Clozapine; Uses, Dosage, Side Effects, Interactions

Clozapine is a synthetic dibenzo-diazepine derivative, atypical antipsychotic Clozapine blocks several neurotransmitter receptors in the brain (dopamine type 4, serotonin type 2, norepinephrine, acetylcholine, and histamine receptors). Unlike traditional antipsychotic agents, it weakly blocks dopamine type 2 receptors. It relieves schizophrenic symptoms (hallucinations, delusions, dementia).

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Clozapine is a tricyclic dibenzodiazepine, classified as an atypical antipsychotic agent. It binds several types of central nervous system receptors and displays a unique pharmacological profile. Clozapine is a serotonin antagonist, with strong binding to 5-HT 2A/2C receptor subtype. It also displays the strong affinity to several dopaminergic receptors but shows only weak antagonism at the dopamine D2 receptor, a receptor commonly thought to modulate neuroleptic activity. Agranulocytosis is a major adverse effect associated with the administration of this agent.

Clozapine is an atypical antipsychotic medication. It is mainly used for schizophrenia that does not improve following the use of other antipsychotic medications. In those with schizophrenia and schizoaffective disorder, it may decrease the rate of suicidal behavior. It is more effective than typical antipsychotics and effective for those who are treatment resistant. Clozapine is a serotonin antagonist, with strong binding to 5-HT 2A/2C receptor subtype. It also displays a strong affinity to several dopaminergic receptors but shows only weak antagonism at the dopamine D2 receptor, a receptor commonly thought to modulate neuroleptic activity. Agranulocytosis is a major adverse effect associated with the administration of this agent.

Mechanism of action of Clozapine

Clozapine’s antipsychotic action is likely mediated through a combination of antogistic effects at D2 receptors in the mesolimbic pathway and 5-HT2A receptors in the frontal cortex. D2 antagonism relieves positive symptoms while 5-HT2A antagonism alleviates negative symptoms. Clozapine is a selective monoaminergic antagonist with high affinity for the serotonin Type 2 (5HT₂), dopamine Type 2 (D2), 1 and 2 adrenergic, and H1 histaminergic receptors. Clozapine acts as an antagonist at other receptors, but with lower potency. Antagonism at receptors other than dopamine and 5HT₂ with similar receptor affinities may explain some of the other therapeutic and side effects of Clozapine. Clozapine’s antagonism of muscarinic M1-5 receptors may explain its anticholinergic effects. Clozapine’s antagonism of histamine H1 receptors may explain the somnolence observed with this drug.

Indications of Clozapine

• Schizophrenia
• Paranoid Disorder
• Borderline Personality Disorder
• Suicidal Behaviour
• Treatment-resistant Schizophrenia
• Advanced dopaminomimetic psychosis
• Treatment-resistant schizophrenia.

Contra-Indications of Clozapine

• Diabetes
• Excessive fat in the blood
• Low amount of magnesium in the blood
• Extreme Loss of Body Water
• Low amount of potassium in the blood
• Overweight
• Decreased Function of Bone Marrow
• Deficiency of Granulocytes a Type of White Blood Cell
• Increased Eosinophils in the Blood
• Abnormal Movements of Face Muscles and Tongue
• Neuroleptic Malignant Syndrome
• Lower Seizure Threshold
• closed angle glaucoma
• Very Rapid Heartbeat – Torsades de Pointes
• Slow Heartbeat
• stroke
• Disorder of the Blood Vessels of the Brain
• The blood clot in a deep vein of the extremities
• Blood Pressure Drop Upon Standing
• Abnormally low blood pressure
• Paralysis of the Intestines
• Constipation
• Liver problems
• Acute Inflammation of the Pancreas
• Enlarged Prostate
• Seizures
• Cannot Empty Bladder
• High Blood Sugar
• abnormal liver function tests
• Susceptible to Breathing Fluid Into Lungs
• a mother who is producing milk and breastfeeding
• Metabolic Syndrome X
• Dementia in an Elderly Person
• Decreased Motility Function of Stomach or Intestines

Dosage of Clozapine

Strengths: 12.5 mg; 25 mg;50 mg; 100 mg; 150 mg; 200 mg;  50 mg/mL

Schizophrenia

• 5 mg orally once or twice a day
• Titration and Maintenance dose: May increase total daily dose in increments of 25 mg to 50 mg per day to a target dose of 300 mg to 450 mg per day (administered in divided doses) by the end of week 2.
• Subsequent dose increases can be in increments of up to 100 mg once or twice weekly.
• Maximum dose: 900 mg per day

Side Effects of Clozapine

The most common

• Blurred vision
• confusion
• dizziness, faintness, or lightheadedness when getting up suddenly from a lying or sitting position
• Chest pain or tightness
• dry mouth
• trembling or shaking of the hands or feet
• stomach pain or cramping
• diarrhea
• a headache
• stomach pain;
• back pain, joint or muscle pain.
• problems with your vision (including color vision);
• sudden chest pain or trouble breathing;
• pain or swelling in one or both legs;
• a migraine headache;
• pale skin, feeling light-headed or short of breath, rapid heart rate, trouble concentrating; or
• feeling like you might pass out.

