Bms166 Slide Antipsychotic Antidepressant

7/28/2019 Bms166 Slide Antipsychotic Antidepressant

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AntipsychoticAntidepressant

Tri Widyawati_Aznan Lelo

BMS_2009


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Antipsychotic


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Introduction

Drugs used in the management of psychosis:

neuroleptics or antipsychotics The termneuroleptic emphasizes the

dru sneurolo ical actions that are commonl

manifested as side effects of treatment The term antipsychotics denotes the ability

of these drugs to abrogate psychosis and

alleviate disordered thinking in schizophrenicpatients


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Psikosa ; psychosis adalah :

= penyakit yang ditandai dengan: sensorium baik,tapiterjadi gangguan pemikiran atau fungsi luhur yang

jelas loss of contact with reality

Pathogenesis :

belum jelas sepenuhnya

faktor genetik? hipotesa-hipotesa :

- atrofi otak

- multiple neurotransmitter- dopamine hypothesis

COMPLEX !!!


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Schizophrenia: a thought disorder characterizedby one or more episodes of psychosis

(impairment in reality testing) Symptoms:

- Positive symptoms: involve the development of

abnormal functions delusions, hallucinations,disorganized speech, and catatonic behavior.

- Negative symptoms: involve the reduction or loss

of normal functions affective flattening, alogia,avolition


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The Dopamine Hypothesis

1. Most antipsychotic drugs strongly block postsynaptic D2

recr in the CNS, especially in the mesolimbic-frontalsystem

2. Drugs that dopaminergic activity:

levodopa ( a precursor), amphetamines (releaser ofdopamine), or apomorphine ( a direct dopamine

agonist) aggravate schizophrenia or produce psychosis

3. Dopamine recr density has been found, post mortem in the brains of schizophrenics who have not been

treated with antipsychotic drugs


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The Dopamine Hypothesis

4. Positron emission tomography (PET): dopamine

recr density5. Succesful treatment of schizophrenic patients has

been reported to change the amount of homovanillic

acid (HVA), a metabolite of dopamine, in the CSF,plasma, and urine.


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D1 Receptor Family D2 Receptor Family

2nd

messenger

systems

cAMP (via Gs)

PIP2 hydrolisis-Ca2+ mobilization (via IP3)

- PKC activation

cAMP (via Gi)

K+ currents voltage-gated Ca2+ currents

Distribution D1 D5 D2 D3 D4

Dopamine Receptor Families

in CNS StriatumNeocortex

HippocampusHypothalamus

StriatumSubs.nigraPituitarygland

Olfac. tubercleNucleusaccumbens

Hypothalamus

Frontalcortex

Medulla

Midbrain


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The mesolimbic system: emotions and

memory mesolimbic hyperactivity isresponsible for the positive symptoms of

Mesocortical system: attention, planning, andmotivated behavior plays a role in the

negative symptom (hipo/hyperactivity?)


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Antipsychotic agents: Chemical Types

1. Phenothiazine derivatives:

- Aliphatic derivatives (eg. Chlorpromazine)- Piperidine derivative (eg. Thioridazine): more potent andmore selective

2. Thioxanthene derivative: thiothixene

- Less potent than their phenothiazine analogs3. Butyrophenone derivatives: haloperidol

- diphenylbutylpiperidine: more potent and to have fewerautonomic effects

4. Miscellaneous structures: pimozide, molindone, loxapine,clozapine, olanzapine, quetiapine, risperidone,ziprasidone, and aripiprazole


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Based on side effect:1. Typical antipsychotics (Dopamine D2 recr antagonist)

- chlorpromazin

- haloperidol

- fluphenazine

2. Atypical antipsychotics (D2 recr, 5-HT2, other CNS recrantagonist)

- clozapine

- risperidone

- sulpiride

- olanzepine


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Distinction between typical and

atypical groups

-- less incidence of extrapyramidal side-effects in

- atyp ca-- efficacy in treatment-resistent group of patients

-- efficacy against negative symptoms


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Typical Antisychotic: Classes

1. Phenothiazines : chlorpromazine

- Aliphatic phenothiazines are less potent

antagonists at D2 receptor than piperazine

,

butyrophenone

2. Butyrophenone: haloperidol


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Typical Antipsychotic

Block D2 receptor : mesolimbic and possibly

mesocortical D2 receptor

Less effective at controlling the negative


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Fenotiazin

Mekanisme kerja.

- Semua antipsikotik bekerja dengan memblok ikatan

dengan reseptor D2.

80 % reseptor D2 harus diblok baru timbul efek antipsikotropik

Hampir semua dopaminergic system.

Largactil = large action


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CLOZAPIN

Merupakan antipsikotik baru, termasuk kelompok

atipikal.

Jarang menyebabkan gangguan extrapiramidal

mengikat reseptor D1 dan D4

Mengantagonis central adrenergic, serotoninergic,histaminergic dan cholinergic receptors.

