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'''Clonazepam''' (marketed by [[Hoffmann-La Roche|Roche]] under the trade-names '''Klonopin''' in the United States and '''Rivotril''' in Europe, South America, Canada, India, and Australia) is a drug which is a [[benzodiazepine]] derivative. It is a highly potent [[anticonvulsant]], [[amnestic]], [[anxiolytic]] and [[muscle relaxant]]. Clonazepam is also used in cases of amphetamine overdose as to reverse some of the adverse effects. | '''Clonazepam''' (marketed by [[Hoffmann-La Roche|Roche]] under the trade-names '''Klonopin''' in the United States and '''Rivotril''' in Europe, South America, Canada, India, and Australia) is a drug which is a [[benzodiazepine]] derivative. It is a highly potent [[anticonvulsant]], [[amnestic]], [[anxiolytic]] and [[muscle relaxant]]. Clonazepam is also used in cases of amphetamine overdose as to reverse some of the adverse effects. |
Latest revision as of 23:58, 8 August 2012
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Clinical data | |
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Pregnancy category | |
Routes of administration | Oral, I.M., I.V, sublingual |
ATC code | |
Legal status | |
Legal status |
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Pharmacokinetic data | |
Bioavailability | 90% |
Metabolism | Hepatic CYP3A4 |
Elimination half-life | 18–50 hours |
Excretion | Renal |
Identifiers | |
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CAS Number | |
PubChem CID | |
DrugBank | |
E number | {{#property:P628}} |
ECHA InfoCard | {{#property:P2566}}Lua error in Module:EditAtWikidata at line 36: attempt to index field 'wikibase' (a nil value). |
Chemical and physical data | |
Formula | C15H10ClN3O3 |
Molar mass | 315.715 |
Clonazepam (marketed by Roche under the trade-names Klonopin in the United States and Rivotril in Europe, South America, Canada, India, and Australia) is a drug which is a benzodiazepine derivative. It is a highly potent anticonvulsant, amnestic, anxiolytic and muscle relaxant. Clonazepam is also used in cases of amphetamine overdose as to reverse some of the adverse effects.
Pharmacology
Clonazepam is a chlorinated derivative of nitrazepam.[1] Clonazepam is classed as a nitrobenzodiazepine along with nitrazepam and flunitrazepam.[2] Aromatic nitro-containing compounds such as clonazepam produce superoxide free radicals during cellular metabolism by endothelial cells. The nitro anion radical produced during clonazepam metabolism rapidly reacts with oxygen to form the free radical superoxide.[3][4]
Clonazepam is chemically related to quinazolines and is a hapten.[5] Like other benzodiazepines, clonazepam acts on benzodiazepine receptors which enhance the binding of GABA to the GABAA receptor which results in inhibitory effects on the central nervous system.[6] Because of its powerful anxiolytic properties, it is said to be among the class of "highly potent" benzodiazepines. Although benzodiazepines are valuable in the treatment of anxiety disorders, they carry a high potential for physical and psychological dependence with profound withdrawal symptoms, especially if discontinued abruptly or overrapidly in certain individuals. Caution is advised when taking this or any benzodiazepine medication longer than a few weeks.
One milligram of clonazepam is approximately equivalent to twenty milligrams of diazepam.[7]
Clonazepam appears to also have a secondary effect on the neurotransmitter serotonin.[8] It 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.[9] Similar results have been found with some other anxiety disorders, but the role of the serotonergic effects enhancing the action of the SSRI treatment remains unclear in these cases due to clonazepam's primary anxiolytic mechanism of action.