More common

• Abdominal or stomach pain, discomfort, or tenderness
• chills or fever
• difficulty with moving
• headache, severe and throbbing
• joint or back pain
• muscle aching or cramping
• muscle pains or stiffness
• chest pressure or squeezing pain in chest
• discomfort in arms, shoulders, neck or upper back
• excessive sweating
• feeling of heaviness, pain, warmth and/or swelling in a leg or in the pelvis
• sudden tingling or coldness in an arm or leg
• sudden slow or difficult speech
• sudden drowsiness or need to sleep
• fast breathing
• sharp pain when taking a deep breath
• fast or slow heartbeat
• coughing up blood
• rust colored urine
• decreased amount of urine

Rare

• Anxiety
• change in vision
• chest pain or tightness
• confusion
• cough
• Agitation
• arm, back, or jaw pain
• blurred vision
• chest pain or discomfort
• convulsions
• extra heartbeats
• fainting
• hallucinations
• headache
• irritability
• lightheadedness
• mood or mental changes
• muscle pain or cramps
• muscle spasm or jerking of all extremities
• nervousness

Drug Interactions of Clozapine

Clozapine may interact with following drug, supplements, & may change the efficasy of the drug

• antihistamines (e.g,. cetirizine, doxylamine, diphenhydramine, hydroxyzine,loratadine)
• anti-Parkinsons medications (e.g., amantadine, apomorphine, bromocriptine, levodopa, pramipexole, ropinirole)
• antipsychotics (e.g., chlorpromazine, , haloperidol,  quetiapine, risperidone)
• antiseizure medications (e.g., clobazam, ethosuximide, felbamate, levetiracetam, phenobarbital, phenytoin, topiramate, valproic acid, zonisamide)
• aripiprazole
• “azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
• baclofen
• barbiturates (e.g., butalbital, pentobarbital, phenobarbital)
• benzodiazepines (e.g., alprazolam, diazepam, lorazepam)
• beta-adrenergic blockers (e.g., atenolol, propranolol, sotalol)
• bupropion
• calcitriol
• calcium channel blockers (e.g., amlodipine, diltiazem, nifedipine, verapamil)
• captopril
• celecoxib
• chloroquine
• cholecalciferol
• cyclosporine
• dantrolene
• domperidone
• “gliptin” diabetes medications (e.g., linagliptin, saxagliptin, sitagliptin)
• gabapentin
• H2 antagonists (e.g., famotidine, ranitidine)
• ipratropium
• macrolide antibiotics (e.g., clarithromycin, erythromycin)
• mirabegron
• mirtazapine
• muscle relaxants
• non-steroidal anti-inflammatory medications (NSAIDs; e.g., diclofenac, ibuprofen, naproxen)
• phosphodiesterase 5 inhibitors (e.g., sildenafil, vardenafil)tadalafil,
• proton pump inhibitors (e.g., lansoprazole, omeprazole)
• quinolone antibiotics (e.g., levofloxacin, norfloxacin, moxifloxacin)
• selective serotonin reuptake inhibitors (SSRIs; e.g., paroxetine, fluoxetine,citalopram)
• serotonin antagonists (anti-emetic medications; e.g., granisetron, ondansetron)
• “statin” anti-cholesterol medications (e.g., atorvastatin, lovastatin,simvastatin)
• tapentadol
• tetracycline
• theophylline
• thiazide diuretics (water pills; e.g., hydrochlorothiazide, indapamide, metolazone)
• tramadol
• tricyclic antidepressants (e.g., amitriptyline, clomipramine, desipramine, trimipramine)
• trimethoprim
• umeclidinium

Pregnancy Catagory of Clozapine

FDA Pregnancy Category C

Pregnancy

Clozapine should be used only if the benefits clearly outweigh the risks. If you become pregnant or intend to become pregnant while taking this medication, contact your doctor immediately.

Lactation

This medication may pass into breast milk. If you are a breastfeeding mother and are taking clozapine, it may affect your baby. Talk to your doctor about whether you should continue breastfeeding. The safety and efficacy of this medication for use by children and adolescents below age 18 have not been established.

References