Clonazepam
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Clonazepam
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| Systematic (IUPAC) name | |
| 6-(2-chlorophenyl)-9-nitro-2,5-diazabicyclo [5.4.0]undeca-5,8,10,12-tetraen-3-one | |
| Identifiers | |
| CAS number | |
| ATC code | N03 |
| PubChem | |
| DrugBank | |
| Chemical data | |
| Formula | C15H10ClN3O3 |
| Mol. mass | 315.715 |
| Pharmacokinetic data | |
| Bioavailability | 90% |
| Metabolism | Hepatic CYP3A4 |
| Half life | 18–50 hours |
| Excretion | Renal |
| Therapeutic considerations | |
| Pregnancy cat. | |
| Legal status | |
| Routes | Oral, I.M., I.V, sublingual |
Clonazepam (marketed by Roche under the trade-names Klonopin in the United States and Rivotril, Ravotril or Rivatril in Europe, South America, Canada, India, and Australia) is a drug which is a benzodiazepine derivative. It is a highly potent anticonvulsant and anxiolytic.[1] Clonazepam is a chlorinated derivative of nitrazepam[2] and a nitrobenzodiazepine like nitrazepam.[3]
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[edit] Pharmacology
Clonazepam's primary mechanism of action is via modulating GABA function in the brain, via the benzodiazepine receptor which in turn leads to enhanced GABAergic inhibition of neuronal firing. In addition clonazepam decreases the utilisation of 5-HT (serotonin) by neurons[4][5] and has been shown to bind tightly to central type benzodiazepine receptors.[6] Because of its strong anxiolytic and anticonvulsant properties, it is said to be among the class of "highly potent" benzodiazepines. The anticonvulsant properties of benzodiazepines are due to inhibition of postsynaptic GABA responses and inhibition of sustained high frequency repetitive firing.[7]
Benzodiazepines, including clonazepam, bind to mouse glial cell membranes with high affinity.[8][9] Clonazepam decreases levels of acetylcholine in cat brain [10] and decreases prolactin release.[11] Benzodiazepines inhibit cold-induced thyroid stimulating hormone (also known as TSH or thyrotropin) release.[12] Benzodiazepines acted via micromolar benzodiazepine binding sites as Ca2+ channel blockers and significantly inhibited depolarization-sensitive calcium uptake in an experiment on rat brain cell components. This has been conjectured as a mechanism for high-dose effects on seizures in the study. [13]
[edit] Mechanism of action
The primary mechanism of action of clonazepam is binding to benzodiazepine receptors, which causes an enhancement of GABA binding. This results in inhibitory effects on the central nervous system.[14] Benzodiazepines, however, do not have any effect on the levels of GABA in the brain.[15] While clonazepam has no effect on GABA levels it in addition has no effect on gaba-aminobutyric acid transaminase. Clonazepam does however affect glutamate decarboxylase activity.[16] Benzodiazepine receptors are found in the central nervous system and have been identified 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.[17]
Benzodiazepine drugs including clonazepam increase the inhibitory processes in the cerebral cortex.[18]
It has shown itself to be highly effective as a short-term (3 weeks) adjunct to SSRI treatment in obsessive-compulsive disorder and clinical depression in reducing SSRI side effects with the combination being superior to SSRI treatment alone in a study funded by the manufacturers of clonazepam, Hoffman LaRoche Inc.[19] Similar results have been found with some other anxiety disorders, but the role of the serotonergic effects enhancing the action of the SSRI treatment remains unclear in these cases due to clonazepam's primary anxiolytic mechanism of action.
