Clonazepam
Encyclopedia
Clonazepamis a benzodiazepine
drug having anxiolytic
, anticonvulsant
, muscle relaxant
, and hypnotic
properties. It is marketed by Roche
under the trade name Klonopin in the United States and Rivotril in Australia, Brazil, Canada and Europe(and in countries like Serbia, Macedonia, Croatia and Montenegro). Other names such as Ravotril, Rivatril, Clonex, Paxam, or Kriadex are known throughout the rest of the world. Clonazepam has an unusually long half-life
of 18–50 hours, making it generally considered to be among the long-acting benzodiazepines. Clonazepam is a chlorinated
derivative of nitrazepam
and therefore a chloro-nitrobenzodiazepine.
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.
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.
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 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.
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.
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.
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.
, and sexual dysfunction
. 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.
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 — physiological dependence 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.
. 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.
. In general, short-term therapy is more effective than long-term therapy with clonazepam for the treatment of epilepsy. 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.
, causing psychosis characterised by dysphoric manifestations, irritability, aggressiveness, anxiety, and hallucinations. 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. 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.
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. Clonazepam is generally not recommended for use in elderly people for insomnia due to its high potency relative to other benzodiazepines.
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
.
Caution using high dosages of clonazepam. Doses higher than 0.5 – 1 mg per day are associated with significant sedation.
Clonazepam may aggravate hepatic porphyria
.
Caution in chronic schizophrenia
. A 1982 double blinded placebo controlled study found clonazepam increases violent behavior in individuals with chronic schizophrenia.
, and likewise clonazepam's level is reduced by carbamazepine. Azole antifungals such as ketoconazole
may inhibit the metabolism of clonazepam. Clonazepam may affect levels of phenytoin
(diphenylhydantoin) by decreasing, or increasing. 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%.
Clonazepam increases the levels of primidone
, and phenobarbital
.
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.
, apnoeic spells, cyanosis
and impaired metabolic responses to cold stress.
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.
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. 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 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.
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 for high-dose effects on seizures in the study.
. 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.
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.
It has an elimination half-life of 19–60 hours. 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.
Clonazepam passes rapidly into the central nervous system, with levels in the brain corresponding with levels of unbound clonazepam in the blood serum. Clonazepam plasma levels are very unreliable amongst patients. Plasma levels of clonazepam can vary as much as tenfold between different patients.
Clonazepam is largely bound to plasma proteins. Clonazepam passes through the blood-brain barrier easily, with blood and brain levels corresponding equally with each other. The metabolites of clonazepam include 7-aminoclonazepam, 7-acetaminoclonazepam and 3-hydroxy clonazepam.
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 e.g. amobarbital
at prescribed doses has resulted in a synergistic potentiation of the effects of each drug leading to serious respiratory depression.
Overdose symptoms may include extreme drowsiness, confusion, muscle weakness, and fainting.
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.
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.
Clonazepamis a benzodiazepine
drug having anxiolytic
, anticonvulsant
, muscle relaxant
, and hypnotic
properties. It is marketed by Roche
under the trade name Klonopin in the United States and Rivotril in Australia, Brazil, Canada and Europe(and in countries like Serbia, Macedonia, Croatia and Montenegro). Other names such as Ravotril, Rivatril, Clonex, Paxam, or Kriadex are known throughout the rest of the world. Clonazepam has an unusually long half-life
of 18–50 hours, making it generally considered to be among the long-acting benzodiazepines. Clonazepam is a chlorinated
derivative of nitrazepam
and therefore a chloro-nitrobenzodiazepine.
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.
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.
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 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.
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.
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.
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.
, and sexual dysfunction
. 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.
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 — physiological dependence 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.
. 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.
. In general, short-term therapy is more effective than long-term therapy with clonazepam for the treatment of epilepsy. 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.
, causing psychosis characterised by dysphoric manifestations, irritability, aggressiveness, anxiety, and hallucinations. 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. 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.
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. Clonazepam is generally not recommended for use in elderly people for insomnia due to its high potency relative to other benzodiazepines.
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
.
Caution using high dosages of clonazepam. Doses higher than 0.5 – 1 mg per day are associated with significant sedation.
Clonazepam may aggravate hepatic porphyria
.
Caution in chronic schizophrenia
. A 1982 double blinded placebo controlled study found clonazepam increases violent behavior in individuals with chronic schizophrenia.
, and likewise clonazepam's level is reduced by carbamazepine. Azole antifungals such as ketoconazole
may inhibit the metabolism of clonazepam. Clonazepam may affect levels of phenytoin
(diphenylhydantoin) by decreasing, or increasing. 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%.
Clonazepam increases the levels of primidone
, and phenobarbital
.
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.
, apnoeic spells, cyanosis
and impaired metabolic responses to cold stress.
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.
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. 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 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.
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 for high-dose effects on seizures in the study.
. 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.
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.
It has an elimination half-life of 19–60 hours. 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.
Clonazepam passes rapidly into the central nervous system, with levels in the brain corresponding with levels of unbound clonazepam in the blood serum. Clonazepam plasma levels are very unreliable amongst patients. Plasma levels of clonazepam can vary as much as tenfold between different patients.
Clonazepam is largely bound to plasma proteins. Clonazepam passes through the blood-brain barrier easily, with blood and brain levels corresponding equally with each other. The metabolites of clonazepam include 7-aminoclonazepam, 7-acetaminoclonazepam and 3-hydroxy clonazepam.
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 e.g. amobarbital
at prescribed doses has resulted in a synergistic potentiation of the effects of each drug leading to serious respiratory depression.
Overdose symptoms may include extreme drowsiness, confusion, muscle weakness, and fainting.
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.
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.
Clonazepamis a benzodiazepine
drug having anxiolytic
, anticonvulsant
, muscle relaxant
, and hypnotic
properties. It is marketed by Roche
under the trade name Klonopin in the United States and Rivotril in Australia, Brazil, Canada and Europe(and in countries like Serbia, Macedonia, Croatia and Montenegro). Other names such as Ravotril, Rivatril, Clonex, Paxam, or Kriadex are known throughout the rest of the world. Clonazepam has an unusually long half-life
of 18–50 hours, making it generally considered to be among the long-acting benzodiazepines. Clonazepam is a chlorinated
derivative of nitrazepam
and therefore a chloro-nitrobenzodiazepine.
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.
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.
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 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.
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.
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.
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.
, and sexual dysfunction
. 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.
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 — physiological dependence 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.
. 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.
. In general, short-term therapy is more effective than long-term therapy with clonazepam for the treatment of epilepsy. 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.
, causing psychosis characterised by dysphoric manifestations, irritability, aggressiveness, anxiety, and hallucinations. 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. 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.
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. Clonazepam is generally not recommended for use in elderly people for insomnia due to its high potency relative to other benzodiazepines.
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
.
Caution using high dosages of clonazepam. Doses higher than 0.5 – 1 mg per day are associated with significant sedation.
Clonazepam may aggravate hepatic porphyria
.
Caution in chronic schizophrenia
. A 1982 double blinded placebo controlled study found clonazepam increases violent behavior in individuals with chronic schizophrenia.
, and likewise clonazepam's level is reduced by carbamazepine. Azole antifungals such as ketoconazole
may inhibit the metabolism of clonazepam. Clonazepam may affect levels of phenytoin
(diphenylhydantoin) by decreasing, or increasing. 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%.
Clonazepam increases the levels of primidone
, and phenobarbital
.
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.
, apnoeic spells, cyanosis
and impaired metabolic responses to cold stress.
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.
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. 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 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.
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 for high-dose effects on seizures in the study.
. 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.
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.
It has an elimination half-life of 19–60 hours. 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.
Clonazepam passes rapidly into the central nervous system, with levels in the brain corresponding with levels of unbound clonazepam in the blood serum. Clonazepam plasma levels are very unreliable amongst patients. Plasma levels of clonazepam can vary as much as tenfold between different patients.
Clonazepam is largely bound to plasma proteins. Clonazepam passes through the blood-brain barrier easily, with blood and brain levels corresponding equally with each other. The metabolites of clonazepam include 7-aminoclonazepam, 7-acetaminoclonazepam and 3-hydroxy clonazepam.
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 e.g. amobarbital
at prescribed doses has resulted in a synergistic potentiation of the effects of each drug leading to serious respiratory depression.
Overdose symptoms may include extreme drowsiness, confusion, muscle weakness, and fainting.
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.
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.
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
drug having anxiolytic
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
, anticonvulsant
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
, muscle relaxant
Muscle relaxant
A muscle relaxant is a drug which affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeutic groups: neuromuscular blockers and spasmolytics...
, and hypnotic
Hypnotic
Hypnotic drugs are a class of psychoactives whose primary function is to induce sleep and to be used in the treatment of insomnia and in surgical anesthesia...
properties. It is marketed by Roche
Hoffmann-La Roche
F. Hoffmann-La Roche Ltd. is a Swiss global health-care company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on the SIX Swiss Exchange....
under the trade name Klonopin in the United States and Rivotril in Australia, Brazil, Canada and Europe(and in countries like Serbia, Macedonia, Croatia and Montenegro). Other names such as Ravotril, Rivatril, Clonex, Paxam, or Kriadex are known throughout the rest of the world. Clonazepam has an unusually long half-life
Biological half-life
The biological half-life or elimination half-life of a substance is the time it takes for a substance to lose half of its pharmacologic, physiologic, or radiologic activity, as per the MeSH definition...
of 18–50 hours, making it generally considered to be among the long-acting benzodiazepines. Clonazepam is a chlorinated
Halogenation
Halogenation is a chemical reaction that incorporates a halogen atom into a molecule in substitution of hydrogen atom. Halogenation takes place in the gas phase. There are four types of halogenation: fluorination, chlorination, bromination, and iodination...
derivative of nitrazepam
Nitrazepam
Nitrazepam is a type of benzodiazepine drug and is marketed in English-speaking countries under the following brand names: Alodorm, Arem, Insoma, Mogadon, Nitrados, Nitrazadon, Ormodon, Paxadorm, Remnos, and Somnite...
and therefore a chloro-nitrobenzodiazepine.
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
Benzodiazepine dependence
Benzodiazepine dependence or benzodiazepine addiction is a condition during which a person is dependent on benzodiazepine drugs. Dependence can be either a psychological dependence, physical dependence, or a combination of the two...
, and benzodiazepine withdrawal syndrome
Benzodiazepine withdrawal syndrome
Benzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal—is the cluster of symptoms which appear when a person who has taken benzodiazepines long term and has developed benzodiazepine dependence stops taking benzodiazepine drug or during dosage reductions...
, which occurs in a third of people treated with clonazepam for longer than four weeks.
