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Clonazepam

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Clonazepam chemical structure
Clonazepam

6-(2-chlorophenyl)-9-nitro-2,5-diazabicyclo[5.4.0]undeca-5,8,10,12-tetraen-3-one
IUPAC name
CAS number
1622-61-3
ATC code

N03AE01

PubChem
2802
DrugBank
APRD00054
Chemical formula {{{chemical_formula}}}
Molecular weight 315.715
Bioavailability 90%
Metabolism Hepatic CYP3A4
Elimination half-life 18–50 hours
Excretion Renal
Pregnancy category
Legal status
Routes of administration Oral, I.M., I.V, sublingual

Clonazepam (marketed by Roche under the trade-names Klonopin in the United States and Rivotril or Rivatril in Europe, South America, Canada, India, and Australia) is a drug which is a benzodiazepine derivative. It is a highly potent anticonvulsant and anxiolytic.[1] Clonazepam, also known as 5-(2-chlorphenyl)-1, 3-dihydro-7-nitro-2H-1, 4benzodiazepin-2-one, or as 6-(2-chlorophenyl)-9-nitro-2, 5-diazabicyclo[5.4.0]undeca-5, 8,10,12-tetraen-3-one (IUPAC name), is structurally related to nitrazepam.[2]

PharmacologyEdit

Clonazepam is a chlorinated derivative of nitrazepam.[3] Clonazepam is classed as a nitrobenzodiazepine along with nitrazepam and flunitrazepam.[4] 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.[5][6] Benzodiazepines, including clonazepam, bind to glial cell membranes with high affinity.[7][8]

Clonazepam decreases levels of acetylcholine[9] and decreases prolactin release.[10] Clonazepam is chemically related to quinazolines and is a hapten.[11] Clonazepam induces melanogenesis in melanoma cells via binding to high affinity sites and modulating cell differentiation.[12]

One milligram of clonazepam is approximately equivalent to twenty milligrams of diazepam.[13] Because of its powerful anxiolytic properties, it is said to be among the class of "highly potent" benzodiazepines. Although benzodiazepines are invaluable 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 over rapidly in certain individuals. Caution is advised when taking this or any benzodiazepine medication longer than a few weeks.

Clonazepam appears to also have a secondary effect on the neurotransmitter serotonin.[14] 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.[15] 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.

Mechanism of actionEdit

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.[16] Benzodiazepines, however, do not have any effect on the levels of GABA in the brain.[17]

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.[18] Benzodiazepine drugs including clonazepam increase the inhibitory processes in the cerebral cortex.[19]

PharmacokineticsEdit

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.[20]

Clonazepam passes rapidly into the central nervous system with levels in the brain corresponding with levels of unbound clonazepam in the blood serum.[21] Clonazepam plasma levels are very unreliable amongst patients. Plasma levels of clonazepam can vary as much as 10 fold between different patients.[22]

Clonazepam is largely bound to plasma proteins.[23] Clonazepam is broken down and metabolised to a benzophenone compound.[24] The metabolites of clonazepam include 7-aminoclonazepam, 7-acetaminoclonazepam, 2-amino-2'-chloro-5-nitrobenzophenone and 2,5-diamino-2'-chlorobenzophenone and 3-hydroxy clonazepam.[25][26]

Tolerance and withdrawalEdit

Tolerance

In humans tolerance to the anticonvulsant effects of clonazepam occurs frequently.[27] 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.[28] Short term therapy is generally more effective than long term therapy with clonazepam for the treatment of epilepsy.[29] 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.[30]

Withdrawal

Sudden withdrawal from clonazepam may 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.[31]

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.[32]

IndicationsEdit

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.[33] 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.[34] 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.[35][36]

Clonazepam may be prescribed for:

In the treatment of acute epilepsy via intravenous administration approximately 72.5 per cent of patients show improved EEG patterns, 17.5 per cent show no improvement and for 10 per cent of patients clonazepam has a paradoxical effect and worsens EEG readings.[39]

Clonazepam is rarely used as a treatment for insomnia. It has not been marketed for the treatment of insomnia mainly because its long half life makes it unsuitable for this application.

