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zotepine an atypical antipsychotic by anant kumar rathi

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  2. 2. CLASSIFICATION OFANTIPSYCHOTICS TYPICAL OR FIRST GENERATION ANTIPSYCHOTICS (FGA)Phenothiazines:- Chlorpromazine Thioridazine Trifluperazine FluphenazineButyrophenones:- Haloperidol DroperidolThioxanthines:- Flupenthixol ZuclopenthixolDibenzoxazepine:- LoxapineDiphenylbutylpiperidine:- Pimozide
  3. 3. CLASSIFICATION OFANTIPSYCHOTICSATYPICAL OR SECOND GENERATION ANTIPSYCHOTICS (SGA)Dibenzodiazepine:- ClozapineThienobenzodiazepine:- OlanzapineDibenzothiazepine:- QuetiapineBenzisoxazole:- ResperidoneBenzisothiazolyl:- ZiprasidoneAripiperidylindole:- AripiprazoleBenzamide:- Amisulpride LevosulprideDibenzothiepine:- Zotepine
  4. 4. Fig.8Click for larger picture 4
  6. 6. Comparison between FGAs &SGAs
  9. 9. SCHIZOPHRENIA - lMPACT A major psychotic disorder Currently conceptualized as a broad syndrome Functionally and socially debilitating chronic illness Constant 1% worldwide life time incidence 10% suicide rate Strong genetic component
  10. 10.  Abnormality of brain neurochemistry neuroanatomy and development Mesolimbic overactivity of dopamine produce positive symptoms Mesocortical underactivity of dopamine and serotonin produce negative and cognitive symptoms Hypofrontality related to serotonin transmission is associated with negative symptoms
  11. 11. Treatment options forschizophrenia 1st Generation Antipsychotics Post synaptic D2 blockade D2 blockade D2 blockade in in in Nigrostriatal Tuberoinfundi Mesolimbic bular pathway area pathway Results in adverse effects Results in as Alleviates adverse hyper positive effects as prolactinemia, symptoms galactorrhea EPS Menstrual
  12. 12. 2nd Generation Antipsychotics Bind toserotonin Less affinity 5HT-2A Less affinity Less affinity to D2 to D2 to D2receptor, receptor in receptor in receptor in Less Tuberoinfun Mesocortica Nigrostriatalaffinity to dibular l pathway pathway D2 pathwayreceptor LowerAlleviates propensity Lower Lower positive to cause propensity propensity negative negative to cause cognitive to cause and hyperprolasymptoms EPS cognitive ctinemia
  13. 13. ZOTEPINE PHARMACOLOGY An atypical antipsychotic Tricyclic substituted Dibenzothiepine drug Developed by Astellas pharma in Japan 1982 Chemically similar to clozapine and quetiapine
  14. 14. Pharmacokinetics Only oral formulation available Well absorbed in GI Tract Bioavailability is 7 to 13% due to extensive first pass hepatic biotransformation Peak plasma conc. within 1 to 4 hrs. Plasma protein binding is 97% Half life is 15 to 24 hrs Steady state conc. reach in 4
  15. 15. Pharmacokinetics Major metabolic route is N-demethylation by Cyt-p450 isozyme 3A2 to norzotepine Norzotepine also has about 30-40% activity of parent compound Eliminated in bile and faeces
  16. 16. Pharmacodynamics Zotepine blocks D1&D2 receptors Implication:- Antipsychotic activity Extra Pyramidal Symptoms Raise serum prolactin Zotepine blocks 5HT2a, 5HT2c, 5HT6, 5HT7 receptors Implication:- Improved cognition, reduced anxiety, Increased sleep & appetite, weight gain Zotepine blocks 5HT receptors more potently than DA receptors Implication:- Explain its atypical behaviour
  17. 17. Pharmacodynamics Zotepine blocks H1 histaminic receptors Implication:- Increased sleep & appetite, weight gain Zotepine blocks alpha adrenergic receptors Implication:- Postural hypotension, dizziness Zotepine blocks M1 cholinergic receptors weakly Implication:- Less anticholinergic adverse effect Zotepine inhibits nor epinephrine reuptake Implication:- Efficacy against depressive negative & cognitive symptoms
