What is/are Clonazepam?
Clonazepam is a benzodiazepine drug having anxiolytic, anticonvulsant, muscle relaxant, sedative, and hypnotic properties. It is marketed by Roche under the trade name Klonopin in the United States, Rivotril in Argentina, Australia, Brazil, Canada, Costa Rica and Italy, and linotril in India, South Korea, Mexico and Europe. Other names such as Ravotril, Rivatril, Clonex, Paxam, Petril or Kriadex are known throughout the rest of the world. Clonazepam has an unusually long elimination half-life of 18–50 hours, making it generally considered to be among the long-acting benzodiazepines. Clonazepam is a chlorinated derivative of nitrazepam and therefore a chloro-nitrobenzodiazepine.
Clonazepam has an intermediate onset of action, with a peak blood levels occurring one to four hours after oral administration. It has high effectiveness rate and low toxicity in overdose but, as most medications, it may have drawbacks due to adverse reactions including paradoxical effects and drowsiness. Other long-term effects of benzodiazepines include tolerance, benzodiazepine dependence, and benzodiazepine withdrawal syndrome, which occurs in a third of people treated with clonazepam for longer than four weeks. Clonazepam is classified as a high potency benzodiazepine.
The benzodiazepine clorazepate may be an alternative to clonazepam due to a slow onset of tolerance and availability in slow-release formulation to counter fluctuations in blood levels. The pharmacological property of clonazepam as with other benzodiazepines is the enhancement of the neurotransmitter GABA via modulation of the GABAA receptor.
Clonazepam may be prescribed for epilepsy. Clonazepam is approved by the Food and Drug Administration for treatment of epilepsy and Panic Disorder. It is approved for treatment of typical and atypical absences, infantile myoclonic, myoclonic and akinetic seizures and also as a second-line agent. An open label study suggested that the combination of valproate, lamotrigine, and a benzodiazepine such as clonazepam could markedly reduce the frequency of drop attacks in patients with generalized or multifocal epilepsies. A subgroup of people with treatment resistant epilepsy may benefit from long-term use of clonazepam; the benzodiazepine clorazepate may be an alternative due to its slow onset of tolerance.
Clonazepam has been found effective in treating epilepsy in children, and the inhibition of seizure activity seemed to be achieved already at low plasma levels of clonazepam. Thus clonazepam is sometimes used for certain rare childhood epilepsies. However, it has been found to be ineffective in the control of infantile spasms. Clonazepam is less effective and potent as an anticonvulsant in bringing infantile seizures under control compared with nitrazepam in the treatment of West syndrome, which is an age-dependent epilepsy affecting the very young.
Clonazepam is mainly prescribed for the acute management of epilepsies. Clonazepam has been found to be effective in the acute control of nonconvulsive status epilepticus. However, the benefits tended to be transient in many of the patients, and the addition of phenytoin for lasting control was required in these patients.
Clonazepam has also been found effective in treating:
- Anxiety disorders
- Certain types of migraines
- Panic disorder
- Initial treatment of mania or acute psychosis together with firstline drugs such as lithium, haloperidol or risperidone
- For the management of the visual effects of HPPD
- Many forms of parasomnia are sometimes treated with clonazepam. Restless legs syndrome can be treated using clonazepam as a third line treatment option as the use of clonazepam is still investigational. Bruxism also responds to clonazepam in the short-term Rapid eye movement behavior disorder responds well to low doses of clonazepam.
- The treatment of acute and chronic akathisia induced by neuroleptics also called antipsychotics.
- Spasticity related to amyotrophic lateral sclerosis.
The effectiveness of clonazepam in the short-term treatment of panic disorder has been demonstrated in controlled clinical trials. Some long-term trials have suggested a benefit of clonazepam for up to three years without the development of tolerance but these trials were not placebo controlled. Clonazepam is also effective in the management of acute mania.
Clonazepam has shown itself to be highly effective as a short-term (3 weeks) adjunct to SSRI treatment in obsessive-compulsive disorder and clinical depression in reducing SSRI side effects with the combination being superior to SSRI treatment alone in a study funded by the manufacturers of clonazepam, Hoffman LaRoche Inc. However, clonazepam may aggravate or cause major depressive disorder (clinical depression) and/or increase anxiety in the long-run, similar to other benzodiazepines in general. Clonazepam may help reduce the severity of tinnitus symptoms.
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 as tablets (0.25 mg, 0.5 mg, 1.0 mg, 2.0 mg) and orally disintegrating tablets (wafers) (0.5 mg), an oral solution (drops), and as a solution for injection or intravenous infusion.
The elderly metabolise benzodiazepines more slowly than younger individuals and are also more sensitive to the effects of benzodiazepines even at similar blood plasma levels. Doses for the elderly are recommended to be about half of that given to younger adults and given for no longer than 2 weeks. Long-acting benzodiazepines such as clonazepam are not generally recommended for the elderly due the risk of drug accumulation.
Caution in the elderly: increased risk of impairments, falls and drug accumulation. Benzodiazepines also require special precaution if used in pregnant, alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders. Clonazepam is generally not recommended for use in elderly people for insomnia due to its high potency relative to other benzodiazepines.
Caution in children: Clonazepam is not recommended for use in those under 18. Use in very young children may be especially hazardous. Of anticonvulsant drugs behavioural disturbances occur most frequently with clonazepam and phenobarbital.
Caution using high dosages of clonazepam. Doses higher than 0.5 – 1 mg per day are associated with significant sedation.
Clonazepam may aggravate hepatic porphyria.
Caution in chronic schizophrenia. A 1982 double blinded placebo controlled study found clonazepam increases violent behavior in individuals with chronic schizophrenia.
Mechanism of action
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 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.
Clonazepam is lipid soluble, and rapidly crosses the blood–brain barrier and penetrates the placenta. It is extensively metabolised into pharmacologically inactive metabolites. Clonazepam is metabolized extensively via nitroreduction by cytochrome P450 enzymes, particularly CYP2C19 and to a lesser extent CYP3A4. Erythromycin, clarithromycin, ritonavir, itraconazole, ketoconazole, nefazodone, and grapefruit juice are inhibitors of CYP3A4 and can affect the metabolism of benzodiazepines. It has an elimination half-life of 19–60 hours Peak blood concentrations of 6.5–13.5 ng/mL were usually reached within 1–2 hours following a single 2 mg oral dose of micronized clonazepam in healthy adults. In some individuals, however, peak blood concentrations were reached at 4–8 hours.
Clonazepam passes rapidly into the central nervous system, with levels in the brain corresponding with levels of unbound clonazepam in the blood serum. Clonazepam plasma levels are very unreliable amongst patients. Plasma levels of clonazepam can vary as much as tenfold between different patients.
Clonazepam is largely bound to plasma proteins. Clonazepam passes through the blood–brain barrier easily, with blood and brain levels corresponding equally with each other. The metabolites of clonazepam include 7-aminoclonazepam, 7-acetaminoclonazepam and 3-hydroxy clonazepam.
A 2006 US government study of nationwide emergency department (ED) visits conducted by SAMHSA found that sedative-hypnotics in the USA were the most frequently implicated pharmaceutical drug in ED visits. Benzodiazepines accounted for the majority of these. Clonazepam was the second most frequently implicated benzodiazepine in ED visits in the study. The study examined the number of times non-medical use of certain drugs were implicated in ED visits; the criteria for non-medical use in this study were purposefully broad, and include for example, drug abuse, accidental or intentional overdose, or adverse reactions resulting from legitimate use of the medication.
This article uses material from the Wikipedia article Clonazepam, which is released under the Creative Commons Attribution-Share-Alike License 3.0.