[edit] Pharmacokinetics
Peak blood concentrations of 6.5–13.5 ng/mL were usually reached within 1–2 hours following a single 2 mg oral dose of micronized clonazepam in healthy adults. In some individuals, however, peak blood concentrations were reached at 4–8 hours.[20]
Clonazepam passes rapidly into the central nervous system with levels in the brain corresponding with levels of unbound clonazepam in the blood serum.[21] Clonazepam plasma levels are very unreliable amongst patients. Plasma levels of clonazepam can vary as much as 10 fold between different patients.[22]
Clonazepam is largely bound to plasma proteins.[23] The metabolites of clonazepam include 7-aminoclonazepam, 7-acetaminoclonazepam and 3-hydroxy clonazepam.[24][25]
[edit] Tolerance and withdrawal
Like all benzodiazepines, clonazepam is a benzodiazepine receptor agonist. Long-term use (more than 2–4 weeks) can lead to a number of problems, including muscle weakness and fatigue, tolerance, physical dependence and withdrawal syndromes upon discontinuation. The benzodiazepine withdrawal syndrome, which may appear during reduction or withdrawal of clonazepam treatment, can be reduced in intensity with gradual reduction of dosage.
Tolerance
In humans tolerance to the anticonvulsant effects of clonazepam occurs frequently.[26] Chronic use of benzodiazepines leads to the development of tolerance with a decrease of benzodiazepine binding sites. The degree of tolerance is more pronounced with clonazepam than with chlordiazepoxide.[27] Short term therapy is generally more effective than long term therapy with clonazepam for the treatment of epilepsy.[28] 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.[29]
Withdrawal
Discontinuation of or reduction in dosage after regular use may result in the clonazepam withdrawal syndrome.[30] Abrupt or over-rapid withdrawal from clonazepam may result in the development of the benzodiazepine withdrawal syndrome with psychotic attacks characterised by dysphoric manifestations, irritability, aggressiveness, anxiety, and hallucinations.[31][32] Sudden withdrawal from clonazepam may also result in withdrawal symptoms including anxiety, irritability and potentially the life threatening condition status epilepticus. Antiepileptic drugs, benzodiazepines such as clonazepam in particular, should be reduced slowly and gradually when discontinuing the drug to reduce withdrawal effects.[33] 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.[34]
[edit] Indications
Clonazepam may be prescribed for:
- Epilepsy[35]
- Anxiety disorders
- Panic disorder [36]
- Initial treatment of mania, together with firstline drugs such as lithium, haloperidol or risperidone
- Restless legs syndrome
- Use as a muscle relaxant (Off Label Use)
- Use as a sedative for sleep (Off Label Use). Not used that often because of clonazepam's long half-life may cause next day effects.
In the treatment of acute epilepsy via intravenous administration approximately 72.5 per cent of patients show improved EEG patterns, 17.5 per cent show no improvement and for 10 per cent of patients clonazepam has a paradoxical effect and worsens EEG readings.[37]
Clonazepam is sometimes used for refractory epilepsies; however, long-term prophylactic treatment of epilepsy has considerable limitations, most notably the loss of antiepileptic effects due to tolerance, which renders the drug useless with long-term use, and also side effects such as sedation, which is why clonazepam and benzodiazepines as a class should generally only be prescribed for the acute management of epilepsies.[38]
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.[39]
Clonazepam has been found to generally be ineffective in the control of infantile spasms.[40] Clonazepam is less effective and potent as an anticonvulsant in bringing infantile seizures under control compared with nitrazepam in the treatment of West syndrome, which is an age-dependent epilepsy affecting the very young. However, as with other epilepies treated with benzodiazepines, long-term therapy becomes ineffective with prolonged therapy, and the side effects of hypotonia and drowsiness are troublesome with clonazepam therapy; other antiepileptic agents are therefore recommended for long-term therapy, possibly Corticotropin (ACTH) or vigabatrin. Clonazepam is therefore not recommended for widespread use in the management of seizures related to West syndrome.[41]
Clonazepam has been used in the management of seizure disorders in children and also for infantile spasms. However, usefulness of clonazepam is limited due to its dose limiting side effects, especially its negative effect on cognition.
[edit] Availability
Clonazepam was approved in the United States as a generic drug in 1997 and is now manufactured and marketed by several companies.
Clonazepam is available in the U.S. as tablets (0.5, 1.0, and 2 mg) and orally disintegrating tablets (wafers) (0.125, 0.25, 0.5, 1.0, and 2 mg). In other countries, clonazepam is usually available as tablets (0.5 and 2 mg), orally disintegrating tablets (0.25, 0.5, 1 and 2 mg) oral solution (drops, 2.5 mg/mL), as well as solution for injection or intravenous infusion, containing 1 mg clonazepam per ampoule (e.g. Rivotril inj.).
