Clonazepam

Clonazepam
Systematic (IUPAC) name
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 YesY
ATC code N03AE01
PubChem CID 2802
DrugBank APRD00054
ChemSpider 2700 YesY
UNII 5PE9FDE8GB YesY
KEGG D00280 YesY
ChEBI CHEBI:3756 YesY
ChEMBL CHEMBL452 YesY
Chemical data
Formula C15H10ClN3O3 
Mol. mass 315.715
SMILES eMolecules & PubChem
 N(what is this?)  (verify)

Clonazepam is a benzodiazepine drug having anxiolytic, anticonvulsant, muscle relaxant, and hypnotic properties.[1] It is marketed by Roche under the trade name Klonopin in the United States and Rivotril in Australia, Brazil, Canada 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 half-life of 18–50 hours, making it generally considered to be among the long-acting benzodiazepines.[2] Clonazepam is a chlorinated derivative of nitrazepam[3] and therefore a chloro-nitrobenzodiazepine.[4]

Benzodiazepines such as clonazepam have a fast onset of action and high effectiveness rate and low toxicity in overdose but have drawbacks due to adverse reactions including paradoxical effects, drowsiness, and cognitive impairment. Cognitive impairments can persist for at least six months after withdrawal of clonazepam; it is unclear whether full recovery of memory functions occurs. 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.[5]

Clonazepam is classified as a high potency benzodiazepine and is sometimes used as a second-line treatment of epilepsy. Clonazepam, like other benzodiazepines, while being a first-line treatment for acute seizures, is not suitable for the long-term treatment of seizures due to the development of tolerance to the anticonvulsant effects. The benzodiazepine clorazepate may be preferred over clonazepam due to a slower onset of tolerance and availability in slow-release formulation to counter fluctuations in blood levels. Clonazepam is also used for the treatment of panic disorder. The pharmacological property of clonazepam as with other benzodiazepines is the enhancement of the neurotransmitter GABA via modulation of the GABAA receptor.[5]

Contents

Medical uses

Clonazepam may be prescribed for the following:

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.[20]

Clonazepam is sometimes used for certain rare childhood epilepsies and for refractory epilepsies; however, long-term prophylactic treatment of epilepsy has considerable limitations, the most notable ones being the loss of antiepileptic effects due to tolerance, which renders the drug ineffective with long term use which is why clonazepam and benzodiazepines as a class are, in general, to be prescribed only for the acute management of epilepsies. However, a subgroup of people with treatment resistant epilepsy may benefit from long-term use of clonazepam; the benzodiazepine clorazepate may be preferred however, due to its slower onset of tolerance.[5]

Clonazepam or diazepam 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.[21]

In general, clonazepam has been found to be ineffective in the control of infantile spasms.[22] 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 epilepsies 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. Furthermore, clonazepam is not recommended for widespread use in the management of seizures related to West syndrome.[23]

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.[24]

Formulations

Klonopin 0.5 mg.
Klonopin 1 mg.
Clonazepam2mg DOJ.jpg

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.

Side effects

Very common

  • Drowsiness[25]
  • Interference with cognitive and motor performance
  • Euphoria

Less common

  • Irritability and aggression[26]
  • Psychomotor agitation[27]
  • Lack of motivation[28]
  • Loss of libido
  • Impaired motor function
    • Impaired coordination
    • Impaired balance
    • Dizziness
  • Cognitive impairments[29]
  • 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.
  • The "hangover effect" some experience not only results from clonazepam's considerably long half-life. Like many other benzodiazepines, when taken as a sleep-aid, clonazepam disrupts or interferes with the brain's delta waves. Delta waves signify the brain's slowest waves (~4 Hz) and occur during Stage 4 sleep, which represents humans' deepest sleep state (our muscles are the most relaxed; breathing slows and becomes shallow), and the stage right before R.E.M. sleep and dreaming (Stage 5). Therefore, upon waking, this disruption of Stage 4 delta wave sleep causes a failure for an adequate brain/body rest or "recharge".

[33][34] While benzodiazepines induce sleep, they tend to produce a poorer quality sleep than natural sleep. Benzodiazepines such as clonazepam suppress REM sleep.[35] After regular use rebound insomnia can occur when discontinuing clonazepam.[36]

  • Benzodiazepines may cause or worsen depression.[5]

Occasional

Rare

  • Psychosis[46]
  • Incontinence[47][48][49]
  • Liver damage[50]
  • Paradoxical behavioural disinhibition[5][51] (most frequently in children, the elderly, and in persons with developmental disabilities)
    • Rage
    • Excitement
    • Impulsivity
    • Worsening of seizures

Long term effects

The long term effects of clonazepam can include depression, disinhibition, and sexual dysfunction.[52] 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.[5]

Withdrawal-related

  • Anxiety, irritability, insomnia
  • Panic attacks, tremor
  • Seizures[53] similar to delirium tremens (with long-term use of excessive doses)

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.[54] 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.[55] 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.

