Alprazolam

 Golongan : Benzodiazepine (anxiolytic)

 Generik : alprazolam.

 Dagang : Xanax, Atarax, Zypras.

 Indikasi :

 Generalized anxiety disorder (IR)

 Panic disorder (IR and XR)

 Gang. Cemas lainnya + insomnia

Ajunctive : Acute mania dan Acute psychosis

 Cara kerja Alprazolam

 Mengikat Bzp rec. pd GABA-A ligand-gated chloride channel

 Meningkatkan efek inhibisi Gaba.

 Meningkatakan aliran chlorida melalui saluran Gaba

 Menghambat aktivitas neuron di Inhibits neuronal activity presumably in amygdala-

centered fear circuits shg menguntungkan utk terapi gangguan cemas.

 Onset efek :

 Bisa pd pemberian pertama sp beberapa minggu kmd.

Respon Alprazolam (+)

 Th/ cemas singkat (bbrp mgg) : bs distop - sesuai kebutuhan.

 Th/ Gg. Cemas kronis:

 Tujuan : remisi penuh, cegah kambuh.

 Mengurangi/menghilangkan gejala,tp tdk menyembuhkan krn bs kambuh

 T/ cemas jangka panjang :

 Ganti SSRI atau SNRI utk maintenen.

 Bzp  6 bln ,gejala(-), tapering off

 Kambuh , ganti :

o SSRI or SNRI;

o benzodiapine ;
 o kombinasi Bzp dan SSRI or SNRI.

Respon terapi Alprazolam (-)

Pertimbangkan :

 Ganti obat lain atau tambahkan obat augmentasi.

 Psikoterapi (CBT).

 Konkomitan substance abuse

 Alprazolam abuse

Diagnosa lain : ok KMU

Kombinasi dg obat augmentasi pd Partial Response/Treatment-Resistance

 Bzp adl augmenting agent(obat penguat efek…): Antipsikotik dan mood stabilizers. , dipakai
utk aumentasi obat:

 SSRIs and SNRIs pd T/ gg. Cemas.

 Tidak rasional jika dikombinasi dg Bzp lain.

 Sbg “anxiolitik” Bzp konkomitan dg sedatif-hipnotik lain utk menidurkan.

Tests periodik

 LFT dan darah lengkap utk px Kejang2 , konkomitan dg KMU/ obat2an lain KMU dlm jangka
panjang.

Efek Samping alprazolam

Mekanisme ES:

 Mekanismanya = efek terapi; ES = respon berlebihan pd rec.Bzp.

 Adaptasi rec.Bzp jangka panjang dependensi, toleransi dan withdrawal Bzp.

 ES umumnya cepat muncul, sering hilang setelah bbrp lama.

ES yg sering terjadi :

✽ Sedation, fatigue, depression

✽ Dizziness, ataxia, slurred speech, weakness

✽ Forgetfulness, confusion

✽ Hyper-excitability, nervousness
 o Rare hallucinations, mania

o Rare hypotension

o Hypersalivation, dry mouth

ES yg berbahaya/menganggu

 Depresi pernafasan, tut bila ada over dosis depresan CNS.

 Jarang ggn fs hati, ginjal ; blood dyscrasias

 BB naik

 Sedasi :

 Jarang

 Pd awal terapi, dosis naik

 Hilang dg waktu

What To Do About Side Effects

 Tunggu (=observasi),  Tunggu ,  Tunggu

 Turunkan dosis.

 Ganti dg alprazolam XR

 Dosis terbesar diberikan sbl tidur, agar saing tdk ngantuk.

 Ganti obat lain.

 Beri flumazenil jika ES nya berat/membahayakan jiwa.

DOSING AND USE Alprazolam (Alp)

Usual Dosage Range

Anxiety : alprazolam IR: 1–4 mg/day

Panic : alprazolam IR: 5–6 mg/day

Panic : alprazolam XR: 3–6 mg/day

Dosage Forms :

Alp. IR tab. 0.25 mg scored ; 0.5 mg , 1 mg ; 2 mg multiscored

Alp IR solution, concentrate 1 mg/mL

Alp XR (extended-release) tab 0.5 mg, 1 mg, 2 mg, 3 mg

How to Dose

 Anxiety, alprazolam IR :

 dimulai 1/3 x ( 0.75 – 1.5 mg/hr),

 naikkan tiap 3-4 hr ; sp 4 mg/hr.

 Panic, alprazolam IR ;

 dimulai 1/3 x 1.5 mg/hr),

 naikkan < 1 mg tiap 3-4 hr ; sp 4 10 mg/hr.

 Panic, alprazolam XR :

 dimulai 1 x 0.5–1 mg/hr,

 naikkan 1 mg/hr 10 mg/hr.

Dosing Tips

 Bzp -sparing strategy : dosis terendah - lama T/ tersingkat.

