Clonazepam is a
benzodiazepineA benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
derivative with highly potent
anticonvulsantThe 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. The goal of an anticonvulsant is to suppress the rapid and...
,
muscle relaxantA 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
anxiolyticAn anxiolytic is a drug used for the treatment of symptoms of anxiety. Anxiolytics have been shown to be useful in the treatment of anxiety disorders, as have antidepressants such as the selective serotonin reuptake inhibitors .Though not anxiolytics, beta-receptor blockers such as propranolol and...
properties. It is marketed by
RocheF. 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-names
Klonopin in the United States, and
Ravotril in Chile. Other names like
Rivotril or
Rivatril are known throughout the large majority of the rest of the world. Clonazepam is a
chlorinatedHalogenation is a chemical reaction that incorporates a halogen atom into a molecule. More specific descriptions exist that specify the type of halogen: fluorination, chlorination, bromination, and iodination....
derivative of
nitrazepamNitrazepam 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 nitrobenzodiazepine.
Indications
Clonazepam may be prescribed for
- Epilepsy
Epilepsy is a common chronic neurological disorder characterized by recurrent unprovoked seizures...
- Anxiety disorder
Anxiety disorder is a blanket term covering several different forms of abnormal and pathological fears and anxieties which only came under the aegis of psychiatry at the very end of the 19th century. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders...
s
- 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...
- Initial treatment of mania
Mania is a severe medical condition characterized by extremely elevated mood, energy, unusual thought patterns and sometimes psychosis...
or acute psychosis together with firstline drugs such as lithiumLithium is a soft, silver-white metal that belongs to the alkali metal group of chemical elements. It is represented by the symbol Li, and it has the atomic number three. Under standard conditions it is the lightest metal and the least dense solid element. Like all alkali metals, lithium is highly...
, haloperidolHaloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines....
or risperidoneRisperidone is an atypical antipsychotic used to treat schizophrenia , the mixed and manic states associated with bipolar disorder, and irritability in children with autism...
- Hyperekplexia
Hyperekplexia is classically characterised by pronounced startle responses to tactile or acoustic stimuli, hypertonia and episodic neonatal apnoea. The hypertonia may be predominantly truncal, attenuated during sleep and less prominent after a year of age...
- Bruxism
Bruxism is characterized by the grinding of the teeth and is typically accompanied by 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...
- Restless legs syndrome
- Rapid eye movement behavior disorder
Rapid eye movement sleep behavior disorder is a sleep disorder that involves abnormal behavior during the sleep phase with rapid eye movement . It was first described in 1986....
- Hallucinogen persisting perception disorder
Hallucinogen Persisting Perception Disorder or HPPD is a disorder characterized by a continual presence of visual disturbances that are reminiscent of those generated by the ingestion of hallucinogenic substances. Previous use of hallucinogens is needed, though not sufficient, for diagnosing...
- The treatment of acute and chronic akathisia
Akathisia, or acathisia, is a syndrome characterized by unpleasant sensations of "inner" restlessness that manifests itself with an inability to sit still or remain motionless...
http://smj.org.uk/1001/aka1001.htmhttp://www3.interscience.wiley.com/journal/120003401/abstract?CRETRY=1&SRETRY=0
- Use as a muscle relaxant (Off Label Use)
- Use as a sedative for sleep (Off Label Use). Its long half-life sometimes makes it useful for treating middle-of-the-night insomnia
Middle-of-the-night insomnia is insomnia characterized by difficulty returning to sleep after awakening in the middle of the night. Also referred to as nocturnal awakenings, middle of the night awakenings and middle insomnia, this category of insomnia is different from initial or sleep-onset...
(waking up too early), but may also lead to next-day effects. Clonazepam can also be used to relax bladder neck tightness to improve symptoms of benign prostatic hypertrophy, also known as BPH.
In the treatment of acute epilepsy via intravenous administration approximately 72.5 percent of patients show improved EEG patterns, 17.5 percent show no improvement and for 10 percent of patients clonazepam has a paradoxical effect and worsens EEG readings.
Clonazepam is sometimes used 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 useless with long-term use, and side-effects such as sedation, which is why clonazepam and benzodiazepines as a class should, in general, be prescribed only for the acute management of epilepsies.
Clonazepam or diazepam has been found to be effective in the acute control of nonconvulsive
status epilepticusStatus epilepticus refers to 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 30 minutes , or recurrent seizures without regaining consciousness between...
. However, the benefits tended to be transient in many of the patients, and the addition of
phenytoinPhenytoin sodium is a commonly used antiepileptic. Phenytoin acts to dampen the unwanted, runaway 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 syndromeWest 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 epilepies treated with benzodiazepines, long-term therapy becomes ineffective with prolonged therapy, and the side-effects of
hypotoniaHypotonia is a disorder that causes 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
vigabatrinVigabatrin is an antiepileptic drugs that inhibits the catabolism of GABA by irreversibly inhibiting GABA transaminase. It is an analog of GABA, but it is not a receptor agonist. It is manufactured and distributed by Lundbeck Inc. . Lundbeck Inc. is a wholly owned subsidiary of H...
. Furthermore, Clonazepam is not recommended for widespread use in the management of seizures related to West syndrome.
Clonazepam has been used in the management of seizure disorders in children and also for infantile spasms. However, usefulness of clonazepam is limited due to its dose-limiting side-effects, especially its negative effect on cognition.
Clonazepam has shown itself to be highly effective as a short-term (3 weeks) adjunct to SSRI treatment in
obsessive-compulsive disorderObsessive–compulsive disorder is a mental disorder characterized by intrusive thoughts that produce anxiety, by repetitive behaviors aimed at reducing anxiety, or by combinations of such thoughts and behaviors...
and
clinical depressionMajor depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and 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.
Availability
Clonazepam was approved in the United States as a
generic drugA generic drug is a drug which isproduced and distributed without patent protection. The generic drug may still have a patent on the formulation but not on the active ingredient....
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.).
