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Antipsychotics

Antipsychotics
Antipsychotics (neuroleptics) are drugs used to
treat psychotic states such as
schizophrenia, delusional disorder, and other
hallucinatory states
MOA
Antipsychotics block various receptors including
cholinergic, adrenergic, serotoninergic, muscarinic,
and histamine receptors
However, their antipsychotic actions are thought to be
due to blocking of dopamine receptors in the CNS,
particularly the D2 receptors in the mesocortical and
mesolimbic systems of the brain
2.1. Dopamine theory
The theory suggests that schizophrenia is caused by
abnormality of DA receptors, in particular D2
Evidences to proof the theory:-
Drugs like Levodopa (DA precursor), Amphitamine (DA release),
Apomorphine & bromochriptine (DA agonists) either aggravate or
produce psychosis de novo in some patients
Most antipsychotic drug act by blocking D2 on mesolimbic system
There is an in DA receptor density in treated & untreated
schizophrenics when compared with normal control
DA receptor density has been found to be ed in the brains of
schizophrenics who have not been treated with antipsychotic drugs
(postmortem)
After successful treatment with antipsychotics, there is change in
the amount of homovanillic acid in the CSF, plasma & urine
Evidences against DA theory
Drugs w/c block DA should bring complete cure
practically, not true
Phencyclidine (NMDA receptor antagonist) produce
much more schizophrenia like symptom
Atypical antipsychotics have less affinity for D2
2.2 . Glutamate Theory
NMDA receptor antagonists (phencyclidine, ketamine
& dizocilpine) produce psychotic symptoms
Reduced glutamate concentrations & glutamate
receptor densities have been reported in postmortem
schizophrenic brains
2.3. Other theories
Many effective antipsychotic drugs, in addition to
blocking DA receptors also act as 5-HT2A receptor
antagonists
5-HT modulates dopamine pathways
Whether 5-HT2A receptor blockade accounts directly
for their antipsychotic effects, or merely reduces
undesirable side effects associated with D2-receptor
antagonists remains controversial.
Antipsychotics
Potency and efficacy
Antipsychotic agents differ in potency
but they do have similar efficacy
The traditional antipsychotics are all equivalent in
efficacy
A drugs potency parallels its affinity for D2
receptors
Haloperidol and thiothixene are high-potency drugs
because they have high affinity for the D2 receptors
Chlorpromazine and thioridazine are low-potency drugs
because they have low affinity for D2 receptors
Antipsychotics
Administration:
in most cases these drugs are given orally; they can be
given intramuscularly if the patient is noncompliant
Absorption and metabolism of traditional
antipsychotics:
They are variably absorbed orally but they pass into the
brain easily and have a large VD
Metabolism occurs by the cytochrome p-450 system in the
liver
Antipsychotics may not become effective for several
weeks.
However, sedation and other side effcts can occur
rapidly
Antipsychotics
Can these drugs cure illnesses such as
schizophrenia?
No. antipsychotics only reduce the symptoms of
the illness; they cannot cure the illness
Classification based on structural difference:
The major classes include:
Phenothiazines
Butyrophenones
Dibenzoxazepines
Thioxanthines,
Broad category of antipschotic drugs
1st generation ('typical') & 2nd generation ('atypical')
No clear distinction b/n them ; however, grouping is
based on
Receptor profile
Incidence of extrapyramidal side effects (less in
atypical group)
Efficacy in 'treatment-resistant' patients
Efficacy against negative symptoms
(2nd generation ) Newer generation cause metabolic
syndrome
Traditional (typical ) antipsychotics
Phenothiazines
chlorpromazine prototype
Fluphenazine
Trifluoperazine
Thioridazine
Perphenazine
Traditional antipsychotics

