PSYCHOPHARMACOLOGY&

ANTIPSYCHOTICS

(thought, mood, stress, anxiety, memory, cognition)

THOUGHT

Psychoses

MOOD (Affective disorders)

Depression/Mania –Bipolar disorder

Mental illnesses

NEUROSES

Anxiety neurosisPhobic neurosisObsessive compulsive disorderPost-traumatic stress disorder Hysterical neurosisPanic disordersReactive depression

Mental illnesses

Psychoses:-thought disorder-loss of reality testing (reasoning)-disorder in perception – hallucinations, illusions, delusions-behavioral alterations (emotion)

Mental illnesses

Psychosis

Psychosis is a thought disorder characterized by

disturbances of reality and perception,

impaired cognitive functioning, and

inappropriate or diminished affect (mood).

Psychosis denotes many mental disorders.

Schizophrenia is a particular kind of psychosis

characterized mainly by a clear sensorium but

a marked thinking disturbance.

Psychosis:

Psychosis can be broadlyCategorized in to 2

groups:1 ORGANIC2 FUNCTIONAL

Psychosis

Schizophrenia

• Pathogenesis is unknown.

• Onset of schizophrenia is in the late teens

early twenties.

• Genetic predisposition -- Familial incidence.

• Multiple genes are involved.

• Afflicts 1% of the population worldwide.

• May or may not be present with anatomical

changes.

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”.

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.

Etiology of Schizophrenia

Schizophrenia is not characterized by any reproducible neurochemical abnormality. However, structural and functional abnormalities have been observed in the brains of schizophrenic patients:

1) Enlarge cerebral ventricles.2) Atrophy of cortical layers.3) Reduced volume of the basal ganglia

IdiopathicBiological Correlates1) Genetic Factors2) Neurodevelopmental abnormalities.3) Environmental stressors.

Psychosis Producing Drugs

1) Levodopa

2) CNS stimulants

a) Cocaine

b) Amphetamines

c) Khat, cathinone, methcathinone

3) Apomorphine

4) Phencyclidine

Many lines of evidence point to the

aberrant increased activity of the

dopaminergic system as being critical

in the symptomatology of schizophrenia.

Dopamine Theory of Schizophrenia

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.

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.

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.

THE DOPAMINERGIC SYSTEM

Catecholamines

Tyrosine Tyrosine hydroxylase

L-Dopa Dopa decarboxylase

Dopamine (DA) Dopamine hydroxylase

Norepinephrine (NE)(Noradrenaline) Phenylethanolamine-

-N-methyltransferase

Epinephrine (EPI)(Adrenaline)

Dopamine Synapse

DA

L-DOPA

Tyrosine

Tyrosine

Dopamine System

• DOPAMINE RECEPTORS

There are at least five subtypes of receptors:ReceptorD1D2D3D4D5

Pharmacodynamics

Anatomic Correlates of Schizophrenia...

Frontal cortexAmygdalaHippocampusNucleus accumbensLimbic Cortex

Areas Associated with Mood and Thought Processes:

DADADADADA

Antipsychotic drugs are alsoknown as Neuroleptics, Ataractic,Major Tranquilizer and Anti-Schizophrenic drugs. A firstgeneration of antipsychotics,known as Typical antipsychotics,was discovered in the 1950s. Mostof the drugs in the secondgeneration, known as Atypical

antipsychotics,have been developed more recently.

ANTIPSYCHOTICS

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

 

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

Antipsychotic drugstraditional/older newer

Low potencyLow potency High potencyHigh potency NEWERNEWER

ChlorpromaziChlorpromazinene

ThioridazineThioridazine

ThiothixeneThiothixene

ExtrapyramidExtrapyramidal symptoms al symptoms LESSLESS

Anti-ch MOREAnti-ch MORE

Haloperidol, Haloperidol, Fluphenazine,TrFluphenazine,Trifluoperazine,Peifluoperazine,Perphennazine, rphennazine, PimozidePimozide