 Ases rutin perlu obat kontinu?

 Resiko dependensi naik dg naiknya dosis & lama terapi.

 Utk Gejala cemas antar-wkt obat: naikan dosis/dibagi lebih frequent/ ganti XR/Top Up
(ektra)

 XR : 1 – 2 kali/hr, jangan diparo.

 Dosis Alp + 1/10 dosis Bzp , 2 kali dosis clonazepam

Overdose

 sedation, confusion, poor

 coordination, diminished reflexes, coma  dead

 Alprazolam saja / + alkohol.

Long-Term Use

 Resiko dependensi : T/ > 12 mgg, tut pd polysubstance abuse.

 Habit Forming

 Alpra. is a Schedule IV drug

 Bisa dependensi dan/ tpleransi.

How to Stop

 Bila mendadak ; riw. Kejang2; dosis > 4 mg  kejang2•

 Tapering : 0.5 mg/3hr

 Kasus sulit: < 0,025 mg / mgg.

 Kasus sangat sulit tapering dg 1%/3hr ( tapering lambat + desensitisasi perilaku

 Yakinkan : gejala kambuh/ withdrawal ?•

 Bzp-dependent anxiety patients dan insulin-dependent diabetics adalah tidak addiksi thd
obatnya.

 Px Bzp-dependent distop obat :

 Gejalanya kambuh.

 Gejala tambah buruk (rebound),

 dan/atau ok gej. withdrawal

Pharmacokinetics

 Dimetabolisir oleh CY P450 3A4

 Metabolitnya tidak aktif.

 T ½ eliminasi=12–15 jam

Drug Interactions

 Alp + CNS depresan efek depresif >

 Inhibitor CY P450 3A4, eg nefa-zodone, fluvoxamine, fluoxetine: jus jeruk  menurunkan

clearance me -naikkan kadar plasma Alp. dan efek sedatif alp.jd kadr Alp hrs diturunkan,

 Azole antifungal agents ( ketoconazole ,itraconazole), macrolide antibiotics, protease

inhibitors: mening-katkan kadar plasma Alp.

 Inducers of CY P450 3A4 (carbamazepine), menurun-kan clearance dan kadar Alpefek terapi
turun.

Other Warnings/Precautions

 Perubahan dosis atas anjuran dokter.

 Px Py Paru  kematian (jarang).

 Riw Pg Zat / alkohaol  meningkatkan resiko dependensi.

 T/ px Depresi  Hypomania ,mania ; mpberat ide2 bunuh diri.

  Hati2 pd px “ obstructive sleep apnea “

 Menyebabkan gangguan pikiran dan perubahan perilaku .

Do Not Use

 Pd px narrow angle-closure glaucoma

 Px memakai ketoconazole or itraconazole (azole antifungal)

 Riw. allergy to alprazolam atau Bzp lainnya.

Pemakaian Alprazolam pd populasi khusus :

Pada pasien-2 :

• Px Gg Ginjal  hati2

• Px Gg Hati : mulai dg dosis rendah: (0,5-0,75 mg/hr) , dibagi 2- 3 dosis

• Px Gg Jantung : Bzp telah dipakai utk T/ Cemas ok IMA (infark)

Elderly

• mulai dg dosis rendah : (0,5-0,75 mg/hr) , dibagi 2- 3 dosis , dimonitor ketat.

Children and Adolescents

• Keamanan dan kemanjurannya blm pasti, tp sering dipakai dlm wkt yg singkat dan dosis rendah.

• Efek jangka panjang blm diketahui.

Sebaiknya dosis rendah, monitor lebih ketat

Pregnancy

 Risk Category D [pd janin terbukti beresiko, manfaat terapi (+) pertimbangkan
pemakaiannya.

 Terbukti meningkatkan kemungkinan cacad pd janin., shg

 Tidak dianjurkan utk T/ cemas pd trimester

 Penghentian : tapering off

 Pemberian pd trimester III  withdrawal effect pd janin.

 Kejang2 yg bisa membahayakan janin.

Breast Feeding

 Rekomondasi : stop obat atau pemberian susu botol.

  SE pd infant : gang makan, sedasi, weight loss.

THE ART OF PSYCHOPHARMACOLOGY-ALP

Potential Advantages

 Onset efeknya cepat.

 Sedasinya kurang dp Bzp lainnya.

 Ada tablet long acting (XR)

Potential Disadvantages

 Efek Euphoria nya bs menyebabkana “abuse”

 Abuse pd px sedang/riw  substance abusers

Primary Target Symptoms

 Panic attacks

 Anxiety

Pearls

Paling populer dikalangan dokter, psikiater.

 Bermanfaat ajunctive T/ dg SSRI; SNRI pd Gg Cemas

 Tidak efektif sbg monoterapi Psikotik; utk ajunktif : mood stabilizers dan antipsikotik.

