Several modifications were realized in positions 1, 2', 4' and 7 from diazepam structure aiming to elucidate structure-activity relationship (SAR). 1 Since the introduction of chlordiazepoxide and diazepam many diazepines have beende- veloped. Use of . triazole or imidazole resulted in highly active substances (e.g. far, most of the structure-activity relationships which have been. Download Citation on ResearchGate | Imidazole anticonvulsants: Structure- activity relationships of [(biphenylyloxy)alkyl]imidazoles | The.
They can sedate patients receiving mechanical ventilation or those in extreme distress. Caution is exercised in this situation due to the risk of respiratory depressionand it is recommended that benzodiazepine overdose treatment facilities should be available.
They also produce amnesiawhich can be useful, as patients may not remember unpleasantness from the procedure. Diazepam and lorazepam are sometimes used. Lorazepam has particularly marked amnesic properties that may make it more effective when amnesia is the desired effect. Tizanidine has been found to have superior tolerability compared to diazepam and baclofen. Lorazepam is most commonly used but clonazepam is sometimes prescribed for acute psychosis or mania;  their long-term use is not recommended due to risks of dependence.
Effectiveness was, however, found in one small study. For that reason, they are contraindicated in people with myasthenia gravissleep apneabronchitisand COPD. Effects of benzodiazepines on newborns In the United States, the Food and Drug Administration has categorized benzodiazepines into either category D or X meaning potential for harm in the unborn has been demonstrated.
Their use by expectant mothers shortly before the delivery may result in a floppy infant syndromewith the newborns suffering from hypotoniahypothermialethargyand breathing and feeding difficulties.
This syndrome may be hard to recognize, as it starts several days after delivery, for example, as late as 21 days for chlordiazepoxide. The symptoms include tremorshypertoniahyperreflexiahyperactivityand vomiting and may last for up to three to six months. If used in pregnancy, those benzodiazepines with a better and longer safety record, such as diazepam or chlordiazepoxideare recommended over potentially more harmful benzodiazepines, such as temazepam  or triazolam.
Using the lowest effective dose for the shortest period of time minimizes the risks to the unborn child. Adverse effects on cognition can be mistaken for the effects of old age. The benefits of withdrawal include improved cognition, alertness, mobility, reduced risk incontinence, and a reduced risk of falls and fractures.
The success of gradual-tapering benzodiazepines is as great in the elderly as in younger people. Benzodiazepines should be prescribed to the elderly only with caution and only for a short period at low doses. The high potency benzodiazepines alprazolam and triazolam and long-acting benzodiazepines are not recommended in the elderly due to increased adverse effects.
Nonbenzodiazepines such as zaleplon and zolpidem and low doses of sedating antidepressants are sometimes used as alternatives to benzodiazepines. However, like antidepressantsthey have little evidence of effectiveness, although antipsychotics have shown some benefit.
Structural activity relationships of benzodiazepines
Benzodiazepines were ranked in this graph 7th in dependence, physical harm, and social harm. They include drowsinessdizziness, and decreased alertness and concentration. Lack of coordination may result in falls and injuries, in particular, in the elderly. Depression and disinhibition may emerge. Hypotension and suppressed breathing hypoventilation may be encountered with intravenous use.
Cases of liver toxicity have been described but are very rare. Feelings of turmoil, difficulty in thinking constructively, loss of sex-drive, agoraphobia and social phobia, increasing anxiety and depression, loss of interest in leisure pursuits and interests, and an inability to experience or express feelings can also occur. Not everyone, however, experiences problems with long-term use.
This included hospitalization, patient transfer, or death, and visits involving a combination of benzodiazepines and non-benzodiapine receptor agonists had almost four-times increased odds of a serious health outcome. One view is that many of the short-term effects continue into the long-term and may even worsen, and are not resolved after stopping benzodiazepine usage.
Another view maintains that cognitive deficits in chronic benzodiazepine users occur only for a short period after the dose, or that the anxiety disorder is the cause of these deficits. While the definitive studies are lacking, the former view received support from a meta-analysis of 13 small studies.
Some of the other impairments reported were decreased IQ, visiomotor coordination, information processing, verbal learning and concentration. The authors of the meta-analysis  and a later reviewer  noted that the applicability of this meta-analysis is limited because the subjects were taken mostly from withdrawal clinics; the coexisting drug, alcohol use, and psychiatric disorders were not defined; and several of the included studies conducted the cognitive measurements during the withdrawal period.
Paradoxical effects[ edit ] Paradoxical reactionssuch as increased seizures in epileptics,  aggressionviolence, impulsivityirritability and suicidal behavior sometimes occur.
Most reports of disinhibition involve high doses of high-potency benzodiazepines. Here we can found two exceptions. First is at chlordiazepoxide and second at fused benzodiazepines.
Fused benzodiazepines like alprazolam, midazolam and triazolam interact with GABA receptors through triazole or imidazole ring. All other benzodiazepines require a keto group at 2nd position. But in-vivo it can undergo oxidative deamination to produce demoxepam with keto group at second position.
This again proved that keto group at 2nd position is essential for activity. It is obvious that drugs or metabolites which are highly polar can undergo direct conjugation and hence directly excreted. A polar functional group at 3rd position increases excretion thereby decrease duration of action. Drugs like lorazepm, oxazepam and temazepam have hydroxyl group at 3rd position making all these drugs polar and easily excretable.
Hence all these drugs have short duration of action.
Oxazepam and lorazepam are highly polar and can be excreted without phase I metabolism. Temazepam also shows a little phase I reaction.
It undergoes demethylation and converted into oxazepam and then excreted. This is essential for activity and saturation of this double bond may decrease the activity. Even shift of the double bond to 3rd and 4ht position decreases the activity. Again all benzodiazepines including fused benzodiazepine ring systems have a phenyl group at 5th position. For example, drugs like diazepam, nitrazepam, oxazepam, temazepam and chlordiazepoxide all have a phenyl group at 5th position.
Substitution on phenyl group also plays a key role in influencing activity. But all positions may not yield favourable results. Those drugs having phenyl group with ortho or diorhto substitution with an electron withdrawing group found to increase activity.
At the same time, para substitution decreases the activity. We can easily observe this in the names of few benzodiazepines. For example, flurazepam has fluoro group and clonazepam has chlorine group Note: This applies to above two drugs only. Actually it has nitro group at 7th position of the benzodiazepine ring. Similarly other drugs like triazolam and midazolam has chlorine and fluorine groups respectively at ortho position of the phenyl ring.
Electron withdrawing groups like halogens or nitro group increase the activity. Higher the electornegativity higher the potency Therefore nitrazepam is more potent than diazepam. We left with positions 6,8 and 9.