Klonopin: Wikis

  

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Clonazepam
Systematic (IUPAC) name
5-(2-chlorphenyl)-7-nitro-2,3-dihydro-1,4-benzodiazepin-2-on
Identifiers
CAS number 1622-61-3
ATC code N03AE01
PubChem 2802
DrugBank APRD00054
ChemSpider 2700
Chemical data
Formula C15H10ClN3O3 
Mol. mass 315.715
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability 90%
Protein binding ~85%
Metabolism Hepatic CYP3A4
Half life 18–50 hours
Excretion Renal
Therapeutic considerations
Pregnancy cat. C(AU) D(US)
Legal status Schedule IV (US)
Routes Oral, I.M., I.V, sublingual
 Yes check.svgY(what is this?)  (verify)

Clonazepam is a benzodiazepine derivative with anticonvulsant, muscle relaxant, and anxiolytic properties.[1] It is marketed by Roche 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 generally considered to be among the long-acting benzodiazepines.[2] Clonazepam is a chlorinated derivative of nitrazepam[3] and therefore a nitrobenzodiazepine.[4]

Contents

Indications

Clonazepam may be prescribed for

The effectiveness of clonazepam in the short-term treatment of panic disorder has been demonstrated in controlled clinical trials. Some long-term trials have suggested a benefit of clonazepam for up to 3 years without the development of tolerance but these trials were not placebo controlled. Clonazepam is also effective in the management of acute mania.[16]

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.[17]

Clonazepam or diazepam has been found to be effective in the acute control of nonconvulsive status epilepticus. However, the benefits tended to be transient in many of the patients, and the addition of phenytoin for lasting control was required in these patients.[18]

In general, Clonazepam has been found to be ineffective in the control of infantile spasms.[19] Clonazepam is less effective and potent as an anticonvulsant in bringing infantile seizures under control compared with nitrazepam in the treatment of West syndrome, which is an age-dependent epilepsy affecting the very young. However, as with other epilepies treated with benzodiazepines, long-term therapy becomes ineffective with prolonged therapy, and the side effects of hypotonia and drowsiness are troublesome with clonazepam therapy; other antiepileptic agents are, therefore, recommended for long-term therapy, possibly Corticotropin (ACTH) or vigabatrin. Furthermore, Clonazepam is not recommended for widespread use in the management of seizures related to West syndrome.[20]

Clonazepam has shown itself to be highly effective as a short-term (3 weeks) adjunct to SSRI treatment in obsessive-compulsive disorder and clinical depression in reducing SSRI side effects with the combination being superior to SSRI treatment alone in a study funded by the manufacturers of clonazepam, Hoffman LaRoche Inc.[21]

Availability

Klonopin 0.5 mg
Klonopin 1 mg
Clonazepam2mg DOJ.jpg

Clonazepam was approved in the United States as a generic drug in 1997 and is now manufactured and marketed by several companies.

Clonazepam is available in the U.S. as tablets (0.5, 1.0, and 2 mg) and orally disintegrating tablets (wafers) (0.125, 0.25, 0.5, 1.0, and 2 mg). In other countries, clonazepam is usually available as tablets (0.5 and 2 mg), orally disintegrating tablets (0.25, 0.5, 1 and 2 mg) oral solution (drops, 2.5 mg/mL), as well as solution for injection or intravenous infusion, containing 1 mg clonazepam per ampoule (e.g. Rivotril inj.).

Side-effects

Common
  • Drowsiness[22]
  • Impairment of cognition, judgment, or memory
  • Irritability and aggression[23]
  • Psychomotor agitation[24]
  • Lack of motivation[25]
  • Loss of libido
  • Impaired motor function
    • Impaired coordination
    • Impaired balance
    • Dizziness
    • Diarrhea
  • Cognitive impairments
    • Increased sleepwalking (If used in treatment of sleepwalking)
    • Auditory hallucinations
    • Short-term memory loss
    • Anterograde amnesia (common with higher doses)
  • Some users report hangover-like symptoms of being drowsy, having a headache, being sluggish, and being irritable after waking up if the medication is taken before sleep. This is likely the result of the medication's long half-life, which continues to affect the user after waking up, as well as its disruption of the REM cycle.
Occasional
Rare
Long term effects

The long term effects of clonazepam can include; depression, disinhibition and sexual dysfunction.[43]

Withdrawal-related
  • Anxiety, irritability, insomnia
  • Panic attacks, tremor
  • Seizures[44] similar to delirium tremens (with long-term use of excessive doses)

Benzodiazepines such as clonazepam can be very effective in controlling status epilepticus, but, when used for longer periods of time, serious side-effects may develop, such as interference with cognitive functions and behavior.[45] Many individuals treated on a long-term basis develop a form of dependence known as "low-dose dependence," as was shown in one double-blind, placebo-controlled study of 34 therapeutic low-dose benzodiazepine users — physiological dependence was demonstrated via flumazenil-precipitated withdrawal.[46] Use of alcohol or other CNS depressants while taking clonazepam greatly intensifies the effects (and side-effects) of the drug. Side-effects of the drug itself are generally benign, but sudden withdrawal after long-term use can cause severe, even fatal, symptoms.