 Bisa utk tr depresi ; bs menyebabkan depresi px lainnya.

 Stop Alp : Resiko kejang2 pd 3 hr pertama , tut bl ada riw ; kejang , trauma kepala, atau
withdrawal zat pd abuser.

 Onset efek klinis bs mendahului plasma half-life (>cepat) ,shg dpt dbrk > 2-3 kali/hr ,
khususnya utk immediate release alprazolam

 Pemberian : fluvoxamine, fluoxetine, atau nefazodone dpt meningkatkan kadar alprazolam

shg pasien sangat ngantuk levels, atau dosis Alprazolam diturunkan sp ½ nya atau lebih .

 Utk tr Insomnia : bs sbg gejala gg jiwa primer atau komorbiditas atau ok KMU.

✽ Alprazolam XR kurang sedatif dp immediate release alpra.

✽ Alprazolam XR: frekuensi pemberian < I.R ; gej interdose <, dan kurang “clockwatching” nya pd
pasien cemas .

 Kenaikan kadar plasma XR > lambat  euphoria & abuse > kecil
  Penurunan kadar plasmaXR > lambat  withdrawal > kecil

✽ Alprozolam XR : durasi onset biologisnya > lama dp clonazepam

✽ Clonazepam dianggap “longacting alprazolam-like anxiolytic” ; Alprazolam XR

dianggap”longer-acting clonazepam-like anxiolytic”; dg keunggulan kurang : euphoria, abuse,
dependence, dan withdrawal problems,

RISPERIDONE
Class :
Nama :
 Atypical antipsychotic
 Brands :
 Serotonin-dopami-ne Antagonist,
 Risperdal (oral)
SDRA;
 CONSTA (im)
 Second generation antipsychotic;
 Generic: Resperidone
 Mood stabilizer

THERAPEUTICS :Commonly Prescribed For (bold for FDA approved)

 Schizophrenia

 Terapi : oral/Consta

 Mencegah kambuh : oral

 Gang.Psikotik lainnya : oral

 Acute mania: oral

 monotherapy and adjunct to lithium or valproate

 Bipolar maintenance

 Bipolar depression

 Gang. Perilaku pada : Demensia ; Anak-2 dan Remaja.

 Problema Gang. Kontrol impuls

CONSTA : long-acting microspheres

intramuscularly, deep , gluteal

How The Drug Works How Long Until It Works

Blokade D2 dopamine Rec. menurunkan Gejala Psikotik dapat membaik dalam 1

gejala positif psikosa ,menstabilkan gejala
afektif,.
Blokade serotonin 2A Rec, meningkatan
release Dopamin kemudian menurunkan
ES/gejala motorik dan memperbaiki gejala
kognitif dan afektif.
minggu, tapi perlu beberapa minggu untuk
berefek penuh pada gejala perilaku yaitu
sampai stabilisasi gejala kognitif dan afektif.
Lama efikasi obat dianjurkan ditunggu :
Umumnya : 4 – 6 mgg bisa sampai

Interaksi pada receptor2 lain bisa berperanan 16 – 20 minggu untuk berespon bagus,
terhadap gejala kognitif
pada efikasi resperidon•

✽ eg pd Rec. Alpha 2 antagonist bs

menimbulkan efek antidepresan.

If it doesnt work

 Ganti antipsikotik atipikal lainnya (olanzapine, quetiapine, ziprasidone, aripiprazole, atau

amisulpride)

 Jika dengan > 2 antipsikotik monoterapi tdk berrespon  pertimbangkan clozapine

 Jika tidak ada antipsikotik atipikal lini pertama yg efektif pertimbangkan :

 Terapi dengan dosis tinggi , atau

 Augmentasi dengan valproate or lamotrigine

 Beberapa pasien perlu antipsikotik konvensional(tipikal)

 Pertimbangkan “tidak patuh” (noncompliance) dan

 Ganti antipsikotik yg efek sampingnya lebih rendah. atau

 Anti psikotik long acting (depot injection)

 Pertimbangkan segera mulai rehabilitasi dan psikoterapi•

 Pertimbangkan adanya concomitant drug abuse

If It Works

 Pada px Skizofrenia :

 Menururunkan gejala Positif.

 Memperbaiki gejala Negatif : agersivitas, gej kognitif & afektif.

  Remisi parsial: menurunkan gejala sp 1/3

 Dengan th/ teratur > 1 thn , 5–15% px  perbaikan gej. > 50–60% (superresponders,
“awakeners” ) dpt bekerja,hidup mandiri, dpt bersosialisasi.

 Px Bipoler : Reduksi gej. sp > ½ nya.