Clonazepam is classified as a high potency benzodiazepine and is sometimes used as a second-line treatment of epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
. 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
Clorazepate
Clorazepate , also known as clorazepate dipotassium, is a drug that is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative, hypnotic and skeletal muscle relaxant properties. Clorazepate is a prodrug for desmethyldiazepam, which is rapidly produced as an active metabolite...
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.
Medical uses
Clonazepam may be prescribed for the following:- EpilepsyEpilepsyEpilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
- Anxiety disorderAnxiety disorderAnxiety disorder is a blanket term covering several different forms of abnormal and pathological fear and anxiety. Conditions now considered anxiety disorders only came under the aegis of psychiatry at the end of the 19th century. Gelder, Mayou & Geddes explains that anxiety disorders are...
s - Panic disorderPanic disorderPanic disorder is an anxiety disorder characterized by recurring severe panic attacks. It may also include significant behavioral change lasting at least a month and of ongoing worry about the implications or concern about having other attacks. The latter are called anticipatory attacks...
- Initial treatment of maniaManiaMania, the presence of which is a criterion for certain psychiatric diagnoses, is a state of abnormally elevated or irritable mood, arousal, and/ or energy levels. In a sense, it is the opposite of depression...
or acute psychosis together with firstline drugs such as lithiumLithium pharmacologyLithium pharmacology refers to use of the lithium ion, Li+, as a drug. A number of chemical salts of lithium are used medically as a mood stabilizing drug, primarily in the treatment of bipolar disorder, where they have a role in the treatment of depression and particularly of mania, both acutely...
, haloperidolHaloperidolHaloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines....
or risperidoneRisperidoneRisperidone is a second generation or atypical antipsychotic, sold under the trade name . It is used to treat schizophrenia , schizoaffective disorder, the mixed and manic states associated with bipolar disorder, and irritability in people with autism... - For the management of the visual effects of HPPD
- HyperekplexiaHyperekplexiaHyperekplexia is a neurologic disorder classically characterised by pronounced startle responses to tactile or acoustic stimuli and hypertonia. The hypertonia may be predominantly truncal, attenuated during sleep and less prominent after a year of age...
- Many forms of parasomniaParasomniaFor the 2008 horror film, see Parasomnia Parasomnias are a category of sleep disorders that involve abnormal and unnatural movements, behaviors, emotions, perceptions, and dreams that occur while falling asleep, sleeping, between sleep stages, or during arousal from sleep...
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. BruxismBruxismBruxism is characterized by the grinding of the teeth and typically includes the clenching of the jaw. It is an oral parafunctional activity that occurs in most humans at some time in their lives. In most people, bruxism is mild enough not to be a health problem...
also responds to clonazepam in the short-term Rapid eye movement behavior disorderRapid eye movement behavior disorderRapid eye movement sleep behaviour disorder is a sleep disorder that involves abnormal behaviour during the sleep phase with rapid eye movement . It was first described in 1986....
responds well to low doses of clonazepam. - The treatment of acute and chronic akathisiaAkathisiaAkathisia, or acathisia, is a syndrome characterized by unpleasant sensations of inner restlessness that manifests itself with an inability to sit still or remain motionless...
induced by neuroleptics also called antipsychotics. - SpasticitySpasticitySpasticity is a feature of altered skeletal muscle performance in muscle tone involving hypertonia, which is also referred to as an unusual "tightness" of muscles...
related to amyotrophic lateral sclerosisAmyotrophic lateral sclerosisAmyotrophic lateral sclerosis , also referred to as Lou Gehrig's disease, is a form of motor neuron disease caused by the degeneration of upper and lower neurons, located in the ventral horn of the spinal cord and the cortical neurons that provide their efferent input...
The effectiveness of clonazepam in the short-term treatment of panic disorder
Panic disorder
Panic disorder is an anxiety disorder characterized by recurring severe panic attacks. It may also include significant behavioral change lasting at least a month and of ongoing worry about the implications or concern about having other attacks. The latter are called anticipatory attacks...
has been demonstrated in controlled clinical trials
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
. 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
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
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
Clorazepate
Clorazepate , also known as clorazepate dipotassium, is a drug that is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative, hypnotic and skeletal muscle relaxant properties. Clorazepate is a prodrug for desmethyldiazepam, which is rapidly produced as an active metabolite...
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
Status epilepticus
Status epilepticus is a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures...
. However, the benefits tended to be transient in many of the patients, and the addition of phenytoin
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
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
West syndrome
West syndrome or West's Syndrome is an uncommon to rare epileptic disorder in infants. It is named after the English physician, William James West , who first described it in an article published in The Lancet in 1841. The original case actually described his own son, James Edwin West...
, 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
Hypotonia
Hypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
and drowsiness are troublesome with clonazepam therapy; other antiepileptic agents are, therefore, recommended for long-term therapy, possibly Corticotropin (ACTH) or vigabatrin
Vigabatrin
Vigabatrin is an antiepileptic drug that inhibits the catabolism of gamma-aminobutyric acid by irreversibly inhibiting GABA transaminase. It is an analog of GABA, but it is not a receptor agonist...
. 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
Obsessive-compulsive disorder
Obsessive–compulsive disorder is an anxiety disorder characterized by intrusive thoughts that produce uneasiness, apprehension, fear, or worry, by repetitive behaviors aimed at reducing the associated anxiety, or by a combination of such obsessions and compulsions...
and clinical depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
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.
Formulations
Clonazepam was approved in the United States as a generic drug
Generic drug
A generic drug is a drug defined as "a drug product that is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use." It has also been defined as a term referring to any drug marketed under its...
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.
Very common
- Drowsiness
- Interference with cognitive and motor performance
- EuphoriaEuphoriaEuphoria is an emotional and mental state defined as a sense of great elation and well being.Euphoria may also refer to:* Euphoria , a genus of scarab beetles* Euphoria, a genus name previously used for the longan and other trees...
Less common
- Irritability and aggression
- Psychomotor agitationPsychomotor agitationPsychomotor agitation is a series of unintentional and purposeless motions that stem from mental tension and anxiety of an individual. This includes pacing around a room, wringing one's hands, pulling off clothing and putting it back on and other similar actions...
- Lack of motivation
- Loss of libido
- Impaired motor function
- Impaired coordination
- Impaired balance
- Dizziness
- Cognitive impairments
- Hallucinations
- Short-term memory loss
- Anterograde amnesiaAnterograde amnesiaAnterograde amnesia is a loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. This is in contrast to retrograde amnesia, where memories...
(common with higher doses)
- Some users report hangoverHangoverA hangover describes the sum of unpleasant physiological effects following heavy consumption of alcoholic beverages. The most commonly reported characteristics of a hangover include headache, nausea, sensitivity to light and noise, lethargy, dysphoria, diarrhea and thirst, typically after the...
-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".
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 may cause or worsen depression.
Occasional
- Serious dysphoriaDysphoriaDysphoria is medically recognized as a mental and emotional condition in which a person experiences intense feelings of depression, discontent and indifference to the world around them.Mood disorders can induce dysphoria, often with a heightened risk of suicide, especially in...
- ThrombocytopeniaThrombocytopeniaThrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
- Serious psychological and psychiatric side-effects
- Induction of seizures or increased frequency of seizures
- Personality changes
- Behavioural disturbances
- ConfusionConFusionConFusion is an annual science fiction convention organized by the Stilyagi Air Corps and its parent organization, the Ann Arbor Science Fiction Association. Commonly, it is held the third weekend of January. It is the oldest science fiction convention in Michigan, a regional, general SF con...
- AtaxiaAtaxiaAtaxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
Rare
- PsychosisPsychosisPsychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
- IncontinenceUrinary incontinenceUrinary incontinence is any involuntary leakage of urine. It is a common and distressing problem, which may have a profound impact on quality of life. Urinary incontinence almost always results from an underlying treatable medical condition but is under-reported to medical practitioners...
- Liver damage
- Paradoxical behavioural disinhibition (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, disinhibitionDisinhibition
Disinhibition is a term in psychology used to describe a lack of restraint manifested in several ways, including disregard for social conventions, impulsivity, and poor risk assessment. Disinhibition affects motor, instinctual, emotional, cognitive and perceptual aspects with signs and symptoms...
, and sexual dysfunction
Sexual dysfunction
Sexual dysfunction or sexual malfunction refers to a difficulty experienced by an individual or a couple during any stage of a normal sexual activity, including desire, arousal or orgasm....
. 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.
Withdrawal-related
- Anxiety, irritability, insomnia, tremors
- Potential to exacerbate existing Panic Disorder upon discontinuation
- Seizures similar to delirium tremensDelirium tremensDelirium tremens is an acute episode of delirium that is usually caused by withdrawal from alcohol, first described in 1813...
(with long-term use of excessive doses)
Benzodiazepines such as clonazepam can be very effective in controlling status epilepticus
Status epilepticus
Status epilepticus is a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures...
, 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
Pharmacotherapy
Pharmacotherapy is the treatment of disease through the administration of drugs. As such, it is considered part of the larger category of therapy....
low-dose benzodiazepine users — physiological dependence was demonstrated via flumazenil
Flumazenil
Flumazenil is a benzodiazepine antagonist available for injection only, and the only benzodiazepine receptor antagonist on the market today.It was first introduced in 1987 by Hoffmann-La Roche under the trade name Anexate, but only approved by...
-precipitated withdrawal.
Use of alcohol or other CNS
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
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 agonistAgonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
. 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
Benzodiazepine withdrawal syndrome
Benzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal—is the cluster of symptoms which appear when a person who has taken benzodiazepines long term and has developed benzodiazepine dependence stops taking benzodiazepine drug or during dosage reductions...
. 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.
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. 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 chlordiazepoxideChlordiazepoxide
Chlordiazepoxide, is a sedative/hypnotic drug and benzodiazepine. It is marketed under the trade names Angirex, Klopoxid, Librax , Libritabs, Librium, Mesural, Multum, Novapam, Risolid, Silibrin, Sonimen and Tropium.Chlordiazepoxide was the first benzodiazepine to be synthesised and...
. In general, short-term therapy is more effective than long-term therapy with clonazepam for the treatment of epilepsy. 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.
Withdrawal
Abrupt or over-rapid withdrawal from clonazepam may result in the development of the benzodiazepine withdrawal syndromeBenzodiazepine withdrawal syndrome
Benzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal—is the cluster of symptoms which appear when a person who has taken benzodiazepines long term and has developed benzodiazepine dependence stops taking benzodiazepine drug or during dosage reductions...
, causing psychosis characterised by dysphoric manifestations, irritability, aggressiveness, anxiety, and hallucinations. Sudden withdrawal may also induce the potentially life threatening condition status epilepticus
Status epilepticus
Status epilepticus is a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures...