Tolerance and withdrawal

Like all benzodiazepines, clonazepam is a benzodiazepine receptor agonist.[47][48]

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.[49][50] Chronic use of benzodiazepines leads to the development of tolerance with a decrease of benzodiazepine binding sites. The degree of tolerance is more pronounced with clonazepam than with chlordiazepoxide.[51] In general, short-term therapy is more effective than long-term therapy with clonazepam for the treatment of epilepsy.[52] 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.[53]

Withdrawal

Abrupt or over-rapid withdrawal from clonazepam may result in the development of the benzodiazepine withdrawal syndrome, causing psychosis characterised by dysphoric manifestations, irritability, aggressiveness, anxiety, and hallucinations.[54][55][56] Sudden withdrawal may also induce the potentially life threatening condition status epilepticus. Antiepileptic drugs, benzodiazepines such as clonazepam in particular, should be reduced slowly and gradually when discontinuing the drug to reduce withdrawal effects.[33] Carbamazepine has been trialed in the treatment of clonazepam withdrawal and has been found to be ineffective in preventing clonazepam withdrawal status epilepticus from occurring.[57]

Special precautions

Caution in the elderly. Increased risk of impairments, falls and drug accumulation. Benzodiazepines also require special precaution if used in the pregnancy, alcohol- or drug-dependent individuals and individuals with comorbid psychiatric disorders.[58] Clonazepam is generally not recommended for use in elderly people for insomnia due to its high potency relative to other benzodiazepines.[59]

Caution in children. Clonazepam is not recommended for use in those under 18. Use in very young children may be especially hazardous. Of anticonvulsant drugs behavioural disturbances occur most frequently with clonazepam and phenobarbital.[58][60]

Caution using high dosages of clonazepam. Doses higher than 0.5 – 1 mg per day are associated with significant sedation.[61]

Clonazepam may aggravate hepatic porphyria.[62][63]

Caution in chronic schizophrenia. A 1982 double blinded placebo controlled study found clonazepam increases violent behavior in individuals with chronic schizophrenia.[64]

Interactions

Clonazepam decreases the levels of carbamazepine,[65][66] and likewise its level is reduced by carbamazepine.[67] Clonazepam may affect levels of phenytoin (diphenylhydantoin) by decreasing,[65][68] or increasing.[69][70] 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%.[71] Clonazepam increases the levels of primidone,[69] and phenobarbital.[72]

Warnings

Clonazepam, like other benzodiazepines, will impair one's ability to drive or operate light or "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 are also inconclusive on whether benzodiazepines such as clonazepam cause developmental deficits or decreases in IQ in the developing fetus when taken by the mother during pregnancy. Clonazepam when used late in pregnancy may result in the development of a severe benzodiazepine withdrawal syndrome in the neonate. Withdrawal symptoms from benzodiazepines in the neonate may include hypotonia, apnoeic spells, cyanosis and impaired metabolic responses to cold stress.[73]

The safety profile clonazepam during pregnancy is less clear than for other benzodiazepines and if benzodiazepines are indicated during pregnancy chlordiazepoxide and diazepam may be a safer choice. The use of clonazepam during pregnancy should only be used if the clinical benefits are believed to outweigh the clinical risks to the fetus. Caution is also required if clonazepam is used during breast feeding. Possible adverse effects of use of benzodiazepines such as clonazepam during pregnancy include; abortion, malformation, intrauterine growth retardation, functional deficits, floppy infant syndrome, carcinogenesis and mutagenesis. Neonatal withdrawal syndrome associated with benzodiazepines include hypertonia, hyperreflexia, restlessness, irritability, abnormal sleep patterns, inconsolable crying, tremors or jerking of the extremities, bradycardia, cyanosis, suckling difficulties, apnea, risk of aspiration of feeds, diarrhea and vomiting, and growth retardation. This syndrome can develop between 3 days and 3 weeks after birth and can have a duration of up to several months. The pathway by which clonazepam is metabolised is usually impaired in new borns. If clonazepam is used during pregnancy or breast feeding it is recommended that serum levels of clonazepam are monitored and signs of central nervous system depression and apnea are also monitored for. In many cases non-pharmacological treatments such as relaxation therapy, psychotherapy and avoidance of caffeine can be an effective and safer alternative to use of benzodiazepines for anxiety in pregnant women.[74]

Pharmacology

Clonazepam's primary mechanism of action is via modulating GABA function in the brain, via the benzodiazepine receptor, which, in turn, leads to enhanced GABAergic inhibition of neuronal firing. In addition clonazepam decreases the utilization of 5-HT (serotonin) by neurons[75][76] and has been shown to bind tightly to central type benzodiazepine receptors.[77] Because of its strong anxiolytic, anticonvulsant and euphoric properties, it is said to be among the class of "highly potent" benzodiazepines.[78] The anticonvulsant properties of benzodiazepines are due to enhancement of synaptic GABA responses and inhibition of sustained high frequency repetitive firing.[79]