Side-effects
Common:
- Drowsiness
- Impairment of cognition, judgment, or memory
- Irritability and aggression
- Psychomotor agitation
- Lack of motivation
- Loss of libido
- Impaired motor function
- Impaired coordination
- Impaired balance
- Dizziness
- Cognitive Impairments
- Increased Sleepwalking (If used in treatment of sleepwalking)
- Auditory Hallucinations
- Short-term memory loss
- Anterograde amnesia
Anterograde amnesia is a loss of the ability to create memories after the event that caused the amnesia occurs. Anterograde amnesia and retrograde amnesia, where memories created prior to the event are lost, can occur together in the same patient...
(common with higher doses)
- Some users report hangover
A 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...
-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
Dysphoria is an unpleasant or uncomfortable mood, such as sadness , anxiety, irritability, or restlessness. Etymologically, it is the opposite of euphoria....
- Thrombocytopenia
Thrombocytopenia is the presence of relatively few platelets in blood.Generally speaking, in humans, a normal platelet count ranges from 150,000 and 450,000 per mm3. These limits, however, are determined by the 2.5th lower and upper percentile, and a deviation does not necessarily imply...
- Serious psychological and psychiatric side-effects
- Induction of seizures or increased frequency of seizures
- Personality changes
- Behavioural disturbances
Rare:
- Psychosis
Psychosis literally 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"...
- Incontinence
Urinary 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...
- Liver damage
- Paradoxical behavioural disinhibition (most frequently in children, the elderly, and in persons with developmental disabilities)
- Rage
- Excitement
- Impulsivity
Long term effects:
The long term effects of clonazepam can include; depression,
disinhibitionDisinhibition 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 dysfunctionSexual 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.-Categories:...
.
Withdrawal-related:
- Anxiety, irritability, insomnia
- Panic attacks, tremor
- Seizures similar to delirium tremens
Delirium 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 epilepticusStatus epilepticus refers to 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 30 minutes , or recurrent seizures without regaining consciousness between...
, but, when used for longer periods of time, serious side-effects may develop, such as interference with cognitive functions and behaviour. 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
therapeuticPharmacotherapy is that area of pharmacy practice that is responsible for ensuring the safe, appropriate, and economical use of drugs in patient care. A speciailist in pharmacotherapy has responsibility for direct patient care, often functions as a member of a multidisciplinary team and is...
low-dose benzodiazepine users — physiological dependence was demonstrated via
flumazenilFlumazenil is a benzodiazepine antagonist....
-precipitated withdrawal.
Use of alcohol or other
CNSThe central nervous system is the part of the nervous system that functions to coordinate the activity of all parts of the bodies of bilaterian animals—that is, all animals more advanced than sponges or jellyfish. In vertebrates, the central nervous system is enclosed in the meninges. It contains...
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 agonist.
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 , is a sedative/hypnotic drug and benzodiazepine derivative. It is marketed under the trade names Klopoxid, Librax , Libritabs, Librium, Mesural, Multum, Novapam, Risolid, Silibrin, Sonimen, Tropium, and Zetran.Chlordiazepoxide has...
. 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—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 reduces the dosage too rapidly...
, causing psychotic attacks characterised by dysphoric manifestations, irritability, aggressiveness, anxiety, and hallucinations. Sudden withdrawal may also induce the potentially the life threatening condition
status epilepticusStatus epilepticus refers to 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 30 minutes , or recurrent seizures without regaining consciousness between...
. Antiepileptic drugs, benzodiazepines such as clonazepam in particular, should be reduced slowly and gradually when discontinuing the drug to reduce withdrawal effects.
CarbamazepineCarbamazepine 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 epilepticusStatus epilepticus refers to 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 30 minutes , or recurrent seizures without regaining consciousness between...
from occurring.
Special precautions
Caution in the elderly. Increased risk of impairments, falls and drug accumulation.
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
phenobarbitalPhenobarbital or phenobarbitone is a barbiturate, first marketed as Luminal by Friedr. Bayer et comp. It is the most widely used anticonvulsant worldwide...
.
Caution using high dosages of clonazepam. Doses higher than 0.5 – 1 mg per day are associated with significant sedation.
Clonazepam may aggravate
hepatic porphyriaHepatic 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
schizophreniaSchizophrenia , from the Greek roots skhizein and phrēn, phren- is a psychiatric diagnosis that describes a mental disorder characterized by abnormalities in the perception or expression of reality...
. A 1982 double blinded placebo controlled study found clonazepam increases violent behavior in in individuals with chronic schizophrenia.
Interactions
Clonazepam decreases the levels of
carbamazepineCarbamazepine is an anticonvulsant and mood stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
, and likewise its level is reduced by carbamazepine.
Clonazepam may affect levels of
phenytoinPhenytoin sodium is a commonly used antiepileptic. Phenytoin acts to dampen the unwanted, runaway 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
primidonePrimidone is an anticonvulsant of the pyrimidinedione class whose active metabolites, phenobarbital and phenylethylmalonamide , are also anticonvulsants...
, and
phenobarbitalPhenobarbital or phenobarbitone is a barbiturate, first marketed as Luminal by Friedr. Bayer et comp. It is the most widely used anticonvulsant worldwide...
.
Warnings
Clonazepam, like many other benzodiazepines, may impair one's ability to drive or operate heavy machinery. The central nervous system depressing effects of the drug can be intensified by alcohol consumption. Benzodiazepines have been shown to cause both psychological and physical dependence. Patients physically dependent on clonazepam should be slowly titrated off under the supervision of a qualified healthcare professional to reduce the intensity of withdrawal or rebound symptoms.
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 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 and also floppy infant syndrome. Withdrawal symptoms from benzodiazepines in the neonate may include
hypotoniaHypotonia is a disorder that causes 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 reluctance to suck, to apnoeic spells,
cyanosisCyanosis is a blue coloration of the skin and mucous membranes due to the presence of > 5g/dl deoxygenated hemoglobin in blood vessels near the skin surface....
, and impaired metabolic responses to cold stress. These symptoms may persist for hours or months after birth. Floppy infant syndrome may occur if benzodiazepines are given close to or during delivery.
Pharmacology
Clonazepam's primary mechanism of action is via modulating
GABAGabâ or gabaa, for the Cebuano people , 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, which, in turn, leads to enhanced GABAergic inhibition of neuronal firing. In addition clonazepam decreases the utilization of 5-HT (serotonin) by neurons and has been shown to bind tightly to central type benzodiazepine receptors. Because of its strong
anxiolyticAn anxiolytic is a drug used for the treatment of symptoms of anxiety. Anxiolytics have been shown to be useful in the treatment of anxiety disorders, as have antidepressants such as the selective serotonin reuptake inhibitors .Though not anxiolytics, beta-receptor blockers such as propranolol and...