[edit] Side effects
- Common
- Drowsiness
- Impairment of cognition and judgment
- Pupil dilation[citation needed]
- Irritability and aggression[42]
- Psychomotor agitation[43]
- Lack of motivation[44]
- Impaired motor function
- Impaired coordination
- Impaired balance
- Dizziness
- Anterograde amnesia (common with higher doses)
- Some users report hangover-like symptoms of being drowsy, having a headache, being sluggish, and being irritable after waking up if the medication is taken before sleep. This is likely the result of the medication's long half-life, which continues to affect the user after waking up, as well as its disruption of the REM cycle.
- Occasional
- Serious dysphoria[45]
- Thrombocytopenia[46]
- Serious psychological and psychiatric side effects[47][48]
- Induction of seizures[49] or increased frequency of seizures[50]
- Personality changes[33]
- Rare
- Psychosis[51]
- Incontinence[52][53][54]
- Paradoxical behavioural disinhibition[55][56][57] (most frequently in children, the elderly, and in persons with developmental disabilities)
- Rage
- Excitement
- Impulsivity
- Withdrawal-related
- Anxiety, irritability, insomnia
- Panic attacks, tremor
- Seizures[58] similar to delirium tremens (with long-term use of excessive doses)
Benzodiazepines such as clonazepam can be very effective in controlling status epilepticus but when used for longer periods of time serious side effects may develop such as interference with cognitive functions and behaviour.[59] 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.[60] Use of alcohol or other CNS depressants while taking clonazepam greatly intensifies the effects (and side effects) of the drug. Side effects of the drug itself are generally benign, but sudden withdrawal after long-term use can cause severe, even fatal, symptoms.
[edit] Special precautions
Caution in the Elderly. Increased risk of impairments, falls and drug accumulation.[citation needed]
Caution in children. Clonazepam is not recommended for use in those under 18. Use in very young children may be especially hazardous. Of anticonvulsant drugs behavioural disturbances occur most frequently with clonazepam and phenobarbital.[61]
Caution using high dosages of clonazepam. Doses higher than 0.5 - 1 mg per day is associated with significant sedation.[62]
Clonazepam may aggravate hepatic porphyria.[63][64]
Caution in schizophrenia. Clonazepam has been found to be not effective in the management of schizophrenia and has been found to increase the risk of violent behavior.[65]
[edit] Interactions
Clonazepam decreases the levels of carbamazepine,[66][67] and likewise be reduced in its levels by carbamazepine.[68] Clonazepam may affect levels of phenytoin (diphenylhydantoin) by decreasing,[66][69] or increasing.[70][71] In turn Phenytoin may lower clonazepam plasma levels, by increasing the speed of clonazepam clearance by approximately 50% and decreasing its half life by 31 per cent.[72] Clonazepam increases the levels of primidone,[70] and phenobarbital.[73]
[edit] Warnings
Clonazepam, like many other benzodiazepines, may impair one's ability to drive or operate heavy machinery. The central nervous system depressing effects of the drug can be augmented by alcohol consumption. Benzodiazepines have been shown to cause both psychological and physical dependence. Patients physically dependent on clonazepam should be slowly titrated off under the supervision of a qualified healthcare professional to reduce the intensity of withdrawal or rebound symptoms.