Benzodiazepines, including clonazepam, bind to mouse glial cell membranes with high affinity.[80][81] Clonazepam decreases release of acetylcholine in cat brain [82] and decreases prolactin release in rats.[83] Benzodiazepines inhibit cold-induced thyroid stimulating hormone (also known as TSH or thyrotropin) release.[84] 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.[85]

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 system.[86][87] Benzodiazepines, however, do not have any effect on the levels of GABA in the brain.[88] 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.[89] Benzodiazepine receptors are found in the central nervous system but are also found in a wide range of peripheral tissues such as longitudinal smooth muscle-myenteric plexus layer, lung, liver and kidney as well as mast cells, platelets, lymphocytes, heart and numerous neuronal and non-neuronal cell lines.[90]

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.[91]

Clonazepam passes rapidly into the central nervous system, with levels in the brain corresponding with levels of unbound clonazepam in the blood serum.[92] Clonazepam plasma levels are very unreliable amongst patients. Plasma levels of clonazepam can vary as much as tenfold between different patients.[93]

Clonazepam is largely bound to plasma proteins.[94] 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.[95] The metabolites of clonazepam include 7-aminoclonazepam, 7-acetaminoclonazepam and 3-hydroxy clonazepam.[96][97]

Overdose

An individual who has consumed too much clonazepam may display one or more of the following symptoms:

  • Coma
  • Hypotension
  • Impaired motor functions
    • Impaired reflexes
    • Impaired coordination
    • Impaired balance
    • Dizziness
  • Labored breathing
  • Mental confusion
  • Somnolence (difficulty staying awake)
  • Nausea

Coma can be cyclic with the individual alternating from a comatose state to a hyperalert state of consciousness, as occurred in a 4-year-old boy who suffered an overdose of clonazepam.[98] The combination of clonazepam and certain barbiturates eg amobarbital at prescribed doses has resulted in a synergistic potentiation of the effects of each drug leading to serious respiratory depression.[99]

Detection in biological fluids

Clonazepam and 7-aminoclonazepam may be quantified in plasma, serum or whole blood in order to monitor compliance in those receiving the drug therapeutically, to confirm the diagnosis in potential poisoning victims or to assist in the forensic investigation in a case of fatal overdosage. Both the parent drug and 7-aminoclonazepam are unstable in biofluids, and therefore specimens should be preserved with sodium fluoride, stored at the lowest possible temperature and analyzed quickly to minimize losses.[100]

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.[citation needed] The study examined the number of times non-medical use of certain drugs were implicated in ED visits; the criteria for non-medical use in this study were purposefully broad, and include for example, drug abuse, accidental or intentional overdose, or adverse reactions resulting from legitimate use of the medication.[101]

