ANTIDEPRESAN

dr Sufi Desrini M.Sc

Tujuan belajar
Memahami jenis antidepresan
Memahami mekanisme kerja antidepresan
Menjelaskan indikasi klinis antidepresan
Menjelaskan efek samping antidepresan
Pendahuluan
Depresi adalah salah satu kondisi psikiatrik yang banyak dijumpai di klinik
Merupakan gangguan mood
Sifat gangguan mulai dari ringan hingga berat yang biasanya juga disertai gejala
psikotik
Depresi menjadi penyebab utama disabiltas dan kematian dini
Biasanya sering dihubungkan dengan gangguan psikiatrik lainnya seperti anxietas,
gangguan makan dan adiksi obat
Pendahuluan
Gejala depresi meliputi unsur biologi dan emosional
Gejala emosional meliputi moodnya rendah, pikiran negatif, menderita, apatis,
pesimis, kepercayaan diri rendah, merasa bersalah, motivasi rendah, anhedonia.
Unsur biologi meliputi gejala hilang minat seksual, gangguan tidur, nafsu makan hilang,
kemunduran dalam berpikir dan bekerja
Terdapat 2 jenis depresi: unipolar depression dan bipolar affective disorder
Teori Patofisiologi Depresi
Teori Monoamin
Hipotesis monoamin:
diusulkan pertama kali oleh Schildkraut tahun 1965
depresi disebabkan oleh defisiensi senyawa monoamin, noradrenalin dan 5-
hidroksitriptamin (5-HT)
Mania ok kelebihan fungsional dr transmiter tsb
Menurut teori tsb, depresi dapat diatasi oleh obat yang dapat meningkatkan
ketersediaan serotonin dan adrenalin, misal MAU inhibitor atau antidpresan trisiklik
Namun ternyata teori tsb tidak mampu menjelaskan mengapa onset obat
antidepresn lama (6-8 minggu) padahal obat-obat tadi bisa meningktkan
ketersediaan neurotransmiter secara cepat
Muncullah hipotesis sensitivitas reseptor
 Teori Patofisiologi Depresi
Teori : Depresi merupakan hasil perubahan patologis pada reseptor, yang diakibatkan
oleh terlalu kecilnya stimulasi monoamin

Besar kecilnya stimulasi oleh neurotransmiter mengakibatkan saraf post-sinap berespon (

sbg kompensasi)

Kalau stimulasi terll keci saraf menjadi lebih sensitif atau jumlah reseptor menjadi
meningkat (up-regulasi)

Kalau stimulasi berlebihan saraf mengalami desensitisasi atau down-regulasi

Obat antidepresan biasanya bekerja meningkatkan neurotransmiterstimulasi saraf

meningkat saraf yang sensitif tadi kembali ke normal

Proses tsb butuh waktu hal ini menjelaskan mengapa aksi obat antidepresan tidak terjd
secara segera
Bukti Farmakologi Pendukung Teori
Monoamin
Obat Prinsip kerja Efek pd pasien depresi
Antidepresan trisiklik Menghambat reuptake Mood meningkat
noradrenalin dan 5-HT
MAU inhibitors Meningkatkan simpanan Mood meningkat
noradrenalin dan 5-HT
Jenis Antidepresan
Inhibitors of monoamine uptake
Selective serotonin (5-HT) reupatake inhibitors (SSRIs) fluoxetine, fluvoxamine, sertraline, paroxetine,
citaprolam
Classical tricyclic antidepressants (TCAs) Imipramine, desipramine, amitriptyline, nortriptylineada
variasi kemampuan menghambat reuptake noradrenalin dan 5-HT
Campuran 5-HT dan noradrenalin reuptake inhibitors venlafaxine
Noradrenaline reupatke inhibitors bupropion, reboxetine dan atomoxetine
Monoamine receptor antagonists
Mirtazapine, trazodone, mianserine merupakan non selektif dan menghambat reseptor amin
termasuk 2 adrenoceptors dan 5-HT receptors
Monoamine oxidase inhibitors (MAOIs)
Inhibitor non kompetitif ireversibel : phenelzine dan tranylcypromine
Inhibitor selektif O-A yang reversibel : moclobemide
Jenis Antidepresan
1. SSRIs selektif thd 5-HT
Efek samping : Nausea, diare, agitasi, insomnia, anorgasmia, menghambat metabolisme
obat, risiko interaksi obat
Fluoxetine: T1/2 24-96 h
Fluvoxamine: T1/2 18-24 h
Sertraline: T1/2 24-36 h