 Teruskan terapi sp “a plateau of improvement”, teruskan :

 Selama 1 thn (Episode I psikosa)

 Selama mungkin (Episode > II)

 Bahkan pada Ep I , tr/ bisa selamanya

 Pada Gg.Bipoler bs mereduksi dan mencegah kambuhnya mania

Best Augmenting Combos for Partial Response or Treatment-Resistance

 Valproic acid (valproate, divalproex, divalproex ER)

Other mood stabilizing

 Anticonvulsants (carba-mazepine, oxcarbazepine, lamotrigine)

 Lithium

 Benzodiazepines

SIDE EFFECTS

 How Drug Causes Side Effects  Notable Side Effects

 Bloking reseptor : Meningkatkan resiko DM & dyslipidemia

 Alpha 1 adrenergic dizzines, ✽Dose-dependent EPS(symptomps)

sedasi, hipotensi.
✽Dose-related hyperprolactinemia
 Dopamine 2 recs.di :
 Tardive dyskinesia .
 Striatum,  ES motorik ,
tut dosis tinggi.  Dizziness, insomnia, headache,
anxiety, sedation
 Pituitary, 
hiperprolaktinemia  Nausea, constipation, abdominal
pain,weight gain
 Mekanisma atipikal antipsikotik
thd insiden : menaikkan BB, DM  Orthostatic hypotension,
dan dislipidemiablm diketahui.  Tachycardia, sexual dysfunction
Life Threatening or
Dangerous Side Effects

 Hyperglycemia, dg : keto-acidosis Weight Gain

or hyperosmolar , coma or death.
 Kasus Weight gain : cukup banyak.
 Px Lansia dementia :  CVA ;
 Jadi problema medik
Stroke, TIA, dead.
 Bisa beda orang
 Meningkatkan kematian mortalitas
dan/antipsikotiknya.
pd lansia dg dementia-related
psychosis Sedation
 Neuroleptic malignant syndrome  Kasusnya cukup banyak.
 Kejang2  Umumnya hanya sementara.

Efek sedasi masing2 antipsikotik berbeda

DOSING AND USE

Usual Dosage Range

 2 - 8 mg/hr – oral utk :

 Psikosa Akut.

 Gangguan Bipolar

 0.5 - 2.0 mg/hr – oral utk :

 Anak-2 dan

 Lanjut usia.

 25–50 mg depot - im , tiap 2 minggu.

Dosage Forms

 Tablet : 0.25; 0.5; 1, 2, 3; 4 mg,

 Orally disintegrating tablets (XR) 0.5 mg, 1 mg, 2 mg

 Liquid 1 mg/mL — 30 mL/botol.

 Risperidone long-acting depot microspheres formulation for deep im inj (gluteal). 25

mg; 37.5 mg; 50 mg vial/kit

How to Dose
  Psikosa non-emergensi

 Dimulai: oral 1 mg/hr; dibagi dalam 2 dosis -> hari berikutnya naikan 1 mg/hr sampai
dosis efektif tercapai

 Umum  maks 16 mg/hr .

 Khusus: efek maks 4 - 8 mg/hr

 Dpt diberikan 1 kph / 2 kph.

 Long-acting risperidone :

 Harus dicoba oral dulu.

 Deep im, gluteal, tiap 2 minggu

 Long-acting risperidone :

 Harus dicoba oral dulu.

 Inj I Consta + Oral antipsiko-tik  3 minggu oral di stop.

 Penyuntik : terlatih.

 Dosis : Consta 25 - > 50 mg/ 2mgg .

 Interval titrasi > 4 mgg.

 Jangan menggabungkan 2 vial Consta, (eg 50 mg/vial , tidak boleh diganti 2 vial @ 25
mg/ suntikan.

Dosing Tips – Oral Formulation

Less may be more: berikan dosis terendah, dg “efikasi stabil”, tanpa mengurangi
efikasinya; oleh karena dapat menurunkan efek samping, terutama pd dosis > 6 mg/hr;

✽ Dosis ter Efektif utk Psikosa ; Gg Bipoler : 2 – 6 mg/hr ( dosis rata2 4,5 mg/hr ).
Dosis ini paling murah dp obat lain.

 Px Gaduh gelisah drpd menaikkan dosis, pertimbangkan augmentasi dg :

benzodiazepin atau antipsikotik tipikal , oral/im.

 Pd partial responders pertimbangkan augmentasi dg : mood stabilizing

anticonvulsant, valproate or lamotrigin.

 di Approved sp 16 mg/hr - oral, tp EPS meningkat pd > 6 mg/hr.

 Risperidone oral solution : tidak kompatibel dg teh atau Cola.

  Anak2 dan Lansia :

 Mulai dg 2 dd  sp dosis maintenen tercapai  1 dd.

 Berikan dosis yg lbh rendah dr dosis umum.

Dosing Tips –Long-Acting Microsphere Depot Formulation

Consta inj. : saat inisiasi onset aksi nya bs terlambat 2 minggu.