  18. 18. Unique pharmacological profileof ZotepineAt low doses (75-150mg/day) it increasesdopaminergic transmissionImplication:- Improves negative and cognitivedeficitsAt high doses (150-300mg/day) it inhibitsdopaminergic transmissionImplication:- Improves positive symptomsInhibits nor epinephrine reuptakeImplication:- Improves affective and cognitivesymptoms
  19. 19. ZOTEPINE: EFFICACY Postsynaptic D2 Antagonist POSITIVE. Excitement /hostility LOW DOS SCHIZOPHRENIA HIGH DOS E E NEGATIVE, Cognitive & Depressive Balance DA Level
  20. 20. EFFICACY Positive symptoms of schizophrenia Schizophrenia in acute exacerbation Negative symptoms of schizophrenia Refractory schizophrenia Efficacy against hostility Efficacy against cognitive symptoms Relapse prevention
  21. 21. SCREENING Weight, Blood Pressure, Fasting blood sugar, Lipid profile Get personal & family history of diabetes, hypertension, cardiovascular disease, smoking Refer such pt. for nutrition, weight management and medical management Whether taking agents that prolong QT Risk of electrolyte disturbances (on diuretics)
  22. 22. DOSINGFor negative symptoms schizophrenia Started in 25 mg t.d.s doses Gradually can be increased up to total of 150 mg/dayFor positive symptoms schizophrenia Started in 50 mg t.d.s doses Gradually can be increased up to total of 300 mg/dayFor critically ill patient it can be used upto450 mg/day
  23. 23. ADVERSE EFFECTS Weight Gain is most common Somnolence is troublesome Extra Pyramidal Symptoms Reduced salivation Hypotension Hyperprolactinemia Constipation Excessive salivation
  24. 24. ADVERSE EFFECTS RARE BUTSERIOUS ECG changes:- QT prolongation, torsades de pointes (dose dependant) Seizures:- Dose related proconvulsive effect Paralysis of intestine:- anorexia, nausea, vomiting, severe constipation, abdominal fullness or flaccidity Neuroleptic Malignant Syndrome:- Fever, muscular rigidity, akinetic mutism, autonomic hyperactivity
  25. 25. Drug interactions Serious fall in blood pressure occur when co administered with adrenaline Additive antihypertensive effect with antiHTNs Additive sedation with CNS depressants as BZDs, barbiturates, anesthetics including alcohol Additive anticholinergic action with anticholinergics, TCAs, antiparkinsons drugs Antagonize the effect of dopaminergic agents Combined use of Phenothiazines may increase risk of seizures Fluoxetine and Diazepam increase plasma conc. Of zotepine.
  26. 26. Warnings and precautions Avoid in patients with:- Coma and Circulatory collapse Encephalitis, Brain tumors, Head injury Hepatic & Hematological disorder Exposed to high environmental temperature Engaged in activities requiring alertness Terfenadine or Astemizole (QT Prolongation)
  27. 27. Warnings and precautions Poisoning ECG changes History of seizures or lobotomy Gout and Nephrolithiasis Narrow angle glaucoma Urinary retention, chronic constipation Obese person Electrolyte disturbances
  28. 28. USE IN SPECIALPOPULATION RENAL IMPAIRMENT:- Start 25 mg b.d, up to max. of 75 mg b.d HEPATIC IMPAIRMENT:- Start 25 mg b.d, up to max. of 75 mg b.d, monitor LFTs CARDIAC IMPAIRMENT:- Used cautiously specially if on antiarrhythmics or drugs causing bradycardia, hypokalemia Elderly:- Start 25 mg b.d, up to max. of 75 mg b.d Children:- Not recommended under age of 18
  29. 29. Over dosage: CNS Depression from somnolence to coma Low BP EPS occurs Restlessness, agitation Convulsions Abnormal ECG, arrhythmia Management:- No specific antidote Symptomatic and maintenance therapies recommended
  30. 30. PREDICTION OF EFFICACY(Lin et al, J Clin Psychiatry 2007) 135 acutely ill DSM-IV schizophrenics in Taiwan. Zotepine 150 mg/day for 4 weeks. 35 drop outs due to inefficacy, adverse effects, or withdrawal of consent. Response rate was 78% in the 100 completers. Response defined as 20% decrease in BPRS. Improvement in BPRS at weeks 1 and 2 each predicted 4-week response.
