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Psikofarmakologi

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

Prinsip pemilihan obat psikofarmaka


1. 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-obat lain Fungsi hepar dan ginjal terkait dosis Tailoring-made Kehamilan? Menyusui?

Golongan Psikofarmaka
Antipsikotik
Antidepresan Anxiolitik/Antianxietas

Hipnotik /Sedatif
Cognitive Enhancer Psikostimulan

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)

Antipsikotik Golongan Tipikal


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

Antipsikotik Golongan Tipikal


Nama Generik Chlorpromazine Fluphenazine Dosis Initial 50-100 mg/h 5 mg/h Dosis Terapeutik 300-1000 mg/h 5-20 mg/h 6.25-50 mg IM/bln 2-20 mg/h Dosis Max 1000mg/h 20mg/h 100 mg 20 mg/h

Fluphenazine Decanoat 12.5-25 mg IM/bln Haloperidol 2-5 mg/h

Haloperidol Decanoat
Perphenazine Trifluoperazine

25-50mgIM/bln
4-8 mg/h 5 mg/h

50-200mg/bln
16-64 mg/h 5-40 mg/h

200 mg
64mg/h 40 mg/h

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 & Histamin

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

Chronic extrapyrimidal effects: Tardive dyskinesia

Antipsikotik Atipikal/ Serotonin-Dopamine Antagonist (SDA)


SDA
Risperidone Olanzapine Quetiapine Clozapine

Starting Dose
1 2 mg/day 5 10 mg 25 mg bid 12.5 mg Day Day Day Day Day Day Day Day

Titration Range
1 mg/2-3 days 5 mg/week 50 mg/day

Max. Dose
4 6 mg/day 10 20 mg/day 300 800 mg/day

Dose increased every 3 days 2: 25 mg 3: 25 mg bid 6: 50 mg bid 9: 75 mg bid 12: 100 mg bid 15: 125 mg bid 18: 150 mg bid 21: 200 mg bid 300 900 mg/day

Guideline for Schizophrenia


Second Generation Antipsychotic (SGA) #1
4 -12 WEEKS

No response

SGA #2
4 -12 WEEKS

No response

Conventional #1
4 12 WEEKS

No response

Clozapine
3 - 9 MONTHS

No response

Two Antipsychotics
(not 2 conventionals)

ECT+/-Antipsychotic Different Antipsychotic


Conventional#2) (Atypical#3,

Neurological Side Effects of Antipsychotic Drugs


Reaction 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 Drugs


Reaction 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

Adverse Reactions
Neurologic seizures with clozapine Cardiovascular and cerbrovascular effects hypotension peripheral a blockade Orthostatic

QT prolongation (thioridazine, ziprasidone, others) Increased risk of stroke in elderly (risperidone, olanzapine)

Weight gain and metabolic effects Prominent with clozapine and olanzapine. Uncommon with ziprasidone and aripiprazole, others. Can increase risk of Type 2 diabetes.

Adverse effects (cont.)


Blood disorders mild leukocytosis, leukopenia, and eosinophilia. Bone marrow suppression or agranulocytosis with clozapine. Others
Skin reactions dermatitis, photsensitivity, sun burn, pigmentary retinopathy (typicals). GI/metabolic jaundice with CPZ; ileus and sialorrhea with clozapine Endocrine hperprolactinemia Sedation due to H1 block Anticholinergic effects mainly typicals

Comparison of Some Antipsychotic Agents


Drug 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 Antipsychotics


Drug 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.

Antidepresan

PHASES OF TREATMENT FOR DEPRESSION

Normalcy Severity Relapse Response

Relapse Recurrence

Symptoms

Disorder

Acute Continuation Maintenance (6-12 weeks) (4-9 months) or more years) (1

Antidepressan
Yang bersifat sedatif: Amitriptyline Imipramine Clomipramine Maproptiline Trazodone Mirtazapine Yang bersifat aktivasi/non-sedatif: Tianeptine Moclobemide SSRI (Fluoxetine,Sertraline,Citalopram,Fluvoxamine)

Tricyclic antidepressants (TCAs):


Amitriptyline has higher sedative and anticholinergic effects and affects serotonin more than imipramine does. Imipramine (Tofranil) discovered as a modification of a phenothiazine (antipsychotic) Clomipramine (Anafranil) has the highest serotonin effect of the TCAs, with little anticholinergic or sedative action. Also for OCD.