,
anticonvulsantThe 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. The goal of an anticonvulsant is to suppress the rapid and...
and euphoric properties, it is said to be among the class of "highly potent" benzodiazepines.
The anticonvulsant properties of benzodiazepines are due to enhancement of
synapticSynaptic may refer to:*anything related to a synapse or to synapsis*Synaptic , a graphical package management program for APT See also*Synaptics, the main laptop touchpad manufacturer...
GABA responses and inhibition of sustained high frequency repetitive firing.
Benzodiazepines, including clonazepam, bind to mouse
glial cellGlial cells, commonly called neuroglia or simply glia , are non-neuronal cells that provide support and nutrition, maintain homeostasis, form myelin, and participate in signal transmission in the nervous system...
membranes with high affinity. Clonazepam decreases release of acetylcholine in cat brain and decreases
prolactinProlactin or Luteotropic hormone is a peptide hormone discovered by Dr. Henry Friesen, primarily associated with lactation. In breastfeeding, the act of an infant suckling the nipple stimulates the production of prolactin, which fills the breast with milk via a process called lactogenesis, in...
release in rats. Benzodiazepines inhibit cold-induced thyroid stimulating hormone (also known as
TSHTSH may refer to:*Their Serene Highnesses, a style used by some Royal houses.*Thyroid-stimulating hormone, a hormone synthesized and secreted by thyrotrope cells *Tanzanian shilling, the currency of Tanzania...
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 systemThe central nervous system is the part of the nervous system that functions to coordinate the activity of all parts of the bodies of bilaterian animals—that is, all animals more advanced than sponges or jellyfish. In vertebrates, the central nervous system is enclosed in the meninges. It contains...
. 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 systemThe central nervous system is the part of the nervous system that functions to coordinate the activity of all parts of the bodies of bilaterian animals—that is, all animals more advanced than sponges or jellyfish. In vertebrates, the central nervous system is enclosed in the meninges. It contains...
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
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 elimination half life of clonazepam is between 20 – 80 hours. Clonazepam does not produce any pharmacologically active metabolites. 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:
- Coma
In medicine, a coma is a profound state of unconsciousness. A comatose person cannot be awakened, fails to respond normally to pain or light, does not have sleep-wake cycles, and does not take voluntary actions....
- Hypotension
In physiology and medicine, hypotension refers to an abnormally low blood pressure. This 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 opposite of hypertension, which is high blood...
- Impaired motor functions
- Impaired reflexes
- Impaired coordination
- Impaired balance
- Dizziness
- Labored breathing
- Mental confusion
- Somnolence
Somnolence 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)
- Nausea
Nausea is the sensation of unease and discomfort in the stomach with an urge to vomit.-Causes:...
Coma can be cyclic with the individual alternating from a comatose state to a hyperalert state of consciousness, as occurred in a 4-year-old boy who suffered an overdose of clonazepam. The combination of clonazepam and certain barbiturates eg
amobarbitalAmobarbital 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.
Drug misuse
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 abuseDrug abuse has a huge range of definitions related to taking a psychoactive drug or performance enhancing drug for a non-therapeutic or non-medical effect. All of these definitions imply a negative judgement of the drug use in question...
, accidental or intentional overdose, or adverse reactions resulting from legitimate use of the medication.
See also
- Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
- Benzodiazepine dependence
Benzodiazepine dependence or benzodiazepine addiction is the condition when a person is dependent on benzodiazepine drugs. Dependence can either be a psychological dependence or a physical dependence or a combination of the two...
- 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 reduces the dosage too rapidly...
- Long term effects of benzodiazepines
The long-term effects of benzodiazepines include drug dependence as well as the possibility of adverse effects on cognitive function, physical, and mental health. There is evidence that reduction or withdrawal from benzodiazepines can lead to a reduction in anxiety symptoms...
External links
- Carlos, Jean-Marc: The Treatment of Panic Disorder http://www.medscape.com/viewarticle/497207
Clonazepam is a
benzodiazepineA benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
derivative with highly potent
anticonvulsantThe 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. The goal of an anticonvulsant is to suppress the rapid and...
,
muscle relaxantA 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
anxiolyticAn anxiolytic is a drug used for the treatment of symptoms of anxiety. Anxiolytics have been shown to be useful in the treatment of anxiety disorders, as have antidepressants such as the selective serotonin reuptake inhibitors .Though not anxiolytics, beta-receptor blockers such as propranolol and...
properties. It is marketed by
RocheF. 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-names
Klonopin in the United States, and
Ravotril in Chile. Other names like
Rivotril or
Rivatril are known throughout the large majority of the rest of the world. Clonazepam is a
chlorinatedHalogenation is a chemical reaction that incorporates a halogen atom into a molecule. More specific descriptions exist that specify the type of halogen: fluorination, chlorination, bromination, and iodination....
derivative of
nitrazepamNitrazepam 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 nitrobenzodiazepine.
Indications
Clonazepam may be prescribed for
- Epilepsy
Epilepsy is a common chronic neurological disorder characterized by recurrent unprovoked seizures...
- Anxiety disorder
Anxiety disorder is a blanket term covering several different forms of abnormal and pathological fears and anxieties which only came under the aegis of psychiatry at the very end of the 19th century. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders...
s
- 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...
- Initial treatment of mania
Mania is a severe medical condition characterized by extremely elevated mood, energy, unusual thought patterns and sometimes psychosis...
or acute psychosis together with firstline drugs such as lithiumLithium is a soft, silver-white metal that belongs to the alkali metal group of chemical elements. It is represented by the symbol Li, and it has the atomic number three. Under standard conditions it is the lightest metal and the least dense solid element. Like all alkali metals, lithium is highly...
, haloperidolHaloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines....
or risperidoneRisperidone is an atypical antipsychotic used to treat schizophrenia , the mixed and manic states associated with bipolar disorder, and irritability in children with autism...
- Hyperekplexia
Hyperekplexia is classically characterised by pronounced startle responses to tactile or acoustic stimuli, hypertonia and episodic neonatal apnoea. The hypertonia may be predominantly truncal, attenuated during sleep and less prominent after a year of age...
