Antipsychotic

Antidepressant

Tri Widyawati_Aznan Lelo

BMS_2009

Antipsychotic

Introduction

• Drugs used in the management of psychosis: neuroleptics or antipsychotics

• The term”neuroleptic” emphasizes the drugs’neurological actions that are commonly drugs’neurological actions that are commonly manifested as side effects of treatment

• The term “antipsychotics” denotes the ability of these drugs to abrogate psychosis and alleviate disordered thinking in schizophrenic patients

Psikosa ; psychosis adalah :

= penyakit yang ditandai dengan: sensorium baik,tapi

terjadi gangguan pemikiran atau fungsi luhur yang

jelas � loss of contact with reality

Pathogenesis :

• belum jelas sepenuhnya

faktor genetik?• faktor genetik?

• hipotesa-hipotesa :

- atrofi otak

- multiple neurotransmitter

- dopamine hypothesis

COMPLEX !!!

• Schizophrenia: a thought disorder characterized by one or more episodes of psychosis (impairment in reality testing)

• Symptoms:

- Positive symptoms: involve the development of abnormal functions→ delusions, hallucinations,

- 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

The Dopamine Hypothesis

1. Most antipsychotic drugs strongly block postsynaptic D2

rec’r in the CNS, especially in the mesolimbic-frontal

system

2. Drugs that ↑ dopaminergic activity:

levodopa ( a precursor), amphetamines (releaser of levodopa ( a precursor), amphetamines (releaser of

dopamine), or apomorphine ( a direct dopamine

agonist)→ aggravate schizophrenia or produce psychosis

3. Dopamine rec’r density has been found, post mortem→

↑ in the brains of schizophrenics who have not been

treated with antipsychotic drugs

The Dopamine Hypothesis

4. Positron emission tomography (PET): ↑ dopamine

rec’r density

5. 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.

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

Distribution

in CNS

D1 D5 D2 D3 D4

•Striatum

•Neocortex

•Hippocampus

•Hypothalamus

•Striatum

•Subs.nigra

•Pituitary

gland

•Olfac. tubercle

•Nucleus

accumbens

•Hypothalamus

•Frontal

cortex

•Medulla

•Midbrain

• The mesolimbic system: emotions and

memory → mesolimbic hyperactivity is

responsible for the positive symptoms of

schizophreniaschizophrenia

• Mesocortical system: attention, planning, and

motivated behavior → plays a role in the

negative symptom (hipo/hyperactivity?)

Antipsychotic agents: Chemical Types

1. Phenothiazine derivatives:

- Aliphatic derivatives (eg. Chlorpromazine)

- Piperidine derivative (eg. Thioridazine): more potent and more selective

2. Thioxanthene derivative: thiothixene

- Less potent than their phenothiazine analogs- Less potent than their phenothiazine analogs

3. Butyrophenone derivatives: haloperidol

- diphenylbutylpiperidine: more potent and to have fewer autonomic effects

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

Based on side effect:

1. Typical antipsychotics (Dopamine D2 rec’r antagonist)

- chlorpromazin

- haloperidol

- fluphenazine

2. Atypical antipsychotics (D2 rec’r, 5-HT2, other CNS rec’r

antagonist)

- clozapine

- risperidone

- sulpiride

- olanzepine

Distinction between “ typical” and

atypical groups

-- less incidence of extrapyramidal side-effects in

- atypical- atypical

-- efficacy in treatment-resistent group of patients

-- efficacy against negative symptoms

Typical Antisychotic: Classes

1. Phenothiazines : chlorpromazine

- Aliphatic phenothiazines are less potent

antagonists at D2 receptor than piperazine

derivative (fluphenazine), thioxanthine and derivative (fluphenazine), thioxanthine and

butyrophenone

2. Butyrophenone: haloperidol

Typical Antipsychotic

• Block D2 receptor : mesolimbic and possibly

mesocortical D2 receptor

• Less effective at controlling the negative

symptoms of schizophreniasymptoms of schizophrenia

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

CLOZAPIN•Merupakan antipsikotik baru, termasuk kelompok

atipikal.

• Jarang menyebabkan gangguan extrapiramidal

�mengikat reseptor D1 dan D4

• Mengantagonis central adrenergic, serotoninergic,

histaminergic dan cholinergic receptors.

