③长期服药可致体重增加、抑郁状态、性功能异常等。
clonazepam
Clonazepam, sold under the brand name Klonopin among others, is a medication used to prevent and treat seizures, panic disorder, and for the movement disorder known as akathisia.[4] It is a tranquilizer of the benzodiazepine class.[4] It is taken by mouth.[4] It begins having an effect within an hour and lasts between 6 and 12 hours.[7]
Common side effects include sleepiness, poor coordination, and agitation.[4] Long-term usemay result in tolerance, dependence, and withdrawal symptoms if stopped abruptly.[4]Dependence occurs in one-third of people who take clonazepam for longer than four weeks.[8] It may increase risk of suicide in people who are depressed.[4][9] If used during pregnancy it may result in harm to the baby.[4] Clonazepam binds to GABAA receptors and increases the effect of the chief inhibitory neurotransmitter gamma-aminobutyric acid(GABA).[8]
Clonazepam was patented in 1960 and went on sale in 1975 in the United States from Roche.[10][11] It is available as a generic medication.[4] The wholesale cost in the developing world is between US$0.01 and US$0.07 per pill.[12] In the United States, the pills are about US$0.40 each.[4] In 2016 it was the 42nd most prescribed medication in the United States with more than 18 million prescriptions.[13] In many areas of the world it is commonly used as a recreational drug.[14][15]
Medical uses
Clonazepam is prescribed for short term management of epilepsy and panic disorder with or without agoraphobia.[16][17]
Seizures
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.
Clonazepam has been found effective in treating epilepsy in children, and the inhibition of seizure activity seemed to be achieved at low plasma levels of clonazepam.[18] As a result, clonazepam is sometimes used for certain rare childhood epilepsies; however, it has been found to be ineffective in the control of infantile spasms.[19] Clonazepam is mainly prescribed for the acute management of epilepsies. Clonazepam has been found to be effective in the acute control of non-convulsive status epilepticus; however, the benefits tended to be transient in many people, and the addition of phenytoin for lasting control was required in these patients.[20]
It is also approved for treatment of typical and atypical absences, infantile myoclonic, myoclonic and akinetic seizures.[21] A subgroup of people with treatment resistant epilepsymay benefit from long-term use of clonazepam; the benzodiazepine clorazepate may be an alternative due to its slow onset of tolerance.[8]
Anxiety disorders
Rivotril (clonazepam) 2mg tablets
Panic disorder with or without agoraphobia.[22]
Clonazepam has also been found effective in treating other anxiety disorders, such as social phobia, but this is an off-label use.[23]
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.[citation needed] Clonazepam is also effective in the management of acute mania.[24]
Muscle disorders
Restless legs syndrome can be treated using clonazepam as a third-line treatment option as the use of clonazepam is still investigational.[25][26] Bruxism also responds to clonazepam in the short-term.[27] Rapid eye movement behavior disorder responds well to low doses of clonazepam.[28]
The treatment of acute and chronic akathisia induced by neuroleptics, also called antipsychotics.[29][30]
Spasticity related to amyotrophic lateral sclerosis.[31]
Alcohol withdrawal syndrome[32]
Other
Benzodiazepines, such as clonazepam, are sometimes used for the treatment of mania or acute psychosis-induced aggression. In this context, benzodiazepines are given either alone, or in combination with other first-line drugs such as lithium, haloperidol or risperidone.[33][34] The effectiveness of taking benzodiazepines along with antipsychotic medication is unknown, and more research is needed to determine if benzodiazepines are more effective than antipsychotics when urgent sedation is required.[34]
Hyperekplexia[35]
Many forms of parasomnia and other sleep disorders are treated with clonazepam.[36]
It is not effective for preventing migraines.[37]
Adverse effects
Common
§ Sedation[38]
§ Motor impairment
Less common
§ Confusion[8]
§ Irritability and aggression[39]
§ Psychomotor agitation[40]
§ Lack of motivation[41]
§ Loss of libido
§ Impaired motor function[vague]
· Impaired coordination
· Impaired balance