Butyrophenones
Haloperidol
Droperidol
Dibenzoxazepines
Loxapine
Thioxanthines
Thiothixene
Clinical uses
Traditional neuroleptics have several therapeutic
uses:
Treatment of any agitated or psychotic state, such as
bipolar disease or schizophrenia
These agents are especially effective for the positive
symptoms of schizophrenia, such as:
Delusions, thought disorders, and hallucinations
Antiemetic therapy due to blockade of dopamine in
the chemoreceptor trigger zone
Thioridazine , however, cannot be used for this purpose
Treatment of tourettes syndrome- haloperidol
Treatment of intractable hiccupschlorpromazine
Antipruritic therapy promethazine (because of
histamine blockade)
Adverse effects
With a few exceptions all of the traditional
antipsychotics have similar toxicities namely:
Sedation, extrapyramidal effects, anticholinergic effects,
and -adrenergic effects (hypotension)
The severity of each AE varies among the classes of
antipsychotic drugs. For example:
High potency drugs such as haloperidol and fluphenazine
produce the greatest extrapyramidal effects and
Low potency drugs such as thioridazine and
chlorpromazine produce the highest anticholinergic effects
Adverse effects
CNS sedationseen markedly with the phenothiazines
Endocrine alterationgalactorrhea, amenorrhea, and
infertility, likely due to blockade of dopamine release from
the pituitary
Anticholinergic effectsdry mouth, constipation, urinary
retention, and blurry vision
Antiadrenergic effectswatch for light-headedness and
orthostatic hypotension secondary to -adrenergic
blockade.
Phenothiazines can cause failure to ejaculate
Extrapyramidal side effectsakathisia (motor
restlessness), parkinsonian syndrome (bradykinic
rigidity,tremor), acute dystonic reactions (slow, prolonged
muscle spasms of tongue, neck, face), neuroleptic
malignant syndrome, and tardive dyskinesia
Adverse effects
Tardive dyskinesia is
a symptom that may occur after prolonged therapy
with neuroleptics (6 months to 1 year)
It is characterized by rhythmical involuntary
movements of the tongue, lips, or jaw.
Patients may also demonstrate puckering of the
mouth, or even chewing movements
There is no known treatment for established cases of
tardive dyskinesia
The syndrome may remit partially or completely if
neuroleptic treatment is withdrawn, although in many
cases it is irreversible.
Anticholinergic agents actually increase the severity of
tardive dyskinesia
Adverse effects

neuroleptic malignant syndrome


Patients who receive neuroleptics for long-term
treatment may experience:
rigidity, altered mental status, cardiac arrhythmias,
hypertension, and life-threatening hyperpyrexia
This disorder is treated with dantrolene, a skeletal
muscle relaxant
Atypical antipsychotic drugs
Clozapine
Risperidone
Olanzapine

In addition to blocking dopamine receptors, atypical


antipsychotics also produce significant blockade on
serotonin (5-HT) receptors
They also are rarely associated with extrapyramidal
side effects
Atypical antipsychotic drugs
Clozapine
It is dibenzodiazepine derivative
It differs from traditional antipsychotics in its potent
blockade of 5-HT2 receptors along with the usual
dopamine blockade
Use:
It has been effective in treating cases of schizophrenia that
are refractory to other neuroleptic drugs
It is especially effective in treating the negative symptoms of
schizophrenia (blunted emotion, withdrawal, reduced ability
to form relationships)
Clozapine causes fewer extrapyramidal side effects than
traditional neuroleptics
Clozapine can cause seizures and a very dangerous
agranulocytosis in 1% to 2% of patients
Weekly blood tests are required for patients receiving clozapine
therapy
Atypical antipsychotic drugs
Risperidone
Is a benzisoxazole drug
Has high affinity for 5-HT2 receptors like clozapine
It also has antidopaminergic (D2) activity
Risperidone exhibits no anticholinergic effects and
diminished extrapyramidal effects
First line agent for t/t of schizophrenia since:
It is effective for both the positive and negative
symptoms of the disease
Atypical antipsychotic drugs
Olanzapine
Blocks both dopamine and serotonin receptors
Effective in the t/t of schizophrenia
It can produce anticholinergic effects as well as
sedation and orthostatic hypotension
Mechanism of Action
All effective antipsychotic drugs block D2 receptors
The degree of blockade on different receptors considerably
varies
Chlorpromazine: 1 > 5-HT2A > D2 > D1
Haloperidole: D2 > 1 > D4 > 5-HT2A> D1>H1
Clozapine: D4 = 1 > 5-HT2A> D1=D2
Aripiprazole: D2= 5-HT2A >D4 > 1 = H1 >>D1
Olanzapine: 5-HT2A >H1>D4>D2> 1 = H1>>D1
Antipsychotic action has shown good correlation with the
capacity to bind to D2 receptor
There is no clear correlation with antipsychotic activity &
the capacity to bind with D1, D3, & D4
Activities on other NT receptors may determine side effect
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