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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.