. Antiepileptic drugs, benzodiazepines such as clonazepam in particular, should be reduced slowly and gradually when discontinuing the drug to reduce withdrawal effects. Carbamazepine
Carbamazepine
Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
has been trialed in the treatment of clonazepam withdrawal and has been found to be ineffective in preventing clonazepam withdrawal status epilepticus
Status epilepticus
Status epilepticus is a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures...
from occurring.
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.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. Clonazepam is generally not recommended for use in elderly people for insomnia due to its high potency relative to other benzodiazepines.
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
Phenobarbital
Phenobarbital or phenobarbitone is a barbiturate, first marketed as Luminal by Friedr. Bayer et comp. It is the most widely used anticonvulsant worldwide, and the oldest still commonly used. It also has sedative and hypnotic properties but, as with other barbiturates, has been superseded by the...
.
Caution using high dosages of clonazepam. Doses higher than 0.5 – 1 mg per day are associated with significant sedation.
Clonazepam may aggravate hepatic porphyria
Hepatic porphyria
Hepatic porphyrias is a form of porphyria in which the enzyme deficiency occurs in the liver.Examples include :* Acute intermittent porphyria* Porphyria cutanea tarda and Hepatoerythropoietic porphyria...
.
Caution in chronic schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
. A 1982 double blinded placebo controlled study found clonazepam increases violent behavior in individuals with chronic schizophrenia.
Interactions
Clonazepam decreases the levels of carbamazepineCarbamazepine
Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
, and likewise clonazepam's level is reduced by carbamazepine. Azole antifungals such as ketoconazole
Ketoconazole
Ketoconazole is a synthetic antifungal drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet.Ketoconazole is...
may inhibit the metabolism of clonazepam. Clonazepam may affect levels of phenytoin
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
(diphenylhydantoin) by decreasing, or increasing. 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%.
Clonazepam increases the levels of primidone
Primidone
Primidone is an anticonvulsant of the pyrimidinedione class, the active metabolites of which, phenobarbital and phenylethylmalonamide , are also anticonvulsants...
, and phenobarbital
Phenobarbital
Phenobarbital or phenobarbitone is a barbiturate, first marketed as Luminal by Friedr. Bayer et comp. It is the most widely used anticonvulsant worldwide, and the oldest still commonly used. It also has sedative and hypnotic properties but, as with other barbiturates, has been superseded by the...
.
Combined use of clonazepam with certain antidepressants, antiepileptics such as phenobarbital
Phenobarbital
Phenobarbital or phenobarbitone is a barbiturate, first marketed as Luminal by Friedr. Bayer et comp. It is the most widely used anticonvulsant worldwide, and the oldest still commonly used. It also has sedative and hypnotic properties but, as with other barbiturates, has been superseded by the...
, phenytoin
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
and carbamazepine
Carbamazepine
Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
, sedative antihistamines, opiates, antipsychotics and alcohol may result in enhanced sedative effects.
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 hypotoniaHypotonia
Hypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
, apnoeic spells, cyanosis
Cyanosis
Cyanosis is the appearance of a blue or purple coloration of the skin or mucous membranes due to the tissues near the skin surface being low on oxygen. The onset of cyanosis is 2.5 g/dL of deoxyhemoglobin. The bluish color is more readily apparent in those with high hemoglobin counts than it is...
and impaired metabolic responses to cold stress.
The safety profile of clonazepam during pregnancy is less clear than for other benzodiazepines and if benzodiazepines are indicated during pregnancy chlordiazepoxide
Chlordiazepoxide
Chlordiazepoxide, is a sedative/hypnotic drug and benzodiazepine. It is marketed under the trade names Angirex, Klopoxid, Librax , Libritabs, Librium, Mesural, Multum, Novapam, Risolid, Silibrin, Sonimen and Tropium.Chlordiazepoxide was the first benzodiazepine to be synthesised and...
and diazepam
Diazepam
Diazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
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
Fetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
. 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
Abortion
Abortion is defined as the termination of pregnancy by the removal or expulsion from the uterus of a fetus or embryo prior to viability. An abortion can occur spontaneously, in which case it is usually called a miscarriage, or it can be purposely induced...
, malformation, intrauterine growth retardation, functional deficits, floppy infant syndrome, carcinogenesis
Carcinogenesis
Carcinogenesis or oncogenesis is literally the creation of cancer. It is a process by which normal cells are transformed into cancer cells...
and mutagenesis
Mutagenesis
Mutagenesis is a process by which the genetic information of an organism is changed in a stable manner, resulting in a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using laboratory procedures...
. Neonatal withdrawal syndrome associated with benzodiazepines include hypertonia
Hypertonia
Hypertonia a condition marked by an abnormal increase in muscle tension and a reduced ability of a muscle to stretch. It is caused by lesions to upper motor neurons in the central nervous system, which carry information from the central nervous system to the muscles and control posture, muscle...
, hyperreflexia
Hyperreflexia
Hyperreflexia is defined as overactive or overresponsive reflexes. Examples of this can include twitching or spastic tendencies, which are indicative of upper motor neuron disease as well as the lessening or loss of control ordinarily exerted by higher brain centers of lower neural pathways...
, restlessness
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, irritability
Irritability
Irritability is an excessive response to stimuli. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessive sensitivity to stimuli; It is usually used to refer to anger or frustration....
, abnormal sleep patterns, inconsolable crying, tremors or jerking of the extremities, bradycardia
Bradycardia
Bradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...
, cyanosis
Cyanosis
Cyanosis is the appearance of a blue or purple coloration of the skin or mucous membranes due to the tissues near the skin surface being low on oxygen. The onset of cyanosis is 2.5 g/dL of deoxyhemoglobin. The bluish color is more readily apparent in those with high hemoglobin counts than it is...
, suckling difficulties, apnea
Apnea
Apnea, apnoea, or apnœa is a term for suspension of external breathing. During apnea there is no movement of the muscles of respiration and the volume of the lungs initially remains unchanged...
, risk of aspiration of feeds, diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
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
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
depression and apnea
Apnea
Apnea, apnoea, or apnœa is a term for suspension of external breathing. During apnea there is no movement of the muscles of respiration and the volume of the lungs initially remains unchanged...
are also monitored for. In many cases non-pharmacological treatments such as relaxation therapy, psychotherapy and avoidance of caffeine
Caffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
can be an effective and safer alternative to use of benzodiazepines for anxiety in pregnant women.
Pharmacology
Clonazepam's primary mechanism of actionMechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect...
is via modulating GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
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. 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 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.
The anticonvulsant properties of benzodiazepines are due to enhancement of synaptic
Synaptic
Synaptic may refer to:*Synapse, part of the nervous system*Synapsis, the pairing of two homologous chromosomes*Synaptic , a Linux graphical package management program for APT See also...
GABA responses and inhibition of sustained high frequency repetitive firing.
Benzodiazepines, including clonazepam, bind to mouse glial cell
Glial cell
Glial cells, sometimes called neuroglia or simply glia , are non-neuronal cells that maintain homeostasis, form myelin, and provide support and protection for neurons in the brain, and for neurons in other parts of the nervous system such as in the autonomous nervous system...
membranes with high affinity. Clonazepam decreases release of acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
in cat brain and decreases prolactin
Prolactin
Prolactin also known as luteotropic hormone is a protein that in humans is encoded by the PRL gene.Prolactin is a peptide hormone discovered by Henry Friesen...
release in rats. Benzodiazepines inhibit cold-induced thyroid stimulating hormone (also known as TSH
TSH
TSH may refer to:* Tanzanian shilling, the currency of Tanzania* Thyroid-stimulating hormone, a hormone synthesized and secreted by thyrotrope cells* Tshiuetin Rail Transportation, a Canadian railway between Labrador and Quebec...
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 for high-dose effects on seizures in the study.
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 systemCentral nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
. 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
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
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.
Pharmacokinetics
Clonazepam is lipid soluble, and rapidly crosses the blood-brain barrierBlood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
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
CYP2C19
Cytochrome P450 2C19 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. It is involved in the metabolism of several...
and to a lesser extent CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
. Erythromycin
Erythromycin
Erythromycin is a macrolide antibiotic that has an antimicrobial spectrum similar to or slightly wider than that of penicillin, and is often used for people who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma and...
, clarithromycin
Clarithromycin
Clarithromycin is a macrolide antibiotic used to treat pharyngitis, tonsillitis, acute maxillary sinusitis, acute bacterial exacerbation of chronic bronchitis, pneumonia , skin and skin structure infections...
, ritonavir
Ritonavir
Ritonavir, with trade name Norvir , is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS....
, itraconazole
Itraconazole
Itraconazole , invented in 1984, is a triazole antifungal agent that is prescribed to patients with fungal infections. The drug may be given orally or intravenously.-Medical uses:...
, ketoconazole
Ketoconazole
Ketoconazole is a synthetic antifungal drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet.Ketoconazole is...
, nefazodone
Nefazodone
Nefazodone is an antidepressant marketed by Bristol-Myers Squibb. Its sale was discontinued in 2003 in some countries due to the rare incidence of hepatotoxicity , which could lead to the need for a liver transplant, or even death. The incidence of severe liver damage is approximately 1 in every...
, and grapefruit juice are inhibitors of CYP34A and can affect the metabolism of benzodiazepines.
It has an elimination half-life of 19–60 hours. 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.
Clonazepam passes rapidly into the central nervous system, with levels in the brain corresponding with levels of unbound clonazepam in the blood serum. Clonazepam plasma levels are very unreliable amongst patients. Plasma levels of clonazepam can vary as much as tenfold between different patients.
Clonazepam is largely bound to plasma proteins. Clonazepam passes through the blood-brain barrier easily, with blood and brain levels corresponding equally with each other. The metabolites of clonazepam include 7-aminoclonazepam, 7-acetaminoclonazepam and 3-hydroxy clonazepam.
Overdose
An individual who has consumed too much clonazepam may display one or more of the following symptoms:- SomnolenceSomnolenceSomnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
(difficulty staying awake) - Mental confusion
- NauseaNauseaNausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
- Impaired motor functions
- Impaired reflexes
- Impaired coordination
- Impaired balance
- Dizziness
- Respiratory depression
- HypotensionHypotensionIn physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
- ComaComaIn medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...
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 e.g. amobarbital
Amobarbital
Amobarbital is a drug that is a barbiturate derivative. It has sedative-hypnotic and analgesic properties. It is a white crystalline powder with no odor and a slightly bitter taste. It was first synthesized in Germany in 1923...
at prescribed doses has resulted in a synergistic potentiation of the effects of each drug leading to serious respiratory depression.
Overdose symptoms may include extreme drowsiness, confusion, muscle weakness, and fainting.
