2. Psychosis
Psychosis refers to a variety of mental disorders
characterized by one
or more of the following
symptoms:
ďdiminished
and
distorted
capacity
to
process
information and draw logical conclusions.
ď
hallucinations,
delusions,
marked
loosening
of
associations.
ďdisorganized behavior, and aggression or violence.
2
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
ďIt is a thought disorder.
ďThe disorder is characterized by a divorcement
from reality in the mind of the person (psychosis).
ďIt 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 âideas of referenceâ.
5
6. Schizophrenia
Positive Symptoms
Hallucinations, delusions, paranoia, ideas of reference.
Negative Symptoms
Apathy, social withdrawal, anhedonia, emotional blunting,
Poor speech âCognitive impairment , extreme
inattentiveness or lack of motivation to interact with the
environment.
These symptoms are progressive and non-responsive to medication .
6
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
ďAntipsychotics are only partially effective in most
(70%) and ineffective for some patients.
ďPhencyclidine, an NMDA receptor antagonist,
produces more schizophrenia-like symptoms in
non-schizophrenic subjects than DA agonists.
ďAtypical antipsychotics have low affinity for D2
receptors.
ďFocus 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.
10
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
22. Traditional
â
Vs. Atypical
â
ďMainly DA
ďDA and 5HT
ďMainly D2
ďD2+D4+5HT
ďTreat mostly POSITIVE
ďTreat POSITIVE and
symptoms
ďMore adverse effects
ďLess useful in refractory
disease
NEGATIVE symptoms
ďLesser adverse effects
ďUseful in refractory
disease
22
23. Mechanism of Action:
-Antipsychotic blocks Dâ
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.
24
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
Dâ receptor at this site.
26
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 tâ â 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 )
28
28. Butyrophenones
Potency
tâ â
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.
tâ â
Other heterocyclics
Pimozide
Specific DA antagonist with little
adrenergic or cholinergic blocking
activity. Used in Gilles de la Tourettâs
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 Dâ receptor
blocking but potent 5-HTâ
antagonistic activity. They
May improve the impaired
Cognitive function in
psychotics.
31
31. Atypical
Clozapine
Blocking activity
A very potent
antipsychotic
Dâ, Dâ, 5HTâ, Îą receptors
Combination of Dâ+5HTâ ,
High affinity for Îąâ, Îąâ and
Hâ receptors
Metabolism
(Enzyme)
By CYP3A4
Risperidone
--
Olanzapine
Potent antipsychotic
Broader spectrum of
efficacy
Monoaminergic (Dâ, 5HTâ,
Îąâ, Îąâ) as well as muscarinic
and Hâ receptors
By CYP1A2 and
Glucuronyl
transferase
Quetiapine
New short- acting
antipsychotic
5HTâĐ, 5HTâ, Dâ, Îąâ, Îąâ and
Hâ receptor
By CYP3A4
Aripiprazole
Unique antipsychotic
which is partial
agonist at Dâ and
5HTâĐ
5HTâ
Ziprasidone
Latest antipsychotic ,
moderately potent
inhibitor.
Combination Dâ+5HTâA/âC
+Hâ + Îąâ,
Na reuptake
--
By CYP2D6 and
CYP3A4
--
tâ â and
Dose
tâ â - 12
hours
Dose - Low
dose <6
mg/day
tâ â 24-30 hours
--
tâ â - 3days
tâ â - 8
hours
32
32. ADVERSE EFFECTS OF TYPICAL
NEUROLEPTICS
ďAnticholinergic (antimuscarinic) side effects:
ďDry mouth, blurred vision, tachycardia,
constipation, urinary retention, impotence
33
33. ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS
ďAntiadrenergic (Alpha-1) side effects:
ďOrthostatic hypotension w/ reflex
tachycardia
ďsedation
34
34. ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS
ďAntihistamine effect: sedation, weight gain
35
35. KEY CONCEPT: DOPAMINE-2
RECEPTOR BLOCKADE IN THE BASAL GANGLIA
RESULTS IN EXTRAPYRAMIDAL MOTOR SIDE EFFECTS
(EPS).
ďDYSTONIA
ďNEUROLEPTIC MALIGNANT SYNDROME
ďPARKINSONISM
ďTARDIVE DYSKINESIA
ďAKATHISIA
36
36. ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS
(Continued)
ďIncreased prolactin secretion (common with all;
from dopamine blockade)
ďWeight gain (common, antihistamine effect?)
ďPhotosensitivity (v. common w/ phenothiazines)
ďLowered seizure threshold (common with all)
ďLeucopenia , agranulocytosis (rare; w/
phenothiazines)
ďRetinal pigmentopathy (rare; w/ phenothiazines)
37
37. ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS
(Continued)
ďChlorpromazine and thioridazine produce marked
autonomic side effects and sedation; EPS tend to be weak
(thioridazine) or moderate (chlorpromazine).
ďHaloperidol, thiothixene and fluphenazine produce weak
autonomic and sedative effects, but EPS are marked.
38
38. MANAGEMENT OF EPS
ďDystonia and parkinsonism: anticholinergic
antiparkinson drugs
ďNeuroleptic malignant syndrome: muscle relaxants, DA
agonists, supportive
ďAkathisia: benzodiazepines, propranolol
ďTardive dyskinesia: increase neuroleptic dose; switch to
clozapine
39
1 ORGANIC
2 FUNCTIONAL â
- SCHIZOPHRENIA
- PARANOID STATES
Apathy =complete lack of emotion or motivation , anhedonia= inability to feel pleasure
Dopamine Hypothesis: excess DA
mesolimbic, mesocortical
DA blockers have antipsychotic actions
DA agonists cause psychosis:
Also increasing 5HT involvement
BLOCK DA and/or 5HT receptors
Slide 4: The synapse and synaptic neurotransmission
Describe the synapse and the process of chemical neurotransmission. Indicate how vesicles containing a neurotransmitter, such as dopamine (the stars), move toward the presynaptic membrane as an electrical impulse arrives at the terminal. Describe the process of dopamine release (show how the vesicles fuse with the presynaptic membrane). Once inside the synaptic cleft, the dopamine can bind to specific proteins called dopamine receptors (in blue) on the membrane of a neighboring neuron. Introduce the idea that occupation of receptors by neurotransmitters causes various actions in the cell; activation or inhibition of enzymes, entry or exit of certain ions. State that you will describe how this happens in a few moments.
Slide 6: Dopamine and the production of cyclic AMP
Using the close-up view, explain what happens when dopamine binds to its receptor. When dopamine binds to its receptor, another protein called a G-protein (in pink) moves up close to the dopamine receptor. The G-protein signals an enzyme to produce cyclic adenosine monophosphate (cAMP) molecules (in green) inside the cell. [Sometimes the signal can decrease production of cAMP, depending on the kind of dopamine receptor and G-protein present.] Point to the dopamine receptor-G-protein/adenylate cyclase complex, and show how cAMP is generated when dopamine binds to its receptor. Indicate that cAMP (point to the cyclic-looking structures) controls many important functions in the cell including the ability of the cell to generate electrical impulses.
Slide 12: Dopamine binding to receptors and uptake pumps in the nucleus accumbens
Explain that cocaine concentrates in areas of the brain that are rich in dopamine synapses. Review dopamine transmission in the nucleus accumbens. Point to dopamine in the synapse and to dopamine bound to dopamine receptors and to uptake pumps on the terminal.
Psychotropic drugs are those having
primary effects on Psyche (mental
processes) and are used for treatment
Of Psychiatric disorders.
One of the primary psychotic disorders in
which the Antipsychotics works is the,
Psychosis