TERAPI FARMAKOLOGI ANTIPSIKOTIK

Transcription

1 TERAPI FARMAKOLOGI ANTIPSIKOTIK dr. sufi desrini M.Sc Blok Kesehatan Jiwa 14/11/2014 [10] 1

2 Tujuan Belajar Mengetahui golongan obat antipsikotik Menjelaskan mekanisme kerja obat Menjelaskan FK dan FD masing-masing obat Menjelaskan indikasi, KI, efeks amping dan interaksi obat 2

3 GENERASI PERTAMA ANTIPSIKOTIK Dikenal dengan nama antipsikotik tipikal, antagonis dopamin, neuroleptik dan antipsikotik klasik Masing2 istilah ada sejarah 3

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5 NEUROLEPTIK Kemampuan obat untuk menyebabkan suatu sindrom yang disebut dengan nama neurolepsis. Sindrom ini mempunyai 3 gambaran utama: Perlambatan psikomotor Emotional quieting Affective indifference Awalnya tanda ini dianggap sbg efikasi antipsikotik, namun kemudian terbukti bahwa efek ini tidak dibuthkan utk kerja obat 5

6 Antipsikotik Tipikal Second generation antipsychotic (SGAs) have atypical properties low risk of extrapyramidal symptoms Obat yg tdk mempunyai sifat atipik antipsikotik tipikal/konvensional Konsep awal atipikal berubah menjd lbh luas yg meliputi gejala kognitif dan negatif definisi direvisi setelah CATIE trial yg gagal mengkonfirmasi bahwa SGA lbh efektif dibanding FGA 6

7 Mekanisme Kerja Belum diketahui Teori dopamine skizofrenia : gejala positif adlh sebagai hasil overaktivitas dalam jalur dopamine mesolimbik. Obat2 yang dapat meningkatkan ketersediaan dopaminergik (L-DOPA, kokain, amfetamin) dapat memicu efek psikomimetik pada individu normal FGA adalah antagonis D2 7

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9 Mesocortical pathway Research on schizophrenia pathophysiology suggests that a dysfunction of this pathway is associated with cognitive impairments and disturbances of emotions and affect (negative symptoms). Blockade of the mesocortical pathway by high doses of first-generation antipsychotics can induce secondary negative symptoms and cognitive effects. 9

10 Mesolimbic pathway: Antipsychotic effects overactivity of this pathway is thought to be involved in the pathophysiology of positive symptoms of schizophrenia. Blockade of D2 receptors in the mesolimbic pathway has been proposed as a possible mechanism of antipsychotic action of first-generation agents. 10

11 Nigrostriatal pathway: Extrapyramidal Symptoms Antagonism of D2 receptors in the nigrostriatal pathway is associated with increased risk of extrapyramidal symptoms. 11

12 Tuberoinfundibular pathway: Hyperprolactinemia Dopamine acts as prolactin-inhibiting factor, D2 blockade increases prolactin levels by promoting its release in the pituitary gland. 12

13 Chemical Classification 13

14 Phenothiazines Drugs in this group share the same three-ring structure with different side chains joined at the nitrogen atom of the middle ring. The activity of the group can be affected by substitutions at position 2 or 10. The phenothiazines are categorized into three subclasses based on substitutions at position 10: aliphatic, piperidine, and piperazine phenothiazines. 14

15 Phenothiazines Chemical chemical class classification Side chain drug phenothiazines Aliphatic (low/mediumpotency agents) Chlorpromazine Levomepromazine Promazine Triflupromazine Piperidine (low/medium potency agents) Mesoridazine Pericyazine Piperazine (medium/high-potency agents) Pipotiazine Thioridazine Perphenazine Fluphenazine 15

16 non-phenothiazine firstgeneration antipsychotics. Chemical Class Butyrophenones (high-potency agents) Drug Benperidol Droperidol Haloperidol Thioxanthenes (low/medium-potency agents) Clopenthixol Flupenthixol Thiothixene Zuclopenthixol 16

17 Non-phenothiazine firstgeneration antipsychotics. Dihydroindolones (low/medium-potency agents) Molindone Dibenzepines (low/medium-potency agents) Diphenylbutylpiperidines (high-potency agents) Clotiapine Loxapine Fluspirilene Pimozide 17