- Bruxism
Bruxism is characterized by the grinding of the teeth and is typically accompanied by 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...
- Restless legs syndrome
- Rapid eye movement behavior disorder
Rapid eye movement sleep behavior disorder is a sleep disorder that involves abnormal behavior during the sleep phase with rapid eye movement . It was first described in 1986....
- Hallucinogen persisting perception disorder
Hallucinogen Persisting Perception Disorder or HPPD is a disorder characterized by a continual presence of visual disturbances that are reminiscent of those generated by the ingestion of hallucinogenic substances. Previous use of hallucinogens is needed, though not sufficient, for diagnosing...
- The treatment of acute and chronic akathisia
Akathisia, or acathisia, is a syndrome characterized by unpleasant sensations of "inner" restlessness that manifests itself with an inability to sit still or remain motionless...
http://smj.org.uk/1001/aka1001.htmhttp://www3.interscience.wiley.com/journal/120003401/abstract?CRETRY=1&SRETRY=0
- Use as a muscle relaxant (Off Label Use)
- Use as a sedative for sleep (Off Label Use). Its long half-life sometimes makes it useful for treating middle-of-the-night insomnia
Middle-of-the-night insomnia is insomnia characterized by difficulty returning to sleep after awakening in the middle of the night. Also referred to as nocturnal awakenings, middle of the night awakenings and middle insomnia, this category of insomnia is different from initial or sleep-onset...
(waking up too early), but may also lead to next-day effects. Clonazepam can also be used to relax bladder neck tightness to improve symptoms of benign prostatic hypertrophy, also known as BPH.
In the treatment of acute epilepsy via intravenous administration approximately 72.5 percent of patients show improved EEG patterns, 17.5 percent show no improvement and for 10 percent of patients clonazepam has a paradoxical effect and worsens EEG readings.
Clonazepam is sometimes used 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 useless with long-term use, and side-effects such as sedation, which is why clonazepam and benzodiazepines as a class should, in general, be prescribed only for the acute management of epilepsies.
Clonazepam or diazepam has been found to be effective in the acute control of nonconvulsive
status epilepticusStatus epilepticus refers to 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 30 minutes , or recurrent seizures without regaining consciousness between...
. However, the benefits tended to be transient in many of the patients, and the addition of
phenytoinPhenytoin sodium is a commonly used antiepileptic. Phenytoin acts to dampen the unwanted, runaway 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 syndromeWest 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 epilepies treated with benzodiazepines, long-term therapy becomes ineffective with prolonged therapy, and the side-effects of
hypotoniaHypotonia is a disorder that causes 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
vigabatrinVigabatrin is an antiepileptic drugs that inhibits the catabolism of GABA by irreversibly inhibiting GABA transaminase. It is an analog of GABA, but it is not a receptor agonist. It is manufactured and distributed by Lundbeck Inc. . Lundbeck Inc. is a wholly owned subsidiary of H...
. Furthermore, Clonazepam is not recommended for widespread use in the management of seizures related to West syndrome.
Clonazepam has been used in the management of seizure disorders in children and also for infantile spasms. However, usefulness of clonazepam is limited due to its dose-limiting side-effects, especially its negative effect on cognition.
Clonazepam has shown itself to be highly effective as a short-term (3 weeks) adjunct to SSRI treatment in
obsessive-compulsive disorderObsessive–compulsive disorder is a mental disorder characterized by intrusive thoughts that produce anxiety, by repetitive behaviors aimed at reducing anxiety, or by combinations of such thoughts and behaviors...
and
clinical depressionMajor depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and 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.
Availability
Clonazepam was approved in the United States as a
generic drugA generic drug is a drug which isproduced and distributed without patent protection. The generic drug may still have a patent on the formulation but not on the active ingredient....
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.).
Side-effects
Common:
- Drowsiness
- Impairment of cognition, judgment, or memory
- Irritability and aggression
- Psychomotor agitation
- Lack of motivation
- Loss of libido
- Impaired motor function
- Impaired coordination
- Impaired balance
- Dizziness
- Cognitive Impairments
- Increased Sleepwalking (If used in treatment of sleepwalking)
- Auditory Hallucinations
- Short-term memory loss
- Anterograde amnesia
Anterograde amnesia is a loss of the ability to create memories after the event that caused the amnesia occurs. Anterograde amnesia and retrograde amnesia, where memories created prior to the event are lost, can occur together in the same patient...
(common with higher doses)
- Some users report hangover
A 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...
-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
Dysphoria is an unpleasant or uncomfortable mood, such as sadness , anxiety, irritability, or restlessness. Etymologically, it is the opposite of euphoria....
- Thrombocytopenia
Thrombocytopenia is the presence of relatively few platelets in blood.Generally speaking, in humans, a normal platelet count ranges from 150,000 and 450,000 per mm3. These limits, however, are determined by the 2.5th lower and upper percentile, and a deviation does not necessarily imply...
- Serious psychological and psychiatric side-effects
- Induction of seizures or increased frequency of seizures
- Personality changes
- Behavioural disturbances
Rare:
- Psychosis
Psychosis literally 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"...
- Incontinence
Urinary 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...
- Liver damage
- Paradoxical behavioural disinhibition (most frequently in children, the elderly, and in persons with developmental disabilities)
- Rage
- Excitement
- Impulsivity
Long term effects:
The long term effects of clonazepam can include; depression,
disinhibitionDisinhibition 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 dysfunctionSexual 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.-Categories:...
.
Withdrawal-related:
- Anxiety, irritability, insomnia
- Panic attacks, tremor
- Seizures similar to delirium tremens
Delirium 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 epilepticusStatus epilepticus refers to 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 30 minutes , or recurrent seizures without regaining consciousness between...
, but, when used for longer periods of time, serious side-effects may develop, such as interference with cognitive functions and behaviour. 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
therapeuticPharmacotherapy is that area of pharmacy practice that is responsible for ensuring the safe, appropriate, and economical use of drugs in patient care. A speciailist in pharmacotherapy has responsibility for direct patient care, often functions as a member of a multidisciplinary team and is...
low-dose benzodiazepine users — physiological dependence was demonstrated via
flumazenilFlumazenil is a benzodiazepine antagonist....