See also

References

  1. ^ Cowen PJ; Green AR, Nutt DJ (March 1981). "Ethyl beta-carboline carboxylate lowers seizure threshold and antagonizes flurazepam-induced sedation in rats". Nature 290 (5801): 54–5. doi:10.1038/290054a0. PMID 6259533. 
  2. ^ "Benzodiazepine Names". non-benzodiazepines.org.uk. http://www.non-benzodiazepines.org.uk/benzodiazepine-names.html. Retrieved 2008-12-29. 
  3. ^ Dreifuss FE; Penry JK, Rose SW, Kupferberg HJ, Dyken P, Sato S (March 1975). "Serum clonazepam concentrations in children with absence seizures". Neurology 25 (3): 255–8. PMID 1089913. 
  4. ^ Robertson MD; Drummer OH (May 1995). "Postmortem drug metabolism by bacteria". J Forensic Sci 40 (3): 382–6. PMID 7782744. 
  5. ^ Rossetti AO; Reichhart MD, Schaller MD, Despland PA, Bogousslavsky J (July 2004). "Propofol treatment of refractory status epilepticus: a study of 31 episodes". Epilepsia 45 (7): 757–63. doi:10.1111/j.0013-9580.2004.01904.x. PMID 15230698. 
  6. ^ Ståhl Y, Persson A, Petters I, Rane A, Theorell K, Walson P (April 1983). "Kinetics of clonazepam in relation to electroencephalographic and clinical effects". Epilepsia 24 (2): 225–31. doi:10.1111/j.1528-1157.1983.tb04883.x. PMID 6403345. 
  7. ^ Cloos, Jean-Marc (2005). "The Treatment of Panic Disorder". Curr Opin Psychiatry 18 (1): 45–50. PMID 16639183. http://www.medscape.com/viewarticle/497207. Retrieved 2007-09-25. 
  8. ^ Curtin F, Schulz P (2004). "Clonazepam and lorazepam in acute mania: a Bayesian meta-analysis". J Affect Disord 78 (3): 201–8. doi:10.1016/S0165-0327(02)00317-8. PMID 15013244. 
  9. ^ Gillies D, Beck A, McCloud A, Rathbone J, Gillies D (2005). "Benzodiazepines alone or in combination with antipsychotic drugs for acute psychosis". Cochrane Database Syst Rev (4): CD003079. doi:10.1002/14651858.CD003079.pub2. PMID 16235313. 
  10. ^ Zhou, L.; Chillag, KL.; Nigro, MA. (Oct 2002). "Hyperekplexia: a treatable neurogenetic disease.". Brain Dev 24 (7): 669–74. doi:10.1016/S0387-7604(02)00095-5. PMID 12427512. 
  11. ^ Schenck, CH.; Arnulf, I.; Mahowald, MW. (Jun 2007). "Sleep and sex: what can go wrong? A review of the literature on sleep related disorders and abnormal sexual behaviors and experiences.". Sleep 30 (6): 683–702. PMID 17580590. 
  12. ^ "[Restless legs syndrome: diagnosis and treatment. Opinion of Brazilian experts]". Arq Neuropsiquiatr 65 (3A): 721–7. Sep 2007. PMID 17876423. 
  13. ^ Trenkwalder, C.; Hening, WA.; Montagna, P.; Oertel, WH.; Allen, RP.; Walters, AS.; Costa, J.; Stiasny-Kolster, K. et al. (Dec 2008). "Treatment of restless legs syndrome: an evidence-based review and implications for clinical practice." (PDF). Mov Disord 23 (16): 2267–302. doi:10.1002/mds.22254. PMID 18925578. http://www.movementdisorders.org/publications/ebm_reviews/treatmentofrls.pdf. 
  14. ^ Huynh, NT.; Rompré, PH.; Montplaisir, JY.; Manzini, C.; Okura, K.; Lavigne, GJ. (2006). "Comparison of various treatments for sleep bruxism using determinants of number needed to treat and effect size.". Int J Prosthodont 19 (5): 435–41. PMID 17323720. 
  15. ^ Ferini-Strambi, L.; Zucconi, M. (Sep 2000). "REM sleep behavior disorder.". Clin Neurophysiol 111 Suppl 2: S136–40. PMID 10996567. 
  16. ^ Nardi, AE.; Perna, G. (May 2006). "Clonazepam in the treatment of psychiatric disorders: an update.". Int Clin Psychopharmacol 21 (3): 131–42. doi:10.1097/01.yic.0000194379.65460.a6. PMID 16528135. 
  17. ^ Isojärvi, JI; Tokola RA (December 1998). "Benzodiazepines in the treatment of epilepsy in people with intellectual disability". J Intellect Disabil Res 42 (1): 80–92. PMID 10030438. 
  18. ^ Tomson T; Svanborg E, Wedlund JE (May-Jun 1986). "Nonconvulsive status epilepticus: high incidence of complex partial status". Epilepsia 27 (3): 276–85. doi:10.1111/j.1528-1157.1986.tb03540.x. PMID 3698940. 
  19. ^ Hrachovy RA, Frost JD Jr, Kellaway P, Zion TE (October 1983). "Double-blind study of ACTH vs prednisone therapy in infantile spasms". J Pediatr 103 (4): 641–5. doi:10.1016/S0022-3476(83)80606-4. PMID 6312008. 
  20. ^ Djurić, M; Marjanović B, Zamurović D (May-Jun 2001). "[West syndrome--new therapeutic approach]". Srp Arh Celok Lek 129 (1): 72–7. PMID 15637997. 
