Chapters 7 & 8

Ionization & Partition

The degree of inoinzation of a drug and a drugs ability to move between water and a oil medium are key to understanding how a particular drug will be absorbed and distributed throughout the body.

All organic compounds can be clasified as either an acid a base or non-ionizable.
(Some inorganic coupounds ionize ie NaCl but are not acids or bases because they are salts of an acid and a base)
We also make salts from organic compounds usually by reacting them with an inorganic acid or base.

Some compounds have both acid and basic functional groups.  They are called zwitter ions.

Can you name common classes of organic compounds that are zwitter ions?

Test yourself -  Which of the following are acids?  bases?  or nonionizable compounds?

Phenol
Sucrose
Iso-octane
Phenobarbital
Aspartame
Cellulose
Cholesterol
Triethylanolamine
Saccharin
Tyrosine
Morphine

The ability of a compound to cross a cell membrane is refered to as its permiability.

For most compounds to cross what is essentially a lipid barrier the compound must be unionized and have some lipid solubility.

Therefor for drugs which are weak acid or weak bases the % of the drug that is unionized has a large impact on the rate of passive transport across a cell emebrane.

The Henderson-Hasselbach equation discribes the relative concentration of the ionized and unionized moieties for week acid and weak bases.

For a weak acid It is based on the simple relationship HA + H₂O = H₃O + A^-

a dissociation constant is calculated as the ratio of the product of the concentrations of the products over the reactants.  (See page 65 eq. 2)

        Ka  =     [H₃O] [A-]                But since water is in great excess we can assume the water term as a constant.
                        [HA] [H₂O]

A similar equation can be obtained for a base.

By taking the negative log of both sides of the equation and recognizing that the ionized form of a weak acid is a base and the ionized form of a weak base is a acid we get the common form of the Henderson Hasselbach

                pH  =  pKa  +  Log [base]/[acid]

Using this equation we can calculate the % ionized for any weak acid or weak base in any physiological fluid.  (see table 7-1 on page 67)

Since only the unionized moiety can diffuse across a lipid membrane at equilibrium the concentration of the unionized moiety will be the same on both sides of the membrane.  (See page 70 figure 7-1)

Lipid Water Partition Coefficient

We now understand that  drug must be unionized to cross a lipid membrane barrier.
There is one other factor that must be considered.  How compatable is the unionized compoud with water or oil.

Even if the compound is unionized will it easily go into a lipid mambrane?

Which of these common substances will easily move from a water solution into a lipid environment?

Dextrose
Alcohol

Why do you think so?

The drug will have a relative affinity for both water and oil and the ration of that is the partition coefficient.

What does a high APC mean??
What is the difference between APC & TPC?