify this syndrome ) Treatment is to discontinue all drugs with anticholinergic activity or reduce the dose. If it fails give Diazepam in larger doses. 2. Medulla at CTZ( therapeutic doses ) & Vomiting Center( larger doses ): Anti- Emetic effect
  41. 41. b). Autonomic Nervous System i). α- Receptors: α – Blockade with initial small dose (orthostatic hypotension & impaired ejaculation) but with chronic dose stimulation occurs. ii). Muscarinic & Nicotinic Receptors: weak action & blocked iii). Histaminergic Receptors: Antihistaminic Effect
  42. 42. Uses a). Psychiatric Uses 1. Schizophrenia some patients do not respond at all. 2. Schizoaffective Disorders antipsychotic with antidepressants, lithium or valproic acid. 3. Manic episode in Bipolar Disorders Olanzapine alone may be useful here which is withdrawn when mania subsides.
  43. 43. 4. Nonmanic Excitated State Benzodiazepines are combined. 5. Tourette’s Syndrome 6. Alzheimer Senile Dementia 7. Anxiety with Emotional Disorders with sedative drugs.
  44. 44. b). Non-psychiatric Uses 1. Anti-emetic due to dopamine receptors blockade at CTZ & Stomach e.g., Prochlorperazine, Benzquinamide. 2. Anti-histaminic for pruritus. 3. Preoperative Sedative Promethazine. 4. As neuroleptanalgesia Droperidol with Fentanyl.
  45. 45. Adverse Effects a). Behavioral Effects Pseudo-depression; Toxic-confusional states: b). Neurological Effects Extra pyramidal Effects: Parkinsonism, Akathisia — uncontrolled restlessness, Acute Dystonic Reactions — spastic retrocolis or torticollis. Tardive Dyskinesia Seizures with chlorpromazine, clozapine.
  46. 46. c). Hypothalamus i). Temperature Regulating Center by depressing it .…Hypothermia ; but in high environmental temperature hyperthermic episode may occur due to failure to lose body temperature. ii). Prolactin Release …. Hyperprolactinemia results: in women amenorrhea - galactorrhea & infertility, and in men loss of libido, impotence & infertility
  47. 47. d). Pituitary i). Increased Melanocyte Hormone Activity – Hyper pigmentation esp. with those drugs which have high antipsychotic activity. ii). Increased Gonadotropin Activity – Delayed Ovulation & Menstruation ; with high doses amenorrhea. iii) . False positive pregnancy test iv). Hyperglycemia in non-diabetic patients. v). Weight gain occurs esp. with clozapine and olanzapine.
  48. 48. e). CVS  Orthostatic hypotension and  High resting pulse rates due to large doses of low potency drugs.  Decreased mean arterial pressure, peripheral resistance and stroke volume but increased heart rate. ECG Cardiac toxicity esp. with thioridazine Ventricular arrhythmias, Conduction block & sudden death; Prolongation of QT interval and abnormal ST- segment & T waves esp. with Sertindol & Ziprasidone ; but all are reversible.
  49. 49. f). Allergic Reactions at skin ( eruption rarely ), liver ( homeostatic jaundice ), Blood ( agranulocytosis ) esp. with clozapine which is potentially fatal but reversible. g). Miscellaneous Ocular Complications Drug Deposits in cornea & lens; retinal deposits with thioridazine associated with browning of vision. Use in Pregnancy Dysmorphogenesis: teratogenesis
  50. 50. Neuroleptic Malignant Syndrome ( life threatening disorder in patients who are extremely sensitive to extra pyramidal effects of antipsychotic; there is Excessive & rapid blockade of postsynaptic dopamine receptors.
  51. 51. Symptoms are:  Muscle rigidity,  Impaired sweating,  Hyperpyrexia,  Leucocytosis.  Autonomic instability with altered B.P & pulse rate.  Creatine kinase isozyme are elevated reflecting muscle damage. D/D  Malignant Hyperthermia [ anesthetic Complication]  Serotonin Syndrome …. [ Tremour, Clonus, Hypereflexia ]
  52. 52. An adverse effect that is common to most phenothiazines is  a: A marked increase in blood pressure  b: Rigidity and tremour at rest especially with prolong use  c: Suppression of lactation  d: A diminished response to CNSdepressants  e: Nausea b
  53. 53. The least likely side effect seen in patient taking chlorpromazine for two months would be  a: Extrapyramidal symptoms  b: Hypotension  c: Lethargy  d: weight gain  e: Nausea & Vomiting e