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.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
Drug abuse
Substance abuse, also known as drug abuse, refers to a maladaptive pattern of use of a substance that is not considered dependent. The term "drug abuse" does not exclude dependency, but is otherwise used in a similar manner in nonmedical contexts...
, accidental or intentional overdose, or adverse reactions resulting from legitimate use of the medication.
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 aminoderivative 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.
- H.L. Newmark, J. Cariss, (1963).
- J.K. Clifton, H.L. Newmark, (1964).
- O. Kller, N. Steiger, N.H. Sternbach, (1964).
- N. Steiger, O. Keller, (1965).
- J.A. Rachlin, A. Focella, (1967).
External links
- Carlos, Jean-Marc: The Treatment of Panic Disorder http://www.medscape.com/viewarticle/497207
Clonazepamis a benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
drug having anxiolytic
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
, anticonvulsant
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
, muscle relaxant
Muscle relaxant
A muscle relaxant is a drug which affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeutic groups: neuromuscular blockers and spasmolytics...
, and hypnotic
Hypnotic
Hypnotic drugs are a class of psychoactives whose primary function is to induce sleep and to be used in the treatment of insomnia and in surgical anesthesia...
properties. It is marketed by Roche
Hoffmann-La Roche
F. Hoffmann-La Roche Ltd. is a Swiss global health-care company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on the SIX Swiss Exchange....
under the trade name Klonopin in the United States and Rivotril in Australia, Brazil, Canada and Europe(and in countries like Serbia, Macedonia, Croatia and Montenegro). Other names such as Ravotril, Rivatril, Clonex, Paxam, or Kriadex are known throughout the rest of the world. Clonazepam has an unusually long half-life
Biological half-life
The biological half-life or elimination half-life of a substance is the time it takes for a substance to lose half of its pharmacologic, physiologic, or radiologic activity, as per the MeSH definition...
of 18–50 hours, making it generally considered to be among the long-acting benzodiazepines. Clonazepam is a chlorinated
Halogenation
Halogenation is a chemical reaction that incorporates a halogen atom into a molecule in substitution of hydrogen atom. Halogenation takes place in the gas phase. There are four types of halogenation: fluorination, chlorination, bromination, and iodination...
derivative of nitrazepam
Nitrazepam
Nitrazepam is a type of benzodiazepine drug and is marketed in English-speaking countries under the following brand names: Alodorm, Arem, Insoma, Mogadon, Nitrados, Nitrazadon, Ormodon, Paxadorm, Remnos, and Somnite...
and therefore a chloro-nitrobenzodiazepine.
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
Benzodiazepine dependence
Benzodiazepine dependence or benzodiazepine addiction is a condition during which a person is dependent on benzodiazepine drugs. Dependence can be either a psychological dependence, physical dependence, or a combination of the two...
, and benzodiazepine withdrawal syndrome
Benzodiazepine withdrawal syndrome
Benzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal—is the cluster of symptoms which appear when a person who has taken benzodiazepines long term and has developed benzodiazepine dependence stops taking benzodiazepine drug or during dosage reductions...
, which occurs in a third of people treated with clonazepam for longer than four weeks.
Clonazepam is classified as a high potency benzodiazepine and is sometimes used as a second-line treatment of epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
. 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
Clorazepate
Clorazepate , also known as clorazepate dipotassium, is a drug that is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative, hypnotic and skeletal muscle relaxant properties. Clorazepate is a prodrug for desmethyldiazepam, which is rapidly produced as an active metabolite...
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.
Medical uses
Clonazepam may be prescribed for the following:- EpilepsyEpilepsyEpilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
- Anxiety disorderAnxiety disorderAnxiety disorder is a blanket term covering several different forms of abnormal and pathological fear and anxiety. Conditions now considered anxiety disorders only came under the aegis of psychiatry at the end of the 19th century. Gelder, Mayou & Geddes explains that anxiety disorders are...
s - Panic disorderPanic disorderPanic disorder is an anxiety disorder characterized by recurring severe panic attacks. It may also include significant behavioral change lasting at least a month and of ongoing worry about the implications or concern about having other attacks. The latter are called anticipatory attacks...
- Initial treatment of maniaManiaMania, the presence of which is a criterion for certain psychiatric diagnoses, is a state of abnormally elevated or irritable mood, arousal, and/ or energy levels. In a sense, it is the opposite of depression...
or acute psychosis together with firstline drugs such as lithiumLithium pharmacologyLithium pharmacology refers to use of the lithium ion, Li+, as a drug. A number of chemical salts of lithium are used medically as a mood stabilizing drug, primarily in the treatment of bipolar disorder, where they have a role in the treatment of depression and particularly of mania, both acutely...
, haloperidolHaloperidolHaloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines....
or risperidoneRisperidoneRisperidone is a second generation or atypical antipsychotic, sold under the trade name . It is used to treat schizophrenia , schizoaffective disorder, the mixed and manic states associated with bipolar disorder, and irritability in people with autism... - For the management of the visual effects of HPPD
- HyperekplexiaHyperekplexiaHyperekplexia is a neurologic disorder classically characterised by pronounced startle responses to tactile or acoustic stimuli and hypertonia. The hypertonia may be predominantly truncal, attenuated during sleep and less prominent after a year of age...
- Many forms of parasomniaParasomniaFor the 2008 horror film, see Parasomnia Parasomnias are a category of sleep disorders that involve abnormal and unnatural movements, behaviors, emotions, perceptions, and dreams that occur while falling asleep, sleeping, between sleep stages, or during arousal from sleep...
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. BruxismBruxismBruxism is characterized by the grinding of the teeth and typically includes the clenching of the jaw. It is an oral parafunctional activity that occurs in most humans at some time in their lives. In most people, bruxism is mild enough not to be a health problem...
also responds to clonazepam in the short-term Rapid eye movement behavior disorderRapid eye movement behavior disorderRapid eye movement sleep behaviour disorder is a sleep disorder that involves abnormal behaviour during the sleep phase with rapid eye movement . It was first described in 1986....
responds well to low doses of clonazepam. - The treatment of acute and chronic akathisiaAkathisiaAkathisia, or acathisia, is a syndrome characterized by unpleasant sensations of inner restlessness that manifests itself with an inability to sit still or remain motionless...
induced by neuroleptics also called antipsychotics. - SpasticitySpasticitySpasticity is a feature of altered skeletal muscle performance in muscle tone involving hypertonia, which is also referred to as an unusual "tightness" of muscles...
related to amyotrophic lateral sclerosisAmyotrophic lateral sclerosisAmyotrophic lateral sclerosis , also referred to as Lou Gehrig's disease, is a form of motor neuron disease caused by the degeneration of upper and lower neurons, located in the ventral horn of the spinal cord and the cortical neurons that provide their efferent input...
The effectiveness of clonazepam in the short-term treatment of panic disorder
Panic disorder
Panic disorder is an anxiety disorder characterized by recurring severe panic attacks. It may also include significant behavioral change lasting at least a month and of ongoing worry about the implications or concern about having other attacks. The latter are called anticipatory attacks...
has been demonstrated in controlled clinical trials
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
. 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
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
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
Clorazepate
Clorazepate , also known as clorazepate dipotassium, is a drug that is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative, hypnotic and skeletal muscle relaxant properties. Clorazepate is a prodrug for desmethyldiazepam, which is rapidly produced as an active metabolite...
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
Status epilepticus
Status epilepticus is a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures...
. However, the benefits tended to be transient in many of the patients, and the addition of phenytoin
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
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
West syndrome
West syndrome or West's Syndrome is an uncommon to rare epileptic disorder in infants. It is named after the English physician, William James West , who first described it in an article published in The Lancet in 1841. The original case actually described his own son, James Edwin West...
, 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
Hypotonia
Hypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
and drowsiness are troublesome with clonazepam therapy; other antiepileptic agents are, therefore, recommended for long-term therapy, possibly Corticotropin (ACTH) or vigabatrin
Vigabatrin
Vigabatrin is an antiepileptic drug that inhibits the catabolism of gamma-aminobutyric acid by irreversibly inhibiting GABA transaminase. It is an analog of GABA, but it is not a receptor agonist...
. 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
Obsessive-compulsive disorder
Obsessive–compulsive disorder is an anxiety disorder characterized by intrusive thoughts that produce uneasiness, apprehension, fear, or worry, by repetitive behaviors aimed at reducing the associated anxiety, or by a combination of such obsessions and compulsions...
and clinical depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
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.
Formulations
Clonazepam was approved in the United States as a generic drug
Generic drug
A generic drug is a drug defined as "a drug product that is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use." It has also been defined as a term referring to any drug marketed under its...
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.
Very common
- Drowsiness
- Interference with cognitive and motor performance
- EuphoriaEuphoriaEuphoria is an emotional and mental state defined as a sense of great elation and well being.Euphoria may also refer to:* Euphoria , a genus of scarab beetles* Euphoria, a genus name previously used for the longan and other trees...
Less common
- Irritability and aggression
- Psychomotor agitationPsychomotor agitationPsychomotor agitation is a series of unintentional and purposeless motions that stem from mental tension and anxiety of an individual. This includes pacing around a room, wringing one's hands, pulling off clothing and putting it back on and other similar actions...
- Lack of motivation
- Loss of libido
- Impaired motor function
- Impaired coordination
- Impaired balance
- Dizziness
- Cognitive impairments
- Hallucinations
- Short-term memory loss
- Anterograde amnesiaAnterograde amnesiaAnterograde amnesia is a loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. This is in contrast to retrograde amnesia, where memories...
(common with higher doses)
- Some users report hangoverHangoverA hangover describes the sum of unpleasant physiological effects following heavy consumption of alcoholic beverages. The most commonly reported characteristics of a hangover include headache, nausea, sensitivity to light and noise, lethargy, dysphoria, diarrhea and thirst, typically after the...
-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".
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 may cause or worsen depression.
Occasional
- Serious dysphoriaDysphoriaDysphoria is medically recognized as a mental and emotional condition in which a person experiences intense feelings of depression, discontent and indifference to the world around them.Mood disorders can induce dysphoria, often with a heightened risk of suicide, especially in...
- ThrombocytopeniaThrombocytopeniaThrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
- Serious psychological and psychiatric side-effects
- Induction of seizures or increased frequency of seizures
- Personality changes
- Behavioural disturbances
- ConfusionConFusionConFusion is an annual science fiction convention organized by the Stilyagi Air Corps and its parent organization, the Ann Arbor Science Fiction Association. Commonly, it is held the third weekend of January. It is the oldest science fiction convention in Michigan, a regional, general SF con...
- AtaxiaAtaxiaAtaxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
Rare
- PsychosisPsychosisPsychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
- IncontinenceUrinary incontinenceUrinary incontinence is any involuntary leakage of urine. It is a common and distressing problem, which may have a profound impact on quality of life. Urinary incontinence almost always results from an underlying treatable medical condition but is under-reported to medical practitioners...
