Dr. RAGHU PRASADA M S
DEPT. OF PHARMACOLOGY
SSIMS & RC.
The most important types of psychosis are:
Affective disorders (e.g. depression, mania)
Organic psychoses (mental disturbances caused by
head injury, alcoholism, or other kinds of organic
Drugs increasing central dopamine activity- L-dopa,
Excessive dopaminergic activity plays a role in the
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.
LSD- 5HT2 agonist –
5-HT has a modulatory effect on dopaminergic
Glutamate-NMDA antagonists –can produce psychotic
The nigrostriatal pathway (coordination of voluntary
Mesolimbic- mesocortical ( behavior )
Tuberoinfundibular- pituitary system (endocrine)
The medulla oblongata (vomit)
Medullary - periventricular pathway ( eating
Hallucinations, delusions, paranoia, ideas of
Apathy, social withdrawal, anhedonia, emotional
blunting, cognitive deficits, extreme inattentiveness
or lack of motivation to interact with the
These symptoms are progressive and non-responsive
There are at least 5 subtypes of receptors:
D1 and D5: mostly involved in postsynaptic
D2, D3, and D4: involved in both pre-and
D2: the predominant subtype in the brain:
regulates mood, emotional stability in the limbic
system and movement control in the basal ganglia.
Blockade of D2 receptors
Firing rate and
DA synthesis, DA
Inactivation of nigrostriatal
and mesolimbic DA
inhibition of dopamine
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
(2) Autonomic Nervous System: block α-adrenergic
and M-Cholinergic receptors and result in
hypotension, dry mouth, constipation and blurred
(3) Endocrine system: increase the release of
prolactin and decrease corticotropin release and
secretion of pituitary growth hormone.
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 than CPZ
DOC- Gilles de la tourette’s syndrome, huntington’s
Adverse effects: severe extrapyramidal symptoms.
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
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
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
Antagonists at 1, m, H1, D2
Most antipsychotics are readily but incompletely
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).
Duration of action longer than expected, metabolites
are present and relapse occurs, weeks after
discontinuation of drug.
Treatment of psychotic disorders: schizophrenia,
Schizo affective disorders -mania, paranoid states,
Drug induced psychosis
Anesthesia in hypothermia and artificial hibernation
(used with pethidine and promethazine).
Intractable hiccups -CPZ
Behavioural Effects (pseudodepression, akinesia,
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.
c) Autonomic Effects (orthostatic hypotension,
d) Metabolic and Endocrine Effects (weight
gain, hyperprolactinemia, loss of libedo,
e) Toxic or allergic effects (agranulocytosis,
choleostatic jaundice- clozapine)