Clozapine
CLOZAPINE
INDICATIONS:
- Suicidal Behaviour.
- Treatment-resistant schizophrenia
- In advanced dopamino-mimetic psychosis.
- Patients intolerant to typical neuroleptic drugs because of EPS/tardive dyskinesia.
- Schizophrenic patients on CPZ (chlorpromazine) develops auditory hallucination should be treated with Clozapine
MECHANISM OF ACTION:
- Selective monoaminergic antagonist.
- High affinity for serotonin Type 2 (5HT2), dopamine Type 2 (D2), 1 & 2 adrenergic, and H1 histaminergic receptors.
- More affinity towards D1 receptors than D2 receptors.
- Clozapine’s antagonism of muscarinic M1-5 receptors may explain its anticholinergic effects.
ACTIONS:
- Anti-psychotic action mediated by combination of antagonistic effects at D2 receptors in mesolimbic pathway & 5-HT2A receptors in frontal cortex.
- D2 antagonism relieves positive symptoms while 5-HT2A antagonism alleviates negative symptoms.
PHARMACOKINETICS:
| Absorption |
Rapid and almost complete |
|---|---|
| Volume of distribution | Not available |
| Protein binding |
97% (bound to serum proteins) |
| Metabolism |
Hepatic
|
| Route of elimination |
Approximately 50% of the administered dose is excreted in the urine and 30% in faeces. |
| Half life |
8 hours (range 4-12 hours) |
ADVERSE EFFECTS:
- Extrapyramidal symptoms (among antipsychotics) are due to D2 blockade in limbic system.
- Rabbit syndrome – Perioral movements.
- Neuroleptic-induced dystonia – Within 7 days of starting or rapidly raising drugs dose.
- Neuroleptic induced-tardive dyskinesia – When taken for less than 3 months/1 months if > 60 years), within 4 weeks of drug withdrawal.
- Neuroleptic-induced akathisia
- Inner restlessness (feeling of discomfort & agitation)
- External restlessness (compulsion to move extremities, pacing, rocking, fidgety movements)
- β-Blocker (Propanolol) is the drug of choice.
NEUROLEPTIC MALIGNANT SYNDROME
- More common with high potency D2 antagonists
- Severe muscle rigidity.
- Elevated temperature with diaphoresis (sweating), tachycardia, elevated/labile BP, & leucocytosis.
- Highest potential to cause metabolic syndrome.
- Should be discontinued if WBC count <3000/mm3.
- Evidence of muscle injury
- Eg. Elevated CPK
- Hyperprolactinemia – D2 receptors blockade in tuberoinfundibular dopamine system.
- Hypogonadism, infertility, amenorrhea, galactorrhoea and gynecomastia.
- More common with typical antipsychotics & risperidone.
DRUG INTERACTIONS:
- Should not be used along with carbamazepine.
Exam Question
- Clozapine is the drug of choice for the schizophrenic patient with poor oral absorption.
- Clozapine is indicated in a patient with schizophrenia & tardive dyskinesia.
- Least extrapyramidal side effects are seen in Clozapine.
- Clozapine may precipitate seizure & agranulocytosis.
- Clozapine should be discontinued if WBC (leukocyte) count <3000/mm3.
- Clozapine should not be used along with carbamazepine.
- Clozapine’s action is more on D1 receptors than D2 receptors.
- Patient of schizophrenia on CPZ (chlorpromazine) develops auditory hallucination should be treated with Clozapine.
- Clozapine is an antipsychotic drug with least extrapyramidal effects.
- Clozapine shows highest potential to cause metabolic syndrome.
Don’t Forget to Solve all the previous Year Question asked on Clozapine
