Antipsychotics

Psychosis and Anti-psychotic Drugs

1. Chetan Rastogi
M.Pharm 1
st
Year Pharmacology
1

2. Psychosis
Psychosis refers to a variety of mental disorders
characterized by one or more of the following
symptoms:
diminished and distorted capacity to process
information and draw logical conclusions.
 hallucinations, delusions, marked loosening of
associations.
disorganized behavior, and aggression or violence.
2

3. Psychosis:
Psychosis can be broadly
Categorized in to 2 groups:
1 ORGANIC
2 FUNCTIONAL
Psychosis
3

4. 1.Acute and chronic organic brain syndromes (cognitive
disorders) such as, Delirium and dementia, prominent features
of confusion, disorientation, defective memory and disorganized
behavior.
2.Functional disorders such as, memory and orientation mostly
retained by emotion, thought, reasoning and behavior are
altered.
3.Schizophrenia (split mind) i.e. splitting of perception and
interpretation from reality- hallucination, inability to think
coherently. Schizophrenia is often described in terms of positive
or negative (deficit) symptoms..
4.Paranoid state i.e. fixed delusions (false beliefs) and loss of
insight in to abnormality.
4

5. Schizophrenia
It is a thought disorder.
The disorder is characterized by a divorcement
from reality in the mind of the person (psychosis).
It may involved visual and auditory hallucinations,
delusions, intense suspicion, feelings of
persecution or control by external forces
(paranoia), depersonalization, and there is
attachment of excessive personal significance to
daily events, called “ideas of reference”.
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6. Schizophrenia
Positive Symptoms
Hallucinations, delusions, paranoia, ideas of reference.
Negative Symptoms
Apathy, social withdrawal, anhedonia, emotional blunting,
Poor speech –Cognitive impairment Poor speech –Cognitive impairment , extreme
inattentiveness or lack of motivation to interact with the
environment.
These symptoms are progressive and non-responsive to medication.
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7. Psychosis Producing Drugs
1)Levodopa
2)CNS stimulants
a)Cocaine
b)Amphetamines
c)Khat, cathinone, methcathinone
3)Apomorphine
4)Phencyclidine

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8. Dopamine Theory of Schizophrenia
Dopamine Correlates:
•Antipsychotics reduce dopamine synaptic activity.
•These drugs produce Parkinson-like symptoms.
•Drugs that increase DA in the limbic system cause
psychosis.
•Drugs that reduce DA in the limbic system
(postsynaptic D2 antagonists) reduce psychosis.
•Increased DA receptor density (Post-mortem, PET).
•Changes in amount of homovanillic acid (HVA), a DA
metabolite, in plasma, urine, and CSF.
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9. Dopamine Theory of Schizophrenia
Evidence against the hypothesis
Antipsychotics are only partially effective in most
(70%) and ineffective for some patients.
Phencyclidine, an NMDA receptor antagonist,
produces more schizophrenia-like symptoms in
non-schizophrenic subjects than DA agonists.
Atypical antipsychotics have low affinity for D2
receptors.
Focus is broader now and research is geared to
produce drugs with less extrapyramidal effects.
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10. Dopamine System
There are four major pathways for the
dopaminergic system in the brain:
I.The Nigro-Stiatal Pathway.
II.The Mesolimbic Pathway.
III.The Mesocortical Pathway.
IV.The Tuberoinfundibular Pathway.
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11. 11

12. Catecholamines
Tyrosine
ß Tyrosine hydroxylase
L-Dopa
ß Dopa decarboxylase
Dopamine (DA)
ß Dopamine b hydroxylase
Norepinephrine (NE)
(Noradrenaline)Phenylethanolamine-
ß -N-methyltransferase
Epinephrine (EPI)
(Adrenaline)
12

13. Dopamine Synapse
DA
L-DOPA
Tyrosine

14. Dopamine System
DOPAMINE RECEPTORS
There are at least five subtypes of receptors:
Receptor
D1
D2
D3
D4
D5
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15. 15

16. Dopamine System
DOPAMINE RECEPTORS
Receptor 2o Messenger System
D1 ÝcAMP
D2 ßcAMP,ÝK+ ch.,ßCa2+ch.
D3 ßcAMP,ÝK+ ch.,ÝCa2+ch.
D4 ßcAMP
D5 ÝcAMP
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17. Dopamine Reuptake
System
17

