What are benzodiazepines ?
The benzodiazepines (BDZ) are psychotropic agents that belong to the GABA agonists and are often referred to as minor tranquillizers. They are used in medicine for their sedative (calming, sleep-enhancing) and anxiolytic (feelings of anxiety-reducing) properties. The muscle-relaxant properties can be both a target as a side effect. The discovery of these resources was a medical breakthrough. especially since these agents are better tolerated, and in overdose are much safer than the hitherto commonly used barbiturates. Benzodiazepines are widely prescribed in the Netherlands each year approximately 10 million prescriptions. Until 2002, the use is increased every year. From 1 January 2009, many of these drugs are only covered in the Netherlands by the health insurance if the doctor a certain code on the prescription (B2 code relating to specific diseases) writes. Nevertheless, the number of problem drug addicts is increasing sharply.
Chemistry
The term benzodiazepine refers to the part of the structure which consists of a benzene ring which is fused to a 7-part-diazepine ring. In the figure so it comes to the top two rings. All medically important benzodiazepines have a 5-aryl substituent and a 1,4-diazepine ring. In the figure is that the lower ring, a phenyl group and the so-called seven-membered ring with at the positions 1 and 4 is a nitrogen atom. An exception is clobazam with a 1.5-diazepine ring. The benzodiazepines comprises the basic skeleton of these rings, and they differ from each other in terms of substituents.
Pharmacology
The effects of BDZs are for the most part due to their effect on the brains. The main effects are sedation, sleep promotion, anxiety reduction, muscle relaxation, amnesia and anticonvulsant properties. These effects are mediated by the BDZs on certain receptors in the brains, namely the GABA-A receptor engagement. The GABA-A receptor consists of five parts, which are built from so-called subunits.
Despite the pharmacological similarities between the BDZs they differ greatly in their clinical utility. In part, this is caused by differences in half-life (duration of action). The majority of benzodiazepines, except oxazepam and lorazepam, are also metabolites that are employed. The half-life may be as high as 100 hours. This is particularly true for substances that have nordazepam as a metabolite, such as, for example, chlordiazepoxide, clorazepate, diazepam, ketazolam, medazepam and prazepam. To illustrate: an agent with a very short half-life can be used to initiate a general anesthetic. A drug with a long half-life can give long-term relief of anxiety and tension.
It is still not clear whether the anxiolytic effects and the sedating effects are the same. Reduces anxiety because the muscles relax and you feel a little lethargic, or is there a specific fear dampening effect? Interactions with other drugs are rare. Of course one should be careful with the concurrent use of alcohol and other substances that reduce alertness. They reinforce each sufmakende operation.
Indications
Sleeping pills (hypnotics)
A list of the preparations: substance name is followed by (a brand name) of benzodiazepines that are used as sleep-inducing drug. Typically, a short acting benzodiazepines chosen for sleep disorders. The elimination half-lives and schedules, see the ChemSpider.
- Very short acting benzodiazepines
- Short acting benzodiazepines
- Intermediate acting
Long acting benzodiazepines are usually prescribed as hypnotics (slaapmiddellen), since they are working during the day. Doctors usually opt for the short-acting drugs, sometimes for very short-acting agents and occasionally for medium- or long-acting agents.
- Long acting benzodiazepines
Flunitrazepam (Rohypnol)
Flunitrazepam, despite its long elimination half-life, still be regarded as a short-acting hypnotic. Since the volume of distribution of flunitrazepam is so large, the duration of action is no longer determined by elimination, but due to the distribution into the tissues (distribution half-life was 3 hours).
Diminishing resources anxiety (anxiolytics)
Not yet listed among sedatives benzodiazepines given especially anxiety-reducing agent:
- alprazolam (Xanax), short- to intermediate-acting
- bromazepam (Lexotanil), medium to long-acting
- chlordiazepoxide (Librium), long-acting
- clobazam (Frisium), long-acting
- clorazepate (Tranxene), clorazepate, long-acting
- diazepam (Valium), long-acting to very long-acting
- flurazepam (Dalmadorm), long-acting
- ketazolam (Unakalm), long-acting
- lorazepam (Temesta), intermediate-acting
- medazepam (Nobrium), (very) long-acting
- midazolam (Dormicum), very short-acting, off-label is used in the palliative sedation and is used as a soothing agent for a (look) operation
- oxazepam (Seresta), short acting, without active metabolite
- prazepam (Reapam), long-acting
Other indications
Sometimes benzodiazepines also prescribed for epilepsy and febrile convulsions. An example of this is clonazepam. This type of medicine namely reduces the incentive sensitivity of the patient, causing epileptic symptoms absence. Additionally, you can choose to use these resources as an anesthetic in the final stages of life.
