Dr. RAGHU PRASADA M S
MBBS,MD
ASSISTANT PROFESSOR
DEPT. OF PHARMACOLOGY
SSIMS & RC.
1
 The most important types of psychosis are:
 Schizophrenia
 Affective disorders (e.g. depression, mania)
 Organic psyc...
 PET studies
 Post-mortem studies
 Drugs increasing central dopamine activity- L-dopa,
amphetamines
 Excessive dopamin...
 LSD- 5HT2 agonist –
 Visual hallucinations
 5-HT has a modulatory effect on dopaminergic
neurones
Glutamate hypothesis...
 The nigrostriatal pathway (coordination of voluntary
movement
 Mesolimbic- mesocortical ( behavior )
 Tuberoinfundibul...
Positive Symptoms-mesolimbic.
 Hallucinations, delusions, paranoia, ideas of
reference.
Negative Symptoms-mesocortical
 ...
 DOPAMINE RECEPTORS
 There are at least 5 subtypes of receptors:
D1 and D5: mostly involved in postsynaptic
inhibition.
...
Presynaptic Effects
Blockade of D2 receptors

Compensatory Effects
 Firing rate and
activity of
nigrostriatal and
mesoli...
Typical Antipsychotics
Phenothiazines –
Aliphatic tertiary amine side chain:Chlorpromazine,
Piperazine moiety: Perphenazin...
 Miscellaneous –Pimozide, Pepenfluridol, Molindone,
Loxapine, Sulpride,
 Atypical Antipsychotics - Clozapine, Quitiapine...
Pharmacologic effects and mechanism:
 CNS: A. Neuroleptic Effect-Antipsychotic drugs probably
owe their therapeutic effec...
Pharmacologic effects:
(2) Autonomic Nervous System: block α-adrenergic
and M-Cholinergic receptors and result in
hypotens...
 Chlorprothixene: mild antipsychotic action,
and antianxiety and antidepressant action.
Haloperidol: control psychomotor excitement
potent antipsychotic, longer t1/2- 24hrs
lesser incidence of autonomic S/E tha...
[Drug dose]
Phenothiazine
Thioxanthene
Butyrophenone
 Unique receptor affinity
Clozapine: D4 = 1>5-HT2 = M>D2 = D1 = 2;H1, low
incidence of EPS, low sedation, no gynacomas...
 Sertindole –long plasma T1/2
 Asenapine –sub lingually
 Effective negetive > positive symptoms
 Effective in patients...
 Most antipsychotics are readily but incompletely
absorbed.
 Significant first-pass metabolism.
 Bioavailability is 25-...
 Treatment of psychotic disorders: schizophrenia,
 Schizo affective disorders -mania, paranoid states,
alcoholic halluci...
Behavioural Effects (pseudodepression, akinesia,
confusion)
Neurological Effects (Parkinsonism, Akathisia,
Dystonia, Tardi...
c) Autonomic Effects (orthostatic hypotension,
impaired ejaculation)
d) Metabolic and Endocrine Effects (weight
gain, hype...
f) Ocular complications (thioridazine only)
g) Cardiac toxicity (Thioridazine T wave
abnormality)
h) Neuroleptic Malignant...
Class antipsychotics
Class antipsychotics
Class antipsychotics
Class antipsychotics
Class antipsychotics
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Class antipsychotics