✽Inisiasi Consta: beri antipsikotik oral 3 minggu (lanjutan/inisiasi)

Steady-state plasma concentrations Consta tercapai setelah 4 suntikan, bertahan sp 4 -

6 mgg dr suntikan terakhir.

Terlambat inj. Consta > 2 mgg inj. Re-inisiasi , dilindungi dg 3 mgg antipsikotik oral. : < 2
mgg , tdk perlu perlindungan oral

Consta hrs disimpan di refrigerator.

Harus dibeli dlm paket utuh ok obat tdk dlm btk larutan ( ½ spuit tidak sama dg ½ dosis).

 Overdose  Titrasi turun dg pelan2 , > 6-8 mgg

- oral, tut utk cross titration.
 Lethalitas dg monoterapi jarang;
sedasi, palpitasi, kejang, TD turun,  Rapid oral discontinuation:
sesak nafas.
  rebound psychosis &
 Long-Term Use
 gejala memberat.
 Mencegah kambuh skizofrenia.
 Pharmacokinetics
 Maintenen :Gg Bipoler & Gg
 Metabilitnya “aktif”
Tingkah Laku
 Dimetabolisir : CYP450 2D6
 Habit Forming
 T ½ Risperidon-oral: 20-24 jam.
 Tidak menyebabkan
ketergantungan  T ½ Long-acting Risp : 3–6 hr
 How to Stop  Eliminasi Consta : + 7–8 .

Drug Interactions

 Meningkatkan efek anti-hipertensi

  Sbg: antagonis levodopa, dopamine agonists

 Kombinasi “obat” yg meningkat-kan kadar plasma Risperidone (tak perlu

penyesuaian dosis) :

 Clozapine: (menurunkan Clearance)

 Fluoxetine & paroxetine

 Inhibitor CYP4502D6

 Pemberian Risp. bsm carbamazepine :  menurunkan kadar plasma Risp.

 Other Warnings/ Precautions

 Hati 2 pd px dg resiko:

 Hipotensif(dehidrasi, kepanasan)

 Pneumonia asprasi, dysphagia

 Priapism

 Do Not Use

 Riw. alergi risperidone

SPECIAL POPULATIONS

 Renal Impairment

 Initial-oral : 2 x 0.5 mg/hr ; mgg 1st ; 2 x 1 mg ; mgg 2nd

 Consta: diberikan ssdh px toleran pd 2 mg/hr – oral.

 Consta : 25 mg/2 mgg. (lindungi oral 3 mgg)

 Hepatic Impairment

 Initial-oral : 2 x 0.5 mg/hr ; mgg 1st ; 2 x 1 mg ; mgg 2nd

 Consta: diberikan ssdh px toleran pd 2 mg/hr – oral

 Consta : 25 mg/2 mgg. (lindungi oral 3 mgg)

 Cardiac Impairment

 Hati2 resiko orthostatic hypotension

✽ Lansia dg atrial fibrillation, menaikan resiko stroke.

  Elderly

 Initial-oral : 2 x 0.5 mg ; naikkan dg 2 x 0.5 mg ; mgg; bila > 2 x 1,5 mg/hr – titrasi tiap
mgg.

 Consta : 25 mg/2 mgg. (lindungi oral 3 mgg)

Pregnancy

 Risk Category C (ada efek buruk pd binatang coba).

 Pd kehamilan gej. Psikotik bs tambah berat, shg perlu terapi.

 Data awal: infant yg terpapar resperidone dlm uterus tdk nampak gej. buruk/efek
samping.

 Risperidone may be preferable to anticonvulsant mood stabilizers if treatment is

required during pregnancy

 Efek hyperprolactinemia pd janin blm diketahui.

Breast Feeding

 Tidak diketahui apakah resperidon di sekresi ke asi

✽ Rekomendasi : stop obat atau pemberian susu botol.

 Ibu menyusui yg minum Resp. harus dimonitor efek sampingnya

Children and Adolescents

 Keamanan dan efektifitasnya blm dpastikan.

✽ Reperidon paling sering dipakai .

 Aman utk Gg Tingkah Laku

 Perlu kontrol yg lebih ketat.

THE ART OF PSYCHOPHARMACOLOGY

 Potential Advantages

 Pada kasus Psikosa dan bipoler yg refrakter thd terapi antipsikotik lain.

 Untuk terapi pasien/kasus:

✽ Demensia dg ciri agresif.

✽ Gg Tingkah laku pd anak.

✽ Non-compliant patients (Costa)

✽ Hasil terapi akan baik jika kepatuhan ditingkatkan (Costa)

 Potential Disadvantages

 Pd px dmn efek hiperprolaktinemi tdk diharapkan ,misal pd: ibu hamil, gadis dg
amenore, premenopause tanpa estrogen replacement terapi)

 Primary Target Symptoms

 Gejala Positif psikosa

 Gejala Negatif psikosa

 Fungsi Kognitif.