  21. ^ Smith WT, Londborg PD, Glaudin V, Painter JR (1998). "Short-term augmentation of fluoxetine with clonazepam in the treatment of depression: a double-blind study". Am J Psychiatry 155 (10): 1339–45. PMID 9766764. http://ajp.psychiatryonline.org/cgi/content/full/155/10/1339. 
  22. ^ Stacy, M. (2002). "Sleep disorders in Parkinson's disease: epidemiology and management.". Drugs Aging 19 (10): 733–9. doi:10.2165/00002512-200219100-00002. PMID 12390050. 
  23. ^ Lander CM; Donnan GA, Bladin PF, Vajda FJ (1979). "Some aspects of the clinical use of clonazepam in refractory epilepsy". Clin Exp Neurol 16: 325–32. PMID 121707. 
  24. ^ Sorel L; Mechler L, Harmant J (1981). "Comparative trial of intravenous lorazepam and clonazepam im status epilepticus". Clin Ther 4 (4): 326–36. PMID 6120763. 
  25. ^ Wollman M; Lavie P, Peled R (1985). "A hypernychthemeral sleep-wake syndrome: a treatment attempt". Chronobiol Int 2 (4): 277–80. doi:10.3109/07420528509055890. PMID 3870855. 
  26. ^ Sjö O; Hvidberg EF, Naestoft J, Lund M (4 April 1975). "Pharmacokinetics and side-effects of clonazepam and its 7-amino-metabolite in man". Eur J Clin Pharmacol 8 (3-4): 249–54. doi:10.1007/BF00567123. PMID 1233220. 
  27. ^ Veall RM; Hogarth HC (22 November 1975). "Letter: Thrombocytopenia during treatment with clonazepam" (PDF). Br Med J 4 (5994): 462. doi:10.1136/bmj.4.5994.462. PMID 1192127.& PMC 1675341. http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1675341&blobtype=pdf. 
  28. ^ Hansson O; Tonnby B (24 March 1976). "[Serious psychological symptoms caused by clonazepam]". Lakartidningen 73 (13): 1209–10. PMID 1263638. 
  29. ^ Barfod S; Wendelboe J (10 October 1977). "[Severe psychiatric side effects of clonazepam treatment. 2 cases]". Ugeskr Laeger 139 (41): 2450. PMID 906141. 
  30. ^ Alvarez N; Hartford E, Doubt C (April 1981). "Epileptic seizures induced by clonazepam". Clin Electroencephalogr 12 (2): 57–65. PMID 7237847. 
  31. ^ Ishizu T, Chikazawa S, Ikeda T, Suenaga E (July 1988). "[Multiple types of seizure induced by clonazepam in an epileptic patient]" (in Japanese). No to Hattatsu 20 (4): 337–9. PMID 3214607. 
  32. ^ Bang F; Birket-Smith E, Mikkelsen B (September 1976). "Clonazepam in the treatment of epilepsy. A clinical long-term follow-up study". Epilepsia 17 (3): 321–4. doi:10.1111/j.1528-1157.1976.tb03410.x. PMID 824124. 
  33. ^ a b Bruni J (7 April 1979). "Recent advances in drug therapy for epilepsy". Can Med Assoc J 120 (7): 817–24. PMID 371777.& PMC 1818965. http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1818965&blobtype=pdf. 
  34. ^ Rosenfeld WE, Beniak TE, Lippmann SM, Loewenson RB (1987). "Adverse behavioral response to clonazepam as a function of Verbal IQ-Performance IQ discrepancy". Epilepsy Res. 1 (6): 347–56. doi:10.1016/0920-1211(87)90059-3. PMID 3504409. 
  35. ^ White MC; Silverman JJ, Harbison JW (February 1982). "Psychosis associated with clonazepam therapy for blepharospasm". J Nerv Ment Dis 170 (2): 117–9. PMID 7057171. 
  36. ^ Williams A; Gillespie M (July 1979). "Clonazepam-induced incontinence". Ann Neurol 6 (1): 86. doi:10.1002/ana.410060127. PMID 507767. 
  37. ^ Sandyk R (August 13, 1983). "Urinary incontinence associated with clonazepam therapy". S Afr Med J 64 (7): 230. PMID 6879368. 
  38. ^ Anders RJ; Wang E, Radhakrishnan J, Sharifi R, Lee M (October 1985). "Overflow urinary incontinence due to carbamazepine". J Urol 134 (4): 758–9. PMID 4032590. 
  39. ^ Olsson R, Zettergren L (May 1988). "Anticonvulsant-induced liver damage". Am. J. Gastroenterol. 83 (5): 576–7. PMID 3364416. 
  40. ^ van der Bijl P, Roelofse JA (1991). "Disinhibitory reactions to benzodiazepines: a review". J. Oral Maxillofac. Surg. 49 (5): 519–23. doi:10.1016/0278-2391(91)90180-T. PMID 2019899. 
  41. ^ Binder RL (March 1987). "Three case reports of behavioral disinhibition with clonazepam". Gen Hosp Psychiatry 9 (2): 151–3. doi:10.1016/0163-8343(87)90028-4. PMID 3569889. 
  42. ^ Kubacki A (October 1987). "Sexual disinhibition on clonazepam". Can J Psychiatry 32 (7): 643–5. PMID 3676996. 
  43. ^ Cohen LS, Rosenbaum JF (October 1987). "Clonazepam: new uses and potential problems". J Clin Psychiatry 48 Suppl: 50–6. PMID 2889724. 