  31. 31. ACUTE EXACERBATION OFSCHIZOPHRENIA: Efficacy outcomes (Petit et al, Psychopharmacol Bull 1996) 8-week study in 13 French centers Zotepine (150-300 mg/day; n=63) HPL (10-20 mg/day; n=63) BPRS, CGI-I, CGI-S outcomes: no differences between groups. SANS improvement: Zotepine > HPL. Improvement curves: Max during weeks 1-2; more gradual, thereafter.
  32. 32. ACUTE EXACERBATION OFSCHIZOPHRENIA: Adverse effects (Petit et al, Psychopharmacol Bull 1996) AIMS, Simpson-Angus scores decreased with zotepine, increased with HPL (significant for latter) No akathisia with zotepine. Weight change: Zotepine, +2.3 kg; HPL, -0.8 kg Pulse raised by 5 bmp with zotepine, nil with HPL No changes in blood pressure Uric acid levels significantly decreased with zotepine but not with HPL.
  33. 33. OPEN-LABEL, 6-WEEK,7-CENTER, INDIAN RCT 238 young adults with DSM-IV schizophrenia Zotepine 25 mg tid vs HPL 5 mg bd Zotepine vs HPL: PANSS +vs s/s improvement, 49% vs 45% PANSS –ve s/s improvement, 42% vs 41% Virtually identical improvement in CGI-S, CGI-I
  34. 34. ASIAN STUDY: POSITIVE SYMPTOMSCHIZOPHRENIA, Efficacy outcomes (Hwang et al, J Formos Med Assoc 2001) 6-week study in 2 Taiwanese centers ICD-10 schizophrenia (n=70; mostly chronic) 17 drop outs, similar between groups Zotepine 150 mg/day vs HPL 9 mg/day Efficacy on PANSS, BPRS, CGI: Zotepine=HPL 20% and 30% response rates: Zotepine=HPL
  35. 35. ASIAN STUDY: POSITIVE SYMPTOMSCHIZOPHRENIA, Adverse effects (Hwang et al, J Formos Med Assoc 2001) No dystonia with zotepine EPS: Zotepine < HPL Weight gain: Zotepine +2.6 kg; HPL +0.4 kg Heart rate increased with zotepine Zotepine adverse effects: Dizziness (38%), sedation (32%), dry mouth (29%), constipation (20%), increased salivation (18%)
  36. 36. EFFICACY AGAINST HOSTILITY(Briken et al, Schiz Res 2002) Open-label RCT in ICD-10 schizophrenia, schizoaffective disorder (n=69)  Zotepine 50-275 (mean 150) mg/day  Olanzapine 2.5-20 (mean, 12) mg/day  Risperidone 1-8 (mean, 4) mg/day Zotepine > risperidone on BPRS measures of hostility (olanzapine efficacy was in between). Benefits persisted after controlling for sedation and improvement in positive symptoms.
  37. 37. EFFICACY AGAINST NEGATIVESYMPTOMS (Fleischhacker et al, Pharmacopsychiatry 1987) 10 chronic schizophrenics with –ve symptoms Zotepine 50-200 mg/day for 8 weeks Significant decrease in SANS No increase in positive symptoms 1 patient had +ve symptom relapse at 3 weeks 2 more patients relapsed during maintenance treatment.
  38. 38. NEGATIVE SYMPTOMS, NEGATIVESTUDY (Moller et al, Pharmacopsychiatry 2004) 80 schizophrenic with stable negative symptoms Zotepine 25-225 mg/day (mean, 130) vs placebo 8-week study Zotepine not significantly superior to placebo on PANSS (positive, negative, general psychopathology subscales), CGI, MADRS, EPS measures.
