Tri Widyawati_Aznan Lelo BMS_2009 Antipsychotic Antidepressant

Antipsychotic

Introduction Drugs used in the management of psychosis: neuroleptics or antipsychotics The term”neuroleptic” emphasizes the 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? 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 D 2 rec’r 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 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 FamilyD2 Receptor Family 2 nd messenger systems ↑ cAMP (via Gs) ↑ PIP 2 hydrolisis -Ca 2+ mobilization (via IP3) - PKC activation ↓ cAMP (via Gi) ↑ K + currents ↓ voltage-gated Ca 2+ currents Distribution in CNS D1D5D2D3D4 Striatum Neocortex Hippocampus Hypothalamus Striatum Subs.nigra Pituitary gland Olfac. tubercle Nucleus accumbens Hypothalamus Frontal cortex Medulla Midbrain Dopamine Receptor Families

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 D 2 rec’r antagonist) - chlorpromazin - haloperidol - fluphenazine 2. Atypical antipsychotics (D 2 rec’r, 5-HT 2, other CNS rec’r 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 D 2 receptor than piperazine derivative (fluphenazine), thioxanthine and butyrophenone 2. Butyrophenone: haloperidol

Typical Antipsychotic Block D 2 receptor : mesolimbic and possibly mesocortical D 2 receptor Less effective at controlling the negative symptoms of schizophrenia

Fenotiazin Mekanisme kerja. - Semua antipsikotik bekerja dengan memblok ikatan dengan reseptor D % reseptor D 2 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 D 2 receptor, 5-HT 2 rec’r, D 4 rec’r More effective than typical antipsychotics at treating the “negative” symptoms of schizophrenia Risperidone: - block D 2,5-HT 2,  -adrenergic (  1 dan  2 ), H 1 rec’r - more effective than haloperidol at combating the positive symptoms of schizophrenia and preventing a relapse of the active phase of the disease Clozapine: -block D 1-5,5-HT 2,  1-adrenergic, H 1 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 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 hypotension Lower potency drugs: cause fewer extrapyramidal side effects

Adverse Pharmacologic Effects TypeManifestationsMechanism ANSLoss of accomodation, dry mouth, Difficulty urinating, constipation Muscarinic cholinoceptor blockade Orthostatic hypotension, impotence, failure to ejaculate Alpha adrenoceptor blockade CNSParkinson’s syndrome, akathisia, dystonia Dopamine receptor blockade Tardive dyskinesiaSupersensitivity of dopamine rec’r Toxic-confusional stateMuscarinic blockade Endocrine systemAmenorrhea-galactorrhea, infertility, impotence Dopamine rec’r blockade resulting in hyperprolactinemia OtherWeight gainPossibly combined H 1 and 5HT 2 blockade

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 Ph’kinetic: -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: men imbulkan 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 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 - 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 =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 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.

FARMAKODINAMIKA BZD47

Side Effects D2 rec’r 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 DrugSedativeExtrapyramidalHypotensive Chlorpromazine hydrochloride+++++IM+++ Mesoridazine besylate++++Oral++ Thioridazine hydrochloride++++ Fluphenazine hydrochloride Perphenazine++ + Trifluoperazine hydrochloride+++++

Thioxanthenes: Side effects DrugSedativeExtrapyramidalHypotensive 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 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-2: role in CNS various behaviors, and in cardiovascular system 5-HT3: role in nausea and vomiting esp. due to Chemotherapy.