Benzodiazepines Introduction One of

a group of structurally related drugs used mainly as sedatives/hypnotics muscle relaxants, and anti-epileptics, and once referred to by the now-deprecated term "minor tranquillizers". These agents are believed to produce therapeutic effects by potentiating the action of gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter. Benzodiazepines were introduced as safer alternatives to barbiturates. They do not suppress REM sleep to the same extent as barbiturates, but have a significant potential for physical and psychological dependence and misuse.

Short-acting benzodiazepines include halaze-pam and triazolam, both with rapid onset of action; alprazolam, flunitrazepam, nitraze-pam, lorazepam, and temazepam, with intermediate onset; and oxazepam, with slow onset. Profound anterograde amnesia ("blackout" and paranoia have been reported with triazolam, as well as rebound insomnia and anxiety. Many clinicians have encountered particularly difficult problems on discontinuing treatment with alprazolam.

Long-acting benzodiazepines include diaze-pam (with the fastest onset of action), cloraze-pate (also fast onset), chlordiazepoxide (intermediate onset), flurazepam (slow onset), and prazepam (slowest onset). The long-acting benzodiazepines may produce a cumulative disabling effect and are more likely than the short-acting agents to cause daytime sedation and motor impairment.

Even when benzodiazepines are taken in therapeutic doses, their abrupt discontinuation induces a withdrawal syndrome in up to 50% of people treated for 6 months or longer. Symptoms are more intense with shorter-acting preparations; with the long-acting ben-zodiazepines, withdrawal symptoms appear one or two weeks after discontinuation and last longer, but are less intense. As with other sedatives, a schedule of slow detoxification is necessary to avoid serious complications such as withdrawal seizures Some benzodiazepines have been used in combination with other psychoactive substances to accentuate euphoria, e g 40-80 mg of diazepam taken shortly before or immediatly after a daily maintenance dose of methadone. Benzodiazepines are frequently misused in conjunction with alcohol or in opioid dependence see multiple drug use).

Fatal overdose is rare with any benzodiazepine unless it is taken concurrently with alcohol or other central nervous system depressants. BENZODIAZEPINES History Leo H

Sternbach, a chemist employed by the pharmaceutical company Hoffman-La Roche, investigated 1955 a substance chlordiazepoxide that had been synthesized already 1947. He noticed that when a certain dose of chlordi-azepoxide was given to a mouse it would loosen its grip on an inclined wire screen and fall to the floor of the test cage. When the mouse was given barbiturates it promptly fell asleep but when given chlordiazepoxide it continued to walk around sniffing the cage in a normal manner. This led to further investigations and chlordiazepoxide was considered as an almost perfect selective "antianxiety" drug that produced less drowsiness than the barbiturates and had a larger safety marginal before overdose death occurred. Chlordiazepoxide was introduced 1960 under the trade name Librium, followed five years later by diaze-pam under the tradename Valium. The introduction of benzodiazepines was an immediate medical and commercial success. They rapidly became the most widely used sedative-hypnotics worldwide. The marketing was aggressive.

The benzodiazepines were important innova tions in the treatment of anxiety disorders and they were rapidly replacing barbiturates, bromides, opioids which were more toxic and had more serious side effects. One of the mayor advantages compared with these older substances was that benzodiazepines were a lot safer. The number of fatal overdoses fell considerably when benzodiazepines were introduced.

The benzodiazepines became so popular that they influenced the whole concept and acceptance of drug-taking. Rolling Stones sang about "Mothers little helper" and it became widely accepted to use benzodiazepines even for minor problems with anxiety and sleeping disorders. The health care professionals were so enthusiastic of the fairly "safe" therapeutic index (the amount needed to induce sedation was much lower than the amount that would cause overdose) and the relatively mild side-effects that they promoted a wide use that was accompanied by intense marketing from the pharmaceutical industry. After a few years the darker sides of the benzodiazepines where reported: the lengthy time it lasted in the body, the ability to induce addiction even at low levels of use, the severity of withdrawal symptoms and the frequent use of the substance in combination with alcohol and other drugs.

Beginning in the 1970 a wave of criticism against what was claimed as the over-prescription of benzodiazepines. Self help groups of people dependent on benzodiazepi-nes was formed. The benzodiazepines was placed under international control in the UN Convention on Psychotropic drugs 1971. In the 1980 a book written by the American journalist Barbara Gordon "I am dancing as fast as I can" played an important role in forming a political opinion against the "overprescrip-tion". In the media several cases of persons who had became violent after use of especially short-acting benzodiazepines were reported. There were also several reports on low-dose dependency. Mainly middle-aged women who had taken low therapeutic doses of benzodi-azepines reported severe withdrawal problems and rebound effects. There were also a more ideological critisism of the frequent use of benzodiazepines for "normal" crises. It was strongly questioned whether it was good practice to prescribe benzodiazepines in life-crises such as divorces, deaths of close relatives, minor family problems or workplace problems and sleeping disturbances. The idea of the critics where that these problems will only be contained, prolonged and worsened by "sedating" them with benzodiazepines. The use of benzodiazepines is still controver sial. While almost all health care professionals agree on the good of their relaxing, sleep-inducing and mucle-relaxant effects and their relative safety, it is still controversial how broad the indications shall be. The more psychoanalytic and psychotherapeutic oriented professionals are generally more restrictive in this sence.

In the 1990 the use of benzodiazepines has culminated in many industrialized countries. The use of Selective Serotenine Reuptake Inhibitors, though they act in a whole different way has partly taken over as the substances of choice especially in treatment of depressions and anxiety.

BENZODIAZEPINES Chemistry and pharmacology All substances in this group has a center of benzodiazdepine. They interact with or act as the naturally occurring neuro-transmitter in the brain called gamma amino butyric acid, or GABA for short. GABA is one of the most important inhibitory neurotrans-mitters. Benzodiazepines greatly increase the actions of GABA and also influence other sedating neurotransmitters such as serotonin and dopamine. The effect is selective and does not influence the whole central nervous system. There have been intensive efforts to isolate an endogenous benzodiazepine-like substance from brain tissue, this has so far not succeeded, but a diazepam binding inhibitor (DBI) peptide has been isolated. Benzodiazepines is eliminated through the liver and through the kidneys, the elimination time is relatively long, it takes for example about a week for most of the diazepam (Val-ium) to leave it. The breakdown-process can be especially long in elderly persons where there is a risk for cumulation. PLASMA HALF LIFE OF BENZODIAZEPINES Chemical name Halflife (hours) Very long acting Flurazepam 90 - 200

Halazepam

Prazepam

Intermediate acting

Chlordiazepoxide 7 - 46

Diazepam 14 - 90

Clonazepam 19 - 50 Short acting

Temazepam 5 - 20

Alprazolam 6 - 20

Oxazepam 6 - 24

Lorazepam 9 - 22 Extremly short acting

Triazolam 2 - 6

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