9. antipsychotics

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  1. 1. Antipsychotics/Major Tranqullizers/Neurolepticsor Anti-schizophrenic drugs Psychosis 1. Schizophrenia 2. Organic Psychosis 3. Affective disorders Depression Mania Manic depressive illness (bipolardepression)
  2. 2. Etiology: Not known Strong but incomplete genetic pre-disposition (1st degree relatives 10%) (2nd monozygotic twin 50%) suicide is about 10% cases
  3. 3. Symptoms: 1.Positive symptom: (result fromNeurochemical Abnormality) Increase do paminergic transmissionRespond well to Rx Delusions often paranoid in nature:cannt be rectified by reasoning
  4. 4. Hallucinations: They may be Visual Auditory Tactile (CD Canine bugs)
  5. 5. c) Thought disorderWild train of thoughts Draw irrational conclusion with the feelingthat thoughts are inserted or withdrawn byan outside agency. Usually not like to be interfered, flight ofideas from one thought to other thought. Broadcast of ideas. d) Abnormal stereotypical behavior,
  6. 6. 2. Negative Symptoms: Result from brain atrophy Dont respond / less responsive to R x Emotional blunting. Poor Socialization Cognitive deficit (Dementia) more irritable.
  7. 7. Neurochemical Basis: 1) Dopamine Theory (Hypothesis byCarlson awarded noble prize inyear 2000) Dopamine hyperactivity in mesolimbicand mesocortical pathway & amygdale positive symptoms of schizophrenia.Proof: Dopamine agonists produce thesesymptoms of schizophrenia e.g. central
  8. 8. 2) Glutamate Theory Glutamate and DA exert excitatory andinhibitory effects respectively on GABA ergicstriatal neurons which project to thalamus andconstitute sensory Gate Glutamate or DA disables the gate anduninhibited sensory input reaches the cortex. Glutamate NMDA (N-methyl deaspartate)recep antagonists: Phencyclidine
  9. 9. 3) 5 HT Theories: 5 HT dysfxn LSD & 5-HT2 Receptors agonists producedschizophrenia like syndrome. Mostly of Anti-psychotics in addition toaffect dopamine also back serotoninreceptors.
  10. 10. 4) Current views:Combination of DA hyperactivity with 5-HT & glutamate dysfxn.
  11. 11. 1) Nigrostriatal Pathway: 75% of dopamine in brain 2) Mesolimbic mesocortical pathway: Projects from neurons near S.Ntolimbic system & Neocortex Behaviorial effects Hyperactivity leads to schizophrenia. 3) Tuberoinfundibular (TubrohypophyScal) Pathway:
  12. 12. 4) Medullary Perventricular Pathway: From neurons of Motor Nucleus of Vagus___ Periventricular nuclei Eating behavior Satiety center ____ Bolimia Nervosa Appetite Cetre _____ Anorexiz Nervosa 5) Incertohypothalamic Pathway: From medial zone incerta tohypothalamus & Amygdala.
  13. 13. 5) Incertohypothalamic Pathway: From medial zone incerta tohypothalamus & Amygdala. Sexual drive, Microvasculatory functionand temperature regulation. 6) Many local Dopaminergic Neurons inolfactory cortex & retina: 7) Dopaminergic transmission inperiphery:
  14. 14. Classification of AntipsychoticDrugsA: Classical / Typical Antipsychotics.I. Phenothiazine Derivatives a. Aliphatic compoundsChlorpromazinePromazine. b. Piperazine Compounds:ProcholorperazinePerphenazine Fluphenazine Trifluperazine c. Piperidine Compounds:Thioridazine Mesoridazine
  15. 15. A) Classical Typical Nemoleptics: 1. Phenothiazines:a) Aliphatic Comp (less potent,sedation & weight gain) Chloropromazine (Largactil) Promazine Triflupromazine
  16. 16. b) Piperidine Derivative: Thioridazine (Melleril, less potent, Anti-Cholinergic) Mesoridazine (metabolite of thioridazine)
  17. 17. c) Piperazine Derivative: Fluphenazine (I/V preparation, slowly, release, Perphenazine Trifluperazine Prochlorperazine Thioperazine.