  44. ^ Lockard JS; Levy RH, Congdon WC, DuCharme LL, Salonen LD (December 1979). "Clonazepam in a focal-motor monkey model: efficacy, tolerance, toxicity, withdrawal, and management". Epilepsia 20 (6): 683–95. doi:10.1111/j.1528-1157.1979.tb04852.x. PMID 115680. 
  45. ^ Vining EP (August 1986). "Use of barbiturates and benzodiazepines in treatment of epilepsy". Neurol Clin 4 (3): 617–32. PMID 3528811. 
  46. ^ Bernik MA; Gorenstein C, Vieira Filho AH (1998). "Stressful reactions and panic attacks induced by flumazenil in chronic benzodiazepine users". Journal of psychopharmacology (Oxford, England) 12 (2): 146–50. PMID 9694026. 
  47. ^ Adjeroud, S; Tonon, Mc; Leneveu, E; Lamacz, M; Danger, Jm; Gouteux, L; Cazin, L; Vaudry, H (May 1987). "The benzodiazepine agonist clonazepam potentiates the effects of gamma-aminobutyric acid on alpha-MSH release from neurointermediate lobes in vitro.". Life sciences 40 (19): 1881–7. doi:10.1016/0024-3205(87)90046-4. PMID 3033417. 
  48. ^ Yokota, K; Tatebayashi, H; Matsuo, T; Shoge, T; Motomura, H; Matsuno, T; Fukuda, A; Tashiro, N (March 2002). "The effects of neuroleptics on the GABA-induced Cl- current in rat dorsal root ganglion neurons: differences between some neuroleptics." (PDF). British journal of pharmacology 135 (6): 1547–55. doi:10.1038/sj.bjp.0704608. PMID 11906969.& PMC 1573270. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=11906969. 
  49. ^ Loiseau P (1983). "[Benzodiazepines in the treatment of epilepsy]". Encephale 9 (4 Suppl 2): 287B–292B. PMID 6373234. 
  50. ^ Scherkl R, Scheuler W, Frey HH (December 1985). "Anticonvulsant effect of clonazepam in the dog: development of tolerance and physical dependence". Arch Int Pharmacodyn Ther 278 (2): 249–60. PMID 4096613. 
  51. ^ Crawley JN; Marangos PJ, Stivers J, Goodwin FK (January 1982). "Chronic clonazepam administration induces benzodiazepine receptor subsensitivity". Neuropharmacology 21 (1): 85–9. doi:10.1016/0028-3908(82)90216-7. PMID 6278355. 
  52. ^ Bacia T; Purska-Rowińska E, Okuszko S (1980). "Clonazepam in the treatment of drug-resistant epilepsy: a clinical short- and long-term follow-up study". Monogr Neural Sci 5: 153–9. PMID 7033770. 
  53. ^ Browne TR (May 1976). "Clonazepam. A review of a new anticonvulsant drug". Arch Neurol 33 (5): 326–32. PMID 817697. 
  54. ^ Sironi VA; Miserocchi G, De Riu PL (April 1984). "Clonazepam withdrawal syndrome". Acta Neurol (Napoli) 6 (2): 134–9. PMID 6741654. 
  55. ^ Sironi VA; Franzini A, Ravagnati L, Marossero F (August 1979). "Interictal acute psychoses in temporal lobe epilepsy during withdrawal of anticonvulsant therapy". J Neurol Neurosurg Psychiatry 42 (8): 724–30. doi:10.1136/jnnp.42.8.724. PMID 490178. 
  56. ^ Jaffe R; Gibson E (June 1986). "Clonazepam withdrawal psychosis". J Clin Psychopharmacol 6 (3): 193. doi:10.1097/00004714-198606000-00021. PMID 3711371. 
  57. ^ Sechi GP; Zoroddu G, Rosati G (September 1984). "Failure of carbamazepine to prevent clonazepam withdrawal statusepilepticus". Ital J Neurol Sci 5 (3): 285–7. doi:10.1007/BF02043959. PMID 6500901. 
  58. ^ a b Authier, N.; Balayssac, D.; Sautereau, M.; Zangarelli, A.; Courty, P.; Somogyi, AA.; Vennat, B.; Llorca, PM. et al. (November 2009). "Benzodiazepine dependence: focus on withdrawal syndrome.". Ann Pharm Fr 67 (6): 408–13. doi:10.1016/j.pharma.2009.07.001. PMID 19900604. 
  59. ^ Wolkove, N.; Elkholy, O.; Baltzan, M.; Palayew, M. (May 2007). "Sleep and aging: 2. Management of sleep disorders in older people.". CMAJ 176 (10): 1449–54. doi:10.1503/cmaj.070335. PMID 17485699. 
  60. ^ Trimble MR; Cull C (1988). "Children of school age: the influence of antiepileptic drugs on behavior and intellect". Epilepsia 29 Suppl 3: S15–9. doi:10.1111/j.1528-1157.1988.tb05805.x. PMID 3066616. 
  61. ^ Hollister LE (1975). "Dose-ranging studies of clonazepam in man". Psychopharmacol Commun 1 (1): 89–92. PMID 1223993. 
  62. ^ Bonkowsky HL; Sinclair PR, Emery S, Sinclair JF (June 1980). "Seizure management in acute hepatic porphyria: risks of valproate and clonazepam". Neurology 30 (6): 588–92. PMID 6770287. 
  63. ^ Reynolds NC Jr; Miska RM (April 1981). "Safety of anticonvulsants in hepatic porphyrias". Neurology 31 (4): 480–4. PMID 7194443. 