The anticonvulsant properties of clonazepam and other benzodiazepines may be in part or entirely due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors. Sustained repetitive firing seems to be limited by benzodiazepines effect of slowing recovery of sodium channels from inactivation.[10]
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.[11]
Indications
Clonazepam is sometimes used for refractory epilepsies; however, long-term prophylactic treatment of epilepsy has considerable limitations, most notably the loss of antiepileptic effects due to tolerance, which renders the drug useless with long-term use, and also side effects such as sedation, which is why clonazepam and benzodiazepines as a class should generally only be prescribed for the acute management of epilepsies.[12] 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. However, as with other epilepies treated with benzodiazepines, long-term therapy becomes ineffective with prolonged therapy, and the side effects of hypotonia and drowsiness are troublesome with clonazepam therapy; other antiepileptic agents are therefore recommended for long-term therapy, possibly Corticotropin (ACTH) or vigabatrin. Clonazepam is therefore not recommended for widespread use in the management of seizures related to West syndrome.[13] Also with long-term use, abrupt or overrapid withdrawal from clonazepam can precipitate withdrawal-related seizures if tolerance and physical dependence have developed.
Clonazepam has been used in the management of seizure disorders in children and also for infantile spasms. However, usefulness of clonazepam is limited due to its deleterious effect on neurological function, especially its negative effect on cognition. Clobazam, a 1,5-benzodiazepine, has shown to be less neurotoxic than 1,4-benzodiazepines such as clonazepam.[14][15]
Clonazepam may be prescribed for:
- Epilepsy[16]
- Anxiety disorders
- Panic attacks due to the often chronic nature of panic disorders, long-term therapy may be advocated. SSRIs are considered the primary drug, along with cognitive-behavioral therapy, with [17]
- Initial treatment of mania, together with firstline drugs such as lithium, haloperidol or risperidone
- Restless legs syndrome
Clonazepam is rarely used as a treatment for insomnia due to its relatively weak hypnotic effects. It has not been marketed for the treatment of insomnia mainly because its long half life makes it unsuitable for this application.
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), orally disintegrating tablets (wafers) (0.125, 0.25, 0.5, 1.0, and 2 mg), liquid solutions (2.5 mg/mL) and for injection (1 mg/mL)
Like all benzodiazepines, clonazepam is a benzodiazepine receptor agonist. Long-term use (more than 2–4 weeks) can lead to a number of problems, including muscle weakness and fatigue, tolerance, physical dependence and withdrawal syndromes upon discontinuation. The benzodiazepine withdrawal syndrome, which may appear during reduction or withdrawal of clonazepam treatment, can be reduced in intensity with gradual reduction of dosage. Clonazepam is sometimes used to help with Methadone withdrawal symptoms
Side effects
Common:
- Drowsiness
- Impairment of cognition and judgment
- Impaired motor function
- Impaired coordination
- Impaired balance
- Dizziness
- Anterograde amnesia (common with higher doses)
Rare:
- Paradoxical disinhibition[18] (most frequently in children, the elderly, and in persons with developmental disabilities)
- Rage
- Excitement
- Irritability
- Impulsivity
- Some users report hangover-like symptoms of being drowsy, having a headache, being sluggish, and being irritable after waking up if the medication is taken before sleep. This is likely the result of the medication's long half-life, which continues to affect the user after waking up, as well as its disruption of the REM cycle.
Withdrawal-related:
- Anxiety, irritability, insomnia
- Panic attacks, tremor
- Seizures similar to delirium tremens (with long-term use of excessive doses)
Many individuals treated on a long-term basis develop a form of dependence known as "low-dose dependence", as was shown in one double-blind, placebo-controlled study of 34 therapeutic low-dose benzodiazepine users—physiological dependence was demonstrated via flumazenil-precipitated withdrawal.[19]
Use of alcohol or other CNS depressants while taking clonazepam greatly intensifies the effects (and side effects) of the drug. Side effects of the drug itself are generally benign, but sudden withdrawal after long-term use can cause severe, even fatal, symptoms.