[edit] Protracted withdrawal
Protracted benzodiazepine withdrawal syndrome, occurs in some individuals after discontinuation of benzodiazepine drugs. Symptoms can persist for months or years. In some cases protracted withdrawal may be due to physicochemical neuronal damage which may be permanent or only slowly reversible.[74]
However not all experts agree. In 1993 the New England Journal of Medicine published a paper claiming that there is no reliable evidence to support the existence of a persistent benzodiazepine withdrawal syndrome, and this alleged syndrome has been described only in anecdotal reports, with patients typically reporting "withdrawal" symptoms not present during or before benzodiazepine treatment that persist for many months or years after treatment is stopped. Experimental neuropharmacologic studies document that all the side effects of benzodiazepines, whether behavioral or neurochemical, disappear within several days or weeks after the drug is eliminated. The weight of evidence indicates that any new symptoms that persist for more than two months after the last dose of a benzodiazepine either are part of the premorbid condition or have appeared by coincidence or as a consequence of the natural history of the underlying illness.[75]
In a more recent medical paper published in 1995 it was claimed that about 10 - 15% of people who withdraw from benzodiazepines develop a protracted withdrawal syndrome. The protracted withdrawal syndrome is due to pharmacological withdrawal symptoms involving the slow reversal of receptor changes which have developed over time due to pharmacological drug tolerance. The protracted withdrawal syndrome persists for many months or years and occasionally some symptoms may be permanent. There is some evidence that chronic use of benzodiazepines cause dose related structural brain damage.[76]
Hoffmann–La Roche pharmaceutical company, the manufacturer of clonazepam, in a 2007 product information publication, acknowledges the existence of protracted benzodiazepine withdrawal syndromes and recommends that its product flumazenil is not used to treat protracted benzodiazepine withdrawal syndromes.[77]
The below list of some protracted withdrawal symptoms comes from a 2004 publication by Professor Ashton.[78]
- Anxiety
- Insomnia
- Depression
- Tinnitus
- Tingling and numbness in limbs
- Muscle pain and tension
- Weakness
- Cramps
- Tremors
- Irritable bowel
- Cognitive dysfunction
[edit] Pregnancy
There is some medical evidence of various malformations e.g. cardiac or facial deformations when used in early pregnancy, however the data is not conclusive. The data is also inconclusive whether benzodiazepines such as clonazepam cause developmental deficits or decreases in IQ when taken during pregnancy. Clonazepam when used late in pregnancy may result in the development of a severe benzodiazepine withdrawal syndrome in the neonate and also floppy infant syndrome. Withdrawal symptoms from benzodiazepines in the neonate may include hypotonia, and reluctance to suck, to apnoeic spells, cyanosis, and impaired metabolic responses to cold stress. These symptoms may persist for hours or months after birth.[79]
[edit] Overdose
An individual who has consumed too much clonazepam will display one or more of the following symptoms:
- Coma
- Hypotension
- Impaired motor functions
- Impaired reflexes
- Impaired coordination
- Impaired balance
- Dizziness
- Labored breathing
- Mental confusion
- Somnolence (difficulty staying awake)
- Nausea
Coma 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.[80] The combination of clonazepam and certain barbiturates eg amobarbital at prescribed doses has resulted in a synergistic potentiation of the effects of each drug leading to serious respiratory depression.[81]
[edit] Recreational use and abuse
Clonazepam is one of the most commonly abused prescription drugs.[82] A nationwide USA government study conducted by SAMHSA found that benzodiazepines in the USA are the most frequently abused pharmaceutical drug with 35% of drug related visits to the Emergency Department involving benzodiazepines. Benzodiazepines are more commonly abused than opiate pharmaceuticals which accounted for 32% of visits to the emergency department. No other pharmaceutical is more commonly abused than benzodiazepines. Males abuse benzodiazepines as commonly as females. Of drugs used in attempted suicide, benzodiazepines are the most commonly used pharmaceutical drug with 26% of attempted suicides involving benzodiazepines. The most commonly abused benzodiazepine is alprazolam. Clonazepam is the 2nd most abused benzodiazepine in the USA. Lorazepam is the 3rd most commonly abused benzodiazepine and diazepam the 4th most commonly abused benzodiazepine in the USA.[83]
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[edit] External links
- Wallace, Christina. "Kpin, a hit drug with teens, can be deadly, officials say." Boston Metro, Wednesday April 12, 2006. Page 2.
- Carlos, Jean-Marc: The Treatment of Panic Disorder http://www.medscape.com/viewarticle/497207
- Rx-List - Clonazepam
- Poisons Information Monograph - Clonazepam
- FDA prescription insert
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