- Liver damage
- Paradoxical behavioural disinhibition (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, disinhibitionDisinhibition
Disinhibition is a term in psychology used to describe a lack of restraint manifested in several ways, including disregard for social conventions, impulsivity, and poor risk assessment. Disinhibition affects motor, instinctual, emotional, cognitive and perceptual aspects with signs and symptoms...
, and sexual dysfunction
Sexual dysfunction
Sexual dysfunction or sexual malfunction refers to a difficulty experienced by an individual or a couple during any stage of a normal sexual activity, including desire, arousal or orgasm....
. 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.
Withdrawal-related
- Anxiety, irritability, insomnia, tremors
- Potential to exacerbate existing Panic Disorder upon discontinuation
- Seizures similar to delirium tremensDelirium tremensDelirium tremens is an acute episode of delirium that is usually caused by withdrawal from alcohol, first described in 1813...
(with long-term use of excessive doses)
Benzodiazepines such as clonazepam can be very effective in controlling status epilepticus
Status epilepticus
Status epilepticus is a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures...
, 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
Pharmacotherapy
Pharmacotherapy is the treatment of disease through the administration of drugs. As such, it is considered part of the larger category of therapy....
low-dose benzodiazepine users — physiological dependence was demonstrated via flumazenil
Flumazenil
Flumazenil is a benzodiazepine antagonist available for injection only, and the only benzodiazepine receptor antagonist on the market today.It was first introduced in 1987 by Hoffmann-La Roche under the trade name Anexate, but only approved by...
-precipitated withdrawal.
Use of alcohol or other CNS
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
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 agonistAgonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
. 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
Benzodiazepine withdrawal syndrome
Benzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal—is the cluster of symptoms which appear when a person who has taken benzodiazepines long term and has developed benzodiazepine dependence stops taking benzodiazepine drug or during dosage reductions...
. 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.
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. 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 chlordiazepoxideChlordiazepoxide
Chlordiazepoxide, is a sedative/hypnotic drug and benzodiazepine. It is marketed under the trade names Angirex, Klopoxid, Librax , Libritabs, Librium, Mesural, Multum, Novapam, Risolid, Silibrin, Sonimen and Tropium.Chlordiazepoxide was the first benzodiazepine to be synthesised and...
. In general, short-term therapy is more effective than long-term therapy with clonazepam for the treatment of epilepsy. 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.
Withdrawal
Abrupt or over-rapid withdrawal from clonazepam may result in the development of the benzodiazepine withdrawal syndromeBenzodiazepine withdrawal syndrome
Benzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal—is the cluster of symptoms which appear when a person who has taken benzodiazepines long term and has developed benzodiazepine dependence stops taking benzodiazepine drug or during dosage reductions...
, causing psychosis characterised by dysphoric manifestations, irritability, aggressiveness, anxiety, and hallucinations. Sudden withdrawal may also induce the potentially life threatening condition status epilepticus
Status epilepticus
Status epilepticus is a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures...
. Antiepileptic drugs, benzodiazepines such as clonazepam in particular, should be reduced slowly and gradually when discontinuing the drug to reduce withdrawal effects. Carbamazepine
Carbamazepine
Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
has been trialed in the treatment of clonazepam withdrawal and has been found to be ineffective in preventing clonazepam withdrawal status epilepticus
Status epilepticus
Status epilepticus is a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures...
from occurring.
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.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. Clonazepam is generally not recommended for use in elderly people for insomnia due to its high potency relative to other benzodiazepines.
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
Phenobarbital
Phenobarbital or phenobarbitone is a barbiturate, first marketed as Luminal by Friedr. Bayer et comp. It is the most widely used anticonvulsant worldwide, and the oldest still commonly used. It also has sedative and hypnotic properties but, as with other barbiturates, has been superseded by the...
.
Caution using high dosages of clonazepam. Doses higher than 0.5 – 1 mg per day are associated with significant sedation.
Clonazepam may aggravate hepatic porphyria
Hepatic porphyria
Hepatic porphyrias is a form of porphyria in which the enzyme deficiency occurs in the liver.Examples include :* Acute intermittent porphyria* Porphyria cutanea tarda and Hepatoerythropoietic porphyria...
.
Caution in chronic schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
. A 1982 double blinded placebo controlled study found clonazepam increases violent behavior in individuals with chronic schizophrenia.
Interactions
Clonazepam decreases the levels of carbamazepineCarbamazepine
Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
, and likewise clonazepam's level is reduced by carbamazepine. Azole antifungals such as ketoconazole
Ketoconazole
Ketoconazole is a synthetic antifungal drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet.Ketoconazole is...
may inhibit the metabolism of clonazepam. Clonazepam may affect levels of phenytoin
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
(diphenylhydantoin) by decreasing, or increasing. 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%.
Clonazepam increases the levels of primidone
Primidone
Primidone is an anticonvulsant of the pyrimidinedione class, the active metabolites of which, phenobarbital and phenylethylmalonamide , are also anticonvulsants...
, and phenobarbital
Phenobarbital
Phenobarbital or phenobarbitone is a barbiturate, first marketed as Luminal by Friedr. Bayer et comp. It is the most widely used anticonvulsant worldwide, and the oldest still commonly used. It also has sedative and hypnotic properties but, as with other barbiturates, has been superseded by the...
.
Combined use of clonazepam with certain antidepressants, antiepileptics such as phenobarbital
Phenobarbital
Phenobarbital or phenobarbitone is a barbiturate, first marketed as Luminal by Friedr. Bayer et comp. It is the most widely used anticonvulsant worldwide, and the oldest still commonly used. It also has sedative and hypnotic properties but, as with other barbiturates, has been superseded by the...
, phenytoin
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
and carbamazepine
Carbamazepine
Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
, sedative antihistamines, opiates, antipsychotics and alcohol may result in enhanced sedative effects.
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 hypotoniaHypotonia
Hypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
, apnoeic spells, cyanosis
Cyanosis
Cyanosis is the appearance of a blue or purple coloration of the skin or mucous membranes due to the tissues near the skin surface being low on oxygen. The onset of cyanosis is 2.5 g/dL of deoxyhemoglobin. The bluish color is more readily apparent in those with high hemoglobin counts than it is...
and impaired metabolic responses to cold stress.
The safety profile of clonazepam during pregnancy is less clear than for other benzodiazepines and if benzodiazepines are indicated during pregnancy chlordiazepoxide
Chlordiazepoxide
Chlordiazepoxide, is a sedative/hypnotic drug and benzodiazepine. It is marketed under the trade names Angirex, Klopoxid, Librax , Libritabs, Librium, Mesural, Multum, Novapam, Risolid, Silibrin, Sonimen and Tropium.Chlordiazepoxide was the first benzodiazepine to be synthesised and...
and diazepam
Diazepam
Diazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
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
Fetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
. 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
Abortion
Abortion is defined as the termination of pregnancy by the removal or expulsion from the uterus of a fetus or embryo prior to viability. An abortion can occur spontaneously, in which case it is usually called a miscarriage, or it can be purposely induced...
, malformation, intrauterine growth retardation, functional deficits, floppy infant syndrome, carcinogenesis
Carcinogenesis
Carcinogenesis or oncogenesis is literally the creation of cancer. It is a process by which normal cells are transformed into cancer cells...
and mutagenesis
Mutagenesis
Mutagenesis is a process by which the genetic information of an organism is changed in a stable manner, resulting in a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using laboratory procedures...
. Neonatal withdrawal syndrome associated with benzodiazepines include hypertonia
Hypertonia
Hypertonia a condition marked by an abnormal increase in muscle tension and a reduced ability of a muscle to stretch. It is caused by lesions to upper motor neurons in the central nervous system, which carry information from the central nervous system to the muscles and control posture, muscle...
, hyperreflexia
Hyperreflexia
Hyperreflexia is defined as overactive or overresponsive reflexes. Examples of this can include twitching or spastic tendencies, which are indicative of upper motor neuron disease as well as the lessening or loss of control ordinarily exerted by higher brain centers of lower neural pathways...
, restlessness
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, irritability
Irritability
Irritability is an excessive response to stimuli. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessive sensitivity to stimuli; It is usually used to refer to anger or frustration....
, abnormal sleep patterns, inconsolable crying, tremors or jerking of the extremities, bradycardia
Bradycardia
Bradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...
, cyanosis
Cyanosis
Cyanosis is the appearance of a blue or purple coloration of the skin or mucous membranes due to the tissues near the skin surface being low on oxygen. The onset of cyanosis is 2.5 g/dL of deoxyhemoglobin. The bluish color is more readily apparent in those with high hemoglobin counts than it is...
, suckling difficulties, apnea
Apnea
Apnea, apnoea, or apnœa is a term for suspension of external breathing. During apnea there is no movement of the muscles of respiration and the volume of the lungs initially remains unchanged...
, risk of aspiration of feeds, diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
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
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
depression and apnea
Apnea
Apnea, apnoea, or apnœa is a term for suspension of external breathing. During apnea there is no movement of the muscles of respiration and the volume of the lungs initially remains unchanged...
are also monitored for. In many cases non-pharmacological treatments such as relaxation therapy, psychotherapy and avoidance of caffeine
Caffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
can be an effective and safer alternative to use of benzodiazepines for anxiety in pregnant women.
Pharmacology
Clonazepam's primary mechanism of actionMechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect...
is via modulating GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
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. 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 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.
The anticonvulsant properties of benzodiazepines are due to enhancement of synaptic
Synaptic
Synaptic may refer to:*Synapse, part of the nervous system*Synapsis, the pairing of two homologous chromosomes*Synaptic , a Linux graphical package management program for APT See also...
GABA responses and inhibition of sustained high frequency repetitive firing.
Benzodiazepines, including clonazepam, bind to mouse glial cell
Glial cell
Glial cells, sometimes called neuroglia or simply glia , are non-neuronal cells that maintain homeostasis, form myelin, and provide support and protection for neurons in the brain, and for neurons in other parts of the nervous system such as in the autonomous nervous system...
membranes with high affinity. Clonazepam decreases release of acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
in cat brain and decreases prolactin
Prolactin
Prolactin also known as luteotropic hormone is a protein that in humans is encoded by the PRL gene.Prolactin is a peptide hormone discovered by Henry Friesen...
release in rats. Benzodiazepines inhibit cold-induced thyroid stimulating hormone (also known as TSH
TSH
TSH may refer to:* Tanzanian shilling, the currency of Tanzania* Thyroid-stimulating hormone, a hormone synthesized and secreted by thyrotrope cells* Tshiuetin Rail Transportation, a Canadian railway between Labrador and Quebec...
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 for high-dose effects on seizures in the study.
