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Clonazepam (n.)
1.(MeSH)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. The mechanism of action appears to involve the enhancement of GAMMA-AMINOBUTYRIC ACID receptor responses.
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Clonazepam (n.) (MeSH)
D03.438.079.080.070.150, Antelepsin (MeSH), Rivotril (MeSH), Ro 5-4023 (MeSH)
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Clonazepam (n.) [MeSH]
Benzodiazepinones[Hyper.]
Wikipedia
Systematic (IUPAC) name | |
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5-(2-chlorophenyl)-7-nitro-2,3-dihydro-1,4-benzodiazepin-2-one | |
Clinical data | |
Trade names | Klonopin |
AHFS/Drugs.com | monograph |
MedlinePlus | a682279 |
Pregnancy cat. | C (AU) D (US) |
Legal status | Prescription Only (S4) (AU) ? (UK) Schedule IV (US) |
Routes | Oral, I.M., I.V, sublingual |
Pharmacokinetic data | |
Bioavailability | 90% |
Protein binding | ~85% |
Metabolism | Hepatic CYP3A4 |
Half-life | 18-50 hours |
Excretion | Renal |
Identifiers | |
CAS number | 1622-61-3 |
ATC code | N03AE01 |
PubChem | CID 2802 |
DrugBank | DB01068 |
ChemSpider | 2700 |
UNII | 5PE9FDE8GB |
KEGG | D00280 |
ChEBI | CHEBI:3756 |
ChEMBL | CHEMBL452 |
Chemical data | |
Formula | C15H10ClN3O3 |
Mol. mass | 315.715 |
SMILES | eMolecules & PubChem |
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Clonazepam[1] is a benzodiazepine drug having anxiolytic, anticonvulsant, muscle relaxant, and hypnotic properties.[2] It is marketed by Roche under the trade name Klonopin in the United States and Rivotril in Argentina, Australia, Brazil, Canada, Mexico and Europe. Other names such as Ravotril, Rivatril, Clonex, Paxam, or Kriadex are known throughout the rest of the world.[citation needed] Clonazepam has an unusually long elimination half-life of 18–50 hours, making it generally considered to be among the long-acting benzodiazepines.[3] Clonazepam is a chlorinated derivative of nitrazepam[4] and therefore a chloro-nitrobenzodiazepine.[5]
Clonazepam has a slow onset with a peak four hours after ingestion. 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.[6] Clonazepam is classified as a high potency benzodiazepine.
The use of clonazepam in long term treatment is inhibited by its ability to induce tolerance to the anticonvulsant effects. However, in a study of patients with epilepsy, the medication could be withdrawn successfully in most patients. In some patients seizures control was reduced after withdrawal, but reintroduction of Clonazepam rapidly resulted in control of the epilepsy. No significant change in cognitive function, mood or behaviour was noted in the patients who discontinued CZP.[7]
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.[6]
Contents |
Clonazepam may be prescribed for the following:
Clonazepam is approved by the Food and Drug Administration for treatment of epilepsy. It is approved for treatment of typical and atypical abcences, infantile myoclonic, myoclonic and akinetic seizures [10] and also as a second-line agent. An open label study suggested that the combination of valproate, lamotrigine, and a benzodiazepines as clonazepame could markedly reduce the frequency of the drop attacks in patients with generalized or multifocal epilepsies.[11] 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.[6]
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.[12] Thus clonazepam is sometimes used for certain rare childhood epilepsies. However, it has been found to be ineffective in the control of infantile spasms.[13] 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.[14]
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.[27]
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.[28]
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 and orally disintegrating tablets (wafers), oral solution (drops), as well as solution for injection or intravenous infusion.[citation needed]
[37][38] While benzodiazepines induce sleep, they tend to produce a poorer quality sleep than natural sleep. Benzodiazepines such as clonazepam suppress REM sleep.[39] After regular use rebound insomnia can occur when discontinuing clonazepam.[40]
The long term effects of clonazepam can include depression, disinhibition, and sexual dysfunction.[56] Long-term use of benzodiazepines is also associated with cognitive impairments that can persist for at least six months post-withdrawal, but it is unclear whether these impairments take more than six months to abate or if they are permanent. Benzodiazepines may cause or worsen depression.[6]
Benzodiazepines such as clonazepam can be very effective in controlling status epilepticus, but, when used for longer periods of time, some potentially serious side-effects may develop, such as interference with cognitive functions and behavior.[58] 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 by flumazenil-precipitated withdrawal.[59] 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.
