What is Benzodiazepine and mechanism of action. What is Pharmacological Actions of Benzodiazepine and uses?

benzodiazepine

Chlordiazepoxide, the first benzodiazepine was accidentally synthesised in 1961. BZD (or the barbiturates) in lower doses act as sedative and antianxiety drugs; at higher doses they act as hypnotics; at still higher doses, they produce anaesthesia; and at further doses, they cause coma and death. BZDS on the other hand can be used as an anaesthetic agent and in very rare cases, death occurs due to high doses of BZD.

Mechanism of Action

BZDS bind to the GABA receptor on the cell membrane. and facilitate the opening of chloride channe! causing the influx of chloride ion. GABA activity causes hyperpolarisation and makes the neuron hypo-excitable. GABA inhibits other neurons, and BZDS potentiate the effect of GABA; this indicates that for maintaining the efficacy of BZDS, GABA should be present the site. i.e., BZDS are of no use if GABA is not present. This potentiation of GABA produces sleep, anxiolytic and anaesthetic effect.

Pharmacological Actions

1) Action on CNS:

 The effect of BZDS results from the action of these drugs on the CNS. The most prominent effects are sedation, hypnosis. muscle relaxation, and anticonvulsant activity. Alprazolam shows antidepressant activity in certain clinical setting. On increasing the dose of BZD. sedation progresses to hypnosis and then to stupor. According to some studies, BZD does rnot cause a true general anaesthesia.

2) Anti Convulsant Activity:

Due to the potent and broad anticonvulsant activity of BZD receptor agonist, it has many therapeutic applications, including petit mal and status epileptics. BZDS do not effect strychnine induced convulsion in animals. For chronic treatment of epilepsies, the BZD agonist is not the first choice, except the certain from epilepsy in children. The reason for tis restriction is the development of tolerance. Clonazepam is used in epilepsy because of its selective anti-convulsant action.

3) Anterograde Amnesia: 

BZDS abolish the memory of events experienced under their influence; this effect is not produced by other CNS depressants. Minor surgical procedures can thus be performed without leaving unpleasant memories.

4) Action on CVS: 

BZDS produce minor CVS effects except in severe intoxication BZD in pre-anacsthetic doses decrease biood pressure and increase heart rate. Diazepam increases coronary low by an action to increase interstitial concentration of adenosine.

5) Action of Respiration: 

BZD agonist at marked sedating doses depresses respiration. This effect is the combination of muscle relaxation and depressed sensitivity of the reticular formation to carbon dioxide. The respiratory depressant effect of opiates is increased by concomitants treatment with BZD agonist.

Drug Interaction 

BZDS show synergism with alcohol and other CNS depressants teading to excessive impairment. Cimetidine and isoniazid delay the metabolism of BZDS.

Newer Non-Benzodiazepines Hypnotics

Buspirone is an  anxiolytic (but not a sedative) and a partial agonist of 5-HTA receptor. Zolpidem is a non-BZD compound which binds to the BZD receptor to potentiate the effects of GABA, and thus acts as a sedative-hypnotic. Non-BZDS produce fewer side effects in comparison to BZDS. The side effects which commonly occur are dizziness, nausea, and headache. They also bind to dopamine receptors, but they have marked 5-HT actions related to anxiety suppression,. since related anxiolytic compounds (e.g ipsapirone and gepirone) exhibit high specificity for 5-HTA receptors. These receptors are inhibitory auto receptors and decrease the release of 5-HT and other mediators. Buspirone canaot control panmc attacks.
 

Benzodiazepine Antagonists

Competitive antagonists of BZDS were discovered in 1981. Flumazenil is the best known BZD antagonist, which was previously reported to not produce any effects on behaviour or on drug-induced convulsions when given on its own; although later it was found to possess anxiogenic and pro-convulsant activity. Flumazenil can reverse the effect of BZD over dosage (this property is used in case of respiratory depression) or can reverse the effect of BZDS used for minor surgical procedures (e.g., midazolam).

Flumazenil when injected produces a rapid and effective action, which however lasts for only 2 hours, and thus drowsiness relapses. This drug can be used in exhausted patients who have taken BZDS in high doses even before the diagnosis is confirmed by a blood test. Convulsions rarely occur in patients being treated with flumazenil, and commonly occur in patients being treated with tricyclic antidepressants. Results show that flumazenil improves the mental state of patients having hepatic enicephalopathy (a severe liver disease) and alcohol intoxication have not been confirmed in controlled trials.