2. Classical TCA groupmenghambat reuptake NA dan 5-HT

Efek sampig: sedasi, efek antikolinergik (mulut kering konstipasi, pandangan kabur dll),
hipotensi postural, kejang, impotens, interaksi dg alkohol dan MAU inhibitors
Risiko overdosis dg gejala ventrikular disritmia jika dikombinasi dg depresan CNS
Imipramine : T1/2 4-18 h
Amitriptyine : T1/2 12-24 h
Jenis Antidepresan
Monoamine receptor antagonist
Mirtazapine : menghambat reseptor 5-HT2c dan 5-HT3
Efek samping sedasi, mulut kering
T1/2 20-40 h

MAO INHIBITORS
Inhibitors MAU-A dan/atau MAO-B
Phenelzine: non selektif , T1/2 1-2 h
Monoamine uptake inhibitors-SSRIs
Selektif inhibitor reupatke 5-HT

Fluoxetine, fluvoxamine, paroxetine, citaprolam dan sertraline

Indikasi :
depresi derajat menengah namun kurang efektif mengatasi depresi
derajat berat
Ansietas
Fluoxetine:ok juga memiliki aktifias antagonis 5-HT2c maka efektif juga
untuk treatment anoreksia dan bulimia
Sertraline inhibitor uptake dopamin (lemah)
Monoamine uptake inhibitors-SSRIs
Aspek farmakokinetika:
Diabsorpsi baik
T1/2 rata rata 18-24 jam
Fluoxetine kerjanya lbh panjang 24-96 jam
Efek terapi baru tampak sekitar 2-4 minggu kemudian
Paroxetine dan fluoxetine tidak boleh dikombinasikan dengan TCAs ok menghambat
metabolisme TCA melalui interaksi dg CYP2D6toksisitas TCA meningkat

Efek samping:
Nausea, anoreksia, insomnia, hilang libido, gagal orgasme
Beberapa efek ini diakibatkan oleh peningkatan stimulasi postsinap reseptor 5-HT akibat
peningkatan konsentrasi obat atau akibat stimulasi reseptor yang sama namun regio
berbeda (reseptor 5-HT1A)
Monoamine uptake inhibitors-SSRIs

Efek samping:
Kombinasi dg MAOIs, SSRIs menyebabkan
sindroma serotonin: ditandai dg tremor, hipertermia,
kolaps KV
SSRI tidak direomendasikan utk mengobat depresi
pd usia kurang dari 18 tahun ok efikasinya masih
diragukan dan efek samping khususnya peningkatan
usaha bunuh diri.
Tricyclic antidepressant drugs

Imipramine, desipramine, amitryptiline,nortriptyline dan clomipramine

Masih digunakan meskipun jauh dari ideal

Dibutuhkan ok kerjanya cepat dan kurang bersiko jika overdosis

Strukturnya hampir sama dg fenotiazin

Tricyclic antidepressant drugs
Mekanisme kerja:
Efeknya segera
Menghambat uptake amin oleh saraf terminal dg cara berkompetisi pd tempat ikatan
transporter amin
Kebanyakan TCA menghambat uptake NA dan 5-HT dan kecil pengaruhnya thd uptake
dopamin
Perbaikan gejala emosi sbg akibat peningkatan transmisi yang diperantarai oleh 5-HT
Perbaikan gejala biologi sbg akibat dr fasilitasi transmisi NA
Metabolitnya memiliki aktifitas farmakologi
TCA juga mempengaruhi reseptor lainnya seperti reseptor muskarinik asetilkolin, reseptor
histamin
Tricyclic antidepressant drugs
Efek samping:
Pada orang normal: TCA sedasi, bingung dan inkoordinasi motorikjuga terjadi pd ps
depresi dalam waktu bbrp hari pengobatan dan berkurang dalam waktu 1-2 minggu
Mempengaruhi kontrol autonom juga
Atropine-like effects : mulut kering, pandangan kabur, konstipasi dan retensi urin.
Interaksi obat:
Jika diberikan bersama obat lain cenderung tjd efek samping berat
Mempengaruhi metabolisme obat lain
Diberikan dg alkoholdepresi napas beratkematian
Intoksikasi akut:
Overdosis berbahaya
Efek utama pd SSP dan jantung
Deliriumkejangkoma dan depresi napas slm bbrp hari
Tricyclic antidepressant drugs