18. ANTIPSYCHOTICS
Antipsychotic drugs are also
known as Neuroleptics, Ataractic,
Major Tranquilizer and Anti-
Schizophrenic drugs. A first
generation of antipsychotics,
known as Typical antipsychotics,
was discovered in the 1950s. Most
of the drugs in the second
generation, known as Atypical antipsychotics,
have been developed more recently.
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19. CLASSIFICATION
A.Typical Antipsychotics: (traditional/older)traditional/older)
1. Phenothiazines:
a. Aliphatic side chain: Chlorpromazine, Triflupromazine
b. Piperidine side chain: Thioridazine
c. Piperazine side chain: Trifluoperazine, perphenazine
Fluphenazine

2. Butyrophenones: Haloperidol, Trifluperidol, Penfluridol,
droperidol, domperidone

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20. 3. Thioxanthenes: Flupenthixol

4. Other heterocyclics: Pimozide, Loxapine, molindone,
sulpiride, amisulpiride, penfluridol, Remoxipride,
metoclopramide

B. Atypical/newer antipsychotics: Clozapine, Risperidone,
Olanzapine, Quetiapine, Aripiprazole, Ziprasidone,
paloparidone
20

21. Low potencyLow potencyHigh potencyHigh potency NEWERNEWER
ChlorpromazinChlorpromazin
ee
ThioridazineThioridazine
ThiothixeneThiothixene
Extrapyramidal Extrapyramidal
symptoms symptoms
LESSLESS
Anti-ch MOREAnti-ch MORE
Haloperidol, Haloperidol,
Fluphenazine,TriflFluphenazine,Trifl
uoperazine,Perphuoperazine,Perph
ennazine, ennazine,
PimozidePimozide
Extrapyramidal-Extrapyramidal-
MORE,MORE,
AntiCh LESSAntiCh LESS
ClozapineClozapine
OlanzapineOlanzapine
QuetiapineQuetiapine
AripiprazoleAripiprazole
RisperidoneRisperidone
ZiprasidoneZiprasidone
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22. Traditional Vs. AtypicalTraditional Vs. Atypical
ßß ßß
Mainly DAMainly DA
Mainly D2Mainly D2
Treat mostly POSITIVE Treat mostly POSITIVE
symptomssymptoms
More adverse effectsMore adverse effects
Less useful in refractory Less useful in refractory
diseasedisease
DA and 5HTDA and 5HT
D2+D4+5HTD2+D4+5HT
Treat POSITIVE and Treat POSITIVE and
NEGATIVENEGATIVE symptoms symptoms
Lesser adverse effectsLesser adverse effects
Useful in refractory Useful in refractory
diseasedisease
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23. Mechanism of Action:
-Antipsychotic blocks D₂
receptors in the brain's
Dopaminergic pathway.
-Some also block or partially
block serotonin receptors
(particularly 5HT
2A, C
and
5HT
1A
receptors)

-But antipsychotic drugs can also
block wide range of receptor
targets.
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24. In the Mesolimbic- Mesocortical and Nigrostriatal
pathway Antipsychotic blocks:
25

