PsychopharmacologyPrianto Djatmiko

Main Psychotropic Drugs

Antipsychotics Antidepressants Mood-Stabilizers Anxiolytics Hypnotics Cognitive-Enhancers Psychostimulants

Prinsip mekanisme kerja obat psikofarmaka

Agonis artinya kerja obat menyerupai sifat neurotransmitter sasaran, berikatan dg reseptor dan memperkuat kerja neurotransmiter tsd di neuron Antagonis artinya kerja obat mem-blok reseptor neurotransmitter sasaran sehingga neurotransmitter tsb tdk dapat berikatan dg neuron.

Prinsip pemilihan obat psikofarmaka1. 2. 3. 4. 5. 6. 7. Efek yang diharapkan berkaitan dengan gejala sasaran Start low go slow Implikasi dari efek samping obat Interaksi dengan obat-bat lain Fungsi hepar dan ginjal terkait dosis Tailoring-made Kehamilan? Menyusui?

Antipsikotik (Neuroleptik)Golongan Tipikal (FGA) Golongan Atipikal (SGA/SDA)

Indikasi: Gangguan Psikotik (Termasuk Psikosis organik) Skizofrenia Depresi berat disertai gejala psikotik Agitasi (Gaduh-gelisah) Delirium Tic vokal (Sindrom Gilles de la tourrete)

Jalur dopaminergik saraf Teori Dopamine-Pathways

1. Jalur nigrostriatal: dari substantianigrakebasal ganglia fungsi gerakan, EPS 2. jalur mesolimbik: dari tegmental area menujukesistemlimbik memori, sikap, kesadaran, prosesstimulus 3. jalur mesocortical : dari tegmental area menujukefrontal cortex kognisi, fungsi sosial, komunikasi, responsterhadapstress

Antipsikotik Golongan Tipikal Phenothiazine Chlorpromazine Thioridazine Perphenazine Fluphenazine Trifluoperazine Butyrophenone Haloperidol Diphenylbutylpiperidine Pimozide Benzamide Sulpiride

First Generation Antipsychotic (FGA) Dosage GuidelinesDrug Chlorpromazine Fluphenazine Starting Dose 50-100 mg/d 5 mg/d Dose Range 300-1000 mg/d 5-20 mg/d Usual Max. Ds 1000mg/d 20mg/d 100mgIM/

Fluphenazine Depot12.5-25 mgI M / 2-3weeks 6.25-50mgIM/2-4weeks

4weeksHaloperidol 2-5 mg/d 2-20 mg/d 20 mg/d 300mg/ 3-4weeks 64mg/d 40 mg/d

Haloperidol Depot 25-50mgIM/2weeks 50-200mg/2-4weeks Perphenazine Trifluoperazine 4-8 mg/d 2 mg bid 16-64 mg/d 5-40 mg/d

Phenothiazines Antipsikotik pertama yg ditemukan & digunakan Chlorpromazine (Largactil, 1952) Thioridazine (Melleril)

Pharmacokinetics: Waktu paruh 24-48 jam Metabolisme di hepar

Pharmacodynamics: Memblok reseptor D2 Jg mem-blok ACh, 5-HT, NE & Histamine:Sedatif, sympathomimetic, anti-emetik

Butyrophenones Haloperidol (Haldol, 1967) Longer half-life: Drug holidays of 3 days A more Specific D2 blocker Little sedation Parkinsonian effects like those of high-potency phenothiazines (Perphenazine, Fluphenazine Trifluoperazine) Acute extrapyrimidal effects: Akathisia: anxious pacing, rocking Acute Dystonia: spasm and posturing Parkinsonism

Chronic extrapyrimidal effects: Tardive dyskinesia

Antipsikotik atipikal (SGA) Clozapin Risperidon Olanzapin Quetiapin Ziprasidon AripiprazolAntagonis reseptor 5-HT, Blokade dopamin rendah

terdapat hubungan kuat antara system dopaminergik dan serotonergik serotonin memodulasi fungsi dopamine

(reductionsinserotoninactivityareassociatedw ith enhancem entsindopam ineactivity) Saat ini lebihbanyak digunakansebagai drug of choice karenarelatif lebihamandari efek sampingekstrapiramidal1/2/2009 Zullies Ikawati's Lecture Notes 26

Second Generation Antipsychotic (SGA) Dosage GuidelinesSGARisperidone Olanzapine Quetiapine Clozapine

Starting Dose1 2 mg/day 5 10 mg 25 mg bid 12.5 mg

Titration Range1 mg/2-3 days 5 mg/week 50 mg/day

Max. Dose Schedule2 6 mg/day (i) 10 20 mg/day 300 800 mg/day

Dose increased every 3 daysDay 2: 25 mg Day 3: 25 mg bid Day 6: 50 mg bid Day 9: 75 mg bid Day 12: 100 mg bid Day 15: 125 mg bid Day 18: 150 mg bid Day 21: 200 mg bid

300 900 mg/day

(i) The risk of EPS is significantly increased by using doses > 6 mg daily

Guideline for SchizophreniaSecond Generation Antipsychotic (SGA) #14 -12 WEEKS

No response

SGA #24 -12 WEEKS

No response

Conventional #14 12 WEEKS

No response

Clozapine3 - 9 MONTHS

No response

Two Antipsychotics(not 2 conventionals)

ECT+/-Antipsychotic Different AntipsychoticConventional#2) (Atypical#3,

Summary of AntipsychoticsDrug Advantages Disadvantages

Chlorpromazine Thioridazine (Mellaril)