Farmakokinetika:
Oral absorpsi cepat
Berikatan kuat dg albumin plasma
Berikatan juga dg jar ekstravaskularvolume distribusi
mnjd lbh besar dan laju eliminasi menjd lbh kecil
Dimetabolisme di hepar: N-demetilasi dan hidroksilasi
cincin
Monoamine Oxidase Inhibitors (MAOIs)
Long acting, irreversible inhibitors of monoamine oxidase
Have been used since the 1950s but have a controversial past
Has potential for serious side effects and potentially fatal
interactions with other drugs and food
MAO is one of two enzymes that break down neurotransmitters 5-
HT and NE
Two types
MAO-A: inhibition causes antidepressant activity
MAO-B: inhibition causes side effects
Irreversible MAOIs
Nonselective: block both A and B types
Form a permanent chemical bond with part of the
MAO enzyme (enzyme function returns only as new
enzyme is biosynthesized)
Have a rapid rate of elimination, excess drug is rapidly
metabolized
Inhibition occurs slowly
Ex: phenelzine (Nardil), tranylcypomine (Parnate),
isocarboxazid (Marplan)
Reversible MAOIs
not available in the U.S. yet
Highly selective in inhibiting MAO-A
Much safer than irreversible MAOIs
Side effects are minimal
Ex: Brofaromine, Pirlindole, Toloxatone, and Moclobemide
New Drug Treatments
COMT inhibitors second of two enzymes that catalyze the
inactivation of DA and NE by decreasing neurotransmitter
levels
Tolcapone specific inhibitor of COMT used in treatment of
Parkinsons
SNRI soon to be available for clinical use
Reboxetine first of its kind to block NE reuptake without also
blocking DA or 5-HT reuptake
Serotonin 5-HT1 Agonists appear to be responsible for
acute antidepressant effects
ANTI ANSIETAS
Ansietas

Physical and emotional distress which

interfere with normal life.
Common Emotional Symptoms of
anxiety

Irasional dan rasa kuatir serta takut berlebihan

Mudah marah
Gelisah
Sulit berkonsentrasi
Merasa tegang
Common Physical Symptoms of
Anxiety

berkeringat
Takikardi
Dispepsia
Nafas pendek
BAK sering dan diare
Insomnia
Fatigue
Types of anxiety

Generalized anxiety disorder

Post-traumatic stress disorder (PTSD).

Obsessive-compulsive disorder (OCD).

Panic disorder

Phobia
 Generalized Anxiety Disorder
(GAD)

Pasien biasanya secara konstan kuatir

mengenai kesehatan, uang, pekerjaan dengan
alasan yang gak jelas
 Obsessive-Compulsive Disorder
(OCD)

An anxiety disorder in which people cannot prevent

themselves from unwanted thoughts or behaviors that
seem impossible to stop as

Washing their hands

WASHING THEIR HANDS
 Panic disorder
An disorder in which people have sudden and intense
attacks of anxiety in certain situations.
 Post-traumatic stress disorder
(PTSD)

An anxiety disorder that affects people who have

experienced a severe emotional trauma, such as rape
or dramatic car accident, or even war.
 Fobia
An intense, uncontrolled fear of a specific situation such
as Open spaces and heights
Treatment of anxiety
Psychotherapy (cognitive behavioral therapy).

Anxiolytics
Classification of anxiolytic drugs:

1. Benzodiazepines ( BDZ ).
2. 5HT1A agonists.
3. 5HT reuptake inhibitors.
4. Antidepressants
5. beta-adrenergic blockers
6. MAO inhibitors
Benzodiazepines
Classifications of Benzodiazepines

- Short acting: (3-5 hours): triazolam

- Intermediate: (6-24 hours)
Alprazolam
Lorazepam
Oxazepam
Estazolam
Temazepam
Classifications of Benzodiazepines

- Long acting: ( 24-72 hours)

Clonazepam
Chlordiazepoxide
Diazepam
Flurazepam
Mechanism of Action
Benzodiazepines act by binding to BZ
receptors in the brain enhance GABA
action on brain chloride channels
opening chloride influx to the cell
hyper- polarization inhibition of brain.