18 Chlorproma zine (Thorazine) Fluphenazi ne (Prolixin) Perphenazi ne (Trilafon) Trifluoperaz ine (Stelazine) Thioridazin e (Mellaril) Mesoridazin e (Serentil) +withdraw n from US market in 2004 Dosag e forms D2 Activity 5HT2 Activity Muscari nic Activity Alpha-1 adrener gic Activity Antihist amine Activity T, I T, L, I, I (LA) T T T T

19 Haloperid ol (Haldol) Molindone (Moban) *discontin ued by manufact urer in 2010 Thiothixen e (Navane) Loxapine (Loxitane) Dosage forms T, L, I, I (LA) D2 Activity 5HT2 Activity Muscari nic Activity Alpha-1 adrener gic Activity T Antihist amine Activity C C highlevel/degree of effect: (+) low (++) moderate (+++) high (++++) very 19

20 Antipsychotic potency: chlorpromazine equivalent doses First-generation antipsychotics can be classified according to their potency. All FGAs are compared to chlorpromazine for equivalence purposes. Potency should not be confused with effectiveness. For example, if we know that haloperidol is more potent that chlorpromazine, it means that a lower dose of haloperidol is required to achieve the same therapeutic effect, but not that haloperidol is more effective than chlorpromazine. 20

21 Antipsychotic potency: chlorpromazine equivalent doses Drug Maudsley Prescribing Guidelines Manual of Clinical Psychopharmaco logy Chlorpromazine 100 mg/day 100 mg/day Fluphenazine 2 mg/day 2 mg/day Trifluoperazine 5 mg/day 5 mg/day Flupentixol 3 mg/day Zuclopentixol 25 mg/day Haloperidol 3 mg/day 2 mg/day Sulpiride 200 mg/day 21

22 Antipsychotic potency: chlorpromazine equivalent doses Sulpiride 200 mg/day Pimozide 2 mg/day Loxapine 10 mg/day 10 mg/day Molindone 10 mg/day Perphenazine 10 mg/day Prochlorperazine 15 mg/day Thioridazine 100 mg/day Thiothixene 4 mg/day 22

23 Adverse Effects Profile Drug Chlorproma zine Fluphenazi ne Sedating effects Anticholin ergic effects Extrapyra midal side effects Hypotensi ve effects High High Low IM-High Low Low Very high Low PO- Moderate Haloperidol Very low Very low Very high Very low Loxapine Moderate Low Moderate Moderate Molindone Very low Low Moderate Low Perphenazi ne Low Low High Low 23

24 Adverse Effects Profile Pimozide Low Low High Very low Pimozide Low Low High Very low Thioridazine High High Low High Thiothixene Low Low High Low Trifluoperazin e Low Low High Low 24

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28 SECOND GENERATION ANTIPSYCHOTICS (ATYPICALS) 28

29 Aripiprazole a second-generation (atypical) antipsychotic approved for the treatment of schizophrenia, bipolar disorder, depression and autism spectrum disorders. Aripiprazole was originally approved in 2002 for the treatment of schizophrenia. Currently, the FDA has approved aripiprazole for the treatment of bipolar disorder (mania and mixed episodes and as maintenance treatment), asadjunctive treatment for major depressive disorder (2006) and for autism spectrum disorders (2007) 29

30 Indication Initial Dose Recommended Dose Maximum Dose Schizophrenia Adults mg/day mg/day 30 mg/day Adolescents 2 mg/day 10 mg/day 30 mg/day Bipolar Disorder Treatment of manic or mixed episodes Bipolar Mania Adults Monotherapy 15 mg/day 15 mg/day 30 mg/day 30

31 Bipolar Mania Adults Adjunt to lithium or valproate Bipolar Mania Pediatric patients Monotherapy or adjunct to lithium or valproate mg/day 15 mg/day 30 mg/day 2 mg/day 10 mg/day 30 mg/day Maintenance treatment Maintenance treatment of bipolar I disorder Major Depressive Disorder Adjunct to antidepressants Doses not available in product monograph. 2-5 mg/day 5-10 mg/day 15 mg/day 31