 Unstable mood ( depressi dan mania )

 Gejala agresif

Pearls

 Diterima luas utk terapi:

1) Agitasi & agresi pd demensia

2) Gejala perilaku pd anak & remaja

 Juga dipakai utk kasus2 yg refrakter dan gejala positif bukan skizof.

 Hanya atipikal Hiperprolaktinemia

 Hiperprolaktinemia pd wanita dg estrogen rendahosteoprosis

 Kurang meningkatkan BB

 Kurang efek sedasinya

 Pd dosis terapi  termurah

 Resiko Stroke : pd Lansia dg atrial fibrilasi.

 Resiko DM & dyslipidemia msh kontroversi

 ES motorik lbh kuat dp antipsikotik lain pd lansia dg Parkinson’s disease or Lewy

Body dementia

 Satu2nya antipsikotik atipikal dg formula inj, Long acting

 SERTRALINE
 Nama : 2) Premenstrual dysphoric disorder
(PMDD)
 Brands : Zoloft , Fridep
3) Panic disorder
 Generic: Sertalin
4) Posttraumatic stress disorder
 Class : SSRI
(PTSD)
(selective serotonin reuptake
inhibitor); sering diklasisifikasikan 5) Social anxiety disorder (social
sbg antidepressant, tp sertralin phobia)
bukanlah sekedar anti depresan
6) Obsessive-compulsive disorder
 Indikasi : (OCD)

1) Major depressive disorder(MDD) 7) Generalized anxiety disorder

(GAD)

How The Drug Works

 Memacu Nts serotonin.

 Memblok serotonin reuptake pump (serotonin transporter)

 Desensitisasi serotonin recep-tors, tut serotonin 1A receptors

 Meningkatkan neurotransmisi serotonin.

✽ Memblok dopamine reuptake pump (dopamine transporter), shg meningkatkan
neurotrans-misi dopamin dan berkontribusi pd efek terapinya.

 Berefek mild antagonist actions at sigma receptors

How Long Until It Works

✽ Bbrp px mengalami peningkat-an energi atau keaktifan pd awal terapi dimulai.

 Onset teurapetiknya: tidak segera, sering terlambat 2 – 4 mgg .

 Jika tidak berefek dlm 6-8 mgg, mungkin perlu naikkan dosis. Atau obat tdk berefek.
•

 Obat bs dilanjutkan selama bbrp tahun utk mencegah kambuhnya gejala.

If It Works

 Tujuan terapi: sembuh dr gejala dan mencegah kambuh.

 Terapi sering mengurangi/ menghilangkan gejala, tp tidak menyembuhkan krn sering

kambuh bila obat dihentikan.

 Terapi dilanjutkan sp seluruh gejala hilang/sangat berkurang (e.g., OCD, PTSD)

 Sejak gejala hilang, lanjutlan terapi sp 1 thn (pd episode I depresi)

 Utk episede ke II. Dst, obat dilanjutkan utk wkt tak terbatas.

 Pd Gangguan cemas juga bs tak terbatas lamnya pemberian obat

 If It Doesn’t Work

1) Partial response; gej.sisa depresi : (insomnia, fatigue, gangguan konsentrasi)

2) Nonresponders = treatment-resistant or treatment-refractory

3) “Poop-out” : inisial responnya bagus, kmd kambuh wlp obatnya diteruskan.

Pertimbangkan :

1) Obat : naikkan dosis, ganti obat atau tambahkan obat aumentasi.

2) Psikoterapi.

3) Evaluasi : diagnosa lain atau ada komorbiditas dg ( KMU , PgZat dll)

4) Bbrp px nampak obat tidak manjur ok aktivasi dari Ggn Bipoler sbg ggn latent atau yg
mendasarinya. Perlu: antidepresan di stop dan diganti mood stabilizer
Best Augmenting Combos for Partial Response or Treatment-Resistance

 • Trazodone, especially for insomnia

 • In the U.S., sertraline (Zoloft) is commonly

 augmented with bupropion (Wellbutrin)

 with good results in a combination

 anecdotally called “Well-loft” (use

 combinations of antidepressants with

 caution as this may activate bipolar

 disorder and suicidal ideation)

 Mirtazapine, reboxetine, or atomoxetine

 (add with caution and at lower doses since

 sertraline could theoretically raise

 atomoxetine levels); use combinations of

 antidepressants with caution as this may

 activate bipolar disorder and suicidal

 ideation

 • Modafinil, especially for fatigue, sleepiness,

 and lack of concentration

 • Mood stabilizers or atypical antipsychotics

 for bipolar depression, psychotic

 depression, treatment-resistant depression,

 or treatment-resistant anxiety disorders

 • Benzodiazepines

 • If all else fails for anxiety disorders,

 consider gabapentin or tiagabine

  • Hypnotics for insomnia

 • Classically, lithium, buspirone, or thyroid

 hormone

SIDE EFFECTS

 How Drug Causes S.E.