Benzodiazepines side effects
The most frequent side effects are a direct consequence of their mechanism of action.
- Daytime sleepiness is the most commonly reported adverse risks for driving and controlling machines, especially at the long-acting agents.
- Decrease in concentration and memory, making the learning of new skills and knowledge becomes difficult. Learning for school or study is difficult.
- Influencing of the quality of sleep. The amount of time dream (REM sleep) decreases. They need it - among others - to learn new things and for the processing of emotions.
- Increased appetite and weight gain.
- Paradoxical effect when used as a sedative which the patient agitated and aggressive behavior may exhibit.
- Decreased libido.
- Skin reactions.
- Feeling hangover after waking up.
- Increased risk of hip fractures.
- Coordination disorders.
Reducing and phasing out the use
With prolonged use occurs tolerance. It has been an increasingly higher doses in order to achieve the same effect. If tolerance occurs, patients getting the chance psychological and physical addiction. If one wants to stop then, withdrawal symptoms may occur. These symptoms are often the same as for which one taking the medicine, such as anxiety and insomnia. In addition to physical symptoms such as tremor, sweating, tingling, gastrointestinal problems etc. occur.
According to a research report published by the IVO used in 1993, about 7% of the Dutch elderly in 2004 (over-55s) and often prolonged (5 or more days per week) benzodiazepines. More than half of them in 1994-1999 to use less or stopped, only about 1% of the elderly in the same period just become prolonged frequent user. In 1992, used in the Netherlands about 450,000 people over a year a BDZ. Chronic use (longer than 3 months) is seldom a good method of treatment. Reasons to reduce the chronic use are: lack of evidence of efficacy in the long-term behavior changes, memory loss and addiction. In the elderly, BDZ-use increases the risk of hip fractures by 50%.
In order to reduce the abuse of benzodiazepines, as of January 1, 2009 in the Netherlands, many of these drugs are no longer reimbursed. It does just about usage because restlessness and anxiety and sleep disorders. Use for anxiety disorders who do not respond to other medications, certain psychiatric disorders, epilepsy and anesthesia in the last phase of life is reimbursed. Additionally diazepam down is also reimbursed by muscle spasms. The effect of the compensation measure was low, many people paid rather than stop.
Finishing Schedule
The potential success of a dose reduction is also dependent on the age, duration of intake, dose, and the severity of the symptoms for which the benzodiazepine was given. The scheme described below is not the only way to cut down. The higher the dose and the longer the use, the more cautious should be made outfitting. This is intended to minimize the withdrawal symptoms.
Step 1. Switching to a benzodiazepine with a long half-life such as diazepam. The changeover should be done gradually. If the patient's benzodiazepine took multiple doses per day, the best single dose is substituted each time. Usually starting dose before bedtime.
Step 2. At each step would be every two weeks with one-tenth or one eighth of the initial dose can be diminished. Phasing 1/8 every 2 weeks lasts 14 weeks. Regular monitoring by a physician is wise. Such small reduction steps are often not possible because there are no tablets are available in small enough doses. The patient or his doctor can ask the pharmacist to make special capsules. Also one can own the tablets manually or with a special pill crusher "break up the correct dosage.
Step 3. When the daily dose of only 0.5 mg diazepam (or its equivalent) is, it must be completely stopped. Additional treatment during taper may consist of behavioral therapy, relaxation therapy, group therapy or the use of an antidepressant or a beta blocker.
In a small proportion of people (long-term) a (high dose of a) have used benzodiazepine, can in no reduction, inadequate reduction or in very rare cases, even after a reduction of 3 to 6 months or longer, the "post-withdrawal syndrome "arise. We speak of this as one takes 2 years after last use (except for a phasing-out period) complaints, which had no or much lesser extent for use of the benzodiazepine. (Long-term withdrawal symptoms) The behavior of the person during the period of the use of the benzodiazepine may play in here. People with a very healthy lifestyle (which sports, healthy eating and drinking and not smoking), have (much) less chance of developing this syndrome, but swallow generally less than benzos passive people. Many people that higher doses of a benzodiazepine use often get a bigger belly ("benzo belly"), or by increased appetite and craving for sweets much thicker and touch through the use of a benzodiazepine often less motivated to live and sports Healthy , which increases the risk of prolonged withdrawal symptoms.