Special precautions
Caution in the Elderly. Increased risk of impairments, falls and drug accumulation.[citation needed]
Caution in children. Clonazepam is not recommended for use in those under 18. Use in very young children may be especially hazardous. Clonazepam was implicated along with the drugs diphenylhydantoin and nitrazepam in the death of a 7 and a half month old girl. She developed inclusions consisting of lamellar profiles, situated in membrane-bound cytosomes which were found mainly in astrocytes, but also in neurones and in axons of peripheral nerves before dying. Lipofuscin bodies were also found to be increased in number.[20]
Protracted withdrawal
10–15% of individuals treated with clonazepam on a long-term basis (in excess of 30 days of continuous use) develop a protracted withdrawal syndrome. Protracted withdrawal lasts for months, years, or a lifetime after clonazepam is discontinued. Protracted withdrawal results from structural brain damage, which is often irreversible.[21] Common protracted withdrawal symptoms include:[22]
- Anxiety
- Insomnia
- Depression
- Tinnitus
- Tingling and numbness in limbs
- Muscle pain and tension
- Weakness
- Cramps
- Tremors
- Irritable bowel
- Cognitive dysfunction
Benzodiazepines including clonazepam may inhibit the glucuronidation of morphine leading to increased levels of and prolongation of the effects of morphine. Clonazepam may inhibit morphine metabolism more than any other benzodiazepine.[23]
Pregnancy
There is some medical evidence of various malformations eg cardiac or facial deformations when used in early pregnancy, however the data is not conclusive. The data is also inconclusive whether benzodiazepines such as clonazepam cause developmental deficits or decreases in IQ when taken during pregnancy. Clonazepam when used late in pregnancy may result in the development of a severe benzodiazepine withdrawal syndrome in the neonate and also floppy infant syndrome. Withdrawal symptoms from benzodiazepines in the neonate may include hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. These symptoms may persist for hours or months after birth.[24]
Overdose
An individual who has consumed too much clonazepam will display one or more of the following symptoms:
- Somnolence (difficulty staying awake)
- Mental confusion
- Hypotension
- Impaired motor functions
- Impaired reflexes
- Impaired coordination
- Impaired balance
- Dizziness
- Coma
Unless combined with other drugs, deep coma or other manifestations of severe central nervous system depression are rare, and the mortality rate associated with poisoning is very low. As with other benzodiazepines, overdose symptoms of clonazepam may be reversed with flumazenil (Romazicon®).
Recreational use and abuse
Relatively few cases of addiction arise from legitimate use of benzodiazepines.[25] If in tablet form, they are most commonly used as a secondary drug to increase the pleasure resulting from a primary drug, or to lessen or prevent some of the primary drug's negative side effects. Clonazepam has been implicated in drug facilitated sexual assaults.[26]
References
- ↑ Dreifuss FE (1975). "Serum clonazepam concentrations in children with absence seizures". Neurology. 25 (3): 255–8. PMID 1089913. Unknown parameter
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ignored (help) - ↑ Robertson MD (1995). "Postmortem drug metabolism by bacteria". J Forensic Sci. 40 (3): 382–6. PMID 7782744. Unknown parameter
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ignored (help) - ↑ Rosen GM (1988). "Synthesis of spin traps specific for hydroxyl radical". J Med Chem. 31 (2): 428–32. PMID 2828624. Unknown parameter
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ignored (help) - ↑ Rosen GM (1984). "Not all aromatic nitro compounds form free radicals". Toxicol Lett. 22 (2): 145–52. PMID 6089382. Unknown parameter
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ignored (help); Unknown parameter|month=
ignored (help) - ↑ Earley JV (1979). "Quinazolines and 1,4-benzodiazepines. LXXXIX: Haptens useful in benzodiazepine immunoassay development". J Pharm Sci. 68 (7): 845–50. PMID 458601. Unknown parameter
|coauthors=
ignored (help); Unknown parameter|month=
ignored (help) - ↑ Skerritt JH (6). "Enhancement of GABA binding by benzodiazepines and related anxiolytics". Eur J Pharmacol. 89 (3–4): 193–8. PMID 6135616. Unknown parameter
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(help) - ↑ Benzodiazepine Comparison Chart,B Jenson,2003
- ↑ Clonazepam treatment of lysergic acid diethylamide-induced hallucinogen persisting perception disorder with anxiety features,Lerner AG et al.,Int Clin Psychopharmacol 18(2):101-5,March 2003
- ↑ Short-Term Augmentation of Fluoxetine With Clonazepam in the Treatment of Depression: A Double-Blind Study, Smith WT et al.,Am J Psychiatry 155:1339-1345, October 1998
- ↑ McLean MJ (1988). "Benzodiazepines, but not beta carbolines, limit high frequency repetitive firing of action potentials of spinal cord neurons in cell culture". J Pharmacol Exp Ther. 244 (2): 789–95. PMID 2450203. Unknown parameter
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ignored (help); Unknown parameter|month=
ignored (help) - ↑ Monograph:Clonazepam:Pharmacokinetics
- ↑ Isojärvi, JI (1998). "Benzodiazepines in the treatment of epilepsy in people with intellectual disability". J Intellect Disabil Res. 42 (1): 80–92. PMID 10030438. Unknown parameter
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ignored (help); Unknown parameter|month=
ignored (help) - ↑ Djurić, M (2001). "[West syndrome--new therapeutic approach]". Srp Arh Celok Lek. 129 (1): 72–7. PMID 15637997. Unknown parameter
|coauthors=
ignored (help); Unknown parameter|month=
ignored (help) - ↑ Farrell K. (1986). "Benzodiazepines in the treatment of children with epilepsy". Epilepsia. 1: 45–5. PMID 3743524.