-precipitated withdrawal.
Use of alcohol or other
CNSThe central nervous system is the part of the nervous system that functions to coordinate the activity of all parts of the bodies of bilaterian animals—that is, all animals more advanced than sponges or jellyfish. In vertebrates, the central nervous system is enclosed in the meninges. It contains...
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 agonist.
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 , is a sedative/hypnotic drug and benzodiazepine derivative. It is marketed under the trade names Klopoxid, Librax , Libritabs, Librium, Mesural, Multum, Novapam, Risolid, Silibrin, Sonimen, Tropium, and Zetran.Chlordiazepoxide has...
. 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—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 reduces the dosage too rapidly...
, causing psychotic attacks characterised by dysphoric manifestations, irritability, aggressiveness, anxiety, and hallucinations. Sudden withdrawal may also induce the potentially the life threatening condition
status epilepticusStatus epilepticus refers to 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 30 minutes , or recurrent seizures without regaining consciousness between...
. Antiepileptic drugs, benzodiazepines such as clonazepam in particular, should be reduced slowly and gradually when discontinuing the drug to reduce withdrawal effects.
CarbamazepineCarbamazepine 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 epilepticusStatus epilepticus refers to 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 30 minutes , or recurrent seizures without regaining consciousness between...
from occurring.
Special precautions
Caution in the elderly. Increased risk of impairments, falls and drug accumulation.
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
phenobarbitalPhenobarbital or phenobarbitone is a barbiturate, first marketed as Luminal by Friedr. Bayer et comp. It is the most widely used anticonvulsant worldwide...
.
Caution using high dosages of clonazepam. Doses higher than 0.5 – 1 mg per day are associated with significant sedation.
Clonazepam may aggravate
hepatic porphyriaHepatic 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
schizophreniaSchizophrenia , from the Greek roots skhizein and phrēn, phren- is a psychiatric diagnosis that describes a mental disorder characterized by abnormalities in the perception or expression of reality...
. A 1982 double blinded placebo controlled study found clonazepam increases violent behavior in in individuals with chronic schizophrenia.
Interactions
Clonazepam decreases the levels of
carbamazepineCarbamazepine is an anticonvulsant and mood stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
, and likewise its level is reduced by carbamazepine.
Clonazepam may affect levels of
phenytoinPhenytoin sodium is a commonly used antiepileptic. Phenytoin acts to dampen the unwanted, runaway 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
primidonePrimidone is an anticonvulsant of the pyrimidinedione class whose active metabolites, phenobarbital and phenylethylmalonamide , are also anticonvulsants...
, and
phenobarbitalPhenobarbital or phenobarbitone is a barbiturate, first marketed as Luminal by Friedr. Bayer et comp. It is the most widely used anticonvulsant worldwide...
.
Warnings
Clonazepam, like many other benzodiazepines, may impair one's ability to drive or operate heavy machinery. The central nervous system depressing effects of the drug can be intensified by alcohol consumption. Benzodiazepines have been shown to cause both psychological and physical dependence. Patients physically dependent on clonazepam should be slowly titrated off under the supervision of a qualified healthcare professional to reduce the intensity of withdrawal or rebound symptoms.
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 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 and also floppy infant syndrome. Withdrawal symptoms from benzodiazepines in the neonate may include
hypotoniaHypotonia is a disorder that causes 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 reluctance to suck, to apnoeic spells,
cyanosisCyanosis is a blue coloration of the skin and mucous membranes due to the presence of > 5g/dl deoxygenated hemoglobin in blood vessels near the skin surface....
, and impaired metabolic responses to cold stress. These symptoms may persist for hours or months after birth. Floppy infant syndrome may occur if benzodiazepines are given close to or during delivery.
Pharmacology
Clonazepam's primary mechanism of action is via modulating
GABAGabâ or gabaa, for the Cebuano people , 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, which, in turn, leads to enhanced GABAergic inhibition of neuronal firing. In addition clonazepam decreases the utilization of 5-HT (serotonin) by neurons and has been shown to bind tightly to central type benzodiazepine receptors. Because of its strong
anxiolyticAn anxiolytic is a drug used for the treatment of symptoms of anxiety. Anxiolytics have been shown to be useful in the treatment of anxiety disorders, as have antidepressants such as the selective serotonin reuptake inhibitors .Though not anxiolytics, beta-receptor blockers such as propranolol and...
,
anticonvulsantThe 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. The goal of an anticonvulsant is to suppress the rapid and...
and euphoric properties, it is said to be among the class of "highly potent" benzodiazepines.
The anticonvulsant properties of benzodiazepines are due to enhancement of
synapticSynaptic may refer to:*anything related to a synapse or to synapsis*Synaptic , a graphical package management program for APT See also*Synaptics, the main laptop touchpad manufacturer...
GABA responses and inhibition of sustained high frequency repetitive firing.
Benzodiazepines, including clonazepam, bind to mouse
glial cellGlial cells, commonly called neuroglia or simply glia , are non-neuronal cells that provide support and nutrition, maintain homeostasis, form myelin, and participate in signal transmission in the nervous system...
membranes with high affinity. Clonazepam decreases release of acetylcholine in cat brain and decreases
prolactinProlactin or Luteotropic hormone is a peptide hormone discovered by Dr. Henry Friesen, primarily associated with lactation. In breastfeeding, the act of an infant suckling the nipple stimulates the production of prolactin, which fills the breast with milk via a process called lactogenesis, in...
release in rats. Benzodiazepines inhibit cold-induced thyroid stimulating hormone (also known as
TSHTSH may refer to:*Their Serene Highnesses, a style used by some Royal houses.*Thyroid-stimulating hormone, a hormone synthesized and secreted by thyrotrope cells *Tanzanian shilling, the currency of Tanzania...
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 systemThe central nervous system is the part of the nervous system that functions to coordinate the activity of all parts of the bodies of bilaterian animals—that is, all animals more advanced than sponges or jellyfish. In vertebrates, the central nervous system is enclosed in the meninges. It contains...
. 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 systemThe central nervous system is the part of the nervous system that functions to coordinate the activity of all parts of the bodies of bilaterian animals—that is, all animals more advanced than sponges or jellyfish. In vertebrates, the central nervous system is enclosed in the meninges. It contains...
