The Half Decent Pharmaceutical Chemistry Blog

Maybe, you don't, I'm afraid. But, to tell you the truth, you're in good company. Some books, for instance, still talk about a benzodiazepine receptor, for which they claim that agonist, antagonist and even inverse agonist were found.

But they are wrong or, at least, partly wrong.
Oddly, though, you can't blame them too much for this: their problem is that they are not pharmaceutical chemists or biologists or biochemists.

Otherwise they would perfectly know that there is NOT a receptor full-stop, but an ALLOSTERIC receptor. And that makes a difference.

You cannot have agonists or antagonists, but activators, inhibitors (beta-CCE) and, in this particular context, a sort of neutralizer, which should inhibits the activity of OTHER allosteric modulators.

This last class is tricky to understand and may have caused the misunderstanding.
Oh, and now you're probably thinking it doesn't exist, but, I'm afraid, you're wrong again: Flumazenil is that neutralizer, although it antagonizes the activity of benzodiazepines only. The other modulators (barbiturates, ethanol, opioids and general anesthetics) are unaltered in their activity.

However, the drug has dramatic importance for treating benzodiazepine overdoses and improve the conditions of people suffering from hepatic encephalopathy. On the other hand, in the presence of high concentrations of tricyclic antidepressants, seizures and arrhythmias will precipitate.

Of course, the difference has no clinical, practical utility, but, still, it's something it be considered, in my opinion.

The benzodiazepine receptor was discovered after barbiturates, however.  These drugs were, thus, the first class of sedatives launched on the market.
Like most of the old drugs, barbiturates have a worse toxicological profile than benzodiazepine, but they are still available, especially due to their low cost.

Moreover, there's one thing where old barbiturates beat newer benzodiazepine: anesthesia.
Thiopental and methohexial penetrate brain tissue (better than benzodiazepines) but their remarkable tissue redistribution and the relative absence of respiratory depression make them the better option.

Both drugs are able to induce sedation, anxiolysis, drowsiness, induce or just facilitate sleep. The major difference between barbiturates and benzodiazepines lies in the therapeutic index: benzodiazepines induce anesthesia at much higher dose than barbiturates. Not to mention coma and death: both can kill you, if the dose is so high that the drug depresses either the respiratory and vasomotor centre in the medulla; but the amount of pentobarbital (now used solely as anesthetic) Marilyn Monroe took was less than that she should have swallowed of any benzodiazepine.



Barbiturates are less selective and can depress the action of glutamic acid too. And even nonsynaptic membrane effects.
To sum up, they are stronger but more furious.

So, benzodiazepines: here they come and don't they look proud?

Some of the changes have dramatically improved pharmacokinetics: oxazepam, for instance, reacts with succinic acid and, in the end, we yield its sodium emisuccinate, water soluble.

However, as you can see some things are paramount: benzene and carbonyl must be co-planar, a substituent on the benzene (position 7) increases affinity, the benzene binding to the central structure increases the activity.

Benzodiazepines (and functional congeners) bind to the said site, which is only in type A GABA receptor (the most common). These receptors are in the central nervous system and, once GABA binds to its own site, these chloride channels open, chloride ions cause hyperpolarization:  this results in inhibition.



Another difference between a benzodiazepine and a barbiturate: while the former increases the frequency of the opening of the channel (ONLY IF GABA IS PRESENT), the latter lengthens the opening period.

Clinical use and adverse effect are linked: higher doses exacerbate every therapeutic usefullness (even respiratory depression follows the same pattern). Although they are very often taken to commit suicide (with alcohol), there is tolerance, which occurs frequently.

You see, old people take benzodiazepines to sleep. These drugs decrease the time needed to fall asleep, prolong stage 2 NREM, reduce REM sleep and stage 4 NREM.
They take the same substance regularly, forever. After some time, there are metabolic or pharmacodynamic tolerances (or both) reducing the effectiveness.

The dose is self-adjusted by the patient who increases the number of administrations, even because it's experiencing physiologic (anxiety, insomnia, excitability and even convulsions) and phychologic dependence.

Sedation is another effect of both types of drugs. However, in this case, anxiolysis, even at therapeutic dose, is associated with impaired cognitive functions and problems with normal motor activities such as driving.

Only barbiturates are reported to cause adverse effects not related to their clinical use (namely, porphyria).