 Theoretically due to increases in serotonin

 concentrations at serotonin receptors in

 parts of the brain and body other than

 those that cause therapeutic actions (e.g.,

 unwanted actions of serotonin in sleep

 centers causing insomnia, unwanted

 actions of serotonin in the gut causing

 diarrhea, etc.)

 ✽ Increasing serotonin can cause

 diminished dopamine release and might

 contribute to emotional flattening, cognitive

 slowing, and apathy in some patients,

 although this could theoretically be

 diminished in some patients by sertraline’s

 dopamine reuptake blocking properties

 • Most side effects are immediate but often

 go away with time, in contrast to most

 therapeutic effects which are delayed and

 are enhanced over time

 • Sertraline’s possible dopamine reuptake

 blocking properties could contribute to

  agitation, anxiety, and undesirable

 activation, especially early in dosing

Notable Side Effects

 Sexual dysfunction (men: delayed

 ejaculation, erectile dysfunction; men andwomen: decreased sexual desire,

 anorgasmia)

 • Gastrointestinal (decreased appetite,

 nausea, diarrhea, constipation, dry mouth)

 • Mostly central nervous system (insomnia

 but also sedation, agitation, tremors,

 headache, dizziness)

 • Note: patients with diagnosed or

 undiagnosed bipolar or psychotic disorders

 may be more vulnerable to CNS-activating

 actions of SSRIs

 • Autonomic (sweating)

 • Bruising and rare bleeding

 • Rare hyponatremia (mostly in elderly

 patients and generally reversible on

 discontinuation of sertraline)

 • Rare hypotension

Life Threatening or Dangerous Side Effects

 Rare seizures

 • Rare induction of mania and activation of suicidal ideation

 Weight Gain

 • Reported but not expected

  • Some patients may actually experience weight loss

 Sedation

 • Reported but not expected

 • Possibly activating in some patients

What To Do About Side Effects

 Wait

 • Wait

 • Wait

 • If sertraline is activating, take in the morning to help reduce insomnia

 • Reduce dose to 25 mg or even 12.5 mg until side effects abate, then increase dose
as tolerated, usually to at least 50 mg/day

 • In a few weeks, switch or add other drugs

Best Augmenting Agents for Side Effects

 Often best to try another SSRI or another antidepressant monotherapy prior

toresorting to augmentation strategies to treat side effects

 • Trazodone or a hypnotic for insomnia

 • Bupropion, sildenafil, vardenafil or tadalafil

 for sexual dysfunction

 • Bupropion for emotional flattening,

 cognitive slowing, or apathy

 • Mirtazapine for insomnia, agitation, and

 gastrointestinal side effects

 • Benzodiazepines for jitteriness and anxiety,

 especially at initiation of treatment and

 especially for anxious patients

 • Many side effects are dose-dependent (i.e.,

 they increase as dose increases, or they

  reemerge until tolerance re-develops)

 • Many side effects are time-dependent (i.e.,

 they start immediately upon dosing and

 upon each dose increase, but go away with

 time)

 • Activation and agitation may represent the

 induction of a bipolar state, especially a

 mixed dysphoric bipolar II condition

 sometimes associated with suicidal

 ideation, and require the addition of

 lithium, a mood stabilizer or an atypical

 antipsychotic, and/or discontinuation of

 sertraline

DOSING AND USE

 Usual Dosage Range

 • 50–200 mg/day

 Dosage Forms

 • Tablets 25 mg scored, 50 mg scored,

 100 mg

How to Dose

 • Depression and OCD: initial 50 mg/day;

 usually wait a few weeks to assess drug

 effects before increasing dose, but can

 increase once a week; maximum generally

 200 mg/day; single dose

  • Panic and PTSD: initial 25 mg/day; increase

 to 50 mg/day after 1 week thereafter,

 usually wait a few weeks to assess drug

 effects before increasing dose; maximum

 generally 200 mg/day; single dose

Dosing Tips

 • All tablets are scored, so to save costs,

 give 50 mg as half of 100 mg tablet, since 100 mg and 50 mg tablets cost about the

 same in many markets

 • Give once daily, often in the mornings to

 reduce chances of insomnia

 • Many patients ultimately require more than

 50 mg dose per day

 • Some patients are dosed above 200 mg

 • Evidence that some treatment-resistant

 OCD patients may respond safely to doses

 up to 400 mg/day, but this is for experts

 and use with caution

 • The more anxious and agitated the patient,

 the lower the starting dose, the slower the

 titration, and the more likely the need for a

 concomitant agent such as trazodone or a

 benzodiazepine

 • If intolerable anxiety, insomnia, agitation,

 akathisia, or activation occur either upon

 dosing initiation or discontinuation,

  consider the possibility of activated bipolar

 disorder and switch to a mood stabilizer or

 atypical antipsychotic

 • Utilize half a 25 mg tablet (12.5 mg) when

 initiating treatment in patients with a

 history of intolerance to previous

 antidepressants

DOSING AND USE

How to Stop

 • Taper to avoid withdrawal effects

 (dizziness, nausea, stomach cramps,

 sweating, tingling, dysesthesias)