Menimbulkan sedasi Prolactin level tidak meningkat *

Dapat terjadi agranulositosis *

Dapat terjadi hipotensi ortostatik Strong anticholinergic activity

Dipergunakan hanya pada kasus yang parah yang tidak

responsif terhadap obat lain.


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Atypical Antipsychotic Block D2 receptor, 5-HT2 recr, D4 recr

More effective than typical antipsychotics at treating thenegative symptoms of schizophrenia

Risperidone:

- block D2,5-HT2, -adrenergic (1 dan 2), H1 recr

- more effective than haloperidol at combating the positivesymptoms of schizophrenia and preventing a relapse of theactive phase of the disease

Clozapine:

- block D1-5,5-HT2, 1-adrenergic , H1 and muscarinic recr- In patients who have failed other antipsychotic drugs

- Not as 1 st line agents agranulocytosis


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Pharmacokinetic

Highly lipophilic

High FPE

Highly bound to plasma protein

Kinetics of elimination typically follow amultiphasic pattern and are not strictly first

order

Acute patients : IM, Chronic therapy: oral


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Pharmacokinetic

Haloperidol and fluphenazine : decanoate

ester slowly hydrolized and release longacting formulation (3-4 weeks)


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Drug Interaction

Antiparkinson drugs

Benzodiazepine : potentiate the sedativeeffect


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Side Effects

High potency drugs: have very high affinity for

D2 recr (higher slectivity of action): fewersedative side effects and cause less postural

Lower potency drugs: cause fewerextrapyramidal side effects


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Adverse Pharmacologic EffectsType Manifestations Mechanism

ANS Loss of accomodation, dry mouth,

Difficulty urinating, constipation

Muscarinic cholinoceptor

blockade

Orthostatic hypotension, impotence,

failure to ejaculate

Alpha adrenoceptor

blockade

CNS Parkinsons s ndrome akathisia Do amine rece tor

dystonia

blockadeTardive dyskinesia Supersensitivity of

dopamine recr

Toxic-confusional state Muscarinic blockade

Endocrine system Amenorrhea-galactorrhea, infertility,impotence

Dopamine recr blockaderesulting in

hyperprolactinemia

Other Weight gain Possibly combined H1 and

5HT2 blockade


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Introduction Depression: a heterogenous disorder that hasbeen characterized and classified in a variety

of ways1. Gejala utama : - Perasaan depressif

- Hilangnya minat/ aktifitas

selama minimal 2 minggu2. Gejala tambahan (biasanya mesti ada 4) :

- Lemas/capek- Gangguan pola tidur.- Konsentrasi terganggu- Rasa bersalah/tak berguna- Rasa putus asa

- Pikiran hendak bunuh diri.


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The pathogenesis: The amine hypothesis

The early 1950-s: reserpine depression in

patients being treated for hypertension andschizophrenia as well as in normal subejects

Reserpin : inhibit the transport of 5 HT, NAand DA into the vesicle.


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MONOAMINE THEORY

1. Reserpin

2. Imipramine (TCA)

3. MAO - I

4. ECT me response CNS the NA & 5-HT


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Hal yang menolak teori monoamine

1. Amfetamine / sabu-sabu, meningkatkan

NE disinaps tapi tidak meningkatkan

mood.

2. Cocaine

3. Tryptophan sintesa 5 HT4. dan blokermemblok NA no

effect on manic.


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Antidepressants1. Tricyclic antidepressant (TCA )

= imipramin

= amitriptin

2. Mono Amine Oxidase Inhibitor (MAO-I ):=fenelzin } non-selective

=tranilsipromin } ,,

=clorgyline } MAO-A selective=moclobemide } ,,

3.Selective 5-HT reuptake inhibitors (SSRI )

=fluoxetine

=sertraline

4.Atypical antidepressants:

= maprotiline

= mianserine, tradozone


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Tricyclic Antidepressant MoA:

- inhibit the re uptake of 5HT and NE from the synaptic cleftby blocking 5HT and NE reuptake transporter

- do not affect DA reuptake

Phkinetic:

- Well absorbed via the GIT- Highly variable FPE

individual dose

CYP2D6

- Lipophilic molecules that bind avidly to PP and to tissues- Inactivated by glucuronidation and eliminated by renal

clearance


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Tricyclic Antidepressant Side effects:

- CV : quinidine like side effect

- Anticholinergic effects

- Antihistamine effects- Antiadrenergic effects


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Mono-Amine-Oxidase Inhibitors (MAO-I )

Ada 2 jenis mono amine oxidase:

= MAO-A=# substrate preference : 5-HT

# target utama dari MAO-I

= MAO-B * substrate preference: fenil-etilamin

*

Kerja farmakologi: menimbulkan peningkatan : 5 HT, NA,DA diotak dan perifer

Berbeda dengan TCA, MAO-I tidak meningkatkan respons

jantung dan p.darah terhadap stimulasi simpatis


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Efek lain: * motor activity

* euphoria

* excitement

** hal ini juga terhadap orang normal

Efek samping:

stimulasi sentral

hepatotoksik interaksi obat :

- cheese reaction

- simpatomimetik- petidin hiperpirexia, gelisah, koma,hipotensi


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Selective Serotonin Re-Uptake Inhibitors(SSRI )

Fluoxetin, paroxetin, sertralin

Keuntungan SSRI :1. Hanya menghambat serotonin

.