  64. ^ Karson CN; Weinberger DR, Bigelow L, Wyatt RJ (December 1982). "Clonazepam treatment of chronic schizophrenia: negative results in a double-blind, placebo-controlled trial". Am J Psychiatry 139 (12): 1627–8. PMID 6756174. 
  65. ^ a b Lander CM; Eadie MJ, Tyrer JH (1975). "Interactions between anticonvulsants". Proc Aust Assoc Neurol 12: 111–6. PMID 2912. 
  66. ^ Pippenger CE (1987). "Clinically significant carbamazepine drug interactions: an overview". Epilepsia 28 (Suppl 3): S71–6. doi:10.1111/j.1528-1157.1987.tb05781.x. PMID 3319544. 
  67. ^ Lai AA, Levy RH; Cutler RE (September 1978). "Time-course of interaction between carbamazepine and clonazepam in normal man". Clinical pharmacology and therapeutics 24 (3): 316–23. PMID 688725. 
  68. ^ Saavedra IN; Aguilera LI, Faure E, Galdames DG (August 1985). "Phenytoin/clonazepam interaction". Ther Drug Monit 7 (4): 481–4. doi:10.1097/00007691-198512000-00022. PMID 4082246. 
  69. ^ a b Windorfer A Jr; Sauer W (1977). "Drug interactions during anticonvulsant therapy in childhood: diphenylhydantoin, primidone, phenobarbitone, clonazepam, nitrazepam, carbamazepin and dipropylacetate". Neuropadiatrie 8 (1): 29–41. doi:10.1055/s-0028-1091502. PMID 321985. 
  70. ^ Windorfer A; Weinmann HM, Stünkel S (March 1977). "[Laboratory controls in long-term treatment with anticonvulsive drugs (author's transl)]". Monatsschr Kinderheilkd 125 (3): 122–8. PMID 323695. 
  71. ^ Khoo KC; Mendels J, Rothbart M, Garland WA, Colburn WA, Min BH, Lucek R, Carbone JJ, Boxenbaum HG, Kaplan SA (September 1980). "Influence of phenytoin and phenobarbital on the disposition of a single oral dose of clonazepam". Clin Pharmacol Ther 28 (3): 368–75. PMID 7408397. 
  72. ^ Bendarzewska-Nawrocka B; Pietruszewska E, Stepień L, Bidziński J, Bacia T (January-Feb 1980). "[Relationship between blood serum luminal and diphenylhydantoin level and the results of treatment and other clinical data in drug-resistant epilepsy]". Neurol Neurochir Pol 14 (1): 39–45. PMID 7374896. 
  73. ^ McElhatton PR (November-Dec 1994). "The effects of benzodiazepine use during pregnancy and lactation". Reprod Toxicol 8 (6): 461–75. doi:10.1016/0890-6238(94)90029-9. PMID 7881198. 
  74. ^ Iqbal, MM.; Sobhan, T.; Ryals, T. (Jan 2002). "Effects of commonly used benzodiazepines on the fetus, the neonate, and the nursing infant.". Psychiatr Serv 53 (1): 39–49. doi:10.1176/appi.ps.53.1.39. PMID 11773648. http://ps.psychiatryonline.org/cgi/content/full/53/1/39. 
  75. ^ Meldrum BS (1986). "Drugs acting on amino acid neurotransmitters". Adv Neurol 43: 687–706. PMID 2868623. 
  76. ^ Jenner P; Pratt JA, Marsden CD (1986). "Mechanism of action of clonazepam in myoclonus in relation to effects on GABA and 5-HT". Adv Neurol 43: 629–43. PMID 2418652. 
  77. ^ Gavish M; Fares F (November 1985). "Solubilization of peripheral benzodiazepine-binding sites from rat kidney" (PDF). J Neurosci 5 (11): 2889–93. PMID 2997409. http://www.jneurosci.org/cgi/reprint/5/11/2889.pdf. 
  78. ^ Chouinard G (2004). "Issues in the clinical use of benzodiazepines: potency, withdrawal, and rebound". J Clin Psychiatry 65 Suppl 5: 7–12. PMID 15078112. 
  79. ^ Macdonald RL; McLean MJ (1986). "Anticonvulsant drugs: mechanisms of action". Adv Neurol 44: 713–36. PMID 2871724. 
  80. ^ Tardy M; Costa MF, Rolland B, Fages C, Gonnard P. (April 1981). "Benzodiazepine receptors on primary cultures of mouse astrocytes". J Neurochem 36 (4): 1587–9. doi:10.1111/j.1471-4159.1981.tb00603.x. PMID 6267195. 
  81. ^ Gallager DW; Mallorga P, Oertel W, Henneberry R, Tallman J (February 1981). "{3H}Diazepam binding in mammalian central nervous system: a pharmacological characterization". J Neurosci 1 (2): 218–25. PMID 6267221. http://www.jneurosci.org/cgi/reprint/1/2/218. 
  82. ^ Petkov V; Georgiev VP, Getova D, Petkov VV (1982). "Effects of some benzodiazepines on the acetylcholine release in the anterior horn of the lateral cerebral ventricle of the cat". Acta Physiol Pharmacol Bulg 8 (3): 59–66. PMID 6133407. 
  83. ^ Grandison L (1982). "Suppression of prolactin secretion by benzodiazepines in vivo". Neuroendocrinology 34 (5): 369–73. doi:10.1159/000123330. PMID 6979001. 
