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Alprazolam 2 mg tablets
| Benzodiazepine | |
|---|---|
| |
| IUPAC name | 5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one |
| Identifiers | |
| CAS number | |
| PubChem | |
| SMILES | O=C1N([H])c2ccccc2C(c3ccccc3)=NC1 |
| Properties | |
| Molecular formula | C15H12N2O |
| Molar mass | 236.26858 |
| Except where noted otherwise, data are given for materials in their standard state (at 25 °C, 100 kPa) Infobox disclaimer and references | |
The benzodiazepines (pronounced [ˌben-zō-dī-ˈa-zə-ˌpēn], or "benzos" for short) are a class of psychoactive drugs considered minor tranquilizers with varying hypnotic, sedative, anxiolytic, anticonvulsant, muscle relaxant and amnesic properties, which are mediated by slowing down the central nervous system.McKernan RM; Rosahl TW, Reynolds DS, Sur C, Wafford KA, Atack JR, Farrar S, Myers J, Cook G, Ferris P, Garrett L, Bristow L, Marshall G, Macaulay A, Brown N, Howell O, Moore KW, Carling RW, Street LJ, Castro JL, Ragan CI, Dawson GR, Whiting PJ. (Jun 2000). "Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype.". Nature neuroscience. 3 (6): 587-92. PMID 10816315. Retrieved on 2007-07-05. Benzodiazepines are useful in treating anxiety, insomnia, agitation, seizures, and muscle spasms, as well as alcohol withdrawal. They can also be used before certain medical procedures such as endoscopies or dental work where tension and anxiety are present, and prior to some unpleasant medical procedures in order to induce sedation and amnesiaBulach R, Myles PS, Russnak M (2004). "Double-blind randomized controlled trial to determine extent of amnesia with midazolam given immediately before general anaesthesia.". Br J Anaesth 94 (3): 300-305. doi:10.1093/bja/aei040. PMID 15567810. for the procedure. Another use is to counteract anxiety-related symptoms upon initial use of SSRIs and other antidepressants, or as an adjunctive treatment. Recreational stimulant users often use benzodiazepines as a means of "coming down" (see: Drug abuse).
The long-term use of benzodiazapines can cause physical dependence. The use of benzodiazepines should therefore commence only after medical consultation and benzodiazepines should be prescribed the smallest dosage possible to provide an acceptable level of symptom relief. Dependence varies with the benzodiazepine used and with the user, with some reporting alprazolam dependence in as little as three days.[citation needed]
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For various benzodiazepines and their respective generic and non-US brand-names, half-lives, and primary uses, see list of benzodiazepines.
The core chemical structure of "classical" benzodiazepine drugs is a fusion between the benzene and diazepine ring systems. Many of these drugs contain the 5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one substructure (see figure to the above right).
Most benzodiazepines are administered orally; however, administration can also occur intravenously, intramuscularly, sublingually or as a suppository. Well-known benzodiazepines and their primary trade names include:
A related class of drugs that also work on the benzodiazepine receptors, the nonbenzodiazepines, has recently been introduced.Lemmer B (2007). "The sleep-wake cycle and sleeping pills". Physiol. Behav. 90 (2-3): 285-93. doi:10.1016/j.physbeh.2006.09.006. PMID 17049955. Nonbenzodiazepines are molecularly distinct from benzodiazepines and have less addictive potential, while still offering benefits very similar to those of benzodiazepines.
Benzodiazepines are commonly divided into three groups by their half-lives: Short-acting compounds have a half-life of less than 12 hours, and have few residual effects if taken before bedtime, but rebound insomnia may occur and they might cause wake-time anxiety. Intermediate-acting compounds have a half-life of 12–24 hours, may have residual effects in the first half of the day. Rebound insomnia however is more common upon discontinuation of short-acting benzodiazepines. Daytime withdrawal symptoms are also a problem with prolonged usage of short-acting benzodiazepines, including daytime anxiety. Long-acting compounds have a half-life greater than 24 hours. "Benzodiazepines: a summary of pharmacokinetic properties.". British journal of clinical pharmacology.. PMID 6133528. (Dec 1990) "Benzodiazepine use in a small community hospital. Appropriate prescribing or not?". South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde.. PMID 2251629. Strong sedative effects typically persist throughout the next day if long-acting preparations are used for insomnia. Accumulation of the compounds in the body may occur. The elimination half-life may greatly vary between individuals, especially the elderly. Shorter-acting compounds are usually best for their hypnotic effects, whereas longer-acting compounds are usually better for their anxiolytic effects. Benzodiazepines with shorter half-lives tend to be able to produce tolerance and addiction quicker, as the drug does not last in the system for as long, with resultant interdose withdrawal phenomenon and next-dose craving. Although short-acting drugs are more commonly prescribed for insomnia, there are exceptions to the rules, such as alprazolam being prescribed as an anxiolytic more than a hypnotic, despite possessing a short half-life.
Benzodiazepines produce a range of effects from depressing to stimulating the central nervous system via modulating the GABAA receptor, the most prolific inhibitory receptor within the brain. The GABAA receptor is made up from 5 subunits out of a possible 19, and GABAA receptors made up of different combinations of subunits have different properties, different locations within the brain, and different activities relative to pharmacological and clinical effects.
Benzodiazepines bind at the interface of the α and γ subunits on the GABA A receptor. Benzodiazepine binding also requires that alpha subunits contain a histidine amino acid residue, (i.e., α1, α2, α3 and α5 containing GABAA receptors). For this reason, benzodiazepines show no affinity for α4 and α6 subunits containing GABAA receptors, which contain an arginine instead of a histidine residue. Other sites on the GABAA receptor also bind neurosteroids, barbiturates and certain anesthetics.Pym LJ, Cook SM, Rosahl T, McKernan RM, Atack JR (2005). "Selective labelling of diazepam-insensitive GABAA receptors in vivo using [3H]Ro 15-4513". Br. J. Pharmacol. 146 (6): 817-25. doi:10.1038/sj.bjp.0706392. PMID 16184188.