Like all benzodiazepines, clonazepam is a benzodiazepine receptor agonist.[60][61] One third of individuals treated with benzodiazepines for longer than four weeks develop a dependence on the drug and experience a withdrawal syndrome upon dose reduction. High dosage and long term use increases the risk and severity of dependence and withdrawal symptoms. Withdrawal seizures and psychosis can occur in severe cases of withdrawal and anxiety and insomnia in less severe cases of withdrawal. Gradual reduction in dosage reduces the severity of the benzodiazepine withdrawal syndrome. Due to the risks of tolerance and withdrawal seizures clonazepam is generally not recommended for the long-term management of epilepsies. Increasing the dose can overcome the effects of tolerance but tolerance to the higher dose may occur and adverse effects may increase. The mechanism of tolerance includes receptor desensitisation, down regulation, receptor uncoupling and alterations in subunit composition and alterations in gene transcription coding.[6]
Tolerance to the anticonvulsant effects of clonazepam occurs in both animals and humans. In humans, tolerance to the anticonvulsant effects of clonazepam occurs frequently.[62][63] Chronic use of benzodiazepines leads to the development of tolerance with a decrease of benzodiazepine binding sites. The degree of tolerance is more pronounced with clonazepam than with chlordiazepoxide.[64] In general, short-term therapy is more effective than long-term therapy with clonazepam for the treatment of epilepsy.[65] 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.[66]
Abrupt or over-rapid withdrawal from clonazepam may result in the development of the benzodiazepine withdrawal syndrome, causing psychosis characterised by dysphoric manifestations, irritability, aggressiveness, anxiety, and hallucinations.[67][68][69] Sudden withdrawal may also induce the potentially 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.[48] 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.[70]
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.[6]
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.[71] Clonazepam is generally not recommended for use in elderly people for insomnia due to its high potency relative to other benzodiazepines.[72]
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.[71][73]
Caution using high dosages of clonazepam. Doses higher than 0.5 – 1 mg per day are associated with significant sedation.[74]
Clonazepam may aggravate hepatic porphyria.[75][76]
Caution in chronic schizophrenia. A 1982 double blinded placebo controlled study found clonazepam increases violent behavior in individuals with chronic schizophrenia.[77]
Clonazepam decreases the levels of carbamazepine,[78][79] and likewise clonazepam's level is reduced by carbamazepine. Azole antifungals such as ketoconazole may inhibit the metabolism of clonazepam.[6] Clonazepam may affect levels of phenytoin (diphenylhydantoin) by decreasing,[78][80] or increasing.[81][82] In turn Phenytoin may lower clonazepam plasma levels, by increasing the speed of clonazepam clearance by approximately 50% and decreasing its half-life by 31%.[83] Clonazepam increases the levels of primidone,[81] and phenobarbital.[84]
Combined use of clonazepam with certain antidepressants, antiepileptics such as phenobarbital, phenytoin and carbamazepine, sedative antihistamines, opiates, antipsychotics and alcohol may result in enhanced sedative effects.[6]
Clonazepam, like other benzodiazepines, will impair one's ability to drive or operate machinery. The central nervous system depressing effects of the drug can be intensified by alcohol consumption. Benzodiazepines have been shown to cause both psychological and physical dependence. Patients physically dependent on clonazepam should be slowly titrated off under the supervision of a qualified healthcare professional to reduce the intensity of withdrawal or rebound symptoms.
