Benzodiazepines
Benzodiazepines (colloquial short form Benzos ) are polycyclic organic compounds based on a bicyclic body in which a benzene - is connected to a diazepine ring . Benzodiazepines have an anxiolytic (anxiety-relieving), sedative (calming), muscle-relaxing (muscle-relaxing) and hypnotic (sleep-promoting to sleep-inducing) effect. Some benzodiazepines also have anticonvulsant (anticonvulsant) properties and are therefore used as anti-epileptic drugs . In animal experiments, they have an analgesic effect (pain reliever). Because of their central nervous effects, this group of substances is one of the psychoactive substances ; some of their representatives are therefore used in medicine as psychotropic drugs. The benzodiazepines diazepam , lorazepam, and midazolam are listed on the World Health Organization's Essential Medicines List. Compared to barbiturates , which have a similar application profile, benzodiazepines have the advantage of a greater distance between the therapeutic and toxic dose and have therefore largely replaced them in medical practice since their market launch.
All benzodiazepines bind to GABA receptors , the most important inhibitory receptors in the central nervous system . Benzodiazepines have not least because of their action on the GABA-budget (similar to ethanol and barbiturates), and because of their high effectiveness and usually rapid onset of action (depending on application) a high potential for dependency . Rapid tolerance development is also not uncommon, which is why long-term therapy is usually avoided.
history
Even before the benzodiazepines, there were effective sleeping pills and sedatives such as bromine , sulfonal and barbiturates ; however, they were associated with more severe side effects and risks. From the group of benzodiazepines, chlordiazepoxide was the first compound on the market. It was developed by Leo Sternbach for the pharmaceutical company Hoffmann-La Roche and marketed in 1960 under the trade name Librium . Based on their pharmacodynamic effects, benzodiazepines were classified as potent anticonvulsants in the 1960s .
In the further course of research mainly compounds with a lactam structure were introduced (R 2 = O ). So also the diazepam developed by Leo Sternbach . It was brought to market in 1963 by Hoffmann-La Roche under the trade name Valium . As early as 1977, diazepam was included in the list of essential drugs of the World Health Organization . In Germany, diazepam was still the most frequently prescribed benzodiazepine in 2005.
Chemistry and structure
Benzodiazepine scaffold |
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All benzodiazepines contain a system of two interconnected ring-shaped structures: the benzene and diazepine rings are condensed to form a bicyclic ring system. Its larger seven-membered unsaturated ring contains two nitrogen atoms and thus belongs to the heterocyclic compounds . According to the Hantzsch-Widman nomenclature for heterocyclic systems, such a ring is referred to as a diazepine. In the case of the benzodiazepines, a benzene ring is fused to the diazepine ring .
As drugs are primarily benzo-1,4-diazepines used (see above structural formula, in the 2'-position of the addition at the 5-position of a further six-membered ring such as benzene phenyl group may be a halogen as a substituent ), cyclohexene or pyridine wear . In clobazam , the only representative of the benzo-1,5-diazepines used, this third ring is bound to its N atom in the 5-position.
The thienodiazepines are structured similarly to the benzodiazepines as heterocycles that contain a diazepine ring; however, a thiophene ring instead of a benzene ring is fused to these in their case .
Z-Drugs have certain structural similarities, but do not have a benzodiazepine base. However, they show a pharmacological action profile similar to the benzodiazepines, since they bind to the same receptors.
pharmacology
Mechanism of action
Benzodiazepines act as allosteric modulators at the GABA A receptor , they complex with the benzodiazepine (BzD) binding site of this ionotropic receptor. This connection changes the shape of the receptor and thus modulates the activation of the receptor. The positive modulation caused by classic benzodiazepines increases the affinity of the inhibitory neurotransmitter GABA at its orthosteric binding site. This increases the likelihood of the chloride channel opening and the influx of chloride ions into the nerve cell is increased, which in turn leads to a lower excitability of the neuron membrane (due to hyperpolarization and short-circuiting of EPSPs ).
Classic benzodiazepines bind to GABA A receptors with the alpha subunits α 1 , α 2 , α 3 and α 5 ; they have no affinity for α 4 and α 6 .
Benzodiazepines have different effects from barbiturates . The following mechanisms are responsible for this:
- Benzodiazepines only work together with GABA and on their own are not able to open the GABA A receptor. They are correctly referred to as positive, negative or, in rare cases, silent / neutral allosteric modulators. The terms agonist , antagonist and inverse agonist do appear in the literature to designate these active ingredients, but they can be misunderstood and should be avoided with pure modulators.
- Benzodiazepines work more strongly on synapses that are low in GABA than on those that are high in GABA.
- Weak transmitter responses are amplified more than strong transmitter responses. One speaks of an activity-dependent effect (use dependence). This effect could also be responsible for a relatively specific effect of the benzodiazepines (anxiolytic, anticonvulsant, central muscle relaxing, sedative / hypnotic, amnestic see below), despite the ubiquitous distribution of the GABA receptors in the brain and spinal cord.
Even high doses of benzodiazepines do not increase the maximum effect (which theoretically could also be achieved with GABA alone). You just lower the dose of GABA, which leads to a maximum effect. In pharmacological terms, they lead to a left shift in the dose-response curve .
Effects
Benzodiazepines work
- anxiolytic (anxiolytic)
- anticonvulsant (anticonvulsant)
- muscle relaxing (muscle relaxing)
- sedative (calming)
- hypnotic (sleep-inducing or compelling)
- amnestic ( no reminder for the duration of the effect)
- slightly mood-enhancing (however, an underlying depressive illness can possibly be exacerbated)
- sometimes euphoric (depending on dosage and intake interval).