In order for GABAA receptors to be sensitive to the action of benzodiazepines, they need to contain both an α and a γ subunit, where the benzodiazepine binds at the interface. Once bound, the benzodiazepine locks the GABAA receptor into a conformation where the neurotransmitter GABA has much higher affinity for the GABAA receptor, increasing the frequency of opening of the associated chloride ion channel and hyperpolarizing the membrane. This potentiates the inhibitory effect of the available GABA, leading to sedatory and anxiolytic effects. As mentioned above, different benzodiazepines can have different affinities for GABAA receptors made up of different collection of subunits. For instance, benzodiazepines with high activity at the α1 are associated with sedation, whereas those with higher affinity for GABAA receptors containing α2 and/or α3 subunits have good anti-anxiety activity.Hevers W, Lüddens H (1998). "The diversity of GABAA receptors. Pharmacological and electrophysiological properties of GABAA channel subtypes". Mol. Neurobiol. 18 (1): 35-86. PMID 9824848. Benzodiazepines also bind to glial cell membranes.Tardy M; Costa MF, Rolland B, Fages C, Gonnard P (Apr 1981). "Benzodiazepine receptors on primary cultures of mouse astrocytes". J Neurochem 36 (4): 1587-9. PMID 6267195.
Clinically-used benzodiazepines are full agonists at the benzodiazepine receptor producing anxiolytic and sedating properties. However, with regular or chronic use the risk of physical dependence increases with demonstratable withdrawal symptoms upon discontinuation or dosage reduction. Benzodiazepines also have abuse potential. The benzodiazepine receptor is a modulatory site for the GABA receptor.
Compounds that bind to the benzodiazepine receptor and enhance the GABA receptor function are termed benzodiazepine receptor agonists and display sedative/hypnotic properties. Compounds that, in the absence of agonist, have no apparent activity but that competitively inhibit the binding of agonists to the receptor are called benzodiazepine receptor antagonists. Ligands that decrease GABA function are termed benzodiazepine receptor inverse agonists. Full inverse agonists have potent convulsant activities.
Some compounds lie somewhere between being full agonists or full antagonists, and are termed either partial agonists or partial antagonists. There has been interest in partial agonists for the benzodiazepine receptor with evidence that complete tolerance may not occur with chronic use, with partial agonists demonstrating continued anxiolytic properties with reduced sedation, dependence, and withdrawal problems.Atack JR (2003). "Anxioselective compounds acting at the GABA(A) receptor benzodiazepine binding site". Current drug targets. CNS and neurological disorders 2 (4): 213-32. PMID 12871032.
The anticonvulsant properties of benzodiazepines may be in part or entirely due to binding to voltage-dependent sodium channels rather than benzodiazepine receptors. Sustained repetitive firing seems to be limited by benzodiazepines effect of slowing recovery of sodium channels from inactivation.McLean MJ; Macdonald RL. (Feb 1988). "Benzodiazepines, but not beta carbolines, limit high-frequency repetitive firing of action potentials of spinal cord neurons in cell culture.". J Pharmacol Exp Ther. 244 (2): 789-95. PMID 2450203.
Benzodiazepines have a number of therapeutic uses, are well-tolerated, and are very safe and effective drugs in the short term for a wide range of conditions.
Benzodiazepines are potent anticonvulsants and have life-saving properties in the acute management of status epilepticus. The most commonly-used benzodiazepines for seizure control are lorazepam and diazepam. A meta-analysis of 11 clinical trials concluded that lorazepam was superior to diazepam in treating persistent seizures.Prasad K; Krishnan PR, Al-Roomi K, Sequeira R. (Jun 2007). "Anticonvulsant therapy for status epilepticus.". British journal of clinical pharmacology. 63 (6): 640-7. PMID 17439538. Although diazepam is much longer-acting than lorazepam, lorazepam has a more prolonged anticonvulsant effect. This is because diazepam is very lipid-soluble and highly protein-bound, and has a very large distribution of unbound drug, resulting in diazepam\'s having only a 20– to 30-minute duration of action against status epilepticus. Lorazepam, however, has a much smaller volume of distribution of unbound drug, which results in a more prolonged duration of action against status epilepticus. Lorazepam can therefore be considered superior to diazepam, at least in the initial stages of treatment of status epilepticus.Treiman DM. (1989). "Pharmacokinetics and clinical use of benzodiazepines in the management of status epilepticus.". Epilepsia. 30 (2): 4-10. PMID 2670537.