GABA (-aminobutyric acid):

is an inhibitory neurotransmitter
GABA AND GABA-A-RECEPTOR
BZDs act as positive allosteric modulators on the gamma amino butyric acid (GABA)-A
receptor.
The GABA-A receptor is a ligand-gated chloride-selective ion channel
GABA is the most common neurotransmitter in the central nervous system, found in high
concentrations in the cortex and limbic system.
GABA is inhibitory in nature and thus reduces the excitability of neurons
GABA produces a calming effect on the brain. (Cascade E, Kalali AH. Use of benzodiazepines in the treatment of
anxiety. Psychiatry (Edgmont) 2008 Sep;5(9):2122)
GABA AND GABA-A-RECEPTOR
The GABA-A receptor complex is composed of 5 glycoprotein subunits, each with
multiple isoforms
GABA AND GABA-A-RECEPTOR

GABA-A receptors contain 2 subunits, 2 subunits, and 1 subunit

Each receptor complex has 2 GABA-binding sites but only 1 BZD-binding site

BZDs bind to the pocket created by the and subunits and induce a conformational change in the GABA-A
receptor, allowing GABA to bind.

BZDs bind to the pocket created by and subunits and induce a conformational change in the GABA-A
receptor. This alteration, in turn, induces a conformational change in the GABA-A receptor's chloride channel that
hyperpolarizes the cell and accounts for GABA's inhibitory effect throughout the central nervous system
The BZD receptor has been classified into several types, based on subunit isoforms and
clinical effects related to each type.

The BZ1 receptor contains the 1 isoform.

The BZ1 receptor is highly concentrated in the cortex, thalamus, and cerebellum

it is responsible for the BZDs' sedative effects and anterograde amnesia and for some of
the anticonvulsive effects of diazepam

Sixty percent of GABA-A receptors contain the 1 subunit.

BZ2 receptors contain the 2 isoform and mediate the anxiolytic and, to a large extent,
the myorelaxant effects of BZDs.

BZ2highly concentrated in areas such as the limbic system, motor neurons, dorsal horn
of spinal cord
 The anxiolytic effects of BZDs are believed to be
mediated through BZ2 receptors located in the limbic
system, and myorelaxant properties are mediated via
2-containing receptors in the spinal cord and motor
neurons.
Benzodiazepine Pharmacokinetics

BZDs can be administered via intramuscular, intravenous, oral, sublingual,

intranasal, or rectal gel forms.
Characteristics of the drugincluding lipid solubility, binding to plasma
proteins, and molecular sizeinfluence the volume of distribution.
BZDs are usually well absorbed by the gastrointestinal tract after oral
administration.
After intravenous administration, BZDs quickly distribute to the brain and
central nervous system.
Absorption of intramuscular administration of lorazepam or midazolam
appears to be rapid and complete
Lorazepam is well absorbed after sublingual administration, reaching peak
levels in 60 minutes.
Benzodiazepine Pharmacokinetics
Following intramuscular injection, absorption of diazepam or
chlordiazepoxide is slow and erratic
Benzodiazepine Pharmacokinetics
BZDs and their metabolites are highly protein bound.
They are widely distributed in the body and preferentially accumulate in lipid-
rich areas such as the central nervous system and adipose tissue
Benzodiazepine Pharmacokinetics
Most BZDs are oxidatively metabolized by the cytochrome P450
enzymes (phase I), conjugated with glucuronide (phase II), and
excreted almost entirely in the urine
Midazolam, one of the short-acting BZDs, produces no active
metabolites
Benzodiazepine Pharmacokinetics
Diazepam, a long-acting BZD, produces the active metabolites
oxazepam, desmethyldiazepam, and temazepam
These metabolites further increase the duration of drug action and should be a
serious consideration in some patient groups, especially the elderly and those with
extensive hepatic disease
Alprazolam

a short-acting high-potency BZD with an elimination half-life of 6-27 hours

Alprazolam is commonly prescribed for panic disorders and anxiety
The recommended dose for anxiety starts with 0.25-0.5 mg tablets, administered by
mouth 3 times per day
The maximum recommended daily dose of alprazolam for anxiolysis should not exceed
4 mg
For panic disorders, the same tablet form and route of administration are
recommended at a maximum recommended dose of 6-10 mg/d
HATI2 REBOUND ANXIETY
Clonazepam

the second high-potency BZD discovered.

