Phenobarbitol Drug Development - 15 . Properties of Phenobarbitol in the Bloodstream

15. Properties of Phenobarbitol in the Bloodstream:

Please remember these concepts:

Many processes can be at equilibrium. But with changes in condition - concentration, temperature - the system will no longer be at equilibrium and will adjust to try to get there again.
The equilibrium concentrations of H₃O⁺ and OH^- are vanishingly small in pure water.
A weak acid or a weak base drug, in water, will disassociate to some extent. The pH of the drug solution will depend upon the pK_a.
Buffers stabilize pH. This stabilized acidity determines the form of drug disassociation in systems. The Henderson-Hasselbach equation conveniently handles drug ionization questions for buffered systems like the body.

In the blood:

The pH is 7.4

A^- + H₃O⁺ <===> HA + H₂O

pH = pK_a - log [A^-]/[HA]

7.4 = 7.4 - log [A^-]/[HA]

0 = log [A^-]/[HA]

1 = [A^-]/[HA]

Ratio of dissociated/associated=1, 50% of each.

This gives us the ratio of ionized to unionized phenobarbital in solution in the blood. It is clear that the ratio of unionized phenobarbital is equal to the ionized. In other words, for every ionized phenobarbital, there is one unionized. Thus the concentration of each species is 50%.

As phenobarbital is transported throughout the body, there is unionized drug available to cross lipid membranes. But as each unionized molecule crosses to a membrane, it is eliminated in the blood compartment, shifting the equilibrium to favor the acceptance of a proton from a molecule of the ionized species. This process repeats itself, favoring equilibrium, attempting to maintain the 50:50 split of ionized to unionized.

Ionized (Dissociated) vs. Unionized Phenobarbitol

Location/pH	Stomach/pH=2	Duodenum/pH=6	Jejunum/pH=7.5	Blood/pH=7.4
Unionized (%)	99.999	96.3	55	50
Ionized(%)	4x10^-4	3.7	45	50

to Properties of Phenobarbitol and Absorption

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