  39. 39. RELAPSE PREVENTION(Cooper et al, Psychopharmacol Berl 2000) 119 patients with chronic, DSM-IIIR schizophrenia Zotepine 150-300 mg/day vs placebo for 26 weeks Drop out due to adverse events, 26% vs 7% Estimated 26-week relapse rate, 9% vs 53% (HR, 0.16; 95% CI, 0.05-0.48) SANS scores did not improve, placebo-level EPS Uric acid levels decreased by 43% with zotepine (unchanged with placebo)
  40. 40. REFRACTORYSCHIZOPHRENIA 45 patients with treatment-resistant schizophrenia Zotepine 137-299 mg/day in monotherapy or as add-on therapy (maintenance dose, 231 mg/day) BPRS decreased from week 2 to week 12 in 29 of 35 evaluable patients. Better outcomes in younger and catatonic patients, and in those with acute exacerbation and shorter illness duration Harada et al (Fortschr Neurol Psychiatr 1991)
  41. 41. EFFICACY: OTHER INDICATIONS Zotepine (12.5-150 mg/day) was effective against Behavioral and Psychological Symptoms of Dementia (BPSD) in a open study of 24 patients (Rainer et al, CNS Drugs 2004) Zotepine is effective against Mania as monotherapy (Amann et al, Bipolar Disord 2005) or in combination with a mood stabilizer (Chan et al, Psychiatry Clin Neurosci 2010). Zotepine reduced Chorea in one patient with Huntington’s disease (Bonelli et al, Human Psychopharmacol 2003).
  42. 42. ADVERSE EFFECTS (UKU scale) (Kondo et al, Ther Drug Monitor 1994) Incidence % of adverse effect of Zotepine in 28 patients Side Effect Week 1 Week 2 Week 3 Week 4Difficulty in concentration 7 11 7 7Asthenia 7 14 14 25Sleepiness 36 29 29 29Falling memory 7 4 4 7Tension 4 7 7 11Dystonia 4 7 4 4Rigidity 0 4 11 18Hypokinesia 7 14 14 29Tremor 7 14 18 18Akathisia 7 25 29 25
  43. 43. ADVERSE EFFECTS (UKU scale)(Kondo et al, Ther Drug Monitor 1994) Incidence % of adverse effect of Zotepine in 28 patients Side Effect Week 1 Week 2 Week 3 Week 4 Accommodation 0 4 0 0 disturbance Increase salivation 4 14 4 7 Reduced salivation 43 32 29 29 Constipation 29 43 46 39 Orthostatic dizziness 21 7 4 4 Headache 7 0 4 4
  44. 44. ADVERSE EFFECTS: ZOTEPINE vs HPL(Riedel et al, Expert Opin Drug Saf 2010)
  45. 45. What constitute an idealAntipsychotic Mood-stabilizingEfficacious for propertiesPositive & negative Low EPS, TDsymptomsCognitive benefits Ideal Weight Neutral Antipsychotic Improved No adverse Function and Long-term health Quality of life Consequences Affordable
  46. 46. TO SUMMARISE 1st discovered in Japan Initially studied in Asian countries Only few studies available Tricyclic Dibenzothiepine molecule Receptor profile:- Dopaminergic blockade(D2&D3 > D1&D4) Serotonergic Blockade( 5HT2A&5HT2C) Inhibit reuptake of norepinephrine All leading to improvement in positive, negative as well as cognitive symptoms and less EPS
  47. 47. TO SUMMARISE As per studies available, it is effective in Acute exacerbation of schizophrenia Refractory schizophrenia Relapse prevention Side Effects:- Weight gain, sedation, dry mouth, EPS, Constipation, hyperprolactinemia
  48. 48. PROS & CONS POTENTIAL ADVANTAGES:- Controlling positive, negative, affective as well as cognitive symptoms POTENTIAL DISADVANTAGES:- lack of studies Not FDA approved Frequent dosing Seizure potential Slow onset of action -------
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