Antipsychotic Drugs
Lec.
Schizophrenia
• incidence – 1%
• prevalence - M=F
• onset - variable
• prognosis - usually poor
Etiology of schizophrenia
• possible primary defect in cortex &
mesolimbic areas of brain is ↑
activation of DA receptors (& ↓
activation of glutamate receptors)
Schizophrenia: Clinical Features
Positive Symptoms Negative Symptoms Cognitive
Disturbance of Decreased expression Poor concentration,
perception of feelings, diminished memory disturbances,
(hallucinations), emotional range, inability to plan,
disturbance of thought poverty of speech, difficulty executing
content (delusions), decreased interests & task, poor abstraction,
disorganization of diminished sense of impaired decision
thought, speech, & purpose & social drive making
behavior
Positive symptom Negative symptom
Organization of the CNS
Dopamine Pathways
Dopamine Pathways & Their
Interactions
major DA pathways associated with：
• thought (cortex)
• movement (nigro-striatal path to basal
ganglia of forebrain)
• endocrine control (pituitary)
• also emetic effects ( in medulla)
Categories of antipsychotics
Typical antipsychotics Atypical antipsychotics
Phenothiazines Clozapine
Haloperidol Rispiridone
Others Olanzapine
Quetiapine
Sertindole
Typical antipsychotics
• Positive
Symptoms
Negative
Symptoms
Cognitive
Symptoms
Typical antipsychotic
• Competitive inhibitors at a variety of
receptors but
• Their antipsychotic effect is , blocking of
dopamine receptor(D2 receptors)
• Linked with the treatment of positive
sypmtoms of schizophrenia(e.g. dellusion
and hallucination)
• Also have common side effects
Atypical antipsychotics
• significantly reduced Positive
Symptoms
side effect
• Improved efficacy
Negative
profile Symptoms
Cognitive
Symptoms
Atypical antipsychotic drugs
The atypical antipsychotics (AAP) (also
known as second generation
antipsychotics (SGAs) , are a group of
antipsychotic drugs.
(antipsychotic drugs in general are also
known
as major tranquilizers and narcoleptic
-s) used to treat psychiatric conditions.
Ideal antipsychotic drug
( “Atypical antipsychotic drug)”
• Decrease in positive symptoms
• No extrapyramidal side effects
• No tardive dyskinesia
• Decrease in negative symptoms
• No endocrine side effects
Route of administration
• Oral route
• Intramascular route
• Intavaneous route
• Usually given once a day at bed times so
sedating effect will be maximal during
sleep.
Mechanism of action of
antipsychotic drugs
DOPAMINE HYPOTHESIS
This explanation received most attention
from researchers.
It suggests that schizophrenia is caused by
over activity of dopaminergic synapses ,
probably those in mesolymbic pathways.
The antipsychotic action of a drug appears
to reflect a blockade at dopamine and
serotonin receptors.
Dopamine hypothesis
• This hypothesis is based on several
observations.
• First, many antipsychotic drug block brain
dopamine receptors.
• Second, dopamine agonist drug
exacerbate schizophrenia.
• Third, an increased density of dopamine
receptors has been detected in certain
region of untreated schizophrenia.
Conti……….
Antagonists at：
• D1 receptors
• D2 receptors
• Adrenergic(α1) receptors
• Muscarinic(M1) receptors
• Serotonin(5-HT) receptors(less)
• Mechanism of antipsychotic action
• Dopamine receptor blockade in mesolimbic-
mesocortical dopaminergic system. The primary
therapeutic action of phenothiazines and
haloperidol appears to involve blockade of the
D2-receptor, which inhibits adenylyl cyclase.
Conti…………
• This system consist of neuron near
substantia nigra.
• The axon of this system project to neuron
in the limbic system and neocortex.
• This system is concerned with the
behavior of the person.
• Antipsychotic produce their beneficial
effect in schizophrenia and other type of
psychosis.
Dopamine Pathways
Conti……..
• D2 receptors are located in caudate ,
putaman , nucleus accumbens.
Possible causes of increased
dopaminergic transmission
Increased postsynaptic response to
dopamine release:
More excitatory input to dopaminergic
neurons
Less inhibitory input to dopaminergic
neurons
More postsynaptic dopamine receptors
More response in post synaptic neuron for
activation of dopamine receptors.
Extra pyramidal (adverse)
effects
• Change in breathing and heart rate
(neurolyptic malignant syndrome)
• Muscle contraction (acute dystonia)
occurring within few days (onset 1 to 2
days) of treatment follow by akathesia.
• Body restlessness (akathesia onset 1 to 2
weeks)
• Tremors and rigidity ( Parkinson-onset 1
to 2 months)
Reduction of white blood cells
• Some atypical antipsychotic medications ,
e.g clozapine may cause a significant
reduction in the number of white blood
cells.
• To control this side effect it may be
necessary to have blood test taken at
regular interval.
Pharmakokinetics
• When used orally they are incompletely
absorbed from The GIT.
• They also undergo significant first past
effect which reduce there bioavailability.
Conti………..
• They are lipid soluble drug because of
there lipid solubility they are widely
distributed in the body and also passed
into the blood brain barrier.
Conti………
• Because of there lipid solubility, they are
stored in the body fat , from where they
are excreted in the urine for a long period
of time.
• There plasma half-life is 8-25 hours
• Many antipsychotics continue to produce
there effect for several weeks after there
administration is stopped.
Clinical use
Schizophrenia:
Many cases of this disease get significant
improvement with antipsychotic. But some
of them do not respond to all these drugs.
Even in cases that are improved with these
drugs complete benefits does not occur.
Conti…………
• Positive symptoms of the disease show
more improvement with antipsychotic
while the negative symptoms show less
improvement.
Affective disorder
• Severe cases of mania require treatment
of antipsychotic.
• Psychosis that occur with depression can
also be treated with antipsychotic.
Delirium and Alzheimer’s
disease
• Delirium can be treated with antipsychotic
drug.
• Antipsychotic can be used in patient with
a type of dementia known as Alzheimer
dementia.