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
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 elimination half life of clonazepam is between 20 – 80 hours. Clonazepam does not produce any pharmacologically active metabolites. 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:
- Coma
In medicine, a coma is a profound state of unconsciousness. A comatose person cannot be awakened, fails to respond normally to pain or light, does not have sleep-wake cycles, and does not take voluntary actions....
- Hypotension
In physiology and medicine, hypotension refers to an abnormally low blood pressure. This 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 opposite of hypertension, which is high blood...
- Impaired motor functions
- Impaired reflexes
- Impaired coordination
- Impaired balance
- Dizziness
- Labored breathing
- Mental confusion
- Somnolence
Somnolence 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)
- Nausea
Nausea is the sensation of unease and discomfort in the stomach with an urge to vomit.-Causes:...
Coma can be cyclic with the individual alternating from a comatose state to a hyperalert state of consciousness, as occurred in a 4-year-old boy who suffered an overdose of clonazepam. The combination of clonazepam and certain barbiturates eg
amobarbitalAmobarbital 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.
Drug misuse
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 abuseDrug abuse has a huge range of definitions related to taking a psychoactive drug or performance enhancing drug for a non-therapeutic or non-medical effect. All of these definitions imply a negative judgement of the drug use in question...
, accidental or intentional overdose, or adverse reactions resulting from legitimate use of the medication.
See also
- Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
- Benzodiazepine dependence
Benzodiazepine dependence or benzodiazepine addiction is the condition when a person is dependent on benzodiazepine drugs. Dependence can either be a psychological dependence or a physical dependence or a combination of the two...
- 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 reduces the dosage too rapidly...
- Long term effects of benzodiazepines
The long-term effects of benzodiazepines include drug dependence as well as the possibility of adverse effects on cognitive function, physical, and mental health. There is evidence that reduction or withdrawal from benzodiazepines can lead to a reduction in anxiety symptoms...
External links
- Carlos, Jean-Marc: The Treatment of Panic Disorder http://www.medscape.com/viewarticle/497207
Clonazepam is a
benzodiazepineA benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
derivative with highly potent
anticonvulsantThe 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. The goal of an anticonvulsant is to suppress the rapid and...
,
muscle relaxantA 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
anxiolyticAn anxiolytic is a drug used for the treatment of symptoms of anxiety. Anxiolytics have been shown to be useful in the treatment of anxiety disorders, as have antidepressants such as the selective serotonin reuptake inhibitors .Though not anxiolytics, beta-receptor blockers such as propranolol and...
properties. It is marketed by
RocheF. 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-names
Klonopin in the United States, and
Ravotril in Chile. Other names like
Rivotril or
Rivatril are known throughout the large majority of the rest of the world. Clonazepam is a
chlorinatedHalogenation is a chemical reaction that incorporates a halogen atom into a molecule. More specific descriptions exist that specify the type of halogen: fluorination, chlorination, bromination, and iodination....
derivative of
nitrazepamNitrazepam 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 nitrobenzodiazepine.
Indications
Clonazepam may be prescribed for
- Epilepsy
Epilepsy is a common chronic neurological disorder characterized by recurrent unprovoked seizures...
- Anxiety disorder
Anxiety disorder is a blanket term covering several different forms of abnormal and pathological fears and anxieties which only came under the aegis of psychiatry at the very end of the 19th century. Current psychiatric diagnostic criteria recognize a wide variety of anxiety disorders...
s
- 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...
- Initial treatment of mania
Mania is a severe medical condition characterized by extremely elevated mood, energy, unusual thought patterns and sometimes psychosis...
or acute psychosis together with firstline drugs such as lithiumLithium is a soft, silver-white metal that belongs to the alkali metal group of chemical elements. It is represented by the symbol Li, and it has the atomic number three. Under standard conditions it is the lightest metal and the least dense solid element. Like all alkali metals, lithium is highly...
, haloperidolHaloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines....
or risperidoneRisperidone is an atypical antipsychotic used to treat schizophrenia , the mixed and manic states associated with bipolar disorder, and irritability in children with autism...
- Hyperekplexia
Hyperekplexia is classically characterised by pronounced startle responses to tactile or acoustic stimuli, hypertonia and episodic neonatal apnoea. The hypertonia may be predominantly truncal, attenuated during sleep and less prominent after a year of age...
- Bruxism
Bruxism is characterized by the grinding of the teeth and is typically accompanied by 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...
- Restless legs syndrome
- Rapid eye movement behavior disorder
Rapid eye movement sleep behavior disorder is a sleep disorder that involves abnormal behavior during the sleep phase with rapid eye movement . It was first described in 1986....
- Hallucinogen persisting perception disorder
Hallucinogen Persisting Perception Disorder or HPPD is a disorder characterized by a continual presence of visual disturbances that are reminiscent of those generated by the ingestion of hallucinogenic substances. Previous use of hallucinogens is needed, though not sufficient, for diagnosing...
- The treatment of acute and chronic akathisia
Akathisia, or acathisia, is a syndrome characterized by unpleasant sensations of "inner" restlessness that manifests itself with an inability to sit still or remain motionless...
http://smj.org.uk/1001/aka1001.htmhttp://www3.interscience.wiley.com/journal/120003401/abstract?CRETRY=1&SRETRY=0
- Use as a muscle relaxant (Off Label Use)
- Use as a sedative for sleep (Off Label Use). Its long half-life sometimes makes it useful for treating middle-of-the-night insomnia
Middle-of-the-night insomnia is insomnia characterized by difficulty returning to sleep after awakening in the middle of the night. Also referred to as nocturnal awakenings, middle of the night awakenings and middle insomnia, this category of insomnia is different from initial or sleep-onset...
(waking up too early), but may also lead to next-day effects. Clonazepam can also be used to relax bladder neck tightness to improve symptoms of benign prostatic hypertrophy, also known as BPH.
In the treatment of acute epilepsy via intravenous administration approximately 72.5 percent of patients show improved EEG patterns, 17.5 percent show no improvement and for 10 percent of patients clonazepam has a paradoxical effect and worsens EEG readings.
Clonazepam is sometimes used 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 useless with long-term use, and side-effects such as sedation, which is why clonazepam and benzodiazepines as a class should, in general, be prescribed only for the acute management of epilepsies.
