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Systematic (IUPAC) name
6-(2-chlorophenyl)- 9-nitro- 2,5-diazabicyclo [5.4.0] undeca- 5,8,10,12- tetraen- 3-one
CAS number 1622-61-3
ATC code N03AE01
PubChem 2802
DrugBank APRD00054
ChemSpider 2700
Chemical data
Formula C15H10ClN3O3 
Mol. mass 315.715
Pharmacokinetic data
Bioavailability 90%
Protein binding ~85%
Metabolism Hepatic CYP3A4
Half life 18–50 hours
Excretion Renal
Therapeutic considerations
Pregnancy cat.


Legal status

Schedule IV(US)

Routes Oral, I.M., I.V, sublingual

Clonazepam is a benzodiazepine derivative with highly potent anticonvulsant, muscle relaxant and anxiolytic properties.[1] It is marketed by Roche under the trade-names Klonopin in the United States, Ravotril in Chile and Rivotril in various other English speaking countries.[2] Clonazepam is a chlorinated derivative of nitrazepam[3] and a nitrobenzodiazepine like nitrazepam.[4] Clonazepam is the second most abused benzodiazepine in the United States.[5]


[edit] Pharmacology

Clonazepam's primary mechanism of action is via modulating GABA function in the brain, via the benzodiazepine receptor which in turn leads to enhanced GABAergic inhibition of neuronal firing. In addition clonazepam decreases the utilization of 5-HT (serotonin) by neurons[6][7] and has been shown to bind tightly to central type benzodiazepine receptors.[8] Because of its strong anxiolytic, anticonvulsant and euphoric properties, it is said to be among the class of "highly potent" benzodiazepines.[9] The anticonvulsant properties of benzodiazepines are due to enhancement of synaptic GABA responses and inhibition of sustained high frequency repetitive firing.[10]

Benzodiazepines, including clonazepam, bind to mouse glial cell membranes with high affinity.[11][12] Clonazepam decreases release of acetylcholine in cat brain [13] and decreases prolactin release in rats.[14] Benzodiazepines inhibit cold-induced thyroid stimulating hormone (also known as TSH or thyrotropin) release.[15] 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.[16]

[edit] 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.[17][18] Benzodiazepines, however, do not have any effect on the levels of GABA in the brain.[19] 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. [20] 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.[21]

[edit] Pharmacokinetics

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.[22]

Clonazepam passes rapidly into the central nervous system with levels in the brain corresponding with levels of unbound clonazepam in the blood serum.[23] Clonazepam plasma levels are very unreliable amongst patients. Plasma levels of clonazepam can vary as much as tenfold between different patients.[24]

Clonazepam is largely bound to plasma proteins.[25] Clonazepam passes through the blood brain barrier easily with blood and brain levels corresponding equally with each other. The elimination half life of clonazepam is between 20 - 80 hours. Clonazepam does not produce any pharmacologically active metabolites.[26] The metabolites of clonazepam include 7-aminoclonazepam, 7-acetaminoclonazepam and 3-hydroxy clonazepam.[27][28]

[edit] Tolerance and withdrawal

Like all benzodiazepines, clonazepam is a benzodiazepine receptor agonist.[29][30]


Tolerance to the anticonvulsant effects of clonazepam occurs in both animals and humans. In humans tolerance to the anticonvulsant effects of clonazepam occurs frequently.[31][32] Chronic use of benzodiazepines leads to the development of tolerance with a decrease of benzodiazepine binding sites. Clonazepam has also been shown to produce effects of miosis, or "pinpointing" of the pupil. The degree of tolerance is more pronounced with clonazepam than with chlordiazepoxide.[33] Short term therapy is generally more effective than long term therapy with clonazepam for the treatment of epilepsy.[34] 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.[35]


Discontinuation of or reduction in dosage after regular use may result in the clonazepam withdrawal syndrome.[36] 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.[37][38] Sudden withdrawal from clonazepam may also 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.[39] 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.[40]

[edit] Indications

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.[45]

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.[46]

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.[47]

Clonazepam has been found to generally be ineffective in the control of infantile spasms.[48] 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.[49]

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 dose limiting side effects, especially its negative effect on cognition.

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.[50]

[edit] Availability

Klonopin 0.5 mg
Klonopin 1 mg
Box of Rivotril 2mg tablets

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.).

[edit] Side effects

  • Drowsiness
  • Impairment of cognition and judgment
  • Irritability and aggression[51]
  • Psychomotor agitation[52]
  • Lack of motivation[53]
  • Loss of libido
  • Impaired motor function
    • Impaired coordination
    • Impaired balance
    • Dizziness
  • Cognitive Impairments
    • Increased Sleepwalking (If used in treatment of sleepwalking)
    • Auditory Hallucinations
    • Short-term memory loss
    • 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.
  • Anxiety, irritability, insomnia
  • Panic attacks, tremor
  • Seizures[70] 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 serious side effects may develop such as interference with cognitive functions and behaviour.[71] 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.[72] 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.

[edit] 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. Of anticonvulsant drugs behavioural disturbances occur most frequently with clonazepam and phenobarbital.[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 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.[77]

[edit] Interactions

Clonazepam decreases the levels of carbamazepine,[78][79] and likewise its level is reduced by carbamazepine.[80] Clonazepam may affect levels of phenytoin (diphenylhydantoin) by decreasing,[78][81] or increasing.[82][83] 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.[84] Clonazepam increases the levels of primidone,[82] and phenobarbital.[85]

[edit] Warnings

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 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.

[edit] 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 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.[86][87]

[edit] Overdose

An individual who has consumed too much clonazepam may 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 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.[88] The combination of clonazepam and certain barbiturates eg amobarbital at prescribed doses has resulted in a synergistic potentiation of the effects of each drug leading to serious respiratory depression.[89]

[edit] See also

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