• Meningkatkan berat badan• Meningkatkan berat badan

• 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.

Atypical Antipsychotic

• Block D2 receptor, 5-HT2 rec’r, D4 rec’r

• More effective than typical antipsychotics at treating the “negative” symptoms of schizophrenia

• Risperidone:

- block D2,5-HT2, α-adrenergic (α1 dan α2), H1 rec’r

- more effective than haloperidol at combating the positive - more effective than haloperidol at combating the positive symptoms of schizophrenia and preventing a relapse of the active phase of the disease

• Clozapine:

- block D1-5,5-HT2, α1-adrenergic , H1 and muscarinic rec’r

- In patients who have failed other antipsychotic drugs

- Not as 1 st line agents → agranulocytosis

Pharmacokinetic

• Highly lipophilic

• High FPE

• Highly bound to plasma protein

• Kinetics of elimination typically follow a • Kinetics of elimination typically follow a

multiphasic pattern and are not strictly first

order

• Acute patients : IM, Chronic therapy: oral

Pharmacokinetic

• Haloperidol and fluphenazine : decanoate

ester →slowly hydrolized and release → long

acting formulation (3-4 weeks)

Drug Interaction

• Antiparkinson drugs

• Benzodiazepine : potentiate the sedative

effect

Side Effects

• High potency drugs: have very high affinity for

D2 rec’r (higher slectivity of action): fewer

sedative side effects and cause less postural

hypotensionhypotension

• Lower potency drugs: cause fewer

extrapyramidal side effects

Adverse Pharmacologic Effects

Type Manifestations Mechanism

ANS Loss of accomodation, dry mouth,

Difficulty urinating, constipation

Muscarinic cholinoceptor

blockade

Orthostatic hypotension, impotence,

failure to ejaculate

Alpha adrenoceptor

blockade

CNS Parkinson’s syndrome, akathisia, Dopamine receptor CNS Parkinson’s syndrome, akathisia,

dystonia

Dopamine receptor

blockade

Tardive dyskinesia Supersensitivity of

dopamine rec’r

Toxic-confusional state Muscarinic blockade

Endocrine system Amenorrhea-galactorrhea, infertility,

impotence

Dopamine rec’r blockade

resulting in

hyperprolactinemia

Other Weight gain Possibly combined H1 and

5HT2 blockade

AntidepressantAntidepressant

Introduction• Depression: a heterogenous disorder that has

been characterized and classified in a variety

of ways1. Gejala utama : - Perasaan depressif

- Hilangnya minat/ aktifitas - 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.

The pathogenesis: The amine hypothesis

• The early 1950-s: reserpine → depression in

patients being treated for hypertension and

schizophrenia as well as in normal subejects

• Reserpin : inhibit the transport of 5 HT, NA

and DA into the vesicle.

MONOAMINE THEORY

1. Reserpin

2. Imipramine (TCA)

3. MAO - I

4. ECT � me response CNS the NA & 5-HT4. ECT � me response CNS the NA & 5-HT

Hal yang menolak teori monoamine

1. Amfetamine / sabu-sabu, meningkatkan

NE disinaps tapi tidak meningkatkan

mood.

2. Cocaine

3. Tryptophan � sintesa 5 – HT3. Tryptophan � sintesa 5 – HT

4. α dan β bloker � memblok NA � no

effect on manic.

Antidepressants1. Tricyclic antidepressant (TCA )

= imipramin

= amitriptin

2. Mono Amine Oxidase Inhibitor (MAO-I ):

=fenelzin } non-selective

=tranilsipromin } ,,

=clorgyline } MAO-A selective=clorgyline } MAO-A selective

=moclobemide } ,,

3.Selective 5-HT re- uptake inhibitors (SSRI )

=fluoxetine

=sertraline

4.Atypical antidepressants:

= maprotiline

= mianserine, tradozone

Tricyclic Antidepressant

• MoA:

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

- do not affect DA reuptake

• Ph’kinetic:

- Well absorbed via the GIT- 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

Tricyclic Antidepressant

• Side effects:

- CV : quinidine like side effect

- Anticholinergic effects

- Antihistamine effects- Antihistamine effects

- Antiadrenergic effects

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

* dihambat oleh selegiline* dihambat oleh selegiline

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 “”

