1. Dr. RAGHU PRASADA M S
MBBS,MD
ASSISTANT PROFESSOR
DEPT. OF PHARMACOLOGY
SSIMS & RC.
1

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.  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.  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.  The nigrostriatal pathway (coordination of voluntary
movement
 Mesolimbic- mesocortical ( behavior )
 Tuberoinfundibular- pituitary system (endocrine)
 The medulla oblongata (vomit)
 Medullary - periventricular pathway ( eating
behavior)

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.  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.

9. 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

10. Typical Antipsychotics
Phenothiazines –
Aliphatic tertiary amine side chain:Chlorpromazine,
Piperazine moiety: Perphenazine, Fluphenazine,
Piperidine moiety: Thioridazine
Thioxanthenes -Flupenthixol, Thiothixene
Butyrophenones -Haloperidol, Droperidol,
Benperidol, Domperidone

11.  Miscellaneous –Pimozide, Pepenfluridol, Molindone,
Loxapine, Sulpride,
 Atypical Antipsychotics - Clozapine, Quitiapine,
Risperidone, Sulpiride, Olanzapine

12. 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

13. 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.

14.  Chlorprothixene: mild antipsychotic action,
and antianxiety and antidepressant action.

15. 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.

16. [Drug dose]
Phenothiazine
Thioxanthene
Butyrophenone

17.  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

18.  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

20.  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.

21.  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

23. 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.

24. 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)

25. 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