 • Many patients tolerate 50% dose reduction

 for 3 days, then another 50% reduction for

 3 days, then discontinuation

 • If withdrawal symptoms emerge during

 discontinuation, raise dose to stop

 symptoms and then restart withdrawal

 much more slowly

Pharmacokinetics

 • Parent drug has 22–36 hour half-life

 Metabolite half-life 62–104 hours

 • Inhibits CYP450 2D6 (weakly at low doses)

 • Inhibits CYP450 3A4 (weakly at low doses)

SPECIAL POPULATIONS

 Renal Impairment

 • No dose adjustment

 • Not removed by hemodialysis

 Hepatic Impairment

 • Lower dose or give less frequently, perhaps

 by half

 Cardiac Impairment

 • Preliminary research suggests that

 sertraline is safe in these patients

 • Treating depression with SSRIs in patients

 with acute angina or following myocardial

 infarction may reduce cardiac events and

 improve survival as well as mood

 Elderly

 • Some patients may tolerate lower doses

 and/or slower titration better •

 Children and Adolescents

 • Use with caution, observing for activation of known or unknown bipolar disorder
and/or suicidal ideation, and strongly consider informing parents or guardian of this
risk so they can help observe child or adolescent patients

 • Approved for use in OCD

 • Ages 6–12: initial dose 25 mg/day

 • Ages 13 and up: adult dosing

 • Long-term effects, particularly on growth, have not been studied

Pregnancy
 Risk Category C [some animal  • For many patients this may mean
studies
 continuing treatment during
 show adverse effects, no pregnancy
controlled studies
 • Neonates exposed to SSRIs or
 in humans] SNRIs late

 • Not generally recommended for  in the third trimester have

use during developed

 pregnancy, especially during first  complications requiring prolonged

trimester
 hospitalization, respiratory
 • Nonetheless, continuous support, and
treatment during
 tube feeding; reported symptoms
 pregnancy may be necessary and are
has not
 consistent with either a direct
 been proven to be harmful to the toxic effect
fetus
 of SSRIs and SNRIs or, possibly, a
 • At delivery there may be more drug
bleeding in
 discontinuation syndrome, and
 the mother and transient include
irritability or
 respiratory distress, cyanosis,
 sedation in the newborn apnea,

 • Must weigh the risk of treatment  seizures, temperature instability,

(first feeding

 trimester fetal development, third  difficulty, vomiting, hypoglycemia,

trimester
 hypotonia, hypertonia,
 newborn delivery) to the child hyperreflexia,
against the
 tremor, jitteriness, irritability, and
 risk of no treatment (recurrence of constant

 depression, maternal health, infant  crying

 bonding) to the mother and child

Breast Feeding  who have had prior depressive
episodes,
 • Some drug is found in mother’s
breast milk  so drug may need to be
reinstituted late in
 • Trace amounts may be present in
nursing  the third trimester or shortly after

 children whose mothers are on  childbirth to prevent a recurrence

sertraline during

 • Sertraline has shown efficacy in  the postpartum period

treating
 • Must weigh benefits of breast
 postpartum depression feeding with

 • If child becomes irritable or  risks and benefits of

sedated, breast antidepressant

 feeding or drug may need to be  treatment versus nontreatment to

both the
 discontinued
 infant and the mother
 • Immediate postpartum period is
a high-risk  • For many patients, this may
mean
 time for depression, especially in
women  continuing treatment during
breast feeding

THE ART OF PSYCHOPHARMACOLOGY

 Potential Advantages  children, girls and women with

 • Patients with atypical depression  galactorrhea, girls and women

with
 (hypersomnia, increased appetite)
 unexplained amenorrhea,
 • Patients with fatigue and low
postmenopausal
energy
 women who are not taking
 • Patients who wish to avoid
estrogen
 hyperprolactinemia (e.g.,
 replacement therapy)
pubescent
 • Patients who are sensitive to the  • Can require dosage titration
prolactinelevating
 Primary Target Symptoms
 properties of other SSRIs
 • Depressed mood
 (sertraline is the one SSRI that
 • Anxiety
generally
 • Sleep disturbance, both insomnia
 does not elevate prolactin)
and
 Potential Disadvantages
 hypersomnia (eventually, but may
 • Initiating treatment in anxious actually
patients with
 cause insomnia, especially short-
 some insomnia term)

 • Patients with comorbid irritable  • Panic attacks, avoidant behavior,

bowel reexperiencing,

 syndrome  hyperarousal