In animal experiments, the benzodiazepine diazepam has an analgesic (analgesic) effect when injected into the spinal cord , particularly in the case of neuropathic pain . It is believed that the effects on the GABA receptor are responsible for this effect.
Benzodiazepines found in psychiatry use in the treatment of anxiety - and restlessness, as rescue medication for epileptic seizures and as a falling asleep and sleeping pills . They are also prescribed as premedication before operations so that the patient is as relaxed and free of fear as possible. Benzodiazepines are also used to induce anesthesia and to supplement operations performed with other narcotics , among other things because of their relatively low effects on the cardiovascular system .
While in animal experiments a withdrawal syndrome can be triggered after one week of continuous administration of the maximum dose , this is only possible in humans in therapeutic doses after at least 8 weeks of exposure. As a rule, it is recommended not to exceed 4 weeks in order to minimize the risk of developing addiction . In summary, the indication for the prescription of benzodiazepines must be viewed critically and the application as short as possible and the dose as low as possible. In the case of long-term treatment, the dangers must be carefully weighed against the therapeutic benefit. Most benzodiazepines are generally not approved for long-term treatment. Exceptions are the antiepileptic benzodiazepines, which, if indicated, often have to be taken for life.
Benzodiazepine preparations are dose-dependent and, depending on the substance, have different degrees of respiratory depression , i.e. i.e., they dampen the respiratory center . Life- threatening intoxications are rare when BZD is taken alone, but the risk increases with simultaneous consumption of alcohol or the simultaneous administration of other CNS-effective preparations, especially the opioids , as these themselves have a strong respiratory depressive effect. In addition, when opioids and benzodiazepines are taken at the same time, their sedative effects are mutually enhanced. There is also a so-called cross - tolerance between benzodiazepines and alcohol . Benzodiazepines affect the reaction time. The driver is unable to drive for at least the first few days of taking benzodiazepine-containing drugs . In the course of continued therapy, the attending physician decides on a case-by-case basis whether driving a motor vehicle or operating dangerous machines is possible again.
Benzodiazepines are considered to be the drugs with the highest rate of abuse worldwide.
There is clear evidence of risks to the human fetus associated with benzodiazepine administration during pregnancy. In animal experiments, there was also evidence of behavioral disorders in the offspring when the dams were given benzodiazepines during pregnancy.
Contraindications
Contraindications to the use of benzodiazepines:
- Myasthenia gravis
- Ataxia , narrow-angle glaucoma
- Known alcohol, drug or medication addiction - also in the past
- Allergy to benzodiazepines
- Sleep apnea syndrome
Antidote
Flumazenil , a reversible competitive antagonist , temporarily reverses the effect of benzodiazepines after intravenous administration (half-life approx. 45 min). In the course of treatment of an acute overdose, it is essential to pay attention to the possible need to continue administering further doses of flumazenil, since the half-life of about 45 minutes is much shorter than that of most benzodiazepines (half-life about 60 min to 120 h).
Individual substances
With a few exceptions such as chlorazepate , the names of benzodiazepine active ingredients often end with -azepam or -zolam . The following table provides an overview of the pharmacological data of the benzodiazepines and marketing information.
Active ingredient | Trade name (s) | Effect type | Chemical name |
Plasma half-life (metabolite half-life ) |
Equivalent dose to 10 mg diazepam | Year of launch |
---|---|---|---|---|---|---|
Adinazolam | Deracyn (FR) | Tranquilizer, anxiolytic | 8-Chloro-1- (dimethylaminomethyl) -6-phenyl-4 H - [1,2,4] triazolo [4,3- a ] [1,4] benzodiazepine | 1.5-3 h | 1976 | |
Alprazolam |
Tafil (D), Xanax (CH, USA), Xanax retard (CH, USA), Xanor (A), various generics (D, A) |
Tranquilizer, anxiolytic | 8-Chloro-1-methyl-6-phenyl-4 H - [1,2,4] -triazolo [4,3- a ] [1,4] benzodiazepine | 12-15 h | 1.5 mg | 1984 |
Bromazepam |
