Hidden chemistry of psychotropic drugs that no one else seems to publish or notice.

Sunday, April 22, 2007

STRUCTURAL POTENCY OF BENZODIAZEPINES - Controlling for Molar Mass

There is already a lot of information about equivalent doses of benzodiazepines on a milligram basis. While this is undoubtedly important for clinical practice, it doesn't give the whole story as to why certain benzos are much more potent than others.

To do this, the therapeutically equivalent doses in milligrams need to be converted to a molar basis and multiplied by their respective bioavailabilities. This tells us exactly how many molecules of a specific benzo (that reach the circulation) are needed to achieve a standard anxiolytic level. This arbitrary standard in most publications is the level produced by 10 mg of oral diazepam (Valium).

This thought experiment should reveal the common characteristics of the benzos that bond strongly to the GABA receptor, and thus require the lowest doses on a micromolar basis.





Judging from the data, the most potent molecules on a molar basis are:
  • Triazolam (Halcion, 1.31 umol)
  • Alprazolam (Xanax, 1.38 umol)
  • Clonazepam (Klonopin, 1.43 umol)
  • Flunitrazepam (1.60 umol)
  • Lorazepam (Ativan, 2.65 umol)
  • Loprazolam (2.90 umol)
  • Lormetazepam (3.58 umol)
  • Eszopiclone (non-benzo, 4.24 umol)
  • Estazolam (4.73 umol)

And the least potent molecules on a molar basis are:

  • Chlordiazepoxide (75 umol)
  • Oxazepam (67 umol)
  • Temazepam (63.9 umol)
  • Zolpidem (Ambien, non-benzo, 59.9 umol)
  • Clobazam (59.9 umol)
  • Ketazolam (53.7 umol)
  • Halazepam (51 umol)
  • Flurazepam (47 umol)

And the remainder are the rest in the middle from Bromazepam (14.61 umol) to Prazepam (41.56 umol). With Diazepam (Valium) right in the middle at 32.67 micromoles.

Among the potent group (drugs requiring less than 5 umol of molecules in the blood), some common traits emerge. Consider the basic benzo skeleton:


The molecules in the most-potent group either have a (1) a nitro group at position 7, (2) an electron-withdrawing group at position 2', or (3) a triazolo group around positions 1 and 2. Or some combination of these three potency-enhancing elements.

3 comments:

b said...

I never knew chemistry could be so sexy

Fraud Blogger said...

Ummm. I see big problems with this chart.

Problem #1:

You're attempting to derive calculations of potency, on a molar basis, from inputs which are, in and of themselves, calculations of potency. The conclusions of your 'study' were already derived by the input of the benzo equivilancy chart.

Problem #2:

Lots of literature out there that triazolam 500 mcg is equal in efficacy to 30mg temazepam as a hypnotic.

Problem #3:

The chart is heavily over-simplistic, especially since the solubility of these substances vary substantially. The chloro-substituted versions of oxazepam and alprazolam, lorazepam and triazolam respectively, obviously, have a much greater level of solubility for rapid absorption. Whereas, diazepam and chlordiazepoxide, being highly lipid soluble, distribute very rapidly throughout the entire body, leaving relatively little of the benzodiazepine in the blood to act upon the brain and CNS (although the diazepam remains in the body for a longer period of time).

Educated Pill Popper said...

Idiot.