Extrapyramidal-Extrapyramidal-MORE,MORE,

AntiCh LESSAntiCh LESS

ClozapineClozapine

OlanzapineOlanzapine

QuetiapineQuetiapine

AripiprazoleAripiprazole

RisperidoneRisperidone

ZiprasidoneZiprasidone

Traditional Vs. Traditional Vs. AtypicalAtypical

• Mainly DAMainly DA• Mainly D2Mainly D2• Treat mostly Treat mostly

POSITIVE POSITIVE symptomssymptoms

• More adverse More adverse effectseffects

• Less useful in Less useful in refractory diseaserefractory disease

• DA and 5HTDA and 5HT• D2+D4+5HTD2+D4+5HT• Treat POSITIVE Treat POSITIVE

and and NEGATIVENEGATIVE symptomssymptoms

• Lesser adverse Lesser adverse effectseffects

• Useful in Useful in refractory diseaserefractory disease

Mechanism of Action:

-Antipsychotic blocks D₂receptors in the brain'sDopaminergic pathway.

-Some also block or partiallyblock serotonin receptors(particularly 5HT2A, C and

5HT1A receptors)

 -But antipsychotic drugs can

alsoblock wide range of

receptortargets.

Dopaminergic pathway in Brain:

Mesolimbic- mesocortical:Control behavior,

cognitivefunction regulated by D₂Receptor.Nigrostriatal: ControlVoluntary Movementregulated by D₁ and D₂receptor.Tuberoinfundibular:Control prolactin

secretionRegulated by D₂ receptor.

In the Mesolimbic- Mesocortical and Nigrostriatal pathway

Antipsychotic blocks:

In the Tuberoinfundibular pathway Antipsychotics block:

Dopamine released at this site regulates the secretion of prolactinfrom anterior the pituitary gland.Antipsychotics blocks D₂ receptor at this site.

Antipsychotic blocks D₂ receptors Some also block or partially block serotonin receptors

Pharmacology of Antipsychotics:Typical Antipsychotics

Phenothiazine

Absorption

Concentration

Metabolism

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 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 (25mg/ml )

Butyrophenones Potency t⅟₂ Dose

Haloperidol Potent antipsychotic Produces few autonomic effects

24 hours. --

Trifluperidol Similar toHaloperidol but slightly more potent

-- --

Penfluridol Exceptional long acting neuroleptic, used for chronic Schizophrenia, affective withdrawl and social mal-adjustment

-- 20-60 mg , once weekly

Thioxanthenes

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

Other heterocyclics

t⅟₂

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)

Atypical Antisychotic drugs

These are newer 2nd

Generation antipsychoticsthat have weak D₂

receptorblocking but potent 5-HT₂antagonistic activity. TheyMay improve the impairedCognitive function inpsychotics.

Atypical Blocking activity Metabolism(Enzyme)

t⅟₂ and Dose

Clozapine A very potent antipsychotic

D₂, D₄, 5HT₂, α receptors

By CYP3A4 t⅟₂ - 12 hours

Risperidone -- Combination of D₂+5HT₂ , High affinity for α₁, α₂ and H₁ receptors

-- Dose - Low dose <6 mg/day

Olanzapine Potent antipsychotic Broader spectrum of efficacy

Monoaminergic (D₂, 5HT₂, α₁, α₂) as well as muscarinic and H₁ receptors

By CYP1A2 and Glucuronyl transferase

t⅟₂ - 24-30 hours

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 By CYP2D6 and CYP3A4

t⅟₂ - 3days

Ziprasidone Latest antipsychotic , moderately potent inhibitor.

Combination D₂+5HT₂A/₂C +H₁ + α₁,Na reuptake

-- t⅟₂ - 8 hours

Adverse effects:

• On CNS: - Drowsiness - lethargy - mental confusion - seizure.• CVS: - Postural hypotension - palpitation - arrythmia in elderly• Anticholinergic: - Dry mouth - blurring of vision - constipation - urinary

inconsistency

• Endocrine: - Hyperprolactinemia - amenorrhoea - infertility - gelactorrhoea and gynaecomastia.• Extrapyramidal disorders: - Parkinsonism - Acute muscular dystonias - Akathisia - Malignant Neuroleptic

Syndrome - Tardive dyskinesia• Miscellaneous: - Weight gain - Blood sugar – lipid rise - worsening of diabetes.