Tolerance and withdrawal

Like all benzodiazepines, clonazepam is a benzodiazepine receptor agonist.[56][57] 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.[5]

Tolerance

Tolerance to the anticonvulsant effects of clonazepam occurs in both animals and humans. In humans, tolerance to the anticonvulsant effects of clonazepam occurs frequently.[58][59] 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.[60] In general, short-term therapy is more effective than long-term therapy with clonazepam for the treatment of epilepsy.[61] 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.[62]

Withdrawal

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.[63][64][65] 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.[44] 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.[66]

Special precautions

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.[5]

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.[67] Clonazepam is generally not recommended for use in elderly people for insomnia due to its high potency relative to other benzodiazepines.[68]

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.[67][69]

Caution using high dosages of clonazepam. Doses higher than 0.5 – 1 mg per day are associated with significant sedation.[70]

Clonazepam may aggravate hepatic porphyria.[71][72]

Caution in chronic schizophrenia. A 1982 double blinded placebo controlled study found clonazepam increases violent behavior in individuals with chronic schizophrenia.[73]

Interactions

Clonazepam decreases the levels of carbamazepine,[74][75] and likewise clonazepam's level is reduced by carbamazepine. Azole antifungals such as ketoconazole may inhibit the metabolism of clonazepam.[5] Clonazepam may affect levels of phenytoin (diphenylhydantoin) by decreasing,[74][76] or increasing.[77][78] 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%.[79] Clonazepam increases the levels of primidone,[77] and phenobarbital.[80]

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.[5]

Warnings

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.

Pregnancy

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.[81]

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.[82]

Pharmacology

Clonazepam's primary mechanism of action is via modulating GABA function in the brain, via 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.[5] In addition clonazepam decreases the utilization of 5-HT (serotonin) by neurons[83][84] and has been shown to bind tightly to central type benzodiazepine receptors.[85] 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.[86] The anticonvulsant properties of benzodiazepines are due to enhancement of synaptic GABA responses and inhibition of sustained high frequency repetitive firing.[87]

Benzodiazepines, including clonazepam, bind to mouse glial cell membranes with high affinity.[88][89] Clonazepam decreases release of acetylcholine in cat brain [90] and decreases prolactin release in rats.[91] Benzodiazepines inhibit cold-induced thyroid stimulating hormone (also known as TSH or thyrotropin) release.[92] 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.[93]

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.[94][95] Benzodiazepines, however, do not have any effect on the levels of GABA in the brain.[96] 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.[97] 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.[98]

Pharmacokinetics

Clonazepam is lipid soluble, and rapidly crosses the blood-brain barrier and penetrates the placenta and into breast milk. 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 CYP34A and can affect the metabolism of benzodiazepines.[99] It has an elimination half-life of 19–60 hours.[5] 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.[100]

Clonazepam passes rapidly into the central nervous system, with levels in the brain corresponding with levels of unbound clonazepam in the blood serum.[101] Clonazepam plasma levels are very unreliable amongst patients. Plasma levels of clonazepam can vary as much as tenfold between different patients.[102]

Clonazepam is largely bound to plasma proteins.[103] Clonazepam passes through the blood-brain barrier easily, with blood and brain levels corresponding equally with each other.[104] The metabolites of clonazepam include 7-aminoclonazepam, 7-acetaminoclonazepam and 3-hydroxy clonazepam.[105][106]

Overdose

An individual who has consumed too much clonazepam may display one or more of the following symptoms:

  • Somnolence (difficulty staying awake)
  • Mental confusion
  • Nausea
  • Impaired motor functions
    • Impaired reflexes
    • Impaired coordination
    • Impaired balance
    • Dizziness
  • Respiratory depression
  • Hypotension
  • Coma

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.[107] 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.[108]

Overdose symptoms may include extreme drowsiness, confusion, muscle weakness, and fainting.[109]

Detection in biological fluids

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.[110]

Recreational use

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.[111]

Chemistry

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.

Clonazepam synthesis.png

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  • clonazepam — noun Etymology: chlor + phenyl + azepam (as in diazepam) Date: 1970 a benzodiazepine C15H10ClN303 used especially as an anticonvulsant in the treatment of epilepsy …   New Collegiate Dictionary

  • clonazepam — /kloh nay zeuh pam /, n. Pharm. a benzodiazepine, C15H10ClN3O3, used in the control of certain epilepsies. [c(h)lo(rophe)n(yl) + (di)azep(in), extracted from the chemical name + am, of uncert. derivation] * * * …   Universalium

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