1. Dr. D. K. Brahma
Department of Pharmacology
NEIGRIHMS, Shillong

2. •
•
Drugs having primary effects on Psyche (mind) and – osis
(diseased or abnormal condition) – overall the mental
process and used for treatment of Psychiatric disorders
History of psychopharmacology:
–
–
–
–
–
•
•
Treatment – to “Dope”
1952 – Chlorpromazine (Reserpine - research)
TCA and MAOI – 1957
Benzodiazepines – 1960
1980 onwards – novel drugs
The disease - often imprecise, overlap and depends on
predominant symptoms – to decide drug therapy types
Types of disorders: DSM IV and ICD 10
Psychoses (Disorder of thought, behaviour and to comprehend
reality)
2. Affective disorders (Disorder of Mood)
3. Neuroses (less serious) – no loss of comprehending of reality
1.

3. •
•
Defn.: These are serious Psychiatric illness with
serious distortion of thought, behaviour, capacity to
recognize reality and of perception (delusion and
hallucinations) - Misperception and misevaluation
(Loss of contact with reality - loss of ability to
comprehend reality)
Classification:
1.
2.
Acute and chronic Brain syndromes (cognitive):
Delirium and Dementia. Toxic or pathological basis is
present - Brain tumor, Drugs etc. Confusion,
disorientation and defective memory and
disorganized behaviors.
Functional disorders: No underlying cause


Schizophrenia (split mind): splitting of perceptions and
interpretations from reality – inability to think coherently
and auditory hallucinations
Paranoid states: Paranoid individuals constantly suspect
(persecutory) the motives of those around them, and
believe that certain individuals, or people in general, are
"out to get them."

4. –
–
–
Delusion: These are fixed, false beliefs that are
outside patient`s culture firmly held. Types –
grandeur/persecutory etc.
Hallucinations: Abnormal sensations. It is a
sensory perception without a source in the
external world. May be visual, auditory,
olfactory and tactile etc.
Illusion: It is a mistaken or false interpretation
of a real sensory experience

5. False Belief
Delusion of Persecution

6. Pic. 1
Pic. 2

7. Little Voice Inside My
Brain.

8. The real shadow of
the hallucinating
person transforms
into the corporal
image.

9. 
Disorders of Mood
 Mania:
elation or irritable mood, reduced sleep,
hyperactivity, uncontrollable thought and
speech. Associated with violent behaviour
 Depression: sadness, loss of interest and
pleasure, worthlessness, guilt, physical and
mental slowing, self-destructive ideation


Bipolar
Unipolar

10. 
Less severe and ability to comprehend reality is not
lost: (mild disorder - anxiety, depression, or
hypochondria)
Anxiety – unpleasant emotional state - concern for
future
2.
Phobic states – fear of specific
persons/objects/situations
3.
Obsessive-compulsive – limited abnormality of
thoughts and behaviour, but recurrent intrusive
thoughts or ritual like behaviour
4.
Reactive depression – physical illness/loss
5.
Post-traumatic stress disorder – war, riots,
earthquakes and tsunami
6.
Hysterical
(Neurotransmitters of mental Illness: Dopaminergic and NA
and 5-HT)
1.

11. 1.
Phenothiazines (S(C6H4)2NH.) :



1.
Butyrophenones:

1.
2.
3.
Aliphatic side chains: Chlorpromazine (CPZ),
Triflupromazine
Piperidine side chain: Thioridazine and
Mesoridazine
Piperazine side chain: Trifluoperazine, Fluphenazine
and Perphenazine
Haloperidol, Trifluperidol
Thioxanthenes: Flupenthixol
Other heterocyclics: Pimozide, Loxapine,
Clozapine
Atypical antipsychotics: Risperidone,
Olanzapine, Quetiapine, Aripiprazole and
Ziprasidone

chondrium

12. • Tricyclic structure – 2 Benzene rings are linked by a sulfur and a nitrogen
atom
• Nature of substitute at position 10 influences pharmacological activity
• Divided into 3 groups on the basis of substitution at position 10

13. 