32 Formulations Tablets Orally disintegrating tablets Liquid formulation IM injection 32

33 General pharmacokinetics and drug interactions Half-life aripiprazole: 75 hours dehydro-aripiprazole: 94 hours Elimination Mainly through hepatic metabolism involving two P450 enzymes: CYP3A4: dose adjustment might be needed in the presence of inhibitors or inducers. 33

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36 Pharmacokinetics of oral administration Absorption Peak plasma concentrations occur within 3 to 5 hours. Can be admininistered with or without food. According to the manufacturer, a study found that plasma concentrations from the oral solution were higher than that from the tablet formulation. Distribution Volume of distribution in studies after IV administration is of 404 L or 4.9L/Kg (extense extravascular distribution) Aripiprazole and dehydro-aripiprazole are greater than 99% bound to serum proteins (primarily albumin) 36

37 Pharmacokinetics of IM administration Median times to the peak plasma concentration: 1 hours and 3 hours. In one pharmacokinetic study [Boulton,2008], intramuscular aripiprazole demonstrated more rapid attainment of plasma aripiprazole concentrations than oral aripiprazole (78% and 5% of peak plasma concentration [Cmax] values at 0.5 hours postdose, respectively). 37

38 Aripiprazole binds to a number of CNS receptors, this includes effects as: partial D2 agonist partial 5-HT1A agonist 5-HT2A antagonist 38

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40 D2 PARTIAL AGONIS What are the implications of D2 partial agonism? Aripiprazole binds to the D2 receptor with the same affinity than dopamine, but has a lower intrinsic efficacy, so the response it triggers is lower than dopamine but higher than an antagonist. 40

41 As partial agonist at D2 receptors, it modulates neurotransmission in dopaminergic pathways (mainly mesolimbic and mesocortical pathway). According to the dopamine theory of schizophrenia, overactivity of the mesolimbic pathway may trigger positive symptoms (hallucinations, delusions). 41

42 Positive symptoms of schizophrenia might be the result of an overactivation of the m 42

43 Aripiprazole reduces dopaminergic activity in the mesolimbic pathway through partia 43

44 The dopamine theory of negative and cognitive symptoms suggests that there is a hypofunction of dopaminergic neurotransmission in the mesocortical pathway. opaminergic activity in the mesocortical pathway is thought to be reduced in schizoph 44

45 One postulated mechanism of action of aripiprazole in schizophrenia is the ability of the drug to increase dopaminergic activity from a subnormal level to normal activity in the mesocortical pathway. artial D2 agonism might increase dopaminergic activity in the mesocortical pathway. 45

46 Key Points Aripiprazole is a partial agonist at D2 receptors. It may act as an antipsychotic by: Lowering dopaminergic neurotransmission in the mesolimbic pathway. Enhancing dopaminergic activity in the mesocortical pathway. It has a lower risk of EPS and hyperprolactinemia than other antipsychotics. 46

47 RISPERIDONE Risperidone is one of the oldest (and least expensive) second-generation antipsychotics. In 1993 the FDA approved it for the treatment of schizophrenia. Like most antipsychotics, risperidone is also effective for the treatment of manic and mixed episodes of bipolar I disorder. It is also one of the few antipsychotics approved for use in children [1]. 47

48 Indication Initial Dose Titration Target Dose Effective Dose Range Schizophren ia Adults 2 mg/day 1-2 mg/day 4-8 mg/day 4-16 mg/day Adolescents 0.5 mg/day mg/day 3 mg/day 1-6 mg/day Bipolar Disorder Treatment of manic or mixed episodes Bipolar Mania Adults 2-3 mg/day 1 mg/day 1-6 mg/day 1-6 mg/day Bipolar Mania Children / Adolescents 0.5 mg/day mg/day 2.5 mg/day mg/day 48

49 Pharmacokinetics of Risperidone Risperidone is a second-generation antipsychotic metabolized by the enzyme cytochrome P450 2D6 (CYP2D6). It is available as long-acting injection (depot injection) as well as oral formulations. 49

50 Formulations Oral formulations: Tablets Orally disintegrating tablets Liquid formulation Long-acting injection: risperidone microspheres (Risperdal Consta) Distribution Volume of distribution: 1-2 L/kg. Risperidone binds to albumin and alpha1-acid glycoprotein. Plasma protein binding: For risperidone: 90% For 9-hydroxyrisperidone: 77% 50