Benzodiazepines possess anti-anxiety properties and can be useful for the short-term treatment of severe anxiety. Benzodiazepines are usually administered orally for the treatment of anxiety; however, occasionally lorazepam or diazepam may be given intravenously for the treatment of panic attacks.[1]
A panel of over 50 peer-nominated internationally recognized experts in the pharmacotherapy of anxiety and depression judged the BZs, especially combined with an antidepressant, as the mainstays of pharmacotherapy for anxiety disorders. Uhlenhuth EH, Balter MB, Ban TA, Yang K (1999). "International study of expert judgment on therapeutic use of benzodiazepines and other psychotherapeutic medications: VI. Trends in recommendations for the pharmacotherapy of anxiety disorders, 1992-1997". Depress Anxiety 9 (3): 107–16. PMID 10356648. Uhlenhuth EH, Balter MB, Ban TA, Yang K (1995). "International study of expert judgement on therapeutic use of benzodiazepines and other psychotherapeutic medications: II. Pharmacotherapy of anxiety disorders". J Affect Disord 35 (4): 153–62. PMID 8749980. Uhlenhuth EH, Balter MB, Ban TA, Yang K (1999). "Trends in recommendations for the pharmacotherapy of anxiety disorders by an international expert panel, 1992-1997". Eur Neuropsychopharmacol 9 Suppl 6: S393–8. PMID 10622685. Uhlenhuth EH, Balter MB, Ban TA, Yang K (1999). "International study of expert judgment on therapeutic use of benzodiazepines and other psychotherapeutic medications: IV. Therapeutic dose dependence and abuse liability of benzodiazepines in the long-term treatment of anxiety disorders". J Clin Psychopharmacol 19 (6 Suppl 2): 23S–29S. PMID 10587281.
Despite increasing focus on the use of antidepressants and other agents for the treatment of anxiety, benzodiazepines have remained a mainstay of anxiolytic pharmacotherapy due to their robust efficacy, rapid onset of therapeutic effect, and generally favorable side effect profile. Stevens JC, Pollack MH (2005). "Benzodiazepines in clinical practice: consideration of their long-term use and alternative agents". J Clin Psychiatry 66 Suppl 2: 21–7. PMID 15762816. Treatment patterns for psychotropic drugs appear to have remained stable over the past decade, with benzodiazepines being the most commonly used medication for panic disorder . Bruce SE, Vasile RG, Goisman RM, et al (2003). "Are benzodiazepines still the medication of choice for patients with panic disorder with or without agoraphobia?". Am J Psychiatry 160 (8): 1432–8. PMID 12900305.
Hypnotic benzodiazepines have strong sedative effects, and certain benzodiazepines therefore are often prescribed for the management of insomnia. Longer-acting benzodiazepines, such as nitrazepam, have side-effects that may persist into the next day, whereas the more intermediate-acting benzodiazepines (for example, temazepam) may have less "hangover" effects the next day.[2] Benzodiazepine hypnotics should be reserved for short-term courses to treat acute conditions, as tolerance and dependence may occur if these benzodiazepines are taken regularly for more than a few weeks.
Benzodiazepines can be very beneficial as premedication before surgery, especially in those that are anxious. Usually administered a couple of hours before surgery, benzodiazepines will bring about anxiety relief and also produce amnesia. Amnesia can be useful in this situation, as patients will not be able to remember any unpleasantness from surgery.[3] Lorazepam can be utilized in patients who are particularly anxious about dental procedures.[4] Alternatively nitrous oxide can be administered in dental phobia due to its sedative and dissociative effects, its fast onset of action, and its extremely short duration of action.
Benzodiazepines can be very useful in intensive care to sedate patients receiving mechanical ventilation, or those in extreme distress or severe pain. Caution should be exercised in this situation due to the occasional scenario of respiratory depression, and benzodiazepine overdose treatment facilities should be available.[5]
In the management of alcohol withdrawal, benzodiazepines can have potentially life-saving effects by ameliorating the alcohol withdrawal syndrome. Delirium tremens, which can be potentially fatal, can be effectively treated by benzodiazepines and often prevented from occurring in the first place. The usual benzodiazepines used in the management of alcohol withdrawal are Chlordiazepoxide (Librium) or diazepam (Valium). Chlormethiazole is an alternative, but is not as well-tolerated as benzodiazepines, and, because it may have more risks associated with it, should only be used in an inpatient setting.[6]
Benzodiazepines are well known for their strong muscle-relaxing properties, and can be useful in the treatment of muscle spasms, for example, Tetanus or spastic disorders [7] and Restless legs syndrome.
Mania, a mood disorder, is a state of extreme mood elevation and is a diagnosable serious psychiatric disorder. Benzodiazepines can be very useful in the short-term treatment of acute mania, until the effects of Lithium or neuroleptics take effect. Benzodiazepines bring about rapid tranquillisation and sedation of the manic individual, therefore benzodiazepines are a very important tool in the management of mania. Both clonazepam and lorazepam are used for the treatment, with some evidence that clonazepam may be superior in the treatment of acute mania.Bottaï T; Hüe B, Hillaire-Buys D, Barbe A, Alric R, Pouget R, Petit P. (Dec 1995). "Clonazepam in acute mania: time-blind evaluation of clinical response and concentrations in plasma.". Journal of affective disorders. 36 (1-2): 21-7. PMID 8988261. Curtin F; Schulz P. (Mar 2004). "Clonazepam and lorazepam in acute mania: a Bayesian meta-analysis.". Journal of affective disorders. 78 (3): 201-8. PMID 15013244.
As in humans, benzodiazepines have a wide range of uses in veterinary practice in the treatment of various disorders and scenarios involving animals.
Midazolam and diazepam are utilized for their anesthetic properties in veterinary practice in combination with other general anesthetic drugs such as ketamine.Yamashita K; Wijayathilaka TP, Kushiro T, Umar MA, Taguchi K, Muir WW. (Jan 2007). "Anesthetic and cardiopulmonary effects of total intravenous anesthesia using a midazolam, ketamine and medetomidine drug combination in horses.". The Journal of veterinary medical science / the Japanese Society of Veterinary Science. 69 (1): 7-13. PMID 17283393. Woolfson MW; Foran JA, Freedman HM, Moore PA, Shulman LB, Schnitman PA. (Oct 1980). "Immobilization of baboons (Papio anubis) using ketamine and diazepam.". Laboratory animal science. 30 (5): 902-4. PMID 7431875.
