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TERAPI FARMAKOLOGI

ANTIPSIKOTIK
dr. sufi desrini M.Sc

Blok Kesehatan Jiwa 14/11/2014 [10]

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Tujuan Belajar

Mengetahui golongan obat antipsikotik

Menjelaskan mekanisme kerja obat

Menjelaskan FK dan FD masing-masing obat


Menjelaskan indikasi, KI, efeks amping dan
interaksi obat

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GENERASI PERTAMA
ANTIPSIKOTIK
Dikenal dengan nama
antipsikotik tipikal, antagonis
dopamin, neuroleptik dan
antipsikotik klasik

Masing2 istilah ada sejarah

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NEUROLEPTIK

Kemampuan obat untuk menyebabkan suatu


sindrom yang disebut dengan nama neurolepsis.

Sindrom ini mempunyai 3 gambaran utama:


Perlambatan psikomotor
Emotional quieting
Affective indifference
Awalnya tanda ini dianggap sbg efikasi antipsikotik,
namun kemudian terbukti bahwa efek ini tidak
dibuthkan utk kerja obat
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Antipsikotik Tipikal
Second generation antipsychotic (SGAs) have
atypical propertieslow risk of extrapyramidal
symptoms

Obat yg tdk mempunyai sifat atipik antipsikotik


tipikal/konvensional
Konsep awal atipikal berubah menjd lbh luas yg
meliputi gejala kognitif dan negatif definisi
direvisi setelah CATIE trial yg gagal
mengkonfirmasi bahwa SGA lbh efektif dibanding
FGA
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Mekanisme Kerja
Belum diketahui
Teori dopamine skizofrenia : gejala positif adlh
sebagai hasil overaktivitas dalam jalur
dopamine mesolimbik.
Obat2 yang dapat meningkatkan ketersediaan
dopaminergik (L-DOPA, kokain, amfetamin)
dapat memicu efek psikomimetik pada
individu normal
FGA adalah antagonis D2

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Mesocortical pathway

Research on schizophrenia
pathophysiology suggests that a
dysfunction of this pathway is
associated with cognitive impairments
and disturbances of emotions and
affect (negative symptoms). Blockade
of the mesocortical pathway by high
doses of first-generation
antipsychotics can induce secondary
negative symptoms and cognitive
effects.
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Mesolimbic pathway: Antipsychotic effects

overactivity of this pathway is


thought to be involved in the
pathophysiology of positive
symptoms of schizophrenia.
Blockade of D2 receptors in the
mesolimbic pathway has been
proposed as a possible
mechanism of antipsychotic
action of first-generation agents.
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Nigrostriatal pathway: Extrapyramidal Symptoms

Antagonism of D2
receptors in the
nigrostriatal pathway is
associated with
increased risk of
extrapyramidal
symptoms. 11
Tuberoinfundibular pathway: Hyperprolactinemia

Dopamine acts as
prolactin-inhibiting
factor, D2 blockade
increases prolactin
levels by promoting its
release in the pituitary
gland.
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Chemical
Classification

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Phenothiazines

Drugs in this group share the same


three-ring structure with different
side chains joined at the nitrogen
atom of the middle ring. The activity
of the group can be affected by
substitutions at position 2 or 10.

The phenothiazines are categorized


into three subclasses based on
substitutions at position 10: aliphatic,
piperidine, and piperazine
phenothiazines.

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Phenothiazines
chemical classification
Chemical class
phenothiazines
Side chain drug
Aliphatic (low/medium- Chlorpromazine
potency agents)
Levomepromazine
Promazine
Triflupromazine
Piperidine (low/medium Mesoridazine
potency agents)
Pericyazine
Pipotiazine
Thioridazine
Piperazine Perphenazine
(medium/high-potency
agents)
Fluphenazine
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non-phenothiazine first-
generation antipsychotics.
Chemical Class Drug
Butyrophenones (high-potency Benperidol
agents)
Droperidol

Haloperidol

Thioxanthenes (low/medium-potency Clopenthixol


agents)
Flupenthixol

Thiothixene

Zuclopenthixol

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Non-phenothiazine first-
generation antipsychotics.