25. In the Tuberoinfundibular pathway
Antipsychotics block:
Dopamine released at
this site regulates the
secretion of prolactin
from anterior
the pituitary gland.
Antipsychotics blocks
D receptor at this site.
₂
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26. Antipsychotic blocks D receptors
₂
Some also block or partially block
serotonin receptors
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27. Pharmacology of Antipsychotics:
Typical Antipsychotics
PhenothiazineAbsorptionConcentrationMetabolism Vd Dose
Chlorpromazine
(CPZ)
More
consistent
effect in IV and
IM
administration
Highly bound to
plasma and tissue
protein
Metabolized in
liver by
CYP2D6
enzyme
Large
20
L/kg
Acute single
dose lasts 6-8
hours t ₂ is
⅟
18-30 hrs
TriflupromazineMore potent
than CPZ
-- -- --
Thioridazine Low potency
with
anticholinergic
action
-- -- --
Trifluoperazine,
Fluphenazine
High potency
with
Autonomic
action
-- -- --Depot IM inj
every 2-4
weeks (25
mg/ml )
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28. Butyrophenones Potency t ₂
⅟
Dose
Haloperidol Potent antipsychotic
Produces few
autonomic effects
24 hours. --
Trifluperidol Similar to
Haloperidol but
slightly more potent
-- --
Penfluridol Exceptional long
acting neuroleptic,
used for chronic
Schizophrenia,
affective withdrawl
and social mal-
adjustment
-- 20-60 mg , once
weekly
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29. Thioxanthenes
Flupenthixol Less sedative than CPZ, indicated for
Schizophrenia and other Psychoses.
Other heterocyclics t ₂
⅟
Pimozide Specific DA antagonist with little
adrenergic or cholinergic blocking
activity. Used in Gilles de la Tourett’s
syndrome and ticks.
Long Duration of action.
48-60 hrs. (after
single dose)
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30. Atypical Antisychotic drugs
These are newer 2
nd
Generation antipsychotics
that have weak D₂ receptor
blocking but potent 5-HT₂
antagonistic activity. They
May improve the impaired
Cognitive function in
psychotics.
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31. Atypical Blocking activityMetabolism
(Enzyme)
t ₂ and
⅟
Dose
Clozapine A very potent
antipsychotic
D₂, D₄, 5HT₂, α receptorsBy CYP3A4 t ₂ - 12
⅟
hours
Risperidone -- Combination of D₂+5HT₂ ,
High affinity for α₁, α₂ and
H₁ receptors
-- Dose - Low
dose <6
mg/day
OlanzapinePotent antipsychotic
Broader spectrum of
efficacy
Monoaminergic (D₂, 5HT₂,
α₁, α₂) as well as muscarinic
and H₁ receptors
By CYP1A2 and
Glucuronyl
transferase
t ₂ -
⅟
24-30 hours
QuetiapineNew short- acting
antipsychotic
5HT₁А, 5HT₂, D₂, α₁, α₂ and
H₁ receptor
By CYP3A4 --
AripiprazoleUnique antipsychotic
which is partial
agonist at D₂ and
5HT₁А
5HT₂ By CYP2D6 and
CYP3A4
t ₂ - 3days
⅟
ZiprasidoneLatest antipsychotic ,
moderately potent
inhibitor.
Combination D₂+5HT₂A/₂C
+H₁ + α₁,
Na reuptake
-- t ₂ - 8
⅟
hours
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32. ADVERSE EFFECTS OF TYPICAL
NEUROLEPTICS
Anticholinergic (antimuscarinic) side effects:
Dry mouth, blurred vision, tachycardia,
constipation, urinary retention, impotence
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33. ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS
Antiadrenergic (Alpha-1) side effects:
Orthostatic hypotension w/ reflex
tachycardia
sedation
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34. ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS
Antihistamine effect: sedation, weight gain
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35. KEY CONCEPT: DOPAMINE-2
RECEPTOR BLOCKADE IN THE BASAL GANGLIA
RESULTS IN EXTRAPYRAMIDAL MOTOR SIDE EFFECTS
(EPS).
DYSTONIA
NEUROLEPTIC MALIGNANT SYNDROME
PARKINSONISM
TARDIVE DYSKINESIA
AKATHISIA
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36. ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS
(Continued)
Increased prolactin secretion (common with all;
from dopamine blockade)
Weight gain (common, antihistamine effect?)
Photosensitivity (v. common w/ phenothiazines)
Lowered seizure threshold (common with all)
Leucopenia , agranulocytosis (rare; w/
phenothiazines)
Retinal pigmentopathy (rare; w/ phenothiazines)
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37. ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS
(Continued)
Chlorpromazine and thioridazine produce marked
autonomic side effects and sedation; EPS tend to be weak
(thioridazine) or moderate (chlorpromazine).
Haloperidol, thiothixene and fluphenazine produce weak
autonomic and sedative effects, but EPS are marked.
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38. MANAGEMENT OF EPS
Dystonia and parkinsonism: anticholinergic
antiparkinson drugs
Neuroleptic malignant syndrome: muscle relaxants, DA
agonists, supportive
Akathisia: benzodiazepines, propranolol
Tardive dyskinesia: increase neuroleptic dose; switch to
clozapine
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