ANTIDEPRESAN. dr Sufi Desrini M.Sc

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 5hidroksitriptamin (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 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

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 noradrenalin dan 5-HT

Mood meningkat

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

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 • 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 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)

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 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

Tricyclic antidepressant drugs 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

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 5HT and NE ◦ Two types ◦ MAO-A: inhibition causes antidepressant activity ◦ MAO-B: inhibition causes side effects

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), isocarboxazid (Marplan)

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 ◦ 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 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-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 (γ-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):21–22)

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 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

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 isoform and 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 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 α2-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 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 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 lipidrich 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 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

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 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 longterm 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