Generic, inexpensive Slight extrapyramidal syndrome; generic Depot form also available (enanthate, decanoate) generic, inexpensive Parenteral form also available; (?) decreased tardive dyskinesia Parenteral form also available; generic

Many adverse effects, especially autonomic 800 mg/d limit; no parenteral form; cardiotoxicity (?) Increased tardive dyskinesia moderate risk of EPS, sedation Uncertain

Fluphenazine (Modecate)

Perphenazine (Trilafon) Thiothixen (Navane)

Haloperidol

Severe extrapyramidal syndrome

Drug Loxapine (Loxitane) Clozapine (Clozaril)* (klo za peen)

Advantages (?) No weight gain May benefit treatmentresistant patients; little extrapyramidal toxicity

Disadvantages Uncertain May cause agranulocytosis in up to 2% of patients; weight gain, hyperglycemia, diabetes, dyslipidemia

Risperidone (Risperdal)*

Broad efficacy; little or no extrapyramidal system dysfunction at low doses

May cause extrapyramidal syndrome or hypotension with higher doses; weight gain, hyperglycemia, diabetes, dyslipidemia

*Atypical (or second generation) antipsychotics

DrugOlanzapine (Zyprexa)*

AdvantagesEffective against negative as well as positive symptoms; little or no extrapyramidal system dysfunction

DisadvantagesWeight gain, hyperglycemia, diabetes, dyslipidemia

Quetiapine (Seroquel)*

Little or no extrapyramidal system dysfunction

Weight gain, hyperglycemia, diabetes, dyslipidemia; cataracts (?)

*Atypical antipsychotics

Drug Ziprasidone (Geodon)*

Advantages less weight gain than other atypicals

Disadvantages prolongs Q-T interval, but no arrhythmias reported yet; somnolence, some EPS

Aripiperazole (Abilify)*

little or no EPS, less weight Akathesia, insomnia, gain, or Q-T changes anxiety. Caution in patients with epilepsy or Alzheimers

Neurological Side Effects of Antipsychotic DrugsReaction Features Time of Maximal Risk 1 to 5 days Proposed Mechanism unknown Treatment

Acute dystonia

Spasm of muscles of tongue, face, neck, back; may mimic seizures; not hysteria

Many treatments can alter, but effects of antimuscarinic agents are diagnostic and curative.*

Akathisia

Motor restlessness: not anxiety or agitation

5 to 60 days

unknown

Reduce dose or change drug; antimuscarinic agents, dephenhydramine, benzodiazepines, or propranolol ++ may help

Parkinsonism

Bradykinesia, 5 to 30 days rigidity, variable tremor, mask facies, shuffling gait

antagonism of dopamine

Antimuscarinic agents helpful+

Neurological Side Effects of Antipsychotic DrugsReaction Features Time of Maximal Risk weeks; can persist for days after stopping neuroleptic Proposed Mechanism Treatment

Neuroleptic Malignant syndrome

catatonia, stupor, fever, unstable blood presure, myoglobinemia; can be fatal

antagonism of stop antipsychotic dopamine may immediately; dantrolene contribute or bromocriptine may help; antimuscarinic agents not effective

Perioral tremor (rabbit syndrome) Tardive dyskinesia

perioral tremor (may after months be a late variant of or years of parkinsonism) treatment oral-facial dyskinesia; widespread choreoathetosis or dystonia after months or years of treatment (worse on withdrawal)

unknown

Antimuscarininic agents often help+

up regulation of striatal D2 receptors

prevention crucial; clozapine or olanzapine may help

Comparison of Some Antipsychotic AgentsDrug Relative Antipsychotic Potency+ +

Sedation

Extrapyramidal+++ +

Anticholinergic+ +++

Hypotension

chlorpromazine (Thorazine) thioridazine (Mellaril)

+++ +++

+++ +++

fluphenazine (Prolixin)haloperidol (Haldol)

++++++

++

++++++

++/-

+++

loxapine (Loxitane)molindone (Moban) clozapine (Clozaril) risperidone (Risperdal)

++++ ++ +++

+++ +++ +

+++ +/+

+/+ +++ +

++ +++ ++

Some Adverse Effects of Second Generation AntipsychoticsDrug Diabetes Extrapyramid al Symptoms Elevated Prolactin QTc Weight Prolongation Gain

Aripiprazole Clozapine* Olanzapine Quetiapine Risperidone

+/++++ ++++ ++ ++

+ +/+ +/+++

+/+/+/+/+++

+/+ + +/+

+/++++ ++++ +++ ++

Ziprasidone

+/-

+

+

++

+/-

*Clozapine is also associated with myocarditis and agranulocytosis; the other secondgeneration antipsychotics are not.

Long Acting Antipsychotic DrugsDrug Fluphenazine Decanoate Modecate Fluphenazine Enanthate Prolixin Enanthate Haloperidol Decanoate Haldol Decanoate Classification Typical Route of Administration Intramuscular Subcutaneous Intramuscular Subcutaneous Intramuscular Duration of Action 2-3 weeks

Typical

2 weeks

Typical

3-4 weeks

Risperidone (Risperdal Consta)

Atypical

Intramuscular

2 weeks

Antipsikotik yang beredar di Indonesia Klorpromazin(generik, Meprosetil, Largactil, Largazine, Promactil) Haloperidol (Lodomer, Govotil, Halonace, Haldol, Seradol, Serenace) Flufenazin(Anatensol) Perfenazin(generik, T rilafon) Proklorperazin(Stemetil) T ioridazin(Melleril) T rifluoperazin(generik, Stelazine, T r