drug Pathways and Chemical Concepts - 15b. Chemical Principles and Phenobarbitol Absorption

15b .Chemical Principles and Phenobarbitol Absorption:

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.

We must consider three chemical principles in the absorption of phenobarbitol:

Intermolecular forces: Like dissolves like
Acid/Base Chemistry: Sufficient unionized drug must be present in the lumen of the duodenum to pass through the walls.
Chemical kinetics: The rate of the transfer of material across the walls must be fast enough to allow the drug to be absorbed before it goes into the jejunum. This depends upon the concentration of the species and the rate constant for the transfer

Conclusions based on observation and chemical principles:

Phenobarbitol is more active than Veronal or barbituric acid. The presence of hydrocarbon groups makes it more lipophilic than the other barbiturates and giving an effective rate constant for transfer.
Considering the pK_a we can see that phenobarbitol is primarily in the unionized form and should be available at high enough concentration for transfer.

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

Once in the blood, sufficient unionized form is present for transfer across the blood-brain barrier.

Effectiveness of Phenobarbitol is the result of structure giving lipophilic behavior and sufficient concentration of the unionized form in the duodenum so that the rate of transfer into the system is high.

to Renal Excretion

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