Efek lain: * motor activity ↑

* euphoria

* excitement

** hal ini juga terhadap orang normal

Efek samping:

• stimulasi sentral

• ↑ appetite • ↑ appetite

• hepatotoksik

• interaksi obat :

- cheese reaction

- simpatomimetik

- petidin� hiperpirexia, gelisah, koma,hipotensi

Selective Serotonin Re-Uptake Inhibitors

(SSRI )

• Fluoxetin, paroxetin, sertralin

• Keuntungan SSRI :

1. Hanya menghambat serotonin

2. Tidak menyebabkan “cheese reaction”2. Tidak menyebabkan “cheese reaction”

• Kerugian SSRI : tidak sekuat TCA untuk depresi berat

Farmakokinetik:

* diserap per-oral dengan baik

* t ½ 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

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- toksisitas akut lebih rendah

- onset of action lebih cepat

- efektif terhadap pasien yang non-responsif

terhadap TCA atau MAO-I

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 uptake -I -hipotensi lebih aman zone uptake -I -hipotensi 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

Duloxetine (Cymbalta ®)

~ Kelompok serotonin and Norepinephrine

reuptake inhibitor (SNRI).

~ Disetujui FDA pada Agustus 2004 untuk

MDD dewasa.

~ Pada September 2004 disetujui untuk

diabetic peripheral neuropathic pain

(DPNP).

~ Juga diteliti untuk stress urinary

incontinence (SUI)

Mekanisme kerja

~ Menghambat reuptake serotonin dan

neropinephrine dengan kuat.

~ Penghambat lemah dari dopamine ~ Penghambat lemah dari dopamine

reuptake.

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

mengurangi AUC ± 10%mengurangi AUC ± 10%

- Terdistribusi luas.

- Lebih 90% terikat dengan protein :

~ Albumin.

~ α1 – acid glycoprotein.

Stress Urinary Incontinence (SUI)

Urinary incontinence � “beser”

Stress urinary incontinence (SUI) :

- Involutary leakage brought on by effort

or exertion, or sneezing or coughing.

Treatment :

- Biasanya kegel exercise

- Behavioural therapy

- Surgery

OBAT ? � Duloxetine.

FARMAKODINAMIKA BZD 47

Side Effects

D2 rec’r antagonist:• Extrapyramidal syndrome

• Neuroleptic malignant syndrome (catatonia, stupor, fever, and autonomic instability)

• Hyperthermia

• Tardive dyskinesia• Tardive dyskinesia

• Increase prolactine secretion: amenorrhea, galactorrhea, false positive pregnancy tests in women, and gynecomastia and ↓ libido in men

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

accomodation

• α adrenergic antagonism: orthostatic hypotension, and failure to ejaculate (men), sedation

Phenothiazines: Side effects

Drug Sedative Extrapyramidal Hypotensive

Chlorpromazine hydrochloride +++ ++ IM+++

Mesoridazine besylate +++ + Oral++

Thioridazine hydrochloride +++ + +++Thioridazine hydrochloride +++ + +++

Fluphenazine hydrochloride + ++++ +

Perphenazine ++ ++ +

Trifluoperazine hydrochloride + +++ +

Thioxanthenes: Side effects

Drug Sedative Extrapyramidal Hypotensive

Chlorprothixene +++ ++ ++

Thiothixene hydrochloride+to++ +++ ++

Interference with the system: 5HT

• Inhibit uptake into CNS (other AA’s)

• Inhibit synthesis: p-chlorophenylalanine (irreversible)

• Inhibit neuronal re-uptake: cocaine, SSRA (e.g. fluoxetine), TCA (e.g. imipramine)

• Inhibit storage-deplete: reserpine• Inhibit storage-deplete: reserpine

• Inhibit metabolism: MAO inhibitors

• Promote release: p-chloroamphetamine - then depletes (e.g. fenfluramine to ↓ appetite)

Non-selective

Serotonin Receptors

• At least 15 types and subtypes

• Multiple transduction mechanisms

• 5HT-1A: role in anxiety/depression

• 5HT-1D: role in migraine• 5HT-1D: role in migraine

• 5HT-2: role in CNS various behaviors, and in cardiovascular system

• 5-HT3: role in nausea and vomiting esp. due to Chemotherapy.