Antipsychotic Antidepressant

Tri Widyawati_Aznan Lelo

BMS_2009

Antipsychotic

Introduction
Drugs used in the management of psychosis: neuroleptics or antipsychotics The termneuroleptic emphasizes the drugsneurological 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? 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, 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 recr in the CNS, especially in the mesolimbic-frontal system 2. Drugs that dopaminergic activity: levodopa ( a precursor), amphetamines (releaser of dopamine), 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

The Dopamine Hypothesis

4. Positron emission tomography (PET): dopamine recr 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.

Dopamine Receptor Families

D1 Receptor Family 2nd messenger systems cAMP (via Gs) PIP2 hydrolisis -Ca2+ mobilization (via IP3) - PKC activation D5 Hippocampus Hypothalamus D2 Receptor Family cAMP (via Gi) K+ currents voltage-gated Ca2+ currents D2 Striatum Subs.nigra Pituitary gland D3 Olfac. tubercle Nucleus accumbens Hypothalamus D4 Frontal cortex Medulla Midbrain

Distribution D1 in CNS Striatum Neocortex

 The mesolimbic system: emotions and memory mesolimbic hyperactivity is responsible for the positive symptoms of schizophrenia 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 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 recr antagonist) - chlorpromazin - haloperidol - fluphenazine 2. Atypical antipsychotics (D2 recr, 5-HT2, other CNS recr
antagonist)

- clozapine - risperidone - sulpiride - olanzepine

Distinction between typical and atypical groups

-- less incidence of extrapyramidal side-effects in - 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 butyrophenone 2. Butyrophenone: haloperidol

Typical Antipsychotic
Block D2 receptor : mesolimbic and possibly mesocortical D2 receptor Less effective at controlling the negative symptoms 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 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 recr, D4 recr More effective than typical antipsychotics at treating the negative symptoms of schizophrenia Risperidone: - block D2,5-HT2, -adrenergic (1 dan 2), H1 recr - 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, 1-adrenergic , H1 and muscarinic recr - 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 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 recr (higher slectivity of action): fewer sedative side effects and cause less postural hypotension Lower potency drugs: cause fewer extrapyramidal side effects

Adverse Pharmacologic Effects

Type ANS Manifestations Loss of accomodation, dry mouth, Difficulty urinating, constipation Orthostatic hypotension, impotence, failure to ejaculate CNS Parkinsons syndrome, akathisia, dystonia Tardive dyskinesia Toxic-confusional state Endocrine system Amenorrhea-galactorrhea, infertility, impotence Weight gain Mechanism Muscarinic cholinoceptor blockade Alpha adrenoceptor blockade Dopamine receptor blockade Supersensitivity of dopamine recr Muscarinic blockade Dopamine recr blockade resulting in hyperprolactinemia Possibly combined H1 and 5HT2 blockade

Other

Antidepressant

Introduction
Depression: a heterogenous disorder that has been characterized and classified in a variety of ways
1. Gejala utama : - Perasaan depressif - Hilangnya minat/ aktifitas selama minimal 2 minggu 2. 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-HT

Hal yang menolak teori monoamine

1. Amfetamine / sabu-sabu, meningkatkan NE disinaps tapi tidak meningkatkan mood. 2. Cocaine 3. Tryptophan sintesa 5 HT 4. dan bloker memblok NA no effect on manic.

Antidepressants
1. 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 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 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

Tricyclic Antidepressant
Side effects: CV : quinidine like side effect Anticholinergic 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

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 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 Kerugian SSRI : tidak sekuat TCA untuk depresi berat

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

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

Obat

Mekanisme Efek kerja samping

seletif thd NA-uptake I -atropin like -sedasi,kejng -mirip TCA -sedasi,bingung -hipotensi -aritmia

Keuntungan t 1/2

Maprotilin

40 jam

Tradozone

Mianserin

weak 5-HT uptake -I =memblok 5-HT2 & alfa receptor =memblok alfa2,5-HT2 H1 = NA release meningkat

(-) atropin-like lebih aman

6-12 j

-sedasi,kejang -alergi

(-) atropin-like (-) aritmia

12 jam

Bupoprion

-oyong,cemas - kejang

lebih aman

12 jam

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 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% - Terdistribusi luas. - Lebih 90% terikat dengan protein : ~ Albumin. ~ 1 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.

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Side Effects
D2 recr antagonist:
Extrapyramidal syndrome Neuroleptic malignant syndrome (catatonia, stupor, fever, and autonomic instability) Hyperthermia Tardive dyskinesia Increase prolactine secretion: amenorrhea, galactorrhea, false positive pregnancy 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 to ejaculate (men), sedation

Phenothiazines: Side effects

Drug Chlorpromazine hydrochloride Mesoridazine besylate Thioridazine hydrochloride Fluphenazine hydrochloride Perphenazine Trifluoperazine hydrochloride Sedative +++ +++ +++ + ++ + Extrapyramidal ++ + + ++++ ++ +++ Hypotensive IM+++ Oral++ +++ + + +

Thioxanthenes: Side effects

Drug Sedative Extrapyramidal Hypotensive

Chlorprothixene

+++

++

++

Thiothixene hydrochloride

+to++

+++

++

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 Non-selective - then depletes (e.g. fenfluramine to appetite)

Serotonin Receptors
At least 15 types and subtypes Multiple transduction mechanisms 5HT-1A: role in anxiety/depression 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.