Midazolam or diazepam can also be used as a sedative anxiolytic to quell anxiety and agitation experienced by animals in veterinary practice, for example, during transport. Pulley AC; Roberts JA, Lerche NW. (Dec 2004). "Four preanesthetic oral sedation protocols for rhesus macaques (Macaca mulatta).". Journal of zoo and wildlife medicine : official publication of the American Association of Zoo Veterinarians. 35 (4): 497-502. PMID 15732590. Sanhouri AA; Jones RS, Dobson H. (Jul-Aug 1991). "Preliminary results on the effects of diazepam on physiological responses to transport in male goats.". The British veterinary journal. 147 (4): 388-9. PMID 1913136. Diazepam has also been found to have tranquillising effects on various animals tested with the following properties; myorelaxation, stress reduction and aggression inhibition.Dilov P; Dimitrov S, Nikolov A, Chaleva E, Panchev I. (1984). "[Pharmacological and clinico-pharmacological studies of diazepam powder in suspensions]". Veterinarno-meditsinski nauki. 21 (3): 96-103. PMID 6740928.
Benzodiazepines are also commonly used for the control of muscular conditions in animals. Diazepam has been prescribed for the effective treatment and control of tremors by veterinarians in animals. Corticosteroids and or Diazepam have been found to be effective for the control of tremors in veterinarian practice.Yamaya Y; Iwakami E, Goto M, Koie H, Watari T, Tanaka S, Takeuchi A, Tokuriki M. (Sep 2004). "A case of shaker dog disease in a miniature dachshund.". The Journal of veterinary medical science / the Japanese Society of Veterinary Science. 66 (9): 1159-60. PMID 15472486. Wagner SO; Podell M, Fenner WR. (15). "Generalized tremors in dogs: 24 cases (1984-1995).". Journal of the American Veterinary Medical Association. 211 (6): 731-5. PMID 9301744. Diazepam has also been used in to control muscle spasms that were the result of tetanus in cats.Polizopoulou ZS; Kazakos G, Georgiadis G, Soubasis N, Koutinas Ch, Koutinas AF. (Dec 2002). "Presumed localized tetanus in two cats.". Journal of feline medicine and surgery. 4 (4): 209-12. PMID 12468315.
Benzodiazepines, such as diazepam, are used in the treatment of various forms of epilepsy in dogs.Bateman SW; Parent JM. (15). "Clinical findings, treatment, and outcome of dogs with status epilepticus or cluster seizures: 156 cases (1990-1995).". Journal of the American Veterinary Medical Association. 215 (10): 1463-8. PMID 10579043. Benzodiazepines have potent anticonvulsant properties and are very effective in the short term in managing seizure disorders in animals. However, with prolonged usage, benzodiazepines tend to lose their anticonvulsant properties. Partial benzodiazepine receptor agonists have shown some promise, with continued efficacy being demonstrated with benzodiazepine receptor partial agonists and also displaying mild withdrawal symptoms upon discontinuation, which may make them superior to benzodiazepines in the long-term management of epilepsy in animals.Löscher W; Potschka H, Rieck S, Tipold A, Rundfeldt C. (Oct 2004). "Anticonvulsant efficacy of the low-affinity partial benzodiazepine receptor agonist ELB 138 in a dog seizure model and in epileptic dogs with spontaneously recurrent seizures.". Epilepsia. 45 (10): 1228-39. PMID 15461677. Phenobarbital is the drug of choice and potassium bromide is the drug of second choice in the treatment of epilepsy in dogs and diazepam is recommended for the treatment at home of cluster seizures.Podell M. (Jul 1996). "Seizures in dogs.". The Veterinary clinics of North America. Small animal practice. 26 (4): 779-809. PMID 8813750.
Lorazepam has been found to be an effective premedication before general anesthesia in bringing about adequate muscular relaxation for veterinary surgery.Singh K; Sobti VK, Bansal PS, Rathore SS. (Dec 1989). "Studies on lorazepam as a premedicant for thiopental anaesthesia in the dog.". Zentralblatt für Veterinärmedizin. Reihe A. 36 (10): 750-4. PMID 2515684.
The benzodiazepine Zolazepam, in combination with Tiletamine, has been used in the tranquilization of wild animals, such as gorillas and polar bears, and has been found to be in terms of reduced side-effects superior to ketamine.Sleeman JM; Cameron K, Mudakikwa AB, Nizeyi JB, Anderson S, Cooper JE, Richardson HM, Macfie EJ, Hastings B, Foster JW. (Mar 2000). "Field anesthesia of free-living mountain gorillas (Gorilla gorilla beringei) from the Virunga Volcano region, Central Africa.". Journal of zoo and wildlife medicine : official publication of the American Association of Zoo Veterinarians. 31 (1): 9-14. PMID 10884117. Cattet MR; Caulkett NA, Polischuk SC, Ramsay MA. (Sep 1999). "Anesthesia of polar bears (Ursus maritimus) with zolazepam-tiletamine, medetomidine-ketamine, and medetomidine-zolazepam-tiletamine.". Journal of zoo and wildlife medicine : official publication of the American Association of Zoo Veterinarians. 30 (3): 354-60. PMID 10572857. Midazolam can also be used along with other drugs in the sedation and capture of wild animals.Nel PJ; Taylor A, Meltzer DG, Haupt MA. (Mar 2000). "Capture and immobilisation of aardvark (Orycteropus afer) using different drug combinations.". Journal of the South African Veterinary Association. 71 (1): 58-63. PMID 10949520.
The side-effects are predictable, as they are intrinsic effects of the drug class of benzodiazepines. Knowing the relative effects of benzodiazepine types will help clinicians prescribe the most appropriate type. For example, lorazepam may not be best treatment choice for the elderly due to its stronger amnesic effects and thus greater potential for aggravating forgetfulness and confusion. But then lorazepam is a good choice for the acute treatment of status epilepticus due to its potent anticonvulsant properties.