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Class antipsychotics

  1. 1. Dr. RAGHU PRASADA M S MBBS,MD ASSISTANT PROFESSOR DEPT. OF PHARMACOLOGY SSIMS & RC. 1
  2. 2.  The most important types of psychosis are:  Schizophrenia  Affective disorders (e.g. depression, mania)  Organic psychoses (mental disturbances caused by head injury, alcoholism, or other kinds of organic disease).
  3. 3.  PET studies  Post-mortem studies  Drugs increasing central dopamine activity- L-dopa, amphetamines  Excessive dopaminergic activity plays a role in the disorder.  The enhancement of function of 5-HT2  Pharmacologically, they are characterized as dopamine receptor antagonists, though many of them also act on other targets, particularly 5-HT receptors, which may contribute to their clinical efficacy.
  4. 4.  LSD- 5HT2 agonist –  Visual hallucinations  5-HT has a modulatory effect on dopaminergic neurones Glutamate hypothesis Phencyclidine, ketamine Glutamate-NMDA antagonists –can produce psychotic symptoms
  5. 5.  The nigrostriatal pathway (coordination of voluntary movement  Mesolimbic- mesocortical ( behavior )  Tuberoinfundibular- pituitary system (endocrine)  The medulla oblongata (vomit)  Medullary - periventricular pathway ( eating behavior)
  6. 6. Positive Symptoms-mesolimbic.  Hallucinations, delusions, paranoia, ideas of reference. Negative Symptoms-mesocortical  Apathy, social withdrawal, anhedonia, emotional blunting, cognitive deficits, extreme inattentiveness or lack of motivation to interact with the environment.  These symptoms are progressive and non-responsive to medication.
  7. 7.  DOPAMINE RECEPTORS  There are at least 5 subtypes of receptors: D1 and D5: mostly involved in postsynaptic inhibition.  D2, D3, and D4: involved in both pre-and postsynaptic inhibition. D2: the predominant subtype in the brain: regulates mood, emotional stability in the limbic system and movement control in the basal ganglia.
  8. 8. Presynaptic Effects Blockade of D2 receptors  Compensatory Effects  Firing rate and activity of nigrostriatal and mesolimbic DA neurons.  DA synthesis, DA metabolism, DA release. Postsynaptic Effects Depolarization Blockade Inactivation of nigrostriatal and mesolimbic DA neurons.  Receptor Supersensitivity Prolonged use-feedback inhibition of dopamine releasedecreased dopamine turnover
  9. 9. Typical Antipsychotics Phenothiazines – Aliphatic tertiary amine side chain:Chlorpromazine, Piperazine moiety: Perphenazine, Fluphenazine, Piperidine moiety: Thioridazine Thioxanthenes -Flupenthixol, Thiothixene Butyrophenones -Haloperidol, Droperidol, Benperidol, Domperidone
  10. 10.  Miscellaneous –Pimozide, Pepenfluridol, Molindone, Loxapine, Sulpride,  Atypical Antipsychotics - Clozapine, Quitiapine, Risperidone, Sulpiride, Olanzapine
  11. 11. Pharmacologic effects and mechanism:  CNS: A. Neuroleptic Effect-Antipsychotic drugs probably owe their therapeutic effects mainly to blockade of D2- receptors (lies in midbrain-cortex and midbrain-limbic system ) Mesolimbic,mesocortical D2  More effective for treating positive symptom B. Antiemetic Effect--- inhibit chemoreceptor trigger zone or directly depress the medullary vomiting center. C. Temperature-regulating Effect--- produce hypothermia
  12. 12. Pharmacologic effects: (2) Autonomic Nervous System: block α-adrenergic and M-Cholinergic receptors and result in hypotension, dry mouth, constipation and blurred vision. (3) Endocrine system: increase the release of prolactin and decrease corticotropin release and secretion of pituitary growth hormone.
  13. 13.  Chlorprothixene: mild antipsychotic action, and antianxiety and antidepressant action.
  14. 14. Haloperidol: control psychomotor excitement potent antipsychotic, longer t1/2- 24hrs lesser incidence of autonomic S/E than CPZ DOC- Gilles de la tourette’s syndrome, huntington’s chorea  Adverse effects: severe extrapyramidal symptoms.
  15. 15. [Drug dose] Phenothiazine Thioxanthene Butyrophenone
  16. 16.  Unique receptor affinity Clozapine: D4 = 1>5-HT2 = M>D2 = D1 = 2;H1, low incidence of EPS, low sedation, no gynacomastia Quetiapine: 5-HT2 = D2 = 1 = 2; H1 drowsiness and postural hypotension Risperidone: 5-HT2 >>1 >H1 >D2 >2>>D1  Aripiprazole-partial agonist at D2 and 5-HT1A  5HT2A agonist- called as DA:5HT stabiliser in CNS  Has long t1/2 of 3 days
  17. 17.  Sertindole –long plasma T1/2  Asenapine –sub lingually  Effective negetive > positive symptoms  Effective in patients refractory to typical neuroleptics  Less liability to cause EPS low affinity for D1 and D2 receptors  Antagonists at 1, m, H1, D2
  18. 18.  Most antipsychotics are readily 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 (>7 L/Kg).  Slow elimination.  Duration of action longer than expected, metabolites are present and relapse occurs, weeks after discontinuation of drug.
  19. 19.  Treatment of psychotic disorders: schizophrenia,  Schizo affective disorders -mania, paranoid states, alcoholic hallucinosis.  Drug induced psychosis  Anesthesia in hypothermia and artificial hibernation (used with pethidine and promethazine).  Nausea ,Vomiting-CPZ  Tourettes syndrome  Huntingtons disease  Preanaesthetic medication  Intractable hiccups -CPZ
  20. 20. Behavioural Effects (pseudodepression, akinesia, confusion) Neurological Effects (Parkinsonism, Akathisia, Dystonia, Tardive Dyskinesia)-  Tardive dyskinesia comprises mainly involuntary movements of face and tongue, but also of trunk and limbs, appearing after months or years of antipsychotic treatment. It may be associated with proliferation of dopamine receptors (possibly presynaptic) in corpus striatum.
  21. 21. c) Autonomic Effects (orthostatic hypotension, impaired ejaculation) d) Metabolic and Endocrine Effects (weight gain, hyperprolactinemia, loss of libedo, impotence) e) Toxic or allergic effects (agranulocytosis, choleostatic jaundice- clozapine)
  22. 22. f) Ocular complications (thioridazine only) g) Cardiac toxicity (Thioridazine T wave abnormality) h) Neuroleptic Malignant Syndrome (life threatening, marked muscle rigidity, sweating, fever, autonomic instability, blood pressure, heart rate, muscle breakdown, CV collapse, arrhythmias mortality
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