- ↑ Munn R (1993). "Open study of clobazam in refractory epilepsy". Pediatr Neurol. 9 (6): 465–9. PMID 7605555. Unknown parameter
|coauthors=
ignored (help); Unknown parameter|month=
ignored (help) - ↑ Rossetti AO (2004). "Propofol treatment of refractory status epilepticus: a study of 31 episodes". Epilepsia. 45 (7): 757–63. PMID 15230698. Unknown parameter
|coauthors=
ignored (help); Unknown parameter|month=
ignored (help) - ↑ Cloos, Jean-Marc (2005). "The Treatment of Panic Disorder". Curr Opin Psychiatry. 18 (1): 45–50. Retrieved 2007-09-25.
- ↑ van der Bijl P, Roelofse JA. Disinhibitory reactions to benzodiazepines: a review. J Oral Maxillofac Surg 1991;49:519-23
- ↑ Bernik MA (1998). "Stressful reactions and panic attacks induced by flumazenil in chronic benzodiazepine users". Journal of psychopharmacology (Oxford, England). 12 (2): 146–50. PMID 9694026. Unknown parameter
|coauthors=
ignored (help) - ↑ Figols J (1986). "Encephalopathy with astrocytic residual bodies. Report of a case and review of the literature". Histol Histopathol. 1 (1): 59–67. PMID 2980102. Unknown parameter
|coauthors=
ignored (help); Unknown parameter|month=
ignored (help) - ↑ Ashton C. (1995). "Protracted Withdrawal from Benzodiazepines: The Post-Withdrawal Syndrome". Psychiatric Annals, U.K. 25 (3): 174–179. Unknown parameter
|month=
ignored (help) - ↑ Protracted Withdrawal from Benzodiazepines: The Post-Withdrawal Syndrome,C Ashton,1995
- ↑ Pacifici GM (1986). "Metabolic interaction between morphine and various benzodiazepines". Acta Pharmacol Toxicol (Copenh). 58 (4): 249–52. PMID 2872767. Unknown parameter
|coauthors=
ignored (help); Unknown parameter|month=
ignored (help) - ↑ McElhatton PR. (1994). "The effects of benzodiazepine use during pregnancy and lactation". Reprod Toxicol. 8 (6): 461–75. PMID 7881198. Unknown parameter
|month=
ignored (help) - ↑ Benzodiazepine use, abuse, and dependence.
- ↑ Hackett J (2). "Extraction and analysis of clonazepam and 7-aminoclonazepam in whole blood using a dual internal standard methodology". Forensic science international. 166 (2–3): 209–17. PMID 16809012. Unknown parameter
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(help)
External links
- Wallace, Christina. "Kpin, a hit drug with teens, can be deadly, officials say." Boston Metro, Wednesday April 12, 2006. Page 2.
- Carlos, Jean-Marc: The Treatment of Panic Disorder http://www.medscape.com/viewarticle/497207
- Rx-List - Clonazepam
- Poisons Information Monograph - Clonazepam
- FDA prescription insert
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