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Clozapine Tablets: Use, Side Effects and Mechanism Action


Clozapine Use For Schizophrenia

Clozapine is very effective medicine for the treatment of psychosis symptoms also know as neuroleptics. Clozapine is not a single medicine use for the treatment of psychosis. This drug is classified as atypical antipsychotics.

This medicine is used as a reserve drug in refractory schizophrenia that means when other medication-related to schizophrenia are not working that time clozapine is show there an action for the treatment of psychosis.
Patient take Medicine
Clozapine Tablets

This medicine are use treatment-resistant schizophrenia that means those patients are fail to the treatment of schizophrenia. Doctor recommended this drug to that patient who fails to treatment with other medication.

This Drug is also used for the reduction of suicidal behavior in schizoaffective disorder. Schizophrenia disease suicidal behavior is one stage. Patient want to kill himself so that patient are kept in watch.

One study conducted to proof the action of this drug as compare with olanzapine and results are found positive.
Total 956 patients are selected for this study and among them all the patients are already attempted for suicide or hospitalized to prevent suicide. All the patients are takeing 200-900 mg/day clozapine and 5-20 mg of olanzapine is given. Patients are treated with clozapine show longer delay in the time to recurrent suicidal behavior. 

Why is clozapine used?

This medicine are use for the treatment of specific mental disorder like psychosis. This drug have some special feature we discus in mechanism action of clozapine. Not only this one single drug are use for the treatment of scizopherinea there are many drug are available. This drug are given when other antipsychotic drugs are not working.

This medicine are also use for the parkinsonism disease. it helps to balance thought disturbance, emotions and behavior of people.
Clozapine is use for the balancing of certain natural neurotransmitter in the brain. In our brain dopamine is very essential neurotransmitter which helps controlling emotion, locomotors action, sharpness of brain. This medication competitively bind with receptor side and mimicking the action of dopamine.

Know some Information before taking clozapine

Don’t take this medicine

  • If patients are allergic to this drug or any excipient use to make formulation.
  • patient have lower blood volume.
  • Lower white blood cell count
  • Any heart problem
  • Previous taking long acting injection of antipsychotics
  • Patient suffer form bone marrow depression
  • Epilepsy patients
  • Persion are addicted with alchol or drugs
  • Patients have kidney problem
  • Inflammation in the heart
  • Patients suffer liver disease like jaundice
  • Person having constipation

Clozapine Side Effects

like other medicine clozapine have some side effects this is important cause this medicine are not use more for the treatment of Schizophrenia.

Very Common Side Effects

  • Sleepiness or unusual drowsiness
  • Sweating
  • Trembling or shaking of hands or feet
  • Weakness or tiredness
  • Fever
  • Fainting
  • Confusion
  • Blurred vision
  • Dizziness

Common side effects

These side effects are show when patient are change antipsychotic medicine to clozapine. Some of Extrapyramidal symptoms are developed due to anticholinergic effects of clozapine.
  • Constipation
  • Bed-wetting
  • Night-time drooling
  • Muscle stiffness
  • Sedation
  • Tremors
  • Orthostatic hypotension
  • Hyperglycemia
  • Weight gain
  • Tardive dyskinesia

Warning and Precautions

This medication have very serious side effects are shown which may kill the patients for continuous use.
  • Agranulocytosis
  • Central nervous system depression
  • Leukopenia
  • Neutropenia
  • Seizure disorder
  • Bone marrow suppression
  • Dementia
  • Hypotension
  • Myocarditis
  • Cardiomyopathy
  • Orthostatic hypotension
  • Bradycardia
  • Syncope
  • Fall
  • Eosinophilia
  • QT interval prolongation
  • Metabolic change
  • Neuroleptic malignant syndrome
  • Hepatotoxicity
  • Pulmonary Embolism
  • Anticholinergic toxicity
  • Interference with cognitive and motor performance

Agranulocytosis

According to study 3% people are affected granulocytopenia which means minimized regular white blood cell count monitoring. Due to the risk of agranulocytosis clozapine is not recomanded all the schizophenia patients. Only this medicine are prescribe those patients who are resistant to or intolerant to other antipsychotics medication. Research suggests that all the patients are regularly monitoring who are treatment of clozapine.

When patient are treated with this medication they must be ensure WBC and differential count must be normal. Monitoring of WBC count Initial 18 weeks if WBC falls below 3500/mm3 or any infection occours immediately stop clozapine for the treatment of Schizophrenia.

There are many clinical trail are conducted from 1962-1990 and results are found that 75% patient are suffer granulocytopenia initial 18 weeks of clozapine. Get more dip Information about Clozapine medicine.

What is Clozapine REMS program?

REMS full from is Risk Evaluation and Mitigation Strategies. Due to severe neutropenia of this antipsychotic agents this program is implement. Those doctor or pharmacist are deals with this medicine they must be enrolled and take training.
Doctor who is prescribe this medicine must be certified with REMS program and completed the training.
Clozapine 3D structure
Clozapine 3D structure

Pharmacy who is dispensing this medicine must be certified with REMS program and complete the training and they directly dispensed to the Patients.
Patients who take this medicine must be enrolled in REMS program and Comply with ANC testing.
Further more Information you check official website www.clozapinerems.com or Call 844-267-8678.

Orthostatic Hypotension, Bradycardia

Hypotension, Bradycardia , syncope and cardiac arrest have occoured when patients are start take this medicine. Initial time these type of side effects are common but after some days these side effects are go away. This reaction is shown in low dose like 12.5 mg once daily.
Use of Clozapine cautiously in patients with cardiovascular disease like myocardial infraction or ischemia, Heart failure or any other heart related disease.