Dihydroindolones (low/medium-potency Molindone


agents)

Dibenzepines (low/medium-potency Clotiapine


agents)
Loxapine

Diphenylbutylpiperidines (high-potency Fluspirilene


agents)
Pimozide

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Alpha-1
Dosag Muscari Antihist
D2 5HT2 adrener
e nic amine
Activity Activity gic
forms Activity Activity
Activity
Chlorproma T, I ++++ ++++ ++++ ++++ ++++
zine
(Thorazine)
Fluphenazi T, L, I, I ++++ ++ + + ++
ne (Prolixin) (LA)
Perphenazi T ++++ ++++ + ++ +++
ne (Trilafon)
Trifluoperaz T ++++ +++ + ++ ++
ine
(Stelazine)
Thioridazin T ++++ ++++ ++++ ++++ ++++
e (Mellaril)
Mesoridazin T ++++ ++++ +++ ++++ ++++
e (Serentil)
+withdraw
n from US
market in 18
2004
Alpha-1
Muscari Antihist
Dosage D2 5HT2 adrener
nic amine
forms Activity Activity gic
Activity Activity
Activity
Haloperid T, L, I, I ++++ ++ + + +
ol (Haldol) (LA)
Molindone T +++ + ++ + +
(Moban)
*discontin
ued by
manufact
urer in
2010
Thiothixen C ++++ + + ++ +++
e
(Navane)
Loxapine C +++ ++++ ++ +++ ++++
(Loxitane)
highLevel/degree of effect:
(+) low
(++) moderate
(+++) high
(++++) very 19
Antipsychotic potency: chlorpromazine equivalent
doses

First-generation antipsychotics can be


classified according to their potency. All
FGAs are compared to chlorpromazine for
equivalence purposes. Potency should not
be confused with effectiveness. For
example, if we know that haloperidol is
more potent that chlorpromazine, it means
that a lower dose of haloperidol is required
to achieve the same therapeutic effect,
but not that haloperidol is more effective
than chlorpromazine.
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Antipsychotic potency: chlorpromazine equivalent
doses

Manual of
Maudsley
Clinical
Drug Prescribing
Psychopharmaco
Guidelines
logy
Chlorpromazine 100 mg/day 100 mg/day
Fluphenazine 2 mg/day 2 mg/day
Trifluoperazine 5 mg/day 5 mg/day
Flupentixol 3 mg/day
Zuclopentixol 25 mg/day
Haloperidol 3 mg/day 2 mg/day
Sulpiride 200 mg/day
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Antipsychotic potency: chlorpromazine equivalent
doses

Sulpiride 200 mg/day

Pimozide 2 mg/day

Loxapine 10 mg/day 10 mg/day

Molindone 10 mg/day

Perphenazine 10 mg/day

Prochlorperazine 15 mg/day

Thioridazine 100 mg/day

Thiothixene 4 mg/day

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Adverse Effects Profile

Anticholin Extrapyra
Sedating Hypotensi
Drug ergic midal side
effects ve effects
effects effects
Chlorproma High High Low IM-High
zine
PO-
Moderate
Fluphenazi Low Low Very high Low
ne
Haloperidol Very low Very low Very high Very low
Loxapine Moderate Low Moderate Moderate
Molindone Very low Low Moderate Low
Perphenazi Low Low High Low
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ne
Adverse Effects Profile

Pimozide Low Low High Very low

Pimozide Low Low High Very low

Thioridazine High High Low High

Thiothixene Low Low High Low

Trifluoperazin Low Low High Low


e

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SECOND GENERATION ANTIPSYCHOTICS
(ATYPICALS)

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Aripiprazole

a second-generation (atypical) antipsychotic approved for the


treatment of schizophrenia, bipolar disorder, depression and
autism spectrum disorders.

Aripiprazole was originally approved in 2002 for the treatment of


schizophrenia.

Currently, the FDA has approved aripiprazole for the treatment of


bipolar disorder (maniaand mixed episodes and as maintenance
treatment), asadjunctive
treatment for major depressive disorder(2006) and for
autism spectrum disorders (2007)

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Recommended
Indication Initial Dose Maximum Dose
Dose

Schizophrenia

Adults 10-15 mg/day 10-15 mg/day 30 mg/day

Adolescents 2 mg/day 10 mg/day 30 mg/day


Bipolar Disorder

Treatment of
manic or mixed
episodes
Bipolar Mania 15 mg/day 15 mg/day 30 mg/day
Adults
Monotherapy

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Bipolar Mania 10-15 mg/day 15 mg/day 30 mg/day
Adults
Adjunt to lithium
or valproate
Bipolar Mania 2 mg/day 10 mg/day 30 mg/day
Pediatric patients
Monotherapy or
adjunct to lithium
or valproate
Maintenance
treatment
Maintenance Doses not
treatment of available in
bipolar I disorder product
monograph.
Major
Depressive
Disorder
Adjunct to 2-5 mg/day 5-10 mg/day 15 mg/day
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antidepressants
Formulations

Tablets
Orally disintegrating tablets
Liquid formulation
IM injection

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General pharmacokinetics and drug interactions

Half-life

aripiprazole: 75 hours
dehydro-aripiprazole: 94 hours
Elimination
Mainly through hepatic metabolism
involving two P450 enzymes:

CYP3A4: dose adjustment might be needed


in the presence of inhibitors or inducers. 33
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Pharmacokinetics of oral administration

Absorption
Peak plasma concentrations occur within 3 to 5 hours.
Can be admininistered with or without food.
According to the manufacturer, a study found that plasma
concentrations from the oral solution were higher than that from the
tablet formulation.
Distribution

Volume of distribution in studies after IV administration is of 404 L


or 4.9L/Kg (extense extravascular distribution)
Aripiprazole and dehydro-aripiprazole are greater than 99% bound
to serum proteins (primarily albumin)

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Pharmacokinetics of IM administration

Median times to the peak plasma concentration: 1


hours and 3 hours.

In one pharmacokinetic study [Boulton,2008],


intramuscular aripiprazole demonstrated more rapid
attainment of plasma aripiprazole concentrations
than oral aripiprazole (78% and 5% of peak plasma
concentration [Cmax] values at 0.5 hours postdose,
respectively).
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Aripiprazole binds to a number of CNS
receptors, this includes effects as:
partialD2agonist
partial5-HT1Aagonist
5-HT2A antagonist

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D2 PARTIAL AGONIS

What are the implications of D2


partial agonism? Aripiprazole
binds to theD2 receptorwith
the same affinity than dopamine,
but has a lower intrinsic efficacy,
so the response it triggers is
lower than dopamine but higher
than an antagonist.

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As partial agonist at D2 receptors, it
modulates neurotransmission in
dopaminergic pathways (mainly
mesolimbic and mesocortical pathway).
According to the dopamine theory of
schizophrenia, overactivity of the
mesolimbic pathway may trigger positive
symptoms (hallucinations, delusions).

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Positive symptoms of schizophrenia might be the result of an overactivation of the m
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Aripiprazole reduces dopaminergic activity in the mesolimbic pathway through partia

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The dopamine theory of negative and cognitive symptoms suggests that there
is a hypofunction of dopaminergic neurotransmission in the mesocortical
pathway.

Dopaminergic activity in the mesocortical pathway is thought to be reduced in schizoph


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One postulated mechanism of action of aripiprazole in schizophrenia is the
ability of the drug to increase dopaminergic activity from a subnormal level to
normal activity in the mesocortical pathway.

Partial D2 agonism might increase dopaminergic activity in the mesocortical pathway.


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Key Points

Aripiprazole is a partial agonist at D2


receptors.
It may act as an antipsychotic by:
Lowering dopaminergic neurotransmission
in the mesolimbic pathway.
Enhancing dopaminergic activity in the
mesocortical pathway.
It has a lower risk of EPS and
hyperprolactinemia than other
antipsychotics. 46
RISPERIDONE
Risperidone is one of the oldest (and
least expensive) second-generation
antipsychotics.
In 1993 the FDA approved it for the
treatment of schizophrenia. Like most
antipsychotics, risperidone is also
effective for the treatment of manic and
mixed episodes of bipolar I disorder.
It is also one of the few antipsychotics
approved for use in children [1].
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Effective
Indication Initial Dose Titration Target Dose
Dose Range
Schizophren
ia
Adults 2 mg/day 1-2 mg/day 4-8 mg/day 4-16 mg/day

Adolescents 0.5 mg/day 0.5-1 mg/day 3 mg/day 1-6 mg/day


Bipolar
Disorder
Treatment of
manic or
mixed
episodes
Bipolar Mania 2-3 mg/day 1 mg/day 1-6 mg/day 1-6 mg/day
Adults

Bipolar Mania 0.5 mg/day 0.5-1 mg/day 2.5 mg/day 0.5-6 mg/day
Children /
Adolescents 48
Pharmacokinetics of
Risperidone
Risperidone is a second-generation
antipsychotic metabolized by
theenzymecytochrome P450 2D6
(CYP2D6). It is available as long-acting
injection (depot injection) as well as oral
formulations.

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Formulations

Oral formulations:
Tablets
Orally disintegrating tablets
Liquid formulation
Long-acting injection: risperidone microspheres
(Risperdal Consta)
Distribution
Volume of distribution: 1-2 L/kg.
Risperidone binds to albumin and alpha1-acid glycoprotein.
Plasma protein binding:
For risperidone: 90%
For 9-hydroxyrisperidone: 77%

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Risperidone metabolism by CYP2D6

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METABOLISM
CYP 2D6 is the enzyme that catalyzes
hydroxylation of risperidone to 9-
hydroxyrisperidone.
The metabolite 9-hydroxyrisperidone
has similar pharmacological activity as
risperidone.
CYP 2D6 is subject to genetic
polymorphism:
Extensive metabolizers convert risperidone
rapidly into 9-hydroxyrisperidone 52
Pharmacokinetics of Oral
Formulations
Absorption

Orally disintegrating tablets and oral solution are bioequivalent to tablets.

Rapidly absorbed after oral administration.

Peak plasma levels achieved within 1 hour.

Linear pharmacokinetics.

Time to reach steady state ( between 4 and 5 half-lives for all drugs):
For risperidone:
1 day in extensive metabolizers.
5 days in poor metabolizers.
For 9-hydroxyrisperidone:
5-6 days, measured in extensive metabolizers.

Food effect: risperidone can be administered with or without meals.

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Pharmacokinetics of Long-
Acting Injection
(Risperidone Microspheres)

Risperidone microspheres release


considerable amounts of drug 3
weeks after injection.
Long-acting risperidone should be
supplemented with oral
risperidone for 3 weeks.
Apparent half-life or risperidone
plus 9-hydroxyrisperidone is 3 to
6 days (related to the erosion of
the microspheres and subsequent
absorption of risperidone).

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Olanzapine

Olanzapine (Zyprexa) is a second-


generation antipsychotic approved
for the treatment of schizophrenia
and bipolar disorder. A combination
of the antidepressant fluoxetine
and olanzapine (OFC,
olanzapine/fluoxetine combination)
is also available under the trade
nameSymbyax.
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List of FDA-Approved Indications

FDA- Approved FDA- Approved


Dosage Dosage
Indication Indication

Schizophrenia Schizophrenia

Schizophrenia in Oral: Start at 5-10 mg Schizophrenia in Oral: Start at 5-10 mg


adults once daily adults once daily
Target: 10 mg/day Target: 10 mg/day
within several days within several days

Schizophrenia in Oral: Start at 2.5-5 mg Schizophrenia in Oral: Start at 2.5-5 mg


adolescents once daily adolescents once daily
Target: 10 mg/day Target: 10 mg/day

Bipolar I Disorder Bipolar I Disorder

Manic or mixed Oral: Start at 10 or 15 Manic or mixed Oral: Start at 10 or 15


episodes in adults mg once daily episodes in adults mg once daily

Manic or mixed Oral: Start at 2.5-5 mg Manic or mixed Oral: Start at 2.5-5 mg
episodes in once daily; Target: 10 episodes in once daily; Target: 10
adolescents mg/day adolescents mg/day

Manic or mixed Oral: Start at 10 mg Manic or mixed Oral: Start at 10 mg


episodes with lithium once daily episodes with lithium once daily
or valproate in adults or valproate in adults 56
Intramuscular formulation

FDA- Approved Indication Dose


Agitation associated with IM: 10 mg (5 mg or 7.5 mg
Schizophrenia and Bipolar I when clinically warranted)
Mania in adults Assess for orthostatic
hypotension prior to
subsequent dosing (max. 3
doses 2-4 hrs apart)

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Olanzapine fluoxetine combination
(OFC)
FDA- Approved Indication Dose
Bipolar I Disorder

Depressive Episodes associated with Oral in combination with fluoxetine:


Bipolar I Disorder in adults Start at 5 mg of oral olanzapine and
20 mg of fluoxetine once daily

Depressive Episodes associated with Oral in combination with fluoxetine:


Bipolar I Disorder in children and Start at 2.5 mg of oral olanzapine
adolescents and 20 mg of fluoxetine once daily

Depression

Treatment Resistant Depression in Oral in combination with fluoxetine:


adults Start at 5 mg of oral olanzapine and
20 mg of fluoxetine once daily

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Mechanism of Action

The mechanism of action of ziprasidone, as


with other drugs having efficacy in
schizophrenia, is unknown. However, it has
been proposed that this drugs efficacy in
schizophrenia is mediated through a
combination of dopamine type 2 (D2) and
serotonin type 2 (5HT2) antagonism. As
with other drugs having efficacy in bipolar
disorder, the mechanism of action of
ziprasidone in bipolar disorder is unknown.
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TERIMAKASIH

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