51 Risperidone metabolism by CYP2D6 51

52 METABOLISM CYP 2D6 is the enzyme that catalyzes hydroxylation of risperidone to 9- hydroxyrisperidone. The metabolite 9-hydroxyrisperidone has similar pharmacological activity as risperidone. CYP 2D6 is subject to genetic polymorphism: Extensive metabolizers convert risperidone rapidly into 9-hydroxyrisperidone 52

53 Pharmacokinetics of Oral Formulations Absorption Orally disintegrating tablets and oral solution are bioequivalent to tablets. Rapidly absorbed after oral administration. Peak plasma levels achieved within 1 hour. Linear pharmacokinetics. Time to reach steady state ( between 4 and 5 half-lives for all drugs): For risperidone: 1 day in extensive metabolizers. 5 days in poor metabolizers. For 9-hydroxyrisperidone: 5-6 days, measured in extensive metabolizers. Food effect: risperidone can be administered with or without meals. 53

54 Pharmacokinetics of Long- Acting Injection (Risperidone Microspheres) Risperidone microspheres release considerable amounts of drug 3 weeks after injection. Long-acting risperidone should be supplemented with oral risperidone for 3 weeks. Apparent half-life or risperidone plus 9-hydroxyrisperidone is 3 to 6 days (related to the erosion of the microspheres and subsequent absorption of risperidone). 54

55 Olanzapine Olanzapine (Zyprexa) is a secondgeneration antipsychotic approved for the treatment of schizophrenia and bipolar disorder. A combination of the antidepressant fluoxetine and olanzapine (OFC, olanzapine/fluoxetine combination) is also available under the trade name Symbyax. 55

56 List of FDA-Approved Indications FDA- Approved Indication Dosage FDA- Approved Indication Dosage Schizophrenia Schizophrenia Schizophrenia in adults Oral: Start at 5-10 mg once daily Target: 10 mg/day within several days Schizophrenia in adults Oral: Start at 5-10 mg once daily Target: 10 mg/day within several days Schizophrenia in adolescents Oral: Start at mg once daily Target: 10 mg/day Schizophrenia in adolescents Oral: Start at mg once daily Target: 10 mg/day Bipolar I Disorder Bipolar I Disorder Manic or mixed episodes in adults Oral: Start at 10 or 15 mg once daily Manic or mixed episodes in adults Oral: Start at 10 or 15 mg once daily Manic or mixed episodes in adolescents Oral: Start at mg once daily; Target: 10 mg/day Manic or mixed episodes in adolescents Oral: Start at mg once daily; Target: 10 mg/day Manic or mixed episodes with lithium or valproate in adults Oral: Start at 10 mg once daily Manic or mixed episodes with lithium or valproate in adults Oral: Start at 10 mg once daily 56

57 Intramuscular formulation FDA- Approved Indication Agitation associated with Schizophrenia and Bipolar I Mania in adults Dose IM: 10 mg (5 mg or 7.5 mg when clinically warranted) Assess for orthostatic hypotension prior to subsequent dosing (max. 3 doses 2-4 hrs apart) 57

58 Olanzapine fluoxetine combination (OFC) FDA- Approved Indication Dose Bipolar I Disorder Depressive Episodes associated with Bipolar I Disorder in adults Depressive Episodes associated with Bipolar I Disorder in children and adolescents Oral in combination with fluoxetine: Start at 5 mg of oral olanzapine and 20 mg of fluoxetine once daily Oral in combination with fluoxetine: Start at 2.5 mg of oral olanzapine and 20 mg of fluoxetine once daily Depression Treatment Resistant Depression in adults Oral in combination with fluoxetine: Start at 5 mg of oral olanzapine and 20 mg of fluoxetine once daily 58

59 Mechanism of Action The mechanism of action of ziprasidone, as with other drugs having efficacy in schizophrenia, is unknown. However, it has been proposed that this drug s efficacy in schizophrenia is mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT2) antagonism. As with other drugs having efficacy in bipolar disorder, the mechanism of action of ziprasidone in bipolar disorder is unknown. 59

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61 TERIMAKASIH 61