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 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 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.
Dopamine Receptor Families D1 Receptor Family 2nd messenger systems
• ↑ cAMP (via Gs) • ↑ PIP2 hydrolisis -Ca2+ mobilization (via IP3) - PKC activation
Distribution D1 in CNS •Striatum •Neocortex
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
• 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 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 -- 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 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 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 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 Type ANS
Manifestations
Mechanism
Loss of accomodation, dry mouth, Difficulty urinating, constipation
Muscarinic cholinoceptor blockade
Orthostatic hypotension, impotence, failure to ejaculate
Alpha adrenoceptor blockade
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
CNS
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. α dan β 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: 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 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 kerja samping
Keuntungan t 1/2
Maprotilin
seletif thd NA-uptake I
Tradozone
weak 5-HT uptake -I =memblok 5-HT2 & alfa receptor =memblok alfa2,5-HT2 H1
-sedasi,bingung -hipotensi -aritmia
(-) atropin-like lebih aman
-sedasi,kejang -alergi
(-) atropin-like (-) aritmia
= NA release meningkat
-oyong,cemas - kejang
lebih aman
Mianserin
Bupoprion
-atropin like -sedasi,kejng -mirip TCA
40 jam
6-12 j
12 jam
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. ~ 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 • 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
+++
+
+++
Fluphenazine hydrochloride
+
++++
+
Perphenazine
++
++
+
Trifluoperazine hydrochloride
+
+++
+
Thioxanthenes: Side effects Drug
Chlorprothixene
Thiothixene hydrochloride
Sedative
Extrapyramidal
Hypotensive
+++
++
++
+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 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.