Benzodiazepines have largely replaced the barbiturates, mainly because benzodiazepines are much safer in terms of overdose. Prior to the introduction of benzodiazepines, barbiturate overdose was of significant concern to both the medical community and the general public. Still, drowsiness, ataxia, confusion, vertigo, impaired judgement, and a number of other effects are common.
The concern is also that, even though they are relatively non-toxic in themselves, benzodiazepines may facilitate suicide by other drugs or means, through disinhibition. However, when combined with other central nervous system depressants such as opiates or alcohol, the risk of overdose and death increases significantly, due to synergistic CNS, respiratory, and cardiovascular system depression. The elderly, alcoholics, and those with underlying medical conditions, e.g., respiratory disease or personality disorder, are at increased risk for both acute adverse reactions and problems arising from long-term use, including dependence, confusion, memory impairment, or overdose. Toxicity and Adverse Consequences of Benzodiazepine Use. Psychiatric Annals (1995). Paradoxical reactions may occur in any individual on commencement of therapy and initial monitoring should take into account the risk of increase in anxiety or suicidal thoughts.Paradoxical Reactions to Benzodiazepines
Benzodiazepines may impair the ability to drive vehicles and to operate machinery. The impairment is worsened by consumption of alcohol, because both act as central nervous system depressants. The effects of long-acting benzodiazepines can also linger to the following day.
Benzodiazepines can cause a wide range of significant behavioral disturbances and cognitive impairment. Cognitive deficits, including concentration and memory-processing problems, are a well-known adverse effect of benzodiazepines and occur at prescribed dose levels. The degree of cognitive impairment will depend on the dose used and individual tolerance level to the drug, with the elderly being more vulnerable to cognitive impairments from benzodiazepines.
Amnesia can be a side-effect of benzodiazepines and can be utilized in a therapeutic setting to reduce unpleasant memories from investigatory medical procedures, e.g., endoscopies. In addition, the amnesic and sedating properties have found favor with criminals as a date-rape drug. All benzodiazepines can be used as date-rape drugs, but flunitrazepam (Rohypnol), clonazepam (Klonopin), midazolam (Versed), and temazepam (Restoril) are the most commonly used.Negrusz A; Gaensslen RE. (Aug 2003). "Analytical developments in toxicological investigation of drug-facilitated sexual assault.". Analytical and bioanalytical chemistry. 376 (8): 1192-7. PMID 12682705.
For a full list of side-effects pertaining to a specific drug, those in the United States should read the patient information, prescriber guide, or manufacturer\'s information as published in the PDR or other such manuals.
Severe behavioral changes resulting from benzodiazepines have been reported including mania, schizophrenia, anger, impulsivity, and hypomania.Cole JO; Kando JC. (1993). "Adverse behavioral events reported in patients taking alprazolam and other benzodiazepines.". The Journal of clinical psychiatry. 54 (49-61): 62-3. PMID 8262890. Individuals with borderline personality disorder appear to have a greater risk of experiencing severe behavioral or psychiatric disturbances from benzodiazepines. Aggression and violent outbursts can also occur with benzodiazepines, particularly when they are combined with alcohol. Recreational abusers and patients on high-dosage regimes may be at an even greater risk of experiencing paradoxical reactions to benzodiazepines. Benzodiazepines — Effects on Human Performance and Behavior. Forensic Science Review (2002). Paradoxical reactions may occur in any individual on commencement of therapy and initial monitoring should take into account the risk of increase in anxiety or suicidal thoughts.Paradoxical Reactions to Benzodiazepines
When benzodiazepines are used as an adjunct in the treatment of seizures, an increase in dosage of the primary agent may be required. The concomitant administration of benzodiazepines and anti-convulsants may precipitate an increase in certain seizure activity, specifically tonic-clonic seizures.
In a letter to the British Medical Journal, it was reported that a high proportion of parents referred for actual or threatened child abuse were taking drugs at the time, often a combination of benzodiazepines and tricyclic antidepressants. Many mothers described that instead of feeling less anxious or depressed, they became more hostile and openly aggressive towards the child as well as to other family members while consuming tranquilizers. The author warned that environmental or social stresses such as difficulty coping with a crying baby combined with the effects of tranquilizers may precipitate a child abuse event. (1) "Letter: Tranquilizers causing aggression.". British medical journal. 1 (5952): 266. PMID 234269.
Paradoxical rage reactions from benzodiazepines are thought to be due to partial deterioration from consciousness, generating automatic behaviors, fixation amnesia, and aggressiveness from disinhibition with a possible serotonergic mechanism playing a role.Senninger JL; Laxenaire M. (1995). "[Violent paradoxal reactions secondary to the use of benzodiazepines]". Annales médico-psychologiques. 153 (4): 278-81. PMID 7618826.
Tolerance develops to many of the therapeutic effects of benzodiazepines rapidly with daily or frequent use. In general, tolerance to the hypnotic and sedative effects occurs within days; however, tolerance to the anxiolytic effects of benzodiazepines takes longer to develop. According to a 1988 report published by the Committee on Safety of Medicines, there is little evidence of continued anxiolytic properties from benzodiazepines after four months of continuous use other than the suppression of withdrawal signs and recommended that prescriptions of benzodiazepines be limited to 2–4 weeks only. (1980) "Systematic review of the benzodiazepines. Committee on the Review of Medicines.". British Medical Journal. Committee on the Review of Medicines.. BENZODIAZEPINES, DEPENDENCE AND WITHDRAWAL SYMPTOMS (PDF) (Jan 1988). Retrieved on 05, 2007 publisher = Medicines and Healthcare products Regulatory Agency.. Retrieved on 07, 2007 publisher = Medicines and Healthcare products Regulatory Agency..