Bromazanil (D), Gityl (D), Lexostad (D), Lexotanil (D, A, CH), Bromazepam OPT (D), Normoc (D), various generics (D, A) |
Tranquilizer, anxiolytic | 7-bromo-2,3-dihydro-5- (2-pyridyl) - 1 H -1,4-benzodiazepin-2-one | 15-28 h | 6 mg | 1977 |
Camazepam | Albego (CH, ES, IT) | Anxiolytic, hypnotic | 7-chloro-1-methyl-2-oxo-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-3-yl N, N-dimethylcarbamate | 6-11 h | 10-20 mg | 1978 |
Chlordiazepoxide |
Librax (CH), Librocol (CH), Limbitrol (A, CH) |
Tranquilizers | 7-chloro-2-methylamino-5-phenyl-3 H -1,4-benzodiazepine-4-oxide | 5–30 h (48–96 h) | 20 mg | 1960 |
Cinolazepam | Gerodorm (BG, CZ, HU, SK, RO) | Hypnotic | 7-chloro-5- (2-fluorophenyl) -2,3-dihydro-3-hydroxy-2-oxo-1 H -1,4-benzodiazepin-1-propionitrile | 4-6 h | 40 mg | 1992 |
Clobazam |
Frisium (D, A), Urbadan (NL), Urbanyl (CH), Noiafren (ES), Castilium (PT) |
Tranquilizer, anxiolytic, anti-epileptic | 7-chloro-1-methyl-5-phenyl-1 H -1,5 -benzodiazepine-2,4 (3 H , 5 H ) -dione | 18 h (36–80–120 h) | 20 mg | 1977 |
Clonazepam |
Rivotril (D, CH), Antelepsin (D) |
Anti-epileptic | 5- (2-chlorophenyl) -2,3-dihydro-7-nitro-1 H -1,4-benzodiazepin-2-one | 30-40 h | 2 mg | 1976 |
Clonazolam | Anti-epileptic | 6- (2-Chlorophenyl) -1-methyl-8-nitro-4 H - s -triazolo [4,3- a ] -1,4-benzodiazepine | 16 h | 0.5 mg | ||
Clorazepate |
Tranxene (international trade name), Tranxilium (D, A, CH) |
Tranquilizers | 7-chloro-2,3-dihydro-2,2-dihydroxy-5-phenyl-1 H -1,4-benzodiazepine-3-carboxylic acid | 2 h [approx. 30–90 h for the active metabolite nordazepam ( N- desmethyldiazepam)] | 20 mg | 1969 |
Cloxazolam |
Olcadil (DE, CH, AT), Akton (BE, LU), Cloxam (PT), Elum (BE), Lubalix (CH), Sepazon (HK, JP) |
Tranquilizers | 10-Chloro-11b- (2-chlorophenyl) -2,3,7,11b-tetrahydro [1,3] oxazolo [3,2- d ] [1,4] benzodiazepin-6-one | (55-75 h) | 4 mg | |
Delorazepam |
Dadumir (IT), EN (IT), various generics (IT) |
Anxiolytic, premedication | 7-chloro-5- (2-chlorophenyl) -1,3-dihydro-1,4-benzodiazepin-2 (2 H ) -one | 80-115 h | 1 mg | 1977 |
Diazepam |
Diazep-CT (D), Faustan (D), Gewacalm (A), Paceum (CH), Psychopax (A, CH), Stesolid (D, A, CH), Valiquid (D), Valium (D, A, CH , L), Valocordin-Diazepam (D), various generics (D, CH) |
Tranquilizer, anti-epileptic, anxiolytic | 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1 H -1,4-benzodiazepin-2-one | 24–48 h [approx. 30–90 h for the active metabolite nordazepam (N-desmethyldiazepam)] | 10 mg | 1963 |
Diclazepam | Tranquilizer, anxiolytic, muscle relaxant | 7-chloro-1-methyl-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one | 42 h | 1 mg | ||
Doxefazepam | Doxans (IT) | Hypnotic | 7-chloro-5- (2-fluorophenyl) -3-hydroxy-1- (2-hydroxyethyl) -2,3-dihydro-1 H -1,4-benzodiazepin-2-one | 3-4 h | 1984 | |
Estazolam |
Domnamid (DK), Eszo (TW), Esilgan (IT) Eurodin (JP), Nuctalon (FR), ProSom (USA), Sedarest (PE) |
Hypnotic | 8-Chloro-6-phenyl-4 H - s -triazolo- [4,3a] [1,4] benzodiazepine | 10–24 h | 1-2 mg | 1975 |
Flualprazolam | 6- (2-Fluorophenyl) -1-methyl-8-chloro-4H- [1,2,4] triazolo [4,3-a] [1,4] benzodiazepine | 20 h | 0.25 mg | |||
Flubromazepam | Hypnotic, anxiolytic, tranquilizer, muscle relaxant, anti-epileptic | 7-Bromo-5- (2-fluorophenyl) -1,3-dihydro-1,4-benzodiazepin-2-one | 106 h | 4 mg | ||
Flubromazolam | 8-Bromo-6- (2-fluorophenyl) -1-methyl-4 H - [1,2,4] triazolo [4,3- a ] [1,4] benzodiazepine | 20 h | 0.25 mg | |||
Fludiazepam | Erispan (JP, TW) | Tranquilizer, hypnotic | 7-chloro-5- (2-fluorophenyl) -1-methyl-1,3-dihydro-2 H -1,4-benzodiazepin-2-one | 10-30 h | 1 mg | |
Flunitrazepam |
Fluninoc (D), Rohypnol (D, A, CH), some generics (D) |
Hypnotic | 5- (2-fluorophenyl) -2,3-dihydro-1-methyl-7-nitro-1 H -1,4-benzodiazepin-2-one | 16-35 h | 0.5-1 mg | 1975 |
Flunitrazolam | 6- (2-Fluorophenyl) -1-methyl-8-nitro-4 H -benzo [ f ] [1,2,4] triazolo [4,3- a ] [1,4] diazepine | 0.5 mg | ||||
Flurazepam |
Dalmadorm (D, CH), Staurodorm (D), Flurazepam Real (D) |
Hypnotic | 7-chloro-1- (2-diethylaminoethyl) -5- (2-fluorophenyl) -2,3-dihydro-1 H -1,4-benzodiazepin-2-one | 1.5 h [approx. 30–90 h for the active metabolite nordazepam (N-desmethyldiazepam)] | 15-30 mg | 1974 |
Flutazolam | Coreminal (JP) | Tranquilizers | 10-chloro-11 b - (2-fluorophenyl) -7- (2-hydroxyethyl) -3,5-dihydro-2 H - [1,3] oxazolo [3,2-d] [1,4] benzodiazepine- 6-one | 3-4 h | 30 mg | |