· Dizziness
§ Cognitive impairments[vague][42]
· Hallucinations[43]
· Short-term memory loss[44]
· Anterograde amnesia (common with higher doses)[45]
§ Some users report hangover-like symptoms of drowsiness, headaches, sluggishness, and irritability upon waking up if the medication was taken before sleep. This is likely the result of the medication's long half-life, which continues to affect the user after waking up.[46][47][48] While benzodiazepines induce sleep, they tend to reduce the quality of sleep by suppressing or disrupting REM sleep.[49] After regular use, rebound insomnia may occur when discontinuing clonazepam.[50]
§ Benzodiazepines may cause or worsen depression.[8]
Occasional
§ Dysphoria[51]
§ Thrombocytopenia[52]
§ Induction of seizures[53][54] or increased frequency of seizures[55]
§ Personality changes[56]
§ Behavioural disturbances[57]
§ Ataxia[8]
Rare
§ Suicide through disinhibition[9]
§ Psychosis[58]
§ Incontinence[59][60][61]
§ Liver damage[62]
§ Paradoxical behavioural disinhibition[8][63] (most frequently in children, the elderly, and in persons with developmental disabilities)
· Rage
· Excitement
· Impulsivity
The long-term effects of clonazepam can include depression,[8] disinhibition, and sexual dysfunction.[64]
Drowsiness
Clonazepam, like other benzodiazepines, may impair a person's ability to drive or operate machinery. The central nervous system depressing effects of the drug can be intensified by alcohol consumption, and therefore alcohol should be avoided while taking this medication. Benzodiazepines have been shown to cause dependence. Patients 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.
Withdrawal-related
§ Anxiety
§ Irritability
§ Insomnia
§ Tremors
§ Headaches
§ Stomach pain
§ Nausea
§ Hallucinations
§ Suicidal thoughts or urges
§ Depression
§ Fatigue
§ Dizziness
§ Sweating
§ Confusion
§ Potential to exacerbate existing panic disorder upon discontinuation
§ Seizures[65] similar to delirium tremens (with long-term use of excessive doses)
Benzodiazepines such as clonazepam can be very effective in controlling status epilepticus, but, when used for longer periods of time, some potentially serious side-effects may develop, such as interference with cognitive functions and behavior.[66] Many individuals treated on a long-term basis develop a dependence. Physiological dependence was demonstrated by flumazenil-precipitated withdrawal.[67] Use of alcohol or other CNS depressants while taking clonazepam greatly intensifies the effects (and side-effects) of the drug.
A recurrence of symptoms of the underlying disease should be separated from withdrawal symptoms.[68]
Tolerance and withdrawal
Like all benzodiazepines, clonazepam is a GABA-positive allosteric modulator.[69][70] 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 increase the risk and severity of dependence and withdrawal symptoms. Withdrawal seizures and psychosis can occur in severe cases of withdrawal, and anxiety and insomnia can occur in less severe cases of withdrawal. A 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 intensify. The mechanism of tolerance includes receptor desensitization, down regulation, receptor decoupling, and alterations in subunit composition and in gene transcription coding.[8]
Tolerance to the anticonvulsant effects of clonazepam occurs in both animals and humans. In humans, tolerance to the anticonvulsant effects of clonazepam occurs frequently.[71][72] Chronic use of benzodiazepines can lead to the development of tolerance with a decrease of benzodiazepine binding sites. The degree of tolerance is more pronounced with clonazepam than with chlordiazepoxide.[73] In general, short-term therapy is more effective than long-term therapy with clonazepam for the treatment of epilepsy.[74] 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.[75]
Abrupt or over-rapid withdrawal from clonazepam may result in the development of the benzodiazepine withdrawal syndrome, causing psychosis characterised by dysphoric manifestations, irritability, aggressiveness, anxiety, and hallucinations.[76][77][78] Sudden withdrawal may also induce the potentially life-threatening condition, status epilepticus. Anti-epileptic drugs, benzodiazepines such as clonazepam in particular, should be reduced in dose slowly and gradually when discontinuing the drug to mitigate withdrawal effects.[56] Carbamazepine has been tested in the treatment of clonazepam withdrawal but was found to be ineffective in preventing clonazepam withdrawal-induced status epilepticus from occurring.[79]