Effect of CPZ and Reserpine on laboratory
animals and psychiatric patients
Differ in Normal and psychotic individuals
In Normal: (Neuroleptic syndrome)
 Effects
are appreciated as neutral or unpleasant
(different from typical Barbiturate action)
 Indifference to surroundings, paucity of thoughts,
psychomotor slowing, emotional quietening, and
tendency to go off to sleep (easily aroused)
 Minimized spontaneous movements, but no ataxia or
slurring of speech

14. 
In psychotics:
 Typical
Psychotic patients – less agitated, more
communicative and responsive
 Aggressive and impulsive behaviour diminishes
 Over a period of days – hallucinations/delusions
and others come to normal
 Neuroleptics
– emotional quietening with
neurological effects – tremor, rigidity,
bradykinesia etc.
 Ataxia and dysarthria do not develope in
normal doses
 Tranquilizers
– major and minor (!)

15. 
All phenothiazines, Butyrophenones and Thioxanthenes have
same antipsychotic efficacy – but potency differs in equieffective
doses

1.
Antipsychotic effects: Low potency – more sedation





1.
2.
3.
4.
Low potency (Aliphatic and piperidines) and high potency (others)
Prompt sedative action (tolerance develops)
Antipsychotic effects take weeks to develop, but no tolerance
Valuable in early treatment - added value in agitated psychotic
patients
But, not used as anxiolytic or sedative
Performance and intelligence are unaffected relatively, but impaired
vigilance – high potency drugs
Extrapyramidal effects: More with high potency drugs (less in
thioridazone and atypical ones)
Lowers seizure threshold – low potency drugs (piperazines - lower
propensity)
Loss of temperature control: High doses – Poikilothermic, medullary
and other vital centres
Antiemetic action – all except thioridazine

16. Drugs
Sedative
Extrapyramidal
Hypotensive
Aliphatic
side chain
+++
++
+++
Piperidine
+++
+
+++
Piperazine
+
+++
+
Haloperidol
+
+++
+
• Low Potency: Fewer EPS H1, α1, and muscarinic
• High Potency: Higher EPS but lower H1, α1, and muscarinic

17. 
Behavioural Effects:
 Conditioned
avoidance response inhibited
(Remember, what is it ??)

18. 
Dopamine Hypothesis: Dopamine theory of
schizophrenia





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Over activity of DA in limbic area
Drugs which increase dopaminergic activity (amphetamines,
levodopa and bromocriptine etc.) – induce or exacerbate
schizophrenia
Density of Dopamine receptors in post mortem of untreated
– increased
PET in treated and untreated – untreated increased
Homovanillic acid (HMV) – changed in treated patients in
CSF and urine
Most antipsychotics block postsynaptic D2 receptors in CNS
except clozapine like atypical ones





Site of action being limbic system and mesocortical areas
But, initial rise in firing of DA neurones and DA activity increases
initially
Followed by tolerance to increased activity of DA in Basal ganglia –
Parkinson like effect
But, no such effect in limbic area - continued blockade
Hypothesis - Not complete, several atypical ones do
not interact with D2 – other receptors - serotonin

19. 
ANS: α-blocking activity
 CPZ
= Tflprmzn > thioridazine > clozapine >
fluphenazine > haloperidol
 More potent compounds – lesser alpha-blocking
property - weak anticholinergic property
 Additionally, Phenothiazines - Weak H1 and anti5HT property
α-blocking, anticholinergic, weak H1 and anti-5HT

Local anaesthetic action

Skeletal muscle – no prominent action, spinal
reflexes are not affected
 Reduce
action)
certain types of spasticity (Basal ganglia

20. Drugs
CPZ
Receptors blocked
α1, D2 and H1
Haloperidol, Fluphenazine D2 only
and Thioxanthenes
Promethazine
D2 and H1
Clozapine, Risperidone
Serotonin

21. 
CVS: Postural hypotension –
 By central and peripheral action
 Almost equal to α-blocking drugs
 Less prominent in psychotics

Endocrine: Increase in release of prolactin –
galactorrhoea and Gynaecomastia
 Reduction in gonadotropin secretion
 ACTH release in response to stress decreased
 GH release reduced
 Decreased ADH release

22. 
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Absorbed orally, but unpredictable and parenterally better
Bioavailability low – enterohepatic circulation
Long biological half life
Bound to plasma protein and tisue protein - Large Vd – 20
L/kg (higher CNS entry than plasma)
Metabolized by liver by hydroxylation
Cumulation action – once a day dose maintenance
Excreted in urine and Bile (6 to 12 months)
Available as tablets 10, 25, 50 and 100 mg tabs, Syr. and
injections