Kerugian SSRI : tidak sekuat TCA untuk depresi berat


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Farmakokinetik:

* diserap per-oral dengan baik* t panjang, terutama fluoxetin (24-96 jam)

* ada delay 2-4 minggu sebelum efektif

* menghambat metabolisme TCA Jangan beri bersama-sama

Efek samping:* nausea, anorexia, insomnia

* libido , gangguan ejakulasi

* bila digabung dengan MAO-I

serotonin syndrome* acute toxicity tidak separah TCA atau MAO-I

sekarang sering digunakan


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Atypical anti-depressants

* heterogenous group

* cara kerja tidak typical sebagian memblok

uptake monoamin, yang lain belum diketahui.* dikatakan bahwa kelompok ini :

- efek sedasi dan antikolinergik lebih lemah

- toksisitas akut lebih rendah- onset of action lebih cepat

- efektif terhadap pasien yang non-responsif

terhadap TCA atau MAO-I


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Obat Mekanisme Efek Keuntungan t 1/2

kerja samping

Mapro- seletif thd -atropin like 40 jam

tilin NA-uptake I -sedasi,kejng

-mirip TCA

Trado- weak 5-HT -sedasi,bingung (-) atropin-like 6-12 j

zone u take -I -hi otensi lebih aman

=memblok -aritmia

5-HT2 &

alfa receptor

Mianserin =memblok -sedasi,kejang (-) atropin-like 12 jam

alfa2,5-HT2 -alergi (-) aritmia

H1

Bupoprion = NA release -oyong,cemas lebih aman 12 jam

meningkat - kejang


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Duloxetine (Cymbalta )

~ Kelompok serotonin and Norepinephrinereuptake inhibitor (SNRI).

~ Disetujui FDA pada Agustus 2004 untukMDD dewasa.

~ Pada September 2004 disetujui untukdiabetic peripheral neuropathic pain

(DPNP).

~ Juga diteliti untuk stress urinaryincontinence (SUI)


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Mekanisme kerja

~ Menghambat reuptake serotonin danneropinephrine dengan kuat.

~ eng am a ema ar opam ne

reuptake.


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Farmakokinetika :

- Diserap sempurna via GIT.

- Diberi dalam bentuk enteric-coated pellet

larut dalam pH > 5.5- Cmax tercapai 6 jam post dose.

- Makanan tidak mempengaruhi Cmax, tapi

mengurang AUC 10

- Terdistribusi luas.

- Lebih 90% terikat dengan protein :

~ Albumin.

~ 1 acid glycoprotein.


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Stress Urinary Incontinence (SUI)

Urinary incontinence beser

Stress urinary incontinence (SUI) :

- Involutary leakage brought on by effortor exertion, or sneezing or coughing.

Treatment :

- Biasanya kegel exercise

- Behavioural therapy- Surgery

OBAT ?

Duloxetine.


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FARMAKODINAMIKA BZD 47


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Side EffectsD2 recr antagonist: Extrapyramidal syndrome

Neuroleptic malignant syndrome (catatonia, stupor, fever, and autonomicinstability)

Hyperthermia

Tardive dyskinesia

Increase prolactine secretion: amenorrhea, galactorrhea, false positivepregnancy tests in women, and gynecomastia and libido in men

Muscarinic and adrenergic receptor antagonist: Anticholinergic effect: dry mouth, constipation, difficulty urinating, loss of

accomodation

adrenergic antagonism: orthostatic hypotension, and failure toejaculate (men), sedation


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Phenothiazines: Side effectsDrug Sedative Extrapyramidal Hypotensive

Chlorpromazine hydrochloride +++ ++ IM+++

Mesoridazine besylate +++ + Oral++

Thioridazine hydrochloride +++ + +++

Fluphenazine hydrochloride + ++++ +

Perphenazine ++ ++ +

Trifluoperazine hydrochloride + +++ +


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Thioxanthenes: Side effectsDrug Sedative Extrapyramidal Hypotensive

Chlorprothixene +++ ++ ++

Thiothixene hydrochloride+to++ +++ ++

Interference with the system: 5HT


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Interference with the system: 5HT

Inhibit uptake into CNS (other AAs)

Inhibit synthesis: p-chlorophenylalanine (irreversible) Inhibit neuronal re-uptake: cocaine, SSRA (e.g.fluoxetine), TCA (e.g. imipramine)

Inhibit storage-deplete: reserpine

Inhibit metabolism: MAO inhibitors

Promote release: p-chloroamphetamine - thendepletes (e.g. fenfluramine to appetite)

Non-selective


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Bms166 Slide Antipsychotic Antidepressant