  84. ^ Camoratto AM; Grandison L (18 April 1983). "Inhibition of cold-induced TSH release by benzodiazepines". Brain Res 265 (2): 339–43. doi:10.1016/0006-8993(83)90353-0. PMID 6405978. 
  85. ^ Taft WC; DeLorenzo RJ (May 1984). "Micromolar-affinity benzodiazepine receptors regulate voltage-sensitive calcium channels in nerve terminal preparations" (PDF). Proc Natl Acad Sci USA 81 (10): 3118–22. doi:10.1073/pnas.81.10.3118. PMID 6328498.& PMC 345232. http://www.pnas.org/cgi/reprint/81/10/3118.pdf. 
  86. ^ Skerritt JH; Johnston GA (May 6, 1983). "Enhancement of GABA binding by benzodiazepines and related anxiolytics". Eur J Pharmacol 89 (3-4): 193–8. doi:10.1016/0014-2999(83)90494-6. PMID 6135616. 
  87. ^ Lehoullier PF, Ticku MK (March 1987). "Benzodiazepine and beta-carboline modulation of GABA-stimulated 36Cl-influx in cultured spinal cord neurons". Eur. J. Pharmacol. 135 (2): 235–8. doi:10.1016/0014-2999(87)90617-0. PMID 3034628. 
  88. ^ Varotto M; Roman G, Battistin L (30 April 1981). "[Pharmacological influences on the brain level and transport of GABA. I) Effect of various antipileptic drugs on brain levels of GABA]". Boll Soc Ital Biol Sper 57 (8): 904–8. PMID 7272065. 
  89. ^ Battistin L, Varotto M, Berlese G, Roman G (February 1984). "Effects of some anticonvulsant drugs on brain GABA level and GAD and GABA-T activities". Neurochem Res 9 (2): 225–31. doi:10.1007/BF00964170. PMID 6429560. 
  90. ^ Hullihan JP; Spector S, Taniguchi T, Wang JK (February 1983). "The binding of {3H}-diazepam to guinea-pig ileal longitudinal muscle and the in vitro inhibition of contraction by benzodiazepines". Br J Pharmacol 78 (2): 321–7. PMID 6131717. http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=2044717&blobtype=pdf. 
  91. ^ "Monograph - Clonazepam -- Pharmacokinetics". Medscape. January 2006. http://www.medscape.com/druginfo/monograph?cid=med&drugid=14403&drugname=Clonazepam+Oral&monotype=monograph&secid=9. Retrieved 2007-12-30. 
  92. ^ Parry GJ (1976). "An animal model for the study of drugs in the central nervous system". Proc Aust Assoc Neurol 13: 83–8. PMID 1029011. 
  93. ^ Gerna M; Morselli PL (January 21, 1976). "A simple and sensitive gas chromatographic method for the determination of clonazepam in human plasma". J Chromatogr 116 (2): 445–50. doi:10.1016/S0021-9673(00)89915-X. PMID 1245581. 
  94. ^ Tokola RA; Neuvonen PJ (1983). "Pharmacokinetics of antiepileptic drugs". Acta neurologica Scandinavica. Supplementum 97: 17–27. doi:10.1111/j.1600-0404.1983.tb01532.x. PMID 6143468. 
  95. ^ Greenblatt DJ, Miller LG, Shader RI (October 1987). "Clonazepam pharmacokinetics, brain uptake, and receptor interactions". J Clin Psychiatry 48 Suppl: 4–11. PMID 2822672. 
  96. ^ Ebel S; Schütz H (February 27, 1977). "[Studies on the detection of clonazepam and its main metabolites considering in particular thin-layer chromatography discrimination of nitrazepam and its major metabolic products (author's transl)]". Arzneimittelforschung 27 (2): 325–37. PMID 577149. 
  97. ^ Edelbroek PM; De Wolff FA (October 1978). "Improved micromethod for determination of underivatized clonazepam in serum by gas chromatography" (PDF). Clinical chemistry 24 (10): 1774–7. PMID 699288. http://www.clinchem.org/cgi/reprint/24/10/1774.pdf. 
  98. ^ Welch TR; Rumack BH, Hammond K (1977). "Clonazepam overdose resulting in cyclic coma". Clin Toxicol 10 (4): 433–6. doi:10.3109/15563657709046280. PMID 862377. 
  99. ^ Honer WG; Rosenberg RG, Turey M, Fisher WA (November 1986). "Respiratory failure after clonazepam and amobarbital" (PDF). Am J Psychiatry 143 (11): 1495. PMID 3777263. http://ajp.psychiatryonline.org/cgi/reprint/143/11/1495b.pdf. 
  100. ^ R. Baselt, Disposition of Toxic Drugs and Chemicals in Man, 8th edition, Biomedical Publications, Foster City, CA, 2008, pp. 335-337.
  101. ^ United States Government; U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES (2006). "Drug Abuse Warning Network, 2006: National Estimates of Drug-Related Emergency Department Visits". Substance Abuse and Mental Health Services Administration. http://dawninfo.samhsa.gov/files/ed2006/DAWN2k6ED.htm. Retrieved 9 February 2009. 

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