Chetan Rastogi
M.Pharm 1st Year Pharmacology

1
Psychosis
Psychosis refers to a variety of mental disorders
characterized by one

or more of the following

symptoms:
dim...
Psychosis
Psychosis:
Psychosis can be broadly
Categorized in to 2 groups:
1 ORGANIC
2 FUNCTIONAL

3
1. Acute and chronic organic brain syndromes (cognitive

disorders) such as, Delirium and dementia, prominent features
of ...
Schizophrenia
It is a thought disorder.
The disorder is characterized by a divorcement

from reality in the mind of the ...
Schizophrenia
Positive Symptoms
Hallucinations, delusions, paranoia, ideas of reference.

Negative Symptoms
Apathy, social...
Psychosis Producing Drugs
1)

Levodopa

2)

CNS stimulants
a)

Cocaine

b)

Amphetamines

c)

Khat, cathinone, methcathino...
Dopamine Theory of Schizophrenia
Dopamine Correlates:
• Antipsychotics reduce dopamine synaptic activity.
• These drugs pr...
Dopamine Theory of Schizophrenia
Evidence against the hypothesis
Antipsychotics are only partially effective in most
(70%...
Dopamine System
There are four major pathways for the
dopaminergic system in the brain:
The Nigro-Stiatal Pathway.
II. The...
11
Catecholamines
Tyrosine
⇓ Tyrosine hydroxylase
L-Dopa
⇓ Dopa decarboxylase
Dopamine (DA)
⇓ Dopamine β hydroxylase
Norepine...
Tyrosine

L-DOPA
DA

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

14
15
Dopamine System
DOPAMINE RECEPTORS







Receptor
D1
D2
D3
D4
D5

2o Messenger System
⇑cAMP
⇓cAMP,⇑K+ ch.,⇓Ca2+ch.
⇓...
Dopamine Reuptake
System

17
ANTIPSYCHOTICS
Antipsychotic drugs are also
known as Neuroleptics, Ataractic,
Major Tranquilizer and AntiSchizophrenic dru...
CLASSIFICATION
A. Typical Antipsychotics: (traditional/older)

1. Phenothiazines:
a. Aliphatic side chain: Chlorpromazine,...
3. Thioxanthenes: Flupenthixol
4. Other heterocyclics: Pimozide, Loxapine, molindone,
sulpiride, amisulpiride, penfluridol...
Low potency
Chlorpromazin
e
Thioridazine
Thiothixene

High potency
Haloperidol,
Fluphenazine,Trifl
uoperazine,Perph
ennazi...
Traditional

⇓

Vs. Atypical

⇓

Mainly DA

DA and 5HT

Mainly D2

D2+D4+5HT

Treat mostly POSITIVE

Treat POSITIVE ...
Mechanism of Action:
-Antipsychotic blocks D₂
receptors in the brain's
Dopaminergic pathway.
-Some also block or partially...
In the Mesolimbic- Mesocortical and Nigrostriatal
pathway Antipsychotic blocks:

25
In the Tuberoinfundibular pathway
Antipsychotics block:

Dopamine released at
this site regulates the
secretion of prolact...
Antipsychotic blocks D₂ receptors

Some also block or partially block
serotonin receptors
27
Pharmacology of Antipsychotics:
Typical Antipsychotics
Phenothiazine

Absorption

Concentration

Metabolism

Vd

Dose

Chl...
Butyrophenones

Potency

t⅟ ₂

Haloperidol

Potent antipsychotic
Produces few
autonomic effects

24 hours.

Trifluperidol
...
Thioxanthenes
Flupenthixol

Less sedative than CPZ, indicated for
Schizophrenia and other Psychoses.

t⅟ ₂

Other heterocy...
Atypical Antisychotic drugs
These are newer 2nd
Generation antipsychotics
that have weak D₂ receptor
blocking but potent 5...
Atypical
Clozapine

Blocking activity
A very potent
antipsychotic

D₂, D₄, 5HT₂, α receptors
Combination of D₂+5HT₂ ,
High...
ADVERSE EFFECTS OF TYPICAL
NEUROLEPTICS
Anticholinergic (antimuscarinic) side effects:
Dry mouth, blurred vision, tachyc...
ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS
Antiadrenergic (Alpha-1) side effects:

Orthostatic hypotension w/ reflex

tachy...
ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS
Antihistamine effect: sedation, weight gain

35
KEY CONCEPT: DOPAMINE-2
RECEPTOR BLOCKADE IN THE BASAL GANGLIA
RESULTS IN EXTRAPYRAMIDAL MOTOR SIDE EFFECTS
(EPS).
DYSTON...
ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS
(Continued)
Increased prolactin secretion (common with all;

from dopamine blocka...
ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS
(Continued)
Chlorpromazine and thioridazine produce marked

autonomic side effect...
MANAGEMENT OF EPS
Dystonia and parkinsonism: anticholinergic

antiparkinson drugs

Neuroleptic malignant syndrome: muscl...
40
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Antipsychotics

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Psychosis and Anti-psychotic Drugs

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  • 1 ORGANIC
    2 FUNCTIONAL –
    - 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
  • Antipsychotics

    1. 1. Chetan Rastogi M.Pharm 1st Year Pharmacology 1
    2. 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. 3. Psychosis Psychosis: Psychosis can be broadly Categorized in to 2 groups: 1 ORGANIC 2 FUNCTIONAL 3
    4. 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. 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. 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. 7. Psychosis Producing Drugs 1) Levodopa 2) CNS stimulants a) Cocaine b) Amphetamines c) Khat, cathinone, methcathinone 3) Apomorphine 4) Phencyclidine 7
    8. 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. 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. 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
    11. 11. 11
    12. 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. 13. Tyrosine L-DOPA DA Dopamine Synapse
    14. 14. Dopamine System DOPAMINE RECEPTORS There are at least five subtypes of receptors: Receptor D1 D2 D3 D4 D5 14
    15. 15. 15
    16. 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. 17. Dopamine Reuptake System 17
    18. 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. 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. 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. 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. 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. 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. 24
    24. 24. In the Mesolimbic- Mesocortical and Nigrostriatal pathway Antipsychotic blocks: 25
    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. 26
    26. 26. Antipsychotic blocks D₂ receptors Some also block or partially block serotonin receptors 27
    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 ) 28
    28. 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. 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. 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. 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 32
    32. 32. ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS Anticholinergic (antimuscarinic) side effects: Dry mouth, blurred vision, tachycardia, constipation, urinary retention, impotence 33
    33. 33. ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS Antiadrenergic (Alpha-1) side effects: Orthostatic hypotension w/ reflex tachycardia sedation 34
    34. 34. ADVERSE EFFECTS OF TYPICAL NEUROLEPTICS Antihistamine effect: sedation, weight gain 35
    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. 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) 37
    37. 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. 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 39
    39. 39. 40
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