Clonazepam is a synthetic benzodiazepine derivative used for myotonic or atonic seizures, absence seizures, and photosensitive epilepsy, anticonvulsant ,Clonazepam appears to enhance gamma-aminobutyric acid receptor responses, although its mechanism of action is not clearly understood. It is seldom effective in generalized tonic-clonic or partial seizures.
Clonazepam is an anticonvulsant used for several types of seizures, including myotonic or atonic seizures, photosensitive epilepsy, and absence seizures, although tolerance may develop. It is seldom effective in generalized tonic-clonic or partial seizures.
Clonazepam, is a medication used to prevent and treat seizures, panic disorder, and for the movement disorder known as akathisia including myotonic or atonic seizures, photosensitive epilepsy, and absence seizures .It is seldom effective in generalized tonic-clonic or partial seizures.
Mechanism of Action of Clonazepam
Clonazepam acts by binding to the benzodiazepine site of the GABA receptors, which enhances the electric effect of GABA binding on neurons, resulting in an increased influx of chloride ions into the neurons. This further results in an inhibition of synaptic transmission across the central nervous system. Allosteric interactions between central benzodiazepine receptors and gamma-aminobutyric acid (GABA) receptors potentiate the effects of GABA. As GABA is an inhibitory neurotransmitter, this results in increased inhibition of the ascending reticular activating system. Benzodiazepines, in this way, block the cortical and limbic arousal that occurs following stimulation of the reticular pathways.
Benzodiazepines do not have any effect on the levels of GABA in the brain.Clonazepam has no effect on GABA levels and has no effect on gamma-aminobutyric acid transaminase. Clonazepam does, however, affect glutamate decarboxylase activity. It differs from other anticonvulsant drugs it was compared to in a study.Clonazepam’s primary mechanism of action is the modulation of GABA function in the brain, by the benzodiazepine receptor, located on GABAA receptors, which, in turn, leads to enhanced GABAergic inhibition of neuronal firing. Benzodiazepines do not replace GABA, but instead enhance the effect of GABA at the GABAAreceptor by increasing the opening frequency of chloride ion channels, which leads to an increase in GABA’s inhibitory effects and resultant central nervous system depression.In addition, clonazepam decreases the utilization of 5-HT (serotonin) by neurons and has been shown to bind tightly to central-type benzodiazepine receptors.Because clonazepam is effective in low milligram doses (0.5 mg clonazepam = 10 mg diazepam), it is said to be among the class of “highly potent” benzodiazepines. The anticonvulsant properties of benzodiazepines are due to the enhancement of synaptic GABA responses, and the inhibition of sustained, high-frequency repetitive firing.Benzodiazepines, including clonazepam, bind to mouse glial cell membranes with high affinity. Clonazepam decreases release of acetylcholine in the feline brain and decreases prolactin release in rats.Benzodiazepines inhibit cold-induced thyroid stimulating hormone (also known as TSH or thyrotropin) release. Benzodiazepines acted via micromolar benzodiazepine binding sites as Ca2+ channel blockers and significantly inhibit depolarization-sensitive calcium uptake in experimentation on rat brain cell components. This has been conjectured as a mechanism for high-dose effects on seizures in the studyClonazepam is a chlorinated derivative of nitrazepam and therefore a chloro-nitro benzodiazepine.
The exact mechanism by which clonazepam exerts its anticonvulsant, sedative, and antipanic effects is unknown. However, it is believed to be related at least in part to the drug’s ability to enhance the activity of gamma-aminobutyric acid (GABA), the principal inhibitory neurotransmitter in the central nervous system.
Indications of Clonazepam
1st choice drug for ,insomnia induce anxiety,convulsion,agitation
- Hypnotic disorder in the short-term management of insomnia, as a sedative and premedicant,
- Akinetic and myoclonic seizures. It can also be used for the treatment of panic disorders.
