Benzodiazepines

Benzodiazepines are the most important and widely used group of anxiolytics (In Germany, 10 - 17 % of the population take a benzodiazepine preparation once in the course of a year. 1 - 2 % of adults take benzodiazepines daily for at least a year). Benzodiazepines are mainly used as anxiolytics and sedatives. Chemically, benzodiazepines are substituted derivatives of a 5-aryl-1,4-diazepine fused to a benzene ring. The large number of substitution possibilities on the benzodiazepine molecular structure explains the large number of representatives of this group of drugs. Thus, benzodiazepines are commercially available in the form of tablets, melting tablets, capsules, drops and as injectables, among others.

The first benzodiazepine, chlordiazepoxide (Librium®), was synthesized in 1950 by Leo Sternbach at Hoffmann-La Roche. Worldwide, benzodiazepines are among the most prescribed medicines.

A distinction is made between:

Short-acting benzodiazepines

• Triazolam (Halcion®): hypnotic; half-life: 1.4 - 4.6 h
• Midazolam (Dormicum®): premedication, induction of anaesthesia, sedation; half-life: 1.5 - 2.5 h

Medium acting benzodiazepines

• Bromazepam (Lexotanil®, Gityl®,Lexostad®⁾: sleep disorders, anxiolysis, half-life: 15 - 28 h
• Alprazolam (Xanax® Xanor®, Tafil® ,Cassadan®): panic disorders, anxiolysis , half-life:12 - 15 h
• Lorazepam (Tavor®,Tavor Expidet®, Temesta®, Ativan® ,Laubeel® ,Tolid® Somagerol®): anxiolysis, sleep disorders, half-life:13 - 14 h
• Oxazepam (Adumbran®, Praxiten®, Sigacalm® ,Uskan®): anxiolysis, sleep disturbances , half-life: 5 - 15 h
• Flunitrazepam ( Rohypnol®, Fluninoc®): hypnotic, induction of anaesthesia, half-life: 10 - 30 h

Long-acting benzodiazepines

• Diazepam (Valium®, Faustan®, Stesolid®, Neurolytril®, Valocordin®): anxiolysis, sedation, seizures, half-life: 24 - 48 h (50 - 80 h)
• Tetrazepam (Musapam®, Musaril® ,Rilex®, Myospasmal®, Spasmorelax®):myotonolytic (muscle relaxant), half-life:18 h (Note: no longer licensed)
• Flurazepam (Dalmadorm®, Staurodorm®): sleep disturbance, half-life: 20 - 100 h
• Clonazepam (Rivotril®, Antelepsin®): seizures, half-life:30 - 40 h
• Clobazam (Frisium®): anxiolysis, seizures, half-life: 20 h
• Chlordiazepoxide (Librium®, Multum®, Radepur®): anxiolysis, half-life: 20 - 50 h

Benzodiazepines bind with high affinity to the alpha subunit of the transmembrane receptor of gammaaminobutyric acid (GABAA receptor - subtype GABAA ) and lead to an enhanced ligand effect of GABA. GABAA receptors are transmembrane protein complexes that function as ion channels. After ligand binding to the receptor, there is an increased chloride influx, which reduces the excitability of the cells through hyperpolarization (inhibitory GABAergic effect). This "sensitization" of the receptor is called "positive allosteric modulation". The central depressant property of benzodiazepines is due to this effect.

Benzodiazepines thus act only in the presence of endogenous GABA. The activity of the receptor channel can never be stronger than is possible due to the physiological binding of GABA(ceiling effect). This explains the wide therapeutic range and safety of benzodiazepines (even in overdose). In contrast, barbiturates can induce respiratory paralysis in overdose because they themselves act GABAergically. Flumazenil is a competitive benzodiazepine antagonist that completely abolishes the benzodiazepine effect.

Benzodiazepines are usually rapidly absorbed and metabolised at different rates depending on the molecular structure. They have a high bioavailability. CYP3A4, CYP2C19 and conjugation with glucuronic acid play the most important role in their metabolism. For example, the degradation of diazepam proceeds in 3 steps:

• In a first step, N-desalkylation to nordiazepam N occurs in the liver, and in a 2nd step, hydroxylation to oxazepam occurs. Oxazepam is glucuronidated in a 3rd step and then excreted as a conjugate via the kidney.

Similarly, many other benzodiazepines are degraded, some in only two steps via hydroxylation and glucuronidation. The intermediates formed in these enzymatic processes are usually also active. Some are responsible for the long-lasting effects of benzodiazepines due to their long half-lives. Medically important, half-lives increase with the age of the patient. In this respect, the dosage must be adjusted in elderly patients.

