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Clonazepam

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Clonazepam, Uses are alone or as an adjunct in the treatment of petit mal variant (Lennox-Gastaut), akinetic, and myoclonic seizures; petit mal (absence) seizures unresponsive to succimides; panic disorder with or without agoraphobia.


Contents

About Clonazepam

Clonazepam is a benzodiazepine and anti-convulsant used in the treatment of seizures and panic disorder. Tolerance develops over time. It is marketed by Roche under the trade-names Klonopin in the United States, Ravotril in Chile and Rivotril in various other English speaking countries. Clonazepam is a chlorinated derivative of nitrazepam and a nitrobenzodiazepine like nitrazepam. Clonazepam is the second most abused benzodiazepine in the United States. Clonazepam's primary mechanism of action is via modulating GABA function in the brain, via the benzodiazepine receptor which in turn leads to enhanced GABAergic inhibition of neuronal firing. 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 of its strong anxiolytic, anticonvulsant and euphoric properties, it is said to be among the class of "highly potent" benzodiazepines. The anticonvulsant properties of benzodiazepines are due to enhancement of synaptic GABA responses and inhibition of sustained high frequency repetitive firing.

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Clonazepam
Systematic (IUPAC) name
6-(2-chlorophenyl)- 9-nitro- 2,5-diazabicyclo [5.4.0] undeca- 5,8,10,12- tetraen- 3-one
Identifiers
CAS number 1622-61-3
ATC code N03AE01
PubChem 2802
DrugBank APRD00054
ChemSpider 2700
Chemical data
Formula C15H10ClN3O3 
Mol. mass 315.715
Pharmacokinetic data
Bioavailability 90%
Protein binding ~85%
Metabolism Hepatic CYP3A4
Half life 18–50 hours
Excretion Renal
Therapeutic considerations
Pregnancy cat.

C(AU) D(US)

Legal status

Schedule IV(US)

Routes Oral, I.M., I.V, sublingual

Benzodiazepines, including clonazepam, bind to mouse glial cell membranes with high affinity. Clonazepam decreases release of acetylcholine in cat 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 study.

Clonazepam exerts its action by binding to the benzodiazepine site of the GABA receptors, which causes an enhancement of the electric effect of GABA binding on neurons resulting in an increased influx of chloride ions into the neurons. This results in an inhibition of synaptic transmission across the central nervous system. Benzodiazepines, however, 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 insofar from other anticonvulsant drugs it was compared to in a study. Benzodiazepine receptors are found in the central nervous system but are also found in a wide range of peripheral tissues such as longitudinal smooth muscle-myenteric plexus layer, lung, liver and kidney as well as mast cells, platelets, lymphocytes, heart and numerous neuronal and non-neuronal cell lines.


Tolerance and withdrawal

Like all benzodiazepines, clonazepam is a benzodiazepine receptor agonist. Tolerance to the anticonvulsant effects of clonazepam occurs in both animals and humans. In humans tolerance to the anticonvulsant effects of clonazepam occurs frequently. Chronic use of benzodiazepines leads to the development of tolerance with a decrease of benzodiazepine binding sites. Clonazepam has also been shown to produce effects of miosis, or "pinpointing" of the pupil. The degree of tolerance is more pronounced with clonazepam than with chlordiazepoxide. Short term therapy is generally more effective than long term therapy with clonazepam for the treatment of epilepsy. Many studies have found that tolerance develops to the anticonvulsant properties of clonazepam with chronic use, which limits its long term effectiveness as an anticonvulsant.

Discontinuation of or reduction in dosage after regular use may result in the clonazepam withdrawal syndrome. Abrupt or over-rapid withdrawal from clonazepam may result in the development of the benzodiazepine withdrawal syndrome with psychotic attacks characterised by dysphoric manifestations, irritability, aggressiveness, anxiety, and hallucinations. Sudden withdrawal from clonazepam may also result in withdrawal symptoms including anxiety, irritability and potentially the life threatening condition status epilepticus. Antiepileptic drugs, benzodiazepines such as clonazepam in particular, should be reduced slowly and gradually when discontinuing the drug to reduce withdrawal effects. Carbamazepine has been trialed in the treatment of clonazepam withdrawal and has been found to be ineffective in preventing clonazepam withdrawal status epilepticus from occurring.


Availability

Clonazepam was approved in the United States as a generic drug in 1997 and is now manufactured and marketed by several companies.

Clonazepam is available in the U.S. as tablets (0.5, 1.0, and 2 mg) and orally disintegrating tablets (wafers) (0.125, 0.25, 0.5, 1.0, and 2 mg). In other countries, clonazepam is usually available as tablets (0.5 and 2 mg), orally disintegrating tablets (0.25, 0.5, 1 and 2 mg) oral solution (drops, 2.5 mg/mL), as well as solution for injection or intravenous infusion, containing 1 mg clonazepam per ampoule (e.g. Rivotril inj.).


International Brand Names for Clonazepam

  • Alti-Clonazepam (CA)
  • Antelepsin® (DE, RO, RU)
  • Apo-Clonazepam® (CA)
  • Clonagin® (AR)
  • Clonapam (CA, CL)
  • Clonax® (AR)
  • Clonazepam Duncan® (AR)
  • Clonazepam Monte Verde® (AR)
  • Clonazepam® (RO)
  • Clonazepamum® (HU, PL)
  • Clonogal® (HU)
  • Clonotril® (CY, RO)
  • Coquan® (CO)
  • Diocam® (AR)
  • Epitril® (IN)
  • Gen-Clonazepam (CA)
  • Iktorivil® (SE)
  • Induzepam® (AR)
  • Kenoket® (MX)
  • Klonopin® (CA)
  • Landsen® (JP)
  • Lonazep® (BD)
  • Neuryl® (AR)
  • Novo-Clonazepam (CA)
  • Nu-Clonazepam (CA)
  • Paxam® (AU, NZ)
  • PMS-Clonazepam (CA)
  • Ravotril® (CL, CZ)
  • Rho-Clonazepam (CA)
  • Rivatril® (FI)
  • Rivoril® (BE)
  • Rivotril® (AR, AT, AU, BD, BE, BR, CA, CH, CO, CR, CZ, DE, DK, DO, ES, FR, GB, GT, HK, HN, HR, HU, ID, IE, IL, IT, LU, MX, NL, NO, NZ, PA, PL, PT, RO, RU, SI, SV, TH, TR, YU, ZA)
  • Solfidin® (AR)
  • Valpax® (CL)