Clonazepam or diazepam has been found to be effective in the acute control of nonconvulsive
status epilepticusStatus epilepticus refers to 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 30 minutes , or recurrent seizures without regaining consciousness between...
. However, the benefits tended to be transient in many of the patients, and the addition of
phenytoinPhenytoin sodium is a commonly used antiepileptic. Phenytoin acts to dampen the unwanted, runaway 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 syndromeWest 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 epilepies treated with benzodiazepines, long-term therapy becomes ineffective with prolonged therapy, and the side-effects of
hypotoniaHypotonia is a disorder that causes 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
vigabatrinVigabatrin is an antiepileptic drugs that inhibits the catabolism of GABA by irreversibly inhibiting GABA transaminase. It is an analog of GABA, but it is not a receptor agonist. It is manufactured and distributed by Lundbeck Inc. . Lundbeck Inc. is a wholly owned subsidiary of H...
. Furthermore, Clonazepam is not recommended for widespread use in the management of seizures related to West syndrome.
Clonazepam has been used in the management of seizure disorders in children and also for infantile spasms. However, usefulness of clonazepam is limited due to its dose-limiting side-effects, especially its negative effect on cognition.
Clonazepam has shown itself to be highly effective as a short-term (3 weeks) adjunct to SSRI treatment in
obsessive-compulsive disorderObsessive–compulsive disorder is a mental disorder characterized by intrusive thoughts that produce anxiety, by repetitive behaviors aimed at reducing anxiety, or by combinations of such thoughts and behaviors...
and
clinical depressionMajor depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and 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.
Availability
Clonazepam was approved in the United States as a
generic drugA generic drug is a drug which isproduced and distributed without patent protection. The generic drug may still have a patent on the formulation but not on the active ingredient....
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.).
Side-effects
Common:
- Drowsiness
- Impairment of cognition, judgment, or memory
- Irritability and aggression
- Psychomotor agitation
- Lack of motivation
- Loss of libido
- Impaired motor function
- Impaired coordination
- Impaired balance
- Dizziness
- Cognitive Impairments
- Increased Sleepwalking (If used in treatment of sleepwalking)
- Auditory Hallucinations
- Short-term memory loss
- Anterograde amnesia
Anterograde amnesia is a loss of the ability to create memories after the event that caused the amnesia occurs. Anterograde amnesia and retrograde amnesia, where memories created prior to the event are lost, can occur together in the same patient...
(common with higher doses)
- Some users report hangover
A 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...
-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
Dysphoria is an unpleasant or uncomfortable mood, such as sadness , anxiety, irritability, or restlessness. Etymologically, it is the opposite of euphoria....
- Thrombocytopenia
Thrombocytopenia is the presence of relatively few platelets in blood.Generally speaking, in humans, a normal platelet count ranges from 150,000 and 450,000 per mm3. These limits, however, are determined by the 2.5th lower and upper percentile, and a deviation does not necessarily imply...
- Serious psychological and psychiatric side-effects
- Induction of seizures or increased frequency of seizures
- Personality changes
- Behavioural disturbances
Rare:
- Psychosis
Psychosis literally 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"...
- Incontinence
Urinary 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...
- Liver damage
- Paradoxical behavioural disinhibition (most frequently in children, the elderly, and in persons with developmental disabilities)
- Rage
- Excitement
- Impulsivity
Long term effects:
The long term effects of clonazepam can include; depression,
disinhibitionDisinhibition 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 dysfunctionSexual 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.-Categories:...
.
Withdrawal-related:
- Anxiety, irritability, insomnia
- Panic attacks, tremor
- Seizures similar to delirium tremens
Delirium 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 epilepticusStatus epilepticus refers to 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 30 minutes , or recurrent seizures without regaining consciousness between...
, but, when used for longer periods of time, serious side-effects may develop, such as interference with cognitive functions and behaviour. 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
therapeuticPharmacotherapy is that area of pharmacy practice that is responsible for ensuring the safe, appropriate, and economical use of drugs in patient care. A speciailist in pharmacotherapy has responsibility for direct patient care, often functions as a member of a multidisciplinary team and is...
low-dose benzodiazepine users — physiological dependence was demonstrated via
flumazenilFlumazenil is a benzodiazepine antagonist....
-precipitated withdrawal.
Use of alcohol or other
CNSThe central nervous system is the part of the nervous system that functions to coordinate the activity of all parts of the bodies of bilaterian animals—that is, all animals more advanced than sponges or jellyfish. In vertebrates, the central nervous system is enclosed in the meninges. It contains...
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 agonist.
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 , is a sedative/hypnotic drug and benzodiazepine derivative. It is marketed under the trade names Klopoxid, Librax , Libritabs, Librium, Mesural, Multum, Novapam, Risolid, Silibrin, Sonimen, Tropium, and Zetran.Chlordiazepoxide has...
. 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—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 reduces the dosage too rapidly...
, causing psychotic attacks characterised by dysphoric manifestations, irritability, aggressiveness, anxiety, and hallucinations. Sudden withdrawal may also induce the potentially the life threatening condition
status epilepticusStatus epilepticus refers to 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 30 minutes , or recurrent seizures without regaining consciousness between...
. Antiepileptic drugs, benzodiazepines such as clonazepam in particular, should be reduced slowly and gradually when discontinuing the drug to reduce withdrawal effects.
CarbamazepineCarbamazepine 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 epilepticusStatus epilepticus refers to 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 30 minutes , or recurrent seizures without regaining consciousness between...
from occurring.
Special precautions
Caution in the elderly. Increased risk of impairments, falls and drug accumulation.
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
phenobarbitalPhenobarbital or phenobarbitone is a barbiturate, first marketed as Luminal by Friedr. Bayer et comp. It is the most widely used anticonvulsant worldwide...
.
Caution using high dosages of clonazepam. Doses higher than 0.5 – 1 mg per day are associated with significant sedation.
Clonazepam may aggravate
hepatic porphyriaHepatic 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
schizophreniaSchizophrenia , from the Greek roots skhizein and phrēn, phren- is a psychiatric diagnosis that describes a mental disorder characterized by abnormalities in the perception or expression of reality...
. A 1982 double blinded placebo controlled study found clonazepam increases violent behavior in in individuals with chronic schizophrenia.