Flutoprazepam | Restas (JP) | Tranquilizers | 7-chloro-1- (cyclopropylmethyl) -5- (2-fluorophenyl) -3 H -1,4-benzodiazepin-2-one | (60–90 h) | 3-4 mg | |
Halazepam |
Alapryl (ES), Pacinone (BE, NL), Paxipam (IT, USA) |
Tranquilizers | 7-chloro-2,3-dihydro-5-phenyl-1- (2,2,2-trifluoroethyl) -1 H -1,4-benzodiazepin-2-one | (30-100 h) | 20 mg | 1981 |
Loprazolam | Sonin (D) | Tranquilizers | 6- (2-Chlorophenyl) -2,4-dihydro-2 - [(4-methyl-1-piperazinyl) methylene] -8-nitro-1 H -imidazo [1,2- a ] [1,4] benzodiazepine -1-on | 8-9 h | 1-1.5 mg | 1987 |
Lorazepam |
Ativan (USA, GB), Lorazepam dura (D), Merlit (A), Tavor (D), Temesta (CH, A, L, B), Tolid (D), various generics |
Tranquilizer, hypnotic, anti-epileptic | ( RS ) -7-chloro-5- (2-chlorophenyl) -2,3-dihydro-3-hydroxy-1 H -1,4-benzodiazepin-2-one | 12.9-16.2 hours | 2 mg | 1963 |
Lormetazepam |
Ergocalm (D), Loramet (CH), Loretam (D), Noctamid (A, D, CH), Sedalam (D), various generics (D) |
Hypnotic | ( RS ) -7-Chloro-5- (2-chlorophenyl) -2,3-dihydro-3-hydroxy-1-methyl-1 H -1,4-benzodiazepin-2-one | 10-14 h | 1 mg | 1980 |
Ketazolam |
Unakalm, Ansieten, Anxon, Loftran, Anseren |
Tranquilizer, anti-epileptic, anxiolytic | 11-chloro-8,12b-dihydro-2,8-dimethyl-12b-phenyl-4 H - [1,3] oxazino [3,2- d ] [1,4] benzodiazepine-4,7 (6 H ) -dion | 50 h (36–200 h, Northazepam ) | 15-20 mg | |
Meclonazepam | (3 S ) -5- (2-Chlorophenyl) -3-methyl-7-nitro-1,3-dihydro-2 H -1,4-benzodiazepin-2-one | 1 mg | ||||
Medazepam |
Rudotel (D), Nobrium (D) |
Tranquilizers | 7-chloro-2,3-dihydro-1-methyl-5-phenyl-1 H -1,4-benzodiazepine | 2–5 h [approx. 30–90 h for the active metabolite nordazepam (N-desmethyldiazepam)] | 20 mg | 1968 |
Metaclazepam | Talis (DE, AT) | Anxiolytic | 7-Bromo-5- (2-chlorophenyl) -2-methoxymethyl-1-methyl-2,3-dihydro-1 H -1,4-benzodiazepine | 16 h | 10 mg | 1988 |
Mexazolam |
Melex (JP), Sedoxil (PT) |
Anxiolytic | 10-Chloro-11b- (2-chlorophenyl) -3-methyl-2,3,7,11b-tetrahydrooxazolo [3,2- d ] [1,4] benzodiazepin-6-one | (74 h) | 10 mg | |
Midazolam |
Buccolam (D, CH), Dormicum (D, CH), various generics (CH) |
Short hypnotic | 8-chloro-6- (2-fluorophenyl) -1-methyl-4 H -imidazo [1,5- a ] [1,4] benzodiazepine | 1.5-2.5 h | 7.5 mg orally (1 mg i.v.) | 1985 |
Nifoxipam | 5- (2-fluorophenyl) -3-hydroxy-7-nitro-1,3-dihydro-2 H -1,4-benzodiazepin-2-one | |||||
Nimetazepam | Erimin (JP) | Hypnotic | 2,3-Dihydro-7-nitro-5-phenyl-1-methyl-1 H -1,4-benzodiazepin-2-one | 18-30 h | 5 mg | |
Nitrazepam |
Dormo-Puren (D), Imeson (D), Mogadan (D), Mogadon (A, CH), Novanox (D), Radedorm (D) |
Hypnotic, anti-epileptic | 2,3-Dihydro-7-nitro-5-phenyl-1 H -1,4-benzodiazepin-2-one | 18-30 h | 5 mg | 1965 |
North Azepam | Tranquilizers | 7-chloro-2,3-dihydro-5-phenyl-1 H -1,4-benzodiazepin-2-one | 50–90 h (8 h) | 20 mg | ||
Oxazepam |
Adumbran (D, A), Anxiolit (A, CH), Durazepam (D), Praxiten (D, A), Seresta (CH), various generics (D) |
Tranquilizers | ( RS ) -7-chloro-2,3-dihydro-3-hydroxy-5-phenyl-1 H -1,4-benzodiazepin-2-one | 5-15 h | 30 mg | 1965 |
Oxazolam |
Sera (TH), Serebon (HK), Serenal (JP) |
Tranquilizers | (2 RS , 11b SR ) -10-Chloro-2-methyl-11b-phenyl-2,3,7,11b-tetrahydro [1,3] oxazolo [3,2-d] [1,4] benzodiazepine-6 (5 H ) -one | 1.5 h [approx. 30–90 h for the active metabolite nordazepam ( N- desmethyldiazepam)] | 40 mg | |
Phenazepam |
Phenazepam (RU), Fenazepam (GE), Fenazepams (LT), Phenzepine (GE) |
Tranquilizers | 7-Bromo-5- (2-chlorophenyl) -1,3-dihydro-1,4-benzodiazepin-2-one | (60 h) | 1 mg | |
Pinazepam |
Domar (IT), Duna (ES, IT) |
Anxiolytic | 7-chloro-5-phenyl-1- (prop-2-in-1-yl) -1,3-dihydro-2 H -1,4-benzodiazepin-2-one | 10-15 h [approx. 30–90 h for the active metabolite nordazepam ( N- desmethyldiazepam)] | 20 mg | 1975 |
Prazepam | Demetrin (CH) | Tranquilizers | 7-chloro-1- (cyclopropylmethyl) -2,3-dihydro-5-phenyl-1 H -1,4-benzodiazepin-2-one | 1.5 h [approx. 30–90 h for the active metabolite nordazepam (N-desmethyldiazepam)] | 20 mg | 1973 |
Pyrazolam | Anxiolytic | 8-Bromo-1-methyl-6- (pyridin-2-yl) -4 H - [1,2,4] triazolo [4,3- a ] [1,4] benzodiazepine | 16-18 h | 1 mg | ||
Quazepam |
Doral (US, JP), Quiedorm (ES) |
Hypnotic | 7-chloro-5- (2-fluorophenyl) -2,3-dihydro-1- (2,2,2-trifluoroethyl) -1 H -1,4-benzodiazepine-2-thione | (25–41 h) | 20 mg | 1985 |
Temazepam |
Normison (CH), Planum (D), Remestan (D), Temazep (D), various generics |
Hypnotic | ( RS ) -7-chloro-3-hydroxy-1-methyl-5-phenyl-1 H -1,4-benzodiazepin-2 (3 H ) -one | 5-13 h | 20 mg | 1969 |
Tetrazepam |