  18. 18. 2. Thioxanthines: (also available asDEPOT preparation) Thiothixene Clopenthixol Flupenthixol Chlorprothixine
  19. 19. 3. Butyrophenones: Haloperiodol Properidol Benperidol
  20. 20. B) Atypical Neuroleptics:Their mechanism of action is differentfrom anti-psychotics Loxapine Clozapoine (Clozanl) ___ A/E: Causeagranulocyctosis ___ Bone marrowdepression
  21. 21. Risperidone ____ commonly used D2 5HT2 selectiveactivity for D4 receptors Olanzapine __ Disadv: cause agranulocytosis Ziprasidone(patients resistant to other drugs. Also Rx of negativeeffects) Sulpirdie (D2 selective) Remazopride Remoxipride Pimozide (D2 selective) long acting indole Quetiapine Aripiprazole
  22. 22. II. Butyrophenone Derivatives Haloperidol DroperidolIII. Thioxanthenes Thiothixene FlupenthixolIV.Rauwolfia Alkalois Reserpine
  23. 23. B. Newer / Atvpical Antipsychotics Miscellaneous Structures. ClopazineOlanzapine Quetiapine Pimazole Pimazole Sulpiride RisperidoneC: Drugs used for Manic-Depressive Disorders: Lithium carbonate
  24. 24. Phenothiazines Chemistry & Structure Pharmacokinetics
  25. 25. MOAAct on a variety of CNS & Peripheral receptors Post synaptic D2 receptor blockade 5 HT2 receptor blockade Muscarinic receptor blockade Ganglion blockade Quinidine like effects Alpha-1 adrenergic blockade Local anaesthetic like activity
  26. 26. MOA of Antipsychotic effect:-Acts by blocking Post Synaptic D2 receptors in Dopaminergic pathways in CNS.Three important Dopaminergic pathways Mesolimbic mesocortical pathway Nigrosticatad pathway Tuboinfundibuar pathwayAdditional Pathways Medullary periventricular pathway Incertohypothalamic pathway
  27. 27. Dopamine Receptors
  28. 28. Ph. Actions a) PTS: No loss of intellectual functions andperformance (clear sensorium) Alteration of deranged thought process Emotional quietening Psychomotor slowing Antagonism of behavior eff. of amphetamine Decreased paranoid idea Decrease initiative Decrease aggressiveness
  29. 29. b) NORMAL (NON -PSYCHOTICS)unpleasant feelings due to Sleepiness, restleseness Autonomic effects : b/c of muscarinicblockade unpleasant feelings due to Sleepiness, restleseness Autonomic effects : b/c of muscarinicblockade
  30. 30. 2. Effect on motor activitya. Decreased spontaneous activityb.Extra Pyramidal symptoms Parkinsonism Acute dystonias Neuroleptic malignant syndrome Akathisia Tardive Dyskinesia Perioral tremor (Rabbit syndrome)
  31. 31. ) DECREASE SEIZURE THRESHOLD: Convulsive potential High dose: cause convulsion causeseizure in patients of epilepsy Aggrevate epilepsy If anti-epilepsy is taken by epilepsy potent,he has to increase the dose Potentiate cause of seizure latent epilepsypatient
  32. 32. 6. Effect on CTZ7. Endocrinal Effects8. Hypothermia/ Hyperthermia
  33. 33. a) ANTICHOLINERGIC b) ADRENOCEPTORS BLOCKADE Orthostatic hypotension Less less with halo oeriod of flupenthixoland eluphenazine and other nonphenothiazines except clozapine c) WEAK GANGLIONIC BLOCKADE: Both symp and P/symp ganglionicblockade . Non blockade cz transmission
  34. 34. B: PERIPHERAL EFFECTS1. Effect on ANS 2. Effect on CVS 3. Quinidine like anti-arrhythmic effect on heart 4. Miscellaneous LA effect Renal effects Effect on Liver Antihistaminic action Skeletal muscle relaxant effect
  35. 35. v) RESP. CONTROL: Depressant effect No permanent effect in N individual No prominent effect in psychotic pt havingN respiration But if he suffers from resp. diseases suchas Asthama them resp. depression
  36. 36. vi) ENDOCRINE EFFECT: hyper prolactinemia and inflextility DA,control prolactin (check its release),if blockhyper prolactinemia manifested byGynecomastia in infertility in male andfemale ix) ANTIEMETIC ACTION: Because of DA recep blockade in CRTZ.Useful in drug induced vomiting and othervomiting except motion sickness and
  37. 37. x) TEMP. REGULATION: Dopaminergic transmission tohypothalamus is blocked. Temperatureregulation is lost person becausepoikelothermic
  38. 38. xiii) SK.MUSCLES: in high doses themselves causeconvulsion and spasm 2) CVS -ve isotropic effects more thioridazinecause death in young children Decrease stroke volume and decreaseCO Decrease TPR and alpha adrenergic
  39. 39. Adverse effects1. Neurological side effectsParkinsonismAcute dystoniasNeuroleptic malignant syndromeAkathisiaTardive DyskinesiaPerioral tremor (Rabbit syndrome)2. ANS effects3. ECG Changes4. Tolerance & Physical Dependence5. Reverse Tolerance or super sensitivity.4. Cholestatic Jaundice
  40. 40. 5. Endocrinal effects6. Hypothermia / Hyperthermia7. Dermatitis8. Opacities in lens and cornea9. Blood Dyscrasias10. Drug Interactions
  41. 41. Therapeutic UsesA. Treatment of Psychiatric patient1. Schizophrenia2. Organic Psychosis3. Bipolar depressionB. Nausea & vomitingC. Alcoholic hallucinitionD. Intractable Hiccough
  42. 42. NEUROLEPTIC POISONING: Can be homicidal less common suicidalless chances occure in extreme ofdisease. Rarely fatal except thio & mesoridazineduer jto cacdio depressive neuromusculal, excitability. Convulsions. Pt. comatosed. Hypothermia, miosis, deep Tendon reflexes. Tachycacdia Thioridazine.
  43. 43. *Monitos vcital fxns. * Gastric lavage with activated charcoal *Saline catharsis (Na2SO4Mgo) * Fluid replacement * Pressor agents. Diaqzepam for seizerres I/V.
  44. 44. PIPERIDINE DERIVATIVE: THIORIDAZINE: Block D2,x-1 & 5HT-2 More potent anti muscacinics Extrapyramidal (packinsonian) symptomsduer jto blockade of D2 and balance isdisturbed, in this case balance is notrdistubedf when cholinergicx activity es. Sinilac B.A (2s-30%) More cacdiotoxic
  45. 45. More macked occulax eff. Deposit in retina browning of vision. Picture res emble that of retinitispigmentosa pt. Potencyrelated to dose.
  46. 46. Newer/ Atypical anti-psychotics