- Clonazepam is used as an anticonvulsant in the treatment of the Lennox-Gastaut syndrome , akinetic and myoclonic seizures. It can also be used for the treatment of panic disorders.
- Akinetic seizures
- Burning mouth syndrome
- Gilles de la tourette’s syndrome
- Lennox-gastaut syndrome (LGS)
- Mixed manic depressive episode
- Panic disorders
- Rapid eye movement sleep disorder
- Restless legs syndrome
- Tardive dyskinesia
- Tremor, essential
- Acute manic episode
- Myoclonic seizures
- Refractory absence Seizures
- The treatment of acute and chronic akathisia induced by neuroleptics, also called antipsychotics.
- Spasticity related to amyotrophic lateral sclerosis.
- Alcohol withdrawal syndrome
- Many forms of parasomnia and other sleep disorders are treated with clonazepam.
Therapeutic Indications of Clonazepam
- Clonazepam is useful alone or as an adjunct in the treatment of the Lennox-Gastaut syndrome (petit mal variant), akinetic and myoclonic seizures. In patients with absence seizures (petit mal) who have failed to respond to succinimides, Klonopin may be useful.
- Clonazepam is indicated for the treatment of panic disorder, with or without agoraphobia, as defined in DSM-IV.
- Panic disorder is characterized by the occurrence of unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks.
- Clonazepam also has been used in patients who experience akathisia while receiving antipsychotic drugs (e.g., for management of schizophrenia) and for the treatment of acute catatonic reactions, whether associated with schizophrenia or other conditions.
- The efficacy of clonazepam as a hypnotic has not been fully evaluated.
- Clonazepam is a high potency benzodiazepine labeled for use as an anticonvulsant. Increasingly, clonazepam has been used in the treatment of a variety of psychiatric disorders.
- The drugs potential clinical applications, including (1) use as an adjunct to neuroleptics for treating psychosis, (2) management of specific psychotropic side effects, (3) alternative treatment for certain pain syndromes, and (4) a primary treatment for severe agitation, atypical psychosis, and anxiety disorders
- This is a report on the efficacy of clonazepam in the treatment of acute mania. The advantages of clonazepam over standard neuroleptics are its rapidity of action, its lack of toxicity, and, particularly important, the fact that it does not cause tardive dyskinesia, a potentially disabling neurological side effect of neuroleptic treatment.
- Benzodiazepines, such as clonazepam, are sometimes used for the treatment of mania or acute psychosis-induced aggression. In this context, benzodiazepines are given either alone, or in combination with other first-line drugs such as lithium, haloperidol or risperidone.
- The effectiveness of taking benzodiazepines along with antipsychotic drugs is unknown, and more research is needed to determine if benzodiazepines are more effective than antipsychotic drugs when urgent sedation is required.
Contra-Indications of Clonazepam
- Having thoughts of suicide
- Alcohol intoxication
- Drug abuse
- Wide-angle glaucoma
- Closed-angle glaucoma
- Decreased lung function
- Chronic lung disease
- Liver problems
- Severe liver disease
- Temporarily stops breathing while wleeping
- Abnormal liver function tests
- Susceptible to breathing fluid into lungs
- Kidney disease with likely reduction in kidney function
- Allergies to Benzodiazepines
Dosage of Clonazepam
Strengths : 0.5 mg, 1 mg, and 2 mg.
- Typical starting dose: 0.25 mg taken twice per day
- Dose increases – Your doctor may increase your dose to 0.5 mg taken two times per day after 3 days.
- Maximum dose – 4 mg per day.
- Dose reduction – Your doctor should decrease your dose slowly when stopping treatment with this drug. They should decrease your dose by no more than 0.125 mg every 3 days. For example, if you were taking 2 mg two times per day, your doctor would decrease your dose to 1.875 mg taken two times per day.
- A typical adult dose to treat seizures may start at 1.5 mg a day, divided into three doses. Your doctor may gradually increase your dose to a maximum daily dose of 20 mg.