Musaril (D), Myolastan (A), Rilex (D), various generics (D, A) |
Myotonolytic (muscle relaxant) | 7-chloro-5- (1-cyclohexenyl) -1-methyl-1 H -1,4-benzodiazepin-2 (3 H ) -one | 18 h | 20 mg | 1981 |
Triazolam | Halcion (D, A, CH) | Hypnotic | 8-chloro-6- (2-chlorophenyl) -1-methyl-4 H -1,2,4-triazolo [4,3- a ] [1,4] benzodiazepine | 1.4-4.6 h | 0.5 mg | 1982 |
A non-psychoactive benzodiazepine is netazepid , which is being developed to treat cancer. Tifluadom is no longer used due to adverse drug effects .
Analytics
Due to the toxicological properties of the benzodiazepines, there is great interest in the legally secure qualitative and quantitative determination in the most varied of objects to be examined. The coupling between gas chromatography , HPLC and mass spectrometry are generally used as analytical methods after adequate sample preparation . For the detection of naturally occurring benzodiazepines in biological materials, such as. B. food, plants, human brain tissue samples from before 1960 u. a., an extensive investigation using GC / MS coupling and radioreceptor assays is available.
Prescription Practice in Germany and Criticism
The prescription of benzodiazepines in Germany decreased from 228 million defined daily therapy doses (DDD) in 1995 to 68 million DDD in 2004.
However, the number of prescriptions on private prescriptions has increased, according to the German Society for Psychiatry, Psychotherapy and Neurology (DGPPN):
“The prescription of benzodiazepines at the expense of the statutory health insurances (GKV) fell from 11 million (1993) to 2.5 million packs (2004), while according to purchasing statistics the dispensing by pharmacies only from 12.7 million to 5.6 Million packs decreased. Z-Drugs (zaleplon, zopiclone, zolpidem) increased in the GKV from 2.1 million (1993) to 3.8 million packs (2004), the dispensing by pharmacies, however, according to purchasing statistics, was much more pronounced of 2.2 million. to 7.4 million packages. The authors Hoffmann, Glaeske, Scharffetter interpret this correctly as an increased prescription on a private prescription. The database does not allow the insurance status (GKV / PKV) of the patient to be determined. However, it seems plausible to assume that the increasing number of prescriptions of benzodiazepine hypnotics on private prescription also apply to persons insured with statutory health insurance. Ultimately, the recommendations of the AkdÄ are based on the assumption that the prescription of benzodiazepine hypnotics on a private prescription by statutory health insurance patients indicates an abuse of this group of substances, which should be made less transparent and understandable through such a prescription. "
Due to the high potential for addiction (which was almost entirely unknown at the time when the first benzodiazepines were launched), but also critical (specialist) press reports, especially on empirical studies that showed a possibly increased risk of dementia, the prescriptions of benzodiazepine-containing drugs in Germany are in the in the last few years until 2018. This is particularly clear with Lorazepam , which took second place among the most prescribed psychotropic drugs in Germany in 2007, but slipped to 15th place by 2013.
Legal position
The legal situation regarding the individual benzodiazepines depends on the respective benzodiazepine and the respective legislation of the country. In 1984, 33 benzodiazepines were classified as Schedule IV drug by the United Nations Convention on Psychotropic Substances . Midazolam (1990) and Brotizolam (1995) were added later. Flunitrazepam was regrouped to Schedule III in 1995 . Phenazepam (also Fenazepam) is used outside of the European Union and is not in the UN Convention.
Germany
With a few exceptions, benzodiazepines are regulated by narcotics law. In many cases, however, drugs containing benzodiazepines are exempt from the provisions of the Narcotics Prescription Ordinance (“exempt preparations”) up to certain maximum levels and can be prescribed on a normal prescription. For this purpose, the legislature has set maximum quantities per divided form (tablet, suppository , ampoule, volume unit for drops) and / or maximum quantities per pack. These maximum quantities are set individually for each individual active ingredient (e.g. 10 mg per divided tablet unit for diazepam) and are derived from Appendix III to the BtMG. Any additional quantities require a BtM prescription .