However, in 1992 Romach and colleagues reported that dose escalation was not a characteristic of long-term alprazolam users, and the majority of patients indicated that alprazolam continued to be effective. Romach MK, Somer GR, Sobell LC, Sobell MB, Kaplan HL, Sellers EM (1992). "Characteristics of long-term alprazolam users in the community". J Clin Psychopharmacol 12 (5): 316–21. PMID 1479048. A 2003 study did not support the hypothesis that long-term use of benzodiazepines frequently results in notable dose escalation. Soumerai SB, Simoni-Wastila L, Singer C, et al (2003). "Lack of relationship between long-term use of benzodiazepines and escalation to high dosages". Psychiatr Serv 54 (7): 1006–11. PMID 12851438.
In a 1-year follow-up study of patients with panic disorder continuing treatment with clonazepam, 90% maintained a positive response without developing significant tolerance. In a 2.5-year follow-up study of alprazolam therapy, little evidence of tolerance emerged. Pollack MH (1990). "Long-term management of panic disorder". J Clin Psychiatry 51 Suppl: 11–3; discussion 50–3. PMID 1970813.
There is also evidence that long-term use may actually worsen anxiety in some people with or without prior psychiatric history as was found in a study of 50 patients.Ashton, CH (1987). "Benzodiazepine Withdrawal: Outcome in 50 Patients". British Journal of Addiction 82: 655-671. A possible explanation for increased anxiety from chronic use of benzodiazepines is that it is a side-effect of tolerance with increasing doses required to suppress withdrawal effects. However, patients should be aware that this could lead to a cycle of increasing doses and worsening side effects. In addition, as dosage is increased, the potential for addiction becomes greater.
Benzodiazepines share a similar mechanism of action with various sedative compounds that act by enhancing the GABAA receptor. Cross tolerance means that one drug will alleviate the withdrawal effects of another. It also means that tolerance of one drug will result in tolerance of another similarly-acting drug. Benzodiazepines are often used for this reason to detoxify alcohol-dependent patients, and can have life-saving properties in preventing and/or treating severe life-threatening withdrawal syndromes from alcohol, such as delirium tremens. However, although benzodiazepines can be very useful in the acute detoxification of alcoholics, benzodiazepines in themselves act as positive reinforcers in alcoholics, by increasing the desire for alcohol. Low doses of benzodiazepines were found to significantly increase the level of alcohol consumed in alcoholics.Poulos CX; Zack M. (2004). "Low-dose diazepam primes motivation for alcohol and alcohol-related semantic networks in problem drinkers.". Behavioural pharmacology. 15 (7): 503-12. PMID 15472572. However, alcoholics dependent on benzodiazepines should not be abruptly withdrawn but be very slowly withdrawn from benzodiazepines as over-rapid withdrawal is likely to produce severe anxiety or panic, which is well known for being a relapse risk factor in alcoholics. See (benzodiazepine withdrawal syndrome).
There is also cross tolerance between alcohol, the benzodiazepines, the barbiturates, and the nonbenzodiazepine drugs, which all act by enhancing the GABAA receptor\'s function via modulating the chloride ion channel function of the GABAA receptor.Khanna JM, Kalant H, Weiner J, Shah G (1992). "Rapid tolerance and cross-tolerance as predictors of chronic tolerance and cross-tolerance". Pharmacol. Biochem. Behav. 41 (2): 355-60. PMID 1574525. World Health Organisation - Assessment of ZopicloneAllan AM, Baier LD, Zhang X (1992). "Effects of lorazepam tolerance and withdrawal on GABAA receptor-operated chloride channels". J. Pharmacol. Exp. Ther. 261 (2): 395-402. PMID 1374467. Rooke KC. (1976). "The use of flurazepam (dalmane) as a substitute for barbiturates and methaqualone/diphenhydramine (mandrax) in general practice.". J Int Med Res. 4 (5): 355-9. PMID 18375.
Long-term benzodiazepine usage, in general, leads to some form of tolerance and/or dependence. However, it is important to distinguish between addiction to and normal physical dependence on benzodiazepines. Intentional abusers of benzodiazepines usually have other substance abuse problems. Benzodiazepines are usually a secondary drug of abuse-used mainly to augment the high received from another drug or to offset the adverse effects of other drugs. Few cases of addiction arise from legitimate use of benzodiazepines. O\'brien CP (2005). "Benzodiazepine use, abuse, and dependence". J Clin Psychiatry 66 Suppl 2: 28–33. PMID 15762817.
Regular use of benzodiazepines at prescribed levels for six weeks was found to produce a significant risk of dependence, with resultant withdrawal symptoms appearing on abrupt discontinuation in a study assessing diazepam and buspirone. However, with abrupt withdrawal after six weeks of treatment with buspirone, no withdrawal symptoms developed.Murphy SM, Owen R, Tyrer P. (1989). "Comparative assessment of efficacy and withdrawal symptoms after 6 and 12 weeks\' treatment with diazepam or buspirone.". The British Journal of Psychiatry : the journal of mental science. 154: 529-34. PMID 2686797. Various studies have shown between 20–100% of patients prescribed benzodiazepines at therapeutic dosages long term are physically dependent and will experience withdrawal symptoms.Ashton, CH (1997 publisher= Cambridge University Press). "Benzodiazepine Dependency", in A Baum, S. Newman, J. Weinman, R. West, C. McManus: Cambridge Handbook of Psychology & Medicine, 376-80.