Overview of use: 4-K rule: Benzodiazepines lead to a rebound phenomenon after only a few months, even at low doses, when they are stopped. The 4-C rule summarises what should be considered when using benzodiazepines:

• Clear indication
• Small dose
• Short duration of use (maximum 14 days)
• No abrupt discontinuation

Benzodiazepines have dose-dependent anxiolytic, sedative, muscle relaxant and anticonvulsant effects. The specification of benzodiazepine action results from the extent to which benzodiazepines occupy GABAA receptors:

• Low doses elicit anxiolytic effects.
• Higher doses produce muscle relaxant and hypnotic effects.
• High doses can suppress status epilepticus

After a few weeks, receptor downregulation results in the development of tolerance, which causes the effects to weaken. This mainly affects the antiepileptic effect.

Pregnancy: Especially prolonged use in late pregnancy may cause floppy infant syndrome in the newborn.

Breast-feeding: see below for the product information of the individual substances.

The range of adverse reactions to benzodiazepines is wide. The following list gives an overview of how different organ systems may react.

psychiatric disorders: restlessness, agitation, irritability, aggressiveness, hallucinations, outbursts of anger, nightmares, psychosis, trigger of depression

Central disorders: fatigue, drowsiness, dullness, impaired responsiveness, dizziness, headache, anterograde amnesia, memory impairment

visual disorders: double vision, blurred images

respiratory disorders: respiratory depression

intestinal disorders: dry mouth, nausea, vomiting, diarrhea, constipation

cardiovascular disorders: blood pressure ↓

muscular disorders: ataxia, risk of falls, intoxication and antidotes for benzodiazepines.

Intoxications: Provided there is no mixed intoxication with other substances, the administration of laxatives and charcoal tablets is usually sufficient. Flumazenil (Anexate®), administered intravenously, is available as a specific antidote. Flumazenil is also a benzodiazepine, but with partial agonist action. Due to its high binding affinity to the GABA receptor, it displaces benzodiazepines from the receptor. Only at very high doses does flumazenil itself have an agonistic effect.

Cutaneous UAW:

• Urticaria and anaphylactic reactions (Haybarger E et al 2016).
• Severe maculopapular exanthema (Palacios Benito R et al 2001) to toxic epidermal necrolysis (TEN syndrome) (Martín-Merino E et al 2015). In a major review, the probability of occurrence of Stevens-Johnson syndrome/TEN for the benzodiazepine group was reported to be 3.21/1million patients (Martín-Merino E et al. 2015).
• Occasionally, the occurrence of "acute generalized pustulosis" has been reported (tetrazepam - Thomas E et al. 2008).
• A lichenoid oral reaction was once described during therapy with lorazepam (Colvard MD et al. 1986)

In combination with CYP-3A4 inhibitors (e.g. cimetidine, diltiazem, erythromycin, clarithromycin), the degradation of benzodiazepines may be inhibited (potentiation of effect!). The synchronous application of phenytoin and barbiturates has the opposite effect (attenuation of effect). Furthermore, interactions with centrally depressant drugs, alcohol and muscle relaxants may be observed. The simultaneous administration of antihypertensives causes an additive reduction in blood pressure.

Reciprocal effect enhancement is possible with centrally depressant pharmaceuticals such as:

• Hypnotics
• Opioids
• Alcohol
• Antiepileptic drugs
• Antidepressants
• Antipsychotics
• Sedating antihistamines

Benzodiazepines are contraindicated in:

• hypersensitivity to the active substance
• acute respiratory insufficiency, obstructive airway disease
• History of dependence
• myasthenia gravis
• Narrow-angle glaucoma
• Ataxias
• Myasthenia gravis
• Co-dependencies

Alphabetical listing of the main benzodiazepines (the typical endings of the benzodiazepines are -azepam and -azolam.):

• Alprazolam (Xanax®).
• Bromazepam (Lexotanil®)
• Chlordiazepoxide (Librium®)
• Clobazam (Urbanyl®)
• Clonazepam (Rivotril®)
• Clorazepate (Tranxillium®)
• Diazepam (Valium®)
• Flunitrazepam (Rohypnol®)
• Flurazepam (Dalmadorm®)
• Halazepam (Pacinone®)
• Ketazolam (Solatran®)
• Lorazepam (Temesta®)
• Lormetazepam (Loramet®)
• Medazepam (Rudotel®, D)
• Midazolam (Dormicum®)
• Nitrazepam (Mogadon®)
• Oxazepam (Anxiolit®)
• Prazepam (Demetrin®)
• temazepam (Normison®)
• triazolam (Halcion®)

The name benzodiazepines is based on the chemical structure of the heterocyclic ring system. The main representative of this group is diazepam (see figure). The usual substitution sites are marked with red numbers. The 1H-benzo-1,4-diazepines carry a six-membered ring in the 5-position like benzene, pyridine or cyclohexene. The tetracyclic benzodiazepines have a five-membered ring with one (midazolam) or 2 nitrogen atoms (e.g., triazolam) attached at N1 and C2.

Antidote in poisoning: benzodiazepine antagonist, e.g. flumazenil (Anexate) i.v.

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