North America
In the United States, benzodiazepines require a prescription and are classified as Schedule IV drugs under the Federal Controlled Substances Act . The most commonly used benzodiazepines in the US and Canada are alprazolam and diazepam , followed by clonazepam and lorazepam . In approximately 1.25 million cases of people being admitted to emergency rooms in the United States for drug abuse in 2011, approximately 358,000 cases involved benzodiazepines, predominantly alprazolam (123,750), clonazepam (61,000), lorazepam (43,000), and diazepam (24,000).
Singapore
In Singapore, nimetazepam is classified as a Class C controlled drug .
literature
- KR Manchester, EC Lomas, L. Waters, FC Dempsey, PD Maskell: The emergence of new psychoactive substance (NPS) benzodiazepines: A review. In: Drug testing and analysis. Volume 10, number 1, January 2018, pp. 37-53, doi: 10.1002 / dta.2211 , PMID 28471096 (review).
- K. Janhsen, P. Roser, K. Hoffmann: The problems of long-term treatment with benzodiazepines and related substances. In: Deutsches Arzteblatt international. Volume 112, number 1–2, January 2015, pp. 1–7, doi: 10.3238 / arztebl.2015.0001 , PMID 25613443 , PMC 4318457 (free full text) (review); German version.
- Guideline of the German Medical Association for dealing with drugs with addiction potential. In: bundesaerztekammer.de. Retrieved May 11, 2017 .
- Harald Schütz : Benzodiazepines A Handbook. Springer-Verlag, Berlin / Heidelberg / New York 1982, ISBN 3-540-11270-7 .
- Harald Schütz: Benzodiazepines II A Handbook. Springer-Verlag, Berlin / Heidelberg / New York 1989, ISBN 3-540-50249-1 .
Web links
- C. Heather Ashton: Benzodiazepines: Modes of Action and Therapeutic Withdrawal (The Ashton Handbook) . Version August 2002.
- Rüdiger Holzbach: Lippstadt Benzo-Check (LBC) . (PDF) for guidance on whether and to what extent possible undesirable effects have already occurred.
- The story in the first: Germany on drugs on YouTube (2015)
Individual evidence
- ↑ a b c d Benzodiazepines. In: Lexikon der Neurologie , Wissenschaft-Online-Lexika; Retrieved May 28, 2009.
- ↑ Kerri Smith: Treating Chronic Pain Without Side Effects In: Der Tagesspiegel , January 2008.
- ↑ WHO Model List (April 2013). (PDF) (No longer available online.) Archived from the original on December 25, 2014 ; accessed on April 5, 2018 .
- ↑ Swiss Recommendations for Anxiety Therapy . ( nanopdf.com [PDF; accessed on April 14, 2018]).
- ↑ Hans Bangen: History of the drug therapy of schizophrenia. Berlin 1992, ISBN 3-927408-82-4 , p. 22f.
- ↑ Gustav Ehrhart , Heinrich Ruschig : Medicines. Development, impact, presentation. Volume 1: Pharmakodynamica. Verlag Chemie, Weinheim 1968, p. 426f.
- ↑ ePsy.de Psychotropic Drugs in Practice 2005.
- ↑ D. Hellwinkel: The systematic nomenclature of organic chemistry. 4th edition. Springer Verlag, Berlin 1998, ISBN 3-540-63221-2 .
- ^ A b American Psychiatric Association : Task Force on Benzodiazepine Dependency: Benzodiazepine dependence, toxicity, and abuse: a task force report of the American Psychiatric Association. American Psychiatric Pub, 1990, ISBN 0-89042-228-1 .
- ↑ Otto-Albrecht Neumüller (Ed.): Römpps Chemie-Lexikon. Volume 2: Cm-G. 8th revised and expanded edition. Franckh'sche Verlagshandlung, Stuttgart 1981, ISBN 3-440-04512-9 , p. 930.
- ↑ Otto-Albrecht Neumüller (Ed.): Römpps Chemie-Lexikon. Volume 6: T-Z. 8th revised and expanded edition. Franckh'sche Verlagshandlung, Stuttgart 1988, ISBN 3-440-04516-1 , p. 4234.
- ↑ E. Sigel, BP Lüscher: A closer look at the high affinity benzodiazepine binding site on GABAA receptors . In: Curr Top Med Chem . tape 11 , no. 2 , 2011, p. 241-246 , PMID 21189125 .
- ↑ Hans Walter Striebel: The anesthesia: Basics and practice. Schattauer Verlag, 2003, ISBN 3-7945-1985-X , pp. 36–37.
- ↑ Claus-Jürgen Estler, Harald Schmidt: Pharmacology and Toxicology. 6th edition. Schattauer Verlag, 2007, ISBN 978-3-7945-2295-8 , pp. 201-206.
- ↑ Kerri Smith: Treating Chronic Pain Without Side Effects In: Der Tagesspiegel , January 2008.
- ↑ Reinhard Larsen: Anesthesia. 8th edition. Elsevier, Urban & Fischer Verlag, 2006, ISBN 3-437-22501-4 , p. 442.
- ↑ Reinhard Larsen: Anesthesia and intensive medicine in cardiac, thoracic and vascular surgery. (1st edition 1986) 5th edition. Springer, Berlin / Heidelberg / New York a. a. 1999, ISBN 3-540-65024-5 , pp. 24-26.