Benzodiazepine dependence is a frequent complication when they are prescribed for or taken for longer than four weeks, with physical dependence and withdrawal symptoms being the most common problem, but also occasionally drug-seeking behavior. Withdrawal symptoms include anxiety, perceptual disturbances, distortion of all the senses, dysphoria, and, in rare cases, psychosis, and epileptic seizures. The risk factors for benzodiazepine dependence are long-term use beyond four weeks, use of high doses, and use of potent short-acting benzodiazepines among those with certain pre-existing personality characteristics such as dependent personalities, and those prone to drug abuse.Marriott S, Tyrer P. (Aug 1993). "Benzodiazepine dependence. Avoidance and withdrawal.". Drug safety : an international journal of medical toxicology and drug experience. 9 (2): 93-103. PMID 8104417.
Previously, physical dependence on benzodiazepines was largely thought to occur only in people on high-therapeutic-dose ranges, and low- or normal-dose dependence was not suspected until the 1970s; and it wasn\'t until the early 1980s that it was confirmed.Lader M. (1991). "History of benzodiazepine dependence.". Journal of substance abuse treatment. 8 (1-2): 53-9. PMID 1675692. However, low-dose dependence is now a recognized clinical disadvantage of benzodiazepines, and severe withdrawal syndromes can occur from these low doses of benzodiazepines even after gradual dose reduction.Lader M. (Dec 1987). "Long-term anxiolytic therapy: the issue of drug withdrawal.". The Journal of clinical psychiatry. 48: 12-6. PMID 2891684. Miura S; Murasaki M (Mar 1992). "The future of 5-HT1A receptor agonists. (Aryl-piperazine derivatives).". Progress in neuro-psychopharmacology & biological psychiatry. 16 (6): 833-45. PMID 1355301. Low dose dependence has now been clearly demonstrated in both animal studies and human studies.Lucki I; Kucharik RF. (1990). "Increased sensitivity to benzodiazepine antagonists in rats following chronic treatment with a low dose of diazepam.". Psychopharmacology. 102 (3): 350-6. PMID 1979180. Rickels K; Case WG, Schweizer EE, Swenson C, Fridman RB. (1986). "Low-dose dependence in chronic benzodiazepine users: a preliminary report on 119 patients.". Psychopharmacology bulletin. 22 (2): 407-15. PMID 2877472.
In an animal study of four baboons on low-dose benzodiazepine treatment, three out of the four baboons demonstrated physical dependence and developed flumazenil-precipitated withdrawal symptoms after only two weeks of low-dose benzodiazepine treatment. Furthermore, the baboons on low-dose therapy did not develop more severe flumazenil-precipitated withdrawal symptoms because low-dose benzodiazepine therapy was continued over a period of 6–10 months, suggesting rapid onset of dependence with benzodiazepines and suggesting that physical dependence was complete after two weeks of chronic, low-dose benzodiazepine treatment.Kaminski BJ; Sannerud CA, Weerts EM, Lamb RJ, Griffiths RR. (Jul 2003). "Physical dependence in baboons chronically treated with low and high doses of diazepam.". Behavioural pharmacology. 14 (4): 331-42. PMID 12838039. In another animal study, physical dependence was demonstrated with withdrawal signs appearing after only seven days of low-dose benzodiazepine treatment, and withdrawal signs appeared after only three days after high-dose treatment, which demonstrated the extremely rapid development of tolerance and dependence on benzodiazepines, at least in baboons. It was also found that previous exposure to benzodiazepines sensitized baboons to the development of physical dependence.Lukas SE; Griffiths RR. (20). "Precipitated diazepam withdrawal in baboons: effects of dose and duration of diazepam exposure.". European journal of pharmacology. 100 (2): 163-71. PMID 6428921.
In humans, chronic, low-therapeutic-dose dependence was clearly demonstrated using flumazenil to show physical dependence and withdrawal signs. Withdrawal symptoms experienced by the chronic therapeutic low-dose subjects included increased ratings of dizziness, blurred vision, heart pounding, feelings of unreality, pins and needles, nausea, sweatiness, noises louder than usual, jitteriness, things moving, sensitivity to touch.Mintzer MZ; Stoller KB, Griffiths RR. (Nov 1999). "A controlled study of flumazenil-precipitated withdrawal in chronic, low-dose benzodiazepine users." 147 (2): 200-9. PMID 10591888. In another study of 34 low-dose benzodiazepine users, physiological dependence was demonstrated by the appearance of withdrawal symptoms in 100% of those who received flumazenil whereas those receiving placebo experienced no withdrawal signs. It was also found that those dependent on low doses of benzodiazepines with a history of panic attacks were at an increased risk of suffering panic attacks due to flumazenil precipitated benzodiazepine withdrawal.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. It has been estimated that 30–45% of chronic low dose benzodiazepine users are dependent and it has been recommended that benzodiazepines even at low dosage be prescribed for a maximum of 7–14 days to avoid dependence.Meier PJ; Ziegler WH, Neftel K. (19). "[Benzodiazepine--practice and problems of its use]". Schweizerische medizinische Wochenschrift. 118 (11): 381-92. PMID 3287602.
Some controversy remains, however, in the medical literature as to the exact nature of low-dose dependence and the difficulty in getting patients to discontinue their benzodiazepines, with some papers attributing the problem to predominantly drug-seeking behavior and drug craving, whereas other papers have found the opposite, attributing the problem to a problem of physical dependence with drug-seeking and craving not being typical of low-dose benzodiazepine users.Linden M; Bär T, Geiselmann B. (May 1998). "Patient treatment insistence and medication craving in long-term low-dosage benzodiazepine prescriptions.". Psychological medicine. 28 (3): 721-9. PMID 9626728. Tyrer P. (1993). "Benzodiazepine dependence: a shadowy diagnosis.". Biochemical Society symposium. 59: 107-19. PMID 7910738.