Pharmacodynamics of TCAs

Tricyclic side effects


TCAs have varying side effects. All TCAs are toxic to the heart at high doses, and are effective agents of suicide. This fact has fueled the search for other antidepressants.

Other antidepressants
Maprotiline (Ludiomil) is based on the TCA molecule. May cause seizures, and accumulates to toxic levels. More lethal than TCAs. Blocks reuptake of NE. Reversible MAOIs or RIMA: moclebemide (Aurorix)

SSRI antidepressants
SSRIs: Selective Serotonine (5-HT) Re-uptake Inhibitors Method of Action: They act within the brain to increase the amount of serotonin in the synaptic gap by inhibiting reuptake. In contrast to other drugs, SSRIs are more potent inhibitors of serotonin reuptake, and they have less of an effect on 1, 2, histaminic, and muscarinic receptors

Measurement of drug action


Modern antidepressant drugs (SSRIs) block the serotonin transporter (SERT)

Pre-synaptic terminal Serotonin transporters (SERT) Synapse


Serotonin

Serotonin reuptake inhibitor (SSRI)

SPECT tracer

Post-synaptic cell

Image available binding sites

SSRIs: Selective Serotonin Reuptake Inhibitors


Fluoxetine (Prozac, 1988): least selective Sertraline (Zoloft): quick action, less side effects Escitalopram (Cipralex) Fluvoxamine (Luvox, 1995): OCD, panic disorders & PTSD

Fluoxetine
Positive effects in one study on adults caused them to be much improved on the CGI scale (J Intellect Disabil Res 1998; 42: 3016)

Children have negative effects that cause discontinuation of the drug such as hyperactivity and agitation (Dev Med Child Neurol
1998; 40: 551-62)

Also reports of producing mania in people with PDDs (J Am


Acad Child Adolesc Psychiatry 1998;37:248-9).

Sertraline
Similar in effects to fluoxetine (Prozac) Improvement in some adults in aggression and selfinjurious behavior (J Clin Psychiarty 1996;57:333-6) Caused hyperactivity in children and agitation despite improvement in anxiety and irritability (J Child
Adolesc Psychopharmacol 1997;7:9-15)

SSRI-Common Side Effects


Insomnia, headache Nausea, anorexia
Diarrhea Constipation

Sexual dysfunction
Decreased libido Anorgasmia

Nervousness, tremor
Myoclonus

SSRI: Other Indications


Anxiety/Panic Bulimia Nervosa MDD OCD-Spectrum Impulse Control

FDA Warning 3/22/2004


The Food and Drug Administration (FDA) requests a Warning Statement in the labeling for certain antidepressants to encourage close observation of adult and pediatric patients treated with these agents for worsening depression or the emergence of suicidality. The drugs that are the focus of this new Warning Statement include: Prozac (fluoxetine); Zoloft (sertraline); Paxil (paroxetine); Luvox (fluvoxamine); Celexa (citalopram); Effexor (venlafaxine) and Remeron (mirtazapine).

Serotonin syndrome
May occur if SSRIs are taken in high doses, especially combined with other serotonin-enhancing drugs, including herbs (valerian) Disorientation, agitation, shivering, diarrhea, increased reflexes, and more May be life-threatening Recover within 48 hours of abstinence

Mood Stabilizer
Used for Bipolar or Manic-Depressive to regulate mood

Mood Stabilizer
Lithium carbonate Lithium is the classic mood stabilizer. Monitoring blood lithium levels (therapeutic range: 0.8 1.2 mEq/L) and look for signs and symptoms of toxicity (such as nausea, vomiting, diarrhea, ataxia) Valproic Acid (Depakene) & Divalproex Sodium (Depakote) Can be very irritating to the stomach. Liver function and CBC should be monitored

Carbamazepine (Tegretol) Can lower white blood cell count. Therapeutic drug monitoring is required. Monitor for signs and symptoms of StevensJohnson syndrome. FDA approved for bipolar disorder
Lamotrigine (Lamictal) Particularly effective for Bipolar depression. Monitor for signs and symptoms of Stevens-Johnson syndrome. Oxcarbazepine (Trileptal) Not FDA approved for bipolar disorder.