- ↑ AWMF online: drug addiction ( Memento from March 26, 2007 in the Internet Archive )
- ↑ Christopher L Sola and Co-Authors: Sedative, Hypnotic, Anxiolytic Use Disorders; Medscape, 2010
- ^ R. Braun, F. von Bruchhausen, Hermann Hager, Hubert Schneemann, Gisela Wurm: Hager's handbook of pharmaceutical practice. Volume 1: Goods and Services. 5th edition. 1995, ISBN 3-540-58958-9 , pp. 474-477.
- ^ The Ashton Manual: Benzodiazepines: How they work and how to withdraw. Retrieved June 5, 2013.
- ↑ Specialist information of the Swiss drug compendium for Dormicum® ampoules. Information as of November 2009.
- ↑ Otto Benkert, Hanns Hippius: Compendium of psychiatric pharmacotherapy. ISBN 978-3-540-78470-8 , p. 335.
- ↑ Frank Schneider, Sabrina Weber (eds.): Clinic Manual - Psychiatry, Psychosomatics and Psychotherapy. Springer, Heidelberg 2008, ISBN 978-3-540-78466-1 , p. 209.
- ↑ GW. Peng: Assay of adinazolam in plasma by liquid chromatography. Ed .: Journal of pharmaceutical sciences. No. 73 , August 1984, p. 1173-1175 , PMID 6491930 .
- ↑ a b c d e f g h i j k l m Frank Schneider: Klinikmanual Psychiatrie, Psychosomatik und Psychotherapie . Springer-Verlag, 2015, ISBN 978-3-642-54571-9 , pp. 302 ( limited preview in Google Book search).
- ↑ J Legheand, G Cuisinaud, N Bernard, M Riotte, J Sassard: Pharmacokinetics of intravenous camazepam in dogs . Ed .: Pharmaceutical Research. 1982, PMID 6127087 (English).
- ↑ a b c d Pharmaceutical Manufacturing Encyclopedia . 3. Edition. tape 1-4 . William Andrew Publishing, Elsevier, 2007, ISBN 978-0-8155-1526-5 ( limited preview in Google Book Search).
- ^ A b P. Riederer, G. Laux, W. Pöldinger: Neuro-Psychopharmaka. A therapy manual . 1st edition. 2 tranquilizers and hypnotics . Springer, 1995, ISBN 3-7091-7357-4 , pp. 384 , doi : 10.1007 / 978-3-7091-6593-5 .
- ↑ Janos Fischer, C. Robin Ganellin: Analogue-based Drug Discovery . 1st edition. Wiley-VCH, 2006, ISBN 3-527-31257-9 , pp. 539 (English).
- ^ A b c Peter Riederer, Gerd Laux: Neuro-Psychopharmaka: A therapy manual . tape 1 . Springer-Verlag, 2013, ISBN 978-3-7091-6674-1 , chap. Historical outline: History of psychotropic drugs , p. 63 (527 pp., Google.de ): "Data on the sale of synthetic psychotropic drugs on the German market"
- ↑ a b c W. Forth, D. Henschler, W. Rummel, K. Starke (eds.): General and special pharmacology and toxicology. 6th edition. BI-Wissenschaftsverlag, 1992, ISBN 3-411-15026-2 , pp. 292-293.
- ↑ P. Riederer, G. Laux, W. Pöldinger (Eds.): Neuro-Psychopharmaka: A therapy manual . tape 1 : General principles of pharmacopsychiatry . Springer, Vienna 1992, ISBN 3-7091-7377-9 , 3.3 Pharmako-EEG, p. 97 , doi : 10.1007 / 978-3-7091-6674-l : "[...] that the dose of the test substance cloxazolam equivalent to 5 mg diazepam was 2 mg [...]"
- ↑ Bjoern Moosmann, Philippe Bisel, Volker Auwärter: Characterization of the designer benzodiazepine diclazepam and preliminary data on its metabolism and pharmacokinetics. In: Drug Testing and Analysis. 2014, doi: 10.1002 / dta.1628 .
- ↑ Doxefazepam. 4.1 Absorption, distribution, metabolism and excretion. (PDF) In: monographs.iarc.fr. IARC Monographs, 2018, accessed March 26, 2019 .
- ↑ János Fischer, C. Robin Ganellin: Analogue-based Drug Discovery . 1st edition. John Wiley & Sons, 2006, ISBN 3-527-31257-9 , pp. 539 .
- ↑ a b c d e Dr. Jan Dreher: Benzodiazepine conversion table. In: psychiatrietogo.de. January 29, 2012, accessed March 30, 2019 .
- ↑ a b Bjoern Moosmann, Volker Auwärter: Designer benzodiazepines - Metabolism and detection ( Memento from April 24, 2016 in the Internet Archive ; PDF)
- ↑ a b Psychotropic dose equivalence in Japan. Table 6 Dose equivalence of anxiolytics, sedatives and hypnotics. In: The Japanese Society of Psychiatric Rating Scales. Retrieved March 11, 2019 .
- ↑ Toshiya Inada, Ataru Inagaki: Psychotropic dose equivalence in Japan. In: Psychiatry and Clinical Neurosciences . tape 69 , no. 8 , 2015, p. 445 , doi : 10.1111 / pcn.12275 , PMID 25601291 (English).
- ↑ K. Rickels, I. Csanalosi, P. Greisman, MJ Mirman, RJ Morris, CC Weise, G. Weiss: Ketazolam and diazepam in anxiety: a controlled study. In: Journal of clinical pharmacology , Volume 20, Number 10, October 1980, pp. 581-589, PMID 6108335 .
- ↑ Ketazolam May Be An Advance Over Diazepam For Anxiety. In: InPharma. 247, 1980, p. 12, doi: 10.1007 / BF03290485 .
- ↑ a b W. Forth, D. Henschler, W. Rummel (Ed.): General and special pharmacology and toxicology. 5th edition. Bibliographisches Institut & F. A. Brockhaus, 1987, ISBN 3-411-03150-6 , p. 558.
- ^ Martin Banger: Evidence-based addiction medicine . Treatment guideline substance-related disorders; with 23 tables. Ed .: Lutz G. Schmidt. 1st edition. Deutscher Ärzteverlag, Cologne 2006, ISBN 3-7691-0520-6 , p. 287 (314 pp., Google.de ).
- ↑ Peter Riederer, Gerd Laux, Walter Pöldinger (eds.): Neuro-Psychopharmaka A Therapy Manual . Tranquilizers and hypnotics. tape 2 . Springer, Vienna 2013, ISBN 978-3-7091-6593-5 , pp. 107 ( google.de ).
- ↑ Teofarma Srl, Agenzia Italiana del Farmaco (Ed.): Riassunto delle caratteristiche Product Properties: DOMAR® . 2010 (Italian, gov.it [PDF]).
- ↑ R. Jochemsen, DD Breimer: Pharmacokinetics of benzodiazepines: metabolic pathways and plasma level profiles. In: Current Medical Research and Opinion . tape 8 , no. 4 , 1984, pp. 60-79 , doi : 10.1185 / 03007998409109545 , PMID 6144464 (English).
- ↑ Jnos Fischer, C. Robin Ganellin: Analogue-based Drug Discovery . John Wiley & Sons, 2006, ISBN 3-527-60749-8 , pp. 538 .
- ↑ G. Famiglini, F. Capriotti, P. Palma, V. Termopoli, A. Cappiello: The Rapid Measurement of Benzodiazepines in a Milk-Based Alcoholic Beverage Using QuEChERS Extraction and GC-MS Analysis. In: J Anal Toxicol. 39 (4), May 2015, pp. 306-312. PMID 25712439
- Jump up ↑ S. Karampela, I. Vardakou, I. Papoutsis, A. Dona, C. Spiliopoulou, S. Athanaselis, C. Pistos: Direct urine analysis for the identification and quantification of selected benzodiazepines for toxicology screening. In: J Chromatogr B Analyt Technol Biomed Life Sci. 902, Aug 1, 2012, pp. 42-46. PMID 22790390
- ↑ EN Sauve, M. Langødegård, D. Ekeberg, AM Øiestad: Determination of benzodiazepines in ante-mortem and post-mortem whole blood by solid-supported liquid-liquid extraction and UPLC-MS / MS. In: J Chromatogr B Analyt Technol Biomed Life Sci. 883-884, Feb 1, 2012, pp. 177-188. PMID 22119506
- ↑ II Papoutsis, SA Athanaselis, PD Nikolaou, CM Pistos, CA Spiliopoulou, CP Maravelias: Development and validation of an EI-GC-MS method for the determination of benzodiazepine drugs and their metabolites in blood: applications in clinical and forensic toxicology. In: J Pharm Biomed Anal. 52 (4), Aug 1, 2010, pp. 609-614. PMID 20172681
- ↑ EL Øiestad, U. Johansen, AM Øiestad, AS Christophersen: Drug screening of whole blood by ultra-performance liquid chromatography-tandem mass spectrometry. In: J Anal Toxicol. 35 (5), Jun 2011, pp. 280-293. PMID 21619723
- ↑ Elisabeth Unseld: Evidence of naturally occurring benzodiazepines in biological material . Dissertation . University of Tübingen, 1989, DNB 900345713 .
- ↑ Possibilities and deficits in the accessibility of selected target groups (socially disadvantaged women and elderly people) through measures and materials to reduce drug abuse and dependency: assessment based on current research results and examples from practice . (PDF) German headquarters for addiction issues, 2006.
- ↑ F. Hoffmann, G. Glaeske, W. Scharffetter: Increasing Hypnotic Consumption on Private Prescriptions in Germany. In: Addiction. 52nd year 2006, issue No. 6, pp. 360–366.
- ^ Opinion on the "Recommendations of the Drugs Commission of the German Medical Association on the Prescription of Hypnotics Containing Benzodiazepine" ( Memento of March 4, 2016 in the Internet Archive ; PDF) German Society for Psychiatry, Psychotherapy and Neurology (DGPPN), September 11, 2008; Retrieved January 17, 2012.
- ↑ Causality unclear: increased dementia rate with benzodiazepines. In: Doctors newspaper. Retrieved April 14, 2018 .
- ↑ a b Benzodiazepines . European Monitoring Center for Drugs and Drug Addiction (EMCDDA)
- ↑ Annex II , Annex III (marketable narcotics ) to the BtMG.
- ↑ Most Common Benzodiazepine Prescriptions . 2010, accessed April 2, 2015.
- ↑ Drug Abuse Warning Network, 2011: National Estimates of Drug-Related Emergency Department Visits, p. 49. (PDF; 911 kB) United States Government, US Department of Health and Human Services , Substance Abuse and Mental Health Services Administration, 5. June 2014, accessed April 2, 2015 .
- ^ Drug Situation Report 2003. (No longer available online.) Central Narcotics Bureau, Singapore Government, Singapore, 2003, archived from the original on September 5, 2011 ; Retrieved September 23, 2011 .