An extensive research had been carried out on the benzodiazepoxide displayed psychotropic activity, in experimental animals. Over 2000 compounds belonging to this series have been synthesised and pharmacological screening of these compounds has been carried out in the search of better tranquilizer, muscle relaxant, anticonvulsant or a sedative hypnotic drug.


All benzodiazepines exhibit hypnotic action to more or less extent with varying degree of metabolism in liver. Hence only those benzodiazepines which are quickly metabolised and excreted, can be used as hypnotics in clinical practices.


Structure-Activity Relationship:


(1) All CNS depressant benzodiazepines are usually substituted 5-cyclohexenyl group.


(2) The chemical nature of substituents at positions 1 to 3 does not affect the activity.


(3) N(4) should usually be substituted with a group with low electron density.


(4) Position 7, if substituted with electron withdrawing groups, results into an enhancement of activity, while substitution elsewhere in this aromatic ring results in decrease in activity. Same holds true, for R'; substitution in phenyl ring on C In addition to their antianxiety action, the benzodiazepines which are exclusively used as hypnotics are summarised in the




Table 7.3: Benzodiazepines versus Barbiturates


Benzodiazepines


2 Act on limbic system, thus reduce


1. Act by depressing the cortical response


2. They can cause true anaesthesia.


alertness and wakefulness. 2. They do not cause true anaesthesia.


3. Sleep induced by benzodiazepines


resembles much with natural sleep.


3. Likely to produce hangover and psychomotor impairment.


4. Overdoses may result into a death.


In overdoses, less chances to cause unconsciousness and respiratory depression and hence relatively more


safe.


5. They get slowly eliminated from the body.


5. They get eliminated more readily than benzodiazepines.


6. Long-term use is rarely indicated.


6. Long-term use is rarely indicated.


Mode of Action of Benzodiazepines:


Barbiturates


(1) In central nervous system, benzodiazepines do not equally affect the activity at all levels and hence cannot be classified as general depressant of CNS.


(2) The midbrain reticular activating system, which is responsible for the maintenance of a wakefulness, is depressed by benzodiazepines. (3) The limbic system incorporates a balanced complex of excitatory and inhibitory components. The antianxiety activity of benzodiazepines may be attributed to the


depressant action of these drugs on the mechanisms which evoke anxiety and aggression.


(4) In convulsions, these drugs neither elevate the threshold for convulsions nor


suppress the repeated stimulation. They just prevent the spread of the seizures.


(5) Just like the action of gamma amino butyric acid, benzodiazepines cause either presynaptic or (rarely) postsynaptic inhibition in polysynaptic neuronal pathways in CNS, affecting the turnover of various neurotransmitters in the brain. This may result in the inter- ference in the transmission processes. Since, benzodiazepines are found to act indirectly. they are not GABA-mimetic in true sense.


Clinical Uses:


(1) As antianxiety agents.


(2) As sedative or to potentiate the action of a hypnotic drug.


(3) Muscle relaxant and anticonvulsant agent.


(4) Psychostimulant agent.


(5) Preanaesthetic medication.


(6) During withdrawal of alcohol in chronic alcoholics.