23. 1.
CNS:




1.
1.
Drowsiness, lethargy and mental confusion
Increased appetite and weight gain
Aggravation of seizures
Postural hypotension, palpitation, inhibition of
ejaculation – more with thioridazine and low
potency drugs
CVS:
Anticholinergic:


1.
Dry mouth, constipation, blurring of vision and
urinary hesitancy - more common with thioridazone
Hypersalivation - clozapine
Endocrine: Hyperprolactinemia. Lowers Gn
hormones but infertility, amenorrhea and
gynaecomastia is uncommon

24. 5. Extrapyramidal disturbances:
Parkinsonism – rigidity, tremor, hypokinesia (1-4 wks)



Acute muscular dystonia (acute onset) – grimacing, tongue
thrusting, torticollis and locked jaw etc. – initial therapy –
resolve spontaneously
Akathisia (1-8 weeks): 20% cases- restlessness, agitation,
compulsive desire to move about





Dose reduction or anticholinergics
rabbit syndrome – years after therapy
Anticholinergics/Propranolol - stoppage
Tardive dyskinesia: constant chewing, pouting, lip licking
etc. – accenuated by anticholinergics – uncommon with
newer ones
Malignant neuroleptic syndrome – Rare, high doses of
potent agents – rigidity, tremor, immobility,
semiconsciousness, fluctuation in BP and Myoglobinemia –
must stop, Dantrolene
6. Weight gain: risk of diabetes worsening – clozapine, less
with Haloperidol. Blue pigmentation of exposed skin,
lenticular opacities and degeneration

25. 7. Hypersensitivity reactions:
 Cholestatic
jaundice – common with CPZ
 Skin rash, urticaria, photosensitivity etc.
 Agrannulocytosis – clozapine
 Myocarditis - clozapine

26. Triflupromazine: More potent than CPZ,
used mainly as antiemetic
1.

Thioridazone: Marked Anticholinergic
action, but less EPS
1.

1.
causes muscle dystonia in children
cardiac arrhythmia and sexual function
retardation
Trifluoperazine and fluphenazine: High
potency, less sedation, more EPS effect

27. 
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
Butyrophenone derivative, Potent antipsychotic
Strong D2 blocker
Preferred in acute schizophrenia in highly agitated
patients
Less autonomic effects, no weight gain and less
epiletogenic
Marked EP effects to produce parkinsonism
Irreversible toxic encephalopathy – used along with
lithium
Orally 1.5 mg to 7.5 mg and 2 – 10 mg IV and
repeated every Hrly upto 30 mg
Available as 0.5 mg, 1.5 mg and 5 mg tablets
E1/2 is 24 hrs

28. • Better control of positive symptoms than negative symptoms

Positive scale
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Delusions
Conceptual disorganization
Hallucinations
Hyperactivity
Grandiosity
Suspiciousness/persecution
Hostility
Relieved by
Antipsychotics

Negative scale

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Blunted affect
Emotional withdrawal
Poor rapport
Passive/apathetic social
withdrawals
Difficulty in abstract thinking
Lack of spontaneity and flow
of conversation
Stereotyped thinking
Less Relieved by
Antipsychotics

29. 


Cognitive, affective and Motor disturbances –
relieved overall
Little improvement in judgment, memory and
orientation
Some patients do not respond (90% responds)
Only symptomatic relieve, does not remove the
cause – lifelong treatment may require

Choices of Drugs: Patient dependent,
empirical and guided by presenting symptoms

Individual patients differ in response to
different drugs

30. Symptoms
Agitated and violent
Drugs
CPZ, Thioridazine and
Haloperidol
Withdrawn and apathetic Trifloperazine and
Fluphenazine
Negative symptoms
Clozapine and
olanzapine, risperidone
and aripiprazole
Mood elevation
Haloperidol, fluphenazine
and olanzepine

31. 

Mania: CPZ or Haloperidol – IM or IV
Organic Brain Syndromes:
 Not
very effective, used as short term therapy
 Acute cases to control aggression
 As adjunct to nonsedatives to control
exacerbations of violent behaviour
 TCAs in depressed ones


Antiemetic and anti-anxiety
Other Uses: Potentiation of anaesthetics,
Intractable Hiccough, Tetanus and
Alcoholic hallucinations

32. 
Pharmacological actions, Mechanism of
action and Adverse effects of CPZ
/Haloperidol