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 systemCentral nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
. 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
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
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.
Pharmacokinetics
Clonazepam is lipid soluble, and rapidly crosses the blood-brain barrierBlood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
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
CYP2C19
Cytochrome P450 2C19 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. It is involved in the metabolism of several...
and to a lesser extent CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
. Erythromycin
Erythromycin
Erythromycin is a macrolide antibiotic that has an antimicrobial spectrum similar to or slightly wider than that of penicillin, and is often used for people who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma and...
, clarithromycin
Clarithromycin
Clarithromycin is a macrolide antibiotic used to treat pharyngitis, tonsillitis, acute maxillary sinusitis, acute bacterial exacerbation of chronic bronchitis, pneumonia , skin and skin structure infections...
, ritonavir
Ritonavir
Ritonavir, with trade name Norvir , is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS....
, itraconazole
Itraconazole
Itraconazole , invented in 1984, is a triazole antifungal agent that is prescribed to patients with fungal infections. The drug may be given orally or intravenously.-Medical uses:...
, ketoconazole
Ketoconazole
Ketoconazole is a synthetic antifungal drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet.Ketoconazole is...
, nefazodone
Nefazodone
Nefazodone is an antidepressant marketed by Bristol-Myers Squibb. Its sale was discontinued in 2003 in some countries due to the rare incidence of hepatotoxicity , which could lead to the need for a liver transplant, or even death. The incidence of severe liver damage is approximately 1 in every...
, and grapefruit juice are inhibitors of CYP34A and can affect the metabolism of benzodiazepines.
It has an elimination half-life of 19–60 hours. 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.
Clonazepam passes rapidly into the central nervous system, with levels in the brain corresponding with levels of unbound clonazepam in the blood serum. Clonazepam plasma levels are very unreliable amongst patients. Plasma levels of clonazepam can vary as much as tenfold between different patients.
Clonazepam is largely bound to plasma proteins. Clonazepam passes through the blood-brain barrier easily, with blood and brain levels corresponding equally with each other. The metabolites of clonazepam include 7-aminoclonazepam, 7-acetaminoclonazepam and 3-hydroxy clonazepam.
Overdose
An individual who has consumed too much clonazepam may display one or more of the following symptoms:- SomnolenceSomnolenceSomnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
(difficulty staying awake) - Mental confusion
- NauseaNauseaNausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
- Impaired motor functions
- Impaired reflexes
- Impaired coordination
- Impaired balance
- Dizziness
- Respiratory depression
- HypotensionHypotensionIn physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
- ComaComaIn medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...
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 e.g. amobarbital
Amobarbital
Amobarbital is a drug that is a barbiturate derivative. It has sedative-hypnotic and analgesic properties. It is a white crystalline powder with no odor and a slightly bitter taste. It was first synthesized in Germany in 1923...
at prescribed doses has resulted in a synergistic potentiation of the effects of each drug leading to serious respiratory depression.
Overdose symptoms may include extreme drowsiness, confusion, muscle weakness, and fainting.
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.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
Drug abuse
Substance abuse, also known as drug abuse, refers to a maladaptive pattern of use of a substance that is not considered dependent. The term "drug abuse" does not exclude dependency, but is otherwise used in a similar manner in nonmedical contexts...
, accidental or intentional overdose, or adverse reactions resulting from legitimate use of the medication.
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 aminoderivative 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.
- H.L. Newmark, J. Cariss, (1963).
- J.K. Clifton, H.L. Newmark, (1964).
- O. Kller, N. Steiger, N.H. Sternbach, (1964).
- N. Steiger, O. Keller, (1965).
- J.A. Rachlin, A. Focella, (1967).
External links
- Carlos, Jean-Marc: The Treatment of Panic Disorder http://www.medscape.com/viewarticle/497207
Clonazepamis a benzodiazepine
Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
drug having anxiolytic
Anxiolytic
An anxiolytic is a drug used for the treatment of anxiety, and its related psychological and physical symptoms...
, anticonvulsant
Anticonvulsant
The anticonvulsants are a diverse group of pharmaceuticals used in the treatment of epileptic seizures. Anticonvulsants are also increasingly being used in the treatment of bipolar disorder, since many seem to act as mood stabilizers, and in the treatment of neuropathic pain. The goal of an...
, muscle relaxant
Muscle relaxant
A muscle relaxant is a drug which affects skeletal muscle function and decreases the muscle tone. It may be used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia. The term "muscle relaxant" is used to refer to two major therapeutic groups: neuromuscular blockers and spasmolytics...
, and hypnotic
Hypnotic
Hypnotic drugs are a class of psychoactives whose primary function is to induce sleep and to be used in the treatment of insomnia and in surgical anesthesia...
properties. It is marketed by Roche
Hoffmann-La Roche
F. Hoffmann-La Roche Ltd. is a Swiss global health-care company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on the SIX Swiss Exchange....
under the trade name Klonopin in the United States and Rivotril in Australia, Brazil, Canada and Europe(and in countries like Serbia, Macedonia, Croatia and Montenegro). Other names such as Ravotril, Rivatril, Clonex, Paxam, or Kriadex are known throughout the rest of the world. Clonazepam has an unusually long half-life
Biological half-life
The biological half-life or elimination half-life of a substance is the time it takes for a substance to lose half of its pharmacologic, physiologic, or radiologic activity, as per the MeSH definition...
of 18–50 hours, making it generally considered to be among the long-acting benzodiazepines. Clonazepam is a chlorinated
Halogenation
Halogenation is a chemical reaction that incorporates a halogen atom into a molecule in substitution of hydrogen atom. Halogenation takes place in the gas phase. There are four types of halogenation: fluorination, chlorination, bromination, and iodination...
derivative of nitrazepam
Nitrazepam
Nitrazepam is a type of benzodiazepine drug and is marketed in English-speaking countries under the following brand names: Alodorm, Arem, Insoma, Mogadon, Nitrados, Nitrazadon, Ormodon, Paxadorm, Remnos, and Somnite...
and therefore a chloro-nitrobenzodiazepine.
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
Benzodiazepine dependence
Benzodiazepine dependence or benzodiazepine addiction is a condition during which a person is dependent on benzodiazepine drugs. Dependence can be either a psychological dependence, physical dependence, or a combination of the two...
, and benzodiazepine withdrawal syndrome
Benzodiazepine withdrawal syndrome
Benzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal—is the cluster of symptoms which appear when a person who has taken benzodiazepines long term and has developed benzodiazepine dependence stops taking benzodiazepine drug or during dosage reductions...
, which occurs in a third of people treated with clonazepam for longer than four weeks.
Clonazepam is classified as a high potency benzodiazepine and is sometimes used as a second-line treatment of epilepsy
Epilepsy
Epilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
. 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
Clorazepate
Clorazepate , also known as clorazepate dipotassium, is a drug that is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative, hypnotic and skeletal muscle relaxant properties. Clorazepate is a prodrug for desmethyldiazepam, which is rapidly produced as an active metabolite...
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.
Medical uses
Clonazepam may be prescribed for the following:- EpilepsyEpilepsyEpilepsy is a common chronic neurological disorder characterized by seizures. These seizures are transient signs and/or symptoms of abnormal, excessive or hypersynchronous neuronal activity in the brain.About 50 million people worldwide have epilepsy, and nearly two out of every three new cases...
- Anxiety disorderAnxiety disorderAnxiety disorder is a blanket term covering several different forms of abnormal and pathological fear and anxiety. Conditions now considered anxiety disorders only came under the aegis of psychiatry at the end of the 19th century. Gelder, Mayou & Geddes explains that anxiety disorders are...
s - Panic disorderPanic disorderPanic disorder is an anxiety disorder characterized by recurring severe panic attacks. It may also include significant behavioral change lasting at least a month and of ongoing worry about the implications or concern about having other attacks. The latter are called anticipatory attacks...
- Initial treatment of maniaManiaMania, the presence of which is a criterion for certain psychiatric diagnoses, is a state of abnormally elevated or irritable mood, arousal, and/ or energy levels. In a sense, it is the opposite of depression...
or acute psychosis together with firstline drugs such as lithiumLithium pharmacologyLithium pharmacology refers to use of the lithium ion, Li+, as a drug. A number of chemical salts of lithium are used medically as a mood stabilizing drug, primarily in the treatment of bipolar disorder, where they have a role in the treatment of depression and particularly of mania, both acutely...
, haloperidolHaloperidolHaloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines....
or risperidoneRisperidoneRisperidone is a second generation or atypical antipsychotic, sold under the trade name . It is used to treat schizophrenia , schizoaffective disorder, the mixed and manic states associated with bipolar disorder, and irritability in people with autism... - For the management of the visual effects of HPPD
- HyperekplexiaHyperekplexiaHyperekplexia is a neurologic disorder classically characterised by pronounced startle responses to tactile or acoustic stimuli and hypertonia. The hypertonia may be predominantly truncal, attenuated during sleep and less prominent after a year of age...
- Many forms of parasomniaParasomniaFor the 2008 horror film, see Parasomnia Parasomnias are a category of sleep disorders that involve abnormal and unnatural movements, behaviors, emotions, perceptions, and dreams that occur while falling asleep, sleeping, between sleep stages, or during arousal from sleep...
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. BruxismBruxismBruxism is characterized by the grinding of the teeth and typically includes the clenching of the jaw. It is an oral parafunctional activity that occurs in most humans at some time in their lives. In most people, bruxism is mild enough not to be a health problem...
also responds to clonazepam in the short-term Rapid eye movement behavior disorderRapid eye movement behavior disorderRapid eye movement sleep behaviour disorder is a sleep disorder that involves abnormal behaviour during the sleep phase with rapid eye movement . It was first described in 1986....
responds well to low doses of clonazepam. - The treatment of acute and chronic akathisiaAkathisiaAkathisia, or acathisia, is a syndrome characterized by unpleasant sensations of inner restlessness that manifests itself with an inability to sit still or remain motionless...
induced by neuroleptics also called antipsychotics. - SpasticitySpasticitySpasticity is a feature of altered skeletal muscle performance in muscle tone involving hypertonia, which is also referred to as an unusual "tightness" of muscles...
related to amyotrophic lateral sclerosisAmyotrophic lateral sclerosisAmyotrophic lateral sclerosis , also referred to as Lou Gehrig's disease, is a form of motor neuron disease caused by the degeneration of upper and lower neurons, located in the ventral horn of the spinal cord and the cortical neurons that provide their efferent input...