Treatment: APA Practice Guidelines 2002


Acute mania/mixed mania:
1st line: lithium or valproate or antipsychotic* 1st line severe: lithium or valproate + antipsychotic*

Acute depression:
1st line: lithium or lamotrigine 1st line severe: lithium + antidepressant

Maintenance
lithium or valproate: Alternatives: lamotrigine, carbamazepine, oxycarbazepine Atypical antipsychotics may be considered

Mood Stabilizers: Lithium


Advantages: 50+ years worldwide experience (FDA-approved 1970) effective in euphoric mania and hypomania inexpensive reduces suicide rate Disadvantages:
slow onset ~ 14 days narrow therapeutic index non-response in > 50% (usually bipolar subtypes) frequent side effects (polyuria, tremor, GI symptoms) and non-compliance discontinuation associated with high relapse rate
Baldessarini RJ, et al. J Clin Psychiatry. 2003;64 Suppl 5:44-52. Goodwin FK, et al. JAMA. 2003 Sep 17;290(11):1467-73. Cavanagh J, et al. Acta Psychiatr Scand. 2004 Feb;109(2):91-5.

Mood Stabilizers: Divalproex


Advantages:
extensive experience (FDA-approved for epilepsy 1983; for bipolar mania 1995) rapid onset (1-4 days) loading dose strategy well-tolerated: 20 mgs/kg 77% moderate to marked response effective in Bipolar subtypes effective for psychotic symptoms plasma levels (50-125 mcg/ml) less cognitive impairment than lithium

Mood Stabilizers: Divalproex


Disadvantages:
sedation transient hair loss weight gain tremor GI upset dose-related thrombocytopenia rare hepatotoxicity, pancreatitis possible Polycystic Ovarian Syndrome plasma level monitoring

Mood Stabilizers: Lamictal


FDA-approved for maintenance treatment of Bipolar I Disorder Black box warning for serious rash (includes
Stevens-Johnson Syndrome and toxic epidermal necrolysis)

Slow titration necessary Interaction with other AEDs (especially valproic acid
and carbamazepine)

ANXIOLITIK

An anxiolytic is a drug prescribed for the treatment of symptoms of anxiety

Types of anxiolytics
Anxiolytics are generally divided into two groups of medication: Benzodiazepines and Non-benzodiazepines

Anxiolytics
Benzodiazepines (BZDs) Barbiturates (BARBs) 5-HT1A receptor agonists: Azaspirodecanedione -Blockers
Buspirone Propranolol Clonidine

2-AR partial agonist


Antidepressants
TCAs, SSRIs

Antihistaminic drugs
Diphenhydramine

Mechanisms of Action
1) Enhance GABAergic Transmission
frequency of openings of GABAergic channels. Benzodiazepines opening time of GABAergic channels. Barbiturates receptor affinity for GABA. BDZs and BARBS

2) Stimulation of 5-HT1A receptors. 3) Inhibit 5-HT2A, 5-HT2C, and 5-HT3 receptors

Pharmacokinetics of Benzodiazepines

Side Effects of Benzodiazepines


Related primarily to the CNS depression and include: drowsiness, excess sedation, impaired coordination, nausea, vomiting, confusion and memory loss. Tolerance develops to most of these effects. Dependence with these drugs may develop. Serious withdrawal syndrome can include convulsions.

Toxicity/Overdose with Benzodiazepines


Drug overdose is treated with flumazenil (a BDZ receptor antagonist, short half-life), but respiratory function should be adequately supported and carefully monitored. Seizures and cardiac arrhythmias may occur following flumazenil administration when BDZ are taken with TCAs. Flumazenil is not effective against BARBs overdose.

BUSPIRONE
Buspirone is an antianxiety agent that acts as a partial agonist at the 5-HT1A receptor presynaptically inhibiting serotonin release and it has an affinity for brain D2 dopamine receptors, where it acts as an antagonist and agonist. Short-term symptomatic relief of excessive anxiety in patients with generalized anxiety disorder.

BUSPIRONE
Buspirone does not have sedative effects and does not potentiate CNS depressants. Has a relatively high margin of safety, few side effects and does not appear to be associated with drug dependence. No rebound anxiety or signs of withdrawal when discontinued

BUSPIRONE
Side effects:
Tachycardia, palpitations, nervousness, GI distress and paresthesias may occur. Causes a dose-dependent pupillary constriction.

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