Benzodiazepine withdrawal syndrome is the symptoms seen when a patient, who has taken the drug for a period of time, stops taking the drug. Benzodiazepine withdrawal is best managed by transferring the physically-dependent patient to an equivalent dose of diazepam because it has the longest half-life of all of the benzodiazepines and is available in low-potency, 2-mg tablets, which can be quartered for small dose reductions.Dr JG McConnell (May 2007). The Clinicopharmacotherapeutics of Benzodiazepine and Z drug dose Tapering Using Diazepam.Professor Heather Ashton (2002). Benzodiazepines: How They Work and How To Withdraw. The speed of benzodiazepine reduction regimes varies from person to person, but is usually 10% every 2–4 weeks. A slow withdrawal, with the patient in control of dosage reductions coupled with reassurance that withdrawal symptoms are temporary, have been found to produce the highest success rates.
There is strong anecdotal evidence that a slow-withdrawal rate significantly reduces the risk of a protracted and/or severe withdrawal state. About 10–15% of people who discontinue benzodiazepines develop protracted withdrawal syndrome. There is no known cure for protracted benzodiazepine withdrawal syndrome except time. Flumazenil, in a placebo-controlled study, seemed to bring about temporary relief of protracted withdrawal symptoms, although the author Lader, et al., noted that further research is required in this area.Professor C Heather Ashton (2004). Protracted withdrawal symptoms from benzodiazepines.Lader, Malcolm; Sally V. Morton (1992). "A pilot study of the effects of flumazenil on symptoms persisting after benzodiazepine withdrawal". Journal of Psychopharmacology 6(3): 357-363.
However, in 1993 the New England Journal of Medicine reported there is no reliable evidence to support the existence of a persistent benzodiazepine withdrawal syndrome, and this alleged syndrome has been described only in anecdotal reports, with patients typically reporting "withdrawal" symptoms not present during or before benzodiazepine treatment that persist for many months or years after treatment is stopped. Experimental neuropharmacologic studies document that all the side effects of benzodiazepines, whether behavioral or neurochemical, disappear within several days or weeks after the drug is eliminated. The weight of evidence indicates that any new symptoms that persist for more than two months after the last dose of a benzodiazepine either are part of the premorbid condition or have appeared by coincidence or as a consequence of the natural history of the underlying illness. Shader RI, Greenblatt DJ (1993). "Use of benzodiazepines in anxiety disorders". N. Engl. J. Med. 328 (19): 1398–405. PMID 8292115.
The Committee on the Review of Medicines (UK) carried out a review into benzodiazepines due to significant concerns of tolerance, drug dependence, and benzodiazepine withdrawal problems and other adverse effects. The committee found that benzodiazepines do not have any antidepressant or analgesic properties, and are therefore unsuitable treatments for conditions such as depression, tension headaches, and dysmenorrhoea. Benzodiazepines are also not beneficial in the treatment of psychosis due to a lack of efficacy. The committee also recommended against benzodiazepines being used in the treatment of anxiety or insomnia in children. The committee was in agreement with the Institute of Medicine (USA) and the conclusions of a study carried out by the White House Office of Drug Policy and the National Institute on Drug Abuse (USA) that there was little evidence that long-term use of benzodiazepine hypnotics are beneficial in the treatment of insomnia due to the development of tolerance. Benzodiazepines tended to lose their sleep-promoting properties within 3–14 days of continuous use, and, in the treatment of anxiety, the committee found that there was little convincing evidence that benzodiazepines retain efficacy in the treatment of anxiety after 4 months of continuous use due to the development of tolerance.
The committee found that regular use of benzodiazepines may cause dependence characterized by tolerance to the therapeutic effects and the development of benzodiazepine withdrawal syndrome, which includes symptoms such as anxiety, apprehension, tremor, insomnia, nausea, and vomiting upon cessation of benzodiazepine use. Withdrawal symptoms tended to develop within 24 hours after the cessation of a short-acting benzodiazepine and within 3–10 days after intermediate-acting benzodiazepines. Withdrawal effects could occur, however, after treatment lasting only 2 weeks at therapeutic-dose levels, but with a higher tendency with habitual use beyond 2 weeks and more likely at higher doses. The withdrawal symptoms may appear to be similar to the original condition before treatment. The committee reported that all benzodiazepine therapy should be withdrawn gradually, that therapy be limited to short-term use only and only in carefully-selected patients.
It was noted in the review that alcohol can potentiate the central nervous system depressant effects of benzodiazepines and should be avoided concomitantly. These effects may affect an individual\'s ability to drive or operate machinery, with the elderly being more prone to these adverse effects. In the neonate, high single doses or repeated low doses have been reported to produce hypotonia, poor sucking, and hypothermia, along with irregularities in the fetal heart. Benzodiazepines should also be avoided during lactation.
Taken together, withdrawal from benzodiazepines should be gradual, as abrupt withdrawal from high doses may cause confusion, toxic psychosis, convulsions, or a condition resembling delirium tremens. Abrupt withdrawal from lower doses may cause depression, nervousness, rebound insomnia, irritability, sweating, and diarrhoea.Committee on the Review of Medicines (29). "Systematic review of the benzodiazepines. Guidelines for data sheets on diazepam, chlordiazepoxide, medazepam, clorazepate, lorazepam, oxazepam, temazepam, triazolam, nitrazepam, and flurazepam. Committee on the Review of Medicines." (pdf). Br Med J. 280 (6218): 910-2. PMID 7388368.