Clonazepam behaves both as a GABA-A receptor agonist in a
highly-potent, long-acting manner and also as a serotonin
agonist.
Clonazepam has anticonvulsant and anxiolytic effects.
One study proved clonazepam to be at least as effective as
lithium for treating acute mania
In association with serotonin reuptake blockers, clonazepam
appears to accelerate treatment response to panic disorder
Clonazepam
In another study, clonazepam proved as effective for treating panic disorders
as alprazolam, and termination did not cause rebound anxiety symptoms
because of clonazepam's long elimination half-life.
Clonazepam displays low lipid solubility, it is less likely to cause anterograde
amnesia compared to the other high-potency BZDs. For example,
clonazepam is half as lipid soluble as alprazolam, so patients' amnesic side
effects are reduced.
Clonazepam also has a relatively weaker binding affinity for GABA-A receptors
than the other high-potency BZDs
Clonazepam, when used to treat panic disorders, should be initiated at a dose
of 0.25 mg Tablets, taken orally twice a day for 3 days, after which the dose
should be increased to 0.5 mg tablets twice daily. The maximum daily dose
should not exceed 1-4 mg.
Clorazepam
For treating seizure disorders, adults should start with 0.5 mg tablets taken orally
3 times per day. For this indication, the maximum daily dose should not
exceed 20 mg
Lorazepam

another high-potency BZD that displays short-acting

characteristics slightly less lipid soluble compared with
alprazolam, suggesting a lower risk of amnesic side effects
compared to alprazolam
binds GABA-A with less affinity than alprazolam but with greater
affinity than clonazepam.
Lorazepam has proven effective as an anticonvulsant and also
works well as an adjunct to antipsychotics in the treatment of
acute agitation and mania
Lorazepam
lorazepam can be used in patients with hepatic or renal
dysfunction with only minor effects on the drug's
pharmacokinetics it undergoes direct glucuronidation without
prior cytochrome p450 metabolism
Lorazepam
Lorazepam dosing largely depends on the indication
For alcohol withdrawal, clinicians prescribe 2 mg tablets orally every 6 hours for
a total of 4 doses, followed by 1 mg every 6 hours for a total of 8 doses.
For anxiolysis, dosing begins with 2-3 mg/d orally, divided into 3 doses per day.
Maximum daily doses should not exceed 10 mg
The safety and effectiveness of oral forms have not been established in
children under the age of 12. However, the same dosing recommendations for
adults apply to children over the age of 12.
For sedation, such as in the intensive care unit (ICU), 0.01-0.1 mg/kg/h
intravenously is recommended.
Diazepam
a long-acting, medium-potency BZD that is used as an anticonvulsant and for
anxiolysis, sedation, and myorelaxation.
Diazepam, one of the most common BZDs used for anxiety,
is available in intramuscular, intravenous, oral, and rectal gel forms
Diazepam interacts with equal affinity on all BZD-sensitive receptors in the central
nervous system
Anxiolytic effects are seen at low doses because of diazepam's interaction with
2-containing receptors in the limbic system.
At higher doses, diazepam may provide myorelaxation in addition to anxiolysis;
the myorelaxant effect is primarily mediated through 2-containing receptors in
the spinal cord and motor neurons and to a lesser extent through interaction with
3-containing receptors
Diazepam
at higher doses, sedation and anterograde amnesia are also noted, but these effects
are 1-mediated
Diazepam is unique in that its metabolism in the liver METABOLITES (oxazepam,
temazepam, and desmethyldiazepam)
when prescribing this drug, clinicians must consider potential side effects related to
active metabolite buildup, such as oversedation and anterograde amnesia. These side
effects can be serious and long-lasting, especially in the elderly and in those with
hepatic or renal dysfunction
Diazepam, when used for anxiety, can be given as 2-10 mg orally, 2-4 times per day
depending on symptom severity and the patient's age
EFEK SAMPING BZD
Common side effects among all BZDs include drowsiness, lethargy, and fatigue.
At higher dosages, impaired motor coordination, dizziness, vertigo, slurred speech,
blurry vision, mood swings, and euphoria can occur s well as hostile or erratic behavior
in some instances
BZDs are eliminated slowly from the body, so repeated doses over a prolonged period
can result in significant accumulation in fatty tissues.
some symptoms of overmedication (impaired thinking, disorientation, confusion, slurred
speech) can appear over ime.
Tolerance, dependence, and withdrawal are adverse effects associated with long-
term use.
INTERAKSI
Drug interaction is another issue with BZDs.
They are metabolized in the liver via the cytochrome
p450 system and subsequently glucuronidated and
renally excreted.
Drugs that either attenuate (oral contraceptive pills,
antifungals, and some antibiotics) or potentiate
(carbamazepine, phenytoin, rifampin, St. John's wort)
cytochrome p450 enzymes will either increase or
decrease the elimination half-life of BZDs, respectively
Interaksi
BZD + OPIOID =Severe adverse effects
TERIMAKASIH