- 1.5 mg orally per day divided into 3 doses; this may be increased in increments of 0.5 mg to 1 mg every 3 days until seizures are adequately controlled or until side effects preclude any further increase.
- Maximum dose: 20 mg/day
- Initial dose – 0.25 mg orally 2 times per day
- Maintenance dose – 1 mg orally per day
- Maximum dose – 4 mg/day
- Up to 10 years of age OR 30 kg body weight: 0.01 mg/kg/day to 0.05 mg/kg/day orally administered in 2 or 3 divided doses
- Maintenance dose – 0.1 to 0.2 mg/kg/day
- 10 years or older OR 30 kg and over – 1.5 mg orally per day divided into 3 doses; this may be increased in increments of 0.5 mg to 1 mg every 3 days until seizures are adequately controlled or until side effects preclude any further increase.
- Maximum dose – 20 mg/day
Side Effects of Clonazepam
The most common
- Irritability and aggression
- Dry mouth
- Abdominal or stomach pain
- cold or flu symptoms such as stuffy nose, sore throat, fever;
- dizziness or lightheadedness
- blurred vision
- pain, redness, or hardening of the skin at the injection site
- Nausea ,vomiting,
- painful or swollen gums
- numbness or heavy feeling in the jaw
- stomach pain,
- reversible hair loss or thinning, and
- chills or fever
- headache, severe and throbbing
- joint or back pain
- muscle aching or cramping
- muscle pains or stiffness
- chest pressure or squeezing pain in chest
- excessive sweating
- sudden drowsiness or need to sleep
- coughing up blood
- liver problems–nausea, upper stomach pain, itching, tired feeling, loss of appetite,
- change in vision
- chest pain or tightness
- arm, back, or jaw pain
- blurred vision
- chest pain or discomfort
- extra heartbeats
- cold and clammy skin
- fast and shallow breathing
- swelling of your feet, legs, or hands purple spot on your skin caused by internal bleeding
- fast or abnormal heart rate or palpitations
- loss of appetite
- lower back, side, or stomach pain
- mental depression
- muscle pain or cramps
- Swelling of your feet or ankles
- Shortness of breath
- Nausea, fever, dark urine, loss of appetite
- Somnolence (difficulty staying awake)
- Mental confusion
- Respiratory arrest
- Vasomotor collapse
Drug Interactions of Clonazepam
Clonazepam may interact with following drugs, supplyments, & may change the efficacy of drugs
- antipsychotics (e.g., chlorpromazine, clozapine, haloperidol, olanzapine, quetiapine, risperidone)
- “azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
- barbiturates (e.g., butalbital, phenobarbital)
- benzodiazepines (e.g.diazepam, lorazepam)
- calcium channel blockers (e.g., amlodipine, diltiazem, nifedipine, verapamil)
- estradiol (birth control pills)
- macrolide antibiotics (e.g., clarithromycin, erythromycin)
- Oral contraceptives (birth control pills)
- muscle relaxants
- proton pump inhibitors (e.g., lansoprazole, omeprazole)
- quinolone antibiotics (e.g., ciprofloxacin, ofloxacin)
- selective serotonin reuptake inhibitors (SSRIs; e.g., citalopram, duloxetine, fluoxetine, paroxetine, sertraline)
- tricyclic antidepressasnts (e.g., amitriptyline, clomipramine, desipramine, trimipramine)
Alcohol may increase your risk of experiencing some of the side effects of clonazepam.
Pregnancy & Lactation of Clonazepam
FDA pregnancy category D
Studies show a risk of adverse effects to the fetus when the mother takes the drug.This drug should only be used during pregnancy in serious cases where it’s needed to treat a dangerous condition in the mother.
Clonazepam passes into breast milk and causes side effects in a child who is breastfed. Talk to your doctor if you breastfeed your child. You may need to decide whether to stop breastfeeding or stop taking this medication.This medication hasn’t been studied in children with panic disorders. It shouldn’t be used for the treatment of this condition in people younger than 18 years.
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