The effectiveness of clonazepam in the short-term treatment of panic disorder
Panic disorder
Panic disorder is an anxiety disorder characterized by recurring severe panic attacks. It may also include significant behavioral change lasting at least a month and of ongoing worry about the implications or concern about having other attacks. The latter are called anticipatory attacks...
has been demonstrated in controlled clinical trials
Clinical trial
Clinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
. 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
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
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
Clorazepate
Clorazepate , also known as clorazepate dipotassium, is a drug that is a benzodiazepine derivative. It possesses anxiolytic, anticonvulsant, sedative, hypnotic and skeletal muscle relaxant properties. Clorazepate is a prodrug for desmethyldiazepam, which is rapidly produced as an active metabolite...
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
Status epilepticus
Status epilepticus is a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures...
. However, the benefits tended to be transient in many of the patients, and the addition of phenytoin
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
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
West syndrome
West syndrome or West's Syndrome is an uncommon to rare epileptic disorder in infants. It is named after the English physician, William James West , who first described it in an article published in The Lancet in 1841. The original case actually described his own son, James Edwin West...
, 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
Hypotonia
Hypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
and drowsiness are troublesome with clonazepam therapy; other antiepileptic agents are, therefore, recommended for long-term therapy, possibly Corticotropin (ACTH) or vigabatrin
Vigabatrin
Vigabatrin is an antiepileptic drug that inhibits the catabolism of gamma-aminobutyric acid by irreversibly inhibiting GABA transaminase. It is an analog of GABA, but it is not a receptor agonist...
. 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
Obsessive-compulsive disorder
Obsessive–compulsive disorder is an anxiety disorder characterized by intrusive thoughts that produce uneasiness, apprehension, fear, or worry, by repetitive behaviors aimed at reducing the associated anxiety, or by a combination of such obsessions and compulsions...
and clinical depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
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.
Formulations
Clonazepam was approved in the United States as a generic drug
Generic drug
A generic drug is a drug defined as "a drug product that is comparable to brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use." It has also been defined as a term referring to any drug marketed under its...
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.
Very common
- Drowsiness
- Interference with cognitive and motor performance
- EuphoriaEuphoriaEuphoria is an emotional and mental state defined as a sense of great elation and well being.Euphoria may also refer to:* Euphoria , a genus of scarab beetles* Euphoria, a genus name previously used for the longan and other trees...
Less common
- Irritability and aggression
- Psychomotor agitationPsychomotor agitationPsychomotor agitation is a series of unintentional and purposeless motions that stem from mental tension and anxiety of an individual. This includes pacing around a room, wringing one's hands, pulling off clothing and putting it back on and other similar actions...
- Lack of motivation
- Loss of libido
- Impaired motor function
- Impaired coordination
- Impaired balance
- Dizziness
- Cognitive impairments
- Hallucinations
- Short-term memory loss
- Anterograde amnesiaAnterograde amnesiaAnterograde amnesia is a loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact. This is in contrast to retrograde amnesia, where memories...
(common with higher doses)
- Some users report hangoverHangoverA hangover describes the sum of unpleasant physiological effects following heavy consumption of alcoholic beverages. The most commonly reported characteristics of a hangover include headache, nausea, sensitivity to light and noise, lethargy, dysphoria, diarrhea and thirst, typically after the...
-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".
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 may cause or worsen depression.
Occasional
- Serious dysphoriaDysphoriaDysphoria is medically recognized as a mental and emotional condition in which a person experiences intense feelings of depression, discontent and indifference to the world around them.Mood disorders can induce dysphoria, often with a heightened risk of suicide, especially in...
- ThrombocytopeniaThrombocytopeniaThrombocytopenia is a relative decrease of platelets in blood.A normal human platelet count ranges from 150,000 to 450,000 platelets per microliter of blood. These limits are determined by the 2.5th lower and upper percentile, so values outside this range do not necessarily indicate disease...
- Serious psychological and psychiatric side-effects
- Induction of seizures or increased frequency of seizures
- Personality changes
- Behavioural disturbances
- ConfusionConFusionConFusion is an annual science fiction convention organized by the Stilyagi Air Corps and its parent organization, the Ann Arbor Science Fiction Association. Commonly, it is held the third weekend of January. It is the oldest science fiction convention in Michigan, a regional, general SF con...
- AtaxiaAtaxiaAtaxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
Rare
- PsychosisPsychosisPsychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
- IncontinenceUrinary incontinenceUrinary incontinence is any involuntary leakage of urine. It is a common and distressing problem, which may have a profound impact on quality of life. Urinary incontinence almost always results from an underlying treatable medical condition but is under-reported to medical practitioners...
- Liver damage
- Paradoxical behavioural disinhibition (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, disinhibitionDisinhibition
Disinhibition is a term in psychology used to describe a lack of restraint manifested in several ways, including disregard for social conventions, impulsivity, and poor risk assessment. Disinhibition affects motor, instinctual, emotional, cognitive and perceptual aspects with signs and symptoms...
, and sexual dysfunction
Sexual dysfunction
Sexual dysfunction or sexual malfunction refers to a difficulty experienced by an individual or a couple during any stage of a normal sexual activity, including desire, arousal or orgasm....
. 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.
Withdrawal-related
- Anxiety, irritability, insomnia, tremors
- Potential to exacerbate existing Panic Disorder upon discontinuation
- Seizures similar to delirium tremensDelirium tremensDelirium tremens is an acute episode of delirium that is usually caused by withdrawal from alcohol, first described in 1813...
(with long-term use of excessive doses)
Benzodiazepines such as clonazepam can be very effective in controlling status epilepticus
Status epilepticus
Status epilepticus is a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures...
, 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
Pharmacotherapy
Pharmacotherapy is the treatment of disease through the administration of drugs. As such, it is considered part of the larger category of therapy....
low-dose benzodiazepine users — physiological dependence was demonstrated via flumazenil
Flumazenil
Flumazenil is a benzodiazepine antagonist available for injection only, and the only benzodiazepine receptor antagonist on the market today.It was first introduced in 1987 by Hoffmann-La Roche under the trade name Anexate, but only approved by...
-precipitated withdrawal.
Use of alcohol or other CNS
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
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 agonistAgonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
. 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
Benzodiazepine withdrawal syndrome
Benzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal—is the cluster of symptoms which appear when a person who has taken benzodiazepines long term and has developed benzodiazepine dependence stops taking benzodiazepine drug or during dosage reductions...
. 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.
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. 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 chlordiazepoxideChlordiazepoxide
Chlordiazepoxide, is a sedative/hypnotic drug and benzodiazepine. It is marketed under the trade names Angirex, Klopoxid, Librax , Libritabs, Librium, Mesural, Multum, Novapam, Risolid, Silibrin, Sonimen and Tropium.Chlordiazepoxide was the first benzodiazepine to be synthesised and...
. In general, short-term therapy is more effective than long-term therapy with clonazepam for the treatment of epilepsy. 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.
Withdrawal
Abrupt or over-rapid withdrawal from clonazepam may result in the development of the benzodiazepine withdrawal syndromeBenzodiazepine withdrawal syndrome
Benzodiazepine withdrawal syndrome—often abbreviated to benzo withdrawal—is the cluster of symptoms which appear when a person who has taken benzodiazepines long term and has developed benzodiazepine dependence stops taking benzodiazepine drug or during dosage reductions...
, causing psychosis characterised by dysphoric manifestations, irritability, aggressiveness, anxiety, and hallucinations. Sudden withdrawal may also induce the potentially life threatening condition status epilepticus
Status epilepticus
Status epilepticus is a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures...
. Antiepileptic drugs, benzodiazepines such as clonazepam in particular, should be reduced slowly and gradually when discontinuing the drug to reduce withdrawal effects. Carbamazepine
Carbamazepine
Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
has been trialed in the treatment of clonazepam withdrawal and has been found to be ineffective in preventing clonazepam withdrawal status epilepticus
Status epilepticus
Status epilepticus is a life-threatening condition in which the brain is in a state of persistent seizure. Definitions vary, but traditionally it is defined as one continuous unremitting seizure lasting longer than 5 minutes, or recurrent seizures without regaining consciousness between seizures...
from occurring.
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.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. Clonazepam is generally not recommended for use in elderly people for insomnia due to its high potency relative to other benzodiazepines.
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
Phenobarbital
Phenobarbital or phenobarbitone is a barbiturate, first marketed as Luminal by Friedr. Bayer et comp. It is the most widely used anticonvulsant worldwide, and the oldest still commonly used. It also has sedative and hypnotic properties but, as with other barbiturates, has been superseded by the...
.
Caution using high dosages of clonazepam. Doses higher than 0.5 – 1 mg per day are associated with significant sedation.
Clonazepam may aggravate hepatic porphyria
Hepatic porphyria
Hepatic porphyrias is a form of porphyria in which the enzyme deficiency occurs in the liver.Examples include :* Acute intermittent porphyria* Porphyria cutanea tarda and Hepatoerythropoietic porphyria...
.
Caution in chronic schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
. A 1982 double blinded placebo controlled study found clonazepam increases violent behavior in individuals with chronic schizophrenia.
Interactions
Clonazepam decreases the levels of carbamazepineCarbamazepine
Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
, and likewise clonazepam's level is reduced by carbamazepine. Azole antifungals such as ketoconazole
Ketoconazole
Ketoconazole is a synthetic antifungal drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet.Ketoconazole is...
may inhibit the metabolism of clonazepam. Clonazepam may affect levels of phenytoin
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
(diphenylhydantoin) by decreasing, or increasing. 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%.
Clonazepam increases the levels of primidone
Primidone
Primidone is an anticonvulsant of the pyrimidinedione class, the active metabolites of which, phenobarbital and phenylethylmalonamide , are also anticonvulsants...
, and phenobarbital
Phenobarbital
Phenobarbital or phenobarbitone is a barbiturate, first marketed as Luminal by Friedr. Bayer et comp. It is the most widely used anticonvulsant worldwide, and the oldest still commonly used. It also has sedative and hypnotic properties but, as with other barbiturates, has been superseded by the...
.
Combined use of clonazepam with certain antidepressants, antiepileptics such as phenobarbital
Phenobarbital
Phenobarbital or phenobarbitone is a barbiturate, first marketed as Luminal by Friedr. Bayer et comp. It is the most widely used anticonvulsant worldwide, and the oldest still commonly used. It also has sedative and hypnotic properties but, as with other barbiturates, has been superseded by the...
, phenytoin
Phenytoin
Phenytoin sodium is a commonly used antiepileptic. Phenytoin acts to suppress the abnormal brain activity seen in seizure by reducing electrical conductance among brain cells by stabilizing the inactive state of voltage-gated sodium channels...
and carbamazepine
Carbamazepine
Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
, sedative antihistamines, opiates, antipsychotics and alcohol may result in enhanced sedative effects.
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 hypotoniaHypotonia
Hypotonia is a state of low muscle tone , often involving reduced muscle strength. Hypotonia is not a specific medical disorder, but a potential manifestation of many different diseases and disorders that affect motor nerve control by the brain or muscle strength...
