ANTIDEPRESAN. dr Sufi Desrini M.Sc

(1)

ANTIDEPRESAN

(2)

Tujuan belajar

◦ Memahami jenis antidepresan

◦ Memahami mekanisme kerja antidepresan ◦ Menjelaskan indikasi klinis antidepresan ◦ Menjelaskan efek samping antidepresan

(3)

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,

(4)

◦ 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

(5)

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

(6)

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 neurotransmiterstimulasi saraf

meningkat  saraf yang sensitif tadi kembali ke normal

Proses tsb butuh waktu hal ini menjelaskan mengapa aksi obat antidepresan tidak terjd

secara segera

(7)

Bukti Farmakologi Pendukung Teori

Monoamin

Obat Prinsip kerja Efek pd pasien depresi

Antidepresan trisiklik Menghambat reuptake

noradrenalin dan 5-HT Mood meningkat MAU inhibitors Meningkatkan simpanan

(8)

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, nortriptylineada

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 α2 adrenoceptors dan 5-HT receptors

Monoamine oxidase inhibitors (MAOIs)

•Inhibitor non kompetitif ireversibel : phenelzine dan tranylcypromine •Inhibitor selektif O-A yang reversibel : moclobemide

(9)

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 group



menghambat 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

(10)

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

(11)

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

(12)

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 CYP2D6toksisitas 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)

(13)

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.

(14)

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

(15)

◦ 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

(16)

◦ Efek samping:

◦ Pada orang normal: TCA  sedasi, bingung dan inkoordinasi motorikjuga 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 alkoholdepresi napas beratkematian

◦ Intoksikasi akut:

◦ Overdosis berbahaya

◦ Efek utama pd SSP dan jantung

◦ Deliriumkejangkoma dan depresi napas slm bbrp hari

(17)

Farmakokinetika:

•Oral



absorpsi cepat

•Berikatan kuat dg albumin plasma

•Berikatan juga dg jar ekstravaskular



volume distribusi

mnjd lbh besar dan laju eliminasi menjd lbh kecil

•Dimetabolisme di hepar: N-demetilasi dan hidroksilasi

cincin

(18)

Monoamine Oxidase Inhibitors (MAOI’s)

◦

Long acting, irreversible inhibitors of monoamine oxidase

◦

Have been used since the 1950’s 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

(19)

Irreversible MAOI’s

◦

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),

(20)

Reversible MAOI’s

◦ not available in the U.S. yet

◦ Highly selective in inhibiting MAO-A ◦ Much safer than irreversible MAOI’s ◦ Side effects are minimal

(21)

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

Parkinson’s

◦

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-HT

₁

Agonists – appear to be responsible for

(22)

(23)

Ansietas

Physical and emotional distress which

interfere with normal life.

(24)

Common Emotional Symptoms of

anxiety

◦ Irasional dan rasa kuatir serta takut berlebihan ◦ Mudah marah

◦ Gelisah

◦ Sulit berkonsentrasi ◦ Merasa tegang

(25)

Common Physical Symptoms of

Anxiety

berkeringat Takikardi Dispepsia Nafas pendek

BAK sering dan diare Insomnia

(26)

Types of anxiety

Generalized anxiety disorder

Post-traumatic stress disorder (PTSD).

Obsessive-compulsive disorder (OCD).

Panic disorder

(27)

Generalized Anxiety Disorder

(GAD)

Pasien biasanya secara konstan kuatir

mengenai kesehatan, uang, pekerjaan dengan

alasan yang gak jelas

(28)

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

(29)

Panic

disorder

An disorder in which people have sudden and intense

attacks of anxiety in certain situations.

(30)

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.

(31)

Fobia

An intense, uncontrolled fear of a specific situation such

as Open spaces and heights

(32)

Treatment of anxiety

◦ Psychotherapy (cognitive behavioral therapy).

(33)

Classification of anxiolytic drugs:

1. Benzodiazepines ( BDZ ).

2. 5HT

_1A

agonists.

3. 5HT reuptake inhibitors.

4. Antidepressants

5. beta-adrenergic blockers

6. MAO inhibitors

(34)

(35)

Classifications of Benzodiazepines

-

Short acting: (3-5 hours):

tria

zolam

-

Intermediate: (6-24 hours)

Alpra

zolam

Lora

zepam

Oxa

zepam

Esta

zolam

Tema

zepam

(36)

Classifications of Benzodiazepines

-

Long acting: ( 24-72 hours)

Clona

zepam

Chlordiazepoxide

Dia

zepam

(37)

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 (γ-aminobutyric acid):

(38)

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):21–22)

(39)

◦ The GABA-A receptor complex is composed of 5 glycoprotein subunits, each with

multiple isoforms

(40)

GABA-A receptors contain 2 α subunits, 2 β subunits, and 1 γ subunit

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

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

BZDs bind to the pocket created by α and γ 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

(41)

The BZD receptor has been classified into several types, based on α subunit isoforms and clinical effects related to each type.

The BZ1 receptor contains the α1 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 α1 subunit.

BZ2 receptors contain the α2 isoformand mediate the anxiolytic and, to a large extent, the myorelaxant effects of BZDs.

BZ2highly concentrated in areas such as the limbic system, motor neurons, dorsal horn

(42)

(43)

◦

The anxiolytic effects of BZDs are believed to be

mediated through BZ2 receptors located in the limbic

system, and myorelaxant properties are mediated via

α2-containing receptors in the spinal cord and motor

neurons.

(44)

Benzodiazepine Pharmacokinetics

◦

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

intranasal, or rectal gel forms.

◦

Characteristics of the drug—including lipid solubility, binding to plasma

proteins, and molecular size—influence 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

(45)

Benzodiazepine Pharmacokinetics

◦

Following intramuscular injection, absorption of

diazepam

or

(46)

Benzodiazepine Pharmacokinetics

◦

BZDs and their metabolites are highly protein bound.

◦

They are widely distributed in the body and preferentially accumulate in

(47)

◦

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

(48)

◦

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

(49)

(50)

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

(51)

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

(52)

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 T

ablets, 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.

(53)

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

(54)

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

(55)

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

(56)

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

(57)

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

α2-containing receptors in the limbic system

.

◦

At higher doses

, diazepam may provide

myorelaxation

in addition to anxiolysis;

the myorelaxant effect is primarily mediated through

α2-containing receptors in

the spinal cord and motor neurons

and to a lesser extent through

interaction with

α3-containing receptors

(58)

Diazepam

◦ at higher doses, sedation and anterograde amnesia are also noted, but these effects

are α1-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

(59)

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