AvailabilityEdit

File:Klonopin0.5mg.jpg
File:Klonopin1mg.jpg
File:Clonazepam1mg.png
File: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 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.).

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.

Side effectsEdit

Common
  • Nausea
  • Drowsiness
  • Impairment of cognition and judgment
  • Irritability and aggression[40]
  • Psychomotor agitation[41]
  • Impaired motor function
    • Impaired coordination
    • Impaired balance
    • Dizziness
  • Anterograde amnesia (common with higher doses)
  • 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.
Occasional
Rare
  • Psychosis[48]
  • Incontinence[49]
  • Paradoxical disinhibition[50] (most frequently in children, the elderly, and in persons with developmental disabilities)
    • Rage
    • Excitement
    • Impulsivity
Withdrawal-related
  • Anxiety, irritability, insomnia
  • Panic attacks, tremor
  • Seizures[51] 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.[52] 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 precautionsEdit

Caution in the Elderly. Increased risk of impairments, falls and drug accumulation.[How to reference and link to summary or text]

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.[53]

Caution using high dosages of clonazepam. Doses higher than 0.5 - 1 mg per day is associated with significant sedation.[54]

Clonazepam may aggravate hepatic porphyria.[55][56]

Caution in schizophrenia. Clonazepam has been found to be not effective in the management of schizophrenia and has been found to increase the risk of violent behavior.[57]

InteractionsEdit

Clonazepam decreases the levels of carbamazepine,[58] and likewise be reduced in its levels by carbamazepine.[59] Clonazepam may affect levels of phenytoin (diphenylhydantoin) by decreasing,[58] or increasing.[60][61] 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 per cent.[62] Clonazepam increases the levels of primidone,[60] and phenobarbital.[63] Cannabidiol a drug with anticonvulsant properties, reduces the anticonvulsant protency of clonazepam.[64]

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.[65]

WarningsEdit

Clonazepam, like many other benzodiazepines, may impair one's ability to drive or operate heavy machinery. The central nervous system depressing effects of the drug can be augmented 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 avoid withdrawal or rebound symptoms.

Protracted withdrawalEdit

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.[66] Common protracted withdrawal symptoms include:[67]

  • Anxiety
  • Insomnia
  • Depression
  • Tinnitus
  • Tingling and numbness in limbs
  • Muscle pain and tension
  • Weakness
  • Cramps
  • Tremors
  • Irritable bowel
  • Cognitive dysfunction

However, in 1993 the New England Journal of Medicine reported there is no reliable evidence to support the existence of a persistent benzodiazepine withdrawal syndrome, and this alleged syndrome has been described only in anecdotal reports, with patients typically reporting "withdrawal" symptoms not present during or before benzodiazepine treatment that persist for many months or years after treatment is stopped. Experimental neuropharmacologic studies document that all the side effects of benzodiazepines, whether behavioral or neurochemical, disappear within several days or weeks after the drug is eliminated. The weight of evidence indicates that any new symptoms that persist for more than two months after the last dose of a benzodiazepine either are part of the premorbid condition or have appeared by coincidence or as a consequence of the natural history of the underlying illness. [68]

PregnancyEdit

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 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.[69]

OverdoseEdit

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

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

Coma may 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.[70]

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). In epileptic patients medicated with benzodiazepines, including clonazepam, flumazenil should not be given, however, even in a benzodiazepine overdose, since it may precipitate status epilepticus. Instead, intubation, controlled or supported ventilation and circulatory support within intensive care is indicated in epileptics overdosed by benzodiazepines. Flumazenil should only be considered as a last resort and administered very slowly, fractionally, after an evaluation by a neurologist, specialised in epilepsy, possibly under continuous EEG-monitoring in order to record possible early signs of a seizure.

Recreational use and abuseEdit

Relatively few cases of addiction arise from legitimate use of benzodiazepines.[71] Despite its classification as a high-potency benzodiazepine, clonazepam is not commonly encountered on the black market. Its unique pharmacological profile seems to provide effective anxiolysis without inducing a significant euphoria, unlike the much more commonly abused alprazolam.

When clonazepam is obtained by drug users, it is 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.[How to reference and link to summary or text] It is important to note, however, that addiction and physical dependence are distinct conditions.[71]

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