There is some medical evidence of various malformations, e.g., cardiac or facial deformations, when used in early pregnancy, however the data is not conclusive. The data are also inconclusive on whether benzodiazepines such as clonazepam cause developmental deficits or decreases in IQ in the developing fetus when taken by the mother during pregnancy. Clonazepam when used late in pregnancy may result in the development of a severe benzodiazepine withdrawal syndrome in the neonate. Withdrawal symptoms from benzodiazepines in the neonate may include hypotonia, apnoeic spells, cyanosis and impaired metabolic responses to cold stress.[85]
The safety profile of clonazepam during pregnancy is less clear than for other benzodiazepines and if benzodiazepines are indicated during pregnancy chlordiazepoxide and diazepam may be a safer choice. The use of clonazepam during pregnancy should only be used if the clinical benefits are believed to outweigh the clinical risks to the fetus. Caution is also required if clonazepam is used during breast feeding. Possible adverse effects of use of benzodiazepines such as clonazepam during pregnancy include; abortion, malformation, intrauterine growth retardation, functional deficits, floppy infant syndrome, carcinogenesis and mutagenesis. Neonatal withdrawal syndrome associated with benzodiazepines include hypertonia, hyperreflexia, restlessness, irritability, abnormal sleep patterns, inconsolable crying, tremors or jerking of the extremities, bradycardia, cyanosis, suckling difficulties, apnea, risk of aspiration of feeds, diarrhea and vomiting, and growth retardation. This syndrome can develop between 3 days and 3 weeks after birth and can have a duration of up to several months. The pathway by which clonazepam is metabolised is usually impaired in new borns. If clonazepam is used during pregnancy or breast feeding it is recommended that serum levels of clonazepam are monitored and signs of central nervous system depression and apnea are also monitored for. In many cases non-pharmacological treatments such as relaxation therapy, psychotherapy and avoidance of caffeine can be an effective and safer alternative to use of benzodiazepines for anxiety in pregnant women.[86]
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 rather enhance the effect of GABA at the GABAA receptor by increasing the opening frequency of chloride ion channels which leads to increased inhibitory effects with resultant central nervous system depression.[6] In addition clonazepam decreases the utilization of 5-HT (serotonin) by neurons[87][88] and has been shown to bind tightly to central type benzodiazepine receptors.[89] Because clonazepam is effective in low milligram doses (0.5 mg clonazepam = 5 mg diazepam), it is said to be among the class of "highly potent" benzodiazepines.[90] The anticonvulsant properties of benzodiazepines are due to enhancement of synaptic GABA responses and inhibition of sustained high frequency repetitive firing.[91]
Benzodiazepines, including clonazepam, bind to mouse glial cell membranes with high affinity.[92][93] Clonazepam decreases release of acetylcholine in cat brain [94] and decreases prolactin release in rats.[95] Benzodiazepines inhibit cold-induced thyroid stimulating hormone (also known as TSH or thyrotropin) release.[96] 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.[97]
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.[98][99] Benzodiazepines, however, do not have any effect on the levels of GABA in the brain.[100] 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.[101] 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.[102]
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.[103] It has an elimination half-life of 19–60 hours.[6] 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.[104]
Clonazepam passes rapidly into the central nervous system, with levels in the brain corresponding with levels of unbound clonazepam in the blood serum.[105] Clonazepam plasma levels are very unreliable amongst patients. Plasma levels of clonazepam can vary as much as tenfold between different patients.[106]
Clonazepam is largely bound to plasma proteins.[107] Clonazepam passes through the blood–brain barrier easily, with blood and brain levels corresponding equally with each other.[108] The metabolites of clonazepam include 7-aminoclonazepam, 7-acetaminoclonazepam and 3-hydroxy clonazepam.[109][110]
An individual who has consumed too much clonazepam may display one or more of the following symptoms:
Coma can be cyclic, with the individual alternating from a comatose state to a hyperalert state of consciousness, as occurred in a 4-year-old boy who suffered an overdose of clonazepam.[111] The combination of clonazepam and certain barbiturates e.g. amobarbital at prescribed doses has resulted in a synergistic potentiation of the effects of each drug leading to serious respiratory depression.[112]
Overdose symptoms may include extreme drowsiness, confusion, muscle weakness, and fainting.[113]
Clonazepam and 7-aminoclonazepam may be quantified in plasma, serum or whole blood in order to monitor compliance in those receiving the drug therapeutically, to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage. Both the parent drug and 7-aminoclonazepam are unstable in biofluids, and therefore specimens should be preserved with sodium fluoride, stored at the lowest possible temperature and analyzed quickly to minimize losses.[114]
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.[115]
Clonazepam, 5-(2-chlorphenyl)-1,3-dihydro-7-nitro-2H-1,4-benzodiazepine-2-one, is synthesized by following a standard scheme of making derivatives of 1,4-benzodiazepines, with the exception that the acceptor nitro group (in this example) on C7 of the benzodiazepine system is introduced at the last stage of synthesis. The synthesis of clonazepam begins with 2-chloro-2′-nitrobenzophenone, which is reduced to 2-chloro-2'-aminobenzophenone by hydrogen over Raney nickel. The amino derivative is amidated by 2-bromoacetyl bromide to give the bromacetamide and is further converted into aminoacetamide upon reaction with ammonia. Upon reaction of this with pyridine, it is cycled into 5-(2-chlorophenyl)-2,3-dihydro-1H-1,4-benzodiazepine-2-one. The nitration of the resulting product in mild conditions (potassium nitrate in sulfuric acid) results in clonazepam.
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