Overdose
Excess doses may result in:
§ Difficulty staying awake
§ Mental confusion
§ Nausea
§ Impaired motor functions
· Impaired reflexes
· Impaired coordination
· Impaired balance
· Dizziness
§ Respiratory depression
§ Low blood pressure
§ Coma
Coma can be cyclic, with the individual alternating from a comatose state to a hyper-alert state of consciousness, which occurred in a 4-year-old boy who suffered an overdose of clonazepam.[80] 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.[81]
Overdose symptoms may include extreme drowsiness, confusion, muscle weakness, and fainting.[82]
Mechanism of action
Clonazepam enhances the activity of the inhibitory neurotransmitter GABA in the central nervous system to give its anticonvulsant, anxiolytic, and muscle relaxant effects.[101] It acts by binding to the benzodiazepine site of the GABA receptors, which enhances the electric effect of GABA binding on neurons, resulting in an increased influx of chloride ions into the neurons. This further results in an inhibition of synaptic transmission across the central nervous system.[102][103]
Benzodiazepines do not have any effect on the levels of GABA in the brain.[104] 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 from other anticonvulsant drugs it was compared to in a study.[105]
Clonazepam's primary mechanism of action is the modulation of GABA function in the brain, by the benzodiazepine receptor, located on GABAAreceptors, which, in turn, leads to enhanced GABAergic inhibition of neuronal firing. Benzodiazepines do not replace GABA, but instead enhance the effect of GABA at the GABAA receptor by increasing the opening frequency of chloride ion channels, which leads to an increase in GABA's inhibitory effects and resultant central nervous system depression.[8] In addition, clonazepam decreases the utilization of 5-HT (serotonin) by neurons[106][107] and has been shown to bind tightly to central-type benzodiazepine receptors.[108] Because clonazepam is effective in low milligram doses (0.5 mg clonazepam = 10 mg diazepam),[109] it is said to be among the class of "highly potent" benzodiazepines.[110] The anticonvulsant properties of benzodiazepines are due to the enhancement of synaptic GABA responses, and the inhibition of sustained, high-frequency repetitive firing.[111]
Benzodiazepines, including clonazepam, bind to mouse glial cell membranes with high affinity.[112][113] Clonazepam decreases release of acetylcholine in the feline brain[114] and decreases prolactin release in rats.[115] Benzodiazepines inhibit cold-induced thyroid stimulating hormone (also known as TSH or thyrotropin) release.[116] 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.[117]
Clonazepam is a chlorinated derivative of nitrazepam.[118][7]
Pharmacokinetics
Clonazepam is lipid-soluble, rapidly crosses the blood–brain barrier, and penetrates the placenta. It is extensively metabolised into pharmacologically inactive metabolites, with only 2% of the unchanged drug excreted in the urine.[119] Clonazepam is metabolized extensively via nitroreduction by cytochrome P450 enzymes, including CYP3A4. Erythromycin, clarithromycin, ritonavir, itraconazole, ketoconazole, nefazodone, cimetidine, and grapefruit juice are inhibitors of CYP3A4 and can affect the metabolism of benzodiazepines.[120] It has an elimination half-life of 19–60 hours.[8] 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.[121]
Clonazepam passes rapidly into the central nervous system, with levels in the brain corresponding with levels of unbound clonazepam in the blood serum.[122] Clonazepam plasma levels are very unreliable amongst patients. Plasma levels of clonazepam can vary as much as tenfold between different patients.[123]
Clonazepam has plasma protein binding of 85%.[124][125] Clonazepam passes through the blood–brain barrier easily, with blood and brain levels corresponding equally with each other.[126] The metabolites of clonazepam include 7-aminoclonazepam, 7-acetaminoclonazepam and 3-hydroxy clonazepam.[127][128] These metabolites are excreted by the kidney.[129]
It is effective for 6–8 hours in children, and 6–12 in adults.[130]