Interactions
Clonazepam decreases the levels of
carbamazepineCarbamazepine is an anticonvulsant and mood stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
, and likewise its level is reduced by carbamazepine.
Clonazepam may affect levels of
phenytoinPhenytoin sodium is a commonly used antiepileptic. Phenytoin acts to dampen the unwanted, runaway 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
primidonePrimidone is an anticonvulsant of the pyrimidinedione class whose active metabolites, phenobarbital and phenylethylmalonamide , are also anticonvulsants...
, and
phenobarbitalPhenobarbital or phenobarbitone is a barbiturate, first marketed as Luminal by Friedr. Bayer et comp. It is the most widely used anticonvulsant worldwide...
.
Warnings
Clonazepam, like many other benzodiazepines, may impair one's ability to drive or operate heavy machinery. The central nervous system depressing effects of the drug can be intensified by alcohol consumption. Benzodiazepines have been shown to cause both psychological and physical dependence. Patients physically dependent on clonazepam should be slowly titrated off under the supervision of a qualified healthcare professional to reduce the intensity of withdrawal or rebound symptoms.
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 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 and also floppy infant syndrome. Withdrawal symptoms from benzodiazepines in the neonate may include
hypotoniaHypotonia is a disorder that causes 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 reluctance to suck, to apnoeic spells,
cyanosisCyanosis is a blue coloration of the skin and mucous membranes due to the presence of > 5g/dl deoxygenated hemoglobin in blood vessels near the skin surface....
, and impaired metabolic responses to cold stress. These symptoms may persist for hours or months after birth. Floppy infant syndrome may occur if benzodiazepines are given close to or during delivery.
Pharmacology
Clonazepam's primary mechanism of action is via modulating
GABAGabâ or gabaa, for the Cebuano people , 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, which, in turn, leads to enhanced GABAergic inhibition of neuronal firing. In addition clonazepam decreases the utilization of 5-HT (serotonin) by neurons and has been shown to bind tightly to central type benzodiazepine receptors. Because of its strong
anxiolyticAn anxiolytic is a drug used for the treatment of symptoms of anxiety. Anxiolytics have been shown to be useful in the treatment of anxiety disorders, as have antidepressants such as the selective serotonin reuptake inhibitors .Though not anxiolytics, beta-receptor blockers such as propranolol and...
,
anticonvulsantThe 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. The goal of an anticonvulsant is to suppress the rapid and...
and euphoric properties, it is said to be among the class of "highly potent" benzodiazepines.
The anticonvulsant properties of benzodiazepines are due to enhancement of
synapticSynaptic may refer to:*anything related to a synapse or to synapsis*Synaptic , a graphical package management program for APT See also*Synaptics, the main laptop touchpad manufacturer...
GABA responses and inhibition of sustained high frequency repetitive firing.
Benzodiazepines, including clonazepam, bind to mouse
glial cellGlial cells, commonly called neuroglia or simply glia , are non-neuronal cells that provide support and nutrition, maintain homeostasis, form myelin, and participate in signal transmission in the nervous system...
membranes with high affinity. Clonazepam decreases release of acetylcholine in cat brain and decreases
prolactinProlactin or Luteotropic hormone is a peptide hormone discovered by Dr. Henry Friesen, primarily associated with lactation. In breastfeeding, the act of an infant suckling the nipple stimulates the production of prolactin, which fills the breast with milk via a process called lactogenesis, in...
release in rats. Benzodiazepines inhibit cold-induced thyroid stimulating hormone (also known as
TSHTSH may refer to:*Their Serene Highnesses, a style used by some Royal houses.*Thyroid-stimulating hormone, a hormone synthesized and secreted by thyrotrope cells *Tanzanian shilling, the currency of Tanzania...
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 systemThe central nervous system is the part of the nervous system that functions to coordinate the activity of all parts of the bodies of bilaterian animals—that is, all animals more advanced than sponges or jellyfish. In vertebrates, the central nervous system is enclosed in the meninges. It contains...
. 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 systemThe central nervous system is the part of the nervous system that functions to coordinate the activity of all parts of the bodies of bilaterian animals—that is, all animals more advanced than sponges or jellyfish. In vertebrates, the central nervous system is enclosed in the meninges. It contains...
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
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 elimination half life of clonazepam is between 20 – 80 hours. Clonazepam does not produce any pharmacologically active metabolites. 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:
- Coma
In medicine, a coma is a profound state of unconsciousness. A comatose person cannot be awakened, fails to respond normally to pain or light, does not have sleep-wake cycles, and does not take voluntary actions....
- Hypotension
In physiology and medicine, hypotension refers to an abnormally low blood pressure. This 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 opposite of hypertension, which is high blood...
- Impaired motor functions
- Impaired reflexes
- Impaired coordination
- Impaired balance
- Dizziness
- Labored breathing
- Mental confusion
- Somnolence
Somnolence 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)
- Nausea
Nausea is the sensation of unease and discomfort in the stomach with an urge to vomit.-Causes:...
Coma can be cyclic with the individual alternating from a comatose state to a hyperalert state of consciousness, as occurred in a 4-year-old boy who suffered an overdose of clonazepam. The combination of clonazepam and certain barbiturates eg
amobarbitalAmobarbital 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.
Drug misuse
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 abuseDrug abuse has a huge range of definitions related to taking a psychoactive drug or performance enhancing drug for a non-therapeutic or non-medical effect. All of these definitions imply a negative judgement of the drug use in question...
, accidental or intentional overdose, or adverse reactions resulting from legitimate use of the medication.
See also
- Benzodiazepine
A benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
- Benzodiazepine dependence
Benzodiazepine dependence or benzodiazepine addiction is the condition when a person is dependent on benzodiazepine drugs. Dependence can either be a psychological dependence or a physical dependence or a combination of the two...
- 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 reduces the dosage too rapidly...
- Long term effects of benzodiazepines
The long-term effects of benzodiazepines include drug dependence as well as the possibility of adverse effects on cognitive function, physical, and mental health. There is evidence that reduction or withdrawal from benzodiazepines can lead to a reduction in anxiety symptoms...
External links
- Carlos, Jean-Marc: The Treatment of Panic Disorder http://www.medscape.com/viewarticle/497207