Psychosis and Anti-psychotic Drugs

1. Chetan Rastogi
M.Pharm 1st 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:
Psychosis can be broadly
Categorized in to 2 groups:
1 ORGANIC
2 FUNCTIONAL
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”.
5

6. Schizophrenia
Positive Symptoms
Hallucinations, delusions, paranoia, ideas of reference.
Negative Symptoms
Apathy, social withdrawal, anhedonia, emotional blunting,
Poor speech –Cognitive impairment , extreme
inattentiveness or lack of motivation to interact with the
environment.
These symptoms are progressive and non-responsive to medication .
6

7. Psychosis Producing Drugs
1)
Levodopa
2)
CNS stimulants
a)
Cocaine
b)
Amphetamines
c)
Khat, cathinone, methcathinone
3)
Apomorphine
4)
Phencyclidine
7

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.
8

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.
9

10. Dopamine System
There are four major pathways for the
dopaminergic system in the brain:
The Nigro-Stiatal Pathway.
II. The Mesolimbic Pathway.
III. The Mesocortical Pathway.
IV. The Tuberoinfundibular Pathway.
I.
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11. 11

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

13. Tyrosine
L-DOPA
DA
Dopamine Synapse

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
D1
D2
D3
D4
D5
2o Messenger System
⇑cAMP
⇓cAMP,⇑K+ ch.,⇓Ca2+ch.
⇓cAMP,⇑K+ ch.,⇑Ca2+ch.
⇓cAMP
⇑cAMP
16

17. Dopamine Reuptake
System
17

18. ANTIPSYCHOTICS
Antipsychotic drugs are also
known as Neuroleptics, Ataractic,
Major Tranquilizer and AntiSchizophrenic 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.
18

19. CLASSIFICATION
A. Typical Antipsychotics: (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
19

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 potency
Chlorpromazin
e
Thioridazine
Thiothixene
High potency
Haloperidol,
Fluphenazine,Trifl
uoperazine,Perph
ennazine,
Pimozide
Extrapyramidal
Extrapyramidalsymptoms
MORE,
LESS
AntiCh LESS
NEWER
Clozapine
Olanzapine
Quetiapine
Aripiprazole
Risperidone
Ziprasidone
21

22. Traditional
⇓
Vs. Atypical
⇓
Mainly DA
DA and 5HT
Mainly D2
D2+D4+5HT
Treat mostly POSITIVE
Treat POSITIVE and
symptoms
More adverse effects
Less useful in refractory
disease
NEGATIVE symptoms
Lesser adverse effects
Useful in refractory
disease
22

23. Mechanism of Action:
-Antipsychotic blocks D₂
receptors in the brain's
Dopaminergic pathway.
-Some also block or partially
block serotonin receptors
(particularly 5HT2A, C and
5HT1A 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
D₂ receptor at this site.
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26. Antipsychotic blocks D₂ receptors
Some also block or partially block
serotonin receptors
27

27. Pharmacology of Antipsychotics:
Typical Antipsychotics
Phenothiazine
Absorption
Concentration
Metabolism
Vd
Dose
Chlorpromazine
(CPZ)
More
Highly bound to
consistent
plasma and tissue
effect in IV and protein
IM
administration
Metabolized in
liver by
CYP2D6
enzyme
Large
20
L/kg
Acute single
dose lasts 6-8
hours t⅟₂ is
18-30 hrs
Triflupromazine
More 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
t⅟ ₂
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 maladjustment
--
Dose
--
--
20-60 mg , once
weekly
29

29. Thioxanthenes
Flupenthixol
Less sedative than CPZ, indicated for
Schizophrenia and other Psychoses.
t⅟ ₂
Other heterocyclics
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)
30

30. Atypical Antisychotic drugs
These are newer 2nd
Generation antipsychotics
that have weak D₂ receptor
blocking but potent 5-HT₂
antagonistic activity. They
May improve the impaired
Cognitive function in
psychotics.
31

31. Atypical
Clozapine
Blocking activity
A very potent
antipsychotic
D₂, D₄, 5HT₂, α receptors
Combination of D₂+5HT₂ ,
High affinity for α₁, α₂ and
H₁ receptors
Metabolism
(Enzyme)
By CYP3A4
Risperidone
--
Olanzapine
Potent antipsychotic
Broader spectrum of
efficacy
Monoaminergic (D₂, 5HT₂,
α₁, α₂) as well as muscarinic
and H₁ receptors
By CYP1A2 and
Glucuronyl
transferase
Quetiapine
New short- acting
antipsychotic
5HT₁А, 5HT₂, D₂, α₁, α₂ and
H₁ receptor
By CYP3A4
Aripiprazole
Unique antipsychotic
which is partial
agonist at D₂ and
5HT₁А
5HT₂
Ziprasidone
Latest antipsychotic ,
moderately potent
inhibitor.
Combination D₂+5HT₂A/₂C
+H₁ + α₁,
Na reuptake
--
By CYP2D6 and
CYP3A4
--
t⅟ ₂ and
Dose
t⅟₂ - 12
hours
Dose - Low
dose <6
mg/day
t⅟₂ 24-30 hours
--
t⅟₂ - 3days
t⅟₂ - 8
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
35

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
36

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.
38

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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