Clozapine

MECHANISM OF ACTION:
  • Clozapine is classified as an atypical antipsychotic drug because it binds to serotonin as well as dopamine receptors.
  • Clozapine is an antagonist at the 5-HT2A subunit of the serotonin receptor, putatively improving depression, anxiety, and the negative cognitive symptoms associated with schizophrenia.
  • A direct interaction of clozapine with the GABAB receptor has also been shown.
  • Clozapine induces the release of glutamate and D-serine, an agonist at the glycine site of the NMDA receptor, from astrocytes,and reduces the expression of astrocytic glutamate transporters.
  • These are direct effects that are also present in astrocyte cell cultures not containing neurons. 
  • Clozapine prevents impaired NMDA receptor expression caused by NMDA receptor antagonists.
INDICATION:
  • Clozapine has been approved for,
  • Patients with schizophrenia who have failed to respond adequately to typical neuroleptic drugs (treatment-resistant schizophrenia)
  • Patients who are intolerant of typical neuroleptic drugs because of EPS or tardive dyskinesia
  • Patients who are at high risk for suicide
  • Drug of choice for schizophrenic patient with poor oral absorption 
SIDE EFFECTS:
  • Severe Neutropenia 
  • Orthostatic Hypotension, Bradycardia, and Syncope
  • Seizures 
  • Myocarditis and Cardiomyopathy
  • Increased Mortality in Elderly Patients with Dementia-Related Psychosis.
  • Eosinophilia
  • QT Interval Prolongation 
  • Metabolic Changes (Hyperglycemia and Diabetes Mellitus, Dyslipidemia, and Weight Gain) 
  • Neuroleptic Malignant Syndrome .
  • Fever 
  • Pulmonary Embolism.
  • Anticholinergic Toxicity .
  • Interference with Cognitive and Motor Performance.
  • Tardive Dyskinesia.
  • Cerebrovascular Adverse Reactions .
  • Recurrence of Psychosis and Cholinergic Rebound after Abrupt Discontinuation
Exam Question
  • Clozapine is the Drug of choice for schizophrenic patient with poor oral absorption.
  • Resistant schizophrenia is indication for use of clozapine
  • Agranulocytosis, seizure are common side effects of clozapine
  • Drug of choice for the treatment of negative symptoms of schizophrenia is clozapine
  • Clozapine has highest potential to cause metabolic syndrome
  • Extrapyramidal side-effect least seen with Clozapine

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