benzodiazepine

created by dem bones
(thing) by leighton (4.7 y) (print)   ?   (I like it!) Sun Jun 10 2001 at 1:54:10
ben'zo*di*a"ze*pine (-aah"ze*peen, -ay"ze*pine)

Benzodiazepines and their generic names:


Brand Name.....Generic Name........Mean Half-Life (in hours)

Ativan.........lorazepam...........15
Centrax........prazepam............60
Dalmane........flurazepam..........80
Dormalin.......quazepam............35
Halcion........triazolam............2.5
Klonopin.......clonazepam..........30
Librium*.......chlordiazepoxide*...10*
Mogadon........nitrazepam..........??
Paxipam*.......halazepam*..........14*
ProSom.........estazolam...........18
Restoril.......temazepam...........12
Serax..........oxazepam.............8
Tranxene.......chlorazepate........60
Valium*........diazepam*...........24*
Versed.........midazolam............2.5
Xanax..........alprazolam..........12

Drugs with an asterisk also contain nordiazepam, which has a half-life of 60 hours.

Also, this list is probably incomplete; drug companies make new benzodiazepines all the time. If the generic name ends in -zepam or -zolam, it's likely a benzodiazepine.

(thing) by paraclete (2.4 mon) (print)   ?   (I like it!) 7 C!s Wed May 25 2005 at 23:07:06

Benzodiazepines are a large group of drugs that are used as muscle relaxants, anticonvulsants, sedative-hypnotics and anxiolytics. The first benzodiazepine to be discovered was chlordiazepoxide in 1954. It was the result of an unexpected reaction during the investigation of a group of compounds called benzheptoxdiazines by Dr. Leo Sternbach for the pharmaceutical company Hoffman La Roche. The basic chemical structure of benzodiazepines consists of a seven-membered ring fused to an aromatic ring, with four main substitutent groups that can be modified without loss of activity (Rang et al, 2003).

Discovery

The discovery of benzodiazepines is a great example of the lottery of life. Dr. Sternbach first worked on benzheptoxdiazines as part of his PhD research at Jagiellonian University in Krakow. He revisited this work 20 yrs later when working as a Group Chief for Hoffman La Roche. At this point, the race was on for a pharmaceutical company to develop a replacement for the addictive and clinically dangerous barbiturates. He synthesised a variety of different compounds, but all unfortunately proved to be pharmacologically inert. Finally, he treated one of the compounds he had created with methylamine, producing a white, water soluble, crystalline powder. Distractions at work meant that he didn't have time to investigate this powder immediately, and so he shelved the substance for later investigation.

Two years later, his research assistant was cleaning Dr. Sternbach's lab when he came across the bottle containing the compound. He asked Dr. Sternbach if he should throw the sample away or send it for testing. After a few moments thought, Dr. Sternbach decided to send it away for further analysis. The report that he received back stated that the substance has hypnotic, sedative, and antistrychnine effects in mice similar to meprobamate. In February of 1960, the drug was approved by the FDA and released onto the market under the trade name Librium. It was followed in 1963 by Valium and then in 1965 by Serax. The benzodiazepine drugs have made millions and millions of dollars for Hoffman La Roche; they could so easily have been thrown away in a lab clear out.

Types of Benzodiazepine

There are many, many different types of benzodiazepines; over the years, the number that are available to prescribe (in the UK, at least) have fallen for a variety of different reasons. For example, flunitrazepam (Rohypnol) is no longer available due to it being abused as a 'date rape' drug. Another, triazolam (Halcion), has been withdrawn in the UK because of its side-effect profile. Benzodiazepines are usually differentiated into hypnotics or anxiolytics by their length of duration of action. Those with a short term duration of action are used as hypnotics, those with a longer duration are used as anxiolytics. Below is a list of the drugs currently available for prescription in the UK.

Benzodiazepines are also drugs of abuse and go by a variety of other names, including and not limited to: jellies, benzos, eggs, norries, rugby balls, vallies, moggies, mazzies, roofies and downers. They are also sometimes incorrectly called 'minor tranquillisers' (in comparison to anti-psychotic medications, which are incorrectly referred to as 'major tranquillisers').

