Clonazepam is a benzodiazepine and anti-convulsant used in the treatment of seizures and panic disorder. It is marketed by Roche under the trade -names Klonopin in the US, Ravotril in Chile and Rivotril in various other English speaking countries. Clonazepam is a chlorinated derivative of nitrazepam and a nitrobenzodiazepine like nitrazepam. Clonazepam is the second most abused benzodiazepine in the US. 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 and has been shown to bind tightly to central type benzodiazepine receptors. Because of its strong anxiolytic, anticonvulsant and euphoric properties, it is said to be among the class of “highly potent” benzodiazepines. The anticonvulsant properties of benzodiazepines are due to enhancement of synaptic GABA responses and inhibition of sustained high frequency repetitive firing.
Benzodiazepines, including clonazepam, bind to mouse glial cell membranes with high affinity. Clonazepam decreases release of acetylcholine in cat brain and decreases prolactin release in rats. Benzodiazepines inhibit cold-induced thyroid stimulating hormone (also known as TSH or thyrotropin) release. 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 forhigh-dose effects on seizures in the study.
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 transmissionacross the central nervous system. Benzodiazepines, however, do not have any effect on the levels of GABA in the brain. 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. 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.
Clonazepam may be prescribed for the following:
·Initial treatment of mania or acute psychosis together with firstline drugs such as lithium, haloperidol or risperidone
·Many forms of parasomnia are sometimes treated with clonazepam. Restless legs syndrome can be treated using clonazepam as a third line treatment option as the use of clonazepam is still investigational. Bruxism also responds to clonazepam in the short -term. Rapid eye movement behavior disorder responds well to low doses of clonazepam.
·The treatment of acute and chronic akathisia induced by neuroleptics also called antipsychotics.
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.
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.
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.
In general, clonazepam has been found to be ineffective in the control of infantile spasms.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. Furthermore, clonazepam is not recommended for widespread use in the management of seizures related to West syndrome.
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.
·Interference with cognitive and motor performance
·Irritability and aggression
·Lack of motivation
·Loss of libido
·Impaired motor function
·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. While benzodiazepines induce sleep, they tend to produce a poorer quality sleep than natural sleep. Benzodiazepines such as clonazepam suppress REM sleep. After regular use rebound insomnia can occur when discontinuing clonazepam.
Benzodiazepines can cause or worsen depression
·Serious psychological and psychiatric side-effects
·Induction of seizures or increased frequency of seizures
·Paradoxical behavioural disinhibition (most frequently in children , the elderly, and in persons with developmental disabilities)
·Worsening of seizures
Long term effects
The long term effects of clonazepam can include depression, disinhibition and sexual dysfunction. Long-term use of benzodiazepines is also associated with cognitive impairments that can persist for at least 6 months post-withdrawal, but it is unclear whether these impairments take more than six months to abate of if they are permanent. Benzodiazepines may cause or worsen depression.
·Anxiety, irritability, insomnia
·Panic attacks, tremor
·Seizures 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. 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 – physiologicaldependence was demonstrated via flumazenil-precipitated withdrawal. 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.
An individual who has consumed too much clonazepam may display one or more of the following symptoms:
·Somnolence (difficulty staying awake)
·Impaired motor functions
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. 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.
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.