ANTIPSIKOTIK
dr. sufi desrini M.Sc
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Tujuan Belajar
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GENERASI PERTAMA
ANTIPSIKOTIK
Dikenal dengan nama
antipsikotik tipikal, antagonis
dopamin, neuroleptik dan
antipsikotik klasik
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NEUROLEPTIK
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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
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
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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
Thiothixene
Zuclopenthixol
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Non-phenothiazine first-
generation antipsychotics.
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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
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
Pimozide 2 mg/day
Molindone 10 mg/day
Perphenazine 10 mg/day
Prochlorperazine 15 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
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SECOND GENERATION ANTIPSYCHOTICS
(ATYPICALS)
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Aripiprazole
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Recommended
Indication Initial Dose Maximum Dose
Dose
Schizophrenia
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:
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
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Pharmacokinetics of IM administration
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D2 PARTIAL AGONIS
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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.
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
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.
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Pharmacokinetics of Long-
Acting Injection
(Risperidone Microspheres)
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Olanzapine
Schizophrenia Schizophrenia
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
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Olanzapine fluoxetine combination
(OFC)
FDA- Approved Indication Dose
Bipolar I Disorder
Depression
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Mechanism of Action
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