Mode of Action

Benzodiazepines work selectively to enhance the action of the gamma-aminobutyric acid A (GABAA) receptors. GABAA receptors, located postsynaptically on neurones in the central nervous system, are mediators of fast postsynaptic inhibition. This effect is mediated by the selective permeability of the chloride (Cl-) channels that they are associated with; increasing Cl- permeability hyperpolarises the cell, thereby reducing its excitability.

The benzodiazepines exert this effect by binding to an accessory site (the 'benzodiazepine receptor') on the gamma (γ) subunit of the GABAA receptor. This allosteric interaction results in the facilitated binding of GABA to the receptor, and an enhancement of its agonist effect.

Pharmacological Effects

The main clinical effects of benzodiazepines are:

Reduction of anxiety and aggression - Benzodiazepines have an anxiolytic effect, and have even been shown to produce a marked 'taming' effect on animals. They are used mainly to treat acute anxiety states, but in the past were given out indiscriminately by well-meaning doctors to anyone who felt 'stressed'. Unfortunately, benzodiazepines are addictive and this lead to many people becoming needlessly dependant on them. There are now strict regulations in place in the UK governing the prescribing of benzodiazepines to patients in order to prevent abuse of these drugs. Most anxiety problems are now treated using a combination of anti-depressants and behavioural therapy.

Sedation and induction of sleep - Benzodiazepines decrease the time taken to sleep, and increase the total duration of sleep (but only for those who normally sleep less than 6 hours a night). However, these effects decline after a couple of weeks of continuous use. For this reason, plus the risk of addiction, benzodiazepines should only ever be used as a temporary solution to treat insomnia.

Reduction of muscle tone and co-ordination - Patients with anxiety tend to have increased muscle tone that may contribute to the aches and pains, including headache, which they experience. Benzodiazepines reduce muscle tone by a central action that is independent of their sedative effect, but it is as yet unclear how they do this. This property of benzodiazepines is taken advantage of in general anaesthesia.

Anticonvulsant effect - Benzodiazepines are highly effective anticonvulsants against chemically induced convulsions, but not as effective with electrically induced ones. Diazepam is given intravenously during life-threatening status epilepticus attacks in an attempt to control seizures.

Anterograde amnesia - Benzodiazepines can obliterate memories of events experienced while under their influence, an effect not seen with other CNS depressants. Minor surgical procedures can thus be performed without leaving unpleasant memories.

Unwanted Effects

Acute Toxicity - When taken as an overdose, benzodiazepines cause prolonged sleep without any other serious effects. However, if taken in overdose with other central nervous system depressants, particularly alcohol, they can cause severe, and possibly life-threatening, respiratory depression. However, there is an effective antidote to benzodiazepines, flumazenil, which acts as an antagonist at the benzodiazepine receptor. Flumazenil is often given as standard to any patients admitted to hospital in a coma with respiratory depression, even if it hasn't been confirmed that the patient has overdosed on benzodiazepines.

Side-effects - The main side-effects of benzodiazepines are drowsiness, confusion, amnesia and impaired coordination, which considerably affects manual skills such as driving performance. Other unwanted side-effects can include headache, vertigo, hypotension, salivation changes, gastro-intestinal disturbances, visual disturbances, dysarthria, tremor, changes in libido, incontinence and urinary retention.

Tolerance and Dependence - The main drawback of benzodiazepines is that they cause tolerance and dependence. Patients who stop benzodiazepine treatment after weeks or months of regular use experience an increase in their symptoms of anxiety, together with tremor and dizziness. The withdrawal syndrome seen with benzodiazepines is similar to that of barbiturate withdrawal, and is comparable to that of alcohol withdrawal. Symptoms include anxiety, irritability, tachycardia, increased respiratory rate, muscle pain, nausea, tremors, hallucinations, confusion, and seizures. These symptoms can make it very difficult for patients to stop taking their medication without in-hospital treatment (detox). In order to avoid these problems, it is recommended that paitents are prescribed benzodiazepines for a maximum of four weeks.

References

  • British National Formulary - www.bnf.org
  • Rang H P, Dale M M, Ritter J M, Moore P K, 2003, Pharmacology, 5th edition, Churchill Livingstone, 515-522
  • Talk to Frank - www.talktofrank.com Drug information site for young people.

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