thank u so much benzyme - swim is proceeding now.
Pics will be uploaded as the steps are taken.
i just found this and thought it was interesting enough to post here for everyone to read.
found here :
http://www.maps.org/old_forum/2003/msg00141.html
René asked,
> understand. If an alkaloid needs to be converted into a fat-soluble
freebase
> before it can enter the brain then how does it do that?
Most strict water soluble compounds *are* excluded from the brain. The
secret is that psilocin is a slightly fat soluble at physiological pH.
Here's a little acid-base chemistry discussion for whoever's interested. I
hope its not too long-winded. It would help to review the
Henderson-Haselbalch equation.
Molecules that ionize by either giving up or accepting protons (except
strong acids like HCl and strong bases like NaOH) exist in an equilibrium
between the protonated form and the unprotonated form in aqueous solutions.
Whether the protonated form is charged or uncharged depends on whether the
molecule is a weak acid or a weak base. A weak acid (e.g. acetic acid) is
mostly protonated and hence mostly uncharged and hence fat soluble at acidic
pHs; it is unprotonated, charged, and water soluble at basic pHs. The
converse is true of weak bases like alkaloids. Let's assume for a moment
that psilocin is a simple weak base alkaloid. Each molecule has a
characteristic dissociation constant for the proton (acid dissociation
constant, Ka) whose value depends upon the chemical structure of the
molecule. The Ka is usually described in negative log form, pKa. When the
pH of the solution = the pKa of any molecule, precisely half the molecules
are protonated and half are unprotonated. For a weak base like psilocin,
the pKa is probably around 9.5. So at pH 9.5, half the psilocin would be
fat soluble and half would be water soluble. But the body is not at pH 9.5,
it is at pH 7.4. So the psilocin will be more protonated and therefore more
charged at physiological pH. Because the pH scale is a log scale, for every
pH unit you move away from the pKa, you get a 10-fold change in the number
of molecules that are protonated (or unprotonated, depending on which way
you move). Therefore, at physiological pH (7.4, about 2 log units away from
psilocin's pKa), there are about 100 protonated, charged, water soluble
psilocin molecules for each 1 unprotonated, uncharged, fat soluble psilocin
molecule. So about 1% of the entire psilocin population can penetrate the
blood-brain barrier at any given time. Of course, as drug crosses into the
brain, more becomes uncharged on the blood side to maintain the equilibrium,
so you always have 1% of the population that can cross. We know what
happens next.
But psilocin isn't a simple weak base molecule. To complicate things, the
hydroxyl group on psilocin is also subject to ionization, but I have no idea
what its pKa is.
To complicate things even more, Dr. Nichols once did an NMR study of the
conformation of psilocin in solution and reported that the side-chain amine
folds back to interact with the 4-hydroxyl group, so you could have some
sort of hydrogen bonding going on between the hydroxyl and the lone pair
electrons of the amine. That may drastically change the pKa.
> switch from a water-soluble salt form into a fat-soluble freebase. But
body
> fluids are normally sligtly acidic.
Actually, pH 7.4 is slightly basic.
Nicholas V. Cozzi, Ph.D.
Department of Pharmacology and Toxicology
Brody School of Medicine
East Carolina University
Greenville, NC 27834
