Tag: Clozapine

Clozapine


Clozapine


First Atypical antipsychotic and is Drug of Choice in RESISTANT Schizophrenia

Low D2 Affinity [Lack of Extrapyramidal S/E]and Strong D4 Affinity

Antagonist of 5HT2A, D1, D3 and Alpha-adrenergic receptor

Preferred Antipsychotic in patient who with EPM side effects including tardive dyskinesia

S/E – Sedation, Syncope, hypotension, tachycardia, Nausea & Vomiting, Weight Gain [Highest], constipation, sialorrhea [Hypersalivation], agranulocytosis, myocarditis, seizures [Dose Dependent]

WBC count monitored regularly [Stop if WBC < 3000/mm3 or Neutrophils <1500/mm3]

Should not be started if WBC Count < 3500/mm3.

Should not be started with Carbamazepine as both are bone marrow suppressants

Clozapine

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

Clozapine

Clozapine

Q. 1

Drug of choice for schizophrenic patient with poor oral absorption is?

 A Haloperidol
 B

Fluphenazine

 C Clozapine
 D

Olanzapine

Q. 1

Drug of choice for schizophrenic patient with poor oral absorption is?

 A Haloperidol
 B

Fluphenazine

 C Clozapine
 D

Olanzapine

Ans. C

Explanation:

Clozapine REF: Kaplan and sadock’s synopsis in psychiatry 10th ed p. 489-490

Antipsychotics can be categorized into two main groups: the older conventional antipsychotics, which have also been called first-generation antipsychotics or dopamine receptor antagonists (DRA), and the newer drugs, which have been called second-generation antipsychotics or serotonin dopamine antagonists (SDAs)

Strategies for Poor Responders of Antipsychotic:

  • It may suggest that the patient is a rapid metabolizer of the antipsychotic or that the drug is not being adequately absorbed.
  • Changing to another drug is preferable to changing to a high dose.
  • If a patient has responded poorly to a conventional DRA, it is unlikely that this individual will do well on another DRA. Changing to an SDA is more likely to be helpful.
  • Clozapine is effective for patients who respond poorly to DRAs. Double-blind studies comparing clozapine to other antipsychotics indicated that clozapine had the clearest advantage over conventional drugs in patients with the most severe psychotic symptoms, as well as in those who had previously responded poorly to other antipsychotics.

Q. 2

Drug of choice for schizophrenic patient with poor oral absorption is:

 A Haloperidol
 B Fluphenazine
 C Clozapine
 D Olanzapirte
Q. 2

Drug of choice for schizophrenic patient with poor oral absorption is:

 A Haloperidol
 B Fluphenazine
 C Clozapine
 D Olanzapirte
Ans. C

Explanation:

Clozapine


Q. 3

Clozapine was the first antipsychotic drug. Which of the following is an indication for the use of Clozapine?

 A

Resistant schizophrenia

 B

Akathesia

 C

First drug to be used for schizpophrenia

 D

Used for schizophrenia with depression

Q. 3

Clozapine was the first antipsychotic drug. Which of the following is an indication for the use of Clozapine?

 A

Resistant schizophrenia

 B

Akathesia

 C

First drug to be used for schizpophrenia

 D

Used for schizophrenia with depression

Ans. A

Explanation:

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
Ref: Meltzer H.Y., Bobo W.V., Heckers S.H., Fatemi H.S. (2008). Chapter 16. Schizophrenia. In M.H. Ebert, P.T. Loosen, B. Nurcombe, J.F. Leckman (Eds),CURRENT Diagnosis & Treatment: Psychiatry, 2e.

Q. 4

A 26-year-old man with schizophrenia and tardive dyskinesia. Which is the most appropriate pharmacotherapeutic agent?

 A

Clozapine

 B

Valproic acid

 C

Haloperidol

 D

Paroxetine

Q. 4

A 26-year-old man with schizophrenia and tardive dyskinesia. Which is the most appropriate pharmacotherapeutic agent?

 A

Clozapine

 B

Valproic acid

 C

Haloperidol

 D

Paroxetine

Ans. A

Explanation:

Valproic acid is an anticonvulsant used as a mood stabilizer. It is found useful in the treatment of mania in a bipolar disorder.
It has also been valuable in the treatment of rapid cycling bipolar patients.
Paroxetine is an example of a selective serotonin reuptake inhibitor (SSRI), which is a newer form of antidepressant.
The SSRis are being found to be as effective as the tricyclic antidepressants.

Haloperidol is an example of a neuroleptic or antipsychotic medication useful in the management of acute psychosis, as well as long-term care. Clozapine is a newer atypical antipsychotic medication.

It is not associated with tardive dyskinesia as are the older neuroleptics.
This makes it a drug of choice for individuals who have developed signs of tardive dyskinesia after using other neuroleptics.
Problems with agranulocytosis prevent clozapine from being used as a “first line” neuroleptic. 
 
Ref: Meltzer H.Y., Bobo W.V., Heckers S.H., Fatemi H.S. (2008). Chapter 16. Schizophrenia. In M.H. Ebert, P.T. Loosen, B. Nurcombe, J.F. Leckman (Eds),CURRENT Diagnosis & Treatment: Psychiatry, 2e.

Q. 5

Least Extrapyrimidal S/E are seen in

 A

Halo peridol

 B

Thioridazine

 C

Clozapine

 D

CPZ

Q. 5

Least Extrapyrimidal S/E are seen in

 A

Halo peridol

 B

Thioridazine

 C

Clozapine

 D

CPZ

Ans. C

Explanation:

C i.e. Clozapine 


Q. 6

All the following statement about clozapine are true except

 A

It is used in schizophrenia

 B

May precipitate seizure

 C

May cause agranulocytosis

 D

Extrapyrimidal side effects are seen

Q. 6

All the following statement about clozapine are true except

 A

It is used in schizophrenia

 B

May precipitate seizure

 C

May cause agranulocytosis

 D

Extrapyrimidal side effects are seen

Ans. D

Explanation:

D i.e. Extrapyramidal side effects are seen


Q. 7

Not true about clozapine is :

 A

Should be discontinued if WBC (leukocyte) count <3000/mm3

 B

Blood level should be maintained <350 ng/ml to avoid agnanulocytosis

 C

Should not be used along with carbamazepine

 D

The action is more on D1 receptors than D2 receptors

Q. 7

Not true about clozapine is :

 A

Should be discontinued if WBC (leukocyte) count <3000/mm3

 B

Blood level should be maintained <350 ng/ml to avoid agnanulocytosis

 C

Should not be used along with carbamazepine

 D

The action is more on D1 receptors than D2 receptors

Ans. B

Explanation:

B i.e. Blood level should be maintained <350 ng/ml to avoid agnanulocytosis)


Q. 8

A patient of schizophrenia on CPZ (chlorpromazine) develops auditory hallucination again. The next drug to  be given is

 A

Haloperidol

 B

Clozapine

 C

Suipride

 D

Tianeptin

Q. 8

A patient of schizophrenia on CPZ (chlorpromazine) develops auditory hallucination again. The next drug to  be given is

 A

Haloperidol

 B

Clozapine

 C

Suipride

 D

Tianeptin

Ans. B

Explanation:

B i.e. Clozapine


Q. 9

A patient of depression is getting chlorpromazine, but his auditory hallucination are not controlled. The next drug is given

 A

Haloperidol

 B

Clozapine

 C

Suipride

 D

Tianeptin

Q. 9

A patient of depression is getting chlorpromazine, but his auditory hallucination are not controlled. The next drug is given

 A

Haloperidol

 B

Clozapine

 C

Suipride

 D

Tianeptin

Ans. B

Explanation:

B i.e. Clozapine

Clozapine is an antipsychotic drug with least extrapyramidal side effectsQ, i.e. it has least chances of producing muscular dystonia, akathisia, malignant neuroleptic syndrome, & tardive dyskinesiaQ.

The patient who has depression & auditory hallucinations & is being treated with CPZ i.e. the patient is a case of schizophrenia. The patient is a case of resistant schizophrenia as the auditory hallucinations are not responding to treatment. As you must know – Auditory hallucinations are first symptom to go with treatment & also 1st symptom to reappear after drug resistanceQ.


Q. 10

Antipsychotic drug with least extrapyramidal effects is :

 A

Clozapine

 B

Risperidone

 C

Thioridazine

 D

Chlorpromazine

Q. 10

Antipsychotic drug with least extrapyramidal effects is :

 A

Clozapine

 B

Risperidone

 C

Thioridazine

 D

Chlorpromazine

Ans. A

Explanation:

A i.e. Clozapine


Q. 11

Adverse effect of clozapine:

 A

Hypertension

 B

Sialorrhea

 C

Extrapyramidal S/E

 D

Neuroleptic malignant syndrome

Q. 11

Adverse effect of clozapine:

 A

Hypertension

 B

Sialorrhea

 C

Extrapyramidal S/E

 D

Neuroleptic malignant syndrome

Ans. B

Explanation:

B i.e. Sialorrhea


Q. 12

An elderly woman suffering from schizophrenia is on antipsychotic medication. She developed purposeless involuntary facial and limb movements, constant chewing and puffing of cheeks. Which of the following drugs is least likely to be involved in this side effect:

 A

Halperidol

 B

Clozapine

 C

Fluphenazine

 D

Loxapine

Q. 12

An elderly woman suffering from schizophrenia is on antipsychotic medication. She developed purposeless involuntary facial and limb movements, constant chewing and puffing of cheeks. Which of the following drugs is least likely to be involved in this side effect:

 A

Halperidol

 B

Clozapine

 C

Fluphenazine

 D

Loxapine

Ans. B

Explanation:

B i.e. Clozapine


Q. 13

Drug treatment of schizophrenic are:

 A

Trifluperazine

 B

Clozapine

 C

Haloperidol

 D

All

Q. 13

Drug treatment of schizophrenic are:

 A

Trifluperazine

 B

Clozapine

 C

Haloperidol

 D

All

Ans. D

Explanation:

A i.e. Trifluperazine; B i.e. Clozapine; C i.e. Haloperidol


Q. 14

All are side effects of Clozapine, except ‑

 A

Granulocytopenia

 B

Seizures

 C

Sedation

 D

Extrapyramidal side effects

Q. 14

All are side effects of Clozapine, except ‑

 A

Granulocytopenia

 B

Seizures

 C

Sedation

 D

Extrapyramidal side effects

Ans. D

Explanation:

Ans. is ‘d’ i.e., Extrapyramidal side effects

Side effects of clozapine

o Agranulocytosis             o Unstable BP & Tachycardia                 o Worsening of diabetes                     o Seisures

o Urinary incontinence      o Hypersalivation (sialorrhoea)              o Weight gain                                   o Sedation


Q. 15

Extrapyramidal side-effect least seen with ‑

 A

Clozapine

 B

Haloperidol

 C

Thioridazine

 D

Fluphenozine

Q. 15

Extrapyramidal side-effect least seen with ‑

 A

Clozapine

 B

Haloperidol

 C

Thioridazine

 D

Fluphenozine

Ans. A

Explanation:

Ans. is ‘a’ i.e., Clozapine

o Antipsychotics with no extrapyramidal effects.

1. Clozapine                  2. Aripiprazole                      3. Quetiapine

o Amongst typical antipsychotics, thioridazone has least extrapyramidal effects.


Q. 16

Which of the following is not a side effect of clozapine –

 A

Agranulocytosis

 B

Seizure

 C

Sialosis

 D

Weight loss

Q. 16

Which of the following is not a side effect of clozapine –

 A

Agranulocytosis

 B

Seizure

 C

Sialosis

 D

Weight loss

Ans. D

Explanation:

Ans. is ‘d’ i.e., Weight loss

Clozapine causes weight gain.


Q. 17

Drug of choice for the treatment of negative symptoms of schizophrenia is –

 A

Chlorpromazine

 B

Haloperidol

 C

Clozapine

 D

Doxepin

Q. 17

Drug of choice for the treatment of negative symptoms of schizophrenia is –

 A

Chlorpromazine

 B

Haloperidol

 C

Clozapine

 D

Doxepin

Ans. C

Explanation:

Ans. is ‘c’ i.e., Clozapine

o Drugs for negative symptoms

  • Clozapine 
  • Olanzapine 
  • Risperidone 
  • Aripiprazole 
  • Ziprazidone

Q. 18

Refractory schizophrenia – What is the treatment of choice

 A

Haloperidol

 B

Flupenthixol

 C

Trifluoperazine

 D

Clozapine

Q. 18

Refractory schizophrenia – What is the treatment of choice

 A

Haloperidol

 B

Flupenthixol

 C

Trifluoperazine

 D

Clozapine

Ans. D

Explanation:

Ans. is ‘d’ i.e., Clozapine

o Clozapine (but not the newer atypicals) is more effective than classical agents for resistant schizophrenia.


Q. 19

Which of the following has highest potential to cause metabolic syndrome?

 A

Clozapine

 B

Risperidone

 C

Quetiapine

 D

Aripiprazole

Q. 19

Which of the following has highest potential to cause metabolic syndrome?

 A

Clozapine

 B

Risperidone

 C

Quetiapine

 D

Aripiprazole

Ans. A

Explanation:

Ans. is ‘a’ i.e. Clozapine

Potential of antipsychotic drugs to cause metabolic syndrome

  • High Potential: Clozapine, Olanzapine, Chlorpromazine, thioridazine
  • Intermediate potential: Quetiapine
  • Low potential: Risperidone, Paliperidone
  • Least potential: Iloperidone, aripiprazole, asenapine, ziprasidone.

Q. 20

A young patient of schizophrenia is intolerant to anti-psychotic medications. Which drug is most preferred for such a patient:           

March 2012

 A

Clozapine

 B

Olanzapine

 C

Riseperidone

 D

Haloperidol

Q. 20

A young patient of schizophrenia is intolerant to anti-psychotic medications. Which drug is most preferred for such a patient:           

March 2012

 A

Clozapine

 B

Olanzapine

 C

Riseperidone

 D

Haloperidol

Ans. A

Explanation:

Ans: A i.e. Clozapine

About 30% of patients do not respond to antipsychotics, or are intolerant to them, usually because of extrapyramidal side effects. The only proven drug intervention for this group is clozapine, which is effective in between a third and a half of such patients.


Q. 21

Which of the following is the drug of choice for medication-resistant schizophrenia:       

September 2009

 A

Haloperidol

 B

Chlorpromazine

 C

Clozapine

 D

Flupentixol

Q. 21

Which of the following is the drug of choice for medication-resistant schizophrenia:       

September 2009

 A

Haloperidol

 B

Chlorpromazine

 C

Clozapine

 D

Flupentixol

Ans. C

Explanation:

Ans. C: Clozapine

Clozapine

  • It may inhibit serotonin, muscarinic, and dopamine effects.
  • Revolutionized treatment of medication-resistant schizophrenia.
  • Effective in 30% of patients in whom other medications have failed.
  • May improve tardive dyskinesia resulting from long-term use of traditional antipsychotics.
  • Major drawback of reversible agranulocytosis occurs in 1-2%
  • Interactions-Epinephrine and phenytoin may decrease effects; tricyclic antidepressants, neuroleptics, CNS depressants, guanabenz, and anticholinergics may increase effects
  • Contraindications-Documented hypersensitivity; WBC (less than 3500 cells per millimeter cube) before or during therapy.
  • Precautions-Pregnancy, Do not abruptly stop the medication; to minimize risk of agranulocytosis.

Q. 22

Drug causing agranulocytosis ‑

 A

Pimozide

 B

Clozapine

 C

Risperidone

 D

Olanzapine

Q. 22

Drug causing agranulocytosis ‑

 A

Pimozide

 B

Clozapine

 C

Risperidone

 D

Olanzapine

Ans. B

Explanation:

Ans. is ‘b’ i.e., Clozapine

Agranulocytosis is a known side effect of clozapine

“Because of the risk of agranulocytosis, patients, recieving clozapine must have weekly blood counts for the first 6 months and every 3 weeks thereafter”

Side effects of clozapine

  • Agranulocytosis
  • Unstable BP & Tachycardia 
  • Worsening of diabetes
  • Seisures
  • Urinary incontinence
  • Hypersalivation (sialorrhoea) 
  • Weight gain
  • Sedation


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