, apnoeic spells, cyanosis
Cyanosis
Cyanosis is the appearance of a blue or purple coloration of the skin or mucous membranes due to the tissues near the skin surface being low on oxygen. The onset of cyanosis is 2.5 g/dL of deoxyhemoglobin. The bluish color is more readily apparent in those with high hemoglobin counts than it is...
and impaired metabolic responses to cold stress.
The safety profile of clonazepam during pregnancy is less clear than for other benzodiazepines and if benzodiazepines are indicated during pregnancy chlordiazepoxide
Chlordiazepoxide
Chlordiazepoxide, is a sedative/hypnotic drug and benzodiazepine. It is marketed under the trade names Angirex, Klopoxid, Librax , Libritabs, Librium, Mesural, Multum, Novapam, Risolid, Silibrin, Sonimen and Tropium.Chlordiazepoxide was the first benzodiazepine to be synthesised and...
and diazepam
Diazepam
Diazepam , first marketed as Valium by Hoffmann-La Roche is a benzodiazepine drug. Diazepam is also marketed in Australia as Antenex. It is commonly used for treating anxiety, insomnia, seizures including status epilepticus, muscle spasms , restless legs syndrome, alcohol withdrawal,...
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
Fetus
A fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
. 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
Abortion
Abortion is defined as the termination of pregnancy by the removal or expulsion from the uterus of a fetus or embryo prior to viability. An abortion can occur spontaneously, in which case it is usually called a miscarriage, or it can be purposely induced...
, malformation, intrauterine growth retardation, functional deficits, floppy infant syndrome, carcinogenesis
Carcinogenesis
Carcinogenesis or oncogenesis is literally the creation of cancer. It is a process by which normal cells are transformed into cancer cells...
and mutagenesis
Mutagenesis
Mutagenesis is a process by which the genetic information of an organism is changed in a stable manner, resulting in a mutation. It may occur spontaneously in nature, or as a result of exposure to mutagens. It can also be achieved experimentally using laboratory procedures...
. Neonatal withdrawal syndrome associated with benzodiazepines include hypertonia
Hypertonia
Hypertonia a condition marked by an abnormal increase in muscle tension and a reduced ability of a muscle to stretch. It is caused by lesions to upper motor neurons in the central nervous system, which carry information from the central nervous system to the muscles and control posture, muscle...
, hyperreflexia
Hyperreflexia
Hyperreflexia is defined as overactive or overresponsive reflexes. Examples of this can include twitching or spastic tendencies, which are indicative of upper motor neuron disease as well as the lessening or loss of control ordinarily exerted by higher brain centers of lower neural pathways...
, restlessness
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, irritability
Irritability
Irritability is an excessive response to stimuli. The term is used for both the physiological reaction to stimuli and for the pathological, abnormal or excessive sensitivity to stimuli; It is usually used to refer to anger or frustration....
, abnormal sleep patterns, inconsolable crying, tremors or jerking of the extremities, bradycardia
Bradycardia
Bradycardia , in the context of adult medicine, is the resting heart rate of under 60 beats per minute, though it is seldom symptomatic until the rate drops below 50 beat/min. It may cause cardiac arrest in some patients, because those with bradycardia may not be pumping enough oxygen to their heart...
, cyanosis
Cyanosis
Cyanosis is the appearance of a blue or purple coloration of the skin or mucous membranes due to the tissues near the skin surface being low on oxygen. The onset of cyanosis is 2.5 g/dL of deoxyhemoglobin. The bluish color is more readily apparent in those with high hemoglobin counts than it is...
, suckling difficulties, apnea
Apnea
Apnea, apnoea, or apnœa is a term for suspension of external breathing. During apnea there is no movement of the muscles of respiration and the volume of the lungs initially remains unchanged...
, risk of aspiration of feeds, diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
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
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
depression and apnea
Apnea
Apnea, apnoea, or apnœa is a term for suspension of external breathing. During apnea there is no movement of the muscles of respiration and the volume of the lungs initially remains unchanged...
are also monitored for. In many cases non-pharmacological treatments such as relaxation therapy, psychotherapy and avoidance of caffeine
Caffeine
Caffeine is a bitter, white crystalline xanthine alkaloid that acts as a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants...
can be an effective and safer alternative to use of benzodiazepines for anxiety in pregnant women.
Pharmacology
Clonazepam's primary mechanism of actionMechanism of action
In pharmacology, the term mechanism of action refers to the specific biochemical interaction through which a drug substance produces its pharmacological effect...
is via modulating GABA
Gabâ
Gabâ or gabaa, for the people in many parts of the Philippines), is the concept of a non-human and non-divine, imminent retribution. A sort of negative karma, it is generally seen as an evil effect on a person because of their wrongdoings or transgressions...
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. 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 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.
The anticonvulsant properties of benzodiazepines are due to enhancement of synaptic
Synaptic
Synaptic may refer to:*Synapse, part of the nervous system*Synapsis, the pairing of two homologous chromosomes*Synaptic , a Linux graphical package management program for APT See also...
GABA responses and inhibition of sustained high frequency repetitive firing.
Benzodiazepines, including clonazepam, bind to mouse glial cell
Glial cell
Glial cells, sometimes called neuroglia or simply glia , are non-neuronal cells that maintain homeostasis, form myelin, and provide support and protection for neurons in the brain, and for neurons in other parts of the nervous system such as in the autonomous nervous system...
membranes with high affinity. Clonazepam decreases release of acetylcholine
Acetylcholine
The chemical compound acetylcholine is a neurotransmitter in both the peripheral nervous system and central nervous system in many organisms including humans...
in cat brain and decreases prolactin
Prolactin
Prolactin also known as luteotropic hormone is a protein that in humans is encoded by the PRL gene.Prolactin is a peptide hormone discovered by Henry Friesen...
release in rats. Benzodiazepines inhibit cold-induced thyroid stimulating hormone (also known as TSH
TSH
TSH may refer to:* Tanzanian shilling, the currency of Tanzania* Thyroid-stimulating hormone, a hormone synthesized and secreted by thyrotrope cells* Tshiuetin Rail Transportation, a Canadian railway between Labrador and Quebec...
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 for high-dose effects on seizures in the study.
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 systemCentral nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
. 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
Central nervous system
The central nervous system is the part of the nervous system that integrates the information that it receives from, and coordinates the activity of, all parts of the bodies of bilaterian animals—that is, all multicellular animals except sponges and radially symmetric animals such as jellyfish...
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.
Pharmacokinetics
Clonazepam is lipid soluble, and rapidly crosses the blood-brain barrierBlood-brain barrier
The blood–brain barrier is a separation of circulating blood and the brain extracellular fluid in the central nervous system . It occurs along all capillaries and consists of tight junctions around the capillaries that do not exist in normal circulation. Endothelial cells restrict the diffusion...
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
CYP2C19
Cytochrome P450 2C19 , a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the body. It is involved in the metabolism of several...
and to a lesser extent CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
. Erythromycin
Erythromycin
Erythromycin is a macrolide antibiotic that has an antimicrobial spectrum similar to or slightly wider than that of penicillin, and is often used for people who have an allergy to penicillins. For respiratory tract infections, it has better coverage of atypical organisms, including mycoplasma and...
, clarithromycin
Clarithromycin
Clarithromycin is a macrolide antibiotic used to treat pharyngitis, tonsillitis, acute maxillary sinusitis, acute bacterial exacerbation of chronic bronchitis, pneumonia , skin and skin structure infections...
, ritonavir
Ritonavir
Ritonavir, with trade name Norvir , is an antiretroviral drug from the protease inhibitor class used to treat HIV infection and AIDS....
, itraconazole
Itraconazole
Itraconazole , invented in 1984, is a triazole antifungal agent that is prescribed to patients with fungal infections. The drug may be given orally or intravenously.-Medical uses:...
, ketoconazole
Ketoconazole
Ketoconazole is a synthetic antifungal drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet.Ketoconazole is...
, nefazodone
Nefazodone
Nefazodone is an antidepressant marketed by Bristol-Myers Squibb. Its sale was discontinued in 2003 in some countries due to the rare incidence of hepatotoxicity , which could lead to the need for a liver transplant, or even death. The incidence of severe liver damage is approximately 1 in every...
, and grapefruit juice are inhibitors of CYP34A and can affect the metabolism of benzodiazepines.
It has an elimination half-life of 19–60 hours. 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.
Clonazepam passes rapidly into the central nervous system, with levels in the brain corresponding with levels of unbound clonazepam in the blood serum. Clonazepam plasma levels are very unreliable amongst patients. Plasma levels of clonazepam can vary as much as tenfold between different patients.
Clonazepam is largely bound to plasma proteins. Clonazepam passes through the blood-brain barrier easily, with blood and brain levels corresponding equally with each other. The metabolites of clonazepam include 7-aminoclonazepam, 7-acetaminoclonazepam and 3-hydroxy clonazepam.
Overdose
An individual who has consumed too much clonazepam may display one or more of the following symptoms:- SomnolenceSomnolenceSomnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
(difficulty staying awake) - Mental confusion
- NauseaNauseaNausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
- Impaired motor functions
- Impaired reflexes
- Impaired coordination
- Impaired balance
- Dizziness
- Respiratory depression
- HypotensionHypotensionIn physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
- ComaComaIn medicine, a coma is a state of unconsciousness, lasting more than 6 hours in which a person cannot be awakened, fails to respond normally to painful stimuli, light or sound, lacks a normal sleep-wake cycle and does not initiate voluntary actions. A person in a state of coma is described as...
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 e.g. amobarbital
Amobarbital
Amobarbital is a drug that is a barbiturate derivative. It has sedative-hypnotic and analgesic properties. It is a white crystalline powder with no odor and a slightly bitter taste. It was first synthesized in Germany in 1923...
at prescribed doses has resulted in a synergistic potentiation of the effects of each drug leading to serious respiratory depression.
Overdose symptoms may include extreme drowsiness, confusion, muscle weakness, and fainting.
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.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
Drug abuse
Substance abuse, also known as drug abuse, refers to a maladaptive pattern of use of a substance that is not considered dependent. The term "drug abuse" does not exclude dependency, but is otherwise used in a similar manner in nonmedical contexts...
, accidental or intentional overdose, or adverse reactions resulting from legitimate use of the medication.
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 aminoderivative 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.
- H.L. Newmark, J. Cariss, (1963).
- J.K. Clifton, H.L. Newmark, (1964).
- O. Kller, N. Steiger, N.H. Sternbach, (1964).
- N. Steiger, O. Keller, (1965).
- J.A. Rachlin, A. Focella, (1967).
External links
- Carlos, Jean-Marc: The Treatment of Panic Disorder http://www.medscape.com/viewarticle/497207