Fall

Some time antipsychotic medicine may cause somnolence, postural hypotension, motor and sensory instability which may leads to fall and cosciquently fracture and injury. Those patient are enjury or ill or taking other medication they have risk to taking this medication.

Myocarditis and Cardiomyopathy

Clozapine tablets eating people have the chances of myocarditis and cardiomyopathy. This reaction is very serious. Discontinue of the antipsychotic medicine have the more chance of myocarditis. Those patient have any history  clozapine related to myocarditis they are not take any chance further to take this medicine. However if treatment of antipsychotic is necessary then your doctor is consult with a cardiologist and give clozapine with close monitoring.

Possibility of myocarditis and cardiomyopathy is more in those patient who are treatment with this antipsychotic along with cheast pain, dyspnea, persitant tachycardia at rest, palpitation, fever, flu like symptoms, hypotension, other sign and symptomsof heart failure.

Eosinophilia

Blood eosinophil count is increase upto 700/uL, According to clinical trail study it was found that 1% of patients are suffer eosinophilla. At the first month of the treatment of scizophenia it shown.

If eosinophllia is developed at the time of treatment with antipsychotic medication then some sign and symptoms are developed like rash or other allergic reaction, myocarditis and other organ disease related to eosinophilia. If systemic disease is suspected then immediately stop the medication.

Hyperglycemia and Diabetes mellitus

All the atypical antipsychotics drug have been associated with metabolic change that can increase cardiovascular and cerebrovascular risk. This metabolic change include hyperglycemia, dyslipidemia and weight gain. In some case ketoacidosis or hyperosmolar coma or death is happened.

According to epidemiological study Atypical antipsychotic medicine taking is directly impacted the increase of blood sugar level but the mechanism is not known.
Before taking antipsychotic medicine check patient blood glucose level, if blood sugar level is increase after some period of taking this medicine stop the medication. Symptoms like polydipsia, polyuria, polyphagia and weakness.

Weight Gain

According to 11 different clinical trail study it was concluded that those patients are taking Clozapine tablets for the treatment of schizophrenia >=7% of body weight is increase. Patients cholesterol level is also increase.

Tradive dyskinesia

those patients are treated with clozapine has occurred tardive dyskinesia. Syndrome consist of potentially irreversible, involuntary, dyskinetics movements. These syndrome are seen when patients are taking higher dose or low dose for long time. So doctor prescribe this medicine in this manner so that lower the risk of developing Tradive dyskinesia.

Mechanism action of clozapine

All the antipsychotic drugs are competitively bind with dopaminergic receptor to show mechanism of action.
physiology of schizophenia
Process of  schizophenia

Normally all the antipsychotic drug are bind with D2 Receptor but Clozapine are more like to bind with D4 dopaminergic receptor. Some portion of our body is like bind with this medicine like frontal cortex and amygdala but low in the basal ganglia due to this nature of this drug more effectively work for schizophrenia without any side effects.

This medicine is has high affinity for 5-HT receptor along with its subtype like 5-HT2,5-HT3,5-HT6. Clozapine is also like to bind with muscarinic A1 and A2 receptor.

Pharmacokinetics and Metabolism of Clozapine

When this medicine is taking orally rapidly absorbed and 27-50% of the dose is rich in systemic circulation. Plasma concentration is varied patient to patient.
It is easily pass the blood-brain barrio and distribution in breast milk. Plasma protein binding capacity is 95%. Slowly plasma pick is achieved but it takes time 7-10 day when regular taking of medicine.

This medicine is not showing the effect immediately it take much time to show effect. Normally the effect of medicine is show when patient continue this medication at least two year.    

Adverse Reaction of clozapine

  • Recurrence of psychosis and cholinergic rebound after abrupt Discontinuation
  • Cerebrovascular adverse reaction
  • Interference with cognitive and motor performance
  • Pulmonary embolism
  • Neuroleptic malignant syndrome
  • Various metabolic changes
  • Increase mortality in elderly patients with dementia related psychosis
  • QT interval prolongation

Clozapine use in pregnancy

There are no any study on pregnant women. So no any information that clozapine is harmful for a fetus or not. According to clinical consideration, any bad situation patient is discontinue or change antipsychotic drug at the time of pregancy. So neonates are exposed to antipsychotic medicine so monitor the neonate for the symptoms of agitation, hypertonia, hypotonia, tremor,  somnolence and feeding difficulties.

Clozapine Drug Interaction

This drug are induced or inhibits the cytochrome enzyme like CYP1A2, CYP3A4, CYP2D6.

Concomitantly use of clozapine and CYP1A2 inhibitor can increase the plasma level of antipsychotic medicine that leads to adverse reaction. So reduce the dose of clozapine one third from original dose when concomitantly administered with strong CYP1A2 inhibitor. If patients are take low CYP1A2 inhibitor like oral contraceptive and caffeine then original dose of antipsychotic can take along with it but patients are monitor.

Concomitantly taking of clozapine and CYP2D6 or CYP3A4 inhibitors like cimetidine, citalopram, erythromycin, paroxetine, bupropion etc are increase clozapine level leads to  adverse reaction.  

Clozapine dosage

Clozapine is started form the dose of 12.5 mg per day after one week increase 12.5 mg two dose per day. Gradually increase dose 25 mg to 50 mg per day if patients have no any side effect. Dose is increase 300 mg per day this is required two to three weeks. Maximum dose is 450 mg/day. Best time for taking the clozapine is is night time because of some patients have sedation problem.

Reference:
Wikipedia, Paper publish